Pharmaceutical compositions comprising prasugrel and cyclodextrin derivatives and methods of making and using the same

1. A pharmaceutical composition comprising:

prasugrel, and

a cyclodextrin derivative of Formula I:

wherein

the cyclodextrin derivative is present in a ratio of 100:1 to 700:1 by weight relative to the prasugrel;

n is 4, 5 or 6;

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from: —OH, a straight-chain or branched —O—(C 1 -C 8 -(alkylene))-SO 3 − group, a substituted or unsubstituted straight-chain, branched, or cyclic —O—(C 1 -C 10 ) group, a substituted straight-chain, branched, or cyclic —S—(C 1 -C 10 ) group, and a saccharide; and

wherein the composition is formulated for oral or parenteral administration.

2. The pharmaceutical composition of claim 1 , further comprising at least one pharmaceutically acceptable excipient.

3. The pharmaceutical composition of claim 1 , wherein the bioavailability of the prasugrel in the composition is greater than an equimolar amount of prasugrel alone.

4. The pharmaceutical composition of claim 2 , wherein the time to therapeutic onset of prasugrel is reduced by at least 20%.

5. 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.

6. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition has a pH of 2 to 4.

7. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition has a pH of 4 to 9.

8. A pharmaceutical composition comprising

prasugrel, and

a cyclodextrin derivative of Formula I:

wherein the cyclodextrin derivative is present in a ratio of at least 700:1 by weight relative to the prasugrel;

n is 4, 5 or 6;

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from: —OH, a straight-chain or branched —O—(C 1 -C 8 -(alkylene))-SO 3 − group, a substituted or unsubstituted straight-chain, branched, or cyclic —O—(C 1 -C 10 ) group, a substituted straight-chain, branched, or cyclic —S—(C 1 -C 10 ) group, and a saccharide; and

wherein the composition is formulated for oral or parenteral administration.

9. The pharmaceutical composition of any of claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 4 , R 7 , R 8 and R 9 is a —O-(hydroxy-substituted-C 3 ) group.

10. The pharmaceutical composition of any of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently —OH or a straight-chain or branched —O—(C 1 -C 8 -(alkylene))-SO 3 − group, and wherein the degree of substitution with a straight-chain or branched —O—(C 1 -C 8 -(alkylene))-SO 3 − group is 4 to 8 per cyclodextrin derivative.

11. The pharmaceutical composition of claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is substituted with a —O-(straight-chain C4-(alkylene))-SO 3 − group.

12. The pharmaceutical composition of claim 1 , wherein the cyclodextrin derivative is a compound of formula II:

wherein R═(H) 21-x or (—(CH 2 ) 4 —SO 3 − Na + ) x , and wherein x=6.0-7.1.

13. 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 surface tension modifier, a volatility modifier, a viscosity modifier, and combinations thereof.

14. The pharmaceutical composition of claim 1 , further comprising a sweetener.

15. The pharmaceutical composition of claim 1 , wherein the composition is selected from the group consisting of a solution, a suspension, and an emulsion.

16. The pharmaceutical composition of claim 1 , wherein the composition further comprises 1 mg to 120 mg of prasugrel.

17. 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, comprising administering a pharmaceutical composition according to claim 2 to a subject in need thereof.

18. The method of claim 17 , wherein the composition is administered as a unit dosage form comprising a maintenance dose of 1 mg to 20 mg of prasugrel.

19. The method of claim 17 , wherein the composition is administered as a unit dosage form comprising a loading dose comprising 20 mg to 120 mg of prasugrel.

20. The method of claim 17 , wherein the disorder is 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.

21. The method of claim 17 , further comprising administering 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 Ilb/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 α-adrenergic agonist, a β-adrenergic antagonist, and combinations thereof.

22. The method of claim 17 , further comprising administering a second therapeutic agent selected from: 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, 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, 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 hirudin, disulfatohirudin bivalirudin, desirudin, lepirudin, acenocoumarol, dicoumarol, ethyl biscoumacetate, phenprocoumon, clorindione, diphenadione, phenindione, tioclomarol, warfarin, chlorothiazide, hydrochlorothiazide, ethacrynic acid, furosemide, amiloride, chlorothiazide, hydrochlorothiazide, atorvastatin, fluvastatin, lovastatin, 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, sotalol, adenosine, atropine, digoxin, doxazosin, terazosin, prazosin, and combinations thereof.