Compositions for sustained release of analgesic agents, and methods of making and using the same

INTRODUCTION

[0002] In order to provide local or regional blockade for extended periods, clinicians often use analgesics administered through a catheter or syringe to a site where the pain is to be blocked. This method of treatment requires repeated administration when the pain is to be blocked for more than a short period of time, e.g., for more than one day. The anesthetic is typically administered as a bolus or through an indwelling catheter connected to an infusion pump. These methods have the disadvantage of potentially causing irreversible damage to nerves or surrounding tissues due to fluctuations in concentration and high levels of anesthetic. In addition, anesthetics administered by these methods often travel beyond the target area, and are not delivered in a linear, continuous manner. As a result, analgesia rarely lasts for longer than six to twelve hours, more typically four to six hours. In the case of a pump, the infusion lines are difficult to position and secure, the patient has limited, encumbered mobility and, when the patient is a small child or mentally impaired, may accidentally disengage the pump.

[0003] Sustained release compositions could potentially provide for a sustained, controlled, constant localized release for longer periods of time than can be achieved by injection or topical administration. These devices typically consist of a polymeric matrix or liposome from which drug is released by diffusion and/or degradation of the matrix. The release pattern is usually principally determined by the matrix material, as well as by the percent loading, method of manufacture, type of drug being administered and type of device, for example, microsphere. A major advantage of a biodegradable sustained release system over others is that it does not require the surgical removal of the drug depleted device, which is slowly degraded and absorbed by the patient's body, and ultimately cleared along with other soluble metabolic waste products.

[0004] In part, the present invention is directed to a formulation that permits convenient administration of an analgesic agent such that the analgesic is released in a sustained manner and is effective over an extended period of time.

SUMMARY OF THE INVENTION

[0005] In part, the present invention is directed to a polymer system, such as a biocompatible and optionally biodegradable polymer, comprising an analgesic agent, such as lidocaine or an analog thereof, methods for treatment using the subject polymers, and methods of making and using the same.

[0006] In certain embodiments, a large percentage of the subject composition may be an analgesic agent. For example, the analgesic agent, such as lidocaine or an analog thereof, or an analgesic agent having a melting point below about 120° C., below about 100° C., or below about 80° C., may comprise 10 to 50% or more of the subject composition, e.g., at least 20%, at least 25%, at least 30%, or more of the composition. The subject compositions allow high loading levels of an analgesic agent to be incorporated, which allows in certain cases a smaller amount of the subject compositions to be used for treatment with the same therapeutic effect.

[0007] In certain embodiments, a subject composition further comprises an excipient having a high melting point. Examples of such excipients include cholesterol, ethycellulose, egg phosphatidylcholine (PC), magnesium stearate, polyvinyl pyrrolidone (PVP), and mixtures thereof. Other suitable excipients are known to those of skill in the art, and may be selected such that the combination of excipient, analgesic, and polymer may be formulated into microparticles such as microspheres and nanospheres. For example, the use of such excipients, in certain embodiments, allow for microspheres and microparticles of the subject biocompatible polymers with higher loading levels of an analgesic agent to be prepared than would be possible in the absence of such excipient. In certain embodiments, a subject composition includes an excipient having a melting point above about 100° C., or above about 120° C. In certain embodiments, the melting point of the excipient is greater than the melting point of the analgesic agent incorporated in the subject compositions. In certain embodiments, the excipient is soluble in organic solvents, such as chloroform, methylene chloride, ether, tetrahydrofuran, or hexane. In certain embodiments, the ratio of excipient to polymer is between 10:1 and 1:10.

[0008] In certain embodiments, administration of the subject polymers results in sustained release of an encapsulated analgesic agent for a period of time and in an amount that is not possible with other modes of administration of the analgesic agent. In certain embodiments, such administration results in therapeutically effective relief of pain for a prolonged period, such as a day or more, three days or more, or even a week or more. For example, administration of a therapeutically effective amount of the composition to a rat may result in doubling of a paw withdrawal latency time in a hot plate test for at least 3 days. In certain embodiments, a single dose of microspheres may contain more than about 2 mg/kg of an analgesic, even more than about 5 mg/kg, or even more than 10 mg/kg of an analgesic.

[0009] The subject compositions, and methods of making and using the same, achieve a number of desirable results and features, one or more of which (if any) may be present in any particular embodiment of the present invention: (i) a single dose of a subject composition may achieve the desired therapeutically beneficial response through sustained release of an analgesic agent; (ii) sustained release of an analgesic agent from a biocompatible and optionally biodegradable polymer composition; (iii) novel treatment regimens for prevention or relief of pain using the subject compositions for sustained delivery of an analgesic agent; (iv) high levels of loading (by weight), e.g. greater than 10% and up to 50% or more, of an analgesic agent in biocompatible and optionally biodegradable polymers; (v) lyophilization, spray-drying, or other drying technique applied to the subject compositions and subsequent rehydration; (vi) co-encapsulation of therapeutic agents in addition to any analgesic agent in biodegradable polymers; or (vii) an augmenting compound, as discussed in greater detail below, for supplementing, improving or reinforcing the activity of the analgesic agent.

[0010] In one aspect, the subject polymers may be biocompatible, biodegradable or both. In certain embodiments, the subject polymers contain phosphorus linkages, including, for example, phosphate, phosphonate and phosphite. In other embodiments, the monomeric units of the present invention have the structures described in the claims appended below, which are hereby incorporated by reference in their entirety into this Summary. In the subject polymers, an in particular in those embodiments containing a phosphorus linkage, the chemical structure of certain of the monomeric units may be varied to achieve a variety of desirable physical or chemical characteristics, including for example, release profiles or handling characteristics of the resulting polymer composition.

[0011] A number of analgesic agents are contemplated by the present invention, including for example lidocaine. In addition, a number of analgesic agents may in the form of pharmaceutically acceptable salts, such as the hydrochloride salt of lidocaine. Use of such analgesic salts, in certain embodiments, allows for microspheres and microparticles of the subject biocompatible polymers with higher loading levels of the analgesic salt to be prepared as compared to use of the corresponding analgesic agent.

[0012] In certain embodiments, other materials may be encapsulated in the subject polymer in addition to an analgesic agent, such as lidocaine or an analog thereof, to alter the physical and chemical properties of the resulting polymer, including for example, the release profile of the resulting polymer composition for the analgesic agent. Examples of such materials include biocompatible plasticizers, delivery agents, fillers and the like.

[0013] The present invention provides a number of methods of making the subject compositions. In part, the subject invention is directed to preparation of the polymeric formulations comprising an analgesic agent, such as lidocaine. Examples of such methods include those disclosed in appended claims, which are hereby incorporated by reference in their entirety into this Summary.

[0014] In certain embodiments, the subject compositions are in the form of microspheres. In other embodiments, the subject compositions are in the form of nanospheres. In one aspect, the subject compositions of the present invention may be lyophilized or subjected to another appropriate drying technique such as spray drying and subsequently rehydrated for ready use.

[0015] In another aspect, the present invention is directed to methods of using the subject polymer compositions for prophylactic or therapeutic treatment. In certain instances, the subject compositions may be used to prevent or relieve pain in a patient. In certain embodiments, use of the subject compositions, which release in a sustained manner an analgesic agent allow for different treatment regimens than are possible with other modes of administration of such therapeutic agent.

[0016] In another aspect, the efficacy of treatment using the subject compositions may be compared to treatment regimens known in the art in which an analgesic agent is not encapsulated within a subject polymer.

[0017] In another aspect, the subject polymers may be used in the manufacture of a medicament for any number of uses, including for example treating any disease or other treatable condition of a patient. In still other aspects, the present invention is directed to a method for formulating polymers of the present invention in a pharmaceutically acceptable carrier.

[0018] In another aspect, the present invention may be spray dried and subsequently rehydrated for ready use or injected as powder using an appropriate powder injecting device.

[0019] In other embodiments, this invention contemplates a kit including subject compositions, and optionally instructions for their use. Uses for such kits include, for example, therapeutic applications. In certain embodiments, the subject compositions contained in any kit have been lyophilized and require rehydration before use.

[0020] These embodiments of the present invention, other embodiments, and their features and characteristics will be apparent from the description, drawings, and claims that follow.

BRIEF DESCRIPTION OF THE DRAWINGS

[0021]
FIG. 1 depicts the release of lidocaine from microspheres in vitro administered over time.

[0022]
FIGS. 2 and 3 show concentrations of lidocaine in rat plasma following administration of lidocaine-containing microspheres.

[0023]
FIG. 4 illustrates the morphology of microspheres of a subject composition.

[0024]
FIG. 5 presents results of experiments relating to in vitro release of lidocaine from microspheres of a subject composition.

[0025]
FIG. 6 shows the duration of analgesic activity resulting from lidocaine encapsulated in microspheres of a subject composition in comparison with other delivery methods.

[0026]
FIG. 7 shows the duration of analgesic activity resulting from administration of the subject compositions in rats using the Randall-Selitto test.

[0027]
FIGS. 8 and 9 show the duration of analgesic activity resulting from administration of the subject compositions in rats in a peri-sciatic nerve block model.

[0028]
FIG. 10 shows the result of the duration of analgesic activity resulting from administration of the subject compositions to guinea pigs in a pin-prick model.

[0029]
FIG. 11 shows the plasma concentrations of lidocanine in rats over time after administration of several subject compositions containing lidocaine HCl as the analgesic agent.

DETAILED DESCRIPTION OF THE INVENTION

[0030] 1. Overview

[0031] The present invention relates to pharmaceutical compositions for the delivery of analgesic agents, such as lidocaine, or analogs thereof, e.g., for the prevention or relief of pain. In certain embodiments, biodegradable, biocompatible polymers may be used to allow for sustained release of an encapsulated analgesic agent. The present invention also relates to methods of administering such pharmaceutical compositions, e.g., as part of a treatment regimen, for example, subcutaneously or intramuscularly.

[0032] Lidocaine and other caine analgesics have been used widely in local areas to control pain. These regions may be surgical resection sites, open wounds or any otherwise afflicted areas, such as cavities. For example, the need for this type of administration may arise in the treatment of incisional wounds following surgery as well as more serious traumas such as wounds caused by accidents or recesses or cavities caused by the removal of tumors from bones. Although the drug is effective in reducing the pain, the effect typically will last only couple of hours. For local administrations to be most effective, however, the effect of the agent once administered must be prolonged over a period of time, i.e., longer period than can be achieved by simple bolus administration of a drug. One approach by which this has been achieved is by addition of vasoconstrictive agents (e.g., epinephrine) to slow down the rate of clearance from the site of application. Another approach is the incorporation of the drug into polymeric forms such paste or as solid particles of microscopic size, i.e., microparticles and/or microspheres.

[0033] Lidocaine and bupivacaine have demonstrated effectiveness in alleviating tinnitus, or ringing of the ears (Weinmeister, K. P. Reg. Anesth Pain Med 2000 Jan-Feb; 25(1):67-8; “Lidocaine Perfusion of the Inner Ear plus IV Lidocaine or Intractable Tinnitus,” are John J. Shea and Xianxi Ge, American Otological Society meeting, May 13-14, 2000). Sustained, local release of an analgesic such as lidocaine or bupivacaine in the ear would avoid difficulties associated with frequent injections and side effects which may result from sustained systemic levels of analgesic. For the treatment of tinnitus, the compositions are used to ameliorate the false perception of sound, such as a ringing sound, in a patient, in some cases resulting in an improvement in hearing. Tests for efficacy may be performed in humans after obtaining data indicative of the compound's safety, or an animal model may be employed (Zhang, et al. Neurosci Lett 1998, 250(3), 197-200).

[0034] In certain aspects, the subject pharmaceutical compositions, upon contact with body fluids including blood, spinal fluid, lymph or the like, release the encapsulated drug over a sustained or extended period (as compared to the release from an isotonic saline solution). Such a system may result in prolonged delivery (over, for example, 8 to 800 hours, preferably 24 to 480 or more hours) of effective amounts (e.g., 0.0001 mg/kg/hour to 10 mg/kg/hour) of the drug. This dosage form may be administered as is necessary depending on the subject being treated, the severity of the affliction, the judgment of the prescribing physician, and the like.

[0035] 2. Definitions

[0036] For convenience, before further description of the present invention, certain terms employed in the specification, examples, and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art.

[0037] The terms “local anesthetic”, “analgesic” and “analgesic agent” are art-recognized and include drugs and agents that provide local numbness or pain relief. A variety of different analgesics are known in the art, including lidocaine, dibucaine, bupivacaine, cocaine, etidocaine, hexylcaine, mepivacaine, prilocaine, benzocaine, butamben, butanilicaine, trimecaine, chloroprocaine, procaine, propoxycaine, articaine, ropivacaine, tetracaine, and xylocaine. The compound may be employed as a neutral compound or in the form of a pharmaceutically acceptable salt, for example, the hydrochloride, bromide, acetate, citrate, or sulfate.

[0038] The term “access device” is an art-recognized term and includes any medical device adapted for gaining or maintaining access to an anatomic area. Such devices are familiar to artisans in the medical and surgical fields. An access device may be a needle, a catheter, a cannula, a trocar, a tubing, a shunt, a drain, or an endoscope such as an otoscope, nasopharyngoscope, bronchoscope, or any other endoscope adapted for use in the head and neck area, or any other medical device suitable for entering or remaining positioned within the preselected anatomic area.

[0039] The terms “biocompatible polymer” and “biocompatibility” when used in relation to polymers are art-recognized. For example, biocompatible polymers include polymers that are neither themselves toxic to the host (e.g., an animal or human), nor degrade (if the polymer degrades) at a rate that produces monomeric or oligomeric subunits or other byproducts at toxic concentrations in the host. In certain embodiments of the present invention, biodegradation generally involves degradation of the polymer in an organism, e.g., into its monomeric subunits, which may be known to be effectively non-toxic. Intermediate oligomeric products resulting from such degradation may have different toxicological properties, however, or biodegradation may involve oxidation or other biochemical reactions that generate molecules other than monomeric subunits of the polymer. Consequently, in certain embodiments, toxicology of a biodegradable polymer intended for in vivo use, such as implantation or injection into a patient, may be determined after one or more toxicity analyses. It is not necessary that any subject composition have a purity of 100% to be deemed biocompatible; indeed, it is only necessary that the subject compositions be biocompatible as set forth above. Hence, a subject composition may comprise polymers comprising 99%, 98%, 97%, 96%, 95%, 90%, 85%, 80%, 75% or even less of biocompatible polymers, e.g., including polymers and other materials and excipients described herein, and still be biocompatible.

[0040] To determine whether a polymer or other material is biocompatible, it may be necessary to conduct a toxicity analysis. Such assays are well known in the art. One example of such an assay may be performed with live carcinoma cells, such as GT3TKB tumor cells, in the following manner: the sample is degraded in 1M NaOH at 37° C. until complete degradation is observed. The solution is then neutralized with 1M HCl. About 200 μL of various concentrations of the degraded sample products are placed in 96-well tissue culture plates and seeded with human gastric carcinoma cells (GT3TKB) at 104/well density. The degraded sample products are incubated with the GT3TKB cells for 48 hours. The results of the assay may be plotted as % relative growth vs. concentration of degraded sample in the tissue-culture well. In addition, polymers and formulations of the present invention may also be evaluated by well-known in vivo tests, such as subcutaneous implantations in rats to confirm that they do not cause significant levels of irritation or inflammation at the subcutaneous implantation sites.

[0041] The term “biodegradable” is art-recognized, and includes polymers, compositions and formulations, such as those described herein, that are intended to degrade during use. Biodegradable polymers typically differ from non-biodegradable polymers in that the former may be degraded during use. In certain embodiments, such use involves in vivo use, such as in vivo therapy, and in other certain embodiments, such use involves in vitro use. In general, degradation attributable to biodegradability involves the degradation of a biodegradable polymer into its component subunits, or digestion, e.g., by a biochemical process, of the polymer into smaller, non-polymeric subunits. In certain embodiments, two different types of biodegradation may generally be identified. For example, one type of biodegradation may involve cleavage of bonds (whether covalent or otherwise) in the polymer backbone. In such biodegradation, monomers and oligomers typically result, and even more typically, such biodegradation occurs by cleavage of a bond connecting one or more of subunits of a polymer. In contrast, another type of biodegradation may involve cleavage of a bond (whether covalent or otherwise) internal to side chain or that connects a side chain to the polymer backbone. For example, a therapeutic agent or other chemical moiety attached as a side chain to the polymer backbone may be released by biodegradation. In certain embodiments, one or the other or both generally types of biodegradation may occur during use of a polymer. As used herein, the term “biodegradation” encompasses both general types of biodegradation.

[0042] The degradation rate of a biodegradable polymer often depends in part on a variety of factors, including the chemical identity of the linkage responsible for any degradation, the molecular weight, crystallinity, biostability, and degree of cross-linking of such polymer, the physical characteristics of the implant, shape and size, and the mode and location of administration. For example, the greater the molecular weight, the higher the degree of crystallinity, and/or the greater the biostability, the biodegradation of any biodegradable polymer is usually slower. The term “biodegradable” is intended to cover materials and processes also termed “bioerodible”.

[0043] In certain embodiments, if the biodegradable polymer also has a therapeutic agent or other material associated with it, the biodegradation rate of such polymer may be characterized by a release rate of such materials. In such circumstances, the biodegradation rate may depend on not only the chemical identity and physical characteristics of the polymer, but also on the identity of any such material incorporated therein.

[0044] In certain embodiments, polymeric formulations of the present invention biodegrade within a period that is acceptable in the desired application. In certain embodiments, such as in vivo therapy, such degradation occurs in a period usually less than about five years, one year, six months, three months, one month, fifteen days, five days, three days, or even one day on exposure to a physiological solution with a pH between 6 and 8 having a temperature of between 25 and 37° C. In other embodiments, the polymer degrades in a period of between about one hour and several weeks, depending on the desired application.

[0045] The term “drug delivery device” is an art-recognized term and refers to any medical device suitable for the application of a drug or therapeutic agent to a targeted organ or anatomic region. The term includes, without limitation, those formulations of the compositions of the present invention that release the therapeutic agent into the surrounding tissues of an anatomic area. The term further includes those devices that transport or accomplish the instillation of the compositions of the present invention towards the targeted organ or anatomic area, even if the device itself is not formulated to include the composition. As an example, a needle or a catheter through which the composition is inserted into an anatomic area or into a blood vessel or other structure related to the anatomic area is understood to be a drug delivery device. As a further example, a stent or a shunt or a catheter that has the composition included in its substance or coated on its surface is understood to be a drug delivery device.

[0046] When used with respect to a therapeutic agent or other material, the term “sustained release” is art-recognized. For example, a subject composition which releases a substance over time may exhibit sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time. For example, in particular embodiments, upon contact with body fluids including blood, spinal fluid, lymph or the like, the polymer matrices (formulated as provided herein and otherwise as known to one of skill in the art) may undergo gradual degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an analgesic such as lidocaine, for a sustained or extended period (as compared to the release from a bolus). This release may result in prolonged delivery of therapeutically effective amounts of any incorporated therapeutic agent. Sustained release will vary in certain embodiments as described in greater detail below.

[0047] The term “delivery agent” is an art-recognized term, and includes molecules that facilitate the intracellular delivery of a therapeutic agent or other material. Examples of delivery agents include: sterols (e.g., cholesterol) and lipids (e.g., a cationic lipid, virosome or liposome).

[0048] The term “microspheres” is art-recognized, and includes substantially spherical colloidal structures, e.g., formed from biocompatible polymers such as subject compositions, having a size ranging from about one or greater up to about 1000 microns. In general, “microcapsules”, also an art-recognized term, may be distinguished from microspheres, because microcapsules are generally covered by a substance of some type, such as a polymeric formulation. The term “microparticles” is art-recognized, and includes microspheres and microcapsules, as well as structures that may not be readily placed into either of the above two categories, all with dimensions on average of less than about 1000 microns. If the structures are less than about one micron in diameter, then the corresponding art-recognized terms “nanosphere,” “nanocapsule,” and “nanoparticle” may be utilized. In certain embodiments, the nanospheres, nancapsules and nanoparticles have a size an average diameter of about 500, 200, 100, 50 or 10 nm.

[0049] A composition comprising microspheres may include particles of a range of particle sizes. In certain embodiments, the particle size distribution may be uniform, e.g., within less than about a 20% standard deviation of the median volume diameter, and in other embodiments, still more uniform or within about 10% of the median volume diameter.

[0050] The phrases “parenteral administration” and “administered parenterally” are art-recognized terms, and include modes of administration other than enteral and topical administration, such as injections, and include, without limitation, intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrastemal injection and infusion.

[0051] The term “treating” is art-recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the disease, disorder or condition, e.g., causing regression of the disease, disorder and/or condition. Treating the disease or condition includes ameliorating at least one symptom of the particular disease or condition, even if the underlying pathophysiology is not affected, such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain.

[0052] The term “fluid” is art-recognized to refer to a non-solid state of matter in which the atoms or molecules are free to move in relation to each other, as in a gas or liquid. If unconstrained upon application, a fluid material may flow to assume the shape of the space available to it, covering for example, the surfaces of an excisional site or the dead space left under a flap. A fluid material may be inserted or injected into a limited portion of a space and then may flow to enter a larger portion of the space or its entirety. Such a material may be termed “flowable.” This term is art-recognized and includes, for example, liquid compositions that are capable of being sprayed into a site; injected with a manually operated syringe fitted with, for example, a 23-gauge needle; or delivered through a catheter. Also included in the term “flowable” are those highly viscous, “gel-like” materials at room temperature that may be delivered to the desired site by pouring, squeezing from a tube, or being injected with any one of the commercially available injection devices that provide injection pressures sufficient to propel highly viscous materials through a delivery system such as a needle or a catheter. When the polymer used is itself flowable, a composition comprising it need not include a biocompatible solvent to allow its dispersion within a body cavity. Rather, the flowable polymer may be delivered into the body cavity using a delivery system that relies upon the native flowability of the material for its application to the desired tissue surfaces. For example, if flowable, a composition comprising polymers according to the present invention it can be injected to form, after injection, a temporary biomechanical barrier to coat or encapsulate internal organs or tissues, or it can be used to produce coatings for solid implantable devices. In certain instances, flowable subject compositions have the ability to assume, over time, the shape of the space containing it at body temperature.

[0053] Viscosity is understood herein as it is recognized in the art to be the internal friction of a fluid or the resistance to flow exhibited by a fluid material when subjected to deformation. The degree of viscosity of the polymer can be adjusted by the molecular weight of the polymer, as well as by mixing the cis- and trans-isomers of the cyclohexane dimethanol in the backbone of the polymer; other methods for altering the physical characteristics of a specific polymer will be evident to practitioners of ordinary skill with no more than routine experimentation. The molecular weight of the polymer used in the composition of the invention can vary widely, depending on whether a rigid solid state (higher molecular weights) desirable, or whether a fluid state (lower molecular weights) is desired.

[0054] The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments, the term includes compositions, polymers and other materials and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[0055] The phrase “pharmaceutically acceptable carrier” is art-recognized, and includes, for example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or solid filler, diluent, solvent or encapsulating material, involved in carrying or transporting any subject composition, from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of a subject composition and not injurious to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0056] The term “pharmaceutically acceptable salts” is art-recognized, and includes relatively non-toxic, inorganic and organic acid addition salts of compositions, including without limitation, analgesic agents, therapeutic agents, other materials and the like. Examples of pharmaceutically acceptable salts include those derived from mineral acids, such as hydrochloric acid and sulfuric acid, and those derived from organic acids, such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Examples of suitable inorganic bases for the formation of salts include the hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc and the like. Salts may also be formed with suitable organic bases, including those that are non-toxic and strong enough to form such salts. For purposes of illustration, the class of such organic bases may include mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and triethylamine; mono-, di- or trihydroxyalkylamines such as mono-, di-, and triethanolamine; amino acids, such as arginine and lysine; guanidine; N-methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; (trihydroxymethyl)aminoethane; and the like. See, for example, J. Pharm. Sci., 66:1-19 (1977).

[0057] A “patient,” “subject,” or “host” to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.

[0058] The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0059] The term “preventing” is art-recognized, and when used in relation to a condition, such as a local recurrence (e.g., pain), a disease such as cancer, a syndrome complex such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition. Thus, prevention of cancer includes, for example, reducing the number of detectable cancerous growths in a population of patients receiving a prophylactic treatment relative to an untreated control population, and/or delaying the appearance of detectable cancerous growths in a treated population versus an untreated control population, e.g., by a statistically and/or clinically significant amount. Prevention of an infection includes, for example, reducing the number of diagnoses of the infection in a treated population versus an untreated control population, and/or delaying the onset of symptoms of the infection in a treated population versus an untreated control population. Prevention of pain includes, for example, reducing the magnitude of, or alternatively delaying, pain sensations experienced by subjects in a treated population versus an untreated control population.

[0060] The phrases “systemic administration,” “administered systemically,” “peripheral administration” and “administered peripherally” are art-recognized, and include the administration of a subject composition, therapeutic or other material at a site remote from the disease being treated. Administration of an agent directly into, onto or in the vicinity of a lesion of the disease being treated, even if the agent is subsequently distributed systemically, may be termed “local” or “topical” or “regional” administration, other than directly into the central nervous system, e.g., by subcutaneous administration, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.

[0061] The phrase “therapeutically effective amount” is an art-recognized term. In certain embodiments, the term refers to an amount of the therapeutic agent that, when incorporated into a polymer of the present invention, produces some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce sensations of pain for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular compound without necessitating undue experimentation.

[0062] In certain embodiments, a therapeutically effective amount of an analgesic, such as lidocaine or an analog thereof, for in vivo use will likely depend on a number of factors, including: the rate of release of the agent from the polymer matrix, which will depend in part on the chemical and physical characteristics of the polymer; the identity of the agent; the mode and method of administration; and any other materials incorporated in the polymer matrix in addition to the analgesic.

[0063] The term “ED50” is art-recognized. In certain embodiments, ED50 means the dose of a drug which produces 50% of its maximum response or effect, or alternatively, the dose which produces a pre-determined response in 50% of test subjects or preparations. The term “LD50” is art-recognized. In certain embodiments, LD50 means the dose of a drug which is lethal in 50% of test subjects. The term “therapeutic index” is an art-recognized term which refers to the therapeutic index of a drug, defined as LD50/ED50.

[0064] The terms “incorporated” and “encapsulated” are art-recognized when used in reference to a therapeutic agent, or other material and a polymeric composition, such as a composition of the present invention. In certain embodiments, these terms include incorporating, formulating or otherwise including such agent into a composition which allows for sustained release of such agent in the desired application. The terms may contemplate any manner by which a therapeutic agent or other material is incorporated into a polymer matrix, including for example: attached to a monomer of such polymer (by covalent or other binding interaction) and having such monomer be part of the polymerization to give a polymeric formulation, distributed throughout the polymeric matrix, appended to the surface of the polymeric matrix (by covalent or other binding interactions), encapsulated inside the polymeric matrix, etc. The term “co-incorporation” or “co-encapsulation” refers to the incorporation of a therapeutic agent or other material and at least one other therapeutic agent or other material in a subject composition.

[0065] More specifically, the physical form in which any therapeutic agent or other material is encapsulated in polymers may vary with the particular embodiment. For example, a therapeutic agent or other material may be first encapsulated in a microsphere and then combined with the polymer in such a way that at least a portion of the microsphere structure is maintained. Alternatively, a therapeutic agent or other material may be sufficiently immiscible in the polymer of the invention that it is dispersed as small droplets, rather than being dissolved, in the polymer. Any form of encapsulation or incorporation is contemplated by the present invention, in so much as the sustained release of any encapsulated therapeutic agent or other material determines whether the form of encapsulation is sufficiently acceptable for any particular use.

[0066] The term “biocompatible plasticizer” is art-recognized, and includes materials which are soluble or dispersible in the compositions of the present invention, which increase the flexibility of the polymer matrix, and which, in the amounts employed, are biocompatible. Suitable plasticizers are well known in the art and include those disclosed in U.S. Pat. Nos. 2,784,127 and 4,444,933. Specific plasticizers include, by way of example, acetyl tri-n-butyl citrate (c. 20 weight percent or less), acetyl trihexyl citrate (c. 20 weight percent or less), butyl benzyl phthalate, dibutyl phthalate, dioctylphthalate, n-butyryl tri-n-hexyl citrate, diethylene glycol dibenzoate (c. 20 weight percent or less) and the like.

[0067] “Small molecule” is an art-recognized term. In certain embodiments, this term refers to a molecule which has a molecular weight of less than about 2000 amu, or less than about 1000 amu, and even less than about 500 amu.

[0068] The term “aliphatic” is an art-recognized term and includes linear, branched, and cyclic alkanes, alkenes, or alkynes. In certain embodiments, aliphatic groups in the present invention are linear or branched and have from 1 to about 20 carbon atoms.

[0069] The term “alkyl” is art-recognized, and includes saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chain, C3-C30 for branched chain), and alternatively, about 20 or fewer. Likewise, cycloalkyls have from about 3 to about 10 carbon atoms in their ring structure, and alternatively about 5, 6 or 7 carbons in the ring structure.

[0070] Moreover, the term “alkyl” (or “lower alkyl”) includes both “unsubstituted alkyls” and “substituted alkyls”, the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain may themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), —CF3, —CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls may be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, —CF3, —CN, and the like.

[0071] The term “aralkyl” is art-recognized, and includes alkyl groups substituted with an aryl group (e.g., an aromatic or heteroaromatic group).

[0072] The terms “alkenyl” and “alkynyl” are art-recognized, and include unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0073] Unless the number of carbons is otherwise specified, “lower alkyl” refers to an alkyl group, as defined above, but having from one to ten carbons, alternatively from one to about six carbon atoms in its backbone structure. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths.

[0074] The term “heteroatom” is art-recognized, and includes an atom of any element other than carbon or hydrogen. Illustrative heteroatoms include boron, nitrogen, oxygen, phosphorus, sulfur and selenium, and alternatively oxygen, nitrogen or sulfur.

[0075] The term “aryl” is art-recognized, and includes 5-, 6- and 7-membered single-ring aromatic groups that may include from zero to four heteroatoms, for example, benzene, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Those aryl groups having heteroatoms in the ring structure may also be referred to as “aryl heterocycles” or “heteroaromatics.” The aromatic ring may be substituted at one or more ring positions with such substituents as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, —CF3, —CN, or the like. The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings (the rings are “fused rings”) wherein at least one of the rings is aromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

[0076] The terms ortho, meta and nara are art-recognized and apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, the names 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

[0077] The terms “heterocyclyl” and “heterocyclic group” are art-recognized, and include 3- to about 10-membered ring structures, such as 3- to about 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles may also be polycycles. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring may be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF3, —CN, or the like.

[0078] The terms “polycyclyl” and “polycyclic group” are art-recognized, and include structures with two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbons are common to two adjoining rings, e.g., the rings are “fused rings”. Rings that are joined through non-adjacent atoms, e.g., three or more atoms are common to both rings, are termed “bridged” rings. Each of the rings of the polycycle may be substituted with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulflhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, —CF3, —CN, or the like.

[0079] The term “carbocycle” is art recognized and includes an aromatic or non-aromatic ring in which each atom of the ring is carbon. The flowing art-recognized terms have the following meanings: “nitro” means —NO2; the term “halogen” designates —F, —Cl, —Br or —I; the term “sulfhydryl” means —SH; the term “hydroxyl” means —OH; and the term “sulfonyl” means —SO2−.

[0080] The terms “amine” and “amino” are art-recognized and include both unsubstituted and substituted amines, e.g., a moiety that may be represented by the general formulas:

[0081] wherein R50, R51 and R52 each independently represent a hydrogen, an alkyl, an alkenyl, —(CH2)m—R61, or R50 and R51, taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In certain embodiments, only one of R50 or R51 may be a carbonyl, e.g., R50, R51 and the nitrogen together do not form an imide. In other embodiments, R50 and R51 (and optionally R52) each independently represent a hydrogen, an alkyl, an alkenyl, or —(CH2)m—R61. Thus, the term “alkylamine” includes an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, i.e., at least one of R50 and R51 is an alkyl group.

[0082] The term “acylamino” is art-recognized and includes a moiety that may be represented by the general formula:

[0083] wherein R50 is as defined above, and R54 represents a hydrogen, an alkyl, an alkenyl or —(CH2)m—R61, where m and R61 are as defined above.

[0084] The term “amido” is art-recognized as an amino-substituted carbonyl and includes a moiety that may be represented by the general formula:

[0085] wherein R50 and R51 are as defined above. Certain embodiments of the amide in the present invention will not include imides which may be unstable.

[0086] The term “alkylthio” is art-recognized and includes an alkyl group, as defined above, having a sulfur radical attached thereto. In certain embodiments, the “alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl, —S-alkynyl, and —S—(CH2)m—R61, wherein m and R61 are defined above. Representative alkylthio groups include methylthio, ethyl thio, and the like.

[0087] The term “carbonyl” is art-recognized and includes such moieties as may be represented by the general formulas:

[0088] wherein X50 is a bond or represents an oxygen or a sulfur, and R55 represents a hydrogen, an alkyl, an alkenyl, —(CH2)m—R61or a pharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl, an alkenyl or —(CH2)m—R61, where m and R61 are defined above. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula represents an “ester”. Where X50 is an oxygen, and R55 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R55 is a hydrogen, the formula represents a “carboxylic acid”. Where X50 is an oxygen, and R56 is hydrogen, the formula represents a “formate”. In general, where the oxygen atom of the above formula is replaced by sulfur, the formula represents a “thiocarbonyl” group. Where X50 is a sulfur and R55 or R56 is not hydrogen, the formula represents a “thioester.” Where X50 is a sulfur and R55 is hydrogen, the formula represents a “thiocarboxylic acid.” Where X50 is a sulfur and R56 is hydrogen, the formula represents a “thioformate.” On the other hand, where X50 is a bond, and R55 is not hydrogen, the above formula represents a “ketone” group. Where X50 is a bond, and R55 is hydrogen, the above formula represents an “aldehyde” group.

[0089] The terms “alkoxyl” or “alkoxy” are art-recognized and include an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. An “ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of —O-alkyl, —O-alkenyl, —O-alkynyl, —O—(CH2)m—R61, where m and R61 are described above.

[0090] The term “sulfonate” is art-recognized and includes a moiety that may be represented by the general formula:

[0091] in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

[0092] The term “sulfate” is art-recognized and includes a moiety that may be represented by the general formula:

[0093] in which R57 is as defined above.

[0094] The term “sulfonamido” is art-recognized and includes a moiety that may be represented by the general formula:

[0095] in which R50 and R56 are as defined above.

[0096] The term “sulfamoyl” is art-recognized and includes a moiety that may be represented by the general formula:

[0097] in which R50 and R51 are as defined above.

[0098] The term “sulfonyl” is art-recognized and includes a moiety that may be represented by the general formula:

[0099] in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0100] The term “sulfoxido” is art-recognized and includes a moiety that may be represented by the general formula:

[0101] in which R58 is defined above.

[0102] The term “phosphoramidite” is art-recognized and includes moieties represented by the general formulas:

[0103] wherein Q51, R50, R51 and R59 are as defined above.

[0104] The term “phosphonamidite” is art-recognized and includes moieties represented by the general formulas:

[0105] wherein Q51, R50, R51 and R59 are as defined above, and R60 represents a lower alkyl or an aryl.

[0106] Analogous substitutions may be made to alkenyl and alkynyl groups to produce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls, amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls, carbonyl-substituted alkenyls or alkynyls.

[0107] The definition of each expression, e.g. alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure unless otherwise indicated expressly or by the context.

[0108] The term “selenoalkyl” is art-recognized and includes an alkyl group having a substituted seleno group attached thereto. Exemplary “selenoethers” which may be substituted on the alkyl are selected from one of —Se-alkyl, —Se-alkenyl, —Se-alkynyl, and —Se—(CH2)m—R61, m and R61 being defined above.

[0109] The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl, and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate, and nonaflate are art-recognized and refer to trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester, and nonafluorobutanesulfonate ester functional groups and molecules that contain said groups, respectively.

[0110] The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms are art-recognized and represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations.

[0111] Certain monomeric subunits of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers and other compositions of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention.

[0112] If, for instance, a particular enantiomer of a compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.

[0113] It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.

[0114] The term “substituted” is also contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents may be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0115] For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. The term “hydrocarbon” is art recognized and includes all permissible compounds having at least one hydrogen and one carbon atom. For example, permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds that may be substituted or unsubstituted.

[0116] The phrase “protecting group” is art-recognized and includes temporary substituents that protect a potentially reactive functional group from undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed. Greene et al., Protective Groups in Organic Synthesis

[0117]

2

nd
ed., Wiley, New York, (1991).

[0118] The phrase “hydroxyl-protecting group” is art-recognized and includes those groups intended to protect a hydroxyl group against undesirable reactions during synthetic procedures and includes, for example, benzyl or other suitable esters or ethers groups known in the art.

[0119] The term “electron-withdrawing group” is recognized in the art, and denotes the tendency of a substituent to attract valence electrons from neighboring atoms, i.e., the substituent is electronegative with respect to neighboring atoms. A quantification of the level of electron-withdrawing capability is given by the Hammett sigma (a) constant. This well known constant is described in many references, for instance, March, Advanced Organic Chemistry 251-59, McGraw Hill Book Company, New York, (1977). The Hammett constant values are generally negative for electron donating groups (σ(P)=−0.66 for NH2) and positive for electron withdrawing groups (σ(P)=0.78 for a nitro group), σ(P) indicating para substitution. Exemplary electron-withdrawing groups include nitro, acyl, formyl, sulfonyl, trifluoromethyl, cyano, chloride, and the like. Exemplary electron-donating groups include amino, methoxy, and the like.

[0120] Contemplated equivalents of the polymers, subunits and other compositions described above include such materials which otherwise correspond thereto, and which have the same general properties thereof (e.g., biocompatible, analgesic), wherein one or more simple variations of substituents are made which do not adversely affect the efficacy of such molecule to achieve its intended purpose. In general, the compounds of the present invention may be prepared by the methods illustrated in the general reaction schemes as, for example, described below, or by modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are in themselves known, but are not mentioned here.

[0121] 3. Exemplary Subject Compositions

[0122] A. Analgesics and Other Therapeutic Molecules

[0123] A subject composition may comprise an analgesic agent such as lidocaine or an analog thereof. The structures of representative analgesics, e.g., lidocaine, dibucaine, bupivacaine, etidocaine, mepivacaine, prilocaine, benzocaine, butanilicaine, trimecaine, chloroprocaine, procaine, propoxycaine, tocainide, tetracaine, hexylcaine and ropivacaine are presented below.

[0124] The above analgesic agents thus represent a family of related compounds, referred to herein as “caine analgesics”, which have in common 1) a core comprising an aryl ring directly bound to an amide or ester group, and 2) an amino group, which may represent a primary, secondary, or tertiary amine, and may be linked to either the aryl or amide/ester portion of the core. In certain embodiments, a caine analgesic has an aryl core linked to a secondary or tertiary amine through an ester or amide linkage. The term “caine analgesics” includes pharmaceutically acceptable salts of compounds having such common structural features, e.g., lidocaine HCl is a pharmaceutically acceptable salt of lidocaine, and both compounds are “caine analgesics” hereunder. A variety of other suitable analgesics are known in the art, including caine analgesics and others, and such analgesics may be employed in the subject compositions and methods without departing from the spirit or scope of the present invention.

[0125] In certain embodiments, the analgesic used may have a low melting point, e.g., a melting point less than about 120° C., below about 100° C., or below about 80° C. For example, bupivacaine has a melting point below about 110° C., benzocaine has a melting point below about 90° C., lidocaine and dibucaine have melting points below about 70° C., butamben has a melting point below about 60° C., procaine and trimecaine have melting points below about 50° C., and prilocaine has a melting point below about 40° C. Similarly, when a combination of analgesics is used, the combination may have a eutectic melting point below about 120° C., below about 100° C., or below about 80° C., as is known for a combination of, for example, lidocaine and prilocaine (see U.S. Pat. No. 5,993,836).

[0126] Additionally, an analgesic formulation of the present invention may include an “augmenting compound” or “augmenting agent”, such as a glucocorticosteroid. Suitable glucocorticosteroids include dexamethasone, cortisone, prednisone, hydrocortisone, beclomethasone dipropionate, betamethasone, flunisolide, methylprednisone, paramethasone, prednisolone, triamcinolone, alclometasone, amcinonide, clobetasol, fludrocortisone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, fluorometholone, flurandrenolide, halcinonide, medrysone and mometasone and pharmaceutically acceptable mixtures thereof and salts thereof or any other suitable art-known glucocorticosteroid, either naturally occurring or synthetic.

[0127] Examples of non-glucocorticosteroid augmenting compounds which may also be effective when co-administered with an analgesic include alkalinizing agents, non-glucocorticoid steroids such as neuroactive steroids, modulators of gamma amino butyric acid receptors, modulators of ionic transport across cell membranes, antipyretic agents, adrenergic receptor agonists or antagonists, tubulin binding agents, osmotic polysaccharides, agonists and antagonists of potassium ATP channels, Na, K-ATPase inhibitors and enhancers, neurokinin antagonists, phosphatidylinositol-specific phospholipase C (“PLC”) inhibitors, inhibitors of leukocyte glucose metabolism, anti-convulsants, analeptics, tranquilizing agents, antidepressants, convulsants, leukotrienes and prostaglandin agonists and inhibitors, phosphodiesterase agonists and inhibitors, vasoconstrictive agents in sustained release form, and combinations of any of the foregoing. These compounds, both glucocorticoids and non-glucocorticoids, may increase the effectiveness of the analgesic, the duration of the analgesia resulting from administration of the analgesic, and may additionally reduce inflammation or other unwanted symptoms related to the pain.

[0128] In one embodiment, the augmenting agent includes an alkalinizing agent. The alkalinizing augmenting agents used herein preferably raise the pH of the medium in which the analgesic agents in sustained release form are present (e.g., either an injection medium or the environment at the site of injection) to provide a pH from about 6.0 to about 8.5, preferably from about 7.5 to about 8.5. Preferably, the alkalinizing agent may be, for example, a carbonate buffer such as sodium carbonate. Of course, any other alkalinizing agent that is pharmaceutically acceptable for localized injection or infiltration may also be effectively employed.

[0129] The augmenting agents also include non-glucocorticosteroids, e.g., androgens, such as testosterone and its active derivatives, analogs, and metabolites; estrogens, such as estradiol and its active derivatives, analogs, and metabolites and progestins, such as progesterone and its active derivatives, analogs, and metabolites, and mixtures of any of these.

[0130] In another embodiment, the augmenting agent is a neuroactive steroid, such as, e.g., one or more of the class of anesthetic steroids. Neuroactive steroids useful as augmenting agents according to the invention also include those which modulate GABA receptors. Suitable neuroactive steroids include, simply by way of example, althesin and its main component, alphaxalone and active analogs, derivatives and mixtures thereof, as well as 5-alpha-pregnane-3 alpha-21-diol-20-one (tetrahydro-deoxycorticosterone, or “THDOC”) and/or allotetrahydrocortisone (the 17-beta configuration); and dehydroepiandrosterone (“DHE”) and active analogs, derivatives and mixtures thereof. In certain embodiments, the neuroactive steroids are present as an additive in the vehicle carrying the microspheres in a concentration ranging from about 0.01 to about 1 percent by weight, and most preferably from about 0.05 to about 0.5 percent by weight.

[0131] Suitable augmenting agents also include non-steroidal modulators of GABA receptors, including those that are capable of potentiating the inhibitory effects of GABA on those receptors. Such compounds include the benzodiapenes, e.g., diazepam as well as its active derivatives, analogs, and metabolites, and mixtures thereof. In certain embodiments, the diazepam is present as an additive in the vehicle in a concentration ranging from about 0.01 to about 1 percent by weight, or from about 0.05 to about 0.5 percent by weight. Of course, the artisan will appreciate that the potency of benzodiazapenes varies widely, and will adjust these concentration ranges accordingly for other benzodiazapenes, relative to the potency of diazepam.

[0132] In yet another aspect of the invention, the augmenting agent is a modulator of ionic transport across cell membranes. Monovalent and multivalent metal ion transport can be modulated. Agents include, e.g., sodium, potassium and calcium channel modulators (e.g., nifedipine, nitrendipine, verapamil, etc.). In certain embodiments, these also include, but are not limited to, aminopyridine, benzamil, diazoxide, 5,5-diphenylhydantoin, minoxidil, tetrethylammonium and valproic acid. In certain embodiments, the ion transport modulating agent is present as an additive in the vehicle carrying the microspheres in a concentration ranging from about 0.01 to about 5 percent by weight, or from about 0.05 to about 1.5 percent by weight.

[0133] Augmenting agents also include, e.g., antipyretic agents such as aminopyrine, phenazone, dipyrone, apazone, phenylbutazone and derivatives and analogs thereof. Aminopyrine may be included in the vehicle containing the microspheres in a concentration ranging from about 0.01 to about 0.5 percent, or from about 0.05 to about 0.5 percent, by weight.

[0134] Other suitable augmenting agents include, e.g., adrenergic receptor modulators, such as α2 receptor agonists, can also be used as augmenting agents. Simply by way of example, the α2 receptor agonist clonidine provides useful augmentation of local anesthesia, although any other art known α2 receptor modulators capable of augmenting local anesthesia according to the invention may be used. Clonidine may be included in the vehicle containing the microspheres in a concentration ranging from about 0.01 to about 0.5 percent, or from about 0.05 to about 1.0 percent, by weight.

[0135] Tubulin binding agents that are capable of promoting the formation or disruption of cytoplasmic microtubules are may be employed as augmenting agents according to the invention. Such agents include, for example, colchicine and the vinca alkaloids (vincristine and vinblastine) as well as active derivatives, analogs metabolites and mixtures thereof. Of course, some agents may be classified in more than one category, as, for example, colchicine is also known to inhibit glucose metabolism in leukocytes. Colchicine may be included in the vehicle containing the microspheres in a concentration ranging from about 0.01 to about 1.0 percent, or from about 0.05 to about 0.5 percent, by weight.

[0136] Other embodiments of the invention provide potassium-ATP channel agonists for use as augmenting agents. A suitable potassium-ATP channel agonist is, for example, diazoxide, as well as its active derivatives, analogs, metabolites and mixtures thereof are useful as augmenting agents.

[0137] Sodium/potassium ATPase inhibitors are also useful as augmenting agents according to the invention. In certain embodiments, the sodium/potassium ATPase inhibitors are cardiac glycosides that are effective to augment local anesthesia. Cardiac glycosides that are useful according to the invention include, e.g., oubaine, digoxin, digitoxin and active derivatives, analogs, and metabolites, and mixtures of any of these.

[0138] Additionally, augmenting agents according to the invention include, e.g., neurokinin antagonists, such as, e.g., spantide and other peptide inhibitors of substance P receptors that are well known to the art, e.g., as are listed in Receptor and Ion Channel Nomenclature Supplement, Trends in Pharmacological Sciences 18:64-65, the disclosure of which is incorporated by reference herein in its entirety. PLC inhibitors and anti-seizure agents and agents that stabilize cell membrane potential, such as, e.g., benzodiazepines, barbiturates, deoxybarbiturates, carbamazepine, succinamides, valproic acid, oxazalidienbiones, phenacemide and active derivatives, analogs and metabolites and mixtures thereof. In certain embodiments, the anti-seizure augmenting agent is phenytoin, and most preferably is 5,5-diphenylhydantoin.

[0139] “Vasoconstrictive agents” or “vasoconstrictors”, another example of a class of augmenting agents, may also provide effective augmentation of local anesthesia. Sustained release of vasoconstrictor agents, such as epinephrine, can achieve local tissue concentrations that are safe and effective to provide vasoconstrictor activity and to substantially prolong local anesthesia. The local circulatory bed, i.e., blood vessels, remain responsive to the vasoconstrictor agent for prolonged periods, e.g., receptor desensitization or smooth muscle fatigue or tolerance does not prevent the prolongation effect. The gradual release from a sustained release formulation also serves to greatly reduce the risk of toxic reactions such as, e.g., localized tissue necroses.

[0140] As for the previously discussed augmenting agents, vasoconstrictive agents may be administered before, simultaneously with or after the administration of analgesic. In one embodiment of the invention, at least a portion of the vasoconstrictive agent is formulated in a sustained release formulation together with analgesic. In another embodiment, the vasconstrictive agent is prepared in one or separate sustained release formulations. It will be appreciated that by manipulating the loading of, e.g., microspheres containing vasoconstrictor agent, the artisan can determine the number of microspheres necessary to administer a given dose. Thus, simply by way of example, microspheres loaded with about 75 percent by weight of vasoconstrictor agent (or analgesic) will require about half of the microspheres necessary to administer a predetermined dose than will microspheres loaded with about 45 percent by weight of vasoconstrictor agent (or analgesic). The description herein of different exemplary means of administering vasoconstrictive agents applies equally well to other augmenting agents.

[0141] The vasoconstrictor may be included in either a single or combination formulation in an amount ranging from about 0.001 percent to about 90 percent, by weight relative to the total weight of the formulation. Preferably, the vasoconstrictor is included in a sustained release formulation in an amount ranging from about 0.005 percent to about 20%, and more preferably, from about 0.05 percent to about 5 percent, by weight, relative to the total weight of the formulation. When a vasoconstrictor is present in the injection vehicle in immediate release form, it is present in amounts ranging from about 0.01% to about 5 percent, or more, by weight, relative to the injection vehicle. The vasoconstrictor can also be provided in a ratio of local anesthetic, e.g., bupivacaine to vasoconstrictor, ranging from about 10:1 to about 20,000 and preferably from about 100:1 to about 2000:1 and from about 500:1 to about 1500:1.

[0142] Vasoconstrictor agents may formulated into, e.g., sustained release microspheres including both a analgesic, e.g., lidocaine free base or pharmaceutically acceptable salt thereof, and a vasoconstrictor agent. Vasoconstrictor agents may also be formulated into, e.g., sustained release microspheres including analgesic without a vasoconstrictive agent.

[0143] In one embodiment, analgesic and a vasoconstrictor agent or other augmenting agent are administered simultaneously in the form of, e.g., separate microspheres suspended in a single medium suitable for injection or infiltration, or in separate microspheres suitable for injection, e.g., at the same site. In a further embodiment, simply by way of example, administration of sustained release microspheres with combined analgesic and vasoconstrictor agent may also be followed by one or more additional administrations of such combination formulation and/or of microspheres including as the active agent only analgesic or only vasoconstrictor agent. Augmenting agents that are vasoconstrictor agents include, but are not limited to, catecholamines, e.g., epinephrine, norepinephrine and dopamine as well as, e.g., metaraminol, phenylephrine, methoxamine, mephentermine, methysergide, ergotamine, ergotoxine, dihydroergotamine, sumatriptan and analogs, and alpha-1 and alpha-2 adrenergic agonists, such as, e.g., clonidine, guanfacine, guanabenz and dopa (i.e., dihydroxyphenylalanine), methyldopa, ephedrine, amphetamine, methamphetamine, methylphenidate, ethylnorepinephrine, ritalin, pemoline and other sympathomimetic agents, including active metabolites, derivatives and mixtures of any of the foregoing.

[0144] A local anesthetic according to the invention may also be formulated, e.g., in injectable microspheres, in combination with at least one vasoconstrictor augmenting agent according to the invention. In one embodiment, the vasoconstrictor may be included in the vehicle suitable for injection carrying the microspheres. In a further embodiment, at least a portion of the vasoconstrictor may also be formulated into a sustained release formulation, e.g., injectable microspheres, together with the local anesthetic. In a still further embodiment, at least a portion of the vasoconstrictor may be prepared in a separate sustained release formulation.

[0145] In certain embodiments, at least a portion of any of the augmenting agent enumerated above are included in the sustained release formulation, in combination with an analgesic agent or agents in a concentration ranging from about 0.01 to about 30 percent or more, by weight, relative to the weight of the formulation.

[0146] Other augmenting agents according to the invention broadly include any other types and classifications of drugs or active agents known to the art that increase the effective of an analgesic. Such augmenting agents are readily identified by routine screening as discussed hereinbelow using animal sensory protocols well known to the art.

[0147] Other compounds which may be co-administered with an analgesic agent include capsaicin and analogs thereof, adrenaline, cocaine, non-selective p-receptor blockers such as alprenolol, propanolol, and pindolol, selective β-receptor blockers such as metoprolol, lithium cations, and pharmaceuticals the administration of which can cause a sensation of pain.

[0148] B. Polymers

[0149] A variety of polymers may be used in the subject invention. Both non-biodegradable and biodegradable polymers may be used in the subject invention, although biodegradable polymers are preferred. As discussed below, the choice of polymer will depend in part on a variety of physical and chemical characteristics of such polymer and the use to which such polymer may be put. Representative natural polymers include proteins, such as zein, modified zein, casein, gelatin, gluten, serum albumin, or collagen, and polysaccharides, such as cellulose, dextrans, hyaluronic acid, and polymers of alginic acid.

[0150] Representative synthetic polymers include polyphosphazines, poly(vinyl alcohols), polyamides, polycarbonates, polyalkylenes, polyacrylamides, polyanhydrides, poly(phosphoesters), polyalkylene glycols, polyalkylene oxides, polyalkylene terephthalates, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone (PVP), polyglycolides, polysiloxanes, polyphosphates and polyurethanes.

[0151] Synthetically modified natural polymers include alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, and nitrocelluloses. Other like polymers of interest include, but are not limited to, methyl cellulose, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxybutyl methyl cellulose, cellulose acetate, cellulose propionate, cellulose acetate butyrate, cellulose acetate phthalate, carboxymethyl cellulose, cellulose triacetate and cellulose sulfate sodium salt.

[0152] Representative biodegradable polymers include polylactide, polyglycolide, polycaprolactone, polycarbonate, poly(phosphoesters), polyanhydride, polyorthoesters, and natural polymers such as alginate and other polysaccharides including dextran and cellulose, collagen, chemical derivatives thereof (substitutions, additions of chemical groups, for example, alkyl, alkylene, hydroxylations, oxidations, and other modifications routinely made by those skilled in the art), albumin and other hydrophilic proteins, zein and other prolamines and hydrophobic proteins.

[0153] All of the subject polymers may be provided as copolymers or terpolymers. These polymers may be obtained from chemical suppliers or else synthesized from monomers obtained from these suppliers using standard techniques.

[0154] In addition to the listing of polymers above, polymers having phosphorus linkages may be used in the subject invention. Exemplary phosphorus linkages in such polymers include, without limitation, phosphonamidite, phosphoramidite, phosphorodiamidate, phosphomonoester, phosphodiester, phosphotriester, phosphonate, phosphonate ester, phosphorothioate, thiophosphate ester, phosphinate or phosphite. Certain of such polymers may be biodegradable, biocompatible or both.

[0155] The structure of certain of the foregoing polymers having phosphorus linkages may be identified as follows. The term “polymer having phosphorous-based linkages” is used herein to refer to polymers in which the following substructure is present at least a multiplicity of times in the backbone of such polymer:

[0156] wherein, independently for each occurrence of such substructure:

[0157] X1, each independently, represents —O— or —N(R5)—;

[0158] R5 represents —H, aryl, alkenyl or alkyl; and

[0159] R6 is any non-interfering substituent,

[0160] wherein such substructure is responsible in part for biodegradability properties, if any, observed for such polymer in vitro or in vivo. In certain embodiments, R6 may represent an alkyl, aralkyl, alkoxy, alkylthio, or alkylamino group.

[0161] In certain embodiments, such a biodegradable polymer is non-naturally occurring, i.e., a man-made product with no natural source. In other embodiments, R6 is other than —OH or halogen, e.g., is alkyl, aralkyl, aryl, alkoxyl, aralkyoxy or aryloxy. In still other embodiments, the two X1 moieties in such substructure are the same. For general guidance, when reference is made to the “polymer backbone chain” or the like of a polymer, with reference to the above structure, such polymer backbone chain comprises the motif [-X1-P-X1-]. In other polymers, the polymer backbone chain may vary as recognized by one of skill in the art.

[0162] By way of example, but not limitation, a number of representative polymers having phosphorus linkages are described in greater detail below. In certain embodiments, a polymer includes one or more monomeric units of Formula V:

[0163] wherein, independently for each occurrence of such unit:

[0164] X1, each independently, represents —O— or —N(R7)—;

[0165] R7 represents —H, aryl, alkenyl or alkyl;

[0166] L1 is described below;

[0167] R8 represents, for example, —H, alkyl, —O-alkyl, —O-cycloalkyl, aryl, —O-aryl, heterocycle, —O-heterocycle, —N(R9)R10 and other examples presented below;

[0168] R9 and R10, each independently, represent a hydrogen, an alkyl, an alkenyl, —(CH2)m—R11, or R9 and R10, taken together with the N atom to which they are attached complete a heterocycle having from 4 to about 8 atoms in the ring structure;

[0169] m represents an integer in the range of 0-10, preferably 0-6; and

[0170] R 11represents —H, alkyl, aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle.

[0171] L1 may be any chemical moiety as long as it does not materially interfere with the polymerization, biocompatibility or biodegradation (or any combination of those three properties) of the polymer, wherein a “material interference” or “non-interfering substituent” is understood to mean: (i) for synthesis of the polymer by polymerization, an inability to prepare the subject polymer by methods known in the art or taught herein, (ii) for biocompatibility, a reduction in the biocompatibility of the subject polymer so as to make such polymer impracticable for in vivo use; and (iii) for biodegradation, a reduction in the biodegradation of the subject polymer so as to make such polymer impracticable for biodegradation.

[0172] In certain embodiments, L1 is an organic moiety, such as a divalent branched or straight chain or cyclic aliphatic group or divalent aryl group, with in certain embodiments, from 1 to about 20 carbon atoms. In certain embodiments, L1 represents a moiety between about 2 and 20 atoms selected from carbon, oxygen, sulfur, and nitrogen, wherein at least 60% of the atoms are carbon. In certain embodiments, L1 may be an alkylene group, such as methylene, ethylene, 1,2-dimethylethylene, n-propylene, isopropylene, 2,2-dimethylpropylene, n-pentylene, n-hexylene, n-heptylene; an alkenylene group such as ethenylene, propenylene, 2-(3-propenyl)-dodecylene; and an alkynylene group such as ethynylene, proynylene, 1-(4-butynyl)-3-methyldecylene; and the like. Such unsaturated aliphatic groups may be used to cross-link certain embodiments of the present invention.

[0173] Further, L1 may be a cycloaliphatic group, such as cyclopentylene, 2-methylcyclopentylene, cyclohexylene, cyclohexylenedimethylene, cyclohexenylene and the like. L1 may also be a divalent aryl group, such as phenylene, benzylene, naphthalene, phenanthrenylene and the like. Further, L1 may be a divalent heterocyclic group, such as pyrrolylene, furanylene, thiophenylene, alkylyene-pyrrolylene-alkylene, pyridinylene, pyrimidinylene and the like.

[0174] Other examples of L1 may include any of the polymers listed above, including the biodegradable polymers listed above, and in particular polylactide, polyglycolide, polycaprolactone, polycarbonate, polyethylene terephthalate, polyanhydride and polyorthoester, and polymers of ethylene glycol, propylene glycol and the like. Embodiments containing such polymers for L1 may impart a variety of desired physical and chemical properties.

[0175] The foregoing, as with other moieties described herein, may be substituted with a non-interfering substituent, for example, a hydroxy-, halogen-, or nitrogen-substituted moiety.

[0176] R8 represents hydrogen, alkyl, cycloakyl, —O-alkyl, —O-cycloalkyl, aryl, —O-aryl, heterocycle, —O-heterocycle, or —N(R9)R10. Examples of possible alkyl R8 groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, —C8H17 and the like groups; and alkyl substituted with a non-interfering substituent, such as hydroxy, halogen, alkoxy or nitro; corresponding alkoxy groups.

[0177] When R8 is aryl or the corresponding aryloxy group, it typically contains from about 5 to about 14 carbon atoms, or about 5 to about 12 carbon atoms, and optionally, may contain one or more rings that are fused to each other. Examples of particularly suitable aromatic groups include phenyl, phenoxy, naphthyl, anthracenyl, phenanthrenyl and the like.

[0178] When R8 is heterocyclic or heterocycloxy, it typically contains from about 5 to about 14 ring atoms, alternatively from about 5 to about 12 ring atoms, and one or more heteroatoms. Examples of suitable heterocyclic groups include furan, thiophene, pyrrole, isopyrrole, 3-isopyrrole, pyrazole, 2-isoimidazole, 1,2,3-triazole, 1,2,4-triazole, oxazole, thiazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-dioxazole, 1,2,4-dioxazole, 1,3,2-dioxazole, 1,3,4-dioxazole, 1,2,5-oxatriazole, 1,2-pyran, 1,4-pyran, 1,2-pyrone, 1,4-pyrone, 1,2-dioxin, 1,3-dioxin, pyridine, N-alkyl pyridinium, pyridazine, pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine, 1,2-oxazine, 1,3-oxazine, 1,4-oxazine, o-isoxazine, p-isoxazine, 1,2,5-oxathiazine, 1,2,6-oxathiazine, 1,4,2-oxadiazine, 1,3,5-oxadiazine, azepine, oxepin, thiepin, indene, isoindene, benzofuran, isobenzofuran, thionaphthene, isothionaphthene, indole, indolenine, 2-isobenzazole, isoindazole, indoxazine, benzoxazole, anthranil, 1,2-benzopyran, 1,2-benzopyrone, 1,4-benzopyrone, 2,1-benzopyrone, 2,3-benzopyrone, quinoline, isoquinoline, 12,-benzodiazine, 1,3-benzodiazine, naphthyridine, pyrido-[3,4-b]-pyridine, pyrido-[3,2-b]-pyridine, pyrido- [4,3-b]-pyridine, 1,3,2-benzoxazine, 1,4,2-benzoxazine, 2,3,1-benzoxazine, 3,1,4-benzoxazine, 1,2-benzisoxazine, 1,4-benzisoxazine, carbazole, xanthrene, acridine, purine, and the like. In certain embodiments, when R8 is heterocyclic or heterocycloxy, it is selected from the group consisting of furan, pyridine, N-alkylpyridine, 1,2,3- and 1,2,4-triazoles, indene, anthracene and purine rings.

[0179] In certain embodiments, R8 is an alkyl group, an alkoxy group, a phenyl group, a phenoxy group, a heterocycloxy group, or an ethoxy group.

[0180] In still other embodiments, R8, such as an alkyl, may be conjugated to a bioactive substance to form a pendant drug delivery system.

[0181] In certain embodiments, the number of monomeric units in Formula V and other subject formulas that make up the subject polymers ranges over a wide range, e.g., from about 5 to 25,000 or more, but generally from about 100 to 5000, or 10,000. Alternatively, in other embodiments, the number of monomeric units may be about 10, 25, 50, 75, 100, 150, 200, 300 or 400.

[0182] In Formula V and other formulas herein, “*” represents other monomeric units of the subject polymer, which may be the same or different from the unit depicted in the formula in question, or a chain terminating group, by which the polymer terminates. Examples of such chain terminating groups include monofunctional alcohols and amines.

[0183] In another aspect, the polymeric compositions of the present invention include one or more recurring monomeric units represented in general Formula VI:

[0184] wherein Z1 and Z2, respectively, for each independent occurrence is:

[0185] wherein, independently for each occurrence set forth above:

[0186] Q1, Q2 . . . Qs, each independently, represent O or N(R1);

[0187] X1, X2 . . . Xs, each independently, represent —O— or —N(R1);

[0188] the sum of t1, t2 . . . ts is an integer and at least one or more;

[0189] Y1 represents —O—, —S— or —N(R7)—;

[0190] x and y are each independently integers from 1 to about 1000 or more;

[0191] L1 and M1, M2 . . . Ms each independently, represent the moieties discussed below; and

[0192] the other moieties are as defined above.

[0193] M1, M2 . . . Ms (collectively, M) in Formula VI are each independently any chemical moiety that does not materially interfere with the polymerization, biocompatibility or biodegradation (or any combination of those three properties) of the subject polymer. For certain embodiments, M in the formula are each independently: (i) a branched or straight chain aliphatic or aryl group having from 1 to about 50 carbon atoms, or (ii) a branched or straight chain, oxa-, thia-, or aza-aliphatic group having from 1 to about 50 carbon atoms, both optionally substituted. In certain embodiments, the number of such carbon atoms does not exceed 20. In other embodiments, M may be any divalent aliphatic moiety having from 1 to about 20 carbon atoms, including therein from 1 to about 7 carbon atoms.

[0194] M may include an aromatic or heteroaromatic moiety, optionally with non-interfering substituents. In certain embodiments, none of the atoms (usually but not always C) that form the cyclic ring that gives rise to the aromatic moiety are part of the polymer backbone chain.

[0195] Specifically, when M is a branched or straight chain aliphatic group having from 1 to about 20 carbon atoms, it may be, for example, an alkylene group such as methylene, ethylene, 1-methylethylene, 1,2-dimethylethylene, n-propylene, trimethylene, isopropylene, 2,2-dimethylpropylene, n-pentylene, n-hexylene, n-heptylene, n-octylene, n-nonylene, n-decylene, n-undecylene, n-dodecylene, and the like; an alkenylene group such as n-propenylene, 2-vinylpropylene, n-butenylene, 3-thexylbutylene, n-pentenylene, 4-(3-propenyl)hexylene, n-octenylene, 1-(4-butenyl)-3-methyldecylene, 2-(3-propenyl)dodecylene, hexadecenylene and the like; an alkynylene group, such as ethynylene, propynylene, 3-(2-ethynyl)pentylene, n-hexynylene, 2-(2-propynyl)decylene, and the like; or any alkylene, alkenylene or alkynylene group, including those listed above, substituted with a materially non-interfering substituent, for example, a hydroxy, halogen or nitrogen group, such as 2-chloro-n-decylene, 1-hydroxy-3-ethenylbutylene, 2-propyl-6-nitro-10-dodecynylene, and the like. Other M of the present invention include —(CH2)3—, —(CH2)5— and —(CH2)2OCH2—.

[0196] When M is a branched or straight chain oxaaliphatic group having from 1 to about 20 carbon atoms, it may be, for example, a divalent alkoxylene group, such as ethoxylene, 2-methylethoxylene, propoxylene, butoxylene, pentoxylene, dodecyloxylene, hexadecyloxylene, and the like. When M is a branched or straight chain oxaaliphatic group, it may have the formula —(CH2)a—O—(CH2)b— wherein each of a and b, independently, is about 1 to about 7.

[0197] When M is a branched or straight chain oxaaliphatic group having from 1 to about 20 carbon atoms, it may also be, for example, a dioxaalkylene group such as dioxymethylene, dioxyethylene, 1,3-dioxypropylene, 2-methoxy-1,3-dioxypropylene, 1,3-dioxy-2-methylpropylene, dioxy-n-pentylene, dioxy-n-octadecylene, methoxylene-methoxylene, ethoxylene-methoxylene, ethoxylene-ethoxylene, ethoxylene-1-propoxylene, butoxylene-n-propoxylene, pentadecyloxylene-methoxylene, and the like. When M is a branched or straight chain, dioxyaliphatic group, it may have the formula —(CH2)a—O—(CH2b—O—(CH2)c—, wherein each of a, b, and c is independently from 1 to about 7.

[0198] When M is a branched or straight chain thiaaliphatic group, the group may be any of the preceding oxaaliphatic groups wherein the oxygen atoms are replaced by sulfur atoms.

[0199] When M is a branched or straight chain, aza-aliphatic group having from 1 to about 20 carbon atoms, it may be a divalent group such as —CH2NH—, —(CH2)2N—, —CH2(C2H5)N—, -n-C4H9NH—, -t-C4H9NH—, —CH2(C3H7)N—, —C2H5(C2H5)N—, —CH2(C8H17)N—, —CH2NHCH2—, —(CH2)2NCH2—, —CH2(C2H5)NCH2CH2—, -n-C4H9NHCH2—, -t-C4H9NHCH2CH2—, —CH2(C3H7)N(CH2)4—, —C2H5(C2H5)NCH2—, —CH2(C8H17)NCH2CH2—, and the like. When M is a branched or straight chain, amino-aliphatic group, it may have the formula —(CH2)aNR1— or —(CH2)aN(R1)(CH2)b— where R1 is —H, aryl, alkenyl or alkyl and each of a and b is independently from about 1 to about 7.

[0200] x and y of Formula VI each independently represent integers in the range of about 1 to about 1000, e.g., about 1, about 10, about 20, about 50, about 100, about 250, about 500, about 750, about 1000, etc.

[0201] For Formula VI, the average molar ratio of (x or y):L1, assuming ts is equal to one, may vary greatly, typically between about 75:1 and about 2:1. In certain embodiments, the average molar ratio of (x or y):L1, when ts is equal to one, is about 10:1 to about 4:1, and preferably about 5:1. The molar ratio of x:y may also vary; typically, such ratio is about 1. Other possible embodiments may have ratios of 0. 1, 0.25, 0.5, 0.75, 1.5, 2, 3, 4, 10 and the like.

[0202] A number of different polymer structures are contemplated by Formula VI. For example, in certain polymers exemplified by Formula VI, when the sum of t1, t2 . . . ts equals one for each of Z1 and Z2 and Q, M and X for each subunit ts are the same, then Formula VI becomes the following Formula VIa:

[0203] In certain embodiments of Formula VIa (and other subject formulas), x and y may be even integers.

[0204] The above Formula VI (and all of the subject formulae and polymers) encompass a variety of different polymer structures, including block copolymers, random copolymers, random terpolymers and segmented block copolymers and terpolymers. Additional structures for Z of subject monomeric units are set forth below, which exemplify in part the variety of structures contemplated by the present invention:

[0205] In Formula VIb (and other formulas described below), there may be more ts subunits depicted of the same molecular identity of those depicted in the formulas. For example, in Formula VIb, subunits t1 and t2 may be repeated in a sequence, e.g., alternating, in blocks (which may themselves repeat), or in any other pattern or random arrangement. Each subunit may repeat any number of times, and one subunit (e.g., t1) may occur with substantially the same frequency, more often, or less often than another subunit (e.g., t2), such that both subunits may be present in approximately the same amount, or in differing amounts, which may differ slightly or be highly disparate, e.g., one subunit is present nearly to the exclusion of the other. In certain embodiments, the chiral centers of each subunit may be the same or different and may be arranged in an orderly fashion or in a random sequence in each of Z1 and Z2.

[0206] In certain embodiments of Formula VIc, the sum of the number of ts subunits in each of Z1 and Z2 is an even integer. As in other examples of Z1 and Z2, such as described above for Formula VIb, the ts subunits may be distributed randomly or in an ordered arrangement in each of Z1 or Z2.

[0207] In Formula VId, the subunit q1 is comprised of two ts subunits, which may be repeated and arranged as described above for Formula VIb. In certain embodiments, q2 is an even integer, and in other embodiments, the subunits q1 and q2 may be distributed randomly or in an ordered pattern in each of Z1 and Z2. For example, subunits q1 and q2 may be repeated in a sequence, e.g., alternating, in blocks (which may themselves repeat), or in any other pattern or random arrangement. Each subunit may repeat any number of times, and one subunit (e.g., q1) may occur with substantially the same frequency, more often, or less often than another subunit (e.g., q2), such that both subunits may be present in approximately the same amount, or in differing amounts, which may differ slightly or be highly disparate, e.g., one subunit is present nearly to the exclusion of the other.

[0208] In certain embodiments of Formula VIe, the sum of the ts subunits for each of Z1 and Z2 is an even integer. In other embodiments, the each of the subunits t1, t2, and t3 may be distributed randomly or in an ordered arrangement in each of Z1 and Z2. For example, in Formula VIe, subunits t1, t2, and t3 may be repeated in a sequence, e.g., alternating, in blocks (which may themselves repeat), or in any other pattern or random arrangement. Each subunit may repeat any number of times, and one subunit (e.g., t1) may occur with substantially the same frequency, more often, or less often than another subunit (e.g., t3), such that the three subunits may be present in approximately the same amount, or in differing amounts, which may differ slightly or be highly disparate, e.g., two subunits are present nearly to the exclusion of the third.

[0209] In certain embodiments of Formula VI, in which Q, M and X for each subunit are the same, Q1 represents O, M represents a lower alkylene group, and X1 represents O or S, preferably O. For example, M may represent —CH(CH3)— to result in a polymer of Formula VI having a structure represented in Formula VIf:

[0210] In certain embodiments of Formula VIf, as further described in the Exemplification below, L1 represents a lower alkylene chain, such as ethylene, propylene, etc. In certain embodiments, all Y1's represent O. In certain embodiments, R8 represents —O-lower alkyl, such as —OEt.

[0211] In certain embodiments of polymers depicted by Formula VI, the chirality of each subunit is identical, whereas in other embodiments, the chirality is different. By way of example but not limitation, in Formula VIb above, if the chiral centers of all of the subunits are D-enantiomers or L-enantiomers, then the monomeric unit is effectively equivalent to D-lactic acid or L-lactic acid, respectively, thereby giving rise to a region similar to poly(D-lactic acid) or poly-(L-lactic acid), respectively. Conversely, if the two subunits in Formula VIb are comprised of alternating D- and L-enantiomers (e.g., one unit of D-enantiomer, one unit of L-enantiomer, etc.), then the resulting polymeric region is analogous to poly(meso-lactic acid) (i.e., a polymer formed by polymerization of meso-lactide).

[0212] Finally, in certain embodiments of the monomeric units set forth in Formula VI, in which the entire polymer may or may not be composed of such units, the following moieties for Y1, L1, R8 Qs, Xs and Ms may be used (with a variety of different x and y being possible):

1AbbreviationAll Y1'sL1R8L-PL(EG)EOPO—CH2CH2——OCH2CH3L-PL(EG)HOPO—CH2CH2——O(CH2)5CH3D,L-PL(EG)EOP*O—CH2CH2——OCH2CH3D,L-PL(PG)EOP*O—CH2(CH3)CH2——OCH2CH3D-PL(PG)EOPO—CH2(CH3)CH2——OCH2CH3L-PL(PG)EOPO—CH2(CH3)CH2——OCH2CH3D,L-PL(HD)EOP*O

—OCH2CH3D,L-PL(PG)HOP*O—CH2(CH3)CH2——O(CH2)5CH3D,L-PL(PG)EP*O—CH2(CH3)CH2——CH2CH3AbbreviationAll QsAll XsM1M2L-PL(EG)EOPOO—CH(CH3)— (L)N/AL-PL(EG)HOPOO—CH(CH3)— (L)N/AD,L-PL(EG)EOP*OO—CH(CH3)— (L or D)—CH(CH3)— (D or L)D,L-PL(PG)EOP*OO—CH(CH3)— (L or D)—CH(CH3)— (D or L)D-PL(PG)EOPOO—CH(CH3)— (D)N/AL-PL(PG)EOPOO—CH(CH3)— (L)N/AD,L-PL(HD)EOP*OO—CH(CH3)— (L or D)—CH(CH3)— (L or D)D,L-PL(PG)HOP*OO—CH(CH3)— (L or D)—CH(CH3)— (L or D)D,L-PL(PG)EP*OO—CH(CH3)— (L or D)—CH(CH3)— (L or D)*For For D,L-PL(EG)EOP*, D,L-PL(PG)EOP*, D,L-PL(HD)EOP*, D,L-PL(PG)HOP*, and D,L-PL(PG)EP*, if the chiral carbon of M1 has configuration L, then M2 will have configuration D, and vice-versa. The order of the chiral centers in each subunit M1 and M2 for each Z1 and Z2 will be in random order.

[0213] In addition to the particular chiral version of the subject polymers described in the above table, polymers in which the chirality of Ms varies in each subunit M in the subject polymers are also possible. For instance, referring to D,L-PL(EG)EOP by example, a random order of D and L, in varying amounts, are possible for this polymer. In contrast, the table sets forth one such example in which a D and L chiral M are always adjacent, in equal amounts, but that need not always be the case.

[0214] In another embodiment of the present invention, the polymeric compositions of the present invention include one or more recurring monomeric units represented in general Formula VII:

[0215] wherein, independently for each occurrence:

[0216] L2 is a divalent organic group as described in greater detail below; and

[0217] the other moieties are as defined as above.

[0218] In Formula VII, L2 may be a divalent, branched or straight chain aliphatic group, a cycloaliphatic group, or a group of the formula:

[0219] Specific examples of particular divalent, branched or straight chain aliphatic groups include an alkylene group with 1 to 7 carbon atoms, such as 2-methylpropylene or ethylene. Specific examples of cycloaliphatic groups include cycloalkylene groups, such as cyclopentylene, 2-methylcyclopentylene, cyclohexylene and 2-chloro-cyclohexylene; cycloalkenylene groups, such as cyclohexenylene; and cycloalkylene groups having fused or bridged additional ring structures, such as tetralinylene, decalinylene and norpinanylene; or the like.

[0220] In certain embodiments of the monomeric units set forth in Formula VII, in which the entire polymer may or may not be composed of such units, the following moieties for X1, L1 and R8 may be used:

2AbbreviationAll X1All L1L2R8P(trans-CHDM/HOP)O—CH2—

—O(CH2)5CH3trans-1,4-cyclohexylP(cis- and trans-O—CH2—mixture of trans-1,4-—O(CH2)5CH3CHDM/HOP)cyclohexyl and

cis-1,4-cyclohexylP(trans-CHDM/BOP)O—CH2—trans-1,4-cyclohexyl—O(CH2)3CH3P(trans-CHDM/EOP)O—CH2—trans-1,4-cyclohexyl—OCH2CH3

[0221] In another embodiment of the present invention, the polymeric compositions of the present invention include one or more recurring monomeric units represented in general Formula VIII:

[0222] wherein, independently for each occurrence, d is equal to one or more, and optionally two, x is equal to or greater than one, and all of the other moieties are as defined above.

[0223] In certain embodiments of Formula VIII, each of L1 independently may be an alkylene group, a cycloaliphatic group, a phenylene group or a divalent group of the formula:

[0224] wherein D is O, N or S and m is 0 to 3. Alternatively, L1 is a branched or straight chain alkylyene group having from 1 to 7 carbon atoms, such as a methylene, ethylene, n-propylene, 2-methylpropylene, 2,2′-dimethylpropylene group and the like.

[0225] In certain embodiments of the monomeric units set forth in Formula VIII, in which the entire polymer may or may not be composed of such units, the following moieties for X1, L1 and R8 may be used (with a variety of different x possible for each example and with d preferably equal to two):

3AbbreviationAll X1All L1R8P(BHET-EOP/TC)O-CH2CH2--OCH2CH3P(BHDPT-EOP/TC)O-CH2CH(CH3)2CH2--OCH2CH3P(BHDPT-HOP/TC)O-CH2CH(CH3)2CH2--OC6H13P(BHPT-EOP/TC)O-CH2CH2CH2--OCH2CH3P(BHMPT-E0P/TC)OCH2CH2(CH3)CH2--OCH2CH3

[0226] In Formula VIII, the aryl groups represented therein may be substituted with a non-interfering substituent, for example, a hydroxy-, halogen-, or nitrogen-substituted moiety.

[0227] Other phosphorus containing polymers which may be adapted for use in the subject invention, and methods of making the same, are described in the art, including those described in U.S. Pat. Nos. 5,256,765 and 5,194,581; PCT publications WO 98/44020, WO 98/44021, and WO 98/48859; and U.S. applications Ser. Nos. 09/053,649, 09/053,648 and 09/070,204. For all of the above-identified groups, non-interfering substituents may also be present.

[0228] In certain embodiments, the polymers are comprised almost entirely, if not entirely, of the same subunit. Alternatively, in other embodiments, the polymers may be copolymers, in which different subunits and/or other monomeric units are incorporated into the polymer. In certain instances, the polymers are random copolymers, in which the different subunits and/or other monomeric units are distributed randomly throughout the polymer chain. For example, the polymer having units of Formula V may consist of effectively only one type of such subunit, or alternatively two or more types of such subunits. In addition, the polymer may contain monomeric units other than those subunits represented by Formula V.

[0229] In other embodiments, the different types of monomeric units, be they one or more subunits depicted by the subject formulas or other monomeric units, are distributed randomly throughout the chain. In part, the term “random” is intended to refer to the situation in which the particular distribution or incorporation of monomeric units in a polymer that has more than one type of monomeric units is not directed or controlled directly by the synthetic protocol, but instead results from features inherent to the polymer system, such as the reactivity, amounts of subunits and other characteristics of the synthetic reaction or other methods of manufacture, processing or treatment.

[0230] In certain embodiments, the subject polymers may be cross-linked. For example, substituents of the polymeric chain, may be selected to permit additional inter-chain cross-linking by covalent or electrostatic (including hydrogen-binding or the formation of salt bridges), e.g., by the use of a organic residue appropriately substituted.

[0231] The ratio of different subunits in any polymer as described above may vary. For example, in certain embodiments, polymers may be composed almost entirely, if not entirely, of a single monomeric element, such as a subunit depicted in Formula V. Alternatively, in other instances, the polymers are effectively composed of two different subunits, in which the percentage of each subunit may vary from less than 1:99 to more than 99:1, or alternatively 10:90, 15:85, 25:75, 40:60, 50:50, 60:40, 75:25, 85:15, 90:10 or the like. For example, in some instances, a polymer may be composed of two different subunits that may be both represented by the generic Formula V, but which differ in their chemical identity. In certain embodiments, the polymers may have just a few percent, or even less (for example, about 5, 2.5, 1, 0.5, 0.1%) of the subunits having phosphorous-based linkages. In other embodiments, in which three or more different monomeric units are present, the present invention contemplates a range of mixtures like those taught for the two-component systems.

[0232] In certain embodiments, the polymeric chains of the subject compositions, e.g., which include repetitive elements shown in any of the subject formulas, have molecular weights ranging from about 2000 or less to about 1,000,000 or more daltons, or alternatively about 10,000, 20,000, 30,000, 40,000, or 50,000 daltons, more particularly at least about 100,000 daltons, and even more specifically at least about 250,000 daltons or even at least 500,000 daltons. Number-average molecular weight (Mn) may also vary widely, but generally fall in the range of about 1,000 to about 200,000 daltons, preferably from about 1,000 to about 100,000 daltons and, even more preferably, from about 1,000 to about 50,000 daltons. Most preferably, Mn varies between about 8,000 and 45,000 daltons. Within a given sample of a subject polymer, a wide range of molecular weights may be present. For example, molecules within the sample may have molecular weights which differ by a factor of 2, 5, 10, 20, 50, 100, or more, or which differ from the average molecular weight by a factor of 2, 5, 10, 20, 50, 100, or more.

[0233] One method to determine molecular weight is by gel permeation chromatography (“GPC”), e.g., mixed bed columns, CH2Cl2 solvent, light scattering detector, and off-line dn/dc. Other methods are known in the art.

[0234] In certain embodiments, the intrinsic viscosities of the polymers generally vary from about 0.01 to about 2.0 dL/g in chloroform at 40° C., alternatively from about 0.01 to about 1.0 dL/g and, occasionally, from about 0.01 to about 0.5 dL/g.

[0235] The glass transition temperature (Tg) of the subject polymers may vary widely, and depend on a variety of factors, such as the degree of branching in the polymer components, the relative proportion of phosphorous-containing monomer used to make the polymer, and the like. When the article of the invention is a rigid solid, the Tg is often within the range of from about −10° C. to about 80° C., particularly between about 0 and 50° C. and, even more particularly between about 25° C. to about 35° C. In other embodiments, the Tg is preferably low enough to keep the composition of the invention flowable at body temperature. Then, the glass transition temperature of the polymer used in the invention is usually about 0 to about 37° C., or alternatively from about 0 to about 25° C.

[0236] In certain embodiments, substituents of the phosphorus atom, such as R8 in the above formulas, and other components of the subject polymers may permit additional inter-chain cross-linking by covalent or electrostatic interactions (including, for example, hydrogen-binding or the formation of salt bridges) by having a side chain of either of them appropriately substituted as discussed in greater detail below.

[0237] In other embodiments, the polymer composition of the invention may be a flexible or flowable material. When the polymer used is itself flowable, the polymer composition of the invention, even when viscous, need not include a biocompatible solvent to be flowable, although trace or residual amounts of biocompatible solvents may still be present.

[0238] While it is possible that the biodegradable polymer or the biologically active agent may be dissolved in a small quantity of a solvent that is non-toxic to more efficiently produce an amorphous, monolithic distribution or a fine dispersion of the biologically active agent in the flexible or flowable composition, it is an advantage of the invention that, in a preferred embodiment, no solvent is needed to form a flowable composition. Moreover, the use of solvents is preferably avoided because, once a polymer composition containing solvent is placed totally or partially within the body, the solvent dissipates or diffuses away from the polymer and must be processed and eliminated by the body, placing an extra burden on the body's clearance ability at a time when the illness (and/or other treatments for the illness) may have already deleteriously affected it.

[0239] However, when a solvent is used to facilitate mixing or to maintain the flowability of the polymer composition of the invention, it should be non-toxic, otherwise biocompatible, and should be used in relatively small amounts. Solvents that are toxic clearly should not be used in any material to be placed even partially within a living body. Such a solvent also must not cause substantial tissue irritation or necrosis at the site of administration.

[0240] Examples of suitable biocompatible solvents, when used, include N-methyl-2-pyrrolidone, 2-pyrrolidone, ethanol, propylene glycol, acetone, methyl acetate, ethyl acetate, methyl ethyl ketone, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, caprolactam, dimethyl-sulfoxide, oleic acid, or 1-dodecylazacycloheptan-2-one. Preferred solvents include N-methyl-2-pyrrolidone, 2-pyrrolidone, dimethyl sulfoxide, and acetone because of their solvating ability and their biocompatibility.

[0241] In certain embodiments, the subject polymers are soluble in one or more common organic solvents for ease of fabrication and processing. Common organic solvents include such solvents as chloroform, dichloromethane, dichloroethane, 2-butanone, butyl acetate, ethyl butyrate, acetone, ethyl acetate, dimethylacetamide, N-methyl pyrrolidone, dimethylformamide, and dimethylsulfoxide.

[0242] C. Therapeutic Compositions

[0243] In part, a biocompatible polymer composition of the present invention includes both: (a) an analgesic, such as a caine analgesic or a pharmaceutically acceptable salt thereof, e.g., lidocaine, procaine, etidocaine, lidocaine HCl, etc., and (b) a biocompatible and optionally biodegradable polymer, such as one having the recurring monomeric units shown in one of the foregoing formulas, or any other biocompatible and optionally biodegradable polymer mentioned above or known in the art.

[0244] In addition to analgesic agent, the subject compositions may contain a “drug”, “therapeutic agent”, “medicament” or “bioactive substance”, which are biologically, physiologically, or pharmacologically active substances that act locally or systemically in the human or animal body. For example, a subject composition may include an augmenting agent or any of the other compounds discussed above. Various forms of the medicaments or biologically active materials may be used which are capable of being released from the polymer matrix into adjacent tissues or fluids. They may be acidic, basic, or salts. They may be neutral molecules, polar molecules, or molecular complexes capable of hydrogen bonding. They may be in the form of ethers, esters, amides and the like, which are biologically activated when injected into the human or animal body. An analgesic agent is also an example of a “bioactive substance.”

[0245] Any additional bioactive substance in a subject composition may vary widely with the purpose for the composition. The term bioactive agent includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.

[0246] Plasticizers and stabilizing agents known in the art may be incorporated in polymers of the present invention. In certain embodiments, additives such as plasticizers and stabilizing agents are selected for their biocompatibility.

[0247] A composition of this invention may further contain one or more adjuvant substances, such as fillers, thickening agents or the like. In other embodiments, materials that serve as adjuvants may be associated with the polymer matrix. Such additional materials may affect the characteristics of the polymer matrix that results. For example, fillers, such as bovine serum albumin (BSA) or mouse serum albumin (MSA), may be associated with the polymer matrix. In certain embodiments, the amount of filler may range from about 0.1 to about 50% or more by weight of the polymer matrix, or about 2.5, 5, 10, 25, 40 percent. Incorporation of such fillers may affect the biodegradation of the polymeric material and/or the sustained release rate of any encapsulated substance. Other fillers known to those of skill in the art, such as carbohydrates, sugars, starches, saccharides, celluoses and polysaccharides, including mannitose and sucrose, may be used in certain embodiments in the present invention.

[0248] In other embodiments, spheronization enhancers facilitate the production of subject polymeric matrices that are generally spherical in shape. Substances such as zein, microcrystalline cellulose or microcrystalline cellulose co-processed with sodium carboxymethyl cellulose may confer plasticity to the subject compositions as well as implant strength and integrity. In particular embodiments, during spheronization, extrudates that are rigid, but not plastic, result in the formation of dumbbell shaped implants and/or a high proportion of fines, and extrudates that are plastic, but not rigid, tend to agglomerate and form excessively large implants. In such embodiments, a balance between rigidity and plasticity is desirable. The percent of spheronization enhancer in a formulation typically range from 10 to 90% (w/w).

[0249] In certain embodiments, a subject composition includes an excipient. A particular excipient may be selected based on its melting point, solubility in a selected solvent (e.g., a solvent which dissolves the polymer and/or the analgesic agent), and the resulting characteristics of the microparticles.

[0250] Excipients may be included in the subject formulations to allow for high loading levels of analgesic agents in a biodegradable polymer and still allow microparticles and/or microspheres of the resulting composition to be prepared. It was learned that at loading levels in excess of twenty percent of lidocaine with D,L-PL(PG)EOP (as taught in the examples below), spray-dried products were agglomerates with the appearance of melted microspheres. In contrast, microspheres containing higher loading levels of lidocaine and the same polymer could be prepared by spray-drying when cholesterol was added as an excipient, as taught in the examples below. Without wanting to be limited to any theory, it is believed the ability to prepare microspheres of the subject compositions with higher loading levels of an analgesic agent by spray drying is due to the higher melting point of the excipient as compared to the analgesic agent.

[0251] A list of exemplary excipients is presented in Table 1, together with their solubility and melting point characteristics.

4TABLE 1Exemplary excipientsMeltingExcipientsTemperature (° C.)Solubility in Organic SolventsEthyl cellulose130Freely soluble in chloroformCholesterol1471 in 4.5 chloroformPotassium stearate270Practically insolubleSaccharin226Slightly solubleDocusate1531 in 1Mannitol166Practically insolubleNaCl801Practically insolubleBenzoic acid1221 in 4.5 chloroformTartaric acid168Practically insolubleSorbic acid134.51 in 15 chloroformPEG 20,00065Soluble in water, chloroformZinc stearate120Magnesium88.5Warm ethanolstearate

[0252] Excipients may comprise a few percent, about 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50% or higher percentage of the subjetc compositions.

[0253] Buffers, acids and bases may be incorporated in the subject compositions to adjust their pH. Agents to increase the diffusion distance of agents released from the polymer matrix may also be included.

[0254] Disintegrants are substances which, in the presence of liquid, promote the disruption of the subject compositions. Disintegrants are most often used in implants, in which the function of the disintegrant is to counteract or neutralize the effect of any binding materials used in the subject formulation. In general, the mechanism of disintegration involves moisture absorption and swelling by an insoluble material. Examples of disintegrants include croscarmellose sodium and crospovidone which, in certain embodiments, may be incorporated into the polymeric matrices in the range of about 1-20% of total matrix weight. In other cases, soluble fillers such as sugars (mannitol and lactose) may also be added to facilitate disintegration of the implants.

[0255] Other materials may be used to advantage to control the desired release rate of a therapeutic agent for a particular treatment protocol. For example, if the sustained release is too slow for a particular application, a pore-forming agent may be added to generate additional pores in the matrix. Any biocompatible water-soluble material may be used as the pore-forming agent. They may be capable of dissolving, diffusing or dispersing out of the formed polymer system whereupon pores and microporous channels are generated in the system. The amount of pore-forming agent (and size of dispersed particles of such pore-forming agent, if appropriate) within the composition should affect the size and number of the pores in the polymer system.

[0256] Pore-forming agents include any pharmaceutically acceptable organic or inorganic substance that is substantially miscible in water and body fluids and will dissipate from the forming and formed matrix into aqueous medium or body fluids or water-immiscible substances that rapidly degrade to water-soluble substances. Suitable pore-forming agents include, for example, sugars such as sucrose and dextrose, salts such as sodium chloride and sodium carbonate, and polymers such as hydroxylpropylcellulose, carboxymethylcellulose, polyethylene glycol, and PVP. The size and extent of the pores may be varied over a wide range by changing the molecular weight and percentage of pore-forming agent incorporated into the polymer system.

[0257] The charge, lipophilicity or hydrophilicity of any subject polymeric matrix may be modified by attaching in some fashion an appropriate compound to the surface of the matrix. For example, surfactants may be used to enhance wettability of poorly soluble or hydrophobic compositions. Examples of suitable surfactants include dextran, polysorbates and sodium lauryl sulfate. In general, surfactants are used in low concentrations, generally less than about 5%.

[0258] Binders are adhesive materials that may be incorporated in polymeric formulations to bind and maintain matrix integrity. Binders may be added as dry powder or as solution. Sugars and natural and synthetic polymers may act as binders. Materials added specifically as binders are generally included in the range of about 0.5%-15% w/w of the matrix formulation. Certain materials, such as microcrystalline cellulose, also used as a spheronization enhancer, also have additional binding properties.

[0259] Various coatings may be applied to modify the properties of the matrices. Three exemplary types of coatings are seal, gloss and enteric coatings. Other types of coatings having various dissolution or erosion properties may be used to further modify subject matrices behavior, and such coatings are readily known to one of ordinary skill in the art.

[0260] The seal coat may prevent excess moisture uptake by the matrices during the application of aqueous based enteric coatings. The gloss coat generally improves the handling of the finished matrices. Water-soluble materials such as hydroxypropyl cellulose may be used to seal coat and gloss coat implants. The seal coat and gloss coat are generally sprayed onto the matrices until an increase in weight between about 0.5% and about 5%, often about 1% for a seal coat and about 3% for a gloss coat, has been obtained.

[0261] Enteric coatings consist of polymers which are insoluble in the low pH (less than 3.0) of the stomach, but are soluble in the elevated pH (greater than 4.0) of the small intestine. Polymers such as EUDRAGIT, RohmTech, Inc., Malden, Mass., and AQUATERIC, FMC Corp., Philadelphia, Pa., may be used and are layered as thin membranes onto the implants from aqueous solution or suspension or by a spray drying method. The enteric coat is generally sprayed to a weight increase of about one to about 30%, preferably about 10 to about 15% and may contain coating adjuvants such as plasticizers, surfactants, separating agents that reduce the tackiness of the implants during coating, and coating permeability adjusters.

[0262] The present compositions may additionally contain one or more optional additives such as fibrous reinforcement, colorants, perfumes, rubber modifiers, modifying agents, etc. In practice, each of these optional additives should be compatible with the resulting polymer and its intended use. Examples of suitable fibrous reinforcement include PGA microfibrils, collagen microfibrils, cellulosic microfibrils, and olefinic microfibrils. The amount of each of these optional additives employed in the composition is an amount necessary to achieve the desired effect.

[0263] D. Physical Structures of the Subject Compositions

[0264] The subject polymers may be formed in a variety of shapes. For example, in certain embodiments, subject polymer matrices may be presented in the form of microparticles or nanoparticles. Such particles may be prepared by a variety of methods known in the art, including for example, solvent evaporation, spray-drying or double emulsion methods.

[0265] The shape of microparticles and nanoparticles may be determined by scanning electron microscopy. Spherically shaped nanoparticles are used in certain embodiments for circulation through the bloodstream. If desired, the particles may be fabricated using known techniques into other shapes that are more useful for a specific application.

[0266] In addition to intracellular delivery of a therapeutic agent, it also possible that particles of the subject compositions, such as microparticles or nanoparticles, may undergo endocytosis, thereby obtaining access to the cell. The frequency of such an endocytosis process will likely depend on the size of any particle.

[0267] In certain embodiments, solid articles useful in defining shape and providing rigidity and structural strength to the polymeric matrices may be used. For example, a polymer may be formed on a mesh or other weave for implantation. A polymer may also be fabricated as a stent or as a shunt, adapted for holding open areas within body tissues or for draining fluid from one body cavity or body lumen into another. Further, a polymer may be fabricated as a drain or a tube suitable for removing fluid from a post-operative site, and in some embodiments adaptable for use with closed section drainage systems such as Jackson-Pratt drains and the like familiar in the art.

[0268] The mechanical properties of the polymer may be important for the processability of making molded or pressed articles for implantation. For example, the glass transition temperature may vary widely but must be sufficiently lower than the temperature of decomposition to accommodate conventional fabrication techniques, such as compression molding, extrusion or injection molding.

[0269] E. Biodegradability and Release Characteristics

[0270] In certain embodiments, the polymers and blends of the present invention, upon contact with body fluids, undergo gradual degradation. The life of a biodegradable polymer in vivo depends, among other things, upon its molecular weight, crystallinity, biostability, and the degree of crosslinking. In general, the greater the molecular weight, the higher the degree of crystallinity, and the greater the biostability, the slower biodegradation will be.

[0271] If a subject composition is formulated with an analgesic agent or other material, release of such an agent or other material for a sustained or extended period as compared to the release from an isotonic saline solution generally results. Such release profile may result in prolonged delivery (over, say 1 to about 2,000 hours, or alternatively about 2 to about 800 hours) of effective amounts (e.g., about 0.0001 mg/kg/hour to about 10 mg/kg/hour) of the analgesic agent or any other material associated with the polymer.

[0272] A variety of factors may affect the desired rate of hydrolysis of polymers of the subject invention, the desired softness and flexibility of the resulting solid matrix, rate and extent of bioactive material release. Some of such factors include: the selection of the various substituent groups, such as the phosphate group making up the linkage in the polymer backbone (or analogs thereof), the enantiomeric or diastereomeric purity of the monomeric subunits, homogeneity of subunits found in the polymer, and the length of the polymer. For instance, the present invention contemplates heteropolymers with varying linkages, and/or the inclusion of other monomeric elements in the polymer, in order to control, for example, the rate of biodegradation of the matrix.

[0273] To illustrate further, a wide range of degradation rates may be obtained by adjusting the hydrophobicities of the backbones or side chains of the polymers while still maintaining sufficient biodegradability for the use intended for any such polymer. Such a result may be achieved by varying the various functional groups of the polymer. For example, the combination of a hydrophobic backbone and a hydrophilic linkage produces heterogeneous degradation because cleavage is encouraged whereas water penetration is resisted. In another example, it is expected that use of substituent on phosphate in the polymers of the present invention that is lipophilic, hydrophobic or bulky group would slow the rate of degradation. For example, it is expected that conversion of the phosphate side chain to a more lipophilic, more hydrophobic or more sterically bulky group would slow down the rate of biodegradation. Thus, release is usually faster from polymer compositions with a small aliphatic group side chain than with a bulky aromatic side chain.

[0274] One protocol generally accepted in the field that may be used to determine the release rate of any therapeutic agent or other material loaded in the polymer matrices of the present invention involves degradation of any such matrix in a 0.1 M PBS solution (pH 7.4) at 37° C., an assay known in the art. For purposes of the present invention, the term “PBS protocol” is used herein to refer to such protocol.

[0275] In certain instances, the release rates of different polymer systems of the present invention may be compared by subjecting them to such a protocol. In certain instances, it may be necessary to process polymeric systems in the same fashion to allow direct and relatively accurate comparisons of different systems to be made. For example, the present invention teaches several different means of formulating the polymeric matrices of the present invention. Such comparisons may indicate that any one polymeric system releases incorporated material at a rate from about 2 or less to about 1000 or more times faster than another polymeric system. Alternatively, a comparison may reveal a rate difference of about 3, 5, 7, 10, 25, 50, 100, 250, 500 or 750. Even higher rate differences are contemplated by the present invention and release rate protocols.

[0276] In certain embodiments, when formulated in a certain manner, the release rate for polymer systems of the present invention may present as mono- or bi-phasic. Release of any material incorporated into the polymer matrix, which is often provided as a microsphere, may be characterized in certain instances by an initial increased release rate, which may release from about 5 to about 50% or more of any incorporated material, or alternatively about 10, 15, 20, 25, 30 or 40%, followed by a release rate of lesser magnitude.

[0277] The release rate of any incorporated material may also be characterized by the amount of such material released per day per mg of polymer matrix. For example, in certain embodiments, the release rate may vary from about 1 ng or less of any incorporated material per day per mg of polymeric system to about 500 or more ng/day/mg. Alternatively, the release rate may be about 0.05, 0.5, 5, 10, 25, 50, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, or 500 ng/day/mg. In still other embodiments, the release rate of any incorporated material may be 10,000 ng/day/mg or even higher. In certain instances, materials incorporated and characterized by such release rate protocols may include therapeutic agents, fillers, and other substances.

[0278] In another aspect, the rate of release of any material from any polymer matrix of the present invention may be presented as the half-life of such material in the such matrix.

[0279] In addition to the embodiment involving protocols for in vitro determination of release rates, in vivo protocols, whereby in certain instances release rates for polymeric systems may be determined in vivo, are also contemplated by the present invention. Other assays useful for determining the release of any material from the polymers of the present system are known in the art.

[0280] F. Implants and Delivery Systems

[0281] In its simplest form, a biodegradable delivery system for an analgesic agent consists of a dispersion of such a therapeutic agent in a polymer matrix. In other embodiments, an article is used for implantation, injection, or otherwise placed totally or partially within the body, the article comprising the subject compositions. It is particularly important that such an article result in minimal tissue irritation when implanted or injected into vasculated tissue.

[0282] Biodegradable delivery systems, and articles thereof, may be prepared in a variety of ways known in the art. The subject polymer may be melt-processed using conventional extrusion or injection molding techniques, or these products may be prepared by dissolving in an appropriate solvent, followed by formation of the device, and subsequent removal of the solvent by evaporation or extraction.

[0283] Once a system or implant article is in place, it should remain in at least partial contact with a biological fluid, such as blood, internal organ secretions, mucus membranes, cerebrospinal fluid, and the like to allow for sustained release of any encapsulated therpeutic agent, e.g., an analgesic agent.

[0284] 4. Exemplary Methods of Making the Subject Compositions

[0285] In general, the polymers of the present invention may be prepared by melt polycondensation, solution polymerization or interfacial polycondensation. Techniques necessary to prepare the subject polymers are known in the art, and reference is made in particular to U.S. Provisional Application Ser. No. 60/216,462 filed Jul. 6, 2000. and U.S. Provisional Application Ser. No. 60/228,729 filed Aug. 29, 2000, both of which are hereby incorporated in their entirety. The most common general reaction in preparing the subject compositions is a dehydrochlorination between a phosphodichloridate and a diol according to the following equation:

[0286] Certain of the subject polymers may be obtained by condensation between appropriately substituted dichlorides and diols.

[0287] An advantage of melt polycondensation is that it avoids the use of solvents and large amounts of other additives, thus making purification more straightforward. This method may also provide polymers of reasonably high molecular weight. Somewhat rigorous conditions, however, are often required and may lead to chain acidolysis (or hydrolysis if water is present). Unwanted, thermally-induced side reactions, such as cross-linking reactions, may also occur if the polymer backbone is susceptible to hydrogen atom abstraction or oxidation with subsequent macroradical recombination.

[0288] To minimize these side reactions, the polymerization may also be carried out in solution. Solution polycondensation requires that both the prepolymer and the phosphorus component be sufficiently soluble in a common solvent. Typically, a chlorinated organic solvent is used, such as chloroform, dichloromethane or dichloroethane. The solution polymerization is generally run in the presence of equimolar amounts of the reactants and, preferably, an excess of an acid acceptor and a catalyst, such as 4-dimethylaminopyridine (“DMAP”). Useful acid acceptors include tertiary amines as pyridine or triethylamine. The product is then typically isolated from the solution by precipitation in a non-solvent and purified to remove the hydrochloride salt by conventional techniques known to those of ordinary skill in the art, such as by washing with an aqueous acidic solution, e.g., dilute HCl.

[0289] Reaction times tend to be longer with solution polymerization than with melt polymerization. However, because overall milder reaction conditions may be used, side reactions are minimized, and more sensitive functional groups may be incorporated into the polymer. The disadvantages of solution polymerization are that removal of solvents may be difficult.

[0290] Interfacial polycondensation may be used when high molecular-weight polymers are desired at high reaction rates. By such methods, mild conditions minimize side reactions, and the dependence of high molecular weight on stoichiometric equivalence between diol and dichloridate inherent in solution methods is removed. However, hydrolysis of the acid chloride may occur in the alkaline aqueous phase, and sensitive dichloridates that have some solubility in water are generally subject to hydrolysis rather than polymerization. Phase transfer catalysts, such as crown ethers or tertiary ammonium chloride, may be used to bring the ionized diol to the interface to facilitate the polycondensation reaction. The yield and molecular weight of the resulting polymer after interfacial polycondensation are affected by reaction time, molar ratio of the monomers, volume ratio of the immiscible solvents, the type of acid acceptor, and the type and concentration of the chase transfer catalyst.

[0291] Methods for making the present invention may take place at widely varying temperatures, depending upon whether a solvent is used and, if so, which one; the molecular weight desired; the susceptibility of the reactants to form side reactions; and the presence of a catalyst. Usually, the process takes place at a temperature ranging from about 0 to about 235° C. for melt conditions. Somewhat lower temperatures, e.g., for example from about −50 to about 100° C., may be possible with solution polymerization or interfacial polycondensation with the use of either a cationic or anionic catalyst.

[0292] The time required for the process may vary widely, depending on the type of reaction being used, the molecular weight desired and, in general, the need to use more or less rigorous conditions for the reaction to proceed to the desired degree of completion. Typically, however, the synthetic process takes place during a time between about 30 minutes and about 7 days.

[0293] Although the process may be in bulk, in solution, by interfacial polycondensation, or any other convenient method of polymerization, in many instant embodiments, the process takes place under solution conditions. Particularly useful solvents include methylene chloride, chloroform, tetrahydroftiran, di-methyl formamide, dimethyl sulfoxide or any of a wide variety of inert organic solvents.

[0294] In greater detail, polymers of Formula VI may be prepared, at least in part, by reacting a compound having a formula H-Y1-L1-Y1-H, such as 2-aminoethanol, ethylene glycol, ethane dithiol, etc., with a cyclic compound, e.g., having one of the following structures: for example, caprolactone or lactide (lactic acid dimer).

[0295] Thus, the cyclic compound may include one or two subunits ts. For cyclic compounds containing two subunits, the two subunits contained therein may be the same or different.

[0296] For synthesizing, for example, a compound of Formula VI, wherein x and y are on average about 10, an equivalent of ethylene glycol as H-Y1-L1-H may be reacted with 20 equivalents of

[0297] or 10 equivalents of

[0298] because lactic acid dimer contains two monomer units for each equivalent of the cyclic compound. Variation of the ratio of cyclic compound to ethylene glycol or other bifunctional core will likewise vary the values of x and y, although x and y will be substantially equal for a symmetrical bifunctional core (e.g., ethylene glycol) for subject polymers prepared by this method. For an unsymmetrical bifunctional core (e.g., 2-aminoethanol), the ratio of x:y may vary considerably, as will be understood by one of skill in the art and may be determined without undue experimentation.

[0299] Polymers of the present invention may generally be isolated from the reaction mixture by conventional techniques, such as by precipitating out, extraction with an immiscible solvent, evaporation, filtration, crystallization and the like. Typically, the subject polymers are both isolated and purified by quenching a solution of polymer with a non-solvent or a partial solvent, such as diethyl ether or petroleum ether.

[0300] 5. Dosages and Formulations of the Subject Compositions

[0301] In most embodiments, the subject polymers will incorporate the substance to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of an incorporated therapeutic agent or other material as part of a prophylactic or therapeutic treatment. The desired concentration of active compound in the particle will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the compound from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.

[0302] Further, the amounts of local anesthetic, augmenting agent or other bioactive substances will vary depending upon the relative potency of the agents selected, the depth and duration of local anesthesia desired. Additionally, the optimal concentration and/or quantities or amounts of any particular analgesic or augmenting agent may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters include the polymer composition of a particular microsphere preparation, the identity of the local anesthetic, augmenting agent or other bioactive substance utilized, and the clinical use to which the preparation is put, in terms of the site treated for local anesthesia, the type of patient, e.g., human or non-human, adult or child, and the type of sensory stimulus to be anesthetized.

[0303] The concentration and/or amount of any analgesic agent, augmenting agent or other encapsulated material for a given subject composition may readily identified by routine screening in animals, e.g, rats, by screening a range of concentration and/or amounts of the material in question using appropropriate assays, such as the hotplate foot withdrawal assay described hereinbelow. Known methods are also available to assay local tissue concentrations, diffusion rates from microspheres and local blood flow before and after administration of local anesthetic formulations according to the invention. One such method is microdialysis, as reviewed by T. E. Robinson et al., 1991, MICRODIALYSIS IN THE NEUROSCIENCES, Techniques, volume 7, Chapter 1, pages 1-64. The methods reviewed by Robinson may be applied, in brief, as follows. A microdialysis loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop. When microspheres according to the invention are injected adjacent to the loop, released drugs, e.g., an analgesic, optionally vasoconstrictor augmenting agents, etc, are collected in the dialysate in proportion to their local tissue concentrations. The progress of diffusion of the active agents may be determined thereby with suitable calibration procedures using known concentrations of active agents. For example, for the vasoconstrictor augmenting agents, decrements and durations of vasoconstriction effects may be measured by clearance rates of marker substances, e.g., methylene blue or radiolabeled albumen from the local tissue from the microspheres, as well as the local blood flow. Additional related information may be found in U.S. Pat. No. 5,942,241.

[0304] In certain embodiments, the dosage of the subject invention may be determined by reference to the plasma concentrations of the analgesic agent or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity (AUC (0-4)) may be used.

[0305] The polymers of the present invention may be administered by various means, depending on their intended use, as is well known in the art. For example, if subject compositions are to be administered orally, it may be formulated as tablets, capsules, granules, powders or syrups. Alternatively, formulations of the present invention may be administered parenterally as injections (intravenous, intramuscular or subcutaneous), drop infusion preparations, or suppositories. For application by the ophthalmic mucous membrane route, subject compositions may be formulated as eyedrops or eye ointments. These formulations may be prepared by conventional means, and, if desired, the subject compositions may be mixed with any conventional additive, such as an a binder, a disintegrating agent, a lubricant, a corrigent, a solubilizing agent, a suspension aid, an emulsifying agent or a coating agent. In addition, in certain embodiments, subject compositions of the present invention may be lyophilized or subjected to another appropriate drying technique such as spray drying.

[0306] The subject compositions may be administered once, or may be divided into a number of smaller doses to be administered at varying intervals of time, depending in part on the release rate of the compositions and the desired dosage.

[0307] Formulations useful in the methods of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of a subject composition which may be combined with a carrier material to produce a single dose vary depending upon the subject being treated, and the particular mode of administration.

[0308] Methods of preparing these formulations or compositions include the step of bringing into association subject compositions with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a subject composition with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0309] Formulations suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia), each containing a predetermined amount of a subject composition as an active ingredient. Subject compositions of the present invention may also be administered as a bolus, electuary, or paste.

[0310] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically-acceptable carriers and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid ° F, polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

[0311] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.

[0312] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject compositions, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[0313] Suspensions, in addition to the subject compositions, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0314] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the apropriate body cavity and release the encapsulated analgesic.

[0315] Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0316] Dosage forms for transdermal administration of includes powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. A subject composition may be mixed under sterile conditions with a pharmaceutically-acceptable carrier, and with any preservatives, buffers, or propellants which may be required. For transdermal administration, the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties.

[0317] The ointments, pastes, creams and gels may contain, in addition to subject compositions, other carriers, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof

[0318] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0319] Subject compositions may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles. A non-aqueous (e.g., fluorocarbon propellant) suspension may be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compound. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of the polymeric materials together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular compound, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.

[0320] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0321] Certain pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more subject compositions in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

[0322] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

[0323] In certain embodiments, the subject compositions comprise about 5% to about 60%, alternatively about 10% to about 50% of an analgesic agent, such as lidocaine or another caine analgesic or a pharmaceutically acceptable salt thereof, in a biodegradable polymer, such as a phosphorous-based polymer, e.g., D,L-PL(PG)EOP, described in the Exemplification section below. In certain embodiments, a composition comprises at least about 10% of an analgesic agent, more particularly at least about 20%, at least about 25%, or even more than about 30% or 40% of an analgesic agent, such as lidocaine or another caine analgesic or a pharmaceutically acceptable salt thereof. In certain embodiments, the compositions are formulated as microspheres or nanospheres. The compositions may additionally comprise cholesterol or another suitable excipient that improves the physical characteristics, such as flowability, viscosity, glass temperature, ease of preparing microparticles etc., of the subject composition for the particular use. Microsphere compositions may be suspended in a pharmaceutically acceptable solution, such as saline, Ringer's solution, dextran solution, dextrose solution, sorbitol solution, a solution containing polyvinyl alcohol (from about 1% to about 3%, preferably about 2%), or an osmotically balanced solution comprising a surfactant (such as Tween 80 or Tween 20) and a viscosity-enhancing agent (such as gelatin, alginate, sodium carboxymethylcellulose, etc.). In certain embodiments, the composition is administered subcutaneously. In other embodiments, the composition is administered intravenously. For intravenous delivery, the composition is preferably formulated as microspheres on average less than about 15 microns, more particularly less than about 10 microns, and still more particularly less than about 5 microns in average diameter.

[0324] 6. Assays for Measuring Analgesic Effect

[0325] A variety of techniques may be used to measure analgesic effects of subject compositions, e.g., by evaluating the responsiveness of a subject, such as a rat or mouse, to a stimulus that normally provokes a response indicative of a painful sensation. Some of such techniques are described below and in the exemplifications that follow.

[0326] Rat Formalin Test.

[0327] The rat formalin test is an in vivo test of analgesic potency. This test reflects several levels of processing of nociceptive information in the spinal cord. Protracted sensory input generated by the noxious stimulus employed in this test (formalin in the paw) has been shown to induce an acute pain response phase (phase 1) followed by a second phase (phase 2). This second phase is thought to represent a state of facilitated processing evoked by the afferent input present during phase 1 and to involve release of at least two substances, glutamate and a tachykinin, based on other pharmacological evidence (Yamamoto and Yaksh, Pain 1993 Nov. 55(2):227-33; Pain 1993 Jul. 54(l):79-84; Pain 1992 Dec. 51(3):329-34; Anesthesiology 1992 Oct. 77(4):757-63; Life Sci. 1991 49(26):1955-63).

[0328] In the rat formalin test, a standard dose of formalin is injected into the rat paw, and flexions of the paw are quantitated over the following 60-minute period. A biphasic response pattern is typically observed, with numerous responses observed during the period 5 min. after injection (Phase 1) and a second phase (Phase 2) which occurs during the period about 10-60 minutes following injection, in which the mean number of flinches per minute is recorded as a function of time. Quantitation of responses during each phase is made by calculation of area under the curve of flinches/min.

[0329] Randall-Selitto Test.

[0330] As described in Arch. Int. Pharmacodyn. Ther. 111, 409 (1957), oedema can be induced in a rat's hind paw by injecting 0.1 ml of a 20% baker's yeast suspension, carrageenan, or other suitable substance, the oedema causing pronounced mechanohyperalgesia after 4 hours. Pain is then produced by applying increasing pressure (0-450 g/mm2) with a punch (0.2 mm point diameter) or other analgesiometer on the rat's inflamed hind paw. The pressure at which the rat produces a vocalisation reaction is then measured. Animals which produce no vocalisation up to the maximum permitted pressure are deemed to have complete pain relief. The test results are stated as MPE (maximum possible effect) in % in accordance with the formula: 100×(Vt−V0)/(Vmax−V0) where Vt is the value measured after administration of the test substance; V0 is the value measured before administration of the test substance, and Vmax is the maximum value.

[0331] Hot Plate Test.

[0332] The hot plate test (J. Pharmacol. Exp. Ther. 133, 400 (1961)) can be used to determine effectiveness of a subject composition in the event of acute, non-inflammatory, thermal stimulus. For example, rats can be gently held by the body while the plantar aspect of the paw is placed on a hot plate. The baseline (control) latency for the rat to withdraw its paw from the hot-plate (56° C.) may be determined prior to administration of an analgesic composition around the sciatic nerve. A syringe may be used to inject the composition around the sciatic nerve. Thereafter, paw withdrawal latencies are assessed. A 12 sec time limit may be employed in order to prevent damage to the paw.

[0333] Pressure Test.

[0334] Analgesic effects of drugs may be evaluated using the generally accepted paw pressure test as described in C. Stein, Pharm. Biochem. Behavior, 31:445-451 (1988). The animal is gently restrained under paper wadding and incremental pressure applied via a wedge-shaped blunt piston onto an area of 1.75 mm2 of the dorsal surface of the hindpaw by means of a commercially available automated gauge. The pressure required to elicit paw withdrawal (PPT) is determined. Three consecutive trials, separated by 10 sec., may be conducted and the average calculated. The same procedure can be performed on an untreated paw as a control; the sequence of paws can be altered between subjects to reduce “order” effects.

[0335] Exemplification

[0336] The invention now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention and are not intended to limit the invention.

EXAMPLE 1

First Synthesis of D,L-PL(PG)EOP

[0337] All glassware was dried for a minimum of 2 hours at 105° C. and allowed to cool in a desiccator or cooled under a stream of argon gas. A 28.5 g portion of D,L-lactide and 1.5 g of 1,2-propanediol (PG), obtained from Aldrich, Catalog No. 39,803-9, 99.5+%, in a molar ratio of 10:1, were weighed into a 250 mL 3-neck round-bottom flask. The flask was equipped with a gas joint and a stirrer bearing/shaft/paddle assembly. The mixture was evacuated and pressurized with argon five times to remove residual air and moisture. The reaction apparatus was immersed in a preheated oil bath at 135° C., connected to an argon source with an oil bubbler, and stirred at a moderate speed until all of the solid monomer had melted.

[0338] At this time, a volume of stock stannous octoate solution (about 130 mg/ml in toluene of chloroform) equivalent to 3.6 mg tin (120 ppm stannous octoate or equivalent to 35 ppm tin based upon weight of the prepolymer) was added to the melt using a 50 μl syringe. The reaction mixture was allowed to stir under a slight argon pressure for approximately 16 hours. The oil bath temperature was then reduced to about 110° C. and the residual monomer was removed under vacuum. The upper parts of the reaction assembly were heated gently with a heat gun to aid in the monomer removal. The total time under vacuum was 2-3 hours. A reflux condenser was then inserted between the gas joint and the flask in the prepolymer apparatus described above. The molten prepolymer was dissolved by adding 100 mL of chloroform to the reaction flask with stirring.

[0339] Next, 6.9 mL of triethylamine (TEA) and 1.21 g of DMAP were added to the stirring reaction mixture. The reaction mixture was then chilled to about 4° C. in an ice bath. A solution of approximately 2.5 mL of freshly distilled ethyl dichlorophosphate (EOPCl2) in 25 mL of chloroform was prepared in a dropping funnel. The solution in the funnel was added drop wise to the reaction mixture over a period of about 30 minutes. After the addition was complete the reaction mixture was allowed to continue stirring at about 4° C. for 10 minutes and then the ice bath was removed. The reaction mixture was allowed to warm to room temperature over about 1 hour. At this time a significant increase in viscosity of the clear solution was observed. The reaction mixture was then heated to reflux using an oil bath. Over the next hour the solution became cloudy. The reaction mixture was allowed to reflux over two nights, about 38 hours total.

[0340] At this time, a Barret trap was inserted between the condenser and the flask and 88 mL of solvent (⅔ of the total volume) were distilled from the reaction mixture. The Barret trap was removed and the reaction mixture was allowed to reflux for an additional 16 hours with the oil bath temperature between 98-102° C. Next, the oil bath temperature was increased to 115° C. for 2 hours. After this time, the reaction mixture was allowed to cool to room temperature, and 200 mL of dichloromethane was added and transferred to a separatory funnel. The reaction mixture was extracted twice with 100 mL of 0.1 M HCl and twice with 100 mL of saturated sodium chloride solution. The organic layer was isolated, dried overnight in the freezer at about −15° C. over 50 g of sodium sulfate, and filtered twice. The resulting polymer solution was poured into 1500 mL of hexane plus 500 mL of ether. The resulting mass of polymer was dried under vacuum. The Inherent Viscosity (IV) of this material was measured to be 0.39 dL/g.

EXAMPLE 2

Second Synthesis of D,L-PL(PG)EOP

[0341] All glassware was dried for a minimum of 2 hours at 105° C. and allowed to cool in a desiccator or cooled under a stream of argon gas. A 28.5 g portion of D,L-lactide and 1.5 g of PG (molar ratio, 10:1) were weighed into a 250 ml 3-neck round-bottom flask. The flask was equipped with a gas joint and a stirrer bearing/shaft/paddle assembly. The mixture was evacuated and filled with argon five times to remove residual air and moisture. Each time the polymerization vessel was evacuated to a pressure between 0.5 and 10 Torr. The reaction apparatus was immersed in a preheated oil bath at 125° C., connected to an argon source with an oil bubbler, and stirred at a moderate speed until all of the solid monomer had melted. At this time, a volume of stock stannous octoate solution (about 130 mg/ml in toluene) equivalent to 100 ppm stannous octoate (29 ppm Sn) was added to the melt using a syringe. The reaction mixture was allowed to stir under a slight argon pressure for 3 hours. The oil bath temperature was then reduced to about 105° C. and the residual monomer was removed under vacuum. The pressure was maintained as low as possible, typically between 0.5 and 10 Torr. The upper parts of the reaction assembly were heated gently with a heat gun to aid in the monomer removal. The total time under vacuum was 1 hour.

[0342] The prepolymer was cooled to room temperature under argon gas and allowed to stand for 12-18 hours at ambient temperature. The prepolymer was dissolved in 84 ml of chloroform with stirring and 2.5 equivalents of triethylarnine (TEA) and 0.5 equivalents of DMAP were added to the stirring reaction mixture using a powder funnel. The reaction mixture was chilled to about —5 to about −15° C. in a cold bath. A solution of about 1 equivalent of distilled ethyl dichlorophosphate (EOPCl2) in 10 ml of chloroform was prepared in a dropping funnel. The solution in the funnel was added slowly to the reaction mixture over a period of 0.5 hour.

[0343] After the addition was complete, the reaction mixture was allowed to stir at low temperature for 1 hour at −5° C. The reaction was then quenched with 1 ml of anhydrous methanol and stirred for another five minutes. Next, the reaction mixture was transferred to a 0.5 gallon vessel and mixed with 37 g of Dowex DR-2030 IER and 30 g of Dowex M-43, and shaken on a mechanical shaker for 2 hour to remove residual DMAP and TEA free base and salts (the IERs had been washed with several bed volumes of methanol and chloroform and dried under vacuum at ambient temperature for about 18 hours). The resin was removed from the reaction mixture by vacuum filtration through Whatman 54 filter paper.

[0344] The resin was washed with about one bed volume of dichloromethane and the filtrate was concentrated to approximately 50 ml. The viscous filtrate was poured into 200 ml of petroleum ether to precipitate the polymer. The polymer mass was washed with 100 ml of petroleum ether and dried under vacuum. Molecular weights of the polymers were obtained from gel permeation chromatography (GPC) using both differential refractive index detection and a polystyrene calibration curve (CC) and by light scattering detection. The molecular weight and IV data for the polymers prepared by this process are listed in the table below.

5SampleMw (LS), daltonsMw (CC), daltonsIV, dL/g1101,200107,5000.622150,100155,9000.803 85,200 84,300—4 92,600 89,900—

EXAMPLE 3

Synthesis of D,L-PL(EG)EOP

[0345] All glassware was dried for a minimum of 2 hours at 105° C. and allowed to cool in a desiccator or cooled under a stream of argon gas. A 100.0 g portion of D,L-lactide and 4.3 g of ethylene glycol (EG) (molar ratio, 10:1) were weighed into a 1000 ml 3-neck round-bottom flask. The flask was equipped with a gas joint and a stirrer bearing/shaft/paddle assembly. The mixture was evacuated and filled with argon five times to remove residual air and moisture. The reaction apparatus was immersed in a preheated oil bath at 135° C., connected to an argon source with an oil bubbler, and stirred at a moderate speed until all of the solid monomer had melted.

[0346] At this time, a volume of stock stannous octoate solution (about 130 mg/ml in toluene) equivalent to 120 ppm stannous octoate or 35 ppm Sn was added to the melt using a syringe. The reaction mixture was allowed to stir under a slight argon pressure for approximately 16 hours. The oil bath temperature was then reduced to about 110° C. and the residual monomer was removed under vacuum. The upper parts of the reaction assembly were heated gently with a heat gun to aid in the monomer removal. The total time under vacuum was 2-3 hours.

[0347] The molten prepolymer was dissolved in 350 ml of chloroform with stirring and 2.5 equivalents of TEA and 0.5 equivalents of DMAP were added to the stirring reaction mixture using a powder funnel. The reaction mixture was chilled to about −5° C. in a cold bath. A solution of about 1 equivalent of distilled ethyl dichlorophosphate (EOPCl2) in 97 ml of chloroform was prepared in a dropping funnel. The solution in the funnel was added slowly to the reaction mixture over a period of 2 hours. After the addition was complete, the reaction mixture was allowed to stir at low temperature for 45 minutes at −5° C. After 2 hours a significant increase in viscosity of the clear solution was observed. The reaction was then quenched with 6.8 ml of anhydrous methanol and stirred for another five minutes.

[0348] Next, the reaction mixture was transferred to a 0.5 gallon vessel and mixed with 87 g of Dowex HCR-S IER and 104 g of Dowex-43, and shaken on a mechanical shaker for 1 hour to remove residual DMAP and TEA free base and salts (the IERs had been washed with several bed volumes of methanol and dried under vacuum at ambient temperature for about 18 hours). The resin was removed from the reaction mixture by vacuum filtration through Whatman 54 filter paper. The resin was washed with about one bed volume of dichloromethane and the filtrate was concentrated to approximately 150 ml. The viscous filtrate was poured into 2000 ml of hexane to precipitate the polymer. The polymer mass was washed with 2×200 ml of hexane and dried under vacuum. The molecular weights were determined by GPC were 40,400 for Mw (LS) and 42,000 for Mw (CC).

EXAMPLE 4

Synthesis of D,L-PL(HD)EOP

[0349] All glassware was dried for a minimum of 2 hours at 105° C. and allowed to cool in a desiccator or cooled under a stream of argon gas. A 100.0 g portion of D,L-lactide and 8.2 g of 1,6-hexane diol (molar ratio, 10:1) were weighed into a 1000 ml 3-neck round-bottom flask. The flask was equipped with a gas joint and a stirrer bearing/shaft/paddle assembly. The mixture was evacuated and filled with argon five times to remove residual air and moisture. The reaction apparatus was immersed in a preheated oil bath at 135° C., connected to an argon source with an oil bubbler, and stirred at a moderate speed until all of the solid monomer had melted.

[0350] At this time, a volume of stock stannous octoate solution equivalent (about 130 mg/ml in toluene) to 120 ppm stannous octoate or 35 ppm Sn was added to the melt using a syringe. The reaction mixture was allowed to stir under a slight argon pressure for approximately 16 hours. The oil bath temperature was then reduced to about 110° C. and the residual monomer was removed under vacuum. The upper parts of the reaction assembly were heated gently with a heat gun to aid in the monomer removal. The total time under vacuum was 2-3 hours.

[0351] The molten prepolymer was dissolved in 350 ml of chloroform with stirring and 2.5 equivalents of triethylamine (TEA) and 0.5 equivalents of DMAP were added to the stirring reaction mixture using a powder funnel. The reaction mixture was chilled to about −5° C. in a cold bath. A solution of about 1 equivalent of distilled ethyl dichlorophosphate (EOPCl2) in 97 ml of chloroform was prepared in a dropping funnel. The solution in the funnel was added slowly to the reaction mixture over a period of 2 hours. After the addition was complete, the reaction mixture was allowed to stir at low temperature for 45 minutes at −5° C. After 2 hours, a significant increase in viscosity of the clear solution was observed. The reaction was then quenched with 6.8 ml of anhydrous methanol and stirred for another five minutes.

[0352] Next, the reaction mixture was transferred to a 0.5 gallon vessel and mixed with 87 g of Dowex HCR-S IER and 104 g of Dowex-43, and shaken on a mechanical shaker for 1 hour to remove residual DMAP and TEA free base and salts (the IERs had been washed with several bed volumes of methanol and dried under vacuum at ambient temperature for about 18 hours). The resin was removed from the reaction mixture by vacuum filtration through Whatman 54 filter paper. The resin was washed with about one bed volume of dichloromethane and the filtrate was concentrated to approximately 150 ml. The viscous filtrate was poured into 2000 ml of hexane to precipitate the polymer. The polymer mass was washed with 2×200 ml of hexane and dried under vacuum. The molecular weights were determined by GPC were 36,700 for Mw (LS) and 34,100 for Mw (CC). The value for IV was 0.33 dL/g.

EXAMPLE 5

Polymer of PG, DL-lactide, Glycolide, and Ethyl Dichlorophosphate

[0353] All glassware was dried for a minimum of 2 hours at 105° C. and allowed to cool in a desiccator or cooled under a stream of argon gas. A 28.5 g portion of D,L-lactide and 1.5 g of PG (molar ratio, 10:1) were weighed into a 250 ml 3-neck round-bottom flask. The flask was equipped with a gas joint and a stirrer bearing/shaft/paddle assembly and a 125 ml dropping funnel containing 4.6 g of glycolide. The mixture was evacuated and filled with argon five times to remove residual air and moisture. The reaction apparatus was immersed in a preheated oil bath at 135° C., connected to an argon source with an oil bubbler, and stirred at a moderate speed until all of the solid monomer had melted.

[0354] At this time, a volume of stock stannous octoate solution (about 130 mg/ml in toluene) equivalent to 3.6 mg tin (120 ppm stannous octoate or 35 ppm tin) was added to the melt using a 50 μl syringe. The reaction mixture was allowed to stir under a slight argon pressure for approximately 16 hours. At this time the glycolide was melted using a heat gun and added to the polymer melt in the flask. The melt was stirred for an additional 2 hours. The oil bath temperature was then reduced to about 115° C. and the residual monomer was removed under vacuum. The upper parts of the reaction assembly were heated gently with a heat gun to aid in the monomer removal. The total time under vacuum was 2 hours.

[0355] The molten prepolymer was suspended in 84 ml of chloroform with stirring and 2. 5 equivalents of TEA and 0.5 equivalents of DMAP were added to the stirring reaction mixture using a powder funnel. The reaction mixture was chilled to about 4° C. in a cold bath. A solution of about 1 equivalent of distilled ethyl dichlorophosphate (EOPCl2) in 27.5 ml of chloroform was prepared in a dropping funnel. The solution in the funnel was added slowly to the reaction mixture over a period of 1 hour. After the addition was complete, the reaction mixture was allowed to stir at low temperature for another 1.75 hours and then the cold bath was removed. The reaction mixture was allowed to warm to room temperature and stirred for 2 to 18 hours. After 2 hours a significant increase in viscosity of the clear solution was observed. The reaction was then quenched with 1 ml of anhydrous methanol and stirred for another five minutes.

[0356] Next, 37 g of dry Dowex HCR-S IER and 30 g of dry Dowex M-43 were added to the reaction mixture and stirring was continued for another hour to remove residual DMAP and TEA free base and salts. The IERs were removed from the reaction mixture by vacuum filtration through Whatman 54 filter paper. The resin was washed with about one bed volume of dichloromethane and the filtrate was concentrated to approximately 50 ml. The viscous filtrate was poured into 700 ml of petroleum ether to precipitate the polymer and dried under vacuum.

EXAMPLE 6

Synthesis of D,L-PL(PG)HOP

[0357] All glassware was dried for a minimum of 2 hours at 105° C. and allowed to cool in a desiccator or cooled under a stream of argon gas. A 28.5 g portion of D,L-lactide and 1.5 g of PG (molar ratio, 10:1) were weighed into a 250 ml 3-neck round-bottom flask. The flask was equipped with a gas joint and a stirrer bearing/shaft/paddle assembly. The mixture was evacuated and filled with argon five times to remove residual air and moisture. The reaction apparatus was immersed in a preheated oil bath at 135° C., connected to an argon source with an oil bubbler, and stirred at a moderate speed until all of the solid monomer had melted.

[0358] At this time, a volume of stock stannous octoate solution (about 130 mg/ml in toluene) equivalent to 3.6 mg tin (120 ppm stannous octoate or 35 ppm tin) was added to the melt using a 50 μl syringe. The reaction mixture was allowed to stir under a slight argon pressure for approximately 16 hours. The oil bath temperature was then reduced to about 110° C. and the residual monomer was removed under vacuum. The upper parts of the reaction assembly were heated gently with a heat gun to aid in the monomer removal. The total time under vacuum was 2-3 hours.

[0359] The molten prepolymer was dissolved in 100 ml of chloroform with stirring and TEA and DMAP were added to the stirring reaction mixture using a powder funnel. The funnel was rinsed with 10 ml of chloroform. The reaction mixture was chilled to about 4° C. in a cold bath. A solution of about 1 equivalent of distilled hexyl dichlorophosphate (HOPCl2) in 27.5 ml of chloroform was prepared in a dropping funnel. The solution in the funnel was added slowly to the reaction mixture over a period of 1 hour. After the addition was complete, the reaction mixture was allowed to stir at low temperature for another hour and then the cold bath was removed. The reaction mixture was allowed to warm to room temperature and stirred for 2 to 18 hours. After 2 hours a significant increase in viscosity of the clear solution was observed. The reaction was then quenched with 800 μl of anhydrous methanol and stirred for another five minutes.

[0360] Next, Dowex MR-3C ion exchange resin (IER) was added to the reaction mixture and stirring was continued for another hour to remove residual DMAP and TEA free base and salts (the Dowex resin had been washed with several bed volumes of methanol and dried under vacuum at ambient temperature for about 18 hours). The resin was removed from the reaction mixture by vacuum filtration through Whatman 54 filter paper. The resin was washed with about one bed volume of dichloromethane and the filtrate was concentrated to approximately 100 ml. The viscous filtrate (now a somewhat cloudy solution) was poured into 1000 ml of hexane to precipitate the polymer. The polymer mass was washed with 2×200 ml of hexane and dried under vacuum. The molecular weight and IV data for the polymers prepared by this process are listed in the table below.

6SampleMw (LS), daltonsMw (CC), daltonsIV, dL/g164,20058,0000.48268,00062,7000.43

EXAMPLE 7

Synthesis of D,L-PL(PG)EP

[0361] All glassware was dried for a minimum of 2 hours at 105° C. and allowed to cool in a desiccator or cooled under a stream of argon gas. A 28.5 g portion of D,L-lactide and 1.5 g of PG (molar ratio, 10:1) were weighed into a 250 ml 3-neck round-bottom flask. The flask was equipped with a gas joint and a stirrer bearing/shaft/paddle assembly. The mixture was evacuated and filled with argon five times to remove residual air and moisture. The reaction apparatus was immersed in a preheated oil bath at 130° C., connected to an argon source with an oil bubbler, and stirred at a moderate speed until all of the solid monomer had melted.

[0362] At this time, a volume of stock stannous octoate solution (about 130 mg/ml in toluene) equivalent to 120 ppm stannous octoate or 35 ppm Sn was added to the melt using a syringe. The reaction mixture was allowed to stir under a slight argon pressure for 4 hours. The oil bath temperature was then reduced to about 110° C. and the residual monomer was removed under vacuum. The upper parts of the reaction assembly were heated gently with a heat gun to aid in the monomer removal. The total time under vacuum was 2 hours.

[0363] The molten prepolymer was dissolved in 84 ml of chloroform with stirring and 2.5 equivalents of TEA and 0.5 equivalents of DMAP were added to the stirring reaction mixture using a powder funnel. The reaction mixture was chilled to about −5° C. in a cold bath. A solution of about 1 equivalent of distilled ethyl dichlorophosphonate (EPCl2) in 9 ml of chloroform was prepared in a dropping funnel. The solution in the funnel was added slowly to the reaction mixture over a period of 0.5 hour. After the addition was complete, the viscosity of the solution had increased significantly and the reaction mixture was allowed to stir at low temperature for 1 hour at −5° C. The reaction was then quenched with 1 ml of anhydrous methanol and stirred for another five minutes.

[0364] Next, the reaction mixture was transferred to a 0.5 gallon vessel and mixed with 37 g of Dowex DR-2030 IER and 30 g of Dowex-43, and shaken on a mechanical shaker for 2 hour to remove residual DMAP and TEA free base and salts (the IERs had been washed with several bed volumes of methanol and chloroform and dried under vacuum at ambient temperature for about 18 hours). The resin was removed from the reaction mixture by vacuum filtration through Whatman 54 filter paper. The resin was washed with about one bed volume of dichloromethane and the filtrate was concentrated to approximately 50 ml. The viscous filtrate was poured into 200 ml of petroleum ether to precipitate the polymer. The polymer mass was washed with 100 ml of petroleum ether and dried under vacuum. The molecular weight data for the polymers prepared by this process are listed in the table below.

7SampleMw (LS), daltonsMw (CC), Daltons1339,900327,6002369,800360,900

EXAMPLE 8

Synthesis of P(cis- and trans—CHDM/HOP)

[0365] All glassware was dried for a minimum of two hours at 105° C. and allowed to cool in a desiccator or cooled under a stream of argon gas. A reaction assembly consisting of a 1 L three-neck round-bottom flask equipped with a gas joint, a stirrer bearing/shaft/paddle and a dropping funnel. A solution of 20.0 g of 1,4-cyclohexane dimethanol (CHDM) was prepared in 75 ml of anhydrous tetrahydrofuran (THF) and transferred to the reaction vessel. The beaker was rinsed with 25 ml of THF and the wash was transferred to the reaction vessel.

[0366] Next, 29.0 ml of N-methylmorpholine (NMM) and 1.61 g of DMAP were added to the reaction mixture through a powder funnel. A solution of 28.86 g of hexyl dichlorophosphate (HOPCl2) in 30 ml of THF was prepared under argon and transferred to the dropping funnel while the reaction mixture was cooled to 4° C. in a cold bath. The solution in the funnel was added to the reaction mixture over a period of one hour. With 5 to 10 minutes after the start of addition, a white precipitate, presumably the hydrochloride salts of NMM and DMAP, began to form. After the addition was complete the funnel was rinsed with 30 ml of THF. The reaction mixture was stirred for 1 hour at 4° C. and then for either 2 or 18 hours at ambient temperature.

[0367] At the prescribed time, the precipitate was removed from reaction mixture by vacuum filtration. The filtrate was diluted with 100 ml of dichloromethane, transferred to a half-gallon jar and 86.5 of dried Dowex HCR-S IER and 103.8 g of dried Dowex M-43 IER were added to the filtrate. The jar was sealed with a Teflon lined lid and the mixture was agitated on a mechanical shaker for two hours.

[0368] At this time, the IERs were removed by vacuum filtration and the filtrate was concentrated to approximately 100 ml under vacuum. The polymer solution was poured in 2 L of hexane and the resulting fluid material that precipitated was isolated and transferred to a Teflon lined glass dish. The polymer was dried under vacuum to yield a sticky, free flowing viscous liquid. The Mw (LS) data for the polymers prepared by this process are listed in the table below.

8SampleMw (LS), daltonsMw (CC), daltonsIV, dL/g1440055000.142500065000.113400046000.10

EXAMPLE 9

Synthesis of P(BHET/EOP)

[0369] All glassware was dried for a minimum of two hours at 105° C. and allowed to cool in a desiccator or cooled under a stream of argon gas. A reaction assembly consisting of a 500 ml three-neck round-bottom flask equipped with a gas joint, a stirrer bearing/shaft/paddle and a dropping funnel. First, 30.0 g of bis(hydroxyethyl) terephthalate (BHET) and 28.83 g of DMAP were added to the reaction vessel using a powder funnel and mixed with 81 ml of THF. The solids were dissolved with stirring and gentle heating using a heat gun.

[0370] After all solids had dissolved, the reaction mixture was cooled to 4° C. in a cold bath. A solution of 19.2 g of ethyl dichlorophosphate (EOPCl2) in 24 ml of THF was prepared in a 125 ml addition funnel. The solution in the funnel was added to the solution in the flask over a period of 1 hour. Shortly after the addition had begun, a white precipitate, presumably DMAP hydrochloride, began to precipitate from the reaction mixture. After all of the solution in the funnel had been added, the stirrer shaft/paddle became entrapped in a thick, stiff precipitate and stirring ceased. It appears the polymer that had formed at this time was insoluble in the reaction mixture.

[0371] Next, 125 ml of dichloromethane were added and the reaction mixture was swirled by hand until mechanical stirring could be resumed. The reaction mixture was now a homogenous solution containing a white free flowing powder. The reaction mixture was stirred at 4° C. for one hour. The cold bath was removed and the reaction mixture was allowed to warm to ambient temperature and stirred for 16 hours. At this time, the white precipitate was removed from the reaction mixture by vacuum filtration and the filter cake was washed with 100 ml of dichloromethane.

[0372] The resulting filtrate was transferred to a half-gallon jar and treated with 156.92 g of undried Dowex HCR-S IER and 160.92 g of undried Dowex M-43 IER. The resins were washed with 2 bed volumes of methanol and 2 bed volumes of dichloromethane prior to use. The jar was sealed with a Teflon lined lid and shaken on a mechanical shaker for two hours. The resin was removed by vacuum filtration and the filtrate, ˜600 ml, was concentrated to ˜150 ml. The clear solution was poured into 1.2 L of hexane. The thick oil that precipitated was washed with 400 ml of hexane and transferred to a Teflon lined glass dish, dried under vacuum. The molecular weights were determined by GPC were 2200 for Mw (LS) and 2100 for Mw (CC). The value obtained for IV was 0.10 dL/g.

EXAMPLE 10

Synthesis of P(BHET-EOP/TC)

[0373] All glassware was dried for a minimum of two hours at 105° C. and allowed to cool in a desiccator or cooled under a stream of argon gas. A reaction assembly consisting of a 500 ml three-neck round-bottom flask equipped with a gas joint, a stirrer bearing/shaft/paddle and a dropping funnel. First, 30.0 g of BHET and 28.83 g of DMAP were added to the reaction vessel using a powder funnel and mixed with 81 ml of THF and 125 ml of dichloromethane.

[0374] The solids were dissolved with stirring and gentle heating using a heat gun. After all solids had dissolved, the reaction mixture was cooled to 4° C. in a cold bath. A solution of 19.2 g of EOPCl2 in 24 ml of THF was prepared in a 125 ml addition funnel. The solution in the tunnel was added to the solution in the flask over a period of 1 hour. Shortly after the addition had begun, a white precipitate, presumably DMAP hydrochloride, began to precipitate from the reaction mixture. The reaction mixture was stirred at 4° C. for one hour. Next, a solution of 4.79 g of terephthaloyl chloride (TC) in 18 ml of THF was prepared in the addition funnel and added to the solution in the flask over a 30-minute period. The reaction mixture was stirred for one hour at 4° C.

[0375] At this time the cold bath was removed and the reaction was allowed to warm to room temperature and stir for another 20 hours. At this time, the white precipitate was removed from the reaction mixture by vacuum filtration. The resulting filtrate was transferred to a half-gallon jar and treated with 88.5 g of dried Dowex HCR-S IER and 73.8 g of dried Dowex M-43 IER. The jar was sealed with a Teflon-lined lid and shaken on a mechanical shaker for two hours. The resin was removed by vacuum filtration and the filtrate was concentrated to 100 ml. The clear solution was poured into 2 L of hexane. The thick oil that precipitated was transferred to a Teflon-lined glass dish, dried under vacuum. The molecular weights were determined by GPC were 7200 for Mw (LS) and 4000 for Mw (CC). The value obtained for IV was 0.09 dL/g.

[0376] Iin all of the following Examples, unless otherwise stated, the D,L-PL(PG)EOP used may be prepared using the method described in Example 1 or 2 above or Example 27 below, with Example 2 and 27 being the preferred method of synthesis.

EXAMPLE 11

Spray Drying of D,L-PL(PG)EOP Microspheres Containing Lidocaine or Lidocaine HCl

[0377] Lidocaine and D,L-PL(PG)EOP in a fixed ratio (e.g., 10% lidocaine and 90% D,L-PL(PG)EOP) were dissolved in dichloromethane to make about a 5% solution with respect to the polymer. For example, to prepare 100 g microspheres, 10 g of lidocaine and 90 g of D,L-PL(PG)EOP were dissolved in 1800 ml of dichloromethane. The lidocaine-polymer solution was spray-dried using the Buchii Mini Spray Dryer (Model B-191) at inlet temperature of 35° C., pump rate of 1 g/min for drug-polymer solution and 800 L/hr for atomizer gas (nitrogen), and aspiration at 50-80%. This same method may be used to prepare microspheres containing lidocaine HCl instead of lidocaine. The average microsphere diameter prepared by this method was found to be about 15 to 20 microns.

EXAMPLE 12

Spray Drying of D,L-PL(PG)EOP Microspheres Containing Cholesterol and either Lidocaine or Lidocaine HCl

[0378] Lidocaine, D,L-PL(PG)EOP and cholesterol in a fixed ratio were dissolved in dichloromethane to make about a 5% solution with respect to the polymer. For example, to prepare 100 g of microspheres containing 10% lidocaine, 20% cholesterol and 70% D,L-PL(PG)EOP, the corresponding amounts of the materials (i.e., 10 g of lidocaine, 20 g of cholesterol and 70 g of D,L-PL(PG)EOP) were dissolved in 1400 ml of dichloromethane. The resulting solution was then spray dried using the Buchii Mini Spray Dryer (Model B-191) at inlet temperature of 35° C., pump rate of 1 g/min for drug-polymer solution and 800 L/hr for atomizer gas (nitrogen), and aspiration at 50%. This same method may be used to prepare microspheres containing lidocaine HCl instead of lidocaine.

EXAMPLE 13

Spray Drying of D,L-PL(PG)EOP Microspheres Containing Lidocaine and Ethylcellulose

[0379] Lidocaine, D,L-PL(PG)EOP, and ethylcellulose in a fixed ratio were dissolved in dichloromethane to make about a 5% solution with respect to the polymer. For example, to prepare 100 g of microspheres containing 30% lidocaine, 10% ethylcellulose and 60% D,L-PL(PG)EOP, the corresponding amounts of the materials (i.e., 30 g of lidocaine, 10 g of cholesterol and 60 g of D,L-PL(PG)EOP) were dissolved in 1200 ml of dichloromethane. The resulting solution was then spray dried using the Buchii Mini Spray Dryer (Model B-191) at inlet temperature of 35° C., pump rate of 1 g/min for drug-polymer solution and 800 L/hr for atomizer gas (nitrogen), and aspiration at 50%.

EXAMPLE 14

Spray Drying of D,L-PL(PG)EOP Microspheres Containing Lidocaine and PVP

[0380] Lidocaine, D,L-PL(PG)EOP, and PVP in a fixed ratio were dissolved in dichloromethane to make a 5% solution with respect to the polymer or total solids. For example, to prepare 100 g of microspheres containing 50% lidocaine, 10% PVP and 40% D,L-PL(PG)EOP, the corresponding amounts of the materials (i.e., 50 g lidocaine, 10 g cholesterol and 40 g of D,L-PL(PG)EOP) were accurately weighed and dissolved in 800 ml of dichloromethane. The resulting solution was then spray dried using the Buchii Mini Spray Dryer (Model B-191) at inlet temperature of 35° C., pump rate of 1 g/min drug-polymer solution and 800 L/hr for atomizer gas (nitrogen), and aspiration at 50%.

EXAMPLE 15

Preparation of D,L-PL(PG)EOP Microspheres Containing Lidocaine by Solvent Evaporation Method

[0381] Lidocaine and D,L-PL(PG)EOP in a fixed proportion were dissolved in dichloromethane to make about a 20% solution with respect to the polymer. For example, to prepare 10 g of microspheres containing 20% lidocaine and 80% D,L-PL(PG)EOP, the corresponding amounts of the materials (i.e., 2 g lidocaine and 8 g of D,L-PL(PG)EOP) were dissolved in dichloromethane to a volume of 40 ml. The resulting solution was then emulsified into 0.5% polyvinylalcohol (PVA) solution presaturated with lidocaine at a stirring rate of 600 rpm. After stirring for 1-10 minutes, vacuum (about 15-25inches of Hg) was applied to remove the dichloromethane. The microspheres were washed with water pre-saturated with lidocaine and lyophilized.

EXAMPLE 16

Preparation of D,L-PL(PG)EOPmicrospheres Containing Lidocaine and Excipients by Solvent Evaporation Method

[0382] Lidocaine, D,L-PL(PG)EOP and an excipient in a fixed ratio were dissolved in dichloromethane to make about a 20% solution with respect to the polymer. For example, to prepare 10 g of microspheres containing 20% lidocaine, 1% ethylcellulose and 79% D,L-PL(PG)EOP, the corresponding amounts of the materials (i.e., 2.0 g lidocaine, 0.1 g ethylcellulose and 7.9 g of D,L-PL(PG)EOP) were accurately weighed and dissolved in and made up to 40 ml with dichloromethane. The resulting solution was then emulsified into 0.5% polyvinylalcohol (PVA) solution pre-saturated with lidocaine at a stirring rate of 600 rpm. After stirring for 1-10 minutes, vacuum (about 15-25 inches of Hg) was applied to remove the dichloromethane. The microspheres were washed with water pre-saturated with lidocaine and lyophilized.

EXAMPLE 17

Preparation of D,L-PL(PQ)EOP Microparticles Containing Lidocaine

[0383] Lidocaine and D,L-PL(PG)EOP in a fixed ratio were dissolved in dichloromethane, evaporated to dryness and pulverized. For example, to prepare 10 g of microspheres containing 10% lidocaine and 90% D,L-PL(PG)EOP, the corresponding amounts of the materials (i.e., 1.0 g lidocaine and 9.0 g of D,L-PL(PG)EOP) were accurately weighed and dissolved in 20 ml of dichloromethane. The resulting solution was evaporated at 40° C. under nitrogen purge to obtain viscous mass. The viscous mass was cooled to −40° C. and lyophilized for 48 hours. The dried dispersion was subsequently pulverized to a desired size. Another method for preparing microparticles is described in Example 20.

EXAMPLE 18

Preparation of D,L-PL(PG)EOP Microparticles Containing Lidocaine and Excipients

[0384] Lidocaine, excipient and D,L-PL(PG)EOP in a fixed ratio were dissolved in dichloromethane, evaporated to dryness and pulverized. For example, to prepare 10 g of microspheres containing 50% lidocaine, 10% cholesterol and 40% D,L-PL(PG)EOP, the corresponding amounts of the materials (i.e., 5.0 g lidocaine, 1.0 g cholesterol and 4.0 g of D,L-PL(PG)EOP) were accurately weighed and dissolved in 20 ml of dichloromethane. The resulting solution was evaporated at 40° C. under nitrogen purge to obtain viscous mass. The viscous mass was cooled to −40° C. and lyophilized for 48 hours. The dried dispersion was subsequently pulverized to a desired size.

EXAMPLE 19

Preparation of D,L-PL(PO)EOP Microparticles Containing Lidocaine Hydrochloride with or without Excipient

[0385] Lidocaine hydrochloride and D,L-PL(PG)EOP, with or without excipient, in a fixed ratio were weighed and heated at about 150° C. to melt. The molten mass is stirred thoroughly and then cooled (under natural draught or using liquid nitrogen or dry ice). The solid mass is then pulverized to the desired particle size using a suitable comminuting mill.

EXAMPLE 20

Preparation of Paste and Microparticle Formulations

[0386] Microspheres, prepared according to the previous Examples, were mixed with pluronic gel in various ratios. The resulting paste was stored in a syringe. The release of lidocaine from microspheres of a subject composition containing lidocaine and D,L-PL(PG)EOP diluted to different amounts by a pluronic gel over time is shown in FIG. 1.

[0387] Microparticles of the subject compositions may be prepared as follows. Spray dried microspheres, prepared according to any of the methods described herein, may be melted at up to 150-200° C. and cooled rapidly. The resulting material may then be ground to microparticles of desired particle size using a suitable grinder and sieve. By this method, microparticles containing analgesic agents and other materials may prepared, including exicipients, provided the starting microspheres have the same composition as the desired microparticles.

EXAMPLE 21

P(BHET-EOP/TC) Microspheres with Lidocaine

[0388] P(BHET-EOP/TC) prepared in accordane with Example 10 and lidocaine (in various ratios) were dissolved in dichloromethane to make a 25% w/v solution with respect to the polymer. The resulting solution was emulsified into 0.5% polyvinyl alcohol (PVA) solution presaturated with lidocaine. The emulsion was stirred for about 90 minutes or until microspheres hardened. The microsphere suspension was strained through 150 and 20 μm sieves and the fraction on the 20 μm sieve was collected, washed and lyophilized.

EXAMPLE 22

Subcutaneous (SC) Administration of Microspheres

[0389] Two formulations of lidocaine, cholesterol and D,L-PL(PG)EOP, 50/16/34 and 30/23/47, were examined, (given as x/y/z, where x is the percentage of lidocaine, y is the percentage of excipient (cholesterol), and z is the percentage of D,L-PL(PG)EOP). Microspheres of the two formulations were suspended in sterile saline solution (0.9% sodium chloride) with 0.1% polysorbate 80 or vegetable oils and were administered subcutaneously to Sprague-Dawley rats at a dose of 30 mg per rat. The microspheres were prepared in accordance with the method of Example 12. Plasma was obtained for 5 days and analyzed for lidocaine by LC-MS method. The plasma lidocaine concentrations were higher for the 30% loaded microspheres than for the 50% loaded samples (FIG. 2), resulting in maintainance of at least 1 ng/mL plasma concentration of lidocaine for over 70 hours for the 30% loaded microspheres.

EXAMPLE 23

Effect of Lidocaine Dose on Plasma Concentration

[0390] Three formulations of lidocaine, cholesterol and D,L-PL(PG)EOP, 30/58.4/11.6, 50/25/50 and 10/67.5/22.5, were examined, (given as x/y/z, where x is the percentage of lidocaine, y is the percentage of excipient (cholesterol), and z is the percentage of D,L-PL(PG)EOP). Microspheres of the three formulations were administered subcutaneously to rats as described in Example 22 above, and plasma, tested over a period of days, was analysed for lidocaine using the LC/MS method. FIG. 3 shows that the resulting plasma level of lidocaine depends on the dose administered. All three formulations demonstrate that levels of lidocaine are maintained above 1 ng/ml for four days.

[0391] In addition, when injected microsphere samples were retrieved and the residual lidocaine analyzed, about 15% of the lidocaine dose was found to be retained at the injection site after 72 hours when 10% lidocaine in microspheres prepared by solvent evaporation was administered compared to about 0.1% for microspheres prepared by the spray drying method.

EXAMPLE 24

In vivo Clearance of Lidocaine

[0392] A high proportion of lidocaine and the addition of cholesterol allows dosage forms to be designed such that more than 70% of the formulation is cleared from the injection site within two weeks. For example, when microspheres containing 40% lidocaine, 30% cholesterol and 30% D,L-PL(PG)EOP, were administered subcutaneously to rats, less than 30% of the formulation was recovered from the injection site after 7 days. Similar rates of clearance were observed following the administration of formulations containing 30% or 50% lidocaine. In addition, the polymer may be modified to increase the rate of degradation and clearance. An additional study showed that after rats were dosed subcutaneously with 50 mg of microspheres prepared using D,L-PL(PG)EOP with D,L-lactide to PG ratio of 5:1, no residue was seen following visual examination of the injection site after 4 weeks.

EXAMPLE 25

Pharmacokinetics of Lidocaine Formulations

[0393] Although microspheres containing lidocaine may be used for local anesthetic effect, measurable blood levels of lidocaine were observed in animal studies. When various compositions of lidocaine in D,L-PL(PG)EOP microspheres were administered subcutaneously to rats, measurable blood levels of lidocaine were observed for periods up to 96 hours (FIGS. 2 and 3). The concentration of lidocaine in plasma depends on the drug loading as well as on the method of preparation and the dose administered. Data on plasma concentrations following administration of lidocaine/D,L-PL(PG)EOP microspheres for various formulations and dosages is presented in the table below (given as x/y/z, where x is the percentage of lidocaine, y is the percentage of excipient (cholesterol), and z is the percentage of D,L-PL(PG)EOP)).

9MeanMeanMeanMeanC at 24C at 48C at 72CmaxhourshourshoursDose(ng/ml)(ng/ml)(ng/ml)(ng/ml)TmaxFormulation(mg)(n = 5)(n = 5)(n = 5)(n = 5)(hours)50/16/34151962.59.41.31.1<150/16/34302168.448.81.30.4<150/16/34603325.3384.56.20.7<130/23/47151660.425.12.12.5<130/23/47302262.2116.92.71.2<130/23/47603174.6262.425.13.7<1

[0394] It was observed that when lidocaine in D,L-PL(PG)EOP microspheres was administered subcutaneously to rats, the injected dose formed a soft, discoid mass at the injection site. D,L-PL(PG)EOP is known to swell in aqueous milieu and with the incorporation of lidocaine, both the glass transition and melting temperatures were also lowered. The swelling and the low melting temperature may allow the formation of the discoid mass at the injection site from which the drug is slowly released.

EXAMPLE 26

P(BHET-EOP/TC) Microspheres with Lidocaine

[0395] P(BHET-EOP/TC) from Example 10 and lidocaine (4:1 w/w) were dissolved in dichloromethane to make a 25% w/v solution which was emulsified into 0.5% polyvinyl 10 alcohol (PVA) solution presaturated with lidocaine. The emulsion was stirred for about 90 minutes or until microspheres hardened. The microsphere suspension was strained through 150 and 20gm sieves and the fraction on the 20 μm sieved was collected, washed and lyophilized.

[0396] The in vitro release of lidocaine from the microspheres was carried out in PBS (0.1M, pH 7.4) at 37° C. and the released lidocaine was quantified using a HPLC method.

[0397] The HPLC method used Phenomenex Prodigy ODS 2 column, 150 cm.×4.6 mm and acetonitrile (20%) in 40 mM monobasic phosphate buffer adjusted to pH 3.5 with phosphoric acid as mobile phase. The pump rate was 1 ml/min and lidocaine. Quantitation was performed by UV detection at λ 254 μm.

[0398] The morphology of lidocaine-P(BHET-EOP/TC) microspheres is shown in FIG. 4 (such microspheres are known herein as “politerefate”). The microspheres are roughly spherical in shape with volume-weighted median particle size of 59 μm. In vitro release of lidocaine from the microspheres is slow relative to the pure drug (FIG. 5). The T80% (time required for 80% of lidocaine to be released) was about 40 hours and about 95% of the drug was released after 3 days. The corresponding T80% for pure lidocaine was less than 30 minutes (data not shown).

[0399] To evaluate the efficacy of the lidocaine-P(BHET-EOP/TC) microspheres in treating chronic pain, the analgesic effects of the microsphere formulation were compared with lidocaine in saline in the Randall-Selitto model of inflammatory pain. In this model, inflammation and hyperalgesia of the hind paw was induced by subplantar injection of carrageenan beneath the plantar aponeurosis of the left hind paw of the rat. The pain threshold of the inflamed paws was measured using an analgesiometer at 1 and 2 hours after irritant. The treatments were administered into the inflamed paw immediately after the second pre-dose measurement. The pain threshold of the inflamed paw was again measured at 2, 6, 24, 48 and 96 hours post-treatment.

[0400]
FIG. 6 shows the duration of analgesic activity obtained when lidocaine-P(BHET-EOP/TC) microspheres were administered into the inflamed hind paw of a rat. This administration is compared to control (no treatment), normal saline treatment, treatment with lidocaine in normal saline, and administration of P(BHET-EOP/TC) microspheres without lidocaine. The analgesic activity of lidocaine/saline formulation could only be measured at 2 hours post-treatment. On the other hand, prolonged analgesic effect was seen with lidocaine-P(BHET-EOP/TC) microsphere formulations; the analgesic effect was observed at day 3 post-treatment. The analgesiometer readings for the lidocaine-P(BHET-EOP/TC) microsphere-treated rats remained twice as high as those of control rats for three days.

[0401] This study demonstrates that lidocaine may be incorporated into P(BHET-EOP/TC) as microspheres. Approximately 3-5 days of release were achieved with both formulations in vitro. Furthermore, efficacy results in rodent pain model shows that lidocaine-P(BHET-EOP/TC) microsphere formulation is more effective than lidocaine solution in alleviating pain. The analgesic effect was prolonged to 3 days with the microsphere formulation (p<0.001; n=10).

EXAMPLE 27

Large-scale Preparation of D,L-PL(PG)EOP

[0402] A 100 g portion of PG was added to a 3000 ml 3-necked round bottom flask equipped with a gas joint, a stirrer bearing/shaft/paddle assembly, and a Teflon-coated thermocouple. The reaction apparatus was placed in a preheated oil bath at 130° C. and purged with nitrogen for one minute. A 2000 g portion of D,L-lactide was added using a powder addition funnel over a period of 45 minutes. The reaction apparatus was then immersed in the oil so that the oil level was at the bottom of the ground glass joints. The mixture was stirred until all of the solid monomer had melted and the internal temperature had reached approximately 125° C. At this time, a volume of solution of stannous octoate in chloroform equivalent to approximately 400 ppm (117 ppm Sn) was added to the melt using a syringe. The mixture was allowed to stir for approximately 3-16 hours. Then oil bath set point was decreased to approximately 125° C. and any residual unreacted monomer removed using vacuum over approximately 1 hour.

[0403] A 2500 ml portion of chloroform was used to dissolve and transfer the prepolymer to a pre-chilled, 20-liter jacketed reactor, which contained 2.5 equivalents (based on propylene glycol) of triethylamine and 0.5 equivalents of DMAP dissolved in 3600 ml of chloroform. The reactor was equipped with a stirrer bearing/shaft/turbine assembly, a gas joint, a tubing adapter, and a Teflon-coated thermocouple. With stirring and chilled recirculation on the jacket, the solution was cooled to below −15° C. A solution of 1 equivalent (based on propylene glycol, approximately 215 g) of distilled ethyl dichlorophosphate (EOPCl2) in 650 ml chloroform was prepared in a 1000 ml 3-necked round bottom flask equipped with a tubing adapter and a gas joint. The EOPCl2/chloroform solution was added using a piston pump and Teflon tubing over a period of 50 minutes, maintaining the internal temperature at approximately −10° C. Tubing was connected to the gas joints of the flask and reactor to equalize the pressure during the addition. Following the addition, a 50 ml portion of chloroform was added to rinse the flask, feed lines, and pump. The reaction mixture was stirred for 1 hour at low temperature (−8° C. after 1 hour) before the reaction was quenched with 140 ml of anhydrous methanol.

[0404] The reactor was then charged with 3 kg of Dowex DR-2030 IER and 3 kg of Dowex M-43 wetted with approximately 6.5 liters of methylene chloride. The polymer/resin mixture was mixed at low temperature for 3-15 hours, after which it was transferred by vacuum to a stainless steel laboratory Nutsche filter. After filtering off the resin, the polymer solution was pulled through the in-line 8 micron cartridge filter into the concentrator (a similar 10-liter jacketed reactor) where the solution was concentrated with the aid of heated recirculating fluid on the jacket. The 20-liter reactor and the resin in Nutsche were washed with 5 liters of methylene chloride, which were transferred to the concentrator after being stirred for 1 hour. An additional 5 liters of methylene chloride were added to the resin in the Nutsche and added to the concentrator when the solution had been reduced to approximately 6 liters.

[0405] Concentration of the polymer solution continued until approximately 4-5 liters of a viscous solution remained. A portion of 1500 ml of ethyl acetate was then added to the polymer solution. The mixture was mixed until homogenous and precipitated in approximately 10 liters of petroleum ether. After the precipitation mixture was stirred for approximately 5 minutes, the supernatant liquid was decanted. The polymer was then washed with 5 liters of petroleum ether. After the mixture was stirred for 5 minutes. The liquid was again decanted. The polymer was poured into a Teflon-coated pan and placed in the vacuum oven at NMT 50° C. After drying for 24 hours, the polymer was ground into smaller pieces and dried for additional time in a vacuum oven at ambient temperature.

EXAMPLE 28

Assessment of Duration of Analgesic Activity in Rats Using the Randall-Selitto Test

[0406] The duration of analgesic activity of two slow release lidocaine formulations—(i) microspheres of 50% lidocaine HCl and 50% D,L-PL(PG)EOP prepared by the spray drying method taught in Example 11 (known as “LIDOMER microspheres”), and (ii) microparticles of 50% lidocaine HCl and 50% D,L-PL(PG)EOP prepared by the method described in Example 20 starting with the appropriate microspheres prepared by the spray drying method as taught in Example 11, with particle size of less than approximately 75 microns by use of sieve of that dimension (known as “LIDOMER™ microparticles”)—were evaluated in a rat model of carrageenan-induced hyperalgesia, using the Randall-Selitto test. Lidocaine HCl (5%) in saline was also tested as a comparator to the slow release formulations. The experimental groups are listed in Table 2.

10TABLE 2Experimental Groups in Randall-Sellitto TestLIDOMERLidocaine HClDose volumeTreatmentdosedose(ml)Sesame oil control000.1LIDOMER microspheres8mg/rat4mg/rat0.1LIDOMER microparticles8mg/rat4mg/rat0.1

[0407] Briefly, to perform the study, treatments were administered into the inflamed paws of male Wistar rats approximately 2 hours after a subcutaneous injection of 0.1 ml of 1% w/v carrageenan into the hind paw. Pain responses (threshold) were measured at 1 and 2 hours after the irritant (1 and 0 hour pre-dose) and again at 1, 2, 4, 8, 12, 24, 36, 48 and 60 hours post-dose using an analgesiometer. The change in pain thresholds from the 0 hour measurement of test-article treated groups at various post-dose time were compared with those of the sesame oil-treated control group using student's t test.

[0408] The results are summarized in FIG. 7. Lidocaine HCl in saline produced analgesia as determined by elevation in pain responses compared with the vehicle treated group that was significant (p<0.05) at 1 hour post-dose only. The two slow release lidocaine formulations demonstrated longer analgesic activity than the lidocaine/saline formulation. LIDOMER microspheres formulation produced statistically significant analgesia up to 48 hours post dose when compared with sesame oil treated control rats. Although LIDOMER microparticles produced elevation in the pain thresholds up to 8 hours post-dose, these effects were not statistically significant when compared with the sesame oil treated control group.

EXAMPLE 29

Assessment of Duration of Analgesic Activity in Rats Using Peri-sciatic Nerve Block Model

[0409] The duration of analgesic activity of the two slow release lidocaine formulations LIDOMER™ microspheres and LIDOMER™ microparticles, described in Example 28 above, were evaluated in a rat peri-sciatic nerve block model. The duration of analgesic activity was also compared with lidocaine HCl/saline formulation (4%) The experimental groups are listed in Table 3.

11TABLE 3Experimental Groups in Per-Sciatic Nerve Block ModelDose (mg/nerve)TreatmentLIDOMERLidocaine HClPlacebo 0 0(D,L-PL(PG)EOP microspheres only)Lidocaine HCl in salineN/A 40LIDOMER microspheres100 50200100300150LIDOMER microparticles 50 25100 50200100

[0410] Male Sprague-Dawley rats were used for the study. Each treatment group consisted of 6 rats. STIMEX needles and nerve stimulators were used to locate the sciatic nerve non-invasively. After the sciatic nerve has been located, the test articles were injected using a 18 G needle. Successful injection was evidenced by almost immediate local anesthesia and muscle weakness in the injected hind limb. Test paw withdrawal latencies following drug injection were assessed using a hot-plate test, and a 12 sec cut-off was imposed to prevent any possible damage that would confound the results. The hot-plate test consisted of gently holding the body of the animal while the plantar aspect of the paw was placed on the hot-plate. The baseline (control) latency for the rat to withdraw its paw from the hot-plate (52° C.) was determined prior to unilateral injection of test articles around the sciatic nerve of the rat. Local anesthesia was quantified as the Hot-Plate Latency (sec).

[0411] Compared with the lidocaine/saline formulation, the slow release lidocaine formulations (LIDOMER™ microspheres and LIDOMER™ microparticles) resulted in significant increase in the duration of nerve block, as shown in FIGS. 8 and 9.

EXAMPLE 30

Assessment of Duration of Analgesic Activity in Guinea-pig Pin-prick Model

[0412] The duration of analgesic activity of the two slow release lidocaine formulations were evaluated in a guinea-pig pin-prick model. The two formulations were (i) 50% lidocaine, 16% cholesterol and 34% D,L-PL(PG)EOP, prepared as microspheres as described in Example 12 and injected in normal saline containing 0.1% Tween 80, and (ii) 50% lidocaine HCl, 16% cholesterol and 34% D,L-PL(PG)EOP, also prepared as microspheres as described in Example 12 and injected in sesame oil. These two formulations were compared to saline alone, microspheres of D,L-PL(PG)EOP alone and lidocaine (2%) in saline.

[0413] Guinea pig were used for the study. Each treatment group consisted of 5 guinea pigs, with 6 pin pricks tested for each injection site. A 0.25 ml subcutaneous injection was given for each of the formulations with a dosage of 5 mg of lidocaine or its lidocaine HCL equivalent. A positive response was defined as skin flinch or vocal response to the pin-prick stimuli. FIG. 10 shows the results, indicating that the two subject compositions described above result in a longer duration of analgesic affect than the controls.

EXAMPLE 31

Plasma Concentrations of Several Compositions Containing Lidocaine HCl

[0414] Several subject compositions formulations were prepared and tested in rats (Table 4). Microspheres were prepared by the appropriate spray drying methods taught above, and microparticles were prepared using Example 20 above with the appropriate microspheres as starting materials and a 75 micron sieve. Each formulation was suspended in sesame oil and administered to groups of three to five male Sprague-Dawley rats. The route of administration was subcutaneous; the location was in each of the animal's flanks. Blood samples were taken subsequently and plasma prepared. The plasma concentration of lidocaine base was determined by LC/MS.

12TABLE 4% Lidocaine%% D,L-CompositionTypeHClCholesterolPL(PG)EOPMS 50/16/34Microspheres501634MS 50/50Microspheres50—50MS 25/75Microspheres25—75MP 50/50Microparticles50—50

[0415]
FIG. 11 presents the plasma time/concentration profiles for the compositions in Table 4. The profiles for the 50/50 and 25/75 microsphere formulations were somewhat flatter over the first few hours compared to the other dose forms, but the effect was modest.

REFERENCES

[0416] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0417] Patents

[0418] U.S. Pat. Nos. 4,638,045, 5,219,564, 5,099,060, 5,900,249, 5,747,060, 5,505,922, 5,856,342, 5,747,060, 5,942,241, 5,942,543, 5,922,340, 6,075,059, 6,031,007, 6,045,824, 6,046,187, and 5,993,836.

[0419] Publications and Other References

[0420] Ertel et al., (1995) J. Biomedical Materials Res. 29:1337-1348

[0421] Choueka et al., (1996) J. Biomed. Materials Res., 31:35-41

[0422] Langer et al., (1983) Rev. Macro. Chem. Phys. C23(1):61

[0423] Leong et al., (1986) Biomaterials, 7:364

[0424] Yamamoto et al., (1993) Pain, Nov. 55(2):227-33

[0425] Yamamoto et al., (1993) Pain, Jul. 54(1):79-84

[0426] Yamamoto et al., (1992) Pain, Dec. 51(3):329-34

[0427] Yamamoto et al., (1992) Anesthesiology, Oct. 77(4):757-63

[0428] Yamamoto et al., (1991) Life Sci,. 49(26):1955-63

[0429] Stein, C., (1988) Pharm. Biochem. Behavior, 31:445-451

[0430] (1961) J. Pharmacol. Exp. Ther., 133, 400

[0431] (1957) Arch. Int. Pharmacodyn. Ther. 111, 409

[0432] Equivalents

[0433] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Compositions for sustained release of analgesic agents, and methods of making and using the same

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