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Publication numberUS20050031667 A1
Publication typeApplication
Application numberUS 10/815,481
Publication dateFeb 10, 2005
Filing dateMar 31, 2004
Priority dateMar 31, 2003
Also published asCA2520613A1, CA2520613C, CN1777426A, CN102772357A, CN102772357B, DE602004031512D1, EP1610791A1, EP1610791B1, US8852623, US20080311171, US20090162412, US20120258161, US20150151029, WO2004089375A1
Publication number10815481, 815481, US 2005/0031667 A1, US 2005/031667 A1, US 20050031667 A1, US 20050031667A1, US 2005031667 A1, US 2005031667A1, US-A1-20050031667, US-A1-2005031667, US2005/0031667A1, US2005/031667A1, US20050031667 A1, US20050031667A1, US2005031667 A1, US2005031667A1
InventorsRajesh Patel, Louis Bucalo, Lauren Costantini, Sofie Kleppner
Original AssigneePatel Rajesh A., Bucalo Louis R., Lauren Costantini, Sofie Kleppner
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Implantable polymeric device for sustained release of dopamine agonist
US 20050031667 A1
Abstract
The present invention provides compositions, methods, and kits for treatment of Parkinson's disease and other conditions for which treatment with a dopamine agonist is therapeutically beneficial. The invention provides a biocompatible nonerodible polymeric device which releases dopamine agonist continuously with generally linear release kinetics for extended periods of time. Dopamine agonist is released through pores that open to the surface of the polymeric matrix in which it is encapsulated. The device may be administered subcutaneously to an individual in need of continuous treatment with dopamine agonist.
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Claims(56)
1. An implantable device for administration of a dopamine agonist to a mammal in need thereof, comprising a dopamine agonist and a biocompatible, nonerodible polymeric matrix,
wherein said dopamine agonist is encapsulated within said matrix, and wherein when said implantable device is implanted subcutaneously in said mammal, said dopamine agonist is continuously released in vivo over a sustained period of time through pores that open to the surface of said matrix at a rate that results in a plasma level of at least about 0.01 ng/ml at steady state.
2. An implantable device according to claim 1, wherein the polymeric matrix comprises ethylene vinyl acetate copolymer (EVA).
3. An implantable device according to claim 2, wherein said EVA comprises about 33% vinyl acetate.
4. An implantable device according to claim 1, comprising about 10 to about 85% dopamine agonist.
5. An implantable device according to claim 4, wherein said dopamine agonist is selected from the group consisting of apomorphine, lisuride, pergolide, bromocriptine, pramipexole, ropinerole, and rotigotine.
6. An implantable device according to claim 5, wherein said dopamine agonist is apomorphine.
7. An implantable device according to claim 1, wherein the sustained period of time is at least about 3 months.
8. An implantable device according to claim 1, wherein the implantable device is produced by an extrusion process.
9. An implantable device according to claim 8, comprising dimensions of about 2 to about 3 mm in diameter and about 2 to about 3 cm in length.
10. An implantable device according to claim 9, wherein said implantable device releases about 0.1 to about 10 mg of dopamine agonist per day in vitro at steady state.
11. An implantable device according to claim 1, further comprising an anti-inflammatory agent encapsulated within said matrix.
12. An implantable device according to claim 11, wherein said anti-inflammatory agent is a steroid.
13. An implantable device according to claim 11, wherein said anti-inflammatory agent is a nonsteroidal anti-inflammatory drug (“NSAID”).
14. An implantable device according to claim 11, wherein said anti-inflammatory agent is an antihistamine.
15. An implantable device according to claim 1, further comprising an antioxidant encapsulated within said matrix.
16. An implantable device for administration of a dopamine agonist to a mammal in need thereof, comprising a dopamine agonist and a biocompatible, nonerodible polymeric matrix,
wherein said dopamine agonist is encapsulated within said matrix, and
wherein when said implantable device is subcutaneously implanted in a mammal, said dopamine agonist is continuously released in vivo over a sustained period of time through pores that open to the surface of said matrix at a rate of at least about 0.1 mg of dopamine agonist per day at steady state.
17. An implantable device according to claim 16, wherein the polymeric matrix comprises EVA.
18. An implantable device according to claim 17, wherein said EVA comprises 33% vinyl acetate.
19. An implantable device according to claim 16, comprising about 10 to about 85% dopamine agonist.
20. An implantable device according to claim 16, wherein said dopamine agonist is selected from the group consisting of apomorphine, lisuride, pergolide, bromocriptine, pramipexole, ropinerole, and rotigotine.
21. An implantable device according to claim 20, wherein said dopamine agonist is apomorphine.
22. An implantable device according to claim 16, wherein the sustained period of time is at least about 3 months.
23. An implantable device according to claim 16, wherein the implantable device is produced by an extrusion process.
24. An implantable device according to claim 16, further comprising an anti-inflammatory agent encapsulated within said matrix.
25. An implantable device according to claim 24, wherein said anti-inflammatory agent is a steroid.
26. An implantable device according to claim 24, wherein said anti-inflammatory agent is a NSAID.
27. An implantable device according to claim 24, wherein said anti-inflammatory agent is an antihistamine.
28. An implantable device according to claim 18, further comprising an antioxidant encapsulated within said matrix.
29. A method for administration of a dopamine agonist to a mammal in need thereof, the method comprising administering at least one implantable device subcutaneously,
wherein each of said at least one implantable devices comprises a dopamine agonist encapsulated within a biocompatible, nonerodible polymeric matrix,
wherein said dopamine agonist is continuously released in vivo from each of said at least one implantable devices over a sustained period of time through pores that open to the surface of said matrix at a rate that results in a plasma level of at least about 0.01 ng/ml at steady state.
30. A method according to claim 29, wherein said at least one implantable device comprises a multiplicity of individual implantable devices, and wherein the combination of said implantable devices continuously releases dopamine agonist in vivo over a sustained period of time at a rate that results in a plasma level of at least about 0.05 ng/ml at steady state.
31. A method according to claim 29, wherein the polymeric matrix comprises EVA.
32. A method according to claim 31, wherein said EVA comprises about 33% vinyl acetate.
33. A method according to claim 29, wherein each of said at least one implantable devices comprises at about 10 to about 85% dopamine agonist.
34. A method according to claim 33, wherein said dopamine agonist is selected from the group consisting of apomorphine, lisuride, pergolide, bromocriptine, pramipexole, ropinerole, and rotigotine.
35. A method according to claim 34, wherein said dopamine agonist is apomorphine.
36. A method according to claim 29, wherein said mammal has Parkinson's disease.
37. A method according to claim 29, wherein said mammal has toxin- or disease-induced parkinsonism.
38. A method according to claim 29, wherein said mammal has a condition selected from the group consisting of erectile dysfunction and restless leg syndrome.
39. A method according to claim 29, wherein the sustained period of time is at least about 3 months.
40. A method according to claim 29, wherein each of said at least one implantable devices is produced by an extrusion process.
41. A method according to claim 40, wherein each implantable device comprises dimensions of about 2 to about 3 mm in diameter and about 2 to about 3 cm in length.
42. A method according to claim 41, wherein each implantable device releases at least about 0.1 mg of dopamine agonist per day in vitro.
43. A method according to claim 29, wherein each of said at least one implantable devices is subcutaneously implanted at a site selected from the group consisting of the upper arm, the back, and the abdomen.
44. A method according to claim 29, further comprising administration of an anti-inflammatory agent.
45. A method according to claim 44, wherein said anti-inflammatory agent is encapsulated in at least one of said at least one implantable devices.
46. A method according to claim 44, wherein said anti-inflammatory agent is encapsulated within a biocompatible, nonerodible polymeric matrix that does not comprise said dopamine agonist, and wherein said method comprises administration of said polymeric matrix comprising said anti-inflammatory agent subcutaneously.
47. A method according to claim 44, wherein said anti-inflammatory agent is administered via a route selected from the group consisting of local injection, systemic injection, subcutaneous injection, and oral administration.
48. A method according to claim 44, wherein said at least one implantable devices further comprises an antioxidant.
49. A kit comprising at least one implantable device comprising a dopamine agonist encapsulated within a biocompatible, nonerodible polymeric matrix, wherein when said at least one implantable device is implanted subcutaneously in a mammal, said dopamine agonist is continuously released in vivo from each of said at least one implantable devices over a sustained period of time through pores that open to the surface of said matrix at a rate that results in a plasma level of at least about 0.01 ng/ml at steady state and instructions for use in a method of administration of a dopamine agonist to a mammal in need thereof.
50. A kit according to claim 49, wherein said at least one implantable device comprises a multiplicity of individual implantable devices, and wherein when the combination of said implantable devices is implanted subcutaneously in a mammal, said implantable devices continuously release dopamine agonist in vivo over a sustained period of time at a rate that results in a plasma level of at least about 0.05 ng/ml at steady state.
51. A kit according to claim 49, wherein said implantable device releases dopamine agonist at a rate of at least about 0.1 mg per day in vitro.
52. A kit according to claim 49, wherein each of said implantable devices comprises EVA.
53. A kit according to claim 52, wherein said EVA comprises about 33% vinyl acetate.
54. A kit according to claim 49, wherein each of said implantable devices comprises about 10 to about 85% dopamine agonist.
55. A kit according to claim 54, wherein said dopamine agonist is selected from the group consisting of apomorphine, lisuride, pergolide, bromocriptine, pramipexole, ropinerole, and rotigotine.
56. A kit according to claim 55, wherein said dopamine agonist is apomorphine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. provisional application No. 60/459,315, filed on Mar. 31, 2003, which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

The invention provides a nonbioerodible, polymeric device for subcutaneous implantation and sustained release of dopamine agonist for treatment of Parkinson's disease and other conditions for which administration of a dopamine agonist is therapeutically beneficial.

BACKGROUND OF THE INVENTION

Parkinson's disease, a progressive neurodegenerative disorder, is characterized by loss of neurons that synthesize and release dopamine. This loss of dopaminergic neurons manifests itself in symptoms such as rigidity, resting tremors (shaking), poverty of movement (akinesia), slowness of movement (bradykinesis), and changes in gait and posture. Treatment of Parkinson's disease generally is based on therapeutic administration of substances that can compensate for the lack of dopaminergic neurotransmission due to the loss of dopamine-secreting neurons. A classic treatment regime includes chronic oral administration of levodopa, which is decarboxylated in the brain to form dopamine. Often, after several years of treatment with levodopa, abnormalities emerge, including involuntary movements during the “on” phase of clinical improvement and re-emergence of Parkinson's-type symptoms during “off” phases.

Apomorphine, an effective agonist at both dopamine receptors in the nervous system, has been used for treatment of Parkinson's disease in patients that have become resistant to or have developed adverse side effects with associated with chronic levodopa therapy. Typically, due to its short duration of effectiveness, apomorphine is administered by repeated subcutaneous injections or continuous parenteral infusion via a pump. These means of administration are inconvenient, in the case of subcutaneous injection, and technically difficult, in the case of pump administration, especially for Parkinson's patients whose dexterity is impaired due to the disease itself and the movements associated with chronic levodopa treatment. Apomorphine may also be administered transdermally (U.S. Pat. No. 5,562,917), intranasally (U.S. Pat. No. 5,756,483), as a topically-applied gel (U.S. Pat. No. 5,939,094), or sublingually (U.S. Pat. No. 5,994,363). None of these methods permits continuous administration over long periods of time.

Dopamine agonists have also been used for treatment of parkinsonism which results from central nervous system injury by toxin exposure or a disease condition such as encephalitis, erectile dysfunction, restless leg syndrome, and hyperprolactinemia.

There is a need for an improved means of administration that would permit continuous dosing of dopamine agonists over an extended period of time of several months or longer, without the adverse side effects associated with peaks and troughs in plasma levels due to discontinuous dosing, or reliance on cumbersome mechanical equipment such as a pump.

BRIEF SUMMARY OF THE INVENTION

The invention provides compositions (i.e., implantable polymeric devices), methods, and kits for administration of one or more dopamine agonists to a mammal in need thereof.

In one aspect, the invention provides an implantable device for administration of a dopamine agonist to a mammal in need thereof. The implantable device includes at least one dopamine agonist encapsulated in a biocompatible, nonerodible polymeric matrix. After subcutaneous implantation in a mammal, an implantable device of the invention releases dopamine agonist continuously in vivo through pores that open to the surface of the matrix at a rate that results in a plasma level of at least about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, or 10 ng/ml in various embodiments. In some embodiments, an implantable device of the invention includes ethylene vinyl acetate (EVA) as a biocompatible, nonerodible polymer for formation of the polymeric matrix. In various embodiments, the vinyl acetate content of EVA used for preparation of the polymeric matrix is often about 2 to about 40, more often about 10 to about 35, most often about 30 to about 35%. In some embodiments, the vinyl acetate content is about 33%. An implantable device of the invention includes about 10 to about 85% dopamine agonist. In some embodiments, the dopamine agonist is apomorphine, lisuride, pergolide, bromocriptine, pramipexole, ropinerole, or rotigotine. In one embodiment, the dopamine agonist is apomorphine. The dopamine agonist is generally at least a dopamine D2 receptor agonist, but may also be an agonist for the D1 and/or D3 dopamine receptors. Implantable devices often release dopamine agonist continuously in vivo for at least about 3, 6, 9, 12, 15, 18, 21, or 24 months. In some embodiments, implantable devices of the invention are produced using an extrusion process, sometimes producing devices with dimensions of about 2 to about 3 mm in diameter and about 2 to about 3 cm in length, although other shapes and sizes are contemplated and are within the skill of the art. Often, an implantable device of the invention releases dopamine agonist at a rate of at least about 0.1 to about 10 mg/day at steady state in vitro or in vivo. In various embodiments, the implantable devices release dopamine agonist at a rate of at least about 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 mg/day in vitro or in vivo. In some embodiments, a dopamine-containing implantable device may further include an anti-inflammatory agent, for example a steroid, a nonsteroidal anti-inflammatory drug (“NSAID”), or an antihistamine, and/or an antioxidant within the polymeric matrix.

In another aspect, the invention provides a method for administration of a dopamine agonist to a mammal in need thereof. Methods of the invention include subcutaneous administration of at least one implantable device as described above. In some embodiments, the methods include subcutaneous implantation of a multiplicity of the devices. In methods of the invention, the device or devices release dopamine agonist at a steady state level that is therapeutically effective for treatment of a condition for which administration of a dopamine agonist is therapeutically beneficial, for example, Parkinson's disease, toxin- or disease-induced parkinsonism, erectile dysfunction, restless leg syndrome, or hyperprolactinemia. In some embodiments, the dopamine agonist is apomorphine, lisuride, pregolide, bromocriptine, pramipexole, ropinerole, or rotigotine. In one embodiment, the dopamine agonist is apomorphine. Typically, each device, or the combination of a multiplicity of devices, continuously releases at least about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 25, 50, or 100 ng of dopamine agonist per ml of plasma at steady state. Generally, each device releases at least about 0.1 mg of dopamine agonist per day in vitro. In various embodiments, one or a multiplicity of devices is subcutaneously implanted in an individual, for example, on the upper arm, the back, and/or the abdomen.

In some embodiments, one or more anti-inflammatory agents are coadministered along with dopamine agonist. The anti-inflammatory agent may be encapsulated within the same polymeric device as dopamine agonist or in a separate polymeric device that does not contain dopamine agonist, or may be administered via a different route, such as orally or via injection, either simultaneously with implantation of the dopamine agonist-containing devices or at a different time, or on a different schedule such as for example multiple dosing of an oral or injectable formulation. In various embodiments, the anti-inflammatory agent may be a steroid, a NSAID, and/or an antihistamine. In some embodiments, an antioxidant is incorporated into the dopamine agonist-containing polymeric device and is coadministered along with dopamine agonist. In some embodiments, the methods of the invention include administration of another substance in conjunction with administration of dopamine agonist via an implanted polymeric device of the invention. Such substances include, but are not limited to, levodopa, dopamine agonists, catechol-O-methyltranserase inhibitors, or monoamine oxidase inhibitors, administered orally or intravenously.

In another aspect, the invention provides a kit for use in a method of administration of a dopamine agonist to a mammal in need thereof. Kits of the invention include at least one implantable device that includes dopamine agonist encapsulated in a biocompatible, nonerodible polymeric matrix, as described above, and instructions for use. In some embodiments, kits of the invention include a multiplicity of individual dopamine agonist-containing implantable devices.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts in vitro release of apomorphine over time. FIG. 1 shows the average cumulative release of apomorphine HCl (“ApoH”) from implants loaded with 50%, 60%, or 70% ApoH and washed for 30 minutes (FIG. 1A), 60 minutes (FIG. 1B), or 120 minutes (FIG. 1C) in ethanol.

FIG. 2 depicts in vitro release of ApoH and loratidine (“LA”) over time from an implant loaded with 49% ApoH and 21% LA.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides a biocompatible, nonerodible polymeric device, which permits controlled, sustained release of one or more dopamine agonists over extended periods of time when implanted subcutaneously in an individual in need of treatment.

Continuous release of a compound in vivo over an extended duration may be achieved via implantation of a device containing the compound encapsulated, i.e., dispersed, in a nonerodible polymeric matrix. Examples of implantable, nonerodible polymeric devices for continuous drug release are described in, e.g., U.S. Pat. Nos. 4,883,666, 5,114,719, and 5,601,835. Implantation of the device and extended release of dopamine agonist improves compliance with dosing regimens, eliminating the need for repeated injections, ingestion of pills or tablets, or manipulations associated with a mechanical diffusion pump. An implantable, sustained-release device according to the present invention also permits achievement of more constant blood levels of dopamine agonist than injectable or oral dosage forms, thereby permitting lower dosing levels than conventional means of administration, minimizing side effects, and improving therapeutic effectiveness.

Devices of the invention include one or more non-bioerodible polymers. Such polymers release compounds at linear rates for extended time periods of several months or longer, in contrast to bioerodible polymers, which do not exhibit linear release kinetics due to formation of channels in the matrix as it erodes, resulting in increased release rates over time. The present invention includes a biocompatible, nonerodible polymer that exhibits generally linear release kinetics for dopamine agonist in vivo, after an initial burst.

Implantable Polymeric Devices

The invention includes implantable devices for treatment of Parkinson's disease or other conditions for which administration of a dopamine agonists is therapeutically beneficial. Devices of the invention include one or more dopamine agonists encapsulated in a polymeric, nonerodible matrix.

“Dopamine agonist” as used herein refers to a compound which is capable of binding to one or more dopamine receptor subgroups, resulting in beneficial therapeutic effect in an individual treated with the agonist. The dopamine agonists described herein typically are agonists for at least the D2 subgroup of dopamine receptors, and may also be agonists for D1 and/or D3 receptors. In various embodiments, an implantable device of the invention includes apomorphine, lisuride, pergolide, bromocriptine, pramipexole, ropinerole, or rotigotine, or a combination or two or more of these dopamine agonists. In one embodiment, the implantable device includes apomorphine. “Apomorphine” refers to apomorphine and pharmaceutically acceptable salts thereof, such as for example, apomorphine HCl (“ApoH”).

Incorporation of dopamine agonist into the polymeric matrix causes the formation of a series of interconnecting channels and pores that are accessible to the surface for release of the drug. When implanted subcutaneously, devices of the invention continuously release dopamine agonist for an extended period of time with a pseudo or near zero order release rate. After an initial burst following implantation, release rates are typically within about 10-20% of the steady state average.

As used herein, “nonerodible matrix” refers to a polymeric carrier that is sufficiently resistant to chemical and/or physical destruction by the environment of use such that the matrix remains essentially intact throughout the release period. The polymer is generally hydrophobic so that it retains its integrity for a suitable period of time when placed in an aqueous environment, such as the body of a mammal, and stable enough to be stored for an extended period before use. The ideal polymer must also be strong, yet flexible enough so that it does not crumble or fragment during use. Nonerodible matrices remain intact in vivo for extended periods of time, typically months or years. Drug molecules encapsulated in the matrix are released over time via diffusion through channels and pores in a sustained and predictable manner. The release rate can be altered by modifying the percent drug loading, porosity of the matrix, structure of the implantable device, or hydrophobicity of the matrix, or by adding a hydrophobic coating to the exterior of the implantable device.

Where appropriate, a coating that is impermeable to the drug is placed over at least a portion of the device to further regulate the rate of release. For example, a coating of a nonerodible polymeric material, e.g., EVA, or a coating of a nonerodible polymeric material with a lower drug loading than the remainder of the implantable device, may be used. Such a coating may be formed, for example, by co-extrusion with the device.

Typically, ethylene vinyl acetate copolymer (EVA) is used as the polymeric matrix, but other nonerodible materials may be used. Examples of other suitable materials include silicone, hydrogels such as crosslinked poly(vinyl alcohol) and poly(hydroxy ethylmethacrylate), acyl substituted cellulose acetates and alkyl derivatives thereof, partially and completely hydrolyzed alkylene-vinyl acetate copolymers, unplasticized polyvinyl chloride, crosslinked homo- and copolymers of polyvinyl acetate, crosslinked polyesters of acrylic acid and/or methacrylic acid, polyvinyl alkyl ethers, polyvinyl fluoride, polycarbonate, polyurethane, polyamide, polysulphones, styrene acrylonitrile copolymers, crosslinked poly(ethylene oxide), poly(alkylenes), poly(vinyl imidazole), poly(esters), poly(ethylene terephthalate), polyphosphazenes, and chlorosulphonated polyolefines, and combinations thereof.

Implantable devices of the invention are typically formulated with dopamine agonist loading of about 10% to about 85%. Devices are often formulated as compositions that include a polymeric matrix that includes EVA (33% acetate) and any of at least about 10, 20, 30, 40, 50, 55, 60, 65, 70, 75, or 80 to about 85%, or any of about 10 to about 20, about 20 to about 30, about 30 to about 40, about 40 to about 50, about 50 to about 60, about 60 to about 70, about 70 to about 80, or about 80 to about 85% dopamine agonist by weight. Devices may be produced using an extrusion process, wherein ground EVA is blended with dopamine agonist, melted, and extruded into rod-shaped structures. Rods are cut into individual implantable devices of the desired length, packaged, and sterilized prior to use. Other methods for encapsulating therapeutic compounds in implantable polymeric, nonerodible matrices are well known to those of skill in the art. Such methods include, for example, solvent casting (see, e.g., U.S. Pat. Nos. 4,883,666, 5,114,719, and 5,601,835). A skilled artisan would be able to readily determine an appropriate method of preparing such an implantable device, depending on the shape, size, drug loading, and release kinetics desired for a particular type of patient or clinical indication.

Devices of the invention are suitable for sustained release of dopamine agonist for treatment of idiopathic Parkinson's disease or another condition for which administration of dopamine agonist is therapeutically beneficial, such as, for example, toxin- or disease-induced parkinsonism, erectile dysfunction, restless leg syndrome, or hyperprolactinemia. As used herein, “sustained release” refers to the release of dopamine agonist such that the blood concentration remains within the therapeutic range but below toxic levels for an extended duration. Devices of the invention generally exhibit near zero-order pharmacokinetics in vivo, similar to kinetics achieved with an IV drip, but without the need for external medical equipment and personnel associated with intravenous methods. Generally, after implantation, the devices release therapeutically effective amounts of dopamine for periods of several months up to one year or longer.

Multiple implantable devices may be used, or the size and shape of the devices may be modified, to achieve a desired overall dosage. Implantable devices are often about 0.5 to about 10, more often about 1.5 to about 5, often about 2 to about 6, most often about 2 to about 3 cm in length, and are often about 0.5 to about 7, more often about 1.5 to about 5, most often about 2 to about 3 mm in diameter. An implantable device of the invention may release dopamine agonist in vitro or in vivo at a rate of about 0.01 to about 10, about 0.1 to about 10, about 0.25 to about 5, or about 1 to about 3 mg/day in vitro or in vivo. The release rate of implantable devices may also be modified by changing the vinyl acetate content in the EVA polymer matrix. The vinyl acetate content is often about 2 to about 40, more often about 10 to about 35, most often about 30 to about 35% by weight. In one embodiment, the vinyl acetate content is about 33% by weight.

In certain embodiments, devices of the invention may include other substances in addition to dopamine agonist to increase effectiveness of treatment and/or reduce inflammation at the site of administration, or to prevent oxidation of dopamine agonist(s). For example, an anti-inflammatory agent, such as for example, a steroid, examples of which include but are not limited to dexamethasone, triamcinolone, betamethasone, clobetasol, cortisone, hydrocortisone, or a pharmaceutically acceptable salt thereof, or a nonsteroidal anti-inflammatory agent (“NSAID”), examples of which include but are not limited to diclofenac potassium diclofenac sodium, diclofenac sodium with misoprostol, diflunisal, etodolac, fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenamate sodium, mefenamic acid, meloxicam, nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, sulindac, tolmetin, COX-2 inhibitors (e.g., celecoxib, rofecoxib, valdecoxib), acetylated salicylates (e.g., aspirin), nonacetylated salicylates (e.g., choline, magnesium, and sodium salicylates, salicylate), and/or an antihistamine, examples of which include but are not limited to loratadine (“LT”), astemizole, cetrizine dihydrochloride, chlorpheniramine, dexochlorpheniramine, diphenhydramine, mebhydrolin napadisylate, pheniramine maleate, promethazine, or terfenadine, may be encapsulated within an implant to prevent or reduce local inflammation at the site of administration. Any of these agents, or a combination, may be included in the same implant(s) as dopamine agonist or alternatively, may be incorporated into one or more separate implants that do not include dopamine agonist. An antioxidant, e.g., ascorbic acid, sodium metabisulfite, glutathione, may be included in the same implant as dopamine agonist to prevent or reduce oxidation of dopamine agonist during preparation, storage, and/or administration of the implant.

METHODS OF THE INVENTION

The invention provides methods for treatment of idiopathic Parkinson's disease or toxin- or disease-induced parkinsonism, or any other condition for which administration of a dopamine agonist is therapeutically beneficial, e.g., erectile dysfunction, restless leg syndrome, or hyperprolactinemia. “Parkinsonism” as used herein includes conditions resulting from injury to the central nervous system that cause an individual to exhibit symptoms similar to those of Parkinson's disease. Parkinsonism may result, for example, from toxin exposure, for example, carbon monoxide or manganese poisoning or MPTP administration, or from a disease condition such as encephalitis.

Methods of the invention include subcutaneous administration of one or more polymeric implantable devices which each include one or more dopamine agonists encapsulated within a biocompatible, nonerodible polymeric matrix, e.g., EVA, and release of the dopamine agonist(s) in a controlled manner over an extended period of time through multiple pores that open to the surface of the implantable device(s). Often, implantable devices are produced via an extrusion process, as described above.

In various embodiments, the method includes administration of apomorphine, lisuride, pergolide, bromocriptine, pramipexole, ropinerole, or rotigotine, or a combination or two or more of these dopamine agonists. A combination of dopamine agonists may be administered from the same implantable device(s) or may be administered from separate implantable devices. In one embodiment, the method includes administration of apomorphine.

Implantable devices are administered by subcutaneous implantation to an individual in need of treatment with a dopamine agonist. As used herein, “individual” refers to a mammal, such as a human, in need of treatment for Parkinson's disease or parkinsonism, or another condition for which dopamine administration is therapeutically beneficial. Generally, implantable devices are administered by subcutaneous implantation at sites including, but not limited to, the upper arm, back, or abdomen of an individual. Other suitable sites for administration may be readily determined by a medical professional. Multiple implantable devices may be administered to achieve a desired dosage for treatment.

Typically, in a treatment method of the invention, an implantable device or a multiplicity of devices is administered that will release dopamine at a rate that will maintain a therapeutically effective plasma level for an extended period of time of at least about 3, 6, 9, 12, 15, 18, 21, or 24 months. Often, the duration of implantation, with continuous release of dopamine agonist, is from about 3 months to about 2 years, about 3 months to about 1 year, about 3 months to about 9 months, or about 3 months to about 6 months.

The desired dosage rate will depend upon factors such as the underlying condition for which dopamine agonist is being administered, and the physiology of a particular patient, but will be readily ascertainable to physicians. Dopamine agonist is desirably released from one or a multiplicity of implanted devices at a rate that maintains plasma levels of the drug(s) at a therapeutically effective level. Maintenance of dopamine agonist at a fairly constant plasma level often permits dosing at a lower level than with other therapies, such as oral administration.

As used herein, “therapeutically effective amount” or “therapeutically effective level” refers to the amount of dopamine agonist that will render a desired therapeutic outcome, e.g., a level or amount effective to reduce symptoms of Parkinson's disease and/or increase periods of therapeutic effectiveness (“on” periods) for a patient undergoing chronic dopaminergic therapy for idiopathic Parkinson's disease or toxin- or disease-induced parkinsonism, or beneficial treatment, i.e., reduction or alleviation of adverse or undesirable symptoms of a condition treatable with a dopamine agonist, such as erectile dysfunction, restless leg syndrome, or hyperprolactinemia. For treatment of Parkinson's disease or parkinsonism, effectiveness is often associated with reduction in “on”/“off” fluctuations associated with a particular Parkinson's disease treatment regime, such as for example, chronic levodopa administration. An amount that is “therapeutically effective” for a particular patient may depend upon such factors as a patient's age, weight, physiology, and/or the particular symptoms or condition to be treated, and will be ascertainable by a medical professional.

When multiple devices are administered, the combination of the devices releases dopamine agonist at a rate that will achieve a therapeutically effective plasma level. Often, a desirable steady-state plasma level of dopamine agonist in methods of the invention is in the range of about 0.005 to about 100 ng/ml, about 0.01 to about 100 ng/ml, about 0.05 to about 0.65 ng/ml, about 0.2 to about 0.65 ng/ml, about 0.2 to about 45 ng/ml, or about 1 to about 20 ng/ml. In various embodiments, an implantable device of the invention may release dopamine agonist in vivo at a rate that results in a plasma level of at least about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, or 10 ng/ml at steady state. A total release rate from one or a multiplicity of implanted devices that results in delivery of a therapeutically effective amount of dopamine agonist on a daily basis is typically about 0.01 to about 10 mg/day, often about 0.25 to about 5 mg/day, sometimes about 1 to about 3 mg/day, but may be modified depending upon the symptomology involved and the particular patient being treated. For example, for treatment of Parkinson's disease with apomorphine or another dopamine agonist described herein, one or more implantable devices may be used with a total release rate of about 0.01 to about 10 mg/day, about 0.25 to about 5 mg/day, or about 1 to about 3 mg/day apomorphine.

It is anticipated that the implantable devices of the invention will alleviate compliance difficulties, as described above. In methods of the invention, long term continuous release of dopamine agonist generally reduces or eliminates the peaks and troughs of blood concentration associated with other formulations such as oral or injectable dosage forms, which permits dosing at a lower level than traditional treatment regimens. This often reduces or alleviates adverse side effects associated with higher dosages, for example, nausea, vomiting, orthostatic hypotension, hallucinations, delirium, or dyskinesia.

In some methods of the invention, dopamine is administered via an implantable device of the invention in conjunction with another therapy. For example, for Parkinson's or parkinsonism, dopamine agonist may be administered via implantable devices of the invention in conjunction with levodopa, dopamine agonists, catechol-O-methyltransferase (COMT) inhibitors, or monoamine oxidase (MAO) inhibitors, administered orally or intravenously.

Some methods of the invention include coadministration of another substance or substances in conjunction with dopamine agonist. For example, an anti-inflammatory agent or agents, such as a steroid, a NSAID, and/or an antihistamine, may be administered via an implantable device, by local, systemic, or subcutaneous injection, or orally, in conjunction with administration of dopamine agonist in an implantable device of the invention, to reduce or prevent inflammation caused by the agonist(s) at the site of administration of the implant. When the anti-inflammatory agent(s) is administered via an implantable device, it may be included in the same implant as dopamine agonist or in a separate implantable device. An implantable device may include one or more of the anti-inflammatory agents described above. The amount of anti-inflammatory agent administered is an amount expected to be effective to reduce local inflammation associated with administration of dopamine agonist in an implanted device of the invention.

In some methods of the invention, an antioxidant may be included in the dopamine agonist implant to prevent oxidation of the dopamine agonist(s) during preparation, storage, and/or administration of the implant. Generally, the amount of antioxidant incorporated into the implant is an amount sufficient to prevent oxidation of at least a portion, typically substantially all of the dopamine agonist in the implant.

Methods of the invention may be used to treat any subpopulation of Parkinson's disease patients, including, for example, “de novo” patients, e.g, patients who have not previously received treatment, “early stage” patients, e.g., patients who have been treated for a short period of time with another therapy such as levodopa administration but who are not exhibiting adverse side effects from the other therapy, “late stage” patients, e.g., patients who are exhibiting side effects associated with chronic treatment with another therapeutic substance such as levodopa, and “fluctuators,” e.g., patients for whom treatment with another substance such as levodopa fluctuates in effectiveness in an “on”/“off” manner.

Methods of the invention may be used, for example, to decrease motor fluctuations and dyskinesias for treatment of “late stage” patients with motor fluctuations. Continuous dosing via an implantable device of the invention may decrease “off” time and decrease dyskinesias. The methods may also be used, for example, to prevent motor fluctuations and dyskinesias in “early stage” patients who are undergoing pharmacologic therapy for the first time. This group often received monotherapy with a dopamine agonist. Administration via an implantable device of the invention may allow continuous dopamine agonist receptor stimulation, thus decreasing the risk of motor fluctuations and dyskinesias later in treatment. The methods may also be used, for example, to prevent motor fluctuations and dyskinesias in patients on dopamine agonist monotherapy who require 1-dopa supplementation. Since it is difficult to administer 1-dopa with linear dosing kinetics, and motor complications often emerge when 1-dopa is administered, continuous dosing via the implantable devices of the invention may allow continuous dopamine agonist receptor stimulation and decrease the risk of motor fluctuations and dyskinesias at this point in treatment.

Kits

The invention also provides kits for use in treatment of Parkinson's disease or another condition for which dopamine agonist administration is therapeutically beneficial, as described above. The kits contain at least one implantable, nonerodible device of the type herein described, capable of delivering long-term therapeutic levels of dopamine agonist, in suitable packaging, along with instructions providing information to the user and/or health care provider regarding subcutaneous implantation and use of the system for treating a condition for which dopamine agonist administration is therapeutically beneficial, such as, for example, Parkinson's disease, toxin- or disease-induced parkinsonism, erectile dysfunction, restless leg syndrome, or hyperprolactinemia. Kits may also include literature discussing performance of the implantable devices of the invention.

In various embodiment, kits of the invention may include implantable devices that include apomorphine, lisuride, pergolide, bromocriptine, pramipexole, ropinerole, or rotigotine, or combinations of any of these dopamine agonists in the same or separate polymeric implants. In one embodiment, a kit includes one or more implantable devices that include encapsulated apomorphine.

Kits may include a delivery system, i.e., one or a multiplicity of implantable devices, capable of providing sustained release of therapeutic levels of dopamine agonist, e.g., about 0.005 to about 100 ng/ml, about 0.01 to about 100 ng/ml, about 0.05 to about 0.65 ng/ml, about 0.2 to about 0.65 ng/ml, about 0.2 to about 45 ng/ml, or about 1 to about 20 ng/ml, for at least about 3 months. Kits of the invention may include implantable devices each capable of in vivo release of dopamine agonist such that a plasma level of at least about 0.001, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 5, 10, 25, 45, or 100 ng/ml is achieved at steady state. Kits of the invention may include a delivery system capable of releasing about 0.1 to about 10, about 0.25 to about 5, or about 1 to about 3 mg/day dopamine agonist in vitro or in vivo.

The device(s) in a kit may include one or more substances in addition to dopamine agonist, such as one or more an anti-inflammatory agents, such as a steroid, NSAID, or antihistamine, and/or an antioxidant.

In kits of the invention, an implantable device or devices may be preloaded into an apparatus or apparatuses suitable for subcutaneous implantation of the device(s) into a patient, such as, for example, syringes or trocars.

EXAMPLES

The following examples are intended to illustrate but not limit the invention.

Example 1 Materials and Methods

Materials

The following materials were used:

    • Apomorphine HCl, supplied by Hawkins, Inc.
    • Triamcinolone Acetonide, supplied by Spectrum
    • Glutathione, supplied by Aldrich, St. Louis, Mo.
    • Ethylene vinyl acetate copolymer, 33% vinyl acetate, supplied by Southwest Research Institute, San Antonio, Tex.
    • Methanol, ChromAR HPLC Grade, supplied by Mallinckrodt, St. Louis, Mo.
    • Acetonitrile, ChromAR HPLC Grade, supplied by Mallinckrodt, St. Louis, Mo.
    • Trifluoro Acetic Acid, 99%, Spectrochemical grade, supplied by Aldrich Chemicals, St. Louis, Mo.
    • Sodium Dodecyl Sulfate, 99%, supplied by EM Science
    • Ethanol, supplied by Mallinckrodt, St. Louis, Mo.
      HPLC Assays

An HPLC method was used to determine the rate of in vitro release of apomorphine HCl (“ApoH”) or loratidine (“LA”) from the implants. Chromatography was performed using a Zorbax SB-C 18 (250 mm×4.6 mm) column and 60% 0.1 trifluoro acetic acid in water, 15% methanol, 25% acetonitrile as the mobile phase, and a flow rate of 1 ml/min. The injection volume was 10 μl. Detection was accomplished by means of a UV/VIS detector at a wavelength of 270 nm. Instrument control and data acquisition were facilitated using a Waters Millennium (V 2.15) software package. The external calibration was obtained using ApoH or LA standard solutions.

Preparation of Implantable Devices

Implantable devices were prepared using an extrusion process in a Microtruder device (Rancastle, RC-025-CF-RF). In order to facilitate feeding into the extruder and to enable mixing of apomorphine and other substances to be incorporated into the implants, EVA was ground into smaller particle sizes prior to extrusion. The extrusion process was performed under argon gas to prevent oxidation of apomorphine. All blends of copolymer and drug(s) were prepared by rolling in a 120 ml amber bottle for approximately 10 minutes. The blend was then fed through the Microtruder. Parameters that were used for extrusion of ApoH/EVA implants are shown in Table 1, and parameters used for extrusion of implants that included triancinolone (“TA”), glutathione (“GSH”), and/or LA are shown in Table 2.

TABLE 1
Parameters for Extrusions of APO/EVA Implants
Formulations Zone Temperature (° F.)
(Weight Percentage) 1 2 3 Die
APO/EVA 180 185 190 185
(50:50)
APO/EVA 185 195 200 195
(60:40)
APO/EVA 215 230 240 250
(70:30)

TABLE 2
Parameters for Extrusions of APO/EVA/TA/GSH Implants
Formulations Zone Temperature (° F.)
(Weight Percentage) 1 2 3 Die
APO/EVA 190 195 205 200
(60:40)
APO/TA/EVA 215 230 240 248
(60:10:30)
APO/TA/GSH/EVA 215 235 245 255
(60:8:2:30)
APO/LA/EVA 215 226 232 230
(49:21:30)

All of the materials used during the extrusion process were protected from light to prevent light-catalyzed oxidation. The extruder was set to the required temperatures and allowed to reach equilibrium. After the extruder reached equilibrium, approximately 15 grams of blend were extruded and cut into 18-inch rods. The diameter was measured at 2.4 mm. The rods were then cut to the desired implant length of 26 mm.

The implants were then washed by placing them on an aluminum screen and immersing them in ethanol (approximately 50 ml per implant). The implants were washed for approximately 30, 60, or 120 minutes in the ethanol bath. The washed implants were air dried for 10 minutes and oven dried at 40° C. for 1 hour before drying in a vacuum over for 24 hours at 30° C. The implants were packaged into 20 ml glass vials in the presence of argon gas, sealed, and then sterilized by gamma irradiation.

Example 2 In Vitro Characterization of Extruded Implantable Devices

Extruded rods prepared as described above were characterized for total drug load and for rate of drug release.

Assessment of Drug Loading

Implants prepared with 70% ApoH:30% EVA were cut into 2 mm pieces, accurately weighed, and placed into 250 ml volumetric flasks. Approximately 200 ml of methanol was added to each flask and the solution was continuously stirred at room temperature until the implants was dissolved. The solution was then assayed for drug content.

The average ApoH content for unwashed, washed, and sterilized rods was between 66.9 and 67.9% ApoH, corresponding to 95.6 to 97% recovery.

Assessment of Drug Release

Experiments were performed to determine the rate of apomorphine released from the extruded rods. The medium for these studies was 0.5% sodium dodecyl sulfate (“SDS”). Preweighed rods were placed in 100 ml screw cap jars containing 50 ml of medium and placed on an orbital shaker. The orbital shaker was housed in an incubator maintained at 37° C. Sampling was performed by replacing the medium periodically. The samples obtained were analyzed by HPLC.

FIG. 1 shows the release of apomorphine from implants that have been loaded with 50, 60, or 70% apomorphine and that have been washed for 30, 60, or 120 minutes. The in vitro release data indicate that the implants released a high amount of apomorphine during the first few days, then reached steady state between about 3 and 7 days. As the drug load increased, the rate of release ApoH increased for implants washed up to one hour. The data from implants washed for 2 hours showed no significant difference in release rate for the different drug loading levels.

FIG. 2 shows the release of ApoH and LA from a 49% ApoH/21% LA/EVA implant. Both ApoH and LA reached steady state release rates within about 3 days.

Example 3 In Vivo Evaluation of Drug Loaded Implantable Devices

Four MPTP-lesioned, L-DOPA-naïve cynomolgus monkeys were administered three 2.4 mm diameter×2.6 cm length rod-shaped implantable devices prepared as described above, each containing 33% vinyl acetate and loaded with 98 mg+10% apomorphine HCl (68.5% apomorphine). Devices were implanted between the shoulder blades using a trocar. For comparison, three additional MPTP-lesioned, L-DOPA-naïve monkeys received pulsatile daily subcutaneous injections of apomorphine at a dosage of 0.2 mg/kg, which is the minimally-effective dose to achieve “ON” status in the animal.

All of the monkeys that received apomorphine implants were continuously in an “ON” state within one day after implantation, with an average steady state apomorphine level of approximately 0.5-1.0 ng/ml achieved after an initial burst. In contrast, animals that received pulsatile injections were “ON” for only approximately 90 minutes after each administration of apomorphine.

After 8.3 days (range 7-10) of daily apomorphine injections, all animals in the pulsatile injection group developed dyskinesias. However, in the implant group, no animal developed dyskinesia for the duration of the treatment (up to six months). The apomorphine EVA implants provided continuous plasma levels of apomorphine, allowing for continuous stimulation of striatal dopaminergic receptors without onset of dyskinesia, for the six month duration of the evaluation.

Although the foregoing invention has been described in some detail by way of illustration and examples for purposes of clarity of understanding, it will be apparent to those skilled in the art that certain changes and modifications may be practiced without departing from the spirit and scope of the invention. Therefore, the description should not be construed as limiting the scope of the invention, which is delineated by the appended claims.

All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3689634 *Sep 23, 1970Sep 5, 1972Ceskoslovenska Akademie VedProtracted activity oral hydrogel bead
US3717639 *May 4, 1967Feb 20, 1973Little Inc AProcess for the preparation of 1-(2-nitro-3,4-di-lower-alkoxybenzyl)isoquinolines
US4543256 *May 18, 1982Sep 24, 1985Northeastern University(-)-10,1L Methylenedioxy-N-N-propylnoraporphine and methods employing it for inhibiting the effects of epileptic seizures and for prevention and treatment of duodenal ulcers
US4622219 *Jun 17, 1983Nov 11, 1986Haynes Duncan HMethod of inducing local anesthesia using microdroplets of a general anesthetic
US4678809 *Feb 1, 1985Jul 7, 1987Michael PhillipsInjectable fomulations of disulfiram for the treatment of alcoholism
US4725442 *Apr 22, 1986Feb 16, 1988Haynes Duncan HMicrodroplets of water-insoluble drugs and injectable formulations containing same
US4818542 *Mar 31, 1986Apr 4, 1989The University Of Kentucky Research FoundationPorous microspheres for drug delivery and methods for making same
US4861627 *May 1, 1987Aug 29, 1989Massachusetts Institute Of TechnologyPreparation of multiwall polymeric microcapsules
US4883666 *Apr 29, 1987Nov 28, 1989Massachusetts Institute Of TechnologyControlled drug delivery system for treatment of neural disorders
US4897268 *Aug 3, 1987Jan 30, 1990Southern Research InstituteDrug delivery system and method of making the same
US4962091 *May 23, 1986Oct 9, 1990Syntex (U.S.A.) Inc.Controlled release of macromolecular polypeptides
US4983586 *Mar 29, 1988Jan 8, 1991University Of FloridaPharmaceutical formulations for parenteral use
US4994281 *Nov 10, 1987Feb 19, 1991Sanraku IncorporatedPolylactic acid microspheres and process for producing the same
US5024998 *Dec 11, 1989Jun 18, 1991University Of FloridaPharmaceutical formulations for parenteral use
US5114719 *Sep 14, 1989May 19, 1992Sabel Bernhard AExtended drug delivery of small, water-soluble molecules
US5128145 *Aug 2, 1991Jul 7, 1992Alza CorporationDosage form for Parkinson's disease, spasticity and muscle spasms
US5156844 *Feb 26, 1992Oct 20, 1992Brown University Research FoundationNeurological therapy system
US5562917 *Dec 23, 1994Oct 8, 1996Pentech Pharmaceuticals, Inc.Transdermal administration of apomorphine
US5601835 *Jan 12, 1994Feb 11, 1997Massachusetts Institute Of TechnologyPolymeric device for controlled drug delivery to the CNS
US5604198 *May 12, 1994Feb 18, 1997Poduslo; Joseph F.Method to enhance permeability of the blood/brain blood/nerve barriers to therapeutic agents
US5618553 *Jun 7, 1995Apr 8, 1997Houston Biotechnology IncorporatedMethods and compositions for the modulation of cell proliferation and wound healing
US5650173 *Oct 3, 1996Jul 22, 1997Alkermes Controlled Therapeutics Inc. IiPreparation of biodegradable microparticles containing a biologically active agent
US5654008 *Oct 10, 1996Aug 5, 1997Alkermes Controlled Therapeutics Inc. IiPreparation of biodegradable microparticles containing a biologically active agent
US5718921 *Aug 2, 1996Feb 17, 1998Massachusetts Institute Of TechnologyMicrospheres comprising polymer and drug dispersed there within
US5756483 *Mar 18, 1994May 26, 1998Merkus; Franciscus W. H. M.Pharmaceutical compositions for intranasal administration of apomorphine
US5770231 *Feb 28, 1997Jun 23, 1998Alkermes Controlled Therapeutics, Inc. IiMicroencapsulated 3-piperidinyl-substituted 1,2-benzisoxazoles 1,2-benzisothiazoles
US5770606 *Oct 20, 1995Jun 23, 1998Pentech Pharmaceuticals, Inc.Dosage forms and method for ameliorating male erectile dysfunction
US5939094 *Oct 8, 1996Aug 17, 1999Pentech Pharamaceticals, Inc.Transdermal administration of apomorphine
US5965168 *Jan 12, 1998Oct 12, 1999Alkermes Controlled Therapeutics, Inc. IiMicroencapsulated 3-piperidinyl-substituted 1,2-benzisoxazoles and 1,2-benzisothiazoles
US5980948 *Aug 16, 1996Nov 9, 1999Osteotech, Inc.Polyetherester copolymers as drug delivery matrices
US5994363 *Aug 24, 1998Nov 30, 1999Pentech Pharmaceuticals, Inc.Amelioration of apomorphine adverse effects
US6001845 *Jun 10, 1999Dec 14, 1999Schering CorporationCombination of phentolamine and apomorphine for the treatment of human sexual function and dysfunction
US6011043 *Jun 19, 1998Jan 4, 2000Schering CorporationCombination of phentolamine and apomorphine for the treatment of human sexual function and dysfunction
US6117454 *May 27, 1997Sep 12, 2000Medinova Medical Consulting GmbhDrug targeting to the nervous system by nanoparticles
US6136818 *Oct 8, 1999Oct 24, 2000Schering CorporationCombination of phentolamine and apomorphine for the treatment of human sexual function and dysfunction
US6203813 *Oct 9, 1998Mar 20, 2001Lance L. GoobermanPharmaceutical delivery device and method of preparation therefor
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US8017598May 16, 2007Sep 13, 2011Knopp Neurosciences, Inc.Compositions of R(+) and S(−) pramipexole and methods of using the same
US8188065Oct 1, 2009May 29, 2012Osteogenex Inc.Boldine compounds for promoting bone growth
US8263581Feb 11, 2010Sep 11, 2012Jdp Therapeutics, Inc.Non-sedating antihistamine injection formulations and methods of use thereof
US8314083Jul 2, 2010Nov 20, 2012Jdp Therapeutics, Inc.Non-sedating antihistamine injection formulations and methods of use thereof
US8460642Apr 25, 2012Jun 11, 2013OssiFi, Inc.Boldline compounds for promoting bone growth
US8475829 *Apr 6, 2007Jul 2, 2013Nupathe Inc.Implants for the treatment of dopamine associated states
US8475830 *Feb 29, 2008Jul 2, 2013Nupathe Inc.Implants for the treatment of dopamine associated states
US8513259Sep 21, 2011Aug 20, 2013Jdp Therapeutics, Inc.Non-sedating antihistamine injection formulations and methods of use thereof
US8519148Mar 14, 2008Aug 27, 2013Knopp Neurosciences, Inc.Synthesis of chirally purified substituted benzothiazole diamines
US8852623Jun 15, 2012Oct 7, 2014Titan Pharmaceuticals, Inc.Implantable polymeric device for sustained release of dopamine agonist
US20040101550 *Aug 24, 2001May 27, 2004Fred Windt-HankeTransdermal therapeutic system
US20040219191 *Aug 24, 2001Nov 4, 2004Karsten KuhnUse of a dopamine agonist with a short half-life for treating illnesses which can be treated by dopaminergic means
US20050031668 *May 27, 2004Feb 10, 2005Patel Rajesh A.Implantable polymeric device for sustained release of nalmefene
US20110159066 *Nov 2, 2010Jun 30, 2011Sebree Terri BMethods For Treating Parkinson's Disease
US20130189342 *Mar 16, 2011Jul 25, 2013Titan Pharmaceuticals, Inc.Heterogeneous implantable devices for drug delivery
US20130202673 *Mar 13, 2013Aug 8, 2013Titan Pharmaceuticals, Inc.Heterogeneous implantable devices for drug delivery
US20140221451 *Feb 7, 2014Aug 7, 2014The Trustees Of The University Of PennsylvaniaImplants for the treatment of dopamine associated states
WO2010022140A1 *Aug 19, 2009Feb 25, 2010Knopp Neurosciences, Inc.Compositions and methods of using (r)-pramipexole
WO2010039920A2 *Oct 1, 2009Apr 8, 2010Osteogenex Inc.Boldine compounds for promoting bone growth
Classifications
U.S. Classification424/426, 514/295
International ClassificationA61P25/16, A61K31/485, A61K9/16, A61K31/381, A61L31/16, A61K31/48, A61K9/14, A61L31/04, A61K31/428, A61K31/4045, A61K9/00
Cooperative ClassificationA61L2420/04, A61L2300/62, A61L2300/606, A61L2300/602, A61L31/16, A61L31/125, A61L31/10, A61K31/198, A61K9/0024, A61L31/146, A61K31/4045, A61L31/048, A61K31/381, A61K9/1635, A61K9/146, A61K31/48, A61K31/485, A61L2300/41, A61L2300/20, A61L2300/40, A61K31/428
European ClassificationA61L31/04H, A61K9/00M5D, A61K31/48, A61K31/485, A61K9/16H6B, A61K31/428, A61K31/381, A61K31/4045, A61K9/14H6, A61L31/16
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