Patent Application
20080152694
It is well known that drugs work most efficiently in the body of a human or animal if they are delivered locally where needed. When delivered systemically there is a much greater chance for side effects, as all tissues are exposed to large quantities of the drug. However, if the affected area is inside the body, localized drug delivery presents challenges. Local delivery to tissues located in anatomically difficult areas often requires a specialized injection device. This is especially true for injections into the eye.
Many treatments of ocular diseases rely on topical application of solutions (in drops) to the surface of the eye. The usefulness of topical drug application is limited by the significant flux barrier provided by the corneal epithelium and the rapid and extensive pre-corneal loss that occurs as a result of drainage and tear fluid turnover. It has been estimated that typically less than 5% of a topically applied drug permeates the cornea.
Although delivery of high concentrations of drugs as topical formulations has proven to be effective, the delivery of therapeutic doses of drugs to the tissues in the posterior segment of the eye remains a significant challenge. There are numerous diseases affecting the posterior segment, including age-related macular degeneration, diabetic retinopathy, glaucoma, and retinitis pigmentosa. Intravitreal injections provide the most direct approach to delivering drugs to the tissues of the posterior segment and for achieving therapeutic tissue drug levels. However, repeat injections are often required. Most patients would find such injections to be quite unpleasant. Repeat injections may also cause side effects such as retinal detachment, hemorrhage, endophthalmitis and cataract. Repeat injections also increase the potential for infections.
This Summary is provided to introduce a selection of concepts in a simplified form that are further described below in the Detailed Description. This Summary is not intended to identify key features or essential features of the claimed subject matter, nor is it intended to be used as an aid in determining the scope of the claimed subject matter.
In at least some embodiments, a device for delivering drugs to the eye includes components such as a pump, filters and a fluid carrying system. Devices according to at least some embodiments can be used to deliver multiple bolus doses or continuous infusions of drugs to the eye over a longer period of time such as, but not limited to, a few days.
Some embodiments of the invention include implantable drug delivery systems which can be used for targeted delivery of drugs to the eye. Using such systems, small volumes of drugs can be delivered to the eye, either intermittently or continuously, on a short-term or a long-term (e.g., several months or years) basis. In some embodiments, an implanted osmotic pump contains solid or liquid drug (or is in fluid communication with a drug/filter capsule) and delivers drug through a catheter and a needle or other terminal component implanted in an eye.
Both solid and liquid drug formulations can be used. In embodiments using solid drugs, a separate drug vehicle can be used to entrain a portion of a solid drug mass contained in port reservoir or a drug-holding capsule. Examples of vehicles include, but are not limited to, saline, Ringer's solution, Ringer's lactate, artificial vitreous humor, and/or any other vehicle compatible with injection into the anterior chamber and/or posterior segment of the eye or otherwise into ocular tissue. The vehicle is then delivered to the eye or other ocular tissue via an implanted catheter.
The foregoing summary of the invention, as well as the following detailed description of certain embodiments, is better understood when read in conjunction with the accompanying drawings, which are included by way of example and not by way of limitation.
Described herein are at least some embodiments of systems, devices and methods for ophthalmic delivery of drugs, i.e., to delivery of drugs to ocular tissue(s). As used herein, “ocular tissue” refers to the eye, including tissues within the sclera (e.g., the retina) and outside the sclera (e.g., ocular muscles within the orbit). “Ocular tissue” also includes tissues neurologically connected to (but distinct from) the eye, such as the optic nerve, the geniculate nucleus and the visual cortex. Some embodiments include a subcutaneous pump (such as an osmotic pump) and reservoir attached to a catheter. A terminal component is attached to (or is part of) the catheter and is the element from which a drug is released into the eye. In some cases, a terminal component is a soft tissue catheter (e.g., a small-diameter flexible polymeric tube made from, e.g., polyimide, a fluoropolymer, silicone, polyurethane or PVC) which passes through an incision in the sclera and injects fluid into specific regions within the inner eye. In some embodiments (e.g., short term treatment of an acute condition), the terminal component may be a needle. Depth and location of insertion of a terminal component depends on which region is being targeted in the eye or other ocular tissue. The catheter or needle may have an insertion stop which controls the depth of insertion. In most cases, the terminal component may be implanted so as to minimize interference with eye movement. One possible location for an incision to insert a terminal component is in the pars plana. Possible locations for terminating a catheter for drug delivery may be in the vitreous or in the anterior chamber, allowing drugs to be delivered in controlled doses to a precise area of the eye. The terminal end of the catheter may be fixed, for example via suture, surgical tack, a tissue adhesive, or a combination thereof, to tissue near the outer surface of the eye. When attached, the catheter does not affect or otherwise restrict movement of the eye. The pump may be secured in a cavity that has been drilled out by a physician. Such a cavity may be located under the scalp on the mastoid bone or in another location closer to the eye. A drug delivering catheter may lead to the eye or other ocular tissue through a hole drilled in the bone next to the eye.
A terminal component can be implanted within the eyeball or in locations outside the sclera (e.g., behind the eyeball but within the orbit). In some embodiments, most or all of the injection device (including an osmotic pump or other type of fluid moving device) is implanted. Various embodiments could include implantation of all of the injection device in conjunction with a retinal implant. A drug delivery catheter from a pump and reservoir could be bundled together with the wires from an electronic package for a retinal implant so as to avoid the necessity of a second puncture of the eyeball to deliver a desired amount of drug. If desired, however, a terminal component could be installed in one location and a retinal implant installed in a different location within the same eye.
In treating disorders of the optic nerve or neurological pathways from the retina to the visual cortex, the terminal component may be placed in a location between the retina and visual cortex, such as the geniculate nucleus, or in the visual cortex itself. Placement of the drug-releasing terminal component will depend on the tissue in greatest need of treatment and can differ from one patient to another. Placement outside of the eye could be to deliver drugs to the optic nerve or neurons involved in vision that have been affected by diseases or injury (such as trauma, including surgical trauma), vein occlusion or ischemia, diabetic neuropathy, or neurodegeneration due to other causes.
In some embodiments, the drug delivery system may be combined with another type of ocular electrode, with another type of retinal vision prosthesis, etc. As with a retinal implant, a drug delivery catheter could be bundled with the wires from an electronics package for the electrode or other device, thereby minimizing trauma to the eye and enabling delivery of drug near the co-implanted device.
The following description is generally organized into several parts. Part I generally discusses at least some of the ocular conditions that can be treated according to various embodiments, as well as examples of drugs that can be used. Part II generally discusses devices that can be used to deliver drugs to ocular tissue according to at least some embodiments. Several examples follow part II.
Devices such as are described herein can be used to ameliorate numerous disorders affecting the eye. Such disorders include, but are not limited to, ocular infections, inflammatory diseases, neoplastic diseases, and degenerative disorders. Listed in Table 1 are some of the conditions which are believed to be treatable using systems, devices and/or methods such as are described herein.
Drug delivery devices according to at least some embodiments can be used to deliver one or more drugs to a particular target site so as to treat one or more of the conditions listed in Table 1 and/or to treat other conditions. The drug can be in solid, liquid or gel form. As used herein, the term “drug” includes any natural or synthetic, organic or inorganic, physiologically or pharmacologically active substance capable of producing a localized or systemic prophylactic and/or therapeutic effect when administered to an animal or human. A drug includes (i) any active drug, (ii) any drug precursor or pro-drug that may be metabolized within an animal or human to produce an active drug, (iii) combinations of drugs, (iv) combinations of drug precursors, (v) combinations of a drug with a drug precursor, and (vi) any of the foregoing in combination with a pharmaceutically acceptable carrier, excipient(s), slowly-releasing delivery system or formulating agent. As used herein, the term “drug” also includes, but is not limited to, any of one or more of the substances listed in Table 2.
Additional examples are provided herein.
Many ophthalmic diseases and disorders are associated with one or more of angiogenesis, inflammation and degeneration. To treat these and other disorders, devices according to at least some embodiments permit delivery of anti-angiogenic factors; anti-inflammatory factors; factors that retard cell degeneration, promote cell sparing, or promote cell growth; and combinations of the foregoing. Using devices described and/or information provided herein, and based on the indications of a particular disorder, one of ordinary skill in the art can administer any suitable drug (or combination of drugs), such as the drugs described herein, at a desired dosage.
Any suitable biologically active molecules (“BAMs”) may also be delivered according to the devices, systems, and methods of this invention. Such molecules include, but are not limited to, antibodies, cytokines, enzymes, hormones, lymphokines, neuroprotective agents, neurotransmitters, and neurotrophic factors, as well as active fragments and derivatives of the foregoing. At least four types of BAMs are contemplated for delivery using devices according to at least some embodiments: (1) anti-angiogenic factors (2) anti-inflammatory factors, (3) factors that retard cell degeneration (anti-apoptosis agents), promote cell sparing or promote cell growth and (4) neuroprotective agents.
Angiogenesis inhibitors are compounds that reduce or inhibit the formation of new blood vessels in a mammal, and may be useful in the treatment of certain ocular disorders associated with neovascularization. Examples of useful angiogenesis inhibitors include, but are not limited to, the substances listed in Table 3.
As used herein, “bioactive fragments” refer to portions of an intact protein that have at least 30%, at least 70%, or at least 90% of the biological activity of the intact proteins. “Analogs” refer to species and allelic variants of the intact protein, or amino acid replacements, insertions or deletions thereof that have at least 30%, at least 70%, or at least 90% of the biological activity of the intact protein.
Diabetic retinopathy is characterized by angiogenesis. At least some embodiments contemplate treating diabetic retinopathy by implanting devices delivering one or more anti-angiogenic factors either intraocularly, preferably in the vitreous, or periocularly, preferably in the sub-Tenon's region. It may also be desirable to co-deliver one or more neurotrophic factors either intraocularly, periocularly, and/or intravitreally.
Several cytokines including bioactive fragments thereof and analogs thereof have also been reported to have anti-angiogenic activity and thus may be delivered using devices according to one or more embodiments. Examples include, but are not limited to, IL-12 (which reportedly works through an IFN-γ-dependent mechanism) and IFN-α (which has been shown to be anti-angiogenic alone or in combination with other inhibitors). The interferons IFN-α, IFN-β and IFN-γ reportedly have immunological effects, as well as anti-angiogenic properties, that are independent of their anti-viral activities.
Anti-angiogenic factors contemplated for use in at least some embodiments include, but are not limited to, angiostatin, anti-integrins, bFGF-binding molecules, endostatin, heparinase, platelet factor 4, vascular endothelial growth factor inhibitors (VEGF-inhibitors) and vasculostatin. The use of VEGF receptors Flt and Flk is also contemplated. When delivered in the soluble form these molecules compete with the VEGF receptors on vascular endothelial cells to inhibit endothelial cell growth.
VEGF inhibitors contemplated for use in at least some embodiments include, but are not limited to, VEGF-neutralizing chimeric proteins such as soluble VEGF receptors. In particular, one set of examples includes VEGF-receptor-IgG chimeric proteins. Another VEGF inhibitor contemplated for use in at least some embodiments is antisense phosphorothioate oligodeoxynucleotides (PS-ODNs).
It is contemplated that useful angiogenesis inhibitors, if not already known, may be identified using a variety of assays well known and used in the art. Such assays include, for example, the bovine capillary endothelial cell proliferation assay, the chick chorioallantoic membrane (CAM) assay or the mouse corneal assay.
Uveitis involves inflammation. At least some embodiments contemplate treating uveitis by intraocular, vitreal or anterior chamber implantation of devices releasing one or more anti-inflammatory factors. Anti-inflammatory factors contemplated for use in at least some embodiments include, but are not limited to, alpha-interferon (IFN-α), antiflammins, beta-interferon (IFN-β), glucocorticoids and mineralocorticoids from adrenal cortical cells, interleukin-10 (IL-10) and TGF-β. Certain BAMs may have more than one activity. For example, it is believed that IFN-α and IFN-β may have activities as both anti-inflammatory molecules and as anti-angiogenic molecules.
Retinitis pigmentosa is characterized by retinal degeneration. At least some embodiments contemplate treating retinitis pigmentosa by intraocular or vitreal placement of devices secreting one or more neurotrophic factors.
Age-related macular degeneration (wet and dry) involves both angiogenesis and retinal degeneration. At least some embodiments contemplate treating this disorder by using one or more of the herein-described devices to deliver one or more neurotrophic factors intraocularly, preferably to the vitreous, and/or one or more anti-angiogenic factors intraocularly or periocularly, preferably periocularly, most preferably to the sub-Tenon's region.
Factors contemplated for use in retarding cell degeneration, promoting cell sparing, or promoting new cell growth are collectively referred to herein as “neurotrophic factors.” Neurotrophic factors contemplated for use in at least some embodiments include, but are not limited to, acidic fibroblast growth factor (aFGF), basic fibroblast growth factor (bFGF), bone morphogenic proteins (BMP-1, BMP-2, BMP-7, etc.), brain-derived neurotrophic factor (BDNF), cardiotrophin-1 (CT-1), ciliary neurotrophic factor (CNTF), cytokines (such as IL-6, IL-10, CDF/LIF, and IFN-β), EGF, the family of transforming growth factors (including, e.g., TGFβ-1, TGF β-2, and TGF β-3), glial cell line derived neurotrophic factor (GDNF), the hedgehog family (sonic hedgehog, indian hedgehog, and desert hedgehog, etc.), heregulins, insulin-like growth factor-1 (IGF-1), interleukin 1-β (IL1-β), neuregulins, neurotrophin 3 (NT-3), neurotrophin 4/5 (NT-4/5), neurturin, nerve growth factor (NGF), PDGF, TGF-alpha. The preferred neurotrophic factors are GDNF, BDNF, NT-4/5, neurturin, CNTF, and CT-1.
Use of modified, truncated, and mutein forms of the above-mentioned molecules is also contemplated in at least some embodiments. Further, use of active fragments of these growth factors (i.e., those fragments of growth factors having biological activity sufficient to achieve a therapeutic effect) is also contemplated. Also contemplated is use of growth factor molecules modified by attachment of one or more polyethylene glycol (PEG) or other repeating polymeric moieties. Use of combinations of these proteins and polycistronic versions thereof is also contemplated.
Glaucoma is characterized by increased ocular pressure and loss of retinal ganglion cells. Treatments for glaucoma contemplated in at least some embodiments include delivery of one or more neuroprotective agents that protect cells from excitotoxic damage. Such agents include, but are not limited to, cytokines, N-methyl-D-aspartate (NMDA) antagonists and neurotrophic factors. These agents may be delivered intraocularly, preferably intravitreally. Gacyclidine (GK11) is an NMDA antagonist and is believed to be useful in treating glaucoma and other diseases where neuroprotection would be helpful or where there are hyperactive neurons. Additional compounds with useful activity are D-JNK-kinase inhibitors.
The term “drug” includes neuroprotective agents, i.e., agents capable of retarding, reducing or minimizing the death of neuronal cells. Neuroprotective agents may be useful in the treatment of various disorders associated with neuronal cell death (e.g., diabetic retinopathy, glaucoma, macular degeneration (wet and dry), retinitis pigmentosa, etc.). Examples of neuroprotective agents that may be used in at least some embodiments include, but are not limited to, apoptosis inhibitors, cAMP elevating agents, caspase inhibitors, neurotrophic factors and NMDA antagonists (such as gacyclidine and related analogs). Exemplary neurotrophic factors include, but are not limited to, the following: Brain Derived Growth Factor and bioactive fragments and analogs thereof, cytokine-associated neurotrophic factors; Fibroblast Growth Factor and bioactive fragments and analogs thereof, Insulin-like Growth Factors (IGF) and bioactive fragments and analogs thereof (e.g., IGF-I and IGF-II); and Pigment Epithelium Derived Growth Factor and bioactive fragments and analogs thereof. Exemplary cAMP elevating agents include, but are not limited to, the following: 8-(4-chlorophenylthio)-adenosine-3′:5′-cyclic-monophosphate (CPT-cAMP), 8-bromo-cAMP, dibutyryl-cAMP and dioctanoyl-cAMP, cholera toxin, forskolin and isobutyl methylxanthine. Exemplary caspase inhibitors include, but are not limited to, the following: caspase-1 inhibitors (e.g., Ac-N-Me-Tyr-Val-Ala-Asp-aldehyde; SEQ ID NO:1); caspase-2 inhibitors (e.g., Ac-Val-Asp-Val-Ala-Asp-aldehyde; SEQ ID NO:2); caspase-3 inhibitors (e.g., Ac-Asp-Glu-Val-Asp-aldehyde; SEQ ID NO:3); caspase-4 inhibitors (e.g., Ac-Leu-Glu-Val-Asp-aldehyde; SEQ ID NO:4); caspase-6 inhibitors (e.g., Ac-Val-Glu-Ile-Asp-aldehyde; SEQ ID NO:5); caspase-8 inhibitors (e.g., Ac-Asp-Glu-Val-Asp-aldehyde; SEQ ID NO:6); and caspase-9 inhibitors (e.g., Ac-Asp-Glu-Val-Asp-aldehyde; SEQ ID NO:7). Each of the aforementioned caspase inhibitors can be obtained from Bachem Bioscience Inc., PA or Peptides International, Inc., Louisville, Ky.
Devices according to at least some embodiments may be useful in the treatment of a variety of other ocular disorders. For example, a drug delivery device may deliver an anti-infective agent, such as an antibiotic, anti-viral agent or anti-fungal agent, for the treatment of an ocular infection. Similarly, a device may deliver a steroid, for example, hydrocortisone, dexamethasone sodium phosphate or methylprednisolone acetate, for the treatment of an inflammatory disease of the eye. A device may be used to deliver a chemotherapeutic or cytotoxic agent, for example, methotrexate, chlorambucil, cyclosporine, or interferon, for the treatment of an ocular neoplasm. Furthermore, a device may be useful in delivering one or more drugs for the treatment of certain degenerative ocular disorders. Additional examples of such drugs include, but are not limited to, the substances listed in Table 4.
As used herein, an antagonist may comprise, without limitation, an antibody, an antigen binding portion of an antibody, a biosynthetic antibody binding site that binds a particular target protein (e.g., ICAM-1), or an antisense molecule that hybridizes in vivo to a nucleic acid encoding a target protein or a regulatory element associated therewith. An antagonist may also comprise a ribozyme, aptamer, or small molecule that binds to and/or inhibits a target protein (e.g., ICAM-1) or that binds to and/or inhibits, reduces or otherwise modulates expression of nucleic acid encoding a target protein (e.g., ICAM-1).
At least some embodiments may be useful for the treatment of ocular neovascularization, a condition associated with many ocular diseases and disorders and accounting for a majority of severe visual loss. For example, contemplated is treatment of retinal ischemia-associated ocular neovascularization, a major cause of blindness in diabetes and many other diseases; corneal neovascularization, which predisposes patients to corneal graft failure; and neovascularization associated with diabetic retinopathy, central retinal vein occlusion, and possibly age-related macular degeneration.
At least some embodiments may also be used to treat ocular symptoms resulting from diseases or conditions that have both ocular and non-ocular symptoms. Examples include, but are not limited to, AIDS-related disorders such as cytomegalovirus retinitis and disorders of the vitreous, pregnancy-related disorders such as hypertensive changes in the retina, and ocular effects of various infectious diseases (e.g., cyst cercosis, fungal infections, Lyme disease, opthalmonyiasis, parasitic disease, syphilis, toxocara canis, tuberculosis, etc.).
Drugs may be introduced into a cavity of the eye (or to other ocular tissues) either in pure form or as a formulation, for example, in combination with a pharmaceutically acceptable carrier or encapsulated within a release system. The drugs can be homogeneously or heterogeneously distributed within the release system. A variety of release systems may be useful in the practice of the invention, however, the choice of the appropriate system will depend upon rate of drug release required by a particular drug regime. Both non-degradable and degradable release systems can be used. Suitable release systems include polymers and polymeric matrices, non-polymeric matrices, or inorganic and organic excipients and diluents. Release systems may be natural or synthetic. However, synthetic release systems are preferred because generally they are more reliable, more reproducible and produce more defined release profiles. The release system material can be selected so that drugs having different molecular weights are released from a particular cavity by diffusion through or degradation of the material. Embodiments of the invention include drug release via diffusion or degradation using biodegradable polymers, bioerodible hydrogels and protein delivery systems.
Embodiments of the invention can be used to deliver drugs that are in solid or in liquid formulations. Frequently, a solid drug has the advantage of maintaining its stability for longer periods of time. Solid drugs also have a high drug to volume ratio and low surface area. If solid drug is used, properties of a vehicle can be used to control the rate at which drug is removed (whether by dissolution, elution, erosion or some other mechanism or combination of mechanisms) from one or more masses of solid drug, thereby offering a flexibility for modulating a concentration of drug that is delivered to an ocular tissue. As used herein (including the claims), a “vehicle” is a fluid medium used to remove solid drug from one or more masses of solid drug and/or to deliver the removed drug to an ocular tissue. A vehicle can be a bodily fluid such as interstitial fluid, an artificial fluid or a combination of bodily and artificial fluids, and may also contain other materials in addition to a drug being removed and/or delivered. A vehicle may contain such other materials in solution (e.g., NaCl in saline, a solution of an acid or base in water, etc.) and/or suspension (e.g., nanoparticles). Further examples of vehicles are included below.
Drug that is removed from a solid drug mass by a vehicle and retained in that vehicle is sometimes referred to herein as being entrained within (or by) the vehicle. As used herein (including the claims), “entrained” drug includes drug that is eroded from a mass and dissolved in the vehicle, drug that is eroded from a mass and suspended in the vehicle, and drug that is eroded from a mass and adsorbed/absorbed to nanoparticles or other components of the vehicle. A drug that is removed from a solid drug mass and remains within the vehicle in another chemical form (e.g., a salt that results when a basic solid drug mass is placed into contact with an acidic vehicle) is also included within the scope of the phrase “entrained drug.”
Embodiments of the invention include methods for delivering a therapeutically effective concentration of a drug for which either the acidic or basic form of the drug is water insoluble or sparingly soluble. For a drug with acid-base functional groups, the less water soluble form is likely to be more stable, as a consequence of being less prone to solution-dependent decomposition processes, especially if the drug is stored as a solid, for example in a crystalline state. In addition, as a crystalline or amorphous solid, a drug will occupy the smallest possible space, which also facilitates construction of small delivery devices.
According to at least some embodiments in which the basic form of a solid drug is less soluble than an acidic solid form, solid pellets of the basic form are eluted with an acid at a concentration that is substantially the same as the desired drug concentration. In at least some embodiments in which the acidic form of a drug is less soluble than the basic form, solid pellets of the acidic form are eluted with a base at a concentration that is substantially the same as the desired drug concentration. According to at least some additional embodiments, an aqueous solution comprising one or more components having an amphipathic molecule which can solubilize a water-insoluble drug can be used to erode a solid drug pellet to effect delivery of a therapeutically effective amount of the drug.
An advantage of using solid drug in an implanted device is, in at least some embodiments, the ability to store drug in the device using a smaller volume than might be required if a premixed (or other liquid) form of the drug were used. In some cases, this smaller volume enables implantation of a device containing enough drug to provide (when combined with an appropriate vehicle source) substantially continuous long term therapy. This long term therapy can be over a period of days, weeks, or months. In some cases, long term therapy may extend over several years. One example of a basic crystalline or solid amorphous drug suitable for use in methods according to some embodiments is gacyclidine. For example, it is estimated that 18 mg of solid gacyclidine eroded with an appropriate vehicle will deliver 100 μM drug over 4 years at a flow rate of 20 microliters per hour or less. The hydrochloride salt of gacyclidine, its acidic form, is highly water soluble. However, the acidic form of gacyclidine is also unstable at body temperature. By contrast, the basic form of gacyclidine is sparingly soluble in water and is much more stable than its acidic form in the presence of water. Dissolution of the basic form of gacyclidine in water requires the presence of an acid (e.g., hydrochloric acid or lactic acid) to convert the basic form to the water-soluble acidic form. The concentration of gacyclidine in solution will therefore depend on the amount of acid available to convert the basic form to the acid form. This ability of an appropriate vehicle to change the amount of drug dissolved and delivered offers substantial flexibility in changing the concentration of delivered drug, without requiring the changing of a device holding the solid drug, and without loading a different concentration of a therapeutic solution into a liquid reservoir.
Sterile pellets of gacyclidine base can be prepared by mixing sterile solutions of gacyclidine hydrochloride salt with sterile solutions of sodium hydroxide. Solutions of gacyclidine hydrochloride and sodium hydroxide can be sterilized by passage through a sterilizing filter, such as, but not restricted to, a 0.22 μm polyether sulfone, polytetrafluoroethylene, or polyvinylidene difluoride membrane filter. Polyether sulfone membrane filters have low affinity for gacyclidine solutions at room temperature, pH 5.5 and 25° C.; as such these membranes are compatible with sterile filtration of gacyclidine hydrochloride solutions. After mixing, the solutions are centrifuged to collect the liquid form of drug base into a single mass, which solidifies or crystallizes over time to a single mass of solid drug base. A sterile tube, which forms a mass of the desired shape, can be used in the centrifugation process to prepare sterile pellets of uniform size and shape.
Additional embodiments include methods applicable to delivery of other drugs which are water (or other vehicle) soluble in one of an acid or base form and sparingly soluble in the other of the acid or base form. A solid comprised of the less water soluble drug form is eluted or eroded with a compatible vehicle (e.g., Ringer's solution, Ringer's lactate, saline, physiological saline, artificial vitreous humor and/or any other vehicle compatible with injection into the anterior chamber and/or posterior segment of the eye or into other ocular tissue) comprising, as appropriate, either an acid or a base. If the less water-soluble drug form is a basic form, then the vehicle can contain a pharmaceutically acceptable acid, such as hydrochloric acid, monobasic sodium phosphate (e.g., monosodium phosphate), lactic acid, phosphoric acid, citric acid, a sodium salt of citric acid, or lactic acid. If the less water-soluble drug form is an acidic form, then the vehicle can contain a pharmaceutically acceptable base, such as sodium hydroxide, sodium bicarbonate, or choline hydroxide.
Some embodiments can employ solid drug pellets. Those pellets can be crystalline masses or solid amorphous masses. Examples of manufacturing drug pellets are included herein as Examples 1 and 3. A solid drug could also include a combination of crystalline and amorphous masses. The drug can be melt molded into any desired shape or can be pressed into pellets using pressure (with or without binder). Crystalline drug (if available) may be more desirable than amorphous solid drug forms in some cases, as crystalline substances typically are more stable. Crystal lattice energy may also help stabilize the drug. However, the invention is not limited to crystalline drug forms or the use thereof.
The invention is similarly not limited to drugs (or to methods or devices employing drugs) with acid-base functionalities. Embodiments also include dissolution (or removal from a mass by other mechanism) of any drug which is sparingly soluble in water by eluting the drug with a pharmaceutically acceptable vehicle comprising one or more components having an amphipathic molecule, such as monopalmitoyl glycerol or polysorbate 80 (e.g., TWEEN 80®). Other suitable amphipathic molecule components include (but are not limited to) an acyl glycerol, a poly-oxyethylene ester of 12-hydroxysteric acid (e.g., SOLUTOL® HS15), beta-cyclodextrin (e.g., CAPTISOL®), a bile acid such as taurocholic acid, tauroursodeoxycholic acid, cholic acid or ursodeoxycholic acid, a naturally occurring anionic surfactant such as galactocerebroside sulfate, a naturally occurring neutral surfactant such as lactosylceramide or a naturally occurring zwitterionic surfactant such as sphingomyelin, phosphatidyl choline or palmitoyl carnitine. Dissolution (or other removal) can also be accomplished by use of physiological fluid vehicles, such as interstitial fluid or natural (or simulated) tear fluid. Physiological fluid vehicles contain amphipathic molecules, such as proteins and lipids, which are capable of effecting dissolution of a water-insoluble drug. Dissolution can also be carried out without the use of an amphipathic molecule where an acceptable concentration of drug is obtained.
One example of a drug that does not have acid-base functionalities is triamcinolone acetonide. Triamcinolone acetonide is commercially available as a crystalline solid with very low water solubility. If solid pellets of triamcinolone acetonide are exposed to a continuous stream of a vehicle, such as Ringer's solution, the expected concentration of extracted triamcinolone acetonide in solution should be 40 μM or less. A higher concentration of triamcinolone acetonide can be solubilized by including an amphipathic molecule in the vehicle. Such a pharmaceutically acceptable amphipathic molecule would be polysorbate 80 (e.g., TWEEN 80®). The concentration of triamcinolone acetonide solubilized can be increased above its water solubility, 40 μM, by adding the required amount of amphipathic molecule to the vehicle that will support the desired drug concentration. The invention is not limited to methods implemented through use of triamcinolone acetonide, Ringer's solution or polysorbate 80. Any sparingly soluble drug, pharmaceutically acceptable vehicle and pharmaceutically acceptable amphipathic molecule can be used.
Still other embodiments employ nanoparticles. Nanoparticles can maintain a drug in a mobile phase capable of passing through an antibacterial filter. Some embodiments would use, in place of or in combination with an amphipathic drug carrier, a suspension of particles (e.g., nanoparticles) that would have affinity for a drug (e.g., that would adsorb/absorb a drug) and act as carriers. Yet other embodiments include use of pure drug nanoparticles. Embodiments also include combinations of both pure drug nanoparticles and drug adsorbed/absorbed to carrier nanoparticles. Particles according to at least some embodiments would be small enough to pass through an antibacterial filter of 0.22 microns or less. Removal of a drug from a mass thereof using a vehicle having suspended carrier nanoparticles would be advantageous to both drug stability and delivery. Removal of solid drug from a mass of drug nanoparticles would have similar benefits.
In at least some embodiments a vehicle includes a suspension of small carrier particles (100 nm to 0.1 mm in size) or carrier nanoparticles (10 nm to 100 nm in size) having an affinity for the drug(s) to be delivered. Examples of materials from which the carrier particles or nanoparticles could be formed include (but are not limited to) polylactic acid, polyglycolic acid, a co-polymer of lactic acid and glycolic acid, polypropylene, polyethylene and polystyrene. Additional examples of materials from which carrier particles or nanoparticles can be formed include magnetic metals and magnetic metals having a coating to attract a drug (or drugs) of interest. These small carrier particles or nanoparticles will adsorb/absorb or otherwise attract drug that is eroded from a mass of solid drug (which may be stored in a reservoir such as is described herein) by a vehicle in which the carrier particles (or nanoparticles) are suspended.
In some embodiments, a vehicle will be used to erode pure drug nanoparticles from a solid mass composed of such pure drug nanoparticles. Such a solid mass of nanoparticles could be formed by compression and/or by use of a binder.
In some cases, a small amount of acid or amphipathic excipient (e.g., SOLUTOL® HS15, TWEEN 80® or CAPTISOL®) can be employed to facilitate drug elution from a mass of solid drug (or from a mass of solid drug nanoparticles) and transfer of the drug into solution or into a mobile nanoparticle suspension.
In some embodiments, polymeric material used to fabricate carrier nanoparticles is biodegradable (so as to help promote ultimate delivery of drug), commercially available and approved for human use. Polymers of L- and D,L-lactic acid and copolymers of lactic acid and glycolic acid [poly(lactide-co-glycolide)] (available from Lakeshore Biomaterials in Birmingham, Ala.) are examples of polymeric materials that have the potential to meet the desired properties of the polymer for carrier nanoparticles. Nanoparticles small enough to pass through a 0.22 μm antibacterial filter have been fabricated from a 50:50 mix of poly(lactide-co-glycolide) by the solvent displacement method.
Several methods have been employed to fabricate nanoparticles of suitable size. These methods include vaporization methods (e.g., free jet expansion, laser vaporization, spark erosion, electro explosion and chemical vapor deposition), physical methods involving mechanical attrition (e.g., pearlmilling), interfacial deposition following solvent displacement and supercritical CO2. Additional methods for preparing nanoparticles include solvent displacement of a solubilizing solvent and a solvent in which the nanoparticle is not soluble, vibrational atomization and drying in the atomized state, sonication of two liquid streams, use of micropumps (such as ink jet-like systems delivering nano and micro-sized droplets of drug) and continuous flow mixers.
When preparing nanoparticles by the solvent displacement method, a stirring rate of 500 rpm or greater is normally employed. Slower solvent exchange rates during mixing produce larger particles. Fluctuating pressure gradients are fundamental to producing efficient mixing in fully developed turbulence. Sonication is one method that can provide adequate turbulent mixing. Continuous flow mixers (two or more solvent streams) with and without sonication may provide the necessary turbulence to ensure small particle size if the scale is small enough. The solvent displacement method has the advantage of being relatively simple to implement on a laboratory or industrial scale and has produced nanoparticles able to pass through a 0.22 μm filter. The size of nanoparticles produced by the solvent displacement method is sensitive to the concentration of polymer in the organic solvent, to the rate of mixing and to the surfactant employed in the process. Once isolated, a dried or wet pellet of drug particles or drug-laden polymeric particles can be compressed into a solid mass or mixed with a pharmaceutically acceptable binder and compressed into a mass.
Drug-delivery systems according to at least some embodiments include combinations of various implantable components. These components include osmotic pumps, subcutaneous (or transdermal) ports, catheters and terminal components. In some cases, an osmotic pump (and/or a port) and other system components are small enough to permit subcutaneous implantation on the side of a patient's head (or elsewhere on the head), and can be used for delivering drugs to the eye. These components can also be implanted elsewhere on a patient's body, however.
In at least some embodiments, a device employed for removal of drug from a solid drug mass with (and entrainment by) a vehicle can include any chamber capable of holding a less water-soluble form of the drug and permitting a vehicle comprising a dissolving or other removal agent (e.g., acid, base, an amphipathic molecule, a suspension of nanoparticles) to flow past the solid drug. The size of the chamber, rate of vehicle flow and concentration of acid, base, amphipathic molecule or nanoparticles used are determined by the intended application of the drug delivery device and dissolution characteristics (or erosion or other physical characteristics) of the drug substance and/or drug mass, as well as by any required vehicle reservoir and/or pumping system. Determination of the parameters for such a device is within the ability of one skilled in the art, once such a person is provided with the information included herein.
Fluid flow to effect drug dissolution (or removal by other mechanism) can be accomplished by any pump with fluid flow parameters that match the desired application. Such pumps include, but are not limited to, an implantable MEMS pump, an implantable osmotic pump, an implantable peristaltic pump, an implantable piston pump, an implantable piezo-electric pump, etc. Selection of an appropriate pump is similarly within the ability of one skilled in the art, once such a person is provided with the information included herein. In some embodiments, a pump can be fully implanted within a human (or animal) body. In other embodiments, a pump may be external to the body and delivering vehicle through a subcutaneous port or other connection to a reservoir holding solid drug.
Osmotic pump 105 is of a type known in the art. Such pumps (e.g., pumps sold under the trade names DUROS® and CHRONOGESIC® by Durect Corp. of Cupertino Calif.) are known for use in other applications, and are described in, e.g., U.S. Pat. No. 4,034,756. In general, an implanted osmotic pump incorporates osmotic pressure differences to drive a drug at a predefined flow rate related to the aqueous permeability of a membrane in the pump. This mechanism typically uses an osmopolymer, salt, or other material with high osmolality to imbibe liquid from the surrounding tissue environment and expand a compartment volume. This volume increase moves a piston or compresses a flexible reservoir, resulting in expulsion of a liquid from the pump. The piston (or a moveable seal) separates the osmopolymer from a reservoir containing the liquid to be expelled. The pump housing may consist of a semi-permeable body which allows water or appropriate liquid to reach the osmopolymer. The rate of delivery of the pump is determined by the permeability of the pump's outer membrane.
Conventional osmotic pumps hold a liquid formulated drug in the liquid reservoir; such pumps can be used to deliver such a liquid drug formulation to an eye or other ocular tissue in some embodiments. Osmotic pump 105 in
Osmotic mini-pumps can deliver small amounts of liquid continuously for long periods of time. However, it can be difficult to refill an internal fluid reservoir of a conventional osmotic pump. Accordingly, the embodiment of
In at least some embodiments, osmotic pump 105 and drug/filter housing 106 are sized for implantation in specially prepared pockets in a patient's skull. Catheters 107 and 108 may be placed within grooves also prepared on the patient's skull.
The configuration of
Another embodiment of an ophthalmic drug delivery device is shown in
A solid drug reservoir is designed to provide a cavity for fluid to flow around and erode one or more masses of solid drug (e.g., solid drug pellets).
In some embodiments, circular screens are placed inside a drug chamber to further prevent migration of drug pellets. In some cases, at least one of the screens may be removable to allow for replenishment of drug.
An antibacterial filter is similarly not required. For example,
Housings 344 and 346 of drug reservoir 340, housings 364 and 365 of drug reservoir 360, and housings of drug reservoirs in other embodiments can be made of a drug-compatible, corrosion-resistant material such as titanium, stainless steel, platinum, gold, a biocompatible coated metal, a chemically inert polymer such as PTFE (polytetrafluoroethylene), FEP (tetrafluoroethylene-hexafluoropropylene copolymer), PFA (perfluoroalkoxyethylene), other fluoropolymers, or a fluoropolymer-coated metal. During low flow rates at body temperature, drug may tend to adsorb to the walls of the chamber, causing lower than expected concentrations of drug to be delivered to the patient. Fluoropolymers are the best known materials for resisting adsorption. Other fluoropolymers include, but are not limited to, ECTFE (ethylene-chlorotrifluoroethylene copolymer), ETFE (ethylene-tetrafluoroethylene copolymer), MFA (tetrafluoroethylene perfluoro(methylvinyl ether) copolymer), PCTFE (polychloro tri-fluoro ethylene) and PVDF (polyvinylidene difluoride).
As indicated above, drug reservoirs in various embodiments may be opened and closed to allow for replenishment of solid drug. The reservoir components may be threaded (as shown in
A drug cage similar to drug cage 111 (
In at least some embodiments, catheter tubing on the upstream side of a drug reservoir (e.g., tubing for catheter 316 on the pump side of device 310 in
In some embodiments, the solid drug reservoir and a 3-D antibacterial filter are in fluid communication via catheter connection. This is seen generally in
In at least some embodiments, a housing for a drug and filter is made from titanium, gold, platinum or stainless steel and is small enough to be implanted into a human body. The inner diameter is sized so that a 3-D antibacterial filter can be bonded to the inside of the housing. Examples of possible filter sizes (in various embodiments) include but are not limited to 0.22 micron maximum pore size 3-D filters with a physical outer diameter of 0.03 to 0.25″. In still other embodiments the physical outer diameter is between 0.1″ and 0.3″.
Still other embodiments include sensors (e.g., a pressure sensor for glaucoma or a drug sensor) with attached battery and power electronics (power supply, recharging circuitry, etc.) and communication electronics to receive and send information. In these embodiments, the electronics could be bundled with the reservoir section of the device and the sensors could be combined with a wire following the surface of the catheter or contained within one of the lumens of a multi-lumen tubing and exiting within a target ocular tissue.
At least some embodiments include electrophoresis-stimulated delivery of charged drug ions or other particles of drug. For charged drugs, applying an electric field on a fluid containing the drug (or containing nanoparticles that have adsorbed/absorbed drug) can induce the migration of the drug faster than normal diffusion. In the case of gacyclidine, a negative charge on a device exit (e.g., at the end of a catheter) or just outside of a device exit can be used to accelerate the drug delivery to the eye without the need for a pump. A same or similar charge of opposite polarity (e.g., a positive charge in the case of gacyclidine) could similarly be applied to a drug containing compartment (e.g., a chamber in which solid drug is held), thereby enabling drug delivery out of the device without the need for a pump. The electrophoresis environment would induce an electro-osmotic flow to the natural low resistance outlet within the target ocular tissue. The rate of migration of drug to the catheter tip (or the concentration of drug) could be modulated by field strength of the electric charge and other parameters modulated by an appropriate electronics package, battery, recharging assembly, on/off switch, communication circuitry and other electronics. If a drug having an opposite charge is used, then the electronic circuitry would reverse the charges on the electrodes. Electrophoresis-stimulated drug delivery embodiments would be very low power devices in order to promote patient safety, and because small amounts of drug are being delivered. A charged device in an ocular tissue may provide additional benefits to suppress neural degeneration of the optic nerve, e.g., in blind patients and in special circumstances to treat patients with light flashes in the eye or a hyperactive sensitivity to light, as well as to other patients who report benefit from electrical stimulation. In some embodiments (and as described below in connection with
In at least some embodiments, a port is subcutaneously (or transcutaneously) implanted in a patient's body and placed into fluid communication with an implanted catheter and terminal component. The port includes an internal cavity which can be used to hold liquid and/or solid drug(s). A self-sealing elastomeric (e.g., silicone) septum covers the cavity. The septum can also have a drug compatible fluoropolymer laminated lining to minimize drug adsorption. A non-coring needle may be inserted through the septum so as to introduce a fluid into the cavity from an external source. That fluid can be a liquid formulated drug, or may be a liquid vehicle for dissolving (or otherwise entraining) a solid form drug already located within the cavity and delivering that entrained drug to an eye. In some embodiments, a liquid formulated drug is used as a vehicle to entrain an additional solid-form drug contained in the cavity.
The drug-holding cavity of a port may be composed of (or coated with) a drug compatible material (e.g. stainless steel, titanium, platinum, gold or drug compatible polymer). This material may also be biocompatible (so as to prevent tissue rejection), able to withstand repeated refilling and dispensing of the drug and the potential corrosive effects of a drug-containing vehicle, and able to hold drug and remain implanted for an extended period of time without degradation. If a port is to be used for holding a drug in a solid state, the cavity-forming material may be compatible so that the drug does not stick to the cavity walls, and so that cavity surfaces coming into contact with a drug do not adsorb any of the drug. Cavity walls should not, at least in certain embodiments, be permeable to water or physiological fluids.
In some embodiments, and as described in more detail in application 60/807,900, a subcutaneously-implantable port includes two cavities. One of those cavities is in fluid communication with a first lumen of a dual lumen catheter, and the other cavity is in fluid communication with the other lumen. Such an embodiment permits flushing of a target ocular tissue using one side of the port to receive fluid from another source (e.g., an external pump) and using the other side of the port to withdraw fluid from the target ocular tissue.
Delivery of drug to an ocular tissue can also be performed using devices and procedures described in U.S. patent application Ser. No. 11/337,815 (filed Jan. 24, 2006 and titled “Apparatus and Method for Delivering Therapeutic and/or Other Agents to the Inner Ear and to Other Tissues,” published as U.S. Patent Application Publication No. 2006/0264897).
In some embodiments, an electronics package coupled to a drug reservoir (e.g., electronics package 503 in
In at least some additional embodiments, a vehicle used to remove drug from one or more solid drug masses in a reservoir may itself be a pre-mixed suspension of nanoparticles containing a drug (or drugs). In still other embodiments, drug devices according to various embodiments can be used to deliver a pre-mixed suspension of nanoparticles containing a drug (or drugs) without employing a solid drug mass in a reservoir chamber. In either case, the nanoparticles can be drug nanoparticles or nanoparticles of a carrier material to which drug has been absorbed/adsorbed or otherwise attached.
As previously indicated, devices and methods such as are described herein can be used to provide sustained, long term delivery of a drug. Such devices and methods can also be used to provide intermittent drug delivery on a long term basis. For example, a reservoir holding a solid drug mass could be implanted in a patient's body. That reservoir can then be periodically connected (e.g., using a subcutaneous port in fluid communication with the reservoir) to a source of vehicle.
Similar to system 310 shown in
In one or more of the above-described embodiments, an ocular implant can be treated so as to include a thin film coating that includes a drug to be delivered, with that thin film coating slowly releasing the drug after placement of the ocular implant into a target ocular tissue. One example of such an ocular implant 801 is shown in
Coatings used should be both biocompatible and drug compatible. Thin films composed of bioabsorbable polymers are used in some embodiments; erosion of the film helps ensure release of the drug substance from the coating. Examples of suitable bioabsorbable elastomers are described in U.S. Pat. Nos. 5,468,253 and 6,627,246. Useful polymers include mixtures of L-lactide, D-lactide, epsilon-caprolactone, and glycolide. The relative composition of these mixtures can be used to control the rate of coating hydrolysis and adsorption, the rate of drug release, and the strength of the film. Other polymeric materials that can be used to prepare drug-releasing thin films include (but are not limited to) polyamides, polyalkylenes oxalates, poly(amino acids), copoly(ether-esters), poly(iminocarbonates), polyorthoesters, poly(anhydrides), and blends thereof. Naturally occurring polymers that can be degraded in the eye include hyaluronic acid, absorbable biocompatable polysaccharides such as chitosan or starch, fibrin, elastin, fibrinogen, collagen, and fatty acids (and esters thereof). Drug-containing polymers can be applied by spraying solutions containing dissolved polymer and drug on the surface to be coated or by dipping a portion of the implant in these solutions. Highly volatile solvents with low potential for residue or toxicity in the coating process, such as acetone, can be used in such spraying or dipping. Thin films typically provide drug delivery for a few weeks until the therapeutic in the film is exhausted. The thickness will depend on how long drug delivery is desired and the drug loading. Frequently, the thickness is 5-30 microns or less, though other thicknesses are allowed.
Coatings may be used both on implants placed within the sclera and on implants placed outside the sclera.
A 3-D filter element, such as is described above in connection with various embodiments, may be formed in various ways. As one example, a 3-D filter element can be cut or punched from a sheet of material (e.g., a biocompatible polymeric material or porous metallic material) with an appropriately small pore/channel size (such as ≦0.22 microns) for use as an anti-bacterial filter, and with the sheet having a thickness that will yield a filter element of a length that can extend along a flow path for several millimeters. The maximum pore size can be <10 microns, e.g., <2.0 microns or ≦0.22 microns. A metallic 3-D filter element can also be formed by sintering. For example, a fine metal powder such as titanium metal (with the particle diameter selected for the desired resulting pore size) can be tightly packed into a mold with the desired shape for the final filter element. The metal is heated to the point at which the powder particles begin to melt and form attachments to neighboring particles. This results in an intricate porous bonded meshwork which works like a filter, has a tortuous path and has a predetermined macro-external shape. A filter element can alternately be formed from type 316 stainless steel, porous gold, porous platinum or any other biocompatible metal. As used throughout this specification (including the claims), “metal” includes metal alloys. In certain embodiments metal alloys can be made from two materials such as gold and silver and then one metal is removed (e.g., silver dealloyed) to produce a microporous filter material.
As yet another example, micro fibers of an appropriate diameter suitable for an antibacterial filter can be incorporated into an appropriate metal and then burned out (carbon based) or etched out such as silica based ceramics (e.g., fugitive filter fibers) with hydrofluoric acid. Examples of such filter filler components are known in the art. Additional embodiments include a thin filter of the correct pore/channel size layered or laminated onto a larger porous material to provide additional strength to the thin filter. In 3-D filters prepared from polymeric material, lasers or gamma rays may be used to modify the filter materials and so as to allow etching of the pores into the filter material, producing a filter with very uniform pore diameters. Filters with larger pore size can be used together with antibacterial filters to act as a pre-filter to remove particles that may clog the antibacterial filter.
Without limitation and as further examples, a 3-D filter element (whether metallic or polymeric) can have a diameter in the range of about 0.010 inches to 0.400 inches (e.g., about 0.062 inches). The length of a 3-D filter element can be approximately 0.010 inches to 0.200 inches (e.g., about 0.039 inches). The pore size can be, e.g., ≦0.22 microns. Filter elements of other dimensions are acceptable (depending on the application and the device desired) as long as they function as an antibacterial filter; effective pore size is generally more critical than the overall dimensions, though smaller pore sizes increase back pressure.
In certain circumstances a microporous 3-D filter can be used together with an anti-bacterial thin film filter when the removal and replacement of a clogged filter is surgically convenient for the patient. For example, this could be useful when a drug port is used with an enclosed antibacterial filter as part of the assembly. Thin film membrane filters can be assembled with a supporting infrastructure to prevent liquid going around a filter. This can be done with a backing on the membrane filter and o-rings to make a liquid tight seal around the membrane edges.
A 3-D filter element (however formed) can be incorporated into a fluid system in any of a variety of ways. In addition to the incorporations described above (e.g., use of a drug/filter housing), a 3-D filter element can be inserted into a portion of a catheter or other tube (e.g., a catheter formed in part from a flexible biocompatible polymer such as silicone rubber) that is swollen (with a solvent) to allow easy insertion of the filter element into that tube. When the solvent evaporates, the tubing returns to its design diameter and closes around the filter element to make a tight seal. The outside of a 3-D filter element can also be, welded, glued or sealed with tubing to prevent leakage around the sides of the filter element.
In all of the above-described embodiments (as well as other embodiments) in which a 3-D antibacterial filter is employed, variants of those embodiments may employ a membrane filter or other type of antibacterial filter mechanism.
Although various embodiments using an implantable osmotic pump are described above, other types of implantable pumps can be used. Such other types of pumps include MEMS (microelectromechanical systems) pumps (e.g. piezo electric pumps with check valves, mini-peristaltic and other kinds of miniature pumps) containing the appropriate microfluidics.
Suture anchors can be used in many embodiments for securing a catheter and/or terminal component. Suture anchors can be molded directly to a catheter using a liquid silicone elastomer or another suitable biocompatible polymer. Suture anchors can be ring-shaped, but other shapes (e.g., squares, half-rings, thin plates or “ears” with holes for suture thread) can also be employed. Alternatively, suture anchors may be bumps on the surface of the tubing made of silicone elastomer, epoxy, or other kinds of adhesives.
Numerous types of catheters can be used in various embodiments. In at least some embodiments, implanted catheters are formed from drug- and biocompatible materials such as fluoropolymers (e.g., PTFE, FEP, ETFE and PFA), silicone rubber, PVC, PEEK, polyimide, polyethylene, polypropylene and polyurethane. The precise compound selected for a catheter will depend on the material-drug compatibility for the drug to be delivered, as well as the flexibility, lumen size and other specifications required for a particular application. Single-lumen and multi-lumen catheters can be used.
As indicated above, implantable components may be formed from (or include) a variety of biocompatible materials. Drug-contacting surfaces of components are, in at least some embodiments, formed from materials which are compatible with drugs having a pH between 4-9.
Terminal components include electrical ocular implants, and embodiments of the invention include use of an implantable drug delivery device in conjunction with, or as part of, a retinal or other intraocular electrical implant.
Retinal implant 901 is attached to an end of a dual lumen catheter 902. A first lumen 905 is used as a conduit to route conductors 909 from electrodes 906 to a control electronics package (not shown). A second lumen 903 is used to transport a drug containing-fluid (a liquid drug formulation, a vehicle and entrained drug, etc.) to chamber 904 for ultimate delivery to the retina. Lumen 903 may be coupled (directly or via an intervening connection catheter) to any of the implantable drug delivery devices described above. Materials for implant 901 include those described in U.S. Pat. No. 7,181,287, such as silicone or a polymer having a hardness of 50 or less on the Shore A scale, as measured with a durometer. Other materials could also be used. Electrodes 906 can similarly be formed from materials such as those described in U.S. Pat. No. 7,181,287 (e.g., platinum or an alloy thereof, iridium, iridium oxide, titanium nitride), as well as other materials. Conductors 909 could be formed from platinum, an alloy thereof or other material, and include silicone or fluoropolymer sheathes or coatings for insulation and for protection and against interaction with a drug being dispensed.
Other types and configurations of drug delivery implants can also be used, and can be used in a variety of ocular tissues (e.g., the eye, the optic nerve, the visual cortex). A drug delivery implant need not provide electrical stimulation.
Any of the eye conditions identified above can be treated by using one or more of the device and/or system embodiments described above. Any of the drugs described above can be delivered using one or more of the device and/or system embodiments described above. In any of the embodiments discussed above, a system could be free of filters or other components described above.
All patents and patent applications cited in the above specification are expressly incorporated by reference. However, in the event that one of said incorporated patents or applications uses a term in a manner that is different from the manner in which such term is used in the above specification, only the usage in the above specification should be considered (to the extent any language outside the claims need be considered) when construing the claims.
The following specific examples are provided for purposes of illustration only and are not intended to limit the scope of the invention.
Water (500 mL) was brought to a boil. This hot water bath was then used to melt solid gacyclidine base. After placing 35 mg of gacyclidine base in a small glass vial, the vial was incubated in the hot water bath (90-100° C.) until the gacyclidine base melted. Small aliquots (2 μL) of the melted gacyclidine base were then transferred to polypropylene tubes (1.5 mL in size) and allowed to stand at room temperature until the gacyclidine base had solidified.
Solidification of the melted gacyclidine is typically complete within 30 minutes, but can occasionally take many hours. About half of the time, a single solid mass is obtained that slowly grows from a single focus. For those aliquots that result in multiple smaller crystalline/amorphous masses on standing, the tube containing the aliquot can be incubated in a hot water bath (90-100° C.) until it is melted a second time. Upon cooling, a second crop of single solid masses will be obtained. This process can be repeated, as necessary, until all aliquots of gacyclidine base have been converted to single solid masses.
Single solid masses (drug pellets) obtained in this way have an average weight of 1.5±0.3 mg and are hemispheres with a diameter of about 1.9 mm. These drug pellets have sufficient mechanical stability to be detached from the surface on which they are grown and transferred to a dissolution chamber.
A drug chamber similar to the one illustrated in
The highest pH of the eluted drug solution (5.9) was obtained at 0.05 mM hydrochloric acid, and the lowest pH of the eluted drug solution (5.6) was obtained at 3 mM hydrochloric acid. These pH values indicate quantitative conversion of the hydrochloric acid to the drug salt and are consistent with the pH expected for solutions of the hydrochloride salt. As shown in
Aqueous stock solutions of 1.0 M gacyclidine hydrochloride (299.9 mg/mL) and 1.0 M NaOH were prepared. Equal volumes of these solutions were mixed in a 1.7 mL polypropylene vial, then subjected to 30,000-times gravity centrifugal force in a Hermle Z229 minicentrifuge for 5 minutes. Gacyclidine base separated out during centrifugation as an oil and collected at the bottom of the centrifuge tube. Between 7 minutes and 2 hours following mixing of the solutions, the liquid gacyclidine base solidified into a single mass. The aqueous supernatants above the drug pellets were removed by aspiration by use of a sterile needle and syringe. The volumes mixed and the weights of drug pellets recovered are tabulated in Table 5.
Numerous characteristics, advantages and embodiments of the invention have been described in detail in the foregoing description with reference to the accompanying drawings. However, the above description and drawings are illustrative only. The invention is not limited to the illustrated embodiments, and all embodiments of the invention need not necessarily achieve all of the advantages or purposes, or possess all characteristics, identified herein. Various changes and modifications may be effected by one skilled in the art without departing from the scope or spirit of the invention. Although example materials and dimensions have been provided, the invention is not limited to such materials or dimensions unless specifically required by the language of a claim. The elements and uses of the above-described embodiments can be rearranged and combined in manners other than specifically described above, with any and all permutations within the scope of the invention. As used herein (including the claims), “in fluid communication” means that fluid can flow from one component to another; such flow may be by way of one or more intermediate (and not specifically mentioned) other components; and such may or may not be selectively interrupted (e.g., with a valve). As also used herein (including the claims), “coupled” includes two components that are attached (movably or fixedly) by one or more intermediate components.
This application claims the benefit of U.S. Provisional Application Ser. No. 60/807,900 (attorney docket number 006501.00023), filed Jul. 20, 2006 and titled “Devices, Systems and Methods for Ophthalmic Drug Delivery,” hereby incorporated by reference herein.
| Number | Date | Country | |
|---|---|---|---|
| 60807900 | Jul 2006 | US |
