Claims for Patent: 8,236,782

Summary for Patent: 8,236,782

Title:	Pharmaceutical compositions comprising prasugrel and cyclodextrin derivatives and methods of making and using the same
Abstract:	The present invention is directed to pharmaceutical compositions comprising prasugrel and a cyclodextrin derivative, and methods of making and using the same.
Inventor(s):	Mosher; Gerold L. (Kansas City, MO), Machatha; Stephen G. (Waltham, MA), Cushing; Daniel J. (Phoenixville, PA)
Assignee:	Cydex Pharmaceuticals, Inc. (Lawrence, KS)
Application Number:	12/779,850
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 8,236,782
Patent Claims:	1. A pharmaceutical composition comprising: prasugrel, and a cyclodextrin derivative of formula I: ##STR00008## wherein n is 4, 5 or 6, wherein 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 independently selected from: --OH, a straight-chain or branched --O--(C.sub.1-C.sub.8-(alkylene))-SO.sub.3.sup.- group, an optionally substituted straight-chain, branched, or cyclic --O--(C.sub.1-C.sub.10) group, an optionally substituted straight-chain, branched, or cyclic --S--(C.sub.1-C.sub.10) group, and a saccharide, and wherein the cyclodextrin derivative is present in a concentration of at least 100:1 by weight relative to the prasugrel. 2. The pharmaceutical composition of claim 1, wherein the cyclodextrin derivative is present in a concentration of at least 50:1 by mole relative to the prasugrel. 3. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a pH of about 2 to about 4, and wherein the cyclodextrin derivative is present in a ratio of about 100:1 to about 700:1 by weight relative to the prasugrel. 4. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition has a pH of about 4 to about 9, and wherein the cyclodextrin derivative is present in a ratio of at least 700:1 by weight relative to the prasugrel. 5. The pharmaceutical composition of claim 1, wherein at least one of 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 is a --O-(hydroxy-substituted-C.sub.3) group. 6. The pharmaceutical composition of claim 1, wherein 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 independently a straight-chain or branched --O--(C.sub.1-C.sub.8-(alkylene))-SO.sub.3.sup.- group having a degree of substitution of about 4 to about 8 per cyclodextrin derivative, and the remaining substituents are --H. 7. The pharmaceutical composition of claims 1, wherein at least one of 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 is substituted with a --O-(straight-chain C.sub.4-(alkylene))-SO.sub.3.sup.- group. 8. The pharmaceutical composition of claim 1, wherein the cyclodextrin derivative is a compound of formula II: ##STR00009## wherein R.dbd.(H).sub.21-x or (--(CH.sub.2).sub.4--SO.sub.3.sup.-Na.sup.+).sub.x. 9. The pharmaceutical composition of claim 8, wherein x=6.0-7.1. 10. The pharmaceutical composition of claim 1, comprising an agent selected from: a carrier, a diluent, a preservative, an antioxidant, a second therapeutic agent, an acidifying agent, an alkalinizing 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 plasticizer, a solubility-enhancing agent, a stabilizing agent, a sweetener, a surface tension modifier, a volatility modifier, a viscosity modifier, and combinations thereof. 11. A method of decreasing the time to therapeutic onset of prasugrel following administration thereof, the method comprising orally or parenterally administering to a subject in need thereof the pharmaceutical composition of claim 1, wherein the time to therapeutic onset of prasugrel provided by the orally or parenterally administered composition is less than the time to therapeutic onset of prasugrel provided by an orally administered reference composition that excludes the cyclodextrin derivative and contains an equivalent dose of prasugrel. 12. A method of treating a disease, disorder or condition having an etiology associated with platelet aggregation or of a disease, disorder or condition that is therapeutically responsive to prasugrel, the method comprising administering to a subject in need thereof the pharmaceutical composition of claim 1. 13. The method of claim 12, wherein the administering is a maintenance dose of about 1 mg to about 20 mg of prasugrel. 14. The method of claim 12, comprising administering to the subject in need thereof a loading dose comprising about 20 mg to about 120 mg of prasugrel. 15. The method of claim 12, wherein the subject suffers from a disorder selected from: an acute coronary syndrome, a recent myocardial infarction, a recent stroke, an established peripheral arterial disease, ST-segment elevation acute myocardial infarction, non-ST-segment elevation acute coronary syndrome, a recent percutaneous coronary intervention, a recent angioplasty, a thromboembolism, a pulmonary embolism, a deep vein thrombosis, atherosclerosis, diabetes mellitus, a transient ischemic event, a secondary ischemic event, vascular death with established peripheral arterial disease, cardiovascular disease, cerebrovascular disease, angina pectoris, cardiac arrhythmia, sickle cell crisis, and combinations thereof. 16. The method of claim 12, comprising administering to the subject a second therapeutic agent selected from: a nonsteroidal antiinflamatory drug, a selective factor Xa inhibitor, a direct thrombin inhibitor, a prostaglandin analog, an adenosine diphosphate (ADP) inhibitor, a platelet aggregation inhibitor, an antiplatelet agent, a glycoprotein IIb/IIIa inhibitor or antagonist, an antisickling agent, a hemorrheologic agent, a thromobolytic agent, a thrombolytic enzyme, a thromboxane A2 biosynthesis inhibitors, a thromboxane antagonist, a cyclooxygenase inhibitor, an angiotensin antagonist, an endothelin antagonist, a phosphodiesterase inhibitor, an angiotensin converting enzyme (ACE) inhibitors, a neutral endopeptidase inhibitors, an anticoagulants, a diuretic, a tissue plasminogen activator, a modified tissue plasminogen activator, a biologic response modifier, a statin, a calcium channel blocking agent, an anti-arrhythmic agent, an .alpha.-adrenergic agonist, a .beta.-adrenergic antagonist, and combinations thereof 17. The method of claim 12, comprising administering to the subject a second therapeutic agent selected from: an analog or derivative of prasugrel, clopridogrel, diclofenac, droxicam, etolodac, fenoprofen, flurbiprofen, indomethacin, isoxicam, ketoprofen, lornoxicam, meloxicam, mefenamate, naproxen, oxaprozin, piroxicam, sulindac, tenoxicam, apixaban, otamixaban, rivaroxaban, eptifibatide, beraprost, prostacyclin, iloprost, treprostinil, ticagrelor, ticlopidine, abciximab, cloricromen, ditazole, indobufen, picotamide, sulfinpyrazone, abciximab, eptifibatide, tirofiban, cetiedil, alteplase, anistreplase, brinase, drotrecogin alfa, monteplase, reteplase, saruplase, streptokinase, tenecteplase, urokinase, fibrinolysin, ancrod, aspirin, picotamide, ramatroban, seratrodast, aloxiprin, carbasalate calcium, celecoxib, ibuprofen, rofecoxib, candesartan, eprosartan, irbesartran, losartan, olmesartan, telmisartan, valsartan, ambrisentan, atrasentan, bosentan, sitaxentan, tezosentan, cilostazol, dipyridamole, enoximone, milrinone, captopril, enalapril, enaliprilat, spirapril, quinapril, perindopril, ramipril, fosinopril, trandolapril, lisinopril, moexipril, benazapril, candoxatril, ecadotril, candoxatril, ecadotril, unfractionated heparin, ardeparin, bemiparin, certoparin, dalteparin, enoxaparin, fondaparin, fragmin, melagatran, nadroparin, parnaparin, reviparin, tinzaparin, argatroban, dabigatran, melagatran, ximelagatran, defibrotide, ramatroban, antithrombin III, fondaparinux, idraparinux, danaparoid, sulodexide, dermatan sulfate, a synthetic pentasaccharide, a hirudin, disulfatohirudin bivalirudin, desirudin, lepirudin, acenocoumarol, coumatetralyl, dicoumarol, ethyl biscoumacetate, phenprocoumon, clorindione, diphenadione, phenindione, tioclomarol, warfarin, chlorothiazide, hydrochlorothiazide, ethacrynic acid, furosemide, amiloride, chlorothiazide, hydrochlorothiazide, atorvastatin, fluvastatin, lovastatin, pravastatin, pravastatin, rosuvastatin, simvastatin, amlodipine, felodipine, diltiazem, nifedipine, nicardipine, nisoldipine, bepridil, verapamil, dofetilide, ibutilide, metoprolol, propranolol, atenolol, betaxolol, bisoprolol, carvediol, nadolol, nebivolol, timolol, ajmaline, disopyramide, prajmaline, procainamide, quinidine, sparteine, aprindine, lidocaine, mexiletine, tocainide, encainide, flecainide, lorcainide, moricizine, propafenone, acebutolol, pindolol, amiodarone, bretylium, bunaftine, dofetilide, sotalol, adenosine, atropine, digoxin, doxazosin, terazosin, prazosin, and combinations thereof. 18. A unit dosage form comprising: about 1 mg to about 120 mg prasugrel, and a cyclodextrin derivative of formula I: ##STR00010## wherein n is 4, 5 or 6, wherein 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 independently selected from: --OH, a straight-chain or branched --O--(C.sub.1-C.sub.8-(alkylene))-SO.sub.3.sup.- group, an optionally substituted straight-chain, branched, or cyclic --O--(C.sub.1-C.sub.10) group, an optionally substituted straight-chain, branched, or cyclic --S--(C.sub.1-C.sub.10) group, and a saccharide, and wherein the cyclodextrin derivative is present in a concentration of at least 100:1 by weight relative to the prasugrel. 19. The unit dosage form of claim 18, comprising about 1 mg to about 20 mg of prasugrel. 20. The unit dosage form of claim 18, comprising about 20 mg to about 120 mg of prasugrel. 21. The unit dosage form of claim 18, wherein the unit dosage form is a solid. 22. The unit dosage form of claim 21, wherein the solid is a lyophilized solid or an aseptic spray-dried solid. 23. The unit dosage form of claim 18, wherein the prasugrel is in a concentration of about 0.005% to about 2% w/v, the cyclodextrin derivative is in a concentration of about 5% to about 40% w/v, and the unit dosage form is an aqueous solution having a pH of about 2 to about 4. 24. The unit dosage form of claim 23, comprising a 0.1 M buffer, wherein the prasugrel in the unit dosage form degrades by 10% or less over a period of 24 hours. 25. The unit dosage form of claim 18, wherein the prasugrel is in a concentration of about 0.005% to about 1% w/v, the cyclodextrin derivative is in a concentration of about 5% to about 40% w/v, and the unit dosage form is an aqueous solution having a pH of about 4 to about 9. 26. The unit dosage form of claim 25, comprising a 0.1 M buffer, wherein the prasugrel in the unit dosage foam degrades by 20% or less over a period of 24 hours. 27. A method of treating a subject in need thereof, the method comprising orally or parenterally administering the unit dosage form of claim 18 to the subject in need thereof. 28. A method for titrating a subject in need thereof to a therapeutically effective dose of prasugrel, the method comprising: parenterally administering a first dose of the pharmaceutical composition of claim 1 to the subject in need thereof; determining the subject's responsiveness to the first dose of the pharmaceutical composition; and parenterally administering a second dose of the pharmaceutical composition to the subject, wherein the second dose comprises an increased or decreased amount of prasugrel compared to the first dose. 29. The method of claim 28, comprising: repeating the determining, and parenterally administering further doses of the pharmaceutical composition until a desired therapeutic effectiveness is achieved. 30. The method of claim 28, wherein the subject in need thereof suffers from a disorder selected from: an acute coronary syndrome, a recent myocardial infarction, a recent stroke, an established peripheral arterial disease, ST-segment elevation acute myocardial infarction, non-ST-segment elevation acute coronary syndrome, a recent percutaneous coronary intervention, a recent angioplasty, a thromboembolism, a pulmonary embolism, a deep vein thrombosis, atherosclerosis, diabetes mellitus, a transient ischemic event, a secondary ischemic event, vascular death with established peripheral arterial disease, cardiovascular disease, cerebrovascular disease, angina pectoris, cardiac arrhythmia, sickle cell crisis, and combinations thereof. 31. The method of claim 28, comprising administering to the subject a therapeutic agent selected from: a nonsteroidal antiinflamatory drug, a selective factor Xa inhibitor, a direct thrombin inhibitor, a prostaglandin analog, an adenosine diphosphate (ADP) inhibitor, a platelet aggregation inhibitor, an antiplatelet agent, a glycoprotein IIb/IIIa inhibitor or antagonist, an antisickling agent, a hemorrheologic agent, a thromobolytic agent, a thrombolytic enzyme, a thromboxane A2 biosynthesis inhibitors, a thromboxane antagonist, a cyclooxygenase inhibitor, an angiotensin antagonist, an endothelin antagonist, a phosphodiesterase inhibitor, an angiotensin converting enzyme (ACE) inhibitors, a neutral endopeptidase inhibitors, an anticoagulants, a diuretic, a tissue plasminogen activator, a modified tissue plasminogen activator, a biologic response modifier, a statin, a calcium channel blocking agent, an anti-arrhythmic agent, an .alpha.-adrenergic agonist, a .beta.-adrenergic antagonist, and combinations thereof. 32. The method of claim 28, comprising administering to the subject a second therapeutic agent selected from: an analog or derivative of prasugrel, clopridogrel, diclofenac, droxicam, etolodac, fenoprofen, flurbiprofen, indomethacin, isoxicam, ketoprofen, lornoxicam, meloxicam, mefenamate, naproxen, oxaprozin, piroxicam, sulindac, tenoxicam, apixaban, otamixaban, rivaroxaban, eptifibatide, beraprost, prostacyclin, iloprost, treprostinil, ticagrelor, ticlopidine, abciximab, cloricromen, ditazole, indobufen, picotamide, sulfinpyrazone, abciximab, eptifibatide, tirofiban, cetiedil, alteplase, anistreplase, brinase, drotrecogin alfa, monteplase, reteplase, saruplase, streptokinase, tenecteplase, urokinase, fibrinolysin, ancrod, aspirin, picotamide, ramatroban, seratrodast, aloxiprin, carbasalate calcium, celecoxib, ibuprofen, rofecoxib, candesartan, eprosartan, irbesartran, losartan, olmesartan, telmisartan, valsartan, ambrisentan, atrasentan, bosentan, sitaxentan, tezosentan, cilostazol, dipyridamole, enoximone, milrinone, captopril, enalapril, enaliprilat, spirapril, quinapril, perindopril, ramipril, fosinopril, trandolapril, lisinopril, moexipril, benazapril, candoxatril, ecadotril, candoxatril, ecadotril, unfractionated heparin, ardeparin, bemiparin, certoparin, dalteparin, enoxaparin, fondaparin, fragmin, melagatran, nadroparin, parnaparin, reviparin, tinzaparin, argatroban, dabigatran, melagatran, ximelagatran, defibrotide, ramatroban, antithrombin III, fondaparinux, idraparinux, danaparoid, sulodexide, dermatan sulfate, a synthetic pentasaccharide, a hirudin, disulfatohirudin bivalirudin, desirudin, lepirudin, acenocoumarol, coumatetralyl, dicoumarol, ethyl biscoumacetate, phenprocoumon, clorindione, diphenadione, phenindione, tioclomarol, warfarin, chlorothiazide, hydrochlorothiazide, ethacrynic acid, furosemide, amiloride, chlorothiazide, hydrochlorothiazide, atorvastatin, fluvastatin, lovastatin, pravastatin, pravastatin, rosuvastatin, simvastatin, amlodipine, felodipine, diltiazem, nifedipine, nicardipine, nisoldipine, bepridil, verapamil, dofetilide, ibutilide, metoprolol, propranolol, atenolol, betaxolol, bisoprolol, carvediol, nadolol, nebivolol, timolol, ajmaline, disopyramide, prajmaline, procainamide, quinidine, sparteine, aprindine, lidocaine, mexiletine, tocainide, encainide, flecainide, lorcainide, moricizine, propafenone, acebutolol, pindolol, amiodarone, bretylium, bunaftine, dofetilide, sotalol, adenosine, atropine, digoxin, doxazosin, terazosin, prazosin, and combinations thereof. 33. The method of claim 28, comprising diluting the unit dosage form with an aqueous carrier, and then parenterally administering the diluted unit dosage form. 34. The method of claim 33, wherein the unit dosage form is selected from: a concentrated liquid unit dosage, a lyophilized solid unit dosage, an aseptic spray-dried solid unit dosage, and a reconstitutable unit dosage.

Details for Patent 8,236,782

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bausch Health Us, Llc	IPRIVASK	desirudin	For Injection	021271	04/04/2003		2029-05-13
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2029-05-13
Genentech, Inc.	ACTIVASE	alteplase	For Injection	103172	11/13/1987		2029-05-13
Genentech, Inc.	CATHFLO ACTIVASE	alteplase	For Injection	103172	09/04/2001		2029-05-13