Claims for Patent: 8,343,995

Summary for Patent: 8,343,995

Title:	Formulations containing clopidogrel and sulfoalkyl ether cyclodextrin and methods of use
Abstract:	The present invention provides compositions containing clopidogrel, present as a free base or a pharmaceutically acceptable salt thereof, and sulfoalkyl ether cyclodextrin (SAE-CD). The compositions can be liquid, suspension or solid compositions. They can be adapted for oral, peroral or parenteral administration. The SAE-CD serves to aid in dissolution and stabilization of the clopidogrel in aqueous media. The stability of clopidogrel against hydrolytic degradation, thermal degradation, and photolytic degradation are improved. SAE-CD provides improved results over other cyclodextrin derivatives. The SAE-CD-containing composition of clopidogrel can be provided in liquid form, solid form or as a reconstitutable powder. Both ready-to-use and concentrated liquid compositions can be prepared. The liquid composition is optionally available as a clear solution. The compositions herein can be administered perorally or parenterally and provide substantial pharmacokinetic, pharmacodynamic and/or therapeutic advantages over a tablet composition administered perorally and excluding SAE-CD.
Inventor(s):	Mosher; Gerold L. (Kansas City, MO), Wedel; Rebecca L. (Lawrence, KS), Johnson; Karen T. (Lawrence, KS), Machatha; Stephen G. (Waltham, MA), Cowee; Jane A. (Kansas City, MO), Cushing; Daniel J. (Phoenixville, PA)
Assignee:	Cydex Pharmaceuticals, Inc. (Lenexa, KS)
Application Number:	12/597,908
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,343,995
Patent Claims:	1. A composition comprising clopidogrel and a sulfoalkyl ether cyclodextrin (SAE-CD), wherein the SAE-CD is a compound, or a mixture of compounds, of Formula 1: ##STR00003## wherein: n is 4, 5, or 6; R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, and R.sub.9 are each, independently, --O-- or a --O--(C2-C6 alkylene)-SO.sub.3.sup.- group, wherein at least one of R.sub.1 to R.sub.9 is independently a --O--(C.sub.2-C.sub.6 alkylene)-SO.sub.3.sup.- group; and S.sub.1, S.sub.2, S.sub.3, S.sub.4, S.sub.5,S.sub.6,S.sub.7,S.sub.8, and S.sub.9 are each, independently, a pharmaceutically acceptable cation. 2. The composition of claim 1, further comprising an acidifying agent, an alkalinizing agent, an aqueous carrier, an antifungal agent, an antimicrobial agent, an antioxidant, a second therapeutic agent, a buffering agent, a bulking agent, a complexation enhancing agent, a cryoprotectant, a density modifier, an electrolyte, a flavor, a fragrance, a lyophilizing aid, a preservative, a plasticizer, a solubility-enhancing agent, a stabilizing agent, a sweetener, a surface tension modifier, a volatility modifier, a viscosity modifier, or a combination thereof. 3. The composition of claim 1, further comprising a second therapeutic agent selected from the group consisting of: a nonsteroidal antiinflammatory drug, an anticoagulant, a selective factor Xa inhibitor, a direct thrombin inhibitor, an antiplatelet agent, a platelet aggregation inhibitor, a glycoprotein Ilb/IIIa inhibitor, an antisickling agent, a hemorrheologic agent, a thrombolytic agent, a thrombolytic enzyme, and a tissue plasminogen activator. 4. The composition of claim 2, wherein the buffering agent is selected from the group consisting of acetic acid, citric acid, tartaric acid, phosphoric acid, boric acid, and a salt thereof. 5. The composition of claim 2, wherein the composition further comprises a member selected from the group consisting of: a surfactant, a cosolvent, a polymer, an oil, a sugar, and a combination thereof. 6. The composition of claim 1, wherein the composition is adapted for oral, enteral or parenteral administration. 7. The composition of claim 1, wherein the composition further comprises a liquid carrier and the pH of the composition is 5 or greater. 8. The composition of claim 1, wherein the composition further comprises an aqueous liquid carrier and the clopidogrel is present at a concentration equivalent to 0.15 mg/mL to 20 mg/mL of clopidogrel free base. 9. The composition of claim 1, wherein the composition further comprises an aqueous liquid carrier and the SAE-CD is present at a concentration equivalent to 20 mg/mL to 600 mg/mL of clopidogrel free base. 10. The composition of claim 1, wherein the composition is a liquid composition that has been prepared by reconstitution of a reconstitutable solid comprising at least SAE-CD and clopidogrel with an aqueous solution. 11. The composition of claim 1, wherein the composition further comprises a liquid carrier, and the composition is a ready-to-use composition not requiring dilution prior to administration to a subject. 12. The composition of claim 1, wherein the composition further comprises a liquid carrier and is dilutable with an aqueous diluent without significant precipitation of the clopidogrel. 13. The composition of claim 1, further comprising an aqueous liquid carrier, wherein the clopidogrel is present at a concentration equivalent to 0.15-20 mg/mL of clopidogrel free base, and the SAE-CD is present at a concentration of 20 mg/mL to 600 mg/mL. 14. The composition of claim 1, wherein the composition further comprises an aqueous liquid carrier, the pH of the composition is 3.5 or higher, and a molar ratio of the SAE-CD to the clopidogrel is 6:1 to 40:1. 15. The composition of claim 1, wherein the composition further comprises an aqueous liquid carrier, the pH of the composition is 5.5 to 8, and a molar ratio of the SAE-CD to the clopidogrel is 6.5:1 to 12.5:1. 16. The composition of claim 1, further comprising a second therapeutic agent selected from the group consisting of: a drug which is an analog or derivative of clopidogrel, a thienopyridine analog, aspirin, warfarin, unfractionated heparin, low molecular weight heparin, a synthetic pentasaccharide, hirudin, argatroban, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, tirofiban, eptifibatide, abciximab, melagatran, disulfatohirudin, tissue plasminogen activator, a modified tissue plasminogen activator, anistreplase, urokinase, cilostazol, dipyridamole and streptokinase. 17. The composition of claim 1, wherein the clopidogrel exhibits enhanced stability in the presence of the SAE-CD compared to clopidogrel in the presence of an equimolar amount of hydroxypropyl-cyclodextrin (HP-CD). 18. The composition of claim 17, wherein the clopidogrel undergoes a rate of chiral inversion in the presence of the SAE-CD that is reduced compared to a rate of chiral inversion for clopidogrel in the presence of an equimolar amount of a hydroxypropyl-cyclodextrin (HP-CD). 19. The composition of claim 17, wherein the clopidogrel undergoes a rate of degradation in the presence of the SAE-CD that is reduced compared to a rate of clopidogrel degradation in the presence of an equimolar amount of a hydroxypropyl-cyclodextrin (HP-CD). 20. A method of treating a disease, disorder or condition having an etiology associated with platelet aggregation in a patient, the method comprising administering to the patient a therapeutically effective amount of the composition of claim 1. 21. A method of treating myocardial infarction in a patient, comprising administering to the patient a therapeutically effective amount of the composition of claim 1. 22. A method of decreasing the time to therapeutic onset of clopidogrel following administration thereof, the method comprising: administering orally or parenterally, to a subject in need thereof, a therapeutically effective amount of the composition of claim 1, wherein a time to therapeutic onset of the clopidogrel provided by the composition is less than a time to therapeutic onset of clopidogrel provided by an orally administered reference composition excluding the SAE-CD and containing an equivalent dose of clopidogrel. 23. The method of claim 22, wherein the time to peak or target therapeutic effect in the subject is reduced by 10 to 1000 percent. 24. A method of increasing the bleeding time in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of the composition of claim 1, wherein the clopidogrel is present in an amount equivalent to no more than 900 mg of clopidogrel free base, and wherein the bleeding time of the subject increases by at least 10% during a period of no more than 120 min following administration of the composition. 25. A method of decreasing extent of or potential for platelet aggregation in the blood of a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the composition of claim 1, wherein the clopidogrel is present in an amount equivalent to no more than 900 mg of clopidogrel free base, and wherein the percentage of platelet aggregation of the subject decreases by at least 5% during a period of no more than 120 min following administration of the composition. 26. The method of claim 20, wherein the composition further comprises a second therapeutic agent. 27. The method of claim 21, wherein the disease is sickle cell crisis, and the composition further comprises a second therapeutic agent. 28. The method of claim 27, wherein the second therapeutic agent is selected from the group consisting of: drugs included in management protocols for sickle cell patients experiencing pain, fever-febrile illness acute chest syndrome, acute splenic sequestration, aplastic crisis, priapism, acute stroke or neurologic events; folic acid supplementation; hydroxyurea; a NSAID; an antibiotic; an iron chelator; a bronchodilator; a diuretic; an anxiolytic; an .alpha.-agonist; hydralazine; pentoxifylline; diltiazem; a gonatropin-releasing hormone analog; diethylstilbestrol; and combinations thereof. 29. The method of claim 28, wherein the second therapeutic agent is selected from the group consisting of: acetaminophen, ascorbic acid, aspirin, azithromycin, bumetanide, cefotaxime, ceftriaxone, cephalosporins, clindamycin, codeine, deferasirox, deferoximine, diclofenac, diethylstilbestrol, diltiazem, epinephrine, erythromycin, etilefrine, etodolac, fenoprofen, fentanyl, flutamide, folic acid, furosemide, gonadotropin-releasing hormone analogues, hydralazine, hydrocodone, hydromorphone, hydroxyurea, hydroxyzine pamoate, ibuprofen, indomethacin, ketoprofen, ketorolac, lorazepam, meloxicam, meperidine, methadone, midazolam, morphine, nabumetone, naproxen, oxaprozin, oxycodone, penicillin derivative, penicillins, pentoxifylline, phenylephrine, phenylpropanolamine, propoxyphene, pseudoephedrine, remifentanil, sulindac, terbutaline, tolmetin, torsemide, and vancomycin. 30. The composition of claim 1, wherein the clopidogrel is provided as a pharmaceutically acceptable salt. 31. The composition of claim 1, wherein the clopidogrel is provided in optically pure or optically enriched form. 32. The composition of claim 1, wherein the compound of Formula 1 has a degree of substitution of 4-7. 33. The composition of claim 1, wherein SAE-CD is a compound, or mixture of compounds, of the formula SAE.sub.x-R-CD, wherein SAE is selected from the group consisting of: sulfomethyl ether, sulfoethyl ether, sulfopropyl ether, sulfobutyl ether, sulfopentyl ether, and sulfohexyl ether; and x is 1-18 when R is .alpha., 1-21 when R is .beta., or 1-24 when R is .gamma.. 34. The composition of claim 33, wherein the SAE-CD is SBE.sub.x-.beta.-CD, wherein x is 6.0 to 7.1. 35. The composition of claim 33, wherein the SAE is sulfobutyl ether. 36. The composition of claim 1, wherein a molar ratio of the SAE-CD to the clopidogrel is at least 6:1. 37. The composition of claim 1, wherein a molar ratio of the SAE-CD to the clopidogrel is 6:1 to 40:1. 38. The composition of claim 1, wherein a molar ratio of the SAE-CD to the clopidogrel is 6.5:1 to 12.5:1. 39. The composition of claim 1, wherein the composition has a pH of 3.5 or greater, and wherein a molar ratio of the SAE-CD to the clopidogrel is at least 6:1. 40. The composition of claim 1, wherein the composition has a pH of 5.5 or greater, and wherein a molar ratio of the SAE-CD to the clopidogrel is at least 6.5:1. 41. The composition of claim 1, wherein the composition has a pH of 5.5 to 8, and wherein a molar ratio of the SAE-CD to the clopidogrel is at least 6.5:1. 42. The composition of claim 1, wherein the pH of the composition is in the range of 4 to 8. 43. The composition of claim 1, wherein the pH of the composition is in the range of 4 to 6. 44. The composition of claim 1, further comprising an aqueous liquid carrier. 45. The composition of claim 1, further comprising an aqueous liquid carrier, wherein the SAE-CD is present at a concentration of 20 mg/mL to 600mg/mL, and the clopidogrel is present at a concentration equivalent to 0.15 mg/mL to 20 mg/mL of clopidogrel free base. 46. The composition of claim 1, further comprising one or more pharmaceutically acceptable excipients.

Details for Patent 8,343,995

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2039-02-26
Janssen Biotech, Inc.	REOPRO	abciximab	Injection	103575	12/22/1994		2039-02-26