Patent Application
20150104508
Delivery systems of biologically active agents are designed to administer a therapeutically effective amount of one or more biologically active agents to an organ or tissue of a subject at a controlled delivery rate. In some instances, these systems may deliver the compounds over an extended period of time such as over hours, days, or months. As one example of a desirable long-term delivery of a biologically active agent, a biologically active agent delivery composition may be incorporated in a wound dressing for control of a biologically active compound to and release of compounds from the wound site during the course of wound healing. For example, biologically active agents may be delivered over time to a wound in order to control the growth of pathogens. Such biologically active agent delivery systems may include one or more biologically active agent delivery compositions. Biologically active agent delivery compositions may include one or more biologically active agents mixed with or imbedded within one or more matrix materials.
Twin-screw extrusion (TSE) has long been established as a technique for mixing polymer blends, polymer composites, and/or polymer nanocomposites. However, TSE may be unsuitable for combining biologically active agents with polymer matrix materials to form biologically active agent delivery compositions. The shear mixing in TSE is often performed under temperature conditions sufficiently high to maintain the polymer components in the melted state. Such high temperatures may degrade biologically active agents. Furthermore, the long period of exposure to high temperatures resulting from local frictional heating of the agents can accelerate this degradation. Additionally, fillers, binding agents, excipients, and other additives that may be used to control the delivery rate of the agents may not be dispersed effectively throughout the polymer matrix using TSE processes. These limitations may render TSE ineffective for producing biologically active agent delivery systems fabricated from such matrix materials, fillers, and agents. Therefore, a method of compounding one or more biologically active agents with one or more matrix materials, fillers, binding agents, excipients, and other additives may require techniques other than those provided by TSE methods.
As used herein, the term “liquefication” refers to a phase transition of a polymer material from a solid state to a softened, liquid, or near-liquid state. A “liquefication temperature” refers to a temperature at which the polymer material transitions from a solid state to a softened, liquid, or near-liquid state. For a semi-crystalline polymer, a “liquefication temperature” may correspond to a melting point temperature. For an amorphous polymer, a “liquefication temperature” may correspond to a glass transition temperature. Some polymers may exist as combinations or admixtures of semi-crystalline and amorphous phases, and therefore the “liquefication temperature” may refer to either a melting point temperature or a glass transition temperature depending on the material composition.
As used herein, “administration of a biologically active agent to a subject” refers to any route of introducing or delivering the agent to a subject so that it may perform its intended function. Administration can be carried out through any suitable route, including orally, intranasally, parenterally, intravenously, intramuscularly, intraperitoneally, subcutaneously, or topically. Administration may include self-administration or the administration of the agent by another.
As used herein, the term “delivery system” refers to an article in any form, shape, or combination thereof configured to deliver one or more biologically active agents to a subject. Non-limiting examples of shapes may include films, tubing, foams, or any monolithic shape constructed of the compositions disclosed herein. As one illustrative example, a delivery system may include an injection molded component of a device, such as a connector head of a pacemaker or extruded polyurethane tubing as part of a pacemaker lead. Another non-limiting example may include a coating applied to a stent.
As used herein, the term “biostable” refers to the property of being resistant to degradation by processes that may be encountered in vivo. Thus, a biostable material may be a polymer that is resistant to degradation in vivo, such as a polymer resistant to homolytic cleavage of the polymer backbone. Some non-limiting examples of biostable materials may include medical grade silicone rubber, polyurethane, polyolefins such as polyethylene and polypropylene, polyamides, polyether ether ketone, and polyesters. Biostable materials are typically stable over the lifetime of the use of the device. Non-limiting examples of device lifetimes may include about 1 year for a glucose sensor and about 20 years for cardiac pacemaker leads.
As used herein, an “implantable medical device” refers to any type of appliance that is totally or partly introduced into a subject's body or by medical intervention into a natural orifice, and which is intended to remain in situ after the procedure. In some non-limiting examples, the duration of implantation may be essentially for the remaining lifespan of the subject. In other non-limiting examples, the duration of implantation may be temporary. For such temporary implantable medical devices, the lifetime of the implantable device may be limited by the anticipated degradation of the device in situ or its physical removal. Examples of implantable medical devices may include, without limitation, implantable cardiac pacemakers and defibrillators, leads and electrodes for such pacemakers/defibrillators, implantable organ stimulators (including but not limited to nerve, bladder, sphincter, and diaphragm stimulators), cochlear implants, prostheses, vascular grafts, self-expandable stents, balloon-expandable stents, stent-grafts, grafts, artificial heart valves, and cerebrospinal fluid shunts. In some embodiments, implantable medical devices may be administered in one or more of a vascular space, a peritoneal space, a portion of striated muscle, a portion of mucosal tissue, and an optical tissue. Additionally, implantable medical devices may be administered in a natural bodily cavity including intrauterine and rectal administration. In some embodiments, implantable medical devices may include breast and penile implants, cosmetic or reconstructive implants, devices for cell transplantation, drug delivery devices, and electrical signaling or delivery devices. It may be understood that an implantable medical device designed for the localized or systemic delivery of a biologically active agent may be within the scope of such implantable medical devices.
As used herein, the term “therapeutically effective amount” refers to a quantity sufficient to achieve a desired therapeutic and/or prophylactic effect. One non-limiting example of a therapeutically effective amount may include an amount that may result in the prevention of, or a decrease in, symptoms associated with an inflammation due to wound healing. A therapeutically effective amount of a composition administered to a subject may depend on the type and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight, genetic predisposition, and tolerance to drugs. The amount may also depend on the degree, severity, and type of disease. One having ordinary skill in the art will be able to determine appropriate dosages depending on these and other factors. The compositions may also be administered in combination with one or more additional therapeutic compounds. As one non-limiting example, a substitute vitreous material may be administered intravitreally in addition to a pharmaceutical material to a subject having one or more signs or symptoms of an ophthalmic condition. In another example, a “therapeutically effective amount” of an anti-inflammatory drug may be an amount at which the response to an inflammatory event or source of inflammation (e.g., an implanted medical device) may be at least ameliorated.
The term “subject” refers to any animal that can benefit from the administration of the disclosed devices. Thus, subjects may include, without limitation, one or more mammals such as a human, a primate, a dog, a cat, a horse, a cow, a pig, and a rodent. In some embodiments, the subject may be a human. The subjects may be normal, healthy subjects or subjects having, or at risk for developing, a particular biological disease or condition. By way of example only, the subject may be a subject having, or at risk for developing, a foreign body reaction upon implantation of a medical device.
As used herein, the term “biologically active agent” refers to a material that exhibits biological activity in an animal. In some embodiments, the biologically active agent may be composed of small molecules having a molecular weight of less than about 1500 g/mole. Among other non-limiting embodiments, a biologically active agent may include drugs, pro-drugs, vitamins, and cofactors. In still other non-limiting embodiments, a biologically active agent may include macro-molecules including, but not limited to, proteins, nucleic acids, macrolides, and other polymers.
As used herein, a “matrix material” refers to a biocompatible material that may be mixed or compounded with a biologically active agent to form a composition that may be used at least in part to form an implantable medical device. The matrix material may include any biologically compatible material including polymers. Such matrix materials may be used to control the delivery of the biologically active agent to the subject or may form a mechanical reservoir to locate the implantable medical device at a specific tissue site within the subject.
In an embodiment, a method of fabricating a biologically active agent delivery composition may include introducing a polymeric mixture into an extruder, introducing a biologically active agent into the extruder, solid-state shearing the polymeric mixture and the biologically active agent together in an initial zone of the extruder to yield the biologically active agent delivery composition, in which the initial zone has a temperature less than or equal to a liquefication temperature of the polymeric mixture, and dispensing the biologically active agent delivery composition in a particulate form from the extruder.
In an embodiment, a biologically active agent delivery composition may include a polymeric mixture and a biologically active agent, in which the biologically active agent delivery composition is a granular material having an average particle diameter less than or equal to about 100 μm, and is fabricated by a solid-state shearing device operating at least in part at a temperature less than or equal to a liquefication temperature of the polymeric mixture.
In an embodiment, a biologically active agent delivery device may include a biologically active agent delivery composition composed of a polymeric mixture and a biologically active agent, in which the biologically active agent delivery composition is a granular material having an average particle diameter less than or equal to about 100 μm, and is fabricated by a solid-state shearing device operating at least in part at a temperature less than or equal to a liquefication temperature of the polymeric mixture, and in which the biologically active agent delivery composition is fabricated into the biologically active agent delivery device configured for administration into a portion of a body.
In an embodiment, a method of fabricating a biologically active agent delivery device may include introducing a polymeric mixture into an extruder, introducing a biologically active agent into the extruder, solid-state shearing the polymeric mixture and the biologically active agent together in an initial zone of the extruder to yield the biologically active agent delivery composition, in which the initial zone has a temperature less than or equal to a liquefication temperature of the polymeric mixture, dispensing the biologically active agent delivery composition from the extruder, and fabricating the biologically active agent delivery device from the biologically active agent delivery composition.
In an embodiment, a system for fabricating a biologically active agent delivery composition may include at least one barrel section, at least one extrusion screw disposed within the at least one barrel section, a plurality of active elements disposed within the at least one barrel section, wherein the active elements are configured to be operated by the at least one extrusion screw, at least one feed chute configured to deliver one or more of a polymeric mixture and a biologically active agent into the at least one barrel section, and a temperature control system, in which the temperature control system is configured to maintain a temperature of one of more of the one or more barrel sections, the one or more extrusion screws, and the one or more active elements less than or equal to a liquefication temperature of the polymeric mixture.
As disclosed above, twin-screw extrusion (hereafter, “TSE”) techniques may be useful for processing homo-polymers, copolymers, and polymer blends. However, the conditions under which TSE processing may occur can limit its effectiveness for producing compositions and devices composed of one or more polymeric matrix materials and one or more biologically active agents. Solid-state shear pulverization (hereafter, “SSSP”) and solid-state melt-extrusion (hereafter, “SSME”) techniques, however, may achieve better dispersion of heterogeneous nucleating agents in homo-polymers compared to TSE processes. Such techniques may, therefore, be useful for forming well-dispersed compositions of biologically active agents in biocompatible polymeric matrix materials.
A polymeric matrix material may be composed of a polymeric mixture. In some embodiments, the polymeric mixture may be composed of one or more of a homo-polymer, a polymer blend, a combination of a polymer and a filler, and a combination of a polymer and a nanofiller. In some non-limiting examples, the polymeric mixture may be composed of one or more homo-polymers such as a polyolefin, a polyester, a polyamide, an epoxy, and an elastomer or a co-polymer of a polyolefin, a polyester, or a polyamide.
In other non-limiting examples, the polymeric mixture may be composed of a polymer and a filler, in which the filler may be composed of one or more of a cellulose material, a rice husk ash, a talc material, a silica material, a clay material, a modified clay material, a graphite material, a modified graphite material, a graphene, a single-walled carbon nanotube material, a multi-walled carbon nanotube material, and a contrast material for a biological imaging procedure such as barium sulfate. In other non-limiting examples, the polymeric mixture may be composed of a polymer and a nano-filler in which the nano-filler may be composed of one or more of a cellulose material, a rice husk ash, a talc material, a silica material, a clay material, a modified clay material, a graphite material, a modified graphite material, a graphene, a single-walled carbon nanotube material, and a multi-walled carbon nanotube material. Nano-fillers may be distinguished from fillers in that the nano-fillers may have particle sizes of about 1 nm to about 100 nm while fillers may have particle sizes of about 100 μm to about 1 cm. The amount of filler included in a polymeric mixture may range from about 0.001% by weight to about 99% by weight.
In some non-limiting embodiments, such polymeric matrix materials may include one or more biocompatible polymers. Non-limiting examples of such biocompatible polymeric matrix materials may include one or more of a polyolefin, a polyurethane, and a polyether ether ketone. Non-limiting examples of such biocompatible polyolefins may include high density polyethylene and polypropylene. In other non-limiting examples, the polymeric matrix material may be composed of a biocompatible polymer and a biocompatible filler. Non-limiting examples of such biocompatible fillers may include one or more of a cellulose material, a rice husk ash, a talc material, a silica material, a clay material, a modified clay material, a graphite material, a modified graphite material, a graphene, a single-walled carbon nanotube material, a multi-walled carbon nanotube material, and one or more contrast materials for biological imaging procedures, such as barium sulfate. In other non-limiting examples, the polymeric matrix material may be composed of a biocompatible polymer and a biocompatible nano-filler. Non-limiting examples of such biocompatible nano-fillers may include one or more of a cellulose material, a rice husk ash, a talc material, a silica material, a clay material, a modified clay material, a graphite material, a modified graphite material, a graphene, a single-walled carbon nanotube material, a multi-walled carbon nanotube material, and contrast materials for biological imaging procedures. Additional nano-fillers may include metal/metal-oxide nanoparticles having an average size of about 100 nm or less. Non-limiting examples of such metal/metal-oxide nanoparticles may include gold nanoparticles, silver nanoparticles, and titanium dioxide nanoparticles.
In some non-limiting embodiments, a biologically active agent may include one or more of a small organic molecule, a macro molecule, a biological co-factor, a peptide, a protein, and a nucleic acid. Non-limiting examples of such biologically active agents may include one or more of an anti-inflammatory agent, an angiogenic molecule, an anti-infective agent, an anesthetic, a growth factor, an adjuvant, a wound healing factor, a resorbable device component, an immunosuppressive agent, an antiplatelet agent, an anticoagulant, an ACE inhibitor, a cytotoxic agent, an anti-barrier cell compound, a vascularization compound, and an anti-sense nucleic acid. Non-limiting examples of anti-inflammatory agents that may be used may include one or more of steroidal agents (such as dexamethasone and prednisolone) and non-steroidal agents (such as acetyl salicylic acid, acetaminophen, ibuprofen, naproxen, and piroxicam). Non-limiting examples of angiogenic molecules may include one or more of sphingosine-1-phosphate and monobutyrin. Non-limiting examples of immunosuppressive agents may include one or more of cyclosporin A, and rapamycin and its derivatives such as CCI-779, RAD001, and AP23576. In some embodiments, the bioactive agent may include one or more of monobutyrin, S1P (sphingosine-1-phosphate), cyclosporin A, anti-thrombospondin-2, rapamycin (and its derivatives), and dexamethasone. In some non-limiting embodiments, the biologically active agent may be one or more of an anti-inflammatory agent and an angiogenic molecule. In some alternative embodiments, the bioactive agent may include one or more small bioactive molecules such as, but not limited to, monobutyrin.
Disclosed herein are compositions and devices for the delivery of one or more biologically active agents to a subject. Such delivery devices of biologically active agents may include implantable medical devices and wound dressings. Such implantable medical devices and wound dressings may include one or more biologically active agent delivery compositions. Further disclosed herein are biologically active agent delivery devices which may reduce or suppress adverse biological responses associated with implantable devices. In one aspect, the delivery devices may promote vascularization in tissues surrounding the implanted device. In another aspect, these compositions or devices can be designed to vary the rate of delivery of bioactive molecules with a change in the physiological environment surrounding the device. In one embodiment, a biologically active agent delivery device may be composed only of the biologically active agent delivery composition. In an alternative embodiment, such delivery devices may be composed of the composition as well as the matrix material alone. In yet another embodiment, such delivery devices may further include additional components or materials along with the composition and the matrix material. The devices and compositions disclosed herein can be used to deliver a wide variety of biologically active agents.
Many typical methods for fabricating such compositions may rely on heating the matrix material to a liquid or semi-liquid state, mixing biologically active agents with the melt, and then cooling the mixture to a solid state. Alternatively, the matrix material and biologically active agents may be co-dissolved in a solvent which then may be removed during processing. Such methods may not result in well-dispersed bioactive agents in the matrix. Solvent methods may require the use of solvents having high temperatures of vaporization to dissolve the matrix material. Solvent removal through evaporative means may thus require exposing the agents to temperatures that may degrade or destabilize the agents. Additionally, some matrix materials may only be dissolved at temperatures near their liquefication temperatures, thus exposing the biologically active agent to excessive temperatures. However, SSSP and SSME techniques may provide a method for solid admixture of one or more biologically active agents with one or more polymeric matrix materials to form the biologically active composition that may overcome at least some of these limitations.
SSSP techniques alone may result in the temperature of the one or more matrix materials rising above their liquefication temperatures. Such heating may result from the mechanical action of the pulverizing and mixing elements on the matrix material thereby leading to frictional heating to temperatures above the liquefication temperatures of the matrix materials. If the biocompatible polymers become heated above their liquefication temperatures, they may form a melt in which the one or more biologically active agents may be poorly dispersed. Thus, temperature control of the solid state pulveriving systems may be used to maintain all of the components of the system at or below the liquefication temperature of the polymer matrix materials.
Non-limiting examples of the active elements of the extrusion screw 120 may include one or more transport elements 122, mixing elements 124, and pulverizing elements 126, 128. The order, number, or type of the active elements along the extrusion screw 120 may not be limited to the configuration as depicted in
The starting materials, once introduced into the solid-state shear pulverization system, may travel continuously along the length of the enclosure 100 due to the continuous rotation of the extrusion screw 120 and its effects on the active elements 122, 124, 126, 128. The final biologically active agent delivery composition may be delivered by the extrusion screw 120 to a die end configured to dispense the final particulate composition. In this manner, the biologically active agent delivery composition may be continuously processed from introduction of the starting materials into the screw extruder to the receipt of the final particulate composition. Along the length of the extrusion screw 120, the initial mixture of materials may be subjected to mixing, grinding, and pulverizing forces generated by the mixing elements 124, pulverizing elements 126, 128, or other elements as required to achieve the required blending of materials and sizing of the final particulate material.
Although
The enclosure 100 may be divided into effective work zones, as depicted in
It may be understood that the starting materials may be introduced into the SSSP via one or more feed chutes 110 that may deliver all the starting materials into one work zone. Alternatively, some of the starting materials, such as the polymer matrix material, may be introduced in one work zone such as Zone 1, while other starting materials, such as the biologically active agent, may be introduced in a different work zone such as Zone 2.
Work zones Zone 1-Zone 6 may also be defined functionally in terms of their operating temperatures or the mechanical processes occurring therein. Non-limiting examples of such work zones may have physical embodiments as barrel sections (for example, 115). Barrel sections 115 may be composed of segments of metal or other materials that physically surround one or more sections of the extruder screw 120 and one or more active elements such as mixing elements 124. In one non-limiting example, the enclosure 100 may be composed of one or more barrel sections 115 linked together. In another non-limiting example, the one or more barrel sections 115 may be separate structural elements contained within the enclosure 100. The one or more barrel sections 115 may be composed of any suitable material including, without limitation, stainless steel, aluminum, iron, high carbon steel, tempered steel, and surface-hardened metals.
It may be understood that the configuration of the extruder screw 120 and the active elements as disclosed in
As disclosed above, frictional heating of the composition during processing may lead to the mixture being heated to or above a liquefication temperature of at least some component of the mixture, such as a polymeric matrix material. Such frictional heating and liquefication may result in inhomogeneous mixing of the polymeric matrix material and the biologically active agent. Thus, in one embodiment, the temperature of the at least one extrusion screw 120 of the extruder may be controlled to remove at least some of the friction-induced heat from the composition. In one non-limiting embodiment, the temperature of the at least one extrusion screw 120 may be maintained at a temperature less than or equal to the liquefication temperature of the polymeric matrix material. Table I presents exemplary polymeric matrix materials and their liquefication temperatures.
In some non-limiting examples, the temperature of at least one portion of the at least one extrusion screw 120 may be maintained at a temperature of about 35° F. to about 45° F. (about 1.7° C. to about 7.2° C.). Some non-limiting examples of temperatures at which the at least one portion of the at least one extrusion screw 120 may be maintained may include a temperature of about 35° F. (about 1.7° C.), about 37° F. (about 2.8° C.), about 39° F. (about 3.9° C.), about 40° F. (about 4.4° C.), about 42° F. (about 5.6° C.), about 44° F. (about 6.7° C.), about 45° F. (about 7.2° C.), or ranges between any two of these values including endpoints. As one example, the one or more extrusion screw 120 may be maintained at a temperature of about 40° F. (about 4.4° C.). Because the polymeric matrix materials may not have high thermal conductivity, the extrusion screw 120 may be maintained at temperatures significantly lower than the liquefication temperature of the biocompatible matrix material in order to maintain the matrix material in a solid state. For example, it may be necessary to maintain the extrusion screw 120 temperature at about 12° F. (about −11° C.) in order to maintain the polymeric materials at about 38° F. (about 3.3° C.) during the manipulation steps of the extruder.
It may be understood that the material in any of the one or more work zones or barrel sections 115 in an SSSP device as illustrated in
The granular form of the biologically active agent delivery composition produced under the conditions disclosed above may have particle sizes less than about 1 μm. In some non-limiting examples, the particulates composed of the polymer matrix material may be about 1 μm or less. In some non-limiting examples, the particulates composed of the biologically active agent may be about 1 μm or less. In other non-limiting examples, the particulates composed of the biologically active agent may be about 100 nm or less. In still other non-limiting examples, the particulates composed of the biologically active agent may be about 10 nanometers or less. In general, the biologically active agent delivery composition may be composed of particulates of the biologically active agent evenly dispersed throughout the composition and not aggregated in clumps.
Non-limiting examples of the active elements of the extrusion screw 220 may include one or more transport elements 222, pulverizing elements 224, kneading elements 226, and mixing elements 228. The order, number, or type of the active elements along the extrusion screw 220 may not be limited to the configuration as depicted in
Although
The enclosure 200 in which the one or more extrusion screws 220 are housed may be divided into effective work zones, as depicted in
While the SSSP process produces particulate material, the SSME process incorporates an additional melt extrusion step. Consequently, the SSME extruder depicted in
Work zones Zone 1-Zone 6 may be defined functionally in terms of their operating temperatures or the mechanical processes occurring therein. Non-limiting examples of such work zones may have physical embodiments as barrel sections (for example, 215). Barrel sections 215 may be composed of segments of metal or other materials that may physically surround one or more sections of the extruder screw 220 and one or more active elements such as pulverizing elements 224. In one non-limiting example, the enclosure 200 may be composed of one or more barrel sections 215 linked together. In another non-limiting example, the one or more barrel sections 215 may be separate structural elements contained within the enclosure 200. The one or more barrel sections 215 may be composed of any suitable material including, without limitation, stainless steel, aluminum, iron, high carbon steel, tempered steel, and surface-hardened metals.
It may be understood that the configuration of the extruder screw 220 and the active elements as disclosed in
As disclosed above, frictional heating of the combination of one or more biocompatible polymer materials and one or more biologically active agents during processing may lead to the mixture being heated to or above a liquefication temperature of at least some component of the combination. Such frictional heating and liquefication may result in inhomogeneous mixing of the one or more biologically active agents into the biocompatible polymer material during pulverization. In one non-limiting embodiment, the temperature of one or more portions of the at least one extrusion screw 220 having active elements that may pulverize the starting material (for example, in one or more initial zones such as Zone 2 and Zone 3) may be maintained at a temperature less than or equal to the liquefication temperature of the biocompatible polymer material. In some non-limiting examples, the temperature of the one or more portions of the at least one extrusion screw 220 having active elements to pulverize the starting material may be maintained at a temperature of about 35° F. to about 45° F. (about 1.7° C. to about 7.2° C.). Some non-limiting examples of temperatures at which at least one portion of the at least one extrusion screw 220 may be maintained may include a temperature of about 35° F. (about 1.7° C.), about 37° F. (about 2.8° C.), about 39° F. (about 3.9° C.), about 40° F. (about 4.4° C.), about 42° F. (about 5.6° C.), about 44° F. (about 6.7° C.), about 45° F. (about 7.2° C.), or ranges between any two of these values including endpoints.
Similarly, the temperature of one or more portions of the at least one extrusion screw 220 having active elements to mix or knead the melted biologically active agent delivery composition (for example, in one or more heating zones such as Zone 5 and Zone 6) may be maintained at a temperature greater than or equal to the liquefication temperature of the biocompatible polymer material. In some non-limiting examples, the temperature of one or more portions of the at least one extrusion screw 220 having active elements to mix or knead the melted particulate biologically active agent delivery composition may be maintained at a temperature of about 90° F. to about 500° F. (about 32° C. to about 260° C.). Some non-limiting examples of temperatures at which the at least one extrusion screw 220 may be maintained to mix or knead the melted polymer mixture may include a temperature of about 90° F. (about 32° C.), about 199° F. (about 93° C.), about 250° F. (about 121° C.), about 300° F. (about 149° C.), about 351° F. (about 177° C.), about 399° F. (about 204° C.), about 450° F. (about 232° C.), about 500° F. (about 260° C.), or ranges between any two of these values including endpoints. In other non-limiting examples, the melted composition may be maintained at a temperature just sufficient to cause phase melting of the polymer matrix.
It may be understood that temperature control, such as cooling, of the polymeric matrix materials, bioactive agents, and filler materials, either separately or in any combination throughout the manipulations by the screw extrusion device may be accomplished by any appropriate means.
Cooling may be accomplished by cooling one or more portions of the extrusion screw according to the type of manipulation of the material contacting the extrusion screw (for example, in one or more initial zones such as Zone 2 and Zone 3 in
It may be understood that the one or more portions of the enclosure 100, 200, extrusion screw 120, 220, barrel sections 115, 250, and active elements 124, 126, 128, 224, 226, and 228, may be controlled to have any appropriate temperature such as a temperature at or below a liquefication temperature of one or more components of the polymer matrix materials. It may further be understood that each of the one or more portions of the enclosure 100, 200, extrusion screw 120, 220, barrel sections 115, 215, and active elements 124, 126, 128, 224, 226, and 228, may be controlled to have about the same temperature or a different temperature. In some non-limiting examples, the one or more portions of the enclosure 100, 200, extrusion screw 120, 220, barrel sections 115, 215, and active elements 124, 126, 128, 224, 226, and 228, may be controlled to have a temperature less than or equal to about 40° C. In some other non-limiting examples, the one or more portions of the enclosure 100, 200, extrusion screw 120, 220, barrel sections 115, 215, and active elements 124, 126, 128, 224, 226, and 228, may be controlled to have a temperature of about 35° C. to about 45° C.
With respect to SSME processing, heating of the particulate form of the biologically active agent delivery composition may be accomplished by heating one or more portions of the extrusion screw according to the type of manipulation of the polymeric material contacting the extrusion screw (for example, in one or more heating zones such as Zone 5 and Zone 6 in
A biologically active agent delivery device may be fabricated from the biologically active agent delivery composition. Fabrication methods may include those best suited for the type of delivery device and the form of the delivery composition. In one non-limiting example, a delivery composition may be fabricated as a fine particulate material having an average particle diameter of about 1 μm to about 10 μm. Some non-limiting examples an average particle diameter may include a diameter of about 1 μm, about 2 μm, about 3 μm, about 4 μm, about 5 μm, about 6 μm, about 7 μm, about 8 μm, about 9 μm, about 10 μm, or ranges between any two of these values including endpoints.
Such particulate forms of the delivery composition may be fabricated into a delivery device using any useful fabrication techniques including, without limitation, one or more of melt extrusion techniques, injection molding techniques, and compression molding techniques. Delivery devices fabricated from the particulate form of delivery compositions may have any useful form including, without limitation, a ring, a pill, a tube, a multilumen tube, a straight cylinder, and a curved cylinder. Alternatively, particulate forms of the delivery composition may be included directly in wound dressings such as sponges, bandages, gauzes, and similar structures used on superficial wounds. In another non-limiting example, the particulate form of the biologically active agent delivery composition may be compounded with a liquid carrier for injection into a body such as, for example, for intraperitoneal injection. Such particulate forms of active agent delivery compositions may further be incorporated into a variety of implanted biomedical devices including, without limitation, stents, internal sutures, intrauterine devices, and electrostimulation leads.
Table II presents non-limiting examples of compositions of polymeric matrix materials and biologically active agents that may be used according to the methods disclosed herein (values presented as weight percent of a total combination).
Solid-state shear pulverization (SSSP) was performed using an intermeshing, co-rotating twin screw extruder with a diameter (D) of about 25 mm and a length to diameter ratio (L/D) of about 34. The screws were modular in nature and designed as a combination of spiral conveying and bilobe kneading/pulverization elements. For the SSSP apparatus, all of the barrels were continuously cooled by recirculating ethylene glycol/water (60/40 vol/vol) mixture maintained at about −12° C. Polymers, fillers, and/or biologically active agents were delivered to the extruder using constant volume feeders. The barrel sections of the extruder included several kneading elements in an upstream portion of the screws termed the mixing zone. The material exited the mixing zone through a conveying zone that allowed the sheared material to cool before being pulverized downstream in a pulverization zone.
For the SSME apparatus, the barrel temperature was customized to create three distinct zones along the length of the barrel. Zone 1, spanning the beginning length having a L/D ratio of about 16, was designed for solid-state pulverization. This portion of the barrel was continuously cooled at about −12° C. by a circulating ethylene glycol/water mixture. Zone 2 (having an L/D ratio of about 6) included an intermediate barrel maintained at a temperature of about 21° C., where the materials transitioned from the solid-state to a melted-state. Finally, Zone 3 (having an L/D ratio of about 12) included the melt extrusion zone wherein the barrel was heated to about 204° C. by standard cartridge-type electrical heaters. The system incorporated spiral transporting elements (having an L/D ratio of about 8.5) and bilobe kneading elements (having an L/D ratio of about 7.5) in Zone 1, all spiral transporting elements in Zone 2, and spiral transporting elements (having an L/D ratio of about 8.3) and bilobe shearing and mixing elements (having an L/D ratio of about 3.7) in Zone 3. The screw rotation speed was maintained constant at about 200 rpm for set ups.
The present disclosure is not to be limited in terms of the particular embodiments described in this application, which are intended as illustrations of various aspects. Many modifications and variations can be made without departing from its spirit and scope, as will be apparent to those skilled in the art. Functionally equivalent methods and apparatuses within the scope of the disclosure, in addition to those enumerated in this disclosure, will be apparent to those skilled in the art from the foregoing descriptions. Such modifications and variations are intended to fall within the scope of the appended claims. The present disclosure is to be limited only by the terms of the appended claims, along with the full scope of equivalents to which such claims are entitled. It is to be understood that this disclosure is not limited to particular methods, reagents, compounds, or compositions, which can, of course, vary. It is also to be understood that the terminology used in this disclosure is for the purpose of describing particular embodiments only, and is not intended to be limiting.
With respect to the use of substantially any plural and/or singular terms in this disclosure, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth in this disclosure for sake of clarity.
It will be understood by those within the art that, in general, terms used in this disclosure, and especially in the appended claims (for example, bodies of the appended claims) are generally intended as “open” terms (for example, the term “including” should be interpreted as “including but not limited to,” the term “having” should be interpreted as “having at least,” the term “includes” should be interpreted as “includes but is not limited to,” etc.). While various compositions, methods, and devices are described in terms of “comprising” various components or steps (interpreted as meaning “including, but not limited to”), the compositions, methods, and devices can also “consist essentially of” or “consist of” the various components and steps, and such terminology should be interpreted as defining essentially closed-member groups.
It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such an intent will be explicitly recited in the claim, and in the absence of such recitation no such intent is present. For example, as an aid to understanding, the following appended claims may contain usage of the introductory phrases “at least one” and “one or more” to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles “a” or “an” limits any particular claim containing such introduced claim recitation to embodiments containing only one such recitation, even when the same claim includes the introductory phrases “one or more” or “at least one” and indefinite articles such as “a” or “an” (for example, “a” and/or “an” should be interpreted to mean “at least one” or “one or more”); the same holds true for the use of definite articles used to introduce claim recitations. In addition, even if a specific number of an introduced claim recitation is explicitly recited, those skilled in the art will recognize that such recitation should be interpreted to mean at least the recited number (for example, the bare recitation of “two recitations,” without other modifiers, means at least two recitations, or two or more recitations). Furthermore, in those instances where a convention analogous to “at least one of A, B, and C, etc.” is used, in general such a construction is intended in the sense one having skill in the art would understand the convention (for example, “a system having at least one of A, B, and C” would include but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims, or drawings, should be understood to contemplate the possibilities of including one of the terms, either of the terms, or both terms. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.”
As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed in this disclosure also encompass any and all possible subranges and combinations of subranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed in this disclosure can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. From the foregoing, it will be appreciated that various embodiments of the present disclosure have been described for purposes of illustration, and that various modifications may be made without departing from the scope and spirit of the present disclosure. Accordingly, the various embodiments disclosed are not intended to be limiting, with the true scope and spirit being indicated by the following claims.
This application claims benefit of and priority to U.S. Provisional Application No. 61/890,185 entitled “Method to Prepare Drug Delivery Systems using Solid-State Shear Pulverization or Solid-State Melt Extrusion” filed Oct. 12, 2013, the disclosure of which is incorporated by reference herein in its entirety.
| Number | Date | Country | |
|---|---|---|---|
| 61890185 | Oct 2013 | US |
