Extended, controlled-release pharmaceutical compositions using charged polymers

• US 8,425,892 B2
• Filed: 04/28/2003
• Issued: 04/23/2013
• Est. Priority Date: 10/29/2001
• Status: Active Grant

• Current Assignee: Juniper Pharmaceuticals, Inc. (Catalent, Inc.)
• Original Assignee: Columbia Laboratories, Inc. (Catalent, Inc.)
• Inventors: Bologna, William J., Levine, Howard L.
• Primary Examiner(s): VU, JAKE MINH
• Application Number:
  US10/423,920
• Publication Number:
  US 20030211071A1
• Time in Patent Office: 3,648 Days
• Field of Search: 424/486, 424/78.1
• US Class Current: 424/78.1
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/245 Amino benzoic acid types, e.g. procaine, novocaine salicylic acid esters A61K31/60
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• 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 47/12 Carboxylic acids; Salts or anhydrides thereof
• CPC Class Codes: A61K 47/32 Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers , poly(meth)acrylates, or polyvinyl pyrrolidone
• CPC Class Codes: A61K 47/38 Cellulose; Derivatives thereof
• CPC Class Codes: A61K 9/0034 Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
• CPC Class Codes: A61K 9/2027 obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Abstract

The present invention relates to a delivery system for pharmaceutical compositions relying in part on an ionic interaction to control and facilitate release of the treating agent. More specifically, the invention relates to an extended controlled-release system having an ionic treating agent and an ionic polymer, wherein the polymer is sufficiently ionized to release the treating agent in a controlled manner over an extended period of time and the composition does not require an emulsion system for administering the treating agent.

Claims

1. A bioadhesive pharmaceutical composition comprising an ionic treating agent and an ionic polymer, wherein the composition is free of an oil phase;

the polymer is sufficiently ionized to provide bonding with the treating agent to release the treating agent in a controlled manner over an extended period of time; and

the composition is in the form of a gel at the time of administration.

2. The composition of claim 1, wherein the polymer is anionic.

3. The composition of claim 1, wherein the polymer is cationic, and the composition further includes a bioadhesive agent.

4. The composition of claim 2, wherein the treating agent is anionic, and the composition further comprises a cationic complexing agent that forms a complex with the treating agent, which complex bonds to the anionic polymer.

5. The composition of claim 4, wherein the polymer is sufficiently ionized to bond with the treating agent complex as well as to provide bioadhesion of the composition.

6. The composition of claim 2, wherein the polymer is sufficiently ionized to provide bioadhesion.

7. The composition of claim 6, wherein the polymer is a bioadhesive, water swellable, but water-insoluble cross-linked polycarboxylic acid polymer.

8. The composition of claim 7, wherein the polymer comprises polycarbophil.

9. The composition of claim 1, wherein the treating agent is released over a period of at least about 6 hours.

10. The composition of claim 2, wherein the treating agent is released over a period of at least about 12 hours.

11. The composition of claim 7, wherein the treating agent is released over a period of at least about 24 hours.

12. The composition of claim 11, wherein the treating agent is released over a period of two to three days.

13. The composition of claim 12, where the treating agent is released over a period of about 3.5 days.

14. The composition of claim 1, wherein the treating agent is a cationic treating agent.

15. The composition of claim 14, wherein the treating agent includes one or more of amitriptyline, amantadine, amiodarone, meclizine, diphenhydramine, hydroxyzine, or atropine.

16. The composition of claim 14, wherein the treating agent includes one or more of lidocaine, benzocaine, procaine, buprenorphine, morphine, bromocriptine, bupropion, buspirone, butorphanol, chlorpromazine, clindamycin, clonidine, or clomiphene.

17. The composition of claim 14, wherein the treating agent includes one or more of cyclobenzaprine, doxazosin, fentanyl, fluoxetine, leuprolide, octreotide, ondansetron, pioglitazone, oxybutynin, raloxifene, ticlopidine, or terbutaline.

18. The composition of claim 3, wherein the treating agent is an anionic treating agent.

19. The composition of claim 18, wherein the treating agent includes one or more of naproxen, phenobarbital, foscarnet, ganciclovir, acyclorvir, cidofovir, fanciclovir, penciclovir, fosinopril, divalproex, cefuroxime, pravastatin, rabeprazole, or warfarin.

20. A pharmaceutical composition comprising a treating agent and a bioadhesive, water swellable, but water-insoluble cross-linked polycarboxylic acid polymer, wherein the composition is free of an oil phase and is in the form of a gel at the time of administration, and the treating agent comprises one or more of amitriptyline, amantadine, amiodarone, meclizine, diphenhydramine, hydroxyzine, atropine, lidocaine, benzocaine, procaine, buprenorphine, morphine, bromocriptine, bupropion, buspirone, butorphanol, chlorpromazine, clindamycin, clonidine, clomiphene, cyclobenzaprine, doxazosin, fentanyl, fluoxetine, leuprolide, octreotide, ondansetron, pioglitazone, oxybutynin, raloxifene, ticlopidine, or terbutaline and is released in a controlled manner over an extended period of time.

21. The composition of claim 20, wherein the polymer comprises polycarbophil.

22. A pharmaceutical composition comprising a treating agent and a bioadhesive, water swellable, but water-insoluble cross-linked polycarboxylic acid polymer, wherein the composition is free of an oil phase and is in the form of a gel at the time of administration, and the treating agent comprises one or more of naproxen, phenobarbital, foscarnet, ganciclovir, acyclorvir, cidofovir, fanciclovir, penciclovir, fosinopril, divalproex, cefuroxime, pravastatin, rabeprazole, or warfarin and is released in a controlled manner over an extended period of time.

23. The composition of claim 22, wherein the polymer comprises polycarbophil.

24. A pharmaceutical composition for treating or preventing pelvic pain, or for treating or improving infertility, associated with uterine dysrhythmia comprising a therapeutically effective amount of an ionic, anti-dysrhythmic treating agent and a bioadhesive, water swellable, but water-insoluble cross-linked polycarboxylic acid polymer, wherein the composition is free of an oil phase and is in the form of a gel at the time of administration, and the treating agent is released in a controlled manner over an extended period of time.

25. The composition of claim 24, wherein the polymer comprises polycarbophil and the treating agent is lidocaine.

26. A method of treating a disease or condition in a patient in need thereof comprising administering a composition in the form of a gel that comprises a therapeutically effective amount of an ionic treating agent and an ionic polymer;

wherein the polymer is sufficiently ionized to provide bonding with the treating agent;

wherein the composition is free of an oil phase and is in the form of a gel at the time of administration; and

the treating agent is released in a controlled manner over an extended period of time through chemical bonding with the polymer.

27. The method claim 26, wherein the polymer is anionic, and the composition further comprises a cationic complexing agent that forms a complex with the treating agent and bonds also to the anionic polymer.

28. The method of claim 27, wherein the treating agent is released over a period of at least about 6 hours.

29. The method of claim 27, wherein the treating agent includes one or more of amitriptyline, amantadine, amiodarone, meclizine, diphenhydramine, hydroxyzine, atropine, lidocaine, benzocaine, procaine, buprenorphine, morphine, bromocriptine, bupropion, buspirone, butorphanol, chlorpromazine, clindamycin, clonidine, clomiphene, or cyclobenzaprine, doxazosin, fentanyl, fluoxetine, leuprolide, octreotide, ondansetron, pioglitazone, oxybutynin, raloxifene, ticlopidine, or terbutaline.

30. The method of claim 26, wherein the polymer is cationic and the composition further comprises a bioadhesive agent.

31. The method of claim 30, wherein the treating agent includes one or more of naproxen, phenobarbital, foscarnet, ganciclovir, acyclorvir, cidofovir, fanciclovir, penciclovir, fosinopril, divalproex, cefuroxime, pravastatin, rabeprazole, or warfarin.

38. The method of claim 29, wherein the treating agent is terbutaline.

32. A method of treating pelvic pain, or for treating or improving infertility, associated with uterine dysrhythmia comprising vaginally administering a composition that comprises a therapeutically effective amount of an ionic, anti-dysrhythmic treating agent and a bioadhesive, water swellable, but water-insoluble cross-linked polycarboxylic acid polymer, wherein the composition is free of an oil phase and is in the form of a gel at the time of administration, and the treating agent is released in a controlled manner over an extended period of time.

33. The method of claim 32, wherein the polymer comprises polycarbophil and the composition is formulated to release the treating agent over a period of at least two days after administration.

34. A pharmaceutical composition comprising a treating agent and a bioadhesive, water swellable, but water-insoluble cross-linked polycarboxylic acid polymer, wherein the composition is free of an oil phase and is in the form of a gel at the time of administration, and the treating agent comprises one or more agents selected from the group consisting of calcium channel blockers, autocoid agents prostaglandins, and prostaglandin blockers, non-steroidal anti-inflammatory drugs, COX inhibitors, thromboxane synthase inhibitors, and leukotriene inhibitors, wherein the treating agent is in the ionic form and is released in a controlled manner over an extended period of time.

35. The composition of claim 34, wherein the calcium channel blockers are selected from the group consisting of:

amlodipine, bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine, nimodipine, and verapamil; and

the non-steroidal anti-inflammatory drugs are selected from the group consisting of;

diclofenac, etodolac, fenoprofen, lurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, fenamic acid, meloxicam, nabumetone, naproxin, oxaprozin, piroxicam, sulindac, and tolmetin.

36. The composition of claim 34, wherein the autocoid agents are selected from the group consisting of:

prostaglandins and prostaglandin blockers; and

the COX inhibitors are selected from the group consisting of thromboxane synthase inhibitors, and leukotriene inhibitors.

37. The composition of claim 36, wherein the thromboxane synthase inhibitors are selected from the group consisting of:

pirmagrel and dazoxiben; and

the leukotriene inhibitors is zileuton.