USRE39030EExpiredUtility

Fluoxetine enteric pellets and methods for their preparation and use

63
Assignee: LILLY CO ELIPriority: May 29, 1997Filed: Jan 28, 2002Granted: Mar 21, 2006
Est. expiryMay 29, 2017(expired)· nominal 20-yr term from priority
Inventors:Neil R. AndersonRoger G. HarrisonDaniel F. LynchPeter L. Oren
A61P 25/00A61K 9/5078A61P 25/26A61P 25/24A61K 31/138
63
PatentIndex Score
1
Cited by
67
References
75
Claims

Abstract

A superior enteric formulation of the antidepressant drug, fluoxetine, is in the form of enteric pellets of which the enteric layer comprises hydroxypropylmethylcellulose acetate succinate.

Claims

exact text as granted — not AI-modified
1. An enteric fluoxetine pellet comprising a) a core consisting of fluoxetine and one or more pharmaceutically acceptable excipients; b) an optional separating layer comprising a non-reducing sugar and one or more pharmaceutically acceptable excipients; c) an enteric layer comprising hydroxypropylmethylcellulose acetate succinate (HPMCAS) and one or more pharmaceutically acceptable excipients; d) an optional finishing layer. 
     
     
       2. A pellet of  claim 1  wherein the HPMCAS is partially neutralized with ammonium ions to the degree that from about 0% to about 25% of the succinic acid groups are neutralized. 
     
     
       3. A pellet of  claim 2  wherein the HPMCAS is partially neutralized to the degree that from about 0% to about 15% of the succinic acid groups are neutralized. 
     
     
       4. A pellet of  claim 1  wherein the separating layer is present. 
     
     
       5. A pellet of  claim 1  wherein the average particle size of the fluoxetine is about 50 μm or less. 
     
     
       6. A pellet of  claim 5  wherein the core comprises an inert core on which the fluoxetine is deposited as a layer comprising in addition a pharmaceutically acceptable excipient. 
     
     
       7. A pellet of  claim 6  wherein the separating layer is present. 
     
     
       8. A pellet of  claim 7  wherein the HPMCAS is partially neutralized with ammonium ions to the degree that from about 0% to about 25% of the succinic acid groups are neutralized. 
     
     
       9. A pellet of  claim 4  wherein the separating layer comprises a pharmaceutically acceptable sugar. 
     
     
       10. A pellet of  claim 9  wherein the sugar is sucrose. 
     
     
       11. A process for preparing an enteric fluoxetine pellet comprising a) providing a core consisting of fluoxetine and one or more pharmaceutically acceptable excipients; b) optionally, applying to the core a separating layer comprising a non-reducing sugar and one or more pharmaceutically acceptable excipients; c) applying an enteric layer comprising HPMCAS and one or more pharmaceutically acceptable excipients, wherein the HPMCAS is supplied as an aqueous solution or suspension and the application takes place in an apparatus of the fluid bed type; d) optionally, applying a finishing layer. 
     
     
       12. A process of  claim 11  wherein the HPMCAS is fully or partially neutralized with ammonium ions. 
     
     
       13. A process of  claim 12  wherein the HPMCAS is neutralized to the degree that from about 25% to about 100% of the succinic acid groups are neutralized. 
     
     
       14. A process of  claim 11  wherein the separating layer is applied. 
     
     
       15. A process of  claim 14  wherein the separating layer comprises a pharmaceutically acceptable sugar. 
     
     
       16. A process of  claim 15  wherein the sugar is sucrose. 
     
     
       17. A process of  claim 11  wherein the core is prepared by applying fluoxetine and one or more pharmaceutically acceptable excipients to an inert core. 
     
     
       18. A process of  claim 17  wherein the separating layer is applied and comprises a pharmaceutically acceptable sugar. 
     
     
       19. A formulation of  claim 1  containing  20-100  enteric fluoxetine pellets sufficient to administer 60-120  mg base equivalent of fluoxetine, wherein the pellets comprise a core consisting of fluoxetine and one or more pharmaceutically acceptable excipients and an enteric layer comprising hydroxypropyl- methylcellulose acetate succinate  ( HPMCAS )  and one or more pharmaceutically acceptable excipients . 
     
     
       20. A formulation of  claim 1   9  containing  administering about 80-90 mg base equivalent of fluoxetine. 
     
     
       21. A formulation of  claim 1   9  containing  administering about 90 mg base equivalent of fluoxetine. 
     
     
       22. A formulation of  claim 19  wherein the fluoxetine is present as fluoxetine hydrochloride. 
     
     
       23. A formulation of  claim 20  wherein the fluoxetine is present as fluoxetine hydrochloride. 
     
     
       24. A formulation of  claim 21  wherein the fluoxetine is present as fluoxetine hydrochloride. 
     
     
       25. A gelatin capsule containing the formulation of  claim 1   enteric fluoxetine pellets sufficient to administer  60 - 120  mg base equivalent of fluoxetine, wherein the pellets comprise a core consisting of fluoxetine and one or more pharmaceutically acceptable excipients and an enteric layer comprising hydroxypropylmethylcellulose acetate succinate ( HPMCAS )  and one or more pharmaceutically acceptable excipients . 
     
     
       26. A gelatin capsule containing the formulation  of claim  24    25 , wherein about  80 - 90  base equivalents of fluoxetine are administered. 
     
     
       27. A formulation of  claim 1   9  containing the following:
                           Cores             Sucrose-starch nonpareils, 30-35 mesh   100-150         Fluoxetine layer     Fluoxetine hydrochloride   100.5-100.8   mg     Sucrose   20-30   mg     Hydroxypropylmethylcellulose   10-15   mg     Separating layer     Hydroxypropylmethylcellulose   4-12   mg     Sucrose   15-35   mg     Talc, 500 mesh   25-60   mg     Enteric layer     HPMCAS-LF   60-90   mg     Triethyl citrate   10-20   mg     Talc, 500 mesh   15-25   mg     Finishing layer     Color mixture white (HPMC + titanium dioxide)   35-55   mg     HPMC   5-15   mg     Talc   Trace.                                             
 
     
     
       28. A gelatin capsule containing the formulation  of claim  24    25 , wherein about  90  mg base equivalent of fluoxetine are administered. 
     
     
       29. A formulation according to  claim 1   9  wherein the formulation additionally contains pindolol. 
     
     
       30. A method of treating people  a patient suffering from depression, obsessive-compulsive disorder, bulimia, pain, obsessive-compulsive personality disorder, post-traumatic stress disorder, hypertension, atherosclerosis, anxiety, anorexia nervosa, panic, social phobia, stuttering, sleep disorders, chronic fatigue, Alzheimer's disease, alcohol abuse, appetite disorders, weight loss, agoraphobia, improving memory, amnesia, smoking cessation, nicotine withdrawal symptoms, disturbances of mood and/or appetite associated with pre-menstrual syndrome, depressed mood and/or carbohydrate craving associated with pre-menstrual syndrome, disturbances of mood, disturbances of appetite or disturbances which contribute to recidivism associated with nicotine withdrawal, circadian rhythm disorder, borderline personality disorder, hypochondriasis, pre-menstrual syndrome (PMS), late luteal phase dysphoric disorder, pre-menstrual dysphoric disorder, trichotillomania, symptoms following discontinuation of other antidepressants, aggressive/intermittent explosive disorder, compulsive gambling, compulsive spending, compulsive sex, psychoactive substance use disorder, sexual disorder, schizophrenia, premature ejaculation, or psychiatric symptoms selected from stress, worry, anger, rejection sensitivity, and lack of physical energy comprising administering a formulation of  claim 1   9 . 
     
     
       31. A method of  claim 30  employing a formulation containing  20-100  administering about 80-90  mg base equivalent of fluoxetine. 
     
     
       32. A method of  claim 30  employing a formulation containing  administering about 90 mg base equivalent of fluoxetine. 
     
     
       33. A method of  claim 30  wherein the fluoxetine is present as fluoxetine hydrochloride. 
     
     
       34. A method of  claim 31  wherein the fluoxetine is present as fluoxetine hydrochloride. 
     
     
       35. A method of  claim 32  wherein the fluoxetine is present as fluoxetine hydrochloride. 
     
     
       36. A method of  claim 30  employing a formulation containing the following:
                           Cores             Sucrose-starch nonpareils, 30-35 mesh   100-150         Fluoxetine layer     Fluoxetine hydrochloride   100.5-100.8   mg     Sucrose   20-30   mg     Hydroxypropylmethylcellulose   10-15   mg     Separating layer     Hydroxypropylmethylcellulose   4-12   mg     Sucrose   15-35   mg     Talc, 500 mesh   25-60   mg     Enteric layer     HPMCAS-LF   60-90   mg     Triethyl citrate   10-20   mg     Talc, 500 mesh   15-25   mg     Finishing layer     Color mixture white (HPMC + titanium dioxide)   35-55   mg     HPMC   5-15   mg     Talc   Trace.                                             
 
     
     
       37. A method of  claim 30  of treating people  a patient suffering from pain, further comprising the coadministration of morphine, codeine or dextropropoxyphene. 
     
     
       38. A method of  claim 37  employing a formulation containing about  20-100  administering about 80-90  mg base equivalent of fluoxetine. 
     
     
       39. A method of  claim 37  employing a formulation containing  administering about 90 mg base equivalent of fluoxetine. 
     
     
       40. A formulation of  claim 19 , wherein the pellets further comprise a separating layer. 
     
     
       41. A formulation of  claim 40 , wherein the separating layer comprises a non- reducing sugar and one or more pharmaceutically acceptable excipients.   
     
     
       42. A formulation of  claim 19 , wherein the pellets further comprise a finishing layer. 
     
     
       43. A formulation of  claim 40 , wherein the pellets further comprise a finishing layer. 
     
     
       44. A formulation of  claim 41 , wherein the pellets further comprise a finishing layer. 
     
     
       45. A formulation of  claim 21 , wherein the pellets further comprise a separating layer. 
     
     
       46. A formulation of  claim 45 , wherein the separating layer comprises a non- reducing sugar and one or more pharmaceutically acceptable excipients.   
     
     
       47. A formulation of  claim 21 , wherein the pellets further comprise a finishing layer. 
     
     
       48. A formulation of  claim 45 , wherein the pellets further comprise a finishing layer. 
     
     
       49. A formulation of  claim 46 , wherein the pellets further comprise a finishing layer. 
     
     
       50. A gelatin capsule of  claim 25 , wherein the pellets further comprise a separating layer. 
     
     
       51. A gelatin capsule of  claim 50 , wherein the separating layer comprises a non- reducing sugar and one or more pharmaceutically acceptable excipients.   
     
     
       52. A gelatin capsule of  claim 25 , wherein the pellets further comprise a finishing layer. 
     
     
       53. A gelatin capsule of  claim 50 , wherein the pellets further comprise a finishing layer. 
     
     
       54. A gelatin capsule of  claim 51 , wherein the pellets further comprise a finishing layer. 
     
     
       55. A gelatin capsule of  claim 28 , wherein the pellets further comprise a separating layer. 
     
     
       56. A gelatin capsule of  claim 55 , wherein the separating layer comprises a non- reducing sugar and one or more pharmaceutically acceptable excipients.   
     
     
       57. A gelatin capsule of  claim 28 , wherein the pellets further comprise a finishing layer. 
     
     
       58. A gelatin capsule of  claim 55 , wherein the pellets further comprise finishing layer. 
     
     
       59. A gelatin capsule of  claim 56 , wherein the pellets further comprise a finishing layer. 
     
     
       60. A method of  claim 30 , wherein the pellets further comprise a separating layer. 
     
     
       61. A method of  claim 60 , wherein the separating layer comprises a non- reducing sugar and one or more pharmaceutically acceptable excipients.   
     
     
       62. A method of  claim 30 , wherein the pellets further comprise a finishing layer. 
     
     
       63. A method of  claim 60 , wherein the pellets further comprise a finishing layer. 
     
     
       64. A method of  claim 61 , wherein the pellets further comprise a finishing layer. 
     
     
       65. A method of  claim 32 , wherein the pellets further comprise a separating layer. 
     
     
       66. A method of  claim 65 , wherein the separating layer comprises a non- reducing sugar and one or more pharmaceutically acceptable excipients.   
     
     
       67. A method of  claim 32 , wherein the pellets further comprise a finishing layer. 
     
     
       68. A method of  claim 65 , wherein the pellets further comprise a finishing layer. 
     
     
       69. A method of  claim 66 , wherein the pellets further comprise a finishing layer. 
     
     
       70. A method of  claim 30  without an increase in nausea. 
     
     
       71. A method of  claim 32  without an increase in nausea. 
     
     
       72. A method of  claim 36  without an increase in nausea. 
     
     
       73. A method of  claim 37  without an increase in nausea. 
     
     
       74. A method of  claim 38  without an increase in nausea. 
     
     
       75. A method of  claim 39  without an increase in nausea.

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