Enhanced immediate release formulations of topiramate

• US 20080131501A1
• Filed: 12/04/2007
• Published: 06/05/2008
• Est. Priority Date: 12/04/2006
• Status: Abandoned Application

• Current Assignee: Supernus Pharmaceuticals Incorporated
• Original Assignee: Supernus Pharmaceuticals Incorporated
• Inventors: Wang, Hua, Bhatt, Padmanabh P., Liang, Likan
• Application Number:
  US11/987,806
• Publication Number:
  US 20080131501A1
• Time in Patent Office: Days
• US Class Current: 424/452
• CPC Class Codes: A61K 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/26 Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 47/46 Ingredients of undetermined constitution or reaction products thereof, e.g. skin, bone, milk, cotton fibre, eggshell, oxgall or plant extracts
• CPC Class Codes: A61K 47/61 the organic macromolecular compound being a polysaccharide or a derivative thereof
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61K 9/5036 Polysaccharides, e.g. gums, alginate; Cyclodextrin
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 9/12 : Antihypertensives

Abstract

The present invention provides enhanced immediate release formulations of topiramate, in which 80% of the active ingredient is released in the period of time of not more than 30 min. These formulations may be advantageously used for the treatment of acute neurological conditions, such as migraine.

Claims

1. An enhanced immediate release topiramate formulation for administration to a mammalian subject comprising topiramate and at least one agent selected from a group consisting of complexing agents, enhancing agents and combinations thereof, wherein at least 80% of topiramate is dissolved in a time period of not more than 30 minutes.

2. The formulation of claim 1 wherein at least 30% of topiramate is dissolved in not more than 5 min.

3. The formulation of claim 1 wherein said complexing agent is selected from a group consisting of cyclodextrins, benzoates, hydroxybenzoates, polyamides, polyvinylpyrrolidones, pyridoxine HCl, nicotinamide, polyamines, polyethyleneimines, polyvinylpyridine, polylysine, aminopolysaccharides, chitosan, polyanions, oxa- and thia-crown ethers, polyoxalkylenes, and polysiloxanes.

4. The formulation of claim 3 wherein said complexing agent is the cyclodextrin selected from a group consisting of hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and alpha-cyclodextrin, or its derivative.

5. The formulation of claim 1 wherein said enhancing agent is selected from a group consisting of solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.

6. The formulation of claim 5, wherein said enhancing agent is selected from a group consisting of Vitamin E TPGS, glutamic acid, glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins, glycerol-polyethylene glycol oxystearate, PEG-32 glyceryl palmitostearate, sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitan monolaurate, Poloxamer 407, polyethylene glycols, polyvinylpyrrolidones, polyalcohols, polyvinyl alcohols, oleic acid, glyceryl monooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, HPMC, substituted hydroxypropylcellulose, microcrystalline cellulose sodium bicarbonate, calcium citrate, sodium docusate, and menthol.

7. The formulation of claim 4 comprising a complex of topiramate and hydroxypropyl-beta-cyclodextrin.

8. The formulation of claim 7, wherein the degree of complexation of topiramate is about 100%.

9. The formulation of claim 1, wherein at least part of said active ingredient is in the form of micronized particles.

10. The formulation of claim 9, wherein said particles have an average size of from about 1 μ

m to about 100 μ

m.

11. The formulation of claim 1 wherein the amount of topiramate in the formulation is from 0.5 to 3000 mg.

12. The formulation of claim 1, wherein said formulation is administered in a dosage form selected from an aerosol, a spray, an injection, a suppository, and a patch.

13. The formulation of claim 1 wherein said formulation is administered orally.

14. The formulation of claim 13, wherein said formulation is in a dosage form selected from a tablet, a pill, a capsule, a caplet, a bead, a troche, a sachet, a cachet, a pouch, a powder, a solution, a gum, sprinkles, and an orally disintegrating dosage form.

15. The formulation of claim 14, wherein said orally disintegrating dosage form is a fast-disintegrating tablet or a fast-dissolving tablet.

16. The formulation of claim 15, further comprising at least one agent selected from bulking agents, disintegrating agents, binders, lubricants, flow aids, flavoring agents, sweetener, coloring agents, highly soluble materials and combinations thereof.

17. The formulation of claim 1 wherein at least part of said formulation is contained in at least one population of beads.

18. The formulation of claim 17, wherein topiramate is contained in at least one population of beads.

19. The formulation of claim 18, wherein topiramate is complexed with a cyclodextrin.

20. The formulation of claim 19, wherein said cyclodextrin is hydroxypropyl-beta-cyclodextrin.

21. The formulation of claim 18, wherein said beads additionally contain at least one enhancing agent selected from a group consisting of solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.

22. The formulation of claim 21, wherein said enhancing agent is selected from a group consisting of Vitamin E TPGS, glutamic acid, glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins, glycerol-polyethylene glycol oxystearate, PEG-32 glyceryl palmitostearate, sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitan monolaurate, Poloxamer 407, polyethylene glycols, polyvinylpyrrolidones, polyalcohols, polyvinyl alcohols, oleic acid, glyceryl monooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, HPMC, substituted hydroxypropylcellulose, microcrystalline cellulose sodium bicarbonate, calcium citrate, sodium docusate, and menthol.

23. The formulation of claim 17, wherein said at least one population of beads contains at least one enhancing agent selected from a group consisting of solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.

24. The formulation of claim 23, where at least one population of the enhancing agent containing beads contains no topiramate.

25. A method of treatment or prevention of a pathological condition in a mammalian subject, comprising administering to said subject a therapeutically effective amount of an enhanced immediate release (EIR) topiramate formulation comprising topiramate and at least one agent selected from a group consisting of complexing agents, enhancing agents and combinations thereof, wherein at least 80% of topiramate is dissolved in a time period of not more than 30 minutes.

26. The method of claim 25, wherein said condition is selected from a group consisting of epilepsy, migraine, essential tremor, restless limb syndrome, cluster headaches, neuralgia, neuropathic pain, Tourrette'"'"'s syndrome, infantile spasms, perinatal hypoxia ischemia and related damage, glaucoma, ocular disorders, obesity, weight loss, Type II diabetes mellitus, diabetic retinopathy, impaired oral glucose tolerance, diabetic skin lesions, diabetic neuropathy, elevated blood glucose levels, syndrome X, elevated blood pressure, elevated lipids, bipolar disorder, dementia, depression, psychosis, mania, anxiety, schizophrenia, obsessive-compulsive disorder, post-traumatic stress disorder, ADHD, impulse control disorders, borderline personality disorder, addiction, autism, asthma, autoimmune disorders, chronic neurodegenerative disorders, acute neurodegeneration, ALS, sleep apnea and sleep disorders.

27. The method of claim 26 wherein said condition manifests itself in an acute manner.

28. The method of claim 25 wherein at least 30% of the active compound is dissolved in not more than 5 min.

29. The method of claim 27 wherein said condition is migraine.

30. The method of claim 29, wherein said EIR formulation is administered in conjunction with a long-term administration of a migraine-preventative medication.

31. The method of claim 30, wherein the migraine-preventative medication is an extended release topiramate formulation.

32. The method of claim 29, wherein said formulation is administered at the onset of the first symptoms or warning signs of the migraine attack.

33. The method of claim 25, wherein said complexing agent is selected from a group consisting of cyclodextrins, benzoates, hydroxybenzoates, polyvinylpyrrolidones, pyridoxine HCl, nicotinamide, polyamines, polyamides, polyethyleneimines, polyvinylpyridine, polylysine, aminopolysaccharides, chitosan, polyanions, oxa- and thia-crown ethers, polyoxalkylenes, and polysiloxanes.

34. The method of claim 33, wherein said complexing agent is a cyclodextrin selected from a group consisting of hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and alpha-cyclodextrin, or a cyclodextrin derivative.

35. The method of claim 33, wherein said enhancing agent is selected from a group consisting of solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.

36. The method of claim 35, wherein said enhancing agent is selected from a group consisting of Vitamin E TPGS, glutamic acid, glycine, sorbitol, mannose, amylose, maltose, mannitol, lactose, sucrose, glucose, xylitose, dextrins, glycerol-polyethylene glycol oxystearate, PEG-32 glyceryl palmitostearate, sodium lauryl sulfate, polyoxyethylene sorbitan monooleate, benzyl alcohol, sorbitan monolaurate, Poloxamer 407, polyethylene glycols, polyvinylpyrrolidones, polyalcohols, polyvinyl alcohols, oleic acid, glyceryl monooleate, sodium benzoate, cetyl alcohol, sucrose stearate, crospovidone, sodium starch glycolate, croscarmellose sodium, carboxymethylcellulose, starch, pregelatinized starch, HPMC, substituted hydroxypropylcellulose, microcrystalline cellulose sodium bicarbonate, calcium citrate, sodium docusate, and menthol.

37. The method of claim 25, wherein said formulation is administered orally in a dosage form selected from a tablet, a pill, a capsule, a caplet, a bead, a troche, a sachet, a cachet, a pouch, a powder, a solution, a gum, sprinkles, and an orally disintegrating dosage form.

38. The method of claim 37, wherein said formulation is administered as the orally disintegrating dosage form.

39. The method of claim 25, where said formulation is administered in a total dose of from 0.5 to 3000 mg.

61. The method of claim 25, wherein at least part of said active ingredient is in a form of micronized particles.

62. The method of claim 61, wherein said particles have an average size of from about 1 μ

m to about 100 μ

m.

40. A pharmaceutical dosage form comprising a therapeutically effective amount of an enhanced immediate release topiramate formulation comprising topiramate and at least one agent selected from a group consisting of complexing agents, enhancing agents and combinations thereof, wherein at least 80% of topiramate is dissolved in a time period of not more than 30 minutes.

41. The dosage form of claim 40, wherein at least 30% of the active compound is released in the time period of not more that 5 minutes.

42. The dosage form of claim 40, wherein said complexing agent is a cyclodextrin selected from a group comprising hydroxypropyl-beta-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin, and alpha-cyclodextrin, or a cyclodextrin derivative.

43. The dosage form of claim 40, wherein said enhancing agent is selected from a group comprising solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.

44. The dosage form of claim 40, wherein said formulation is administered in a dosage form selected from an aerosol, a spray, an injection, a suppository, and a patch.

45. The dosage form of claim 40, wherein said formulation is administered orally.

46. The dosage form of claim 45 selected from a tablet, a pill, a capsule, a caplet, a bead, a troche, a sachet, a cachet, a pouch, a powder, a solution, a gum, sprinkles and an orally disintegrating dosage form.

47. The dosage form of claim 46, wherein said orally disintegrating dosage form is a fast-dissolving tablet or a fast-disintegrating tablet.

48. The dosage form of claim 47, wherein said tablet is prepared by a process comprising the steps of:

1. preparing a solution or dispersion of topiramate with at least one of the complexing agents, enhancing agents, or a combination thereof;

2. drying the result of step 1;

3. adding at least one agent selected from bulking agents, disintegrating agents, binders, lubricants, flow aids, wetting agents, anti-tack agents, buffering agents flavoring agents, sweetener, coloring agents, highly soluble materials and combinations thereof to the result of step 2;

4. forming the result of step 3 into a tablet.

49. The dosage form of claim 47, wherein said formulation comprises a complex of topiramate with hydroxypropyl-beta-cyclodextrin.

50. The dosage form of claim 49, wherein said formulation additionally comprises at least one enhancing agent selected from a group consisting of solubility enhancing agents, dissolution enhancing agents, absorption enhancing agents, penetration enhancing agents, surface active agents, stabilizing agents, enzyme inhibitors, p-glycoprotein inhibitors, multidrug resistance protein inhibitors and combinations thereof.

51. The dosage form of claim 45, which is a capsule.

52. The dosage form of claim 51, wherein at least part of the EIR topiramate formulation is contained in said capsule in the form of at least one population of beads.

53. The dosage form of claim 51, wherein said capsule comprises a first quantity of the EIR topiramate formulation encapsulated inside said capsule, and a second quantity of the enhanced IR topiramate formulation coated as a layer on an outer surface of the capsule.

54. The dosage form of claim 51, wherein an additional pharmaceutically active ingredient is encapsulated inside the capsule.

55. The dosage form of claim 54, wherein said additional pharmaceutically active ingredient is an extended release formulation of topiramate.

63. The dosage form of claim 40, wherein at least part of said active ingredient is in a form of micronized particles.

64. The dosage form of claim 63, wherein said particles have an average size of from about 1 μ

m to about 100 μ

m.

56. A pharmaceutical dosage form comprising a capsule containing a first pharmaceutical formulation enclosed therein, and a layer of a second pharmaceutical formulation coated on an outer surface of the capsule.

57. The dosage form of claim 56, wherein the first pharmaceutical formulation and the second pharmaceutical formulation comprise the same active ingredient.

58. The dosage form of claim 57, wherein the second pharmaceutical formulation is an immediate release formulation.

59. The dosage form of claim 56, wherein the first pharmaceutical formulation is an immediate release formulation, a delayed release formulation, a sustained release formulation, an extended release formulation, or a combination thereof.

60. The dosage form of claim 56, wherein at least the second pharmaceutical formulation comprises topiramate as an active ingredient.

65. The dosage form of claim 59, wherein at least part of said active ingredient is in a form of micronized particles.

66. The dosage form of claim 65, wherein said particles have an average size of from about 1 μ

m to about 100 μ

m.