PHARMACEUTICAL FORMULATIONS OF PIMAVANSERIN

• US 20070264330A1
• Filed: 05/15/2007
• Published: 11/15/2007
• Est. Priority Date: 05/15/2006
• Status: Abandoned Application

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Schlienger, Nathalie, Thygesen, Mikkel, Ragnar-Tolf, Bo
• Application Number:
  US11/749,110
• Publication Number:
  US 20070264330A1
• Time in Patent Office: Days
• US Class Current: 424/464
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2059 Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/28 Dragees; Coated pills or tablets , e.g. with film or compression coating A61K9/2072 takes precedence, e.g. partially coated tablets A61K9/2072, coated multilayer tablets A61K9/2086, tablets with drug-coated core A61K9/209
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Abstract

Disclosed herein are stable pharmaceutical formulations of pimavanserin, which is useful for treating conditions associated with serotonin receptors.

Claims

1. A pharmaceutical composition, comprising:

pimavanserin; and

at least one pharmaceutically acceptable excipient selected from the group consisting of a sugar, a starch, a cellulose preparation, silicon dioxide aerosol, gelatin, calcium phosphate dibasic, sodium lauryl sulfate, magnesium stearate, sodium stearyl fumarate, talc, polyethylene glycol, and polyvinylpyrrolidone, and combinations thereof.

2. The composition of claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of a sugar, pregelatinized starch, partially pregelatinized starch, microcrystalline cellulose, silicified microcrystalline cellulose, a lactose-cellulose blend, methyl cellulose, silicon dioxide aerosol, gelatin, calcium phosphate dibasic, sodium lauryl sulfate, magnesium stearate, sodium stearyl fumarate, talc, polyethylene glycol, and polyvinylpyrrolidone, and combinations thereof.

3. The composition of claim 2, wherein the silicified microcrystalline cellulose is PROSOLV®

90 or PROSOLV®

50.

4. The composition of claim 2, wherein the silicified microcrystalline cellulose is PROSOLV®

HD90.

5. The composition of claim 2, wherein the silicified microcrystalline cellulose comprises microcrystalline cellulose, colloidal silicon dioxide, colloidal anhydrous silica, and light anhydrous silicic acid.

6. The composition of claim 2, wherein the partially pregelatinized starch is STARCH 1500®

.

7. The composition of claim 2, wherein the lactose-cellulose blend is CELLACTOSE®

80.

8. The composition of claim 1, wherein the pharmaceutically acceptable excipient is selected from the group consisting of pregelatinized starch, partially pregelatinized starch, silicified microcrystalline cellulose, a lactose-cellulose blend, methyl cellulose, sodium stearyl fumarate, and polyvinylpyrrolidone, and combinations thereof.

9. The pharmaceutical composition of claim 1, wherein the pimavanserin is pimavanserin tartrate.

10. The pharmaceutical composition of claim 9, wherein the pimavanserin tartrate is crystalline Form A.

11. The pharmaceutical composition of claim 9, wherein the pimavanserin tartrate is crystalline Form C.

12. The pharmaceutical composition of claim 1, comprising a silicon dioxide aerosol.

13. The composition of claim 12, comprising at least about 0.1% by weight of the silicon dioxide aerosol.

14. The composition of claim 12, comprising at least about 0.5% by weight of the silicon dioxide aerosol.

15. The composition of claim 12, comprising at least about 1.0% by weight of the silicon dioxide aerosol.

16. The composition of claim 12, wherein the silicon dioxide aerosol has a specific surface area from about 175 to about 225 m²/g.

17. The composition of claim 16, wherein the silicon dioxide aerosol is AEROSIL®

200.

18. The composition of claim 12, comprising lactose, microcrystalline cellulose, and magnesium stearate.

19. The composition of claim 18, comprising at least about 50% by weight lactose, at least about 5% by weight microcrystalline cellulose, and at least about 0.5% by weight magnesium stearate.

20. The composition of claim 18, comprising at least about 65% by weight lactose, at least about 10% by weight microcrystalline cellulose, and at least about 1% by weight magnesium stearate.

21. The composition of claim 1, comprising lactose, magnesium stearate, and silicified microcrystalline cellulose.

22. The composition of claim 21, comprising at least about 50% by weight lactose, at least about 0.5% by weight magnesium stearate, and at least about 5% by weight silicified microcrystalline cellulose.

23. The composition of claim 21, comprising at least about 65% by weight lactose, at least about 1% by weight magnesium stearate, and at least about 10% by weight silicified microcrystalline cellulose.

24. The composition of claim 1, comprising partially pregelatinized starch, magnesium stearate, and silicified microcrystalline cellulose.

25. The composition of claim 24, comprising at least about 50% by weight silicified microcrystalline cellulose, at least about 0.5% by weight magnesium stearate, and at least about 5% by weight partially pregelatinized starch.

26. The composition of claim 24, comprising at least about 65% by weight silicified microcrystalline cellulose, at least about 0.5% by weight magnesium stearate, and at least about 5% by weight partially pregelatinized starch.

27. The composition of claim 24, comprising at least about 75% by weight silicified microcrystalline cellulose, at least about 1.0% by weight magnesium stearate, and at least about 5% by weight partially pregelatinized starch.

28. The composition of claim 1, comprising an additional antipsychotic agent.

29. The composition of claim 28, wherein the additional antipsychotic agent is selected from the group consisting of chlorpromazine, mesoridazine, prochlorperazine, thioridazine, Fluphenazine, Perpehnazine, Trifluoperazine, haloperidol, pimozide, clozapine, loxapine, olanzapine, quetiapine, resperidone, ziprasidone, lithium carbonate, Aripiprazole, ETRAFON®

, Droperidol, Thioridazine, Thiothixene, Promethazine, Metoclopramide, Chlorprothixene, TRIAVIL®

, Molindone, Sertindole, Droperidol, Amisulpride, Melperone, Paliperidone, and Tetrabenazine.

30. A method of treating or preventing a condition selected from the group consisting of a neuropsychiatric disorder, a neurodegenerative disorder, and an extrapyramidal disorder, comprising administering to a subject the pharmaceutical composition of claim 1.

31. A method of reducing a side effect of an antipsychotic agent, comprising administering to a subject the pharmaceutical composition of claim 1.

32. The method of claim 31, wherein the side effect is selected from the group consisting of stroke, tremors, sedation, gastrointestinal problems, neurological problems, increased risk of death, cerebrovascular events, movement disorder, dystonia, akathisia, parkinsoniam movement disorder, tardive dyskinesia, cognitive disorders, prolactinemia, catalepsy, psychosis, neuroleptic malignant syndrome, heart problems, pulmonary problems, diabetes, liver failure, suicidality, sedation, orthostatic hypotension, choking, dizziness, tachycardia, blood abnormalities (including abnormal triglyceride levels, increased cholesterol levels, dyslipidemia, and hyperglycemia), syncope, seizures, dysphagia, priapism, thrombotic thrombocytopenic purpura, disruption of body temperature regulation, insomnia, agitation, anxiety, somnolence, aggressive reaction, headache, constipation, nausea, dyspepsia, vomiting, abdominal pain, saliva increase, toothache, rhinitis, coughing, sinusitis, pharyngitis, dyspnea, back pain, chest pain, fever, rash, dry skin, seborrhea, increased upper respiratory infection, abnormal vision, arthralgia, hypoaesthesia, manic reaction, concentration impairment, dry mouth, pain, fatigue, acne, pruritus, myalgia, skeletal pain, hypertension, diarrhea, confusion, asthenia, urinary incontinence, sleepiness, increased duration of sleep, accommodation disturbance, palpitations, erectile dysfunction, ejaculatory dysfunction, orgastic dysfunction, lassitude, increased pigmentation, increased appetite, automatism, increased dream activity, diminished sexual desire, nervousness, depression, apathy, catatonic reaction, euphoria, increased libido, amnesia, emotional liability, nightmares, delirium, yawning, dysarthria, vertigo, stupor, paraesthesia, aphasia, hypoesthesia, tongue paralysis, leg cramps, torticollis, hypotonia, coma, migrain, hyperreflexia, choreoathetosis, anorexia, flatulence, stomatitis, melena, hemorrhoids, gastritis, fecal incontinence, erutation, gastroeophageal reflux, gastroenteritis, esophagitis, tongue discoloration, choleithiasis, tongue edema, diverticulitis, gingivitis, discolored feces, gastrointestinal hemorrhage, hematemesis, edema, rigors, malaise, pallor, enlarged abdomen, ascites, sarcoidosis, flushing, hyperventilation, bronchospasm, pneumonia, tridor, asthma, increased sputum, aspiration, photosensitivity, increased sweating, acne, descreased sweating, alopecia, hyperkeratosis, skin exfoliation, bullous eruption, skin ulceration, aggravated psoriasis, furunculosis, verruca, dermatitis lichenoid, hypertrichosis, genital pruritus, urticaria, ventricular tachycardia, angina pectoris, premature atrial contractions, T wave inversion, ventricular extrasystoles, ST depression, AV block, myocarditis, abnormal accommodation, xerophthalmia, diplopia, eye pain, blepharitis, photopsia, photophobia, abnormal lacrimation, hyponatremia, creatine phosphokinase increase, thirst, weight decrease, decreased serum iron, cachexia, dehydration, hypokalemia, hypoproteinemia, hyperphosphatemia, hypertrigylceridemia, hyperuricemia, hypoglycemia, polyuria, polydipsia, hemturia, dysuria, urinary retention, cystitis, renal insufficiency, arthrosis, synostosis, bursitis, arthritis, menorrhagia, dry vagina, nonpeurperal lactation, amenorrhea, female breast pain, leukorrhea, mastitis, dysmenorrhea, female perineal pain, intermenstrual bleeding, vaginal hemorrhage, increased SGOT, increased SGPT, cholestatic hepatitis, cholecystitis, choleithiasis, hepatitis, hepatocellular damage, epistaxis, superficial phlebitis, thromboplebitis, thrombocytopenia, tinnitus, hyperacusis, decreased hearing, anemia, hypochromic anemia, normocytic anemia, granulocytopenia, leukocytosis, lymphadenopathy, leucopenia, Pelger-Huet anomaly, gynecomastia, male breast pain, antiduretic hormone disorder, bitter taste, micturition disturbances, oculogyric crisis, abnormal gait, involuntary muscle contraction, and increased injury.

33. A pharmaceutical composition, comprising:

pimavanserin tartrate; and

at least about 0.5% of a lubricant.

34. The composition of claim 33, comprising at least about 0.8% by weight of the lubricant.

35. The composition of claim 33, comprising at least about 1% by weight of the lubricant.

36. The composition of claim 33, comprising at least about 1.5% by weight of the lubricant.

37. The composition of claim 33, comprising at least about 2% by weight of the lubricant.

38. The composition of claim 33, wherein the lubricant is magnesium stearate.

39. The composition of claim 33, wherein the lubricant is sodium stearyl fumarate.

40. A wet granulation formulation for use in preparing tablets, the formulation comprising:

pimavanserin tartrate; and

a non-aqueous granulation solvent.

41. The formulation of claim 40, wherein the non-aqueous granulation solvent comprises ethanol.

42. The formulation of claim 40, further comprising mannitol or lactose, pregelatinized or partially pregelatinized starch, and povidone.

43. The formulation of claim 40, further comprising at least about 65% by dry weight mannitol, at least about 2% by dry weight pregelatinized or partially pregelatinized starch, and at least about 0.5% by dry weight povidone.

44. The formulation of claim 40, further comprising at least about 70% by dry weight mannitol, at least about 5% by dry weight pregelatinized or partially pregelatinized starch, and at least about 1% by dry weight povidone.

45. A wet granulation formulation for use in preparing tablets, the formulation comprising:

pimavanserin tartrate; and

less then about 30% by weight of water.

46. The formulation of claim 45, comprising substantially no water.

47. A method of preparing a pharmaceutical tablet, the method comprising:

granulating pimavanserin tartrate using a non-aqueous granulation solvent;

drying the granulation;

blending the granulation with a lubricant; and

compressing the blend into a tablet.

48. The method of claim 47, wherein the non-aqueous granulation solvent comprises ethanol.

49. The method of claim 47, wherein povidone is dissolved in the non-aqueous granulation solvent.

50. The method of claim 47, wherein the granulation further comprises mannitol or lactose, pregelatinized starch, and povidone.

51. The method of claim 47, wherein the lubricant comprises magnesium stearate.

52. A method of preparing a pharmaceutical tablet, the method comprising:

granulating pimavanserin tartrate using less than about 30% by weight of water;

drying the granulation;

blending the granulation with a lubricant; and

compressing the blend into a tablet.

53. A method of preparing a pharmaceutical tablet, the method comprising:

dry blending pimavanserin tartrate with at least one pharmaceutically acceptable excipient selected from the group consisting of a sugar, microcrystalline cellulose, lactose-cellulose blend, calcium phosphate dibasic, silicified microcrystalline cellulose, pregelatinized starch, partially pregelatinized starch, polyvinylpyrrolidone, HPMC, sodium lauryl sulfate, sodium stearyl fumerate, silicon dioxide aerosol, magnesium stearate, talc, polyethylene glycol, and combinations thereof; and

compressing the blend to form a tablet.

54. The method of claim 53, further comprising coating the tablet with a taste-masking film.

55. A pharmaceutical composition, comprising:

pimavanserin; and

a pharmaceutically acceptable excipient, wherein the pharmaceutical composition comprises substantially no sodium starch glycolate or sodium croscarmellose.

56. The composition of claim 55, wherein the pimavanserin is pimavanserin tartrate.

57. A pharmaceutical tablet, comprising:

a core comprising pimavanserin; and

a taste-masking film coating over the core.

58. The tablet of claim 57, where the film coating is an OPADRY®

film.

59. The tablet of claim 57, wherein the pimavanserin is pimavanserin tartrate.

60. A pharmaceutical composition, comprising:

pimavanserin or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable excipient;

wherein the pharmaceutical composition comprises less than about 0.1% of a compound having the structure of Impurity 2;

61. The composition of claim 60, wherein the pharmaceutical composition is substantially free of Impurity 2.

62. The composition of claim 60, wherein the pharmaceutical composition is substantially free of Impurity 2 after storage in a blister package at about 30°

C. and about 65% relative humidity for at least about 10 weeks.

63. A pharmaceutical composition, comprising:

pimavanserin or a pharmaceutically acceptable salt thereof; and

a pharmaceutically acceptable excipient;

wherein the pharmaceutical composition comprises less than about 0.25% of a compound having the structure of Impurity 1;

64. The composition of claim 63, wherein the pharmaceutical composition comprises less than about 0.25% of Impurity 1 after storage in a blister package at about 40°

C. and about 75% relative humidity for at least about 1 month.

65. A pharmaceutical composition, comprising pimavanserin and at least one pharmaceutically acceptable excipient, wherein the composition is formulated such that at least about 80% of the pimavanserin is released from the composition upon administration to a subject.

66. The composition of claim 65, wherein the composition is formulated such that at least about 90% of the pimavanserin is released from the composition upon administration to a subject.