Osmotic Device Containing Amantadine and an Osmotic Salt

• US 20130115249A1
• Filed: 07/18/2012
• Published: 05/09/2013
• Est. Priority Date: 12/03/2004
• Status: Active Grant

• Current Assignee: Osmotica Kereskedelmi Es Szolgaltato Kft (Osmotica Pharmaceuticals Plc)
• Original Assignee: Osmotica Kereskedelmi Es Szolgaltato Kft (Osmotica Pharmaceuticals Plc)
• Inventors: VERGEZ, Juan A., FAOUR, Joaquina, PASTINI, Ana C., RICCI, Marcelo A., MEYER, Glenn A., BIGATTI, Guido S., COPPARI, Marcelo A., BEFUMO, Marcelo F., FELEDER, Ethel C.
• Granted Patent: US 8,574,626 B2
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas

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.

Claims

1-49. -49. (canceled)

50. 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.

51. 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;

b) the amantadine salt and osmotic salt have an ion in common;

c) the weight ratio of amantadine salt to osmotic salt is in the range of 2;

1 to 30;

1;

d) 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;

e) amantadine salt is released through the one or more passageways according to a sigmoidal release profile when the osmotic device is exposed to an aqueous environment of use; and

f) the osmotic device further comprises a drug-containing coat comprising an active ingredient, wherein the coat is exterior to or on the exterior of the semipermeable membrane.

52. The osmotic device of claim 51, 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.

53. The osmotic device of claim 51, wherein the amantadine salt is an inorganic salt.

54. The osmotic device of claim 53, wherein the amantadine salt is a mineral acid salt.

55. The osmotic device of claim 53, wherein the amantadine salt is amantadine hydrochloride.

56. The osmotic device of claim 51, wherein the osmotic salt is a metal halide.

57. The osmotic device of claim 56, wherein the osmotic salt is an alkali metal halide or an earth metal halide.

58. The osmotic device of claim 56, wherein the osmotic salt is sodium chloride.

59. The osmotic device of claim 51, wherein the amantadine salt is amantadine hydrochloride and the osmotic salt is sodium chloride.

60. The osmotic device of claim 51, wherein the ion in common is chloride ion.

61. The osmotic device of claim 51, wherein the weight ratio of amantadine salt to osmotic salt ranges from 2:

1 to 30;

1 or from 4;

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 >

/=6% wt., the amount of cellulose acetate grade 1 in the semipermeable membrane is <

1=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 >

/=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 to 0.4;

1 or is 0.25;

1 to 0.45;

1

62. The osmotic device of claim 51, 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, COX-2 inhibitor.

63. The osmotic device of claim 62, wherein the anti-Parkinson drug is selected from the group consisting of amantadine, selegiline, rasagiline, safinamide, diplagurant and tozadenant.

64. The osmotic device of claim 62, wherein the anti-Parkinson drug is amantadine.

65. The osmotic device of claim 51 further comprising a second active ingredient in the core.

66. The osmotic device of claim 65, 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, COX-2 inhibitor.

67. The osmotic device of claim 66, 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.

68. The osmotic device of claim 66, wherein the narcotic analgesic in the core is selected from the group consisting of codeine, dihydrocodeine, hydrocodone, hydromorphone, levorphanol, morphine, oxycodone and tapentadol.

69. The osmotic device of claim 51, wherein the amantadine salt is released from the core according to a sigmoidal release profile as follows:

70. The osmotic device of claim 51, wherein the amantadine is released from the core according to the following sigmoidal release profile:

71. The osmotic device of claim 51, wherein the amantadine is released from the core according to the following sigmoidal release profile:

72. The osmotic device of claim 51, wherein the amantadine is released from the core according to the following sigmoidal release profile:

73. The osmotic device of claims 64, wherein amantadine is released from the drug-containing coat in an immediate release manner.

74. The osmotic device of claim 51, 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.

75. The osmotic device of claim 73, wherein the unitary core comprises less than 6% of NaCl w/w based upon the weight of the uncoated core, and the semipermeable membrane comprises more than 25% w/w of cellulose acetate grade 1 based upon the weight of the semipermeable membrane.

76. The osmotic device of claim 75, wherein the amantadine is released from the core according to the following sigmoidal release profile:

77. The osmotic device of claim 73, 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.

78. The osmotic device of claim 77, wherein the amantadine is released from the core according to the following sigmoidal release profile:

79. The osmotic device of claim 73, 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.

80. The osmotic device of claim 79, wherein the amantadine is released from the core according to the following sigmoidal release profile:

81. The osmotic device of claim 51, wherein the unitary core comprises less than 6% of NaCl w/w, based upon the weight of the uncoated core.

82. The osmotic device of claim 81, wherein the amantadine is released from the core according to the following sigmoidal release profile:

83. The osmotic device of claim 51, wherein the unitary core comprises more than 6% of NaCl w/w, based upon the weight of the uncoated core.

84. The osmotic device of claim 83, wherein the amantadine is released from the core according to the following sigmoidal release profile:

85. The osmotic device of claim 51, wherein the core and semipermeable membrane comprise:

86. The osmotic device of claim 51, wherein in the core and semipermeable membrane comprise:

87. The osmotic device of claim 51, wherein the core and semipermeable membrane comprise:

88. The osmotic device of claim 51 comprising any of the following formulations:

89. The osmotic device of claim 62 or 66, 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-B-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.

90. 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 claim 51 or 61.

91. 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 claim 51 or 61.

92. The method of claim 90, 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.

93. The method of claim 92, 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) is administered an osmotic device comprising amantadine and a MAO-B inhibitor without concomitant administration of levodopa to the subject.

95. The method of claim 92, 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.

96. The method of claim 92, 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.

97. The method of claim 92, wherein the osmotic device provides a peak plasma level for amantadine within 6 to 8 hours after administration thereof to a subject.

98. The method of claim 97, wherein an osmotic device comprising 160 mg to 320 mg of amantadine provides an AUC_∞

of about 6670 ng·

h/ml to 19000 ng·

h/ml for amantadine when administered once daily.

99. The method of claim 98, wherein the osmotic device provides a Cmax of about 265 ng/ml to 720 ng/ml when administered.

94. (canceled)