Claims for Patent: 8,574,626

Summary for Patent: 8,574,626

Title:	Osmotic device containing amantadine and an osmotic salt
Abstract:	The osmotic devices of the present invention contain a unitary core comprising a salt of amantadine and an osmotic salt, wherein the two salts have an ion in common. The release rate of the amantadine is a sigmoidal release. The osmotic device includes a semipermeable membrane having a controlled porosity that can be adapted as needed to cooperate with the osmotic salt in providing a predetermined drug release profile. The osmotic salt need not be coated and it is in admixture with the amantadine salt. The osmotic device further includes a drug-containing coat external to the semipermeable membrane. The osmotic device can include one or more additional drugs in the core and/or the drug-containing coat.
Inventor(s):	Vergez; Juan A. (Buenos Aires, AR), Faour; Joaquina (Buenos Aires, AR), Pastini; Ana C. (Buenos Aires, AR), Bigatti; Guido S. (Buenos Aires, AR), Meyer; Glenn A. (Wilmington, NC), Feleder; Ethel C. (Buenos Aires, AR), Ricci; Marcelo A. (Buenos Aires, AR), Coppari; Marcelo A. (Buenos Aires, AR), Befumo; Marcelo F. (Buenos Aires, AR)
Assignee:	Osmotica Kereskedelmi es Szolgaltato KFT (Budapest, HU)
Application Number:	13/551,755
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,574,626
Patent Claims:	1. An osmotic device comprising a unitary core surrounded by a semipermeable membrane having at least one passageway there through, wherein: a) the unitary core comprises a mixture of amantadine salt, osmotic salt, and at least one other pharmaceutically acceptable excipient, and the weight ratio of amantadine salt to osmotic salt ranges from 2:1 to 30:1; b) the osmotic salt is not coated with a release rate controlling coating; c) the permeability of the semipermeable membrane is adapted to cooperate with the osmotic salt to control the release profile of amantadine salt from the osmotic device; d) the amantadine salt and osmotic salt have an ion in common; e) amantadine salt is released through the one or more passageways according to a sigmoidal controlled release profile, optionally wherein release of amantadine salt is delayed for a period of time, when the osmotic device is exposed to an aqueous environment of use; f) the semipermeable membrane comprises a cellulose acetate grade 1 and a cellulose acetate grade 2, wherein the weight ratio of a cellulose acetate grade 1 to the total amount of cellulose acetates ranges from 0:1 to 1:1, wherein the cellulose acetate grade 1 comprises 7-10% by wt. of hydroxyl groups, 30-36% by wt. of acetyl groups and a viscosity of 200-280 seconds, and cellulose acetate grade 2 comprises 3-5% by weight of hydroxyl groups, 37-43% by wt. of acetyl groups and a viscosity of 6.0-45.0 seconds; and g) the osmotic device further comprises a drug-containing coat comprising an active ingredient, wherein the coat is external to the semipermeable membrane. 2. The osmotic device of claim 1 wherein: the semipermeable membrane comprises 1.7%-15.0% by wt. of a plasticizer, 33.3%-61.2% by wt. of cellulose acetate grade 1, and 33.3%-61.2% by wt. of cellulose acetate grade 2, wherein the cellulose acetate grade 1 comprises 7-10% by wt. of hydroxyl groups, 30-36% by wt. of acetyl groups and has a viscosity of 200-280 seconds, and the cellulose acetate grade 2 comprises 3-5% by weight of hydroxyl groups, 37-43% by wt. of acetyl groups and has a viscosity of 6.0-45.0 seconds. 3. The osmotic device of claim 2, wherein the device further comprises an inert, completely erodible or water soluble polymer coat partially or completely surrounding and in contact with the semipermeable membrane, and the drug-containing coat is external to the inert polymer coat. 4. The osmotic device of claim 2, wherein the amantadine salt is an inorganic salt. 5. The osmotic device of claim 4, wherein the amantadine salt is a mineral acid salt. 6. The osmotic device of claim 4, wherein the amantadine salt is amantadine hydrochloride. 7. The osmotic device of claim 2, wherein the osmotic salt is a metal halide. 8. The osmotic device of claim 7, wherein the osmotic salt is an alkali metal halide or an earth metal halide. 9. The osmotic device of claim 7, wherein the osmotic salt is sodium chloride. 10. The osmotic device of claim 2, wherein the amantadine salt is amantadine hydrochloride and the osmotic salt is sodium chloride. 11. The osmotic device of claim 2, wherein the ion in common is chloride ion. 12. The osmotic device of claim 1, wherein the weight ratio of amantadine salt to osmotic salt ranges from 2:1 to 30:1, the osmotic device provides a sigmoidal release profile, and: a. the amount of osmotic salt in the core is <6% wt., the amount of cellulose acetate grade 1 in the semipermeable membrane is >25%, the ratio of cellulose acetate grade 1 to total amount of cellulose acetate in the semipermeable membrane is >0.25:1 or is 0.3:1 to 0.7:1; b. the amount of osmotic salt in the core is .gtoreq.6% wt., the amount of cellulose acetate grade 1 in the semipermeable membrane is .ltoreq.25%, the ratio of cellulose acetate grade 1 to total amount of cellulose acetate in the semipermeable membrane is <0.25:1; or c. the amount of osmotic salt in the core is .gtoreq.6% wt., the amount of cellulose acetate grade 1 in the semipermeable membrane is .gtoreq.25%, the ratio of cellulose acetate grade 1 to total amount of cellulose acetate in the semipermeable membrane is 0.25:1 to 0.4:1 or is 0.25:1 to 0.45:1. 13. The osmotic device of claim 2, wherein the active ingredient in the drug-containing coat is selected from the group consisting of an antidepressant, anxiolytic agent, anti-Parkinson drug, dopamine agonist, COMT inhibitor, MAO-B inhibitor, anticholinergic, benzodiazepine, SSRI, nonsteroidal anti-inflammatory agent, non-narcotic analgesic, narcotic analgesic, A2A antagonist, aromatic-L-amino-acid decarboxylase inhibitor, tricyclic antidepressant, tetracyclic antidepressant, dopamine agonist, and COX-2 inhibitor. 14. The osmotic device of claim 13, wherein the anti-Parkinson drug is selected from the group consisting of amantadine, selegiline, rasagiline, safinamide, diplagurant and tozadenant. 15. The osmotic device of claim 13, wherein the anti-Parkinson drug is amantadine. 16. The osmotic device of claim 2 further comprising a second active ingredient in the core. 17. The osmotic device of claim 16, wherein the second active ingredient in the core is selected from the group consisting of antidepressant, anxiolytic agent, anti-Parkinson drug, dopamine agonist, COMT inhibitor, MAO-B inhibitor, anticholinergic, benzodiazepine, SSRI, nonsteroidal anti-inflammatory agent, non-narcotic analgesic, narcotic analgesic, A2A antagonist, aromatic-L-amino-acid decarboxylase inhibitor, tricyclic antidepressant, tetracyclic antidepressant, dopamine agonist, and COX-2 inhibitor. 18. The osmotic device of claim 17, wherein the anti-Parkinson drug in the core is selected from the group consisting of ropinirole, selegiline, diplagurant, tozadenant, levodopa and a combination of levodopa-carbidopa. 19. The osmotic device of claim 17, wherein the narcotic analgesic in the core is selected from the group consisting of codeine, dihydrocodeine, hydrocodone, hydromorphone, levorphanol, morphine, oxycodone and tapentadol. 20. The osmotic device of claim 2, wherein the amantadine salt is released from the core according to a sigmoidal release profile as follows: TABLE-US-00036 Time (hours) Amount Released 0-3 Not less than 5% 0-5 Not less than 18% 0-8 Not less than 39% 0-16 Not less than 76%. 21. The osmotic device of claim 2, wherein the amantadine is released from the core according to the following sigmoidal release profile: TABLE-US-00037 Performance Performance Time Minimum Maximum (hrs) (%) (%) 0.5 0 50 1 25 55 2.5 45 75 4 65 95 8 85 100. 22. The osmotic device of claim 2, wherein the amantadine is released from the core according to the following sigmoidal release profile: TABLE-US-00038 Performance Performance Time Minimum Maximum (hrs) (%) (%) 0.5 0 40 1 10 40 2.5 30 60 4 55 85 8 80 100. 23. The osmotic device of claim 2, wherein the amantadine is released from the core according to the following sigmoidal release profile: TABLE-US-00039 Performance Performance Time Minimum Maximum (hrs) (%) (%) 0.5 0 35 1 15 45 2.5 45 75 4 65 95 8 85 100. 24. The osmotic device of claim 15, wherein amantadine is released from the drug-containing coat in an immediate release manner. 25. The osmotic device of claim 1, wherein the weight ratio of amantadine salt to osmotic salt ranges from 4:1 to 30:1, and the semipermeable membrane comprises a weight ratio of a cellulose acetate grade 1 to the total amount of cellulose acetates from 0.3:1 to 0.7:1. 26. The osmotic device of claim 12, wherein the unitary core comprises less than 6% of NaCl w/w based upon the weight of the uncoated core, the semipermeable membrane comprises more than 25% w/w of cellulose acetate grade 1 based upon the weight of the semipermeable membrane, and the amantadine is released from the core according to the following sigmoidal release profile: TABLE-US-00040 Performance Performance Time Minimum Maximum (hrs) (%) (%) 1 0 4 3 16 27 5 35 59 8 55 83 12 77 100 16 84 100 24 86 100. 27. The osmotic device of claim 12, wherein the unitary core comprises 6% or more of NaCl w/w, based upon the weight of the uncoated core, and the semipermeable membrane comprises 25% w/w or more of cellulose acetate grade 1, based upon the weight of the semipermeable membrane, and the ratio of cellulose acetate grade 1 to the total amount of cellulose acetate in the semipermeable membrane is 0.25:1 to 0.45:1, and the amantadine is released from the core according to the following sigmoidal release profile: TABLE-US-00041 Performance Performance Time Minimum Maximum (hrs) (%) (%) 1 0 4 3 5 20 5 18 43 8 39 73 12 62 99 16 76 100 24 84 100. 28. The osmotic device of claim 12, wherein the unitary core comprises 6% or more of NaCl w/w, based upon the weight of the uncoated core, and the semipermeable membrane comprises 25% w/w or less of cellulose acetate grade 1, based upon the weight of the semipermeable membrane, and the ratio of cellulose acetate grade 1 to the total amount of cellulose acetate in the semipermeable membrane is 0.25:1 or less, and the amantadine is released from the core according to the following sigmoidal release profile: TABLE-US-00042 Performance Performance Time Minimum Maximum (hrs) (%) (%) 1 0 2 3 0 6 5 5 21 8 15 55 12 29 84 16 42 100 24 62 100. 29. The osmotic device of claim 2, wherein the unitary core comprises less than 6% of NaCl w/w, based upon the weight of the uncoated core. 30. The osmotic device of claim 29, wherein the amantadine is released from the core according to the following sigmoidal release profile: TABLE-US-00043 Performance Performance Time Minimum Maximum (hrs) (%) (%) 1 0 4 3 16 27 5 35 59 8 55 83 12 77 100 16 84 100 24 86 100. 31. The osmotic device of claim 2, wherein the unitary core comprises more than 6% of NaCl w/w, based upon the weight of the uncoated core. 32. The osmotic device of claim 31, wherein the amantadine is released from the core according to the following sigmoidal release profile: TABLE-US-00044 Performance Performance Time Minimum Maximum (hrs) (%) (%) 1 0 4 3 5 20 5 18 43 8 39 73 12 62 99 16 76 100 24 84 100. 33. The osmotic device of claim 1, wherein the core comprises: TABLE-US-00045 Ingredient Amount (mg) Core Amantadine HCl 100 First Diluent 7-35 Binder 3-10 Glidant 0.1-2 Lubricant 0.3-3 Sodium Chloride 3.33-50 Second Diluent 3-20. 34. The osmotic device of claim 1, wherein in the core comprises: TABLE-US-00046 Ingredient Amount (mg) Core Amantadine HCl 150 First Diluent 10-55 Binder 4.5-15 Glidant 0.2-3 Lubricant 0.5-5 Sodium Chloride 5-75 Second Diluent 4.5-30. 35. The osmotic device of claim 1, wherein the core comprises: TABLE-US-00047 Ingredient Amount (mg) Core Amantadine HCl 300 First Diluent 20-100 Binder 10-30 Glidant 0.2-5 Lubricant 1-7 Sodium Chloride 10-150 Second Diluent 10-60. 36. The osmotic device of claim 1 comprising any of the following formulations: TABLE-US-00048 Ingredient Amount (mg) A B C Amantadine HCl Strengths 160 240 320 Amantadine HCl 100 180 260 First Diluent 10-42 20-67 30-106 Binder 3-12 4.5-22 10-30 Glidant 0.1-2 0.2-3 0.3-4 Lubricant 0.3-3 0.5-5 1-7 Sodium Chloride 0-50 0-75 0-150 Second Diluent 3-20 4.5-30 10-60 First Coating (semipermeable membrane) Cellulose ester 1 0-20 0-25 0-25 Cellulose ester 2 0-20 0-25 0-25 Plasticizer 0.2-2 0.3-3 -0.4-4 Inert Coating (optional coating) Film forming polymer 0-10 5-15 7-20 Second Coating (drug-containing coating exterior to semipermeable membrane) Amantadine HCl 60 60 60 Film forming polymer 5-25 5-25 5-25 wherein the total amount of cellulose acetate is greater than zero. 37. The osmotic device of claim 13 or 17, wherein the active ingredient in the drug-containing coat or the second active ingredient in the core is independently selected from the group consisting of amantadine, buspirone, citalopram, diplagurant, levodopa, combination of levodopa and carbidopa, benserezide, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine; entacapone, tolcapone, BIA 9-1067 (opicapone), selegiline, rasagiline, safinamide; trihexyphenidyl, benztropine, orphenadrine, procyclidine, ethopropazine, glycopyrrolate, alprazolam, lorazepam, diazepam, clonazepam, fluoxetine, sertraline, paroxetine, fluvoxamine, mirtazapine, doxepin, imipramine, desipramine, trazodone, nortriptyline, minocycline, acetaminophen, aspirin, diclofenac, diflusinal, etodolac, fenbufen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin, tramadol zomepiracadenosine, codeine, dihydrocodeine, hydrocodone, hydromorphone, levorphanol, morphine, oxycodone, tapentadol, preladenant, tozadenant, DT-1133, DT1687, lacosamide, gabapentin, indomethacin, steroids, fluorocortisone, desmopressin, oxybutynin, tolterodine, hyoscyamine, midodrine, phenylephrine, phenylpropanolamine, baclofen, dantrolene, domperidone, mosapride, tegaserod, donepezil, memantine, riluzole, rivastigmine, coenzyme Q10, vitamin E, vitamin C, creatine, ginkgo biloba (plant material or extract), nicotinamide, carnitine, piribedil, buspirone, clozapine, quetiapine, olanzapine, risperidone, aripiprazole, methylphenidate, modafinil, dipraglurant, fipamezole, AFQ056, AQW-051, Neu-120, olesoxime, 17-.beta.-hydroxyepiandrosterone, (+)-phenserine, clavulanic acid, HE-3286, YM-50018, MCD-386, AV-101, SUVN-502, EVP-0334, V-81444, SCH-900800, ADX-88178, NNZ-2591, AEOL-11207, Proximagen, IC-200214, SIG-1012, ADL-5510, TrkB PAM, and G-79. 38. A method of treating a condition, disease or disorder that is therapeutically responsive to amantadine therapy, comprising administering to a subject in need thereof an osmotic device according to any one of claims 2 or 12. 39. A method of treating a condition, disease or disorder that is therapeutically responsive to a combination of amantadine and a second active ingredient, comprising administering to a subject in need thereof an osmotic device according to any one of claims 2 or 12. 40. The method of claim 38, wherein the condition, disease or disorder is selected from the group consisting of Parkinson's disease, Parkinsonism, Parkinsonism associated with cerebral arteriosclerosis, Parkinsonism associated with neurodegenerative disease, dementia associated with Parkinson's disease, senile dementia, relapse in multiple sclerosis thereby providing a reduction thereof, drug-induced extrapyramidal reactions, viral infection, tremors, akinesia, dyskinesia, attention deficit hyperactivity disorder, SSRI-induced sexual dysfunction, levodopa induced dyskinesia, bradykinesia, impulse control disorder, addiction, substance dependence, resistant unipolar depression, bipolar disorder, pain, refractory absence seizure, bipolar disorder, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis, fatigue associated with multiple sclerosis, neurodegenerative disease, neuropathic pain, post-operative pain, refractory absence seizures, brain injury, traumatic brain injury, cerebrovascular condition, movement disorder, cranial nerve disorder, and neuropsychiatric disorders. 41. The method of claim 40, wherein the condition, disease or disorder is Parkinson's disease or Parkinsonism and the subject is administered: a) an osmotic device comprising amantadine as the sole drug or active ingredient; b) an osmotic device comprising amantadine as the sole drug or active ingredient and is concomitantly administered levodopa; or c) an osmotic device comprising amantadine and a MAO-B inhibitor without concomitant administration of levodopa to the subject. 42. The method of claim 40, wherein the condition, disease or disorder is fatigue associated with multiple sclerosis and the subject is administered an osmotic device comprising amantadine as the sole drug or active ingredient. 43. The method of claim 40, wherein the condition, disease or disorder is pain, and the subject is administered an osmotic device comprising amantadine and an active agent selected from the group consisting of a narcotic analgesic, gabapentin and lacosamide. 44. The method of claim 40, wherein the osmotic device provides a peak plasma level for amantadine within 6 to 8 hours after administration thereof to a subject. 45. The method of claim 44, wherein an osmotic device comprising 160 mg to 320 mg of amantadine provides an AUC.sub..infin. of about 6670 ng.h/ml to 19000 ng.h/ml for amantadine when administered once daily. 46. The method of claim 45, wherein the osmotic device provides a Cmax of about 265 ng/ml to 720 ng/ml when administered. 47. The method of claim 39, wherein the condition, disease or disorder is fatigue and the subject is administered an osmotic device comprising amantadine and baclofen. 48. The method of claim 47, wherein: a. the core comprises amantadine and baclofen; b. the core comprises amantadine and the drug-containing coat comprises baclofen; c. the core comprises amantadine, and the drug-containing coat comprises amantadine and baclofen; or d. the core comprises amantadine and baclofen, and the drug-containing coat comprises amantadine and baclofen. 49. The method of claim 48, wherein the osmotic device comprises 65 to 95 mg, 75 to 97.5 mg, 97.5 to 142.5 mg, about 75 to about 100 mg, 80 to 200 mg, 100 mg, 150 mg, 160 mg, 180 mg or 200 mg of amantadine or salt thereof. 50. The method of claim 39, wherein the condition, disease or disorder is attention deficit hyperactivity disorder and the subject is administered an osmotic device comprising amantadine and methylphenidate. 51. The method of claim 50, wherein: a. the core comprises amantadine and methylphenidate; b. the core comprises amantadine and the drug-containing coat comprises methylphenidate; c. the core comprises amantadine, and the drug-containing coat comprises amantadine and methylphenidate; or d. the core comprises amantadine and methylphenidate, and the drug-containing coat comprises amantadine and methylphenidate. 52. The method of claim 51, wherein the osmotic device comprises about 50 mg to about 75 mg, 65 to 320 mg or 100 to 600 mg of amantadine or salt thereof. 53. The method of claim 39, wherein the osmotic device comprises about 50 mg to about 75 mg, 65 to 320 mg or 100 to 600 mg of amantadine or salt thereof. 54. The method of claim 38, wherein the osmotic device comprises about 50 mg to about 75 mg, 65 to 320 mg or 100 to 600 mg of amantadine or salt thereof. 55. The osmotic device of claim 2, wherein the osmotic device comprises about 50 mg to about 75 mg, 65 to 320 mg or 100 to 600 mg of amantadine or salt thereof. 56. The osmotic device of claim 12, wherein the osmotic device comprises about 50 mg to about 75 mg, 65 to 320 mg or 100 to 600 mg of amantadine or salt thereof. 57. The osmotic device of claim 12, wherein the weight ratio of amantadine salt to osmotic salt ranges from 4:1 to 30:1. 58. The method of claim 52, wherein the osmotic device comprises about 50 to 65 mg, 65 to 95 mg, about 75 to about 100 mg, 80 to 200 mg, about 100 to about 300 mg, 160 to 320 mg or 200 to 500 mg of amantadine or salt thereof. 59. The method of claim 58, wherein the osmotic device comprises about 75 to 97.5 mg, 97.5 to 142.5 mg, 200 mg to 400 mg, 100 mg, 150 mg, 160 mg or 180 mg of amantadine or salt thereof. 60. The method of claim 59, wherein the osmotic device comprises 200 mg, 240 mg, 250 mg, 260 mg, 300 mg or 320 mg of amantadine or salt thereof. 61. The method of claim 53, wherein the osmotic device comprises about 50 to 65 mg, 65 to 95 mg, about 75 to about 100 mg, 80 to 200 mg, about 100 to about 300 mg, 160 to 320 mg or 200 to 500 mg of amantadine or salt thereof. 62. The method of claim 61, wherein the osmotic device comprises about 75 to 97.5 mg, 97.5 to 142.5 mg, 200 mg to 400 mg, 100 mg, 150 mg, 160 mg or 180 mg of amantadine or salt thereof. 63. The method of claim 62, wherein the osmotic device comprises 200 mg, 240 mg, 250 mg, 260 mg, 300 mg or 320 mg of amantadine or salt thereof. 64. The method of claim 54, wherein the osmotic device comprises about 50 to 65 mg, 65 to 95 mg, about 75 to about 100 mg, 80 to 200 mg, about 100 to about 300 mg, 160 to 320 mg or 200 to 500 mg of amantadine or salt thereof. 65. The method of claim 64, wherein the osmotic device comprises about 75 to 97.5 mg, 97.5 to 142.5 mg, 200 mg to 400 mg, 100 mg, 150 mg, 160 mg or 180 mg of amantadine or salt thereof. 66. The method of claim 65, wherein the osmotic device comprises 200 mg, 240 mg, 250 mg, 260 mg, 300 mg or 320 mg of amantadine or salt thereof. 67. The osmotic device of claim 55, wherein the osmotic device comprises about 50 to 65 mg, 65 to 95 mg, about 75 to about 100 mg, 80 to 200 mg, about 100 to about 300 mg, 160 to 320 mg or 200 to 500 mg of amantadine or salt thereof. 68. The osmotic device of claim 67, wherein the osmotic device comprises about 75 to 97.5 mg, 97.5 to 142.5 mg, 200 mg to 400 mg, 100 mg, 150 mg, 160 mg or 180 mg of amantadine or salt thereof. 69. The osmotic device of claim 68, wherein the osmotic device comprises 200 mg, 240 mg, 250 mg, 260 mg, 300 mg or 320 mg of amantadine or salt thereof. 70. The osmotic device of claim 56, wherein the osmotic device comprises about 50 to 65 mg, 65 to 95 mg, about 75 to about 100 mg, 80 to 200 mg, about 100 to about 300 mg, 160 to 320 mg or 200 to 500 mg of amantadine or salt thereof. 71. The osmotic device of claim 70, wherein the osmotic device comprises about 75 to 97.5 mg, 97.5 to 142.5 mg, 200 mg to 400 mg, 100 mg, 150 mg, 160 mg or 180 mg of amantadine or salt thereof. 72. The osmotic device of claim 71, wherein the osmotic device comprises 200 mg, 240 mg, 250 mg, 260 mg, 300 mg or 320 mg of amantadine or salt thereof.