Osmotic delivery of therapeutic compounds by solubility enhancement

• US 20050053653A1
• Filed: 09/05/2003
• Published: 03/10/2005
• Est. Priority Date: 09/05/2003
• Status: Active Grant

• Current Assignee: Supernus Pharmaceuticals Incorporated
• Original Assignee: Supernus Pharmaceuticals Incorporated
• Inventors: Kidane, Argaw, Bhatt, Padmanabh P., Bryan, Jones W. Jr., Ray, Shimul K.
• Granted Patent: US 7,611,728 B2
• Time in Patent Office: Days
• US Class Current: 424/463
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention is directed to the oral osmotic delivery of therapeutic compounds that have limited solubility in an aqueous environment due to inherent hydrophobicity or to saturation limitations in the core of the osmotic system. The present invention is suitable for the osmotic delivery of glipizide and other hydrophobic drugs, but runs the spectrum to other therapeutic agents with higher aqueous solubilities, yet having a solubility limitation in an osmotic dosage unit due to high drug load.

Claims

1. An oral osmotic pharmaceutical delivery dosage form, comprising at least one pharmaceutically active agent that has solubility limitations, and meglumine as a solubilizing agent.

2. The oral dosage form of claim 1, which further comprises a high HLB surfactant as a co-solubilizer.

3. The oral dosage form of claim 2, wherein the surfactant is SLS.

4. The oral dosage form of claim 1, wherein the pharmaceutically active agent is one or more of albendazole, albuterol, acyclovir, adriamycin, carbamazepine, oxcarbazepine, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, bicalutamide, busulfan, butenafine, calcipotriene, calcitriol, camptothecin, capsaicin, carotenes, celecoxib, cerivastatin, chlorpheniramine, cimetidine, ciprofloxacin, cisapride, cetirizine, clarithromycin, clemastine, codeine, cyclosporin, danazol, dantrolene, dexchlorpheniramine, digoxin, dirithromycin, donepezil, efavirenz, ergotamine, etodolac, etoposide, famotidine, fentanyl, finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenyloin, frovatriptan, gabapentin, gemfibrozil, glibenclamide, glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen, irinotecan, isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, angiotensin converting enzyme (ACE) or NEP inhibitors, fenofibrate, fexofenadine, flutamide, glipizide, glyburide, isradipine, loratadine, lovastatin, melphalan, nifedipine, leflunomide, loperamide, lycopenes, mifepristone, mefloquine, methadone, methoxsalen, metronidazole, miconazole, midazolam, miglitol, mitoxantrone, nabumetone, nalbuphine, naratriptan, nelfinavir, nilutamide, nizatidine, oxaprozin, paclitaxel, pentazocine, pioglitazone, pizotefin, pravastatin, probucol, pyridostigmine, raloxifene, rofecoxib, repaglinide, rifapentine, rimexolone, rizatriptan, rosiglitazone, saquinavir, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, teniposide, terbinafine, tiagabine, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, zopiclone, proton pump inhibitors such as lansoprazole, esomeprazole, omeprazole, and rabeprazole, MAP kinase inhibitors, ICE inhibitors such as pralnacasan, pseudoephedrine, indomethacin, naproxen, estrogens, testosterones, steroids, phenyloin, ergotamines and cannabinoids, pharmaceutically acceptable salts, isomers, prodrugs and derivatives thereof.

5. The oral dosage form of claim 4, wherein the pharmaceutically active agent is one or more of albuterol, acyclovir, adriamycin, carbamazepine, oxcarbazepine, cyclosporin, griseofulvin, angiotensin converting enzyme (ACE) or NEP inhibitors, fenofibrate, fexofenadine, flutamide, glipizide, glyburide, isradipine, loratadine, lovastatin, melphalan, nifedipine, proton pump inhibitors, MAP kinase inhibitors, pralnacasan, pseudoephedrine, indomethacin, naproxen, estrogens, testosterones, steroids, phenyloin, sumatriptan, ergotamines or cannabinoids, or pharmaceutically acceptable salts, isomers, or prodrugs or derivatives thereof.

6. The oral dosage form of claim 5, wherein the pharmaceutically active agent is one or more of carbamazepine, oxcarbazepine, fenofibrate, fexofenadine, glipizide, lorsoprasole, esomeprazole and rabeprozole, or pharmaceutically acceptable salts, isomers, or prodrugs or derivatives thereof.

7. The oral dosage form of claim 1, wherein the pharmaceutically active agent is one or more of diltiazem HCl, verapamil HCl, metoprolol succinate, quetiapine fumarate, valganciclovir HCl, theophylline, and naproxene sodium.

8. The oral dosage form of claim 6, wherein the pharmaceutically active agent is glipizide.

9. An osmotic pharmaceutical delivery dosage form, comprising:

(a) a semipermeable wall that maintains its integrity during pharmaceutical delivery and which has at least one passageway through it connecting the core of the dosage form with the external environment; and

(b) a core surrounded by the wall, said core containing a composition comprising;

(i) at least one pharmaceutically active agent that has solubility limitations, (ii) at least one non-swelling solubilizing agent that enhances the solubility of the pharmaceutically active agent to such an extent that the drug is solubilized before release from the dosage form; and

(iii) at least one non-swelling osmotic agent.

10. The osmotic dosage form of claim 9, wherein the semipermeable wall is comprised of a water insoluble polymer of cellulose acylate, cellulose ethyl ether, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkyls, or mono-, di- and tricellulose aroyls.

11. The osmotic dosage form of claim 10, wherein the water insoluble polymer is cellulose acetate.

12. The osmotic dosage form of claim 9, wherein the semipermeable wall also contains 0.01% to 20% by weight of a plasticizer.

13. The osmotic dosage form of claim 12, wherein the plasticizer is dibenzyl phthalate, dihexyl phthalate, butyl octyl phthalate, straight chain phthalates of six to eleven carbons, di-isononyl phthalte, di-isodecyl phthalate, triacetin, dioctyl azelate, epoxidized tallate, tri-isoctyl trimellitate, tri-isononyl trimellitate, sucrose acetate isobutyrate, or epoxidized soybean oil.

14. The osmotic dosage form of claim 11, which further comprises a plasticizer selected from triethyl citrate (TEC), propylene glycol (PG), a mixture of TEC and PG in ratios ranging from 25% TEC/75% PG to 75% TEC/25% PG, Tween 80 or other polyoxyethylene sorbitan esters, triacetin, diethyl phthalate, polyethylene glycol, mineral oil, tributyl sebacate, and glycerol.

15. The osmotic dosage form of claim 14, wherein the plasticizer is TEC.

16. The osmotic dosage form of claim 9, wherein the semi-permeable wall represents a weight gain to the dosage form of from about 2% to about 15%.

17. The osmotic dosage form of claim 9, wherein the at least one non-swelling solubilizing agent comprises meglumine.

18. The osmotic dosage form of claim 17, wherein the at least one non-swelling solubilizing agent further comprises a high HLB surfactant.

19. The osmotic dosage form of claim 18, wherein the surfactant is SLS.

20. The osmotic dosage form of claim 9, wherein the pharmaceutically active agent is one or more of albendazole, albuterol, acyclovir, adriamycin, carbamazepine, oxcarbazepine, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, bicalutamide, busulfan, butenafine, calcipotriene, calcitriol, camptothecin, capsaicin, carotenes, celecoxib, cerivastatin, chlorpheniramine, cimetidine, ciprofloxacin, cisapride, cetirizine, clarithromycin, clemastine, codeine, cyclosporin, danazol, dantrolene, dexchlorpheniramine, digoxin, dirithromycin, donepezil, efavirenz, ergotamine, etodolac, etoposide, famotidine, fentanyl, finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenyloin, frovatriptan, gabapentin, gemfibrozil, glibenclamide, glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen, irinotecan, isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, angiotensin converting enzyme (ACE) or NEP inhibitors, fenofibrate, fexofenadine, flutamide, glipizide, glyburide, isradipine, loratadine, lovastatin, melphalan, nifedipine, leflunomide, loperamide, lycopenes, mifepristone, mefloquine, methadone, methoxsalen, metronidazole, miconazole, midazolam, miglitol, mitoxantrone, nabumetone, nalbuphine, naratriptan, nelfinavir, nilutamide, nizatidine, oxaprozin, paclitaxel, pentazocine, pioglitazone, pizotefin, pravastatin, probucol, pyridostigmine, raloxifene, rofecoxib, repaglinide, rifapentine, rimexolone, rizatriptan, rosiglitazone, saquinavir, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, teniposide, terbinafine, tiagabine, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, zopiclone, proton pump inhibitors such as lansoprazole, esomeprazole, omeprazole, and rabeprazole, MAP kinase inhibitors, ICE inhibitors such as pralnacasan, pseudoephedrine, indomethacin, naproxen, estrogens, testosterones, steroids, phenyloin, ergotamines and cannabinoids, pharmaceutically acceptable salts, isomers, prodrugs and derivatives thereof.

21. The osmotic dosage form of claim 20, wherein the pharmaceutically active agent is one or more of albuterol, acyclovir, adriamycin, carbamazepine, oxcarbazepine, cyclosporin, griseofulvin, angiotensin converting enzyme (ACE) or NEP inhibitors, fenofibrate, fexofenadine flutamide, glipizide, glyburide, isradipine, loratadine, lovastatin, melphalan, nifedipine, proton pump inhibitors, MAP kinase inhibitors, pralnacasan, pseudoephedrine, indomethacin, naproxen, estrogens, testosterones, steroids, phenyloin, sumatriptan, ergotamines or cannabinoids, or pharmaceutically acceptable salts, isomers, or prodrugs or derivatives thereof.

22. The osmotic dosage form of claim 21, wherein the pharmaceutically active agent is one or more of carbamazepine, oxcarbazepine, fenofibrate, fexofenadine, glipizide, lorsoprasole, esomeprazole and rabeprozole, or pharmaceutically acceptable salts, isomers, or prodrugs or derivatives thereof.

23. The osmotic dosage form of claim 9, wherein the pharmaceutically active agent is one or more of diltiazem HCl, verapamil HCl, metoprolol, succinate, quetiapine fumarate, valganciclovir HCl, theophylline, and naproxene sodium.

24. The osmotic dosage form of claim 22, wherein the pharmaceutically active agent is glipizide.

25. The osmotic dosage form of claim 9, wherein the core comprises glipizide and meglumine.

26. The osmotic dosage form of claim 25, which further comprises SLS.

27. An solid pharmaceutical composition, comprising a pharmaceutically active agent that has solubility limitations, together with meglumine and a high HLB surfactant as co-solubilizing agents.

28. The composition of claim 27, wherein the surfactant is SLS.

29. The composition of claim 27, wherein the pharmaceutically active agent is one or more of albendazole, albuterol, acyclovir, adriamycin, carbamazepine, oxcarbazepine, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, bicalutamide, busulfan, butenafine, calcipotriene, calcitriol, camptothecin, capsaicin, carotenes, celecoxib, cerivastatin, chlorpheniramine, cimetidine, ciprofloxacin, cisapride, cetirizine, clarithromycin, clemastine, codeine, cyclosporin, danazol, dantrolene, dexchlorpheniramine, digoxin, dirithromycin, donepezil, efavirenz, ergotamine, etodolac, etoposide, famotidine, fentanyl, finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenyloin, frovatriptan, gabapentin, gemfibrozil, glibenclamide, glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen, irinotecan, isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, angiotensin converting enzyme (ACE) or NEP inhibitors, fenofibrate, fexofenadine, flutamide, glipizide, glyburide, isradipine, loratadine, lovastatin, melphalan, nifedipine, leflunomide, loperamide, lycopenes, mifepristone, mefloquine, methadone, methoxsalen, metronidazole, miconazole, midazolam, miglitol, mitoxantrone, nabumetone, nalbuphine, naratriptan, nelfinavir, nilutamide, nizatidine, oxaprozin, paclitaxel, pentazocine, pioglitazone, pizotefin, pravastatin, probucol, pyridostigmine, raloxifene, rofecoxib, repaglinide, rifapentine, rimexolone, rizatriptan, rosiglitazone, saquinavir, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, teniposide, terbinafine, tiagabine, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, zopiclone, proton pump inhibitors such as lansoprazole, esomeprazole, omeprazole, and rabeprazole, MAP kinase inhibitors, ICE inhibitors such as pralnacasan, pseudoephedrine, indomethacin, naproxen, estrogens, testosterones, steroids, phenyloin, ergotamines and cannabinoids, pharmaceutically acceptable salts, isomers, prodrugs and derivatives thereof.

30. The composition of claim 29, wherein the pharmaceutically active agent is one or more of albuterol, acyclovir, adriamycin, carbamazepine, oxcarbazepine, cyclosporin, griseofulvin, angiotensin converting enzyme (ACE) or NEP inhibitors, fenofibrate, fexofenadine flutamide, glipizide, glyburide, isradipine, loratadine, lovastatin, melphalan, nifedipine, proton pump inhibitors, MAP kinase inhibitors, pralnacasan, pseudoephedrine, indomethacin, naproxen, estrogens, testosterones, steroids, phenyloin, sumatriptan, ergotamines or cannabinoids, or pharmaceutically acceptable salts, isomers, or prodrugs or derivatives thereof.

31. The composition of claim 30, wherein the pharmaceutically active agent is one or more of carbamazepine, oxcarbazepine, fenofibrate, fexofenadine, glipizide, lorsoprasole, esomeprazole and rabeprozole, or pharmaceutically acceptable salts, isomers, or prodrugs or derivatives thereof.

32. The composition of claim 27, wherein the pharmaceutically active agent is one or more of diltiazem HCl, verapamil HCl, metoprolol succinate, quetiapine fumarate, valganciclovir HCl, theophylline, and naproxene sodium.

33. The composition of claim 31, wherein the pharmaceutically active agent is glipizide.

34. The composition of claim 27, which is contained within an oral osmotic pharmaceutical delivery device.

35. A process for preparing a solid oral dosage form, comprising mixing one or more pharmaceutically active agents with meglumine and a binder solution, spraying to form granules, drying the granules in a fluid bed, dry screening the granules, lubricating the granules by adding a lubricating agent, followed by dry blending to effect adequate distribution of the tablet lubrication agents, and compressing on a rotary tablet press, thereby obtaining a solid oral dosage form.

36. The process of claim 35, further comprising coating the solid oral dosage form with a semi-permeable wall comprised of a water insoluble polymer of cellulose acylate, cellulose ethyl ether, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkyls, or mono-, di- and tricellulose aroyls.

37. The process of claim 36, further comprising effecting a passageway in said semi-permeable wall, either manually or by way of the addition of a water-soluble substance to the composition of the semi-permeable wall.

38. A method for delivering a pharmaceutical dosage unit to a mammal in need thereof, comprising orally administering an osmotic pharmaceutical delivery dosage form, said dosage form comprising at least one pharmaceutically active agent that has solubility limitations, and meglumine as a solubilizing agent.

39. The method of claim 38, wherein the mammal is a human.

40. The method of claim 38, wherein the pharmaceutically active agent is one or more of albendazole, albuterol, acyclovir, adriamycin, carbamazepine, oxcarbazepine, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, bicalutamide, busulfan, butenafine, calcipotriene, calcitriol, camptothecin, capsaicin, carotenes, celecoxib, cerivastatin, chlorpheniramine, cimetidine, ciprofloxacin, cisapride, cetirizine, clarithromycin, clemastine, codeine, cyclosporin, danazol, dantrolene, dexchlorpheniramine, digoxin, dirithromycin, donepezil, efavirenz, ergotamine, etodolac, etoposide, famotidine, fentanyl, finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenyloin, frovatriptan, gabapentin, gemfibrozil, glibenclamide, glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen, irinotecan, isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, angiotensin converting enzyme (ACE) or NEP inhibitors, fenofibrate, fexofenadine, flutamide, glipizide, glyburide, isradipine, loratadine, lovastatin, melphalan, nifedipine, leflunomide, loperamide, lycopenes, mifepristone, mefloquine, methadone, methoxsalen, metronidazole, miconazole, midazolam, miglitol, mitoxantrone, nabumetone, nalbuphine, naratriptan, nelfinavir, nilutamide, nizatidine, oxaprozin, paclitaxel, pentazocine, pioglitazone, pizotefin, pravastatin, probucol, pyridostigmine, raloxifene, rofecoxib, repaglinide, rifapentine, rimexolone, rizatriptan, rosiglitazone, saquinavir, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, teniposide, terbinafine, tiagabine, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, zopiclone, proton pump inhibitors such as lansoprazole, esomeprazole, omeprazole, and rabeprazole, MAP kinase inhibitors, ICE inhibitors such as pralnacasan, pseudoephedrine, indomethacin, naproxen, estrogens, testosterones, steroids, phenyloin, ergotamines and cannabinoids, pharmaceutically acceptable salts, isomers, prodrugs and derivatives thereof.

41. The method of claim 40, wherein the pharmaceutically active agent is one or more of albuterol, acyclovir, adriamycin, carbamazepine, oxcarbazepine, cyclosporin, griseofulvin, angiotensin converting enzyme (ACE) or NEP inhibitors, fenofibrate, fexofenadine flutamide, glipizide, glyburide, isradipine, loratadine, lovastatin, melphalan, nifedipine, proton pump inhibitors, MAP kinase inhibitors, pralnacasan, pseudoephedrine, indomethacin, naproxen, estrogens, testosterones, steroids, phenyloin, sumatriptan, ergotamines or cannabinoids, or pharmaceutically acceptable salts, isomers, or prodrugs or derivatives thereof.

42. The method of claim 41, wherein the pharmaceutically active agent is one or more of carbamazepine, oxcarbazepine, fenofibrate, fexofenadine, glipizide, lorsoprasole, esomeprazole and rabeprozole, or pharmaceutically acceptable salts, isomers, or prodrugs or derivatives thereof.

43. The method of claim 38, wherein the pharmaceutically active agent is one or more of diltiazem HCl, verapamil HCl, metoprolol succinate, quetiapine fumarate, valganciclovir HCl, theophylline, and naproxene sodium.

44. The method of claim 42, wherein the pharmaceutically active agent is glipizide.

45. A method for treating an abnormal condition in a mammal, comprising orally administering an osmotic dosage form that has a core comprising at least one pharmaceutically active agent that has solubility limitations and meglumine as a solubilizing agent to said mammal, and monitoring the effectiveness of the treatment.

46. The method of claim 45, wherein the mammal is a human.

47. The method of claim 45, wherein the pharmaceutically active agent is one or more of albendazole, albuterol, acyclovir, adriamycin, carbamazepine, oxcarbazepine, amiodarone, amlodipine, amphetamine, amphotericin B, atorvastatin, atovaquone, azithromycin, baclofen, bicalutamide, busulfan, butenafine, calcipotriene, calcitriol, camptothecin, capsaicin, carotenes, celecoxib, cerivastatin, chlorpheniramine, cimetidine, ciprofloxacin, cisapride, cetirizine, clarithromycin, clemastine, codeine, cyclosporin, danazol, dantrolene, dexchlorpheniramine, digoxin, dirithromycin, donepezil, efavirenz, ergotamine, etodolac, etoposide, famotidine, fentanyl, finasteride, fluconazole, flurbiprofen, fluvastatin, fosphenyloin, frovatriptan, gabapentin, gemfibrozil, glibenclamide, glyburide, glimepiride, griseofulvin, halofantrine, ibuprofen, irinotecan, isotretinoin, itraconazole, ivermectin, ketoconazole, ketorolac, lamotrigine, angiotensin converting enzyme (ACE) or NEP inhibitors, fenofibrate, fexofenadine, flutamide, glipizide, glyburide, isradipine, loratadine, lovastatin, melphalan, nifedipine, leflunomide, loperamide, lycopenes, mifepristone, mefloquine, methadone, methoxsalen, metronidazole, miconazole, midazolam, miglitol, mitoxantrone, nabumetone, nalbuphine, naratriptan, nelfinavir, nilutamide, nizatidine, oxaprozin, paclitaxel, pentazocine, pioglitazone, pizotefin, pravastatin, probucol, pyridostigmine, raloxifene, rofecoxib, repaglinide, rifapentine, rimexolone, rizatriptan, rosiglitazone, saquinavir, sibutramine, sildenafil citrate, simvastatin, sirolimus, spironolactone, sumatriptan, tacrine, tacrolimus, tamoxifen, tamsulosin, targretin, tazarotene, teniposide, terbinafine, tiagabine, tizanidine, topiramate, topotecan, toremifene, tramadol, tretinoin, troglitazone, trovafloxacin, verteporfin, vigabatrin, vitamin A, vitamin D, vitamin E, vitamin K, zafirlukast, zileuton, zolmitriptan, zolpidem, zopiclone, proton pump inhibitors such as lansoprazole, esomeprazole, omeprazole, and rabeprazole, MAP kinase inhibitors, ICE inhibitors such as pralnacasan, pseudoephedrine, indomethacin, naproxen, estrogens, testosterones, steroids, phenyloin, ergotamines and cannabinoids, pharmaceutically acceptable salts, isomers, prodrugs and derivatives thereof.

48. The method of claim 47, wherein the pharmaceutically active agent is one or more of albuterol, acyclovir, adriamycin, carbamazepine, oxcarbazepine, cyclosporin, griseofulvin, angiotensin converting enzyme (ACE) or NEP inhibitors, fenofibrate, fexofenadine flutamide, glipizide, glyburide, isradipine, loratadine, lovastatin, melphalan, nifedipine, proton pump inhibitors, MAP kinase inhibitors, pralnacasan, pseudoephedrine, indomethacin, naproxen, estrogens, testosterones, steroids, phenyloin, sumatriptan, ergotamines or cannabinoids, or pharmaceutically acceptable salts, isomers, or prodrugs or derivatives thereof.

49. The method of claim 48, wherein the pharmaceutically active agent is one or more of carbamazepine, oxcarbazepine, fenofibrate, fexofenadine, glipizide, lorsoprasole, esomeprazole and rabeprozole, or pharmaceutically acceptable salts, isomers, or prodrugs or derivatives thereof.

50. The method of claim 45, wherein the pharmaceutically active agent is one or more of diltiazem HCl, verapamil HCl, metoprolol succinate, quetiapine fumarate, valganciclovir HCl, theophylline, and naproxene sodium.

51. The method of claim 49, wherein the pharmaceutically active agent is glipizide.