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(12) Patent Application Publication (10) Pub. No.: US 2005/0008704 A1 Ray Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2005/0008704 A1 Ray Et Al US 2005OOO8704A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2005/0008704 A1 Ray et al. (43) Pub. Date: Jan. 13, 2005 (54) PHARMACEUTICAL COMPOSITION FOR Publication Classification SOLUBILITY ENHANCEMENT OF HYDROPHOBC DRUGS (51) Int. Cl." ....................... A61K 31/704; A61K 31/56; A61K 31/5513; A61K 31/58 (76) Inventors: Anup Kumar Ray, Staten Island, NY (52) U.S. Cl. ......................... 424/486; 514/171; 514/649; (US); Indranil Nandi, Plainsboro, NJ 514/35; 514/221; 514/571; (US); Suresh Palaniswamy, East 514/616; 514/174 Windsor, NJ (US); Pablo Davila, East Windsor, NJ (US); Aakanksha Harshad Vora, Dayton, NJ (US) (57) ABSTRACT Correspondence Address: NOVARTS The present invention provides a pharmaceutical composi CORPORATE INTELLECTUAL PROPERTY tion having enhanced Solubility comprising a drug and ONE HEALTH PLAZA 430/2 polyethylene glycol, wherein the ratio of polyethylene gly EAST HANOVER, NJ 07936-1080 (US) col to drug by weight is from about 0.2:1 to about 10:1, and the polyethylene glycol has a melting point of at least 37 C. (21) Appl. No.: 10/618,545 The pharmaceutical compositions exhibit rapid dissolution upon contact with physiological Solvents, Such as water, (22) Filed: Jul. 11, 2003 Saliva or gastrointestinal fluids. Patent Application Publication Jan. 13, 2005 Sheet 1 of 4 US 2005/0008704 A1 C/D U CS Ea v- S E O 9 g 5 LL a a & : us 5.Ol a Z C pemo SSO % Patent Application Publication Jan. 13, 2005 Sheet 2 of 4 US 2005/0008704 A1 F.G. 2 Modafinil 200-mg AP 900 ml of 0.1 NHC in USPI Q50 rpm 120 100. 80 I 60 20 O 5 10 15 30 45 60 70 Time (minutes) Patent Application Publication Jan. 13, 2005 Sheet 3 of 4 US 2005/0008704 A1 FIG.3 Dissolution Profile of Raloxifene HCL Tablets 60 mg Brand (Lot # 5AH91A; Exp: 10/01/2003) vs RAL:PEG:PS 80 COMPLEX Metd:900 mL, Sodium Acetate Buffer pH 4.5, App II, 50 rpm 6 O f Time (minutes) O 10 20 30 40 50 Patent Application Publication Jan. 13, 2005 Sheet 4 of 4 US 2005/0008704 A1 FIG. 4 Dissolution Profile of Raloxifene HCL Tablets 60 mg Brand (Lot # 5AH91A, Exp. 10/01/2003) (Metd:900 mt, Sodium Acetate Buffer pH 4.5, App ll, 50 rpm 120 110 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 60 - 50 40 Time (minutes) O 1O 20 30 AO 50 60 US 2005/OOO8704 A1 Jan. 13, 2005 PHARMACEUTICAL COMPOSITION FOR 0008 According to another aspect, the invention pro SOLUBILITY ENHANCEMENT OF vides a method of preparing a pharmaceutical composition HYDROPHOBC DRUGS having enhanced Solubility comprising a drug and polyeth ylene glycol, wherein the ratio of polyethylene glycol to FIELD OF THE INVENTION drug by weight is from about 0.2:1 to about 10:1, and the 0001. The present invention provides a pharmaceutical polyethylene glycol has a melting point of at least 37 C., composition having enhanced Solubility comprising a drug Said method comprising: and polyethylene glycol, wherein the ratio of polyethylene glycol to drug by weight is from about 0.2:1 to about 10:1, 0009 (a) combining polyethylene glycol with a drug and the polyethylene glycol has a melting point of at least and optionally one or more excipients to form a 37o C. premix, BACKGROUND OF THE INVENTION 0010) (b) adding a solvent and optionally a surfac 0002 Hydrophobic drugs, i.e., drugs having poor solu tant to the premix formed in Step (a) to form a wet bility in aqueous Solution, present difficult formulation prob granulation; and lems for effective administration to patients. A well-de 0011 (c) drying the wet granulation to form a phar signed formulation must, at a minimum, be capable of maceutical composition which is encapsulated or presenting a therapeutically effective amount of the hydro tableted. phobic drug to the desired absorption site, in an absorbable form. Even this minimal functionality is difficult to achieve 0012. According to another aspect, the invention pro with hydrophobic drugs because of the slow disintegration vides a method of preparing a pharmaceutical composition or dissolution. Especially in intestinal fluid, a drug that does having enhanced Solubility comprising a drug and polyeth not dissolve Sufficiently cannot pass via the intestinal wall ylene glycol, wherein the ratio of polyethylene glycol to membrane into the bloodstream, and is simply excreted by drug by weight is from about 0.2:1 to about 10:1, and the the individual via their intestinal tract without providing a polyethylene glycol has a melting point of at least 37 C., therapeutic benefit. Said method comprising: 0.003 Moreover, when such poorly soluble drugs are formed into tablets, the process used to prepare the tablets 0013 (a) combining a drug and optionally one or may further reduce the disintegrating or dissolving proper more excipients to form a premix, ties of Such drugs. A tableting process generally requires high compression of pharmaceutical ingredients which hin 0014) (b") adding a mixture comprising a solvent and ders the disintegration and wetting of the interior portion of polyethylene glycol to the premix formed in Step (a") the tablet which reduces the disintegrating or dissolving to form a wet granulation; and properties of the tablet. Thus, to increase the dissolution rate, 0015 (c) drying the wet granulation to form a pharma tablets are commonly formulated with relatively large ceutical composition which is encapsulated or tableted. amounts of disintegrant and carrier materials. However, increasing the amount of disintegrant and carrier material 0016. According to another aspect, the invention pro deleteriously effects either the size of the tablet or the drug vides a method of preparing a pharmaceutical composition loading of the tablet. having enhanced Solubility comprising a drug and polyeth 0004 U.S. Pat. Nos. 5,811,120 and 5,972,383 describe ylene glycol, wherein the ratio of polyethylene glycol to pharmaceutical formulations containing a hydrophobic drug by weight is from about 0.2:1 to about 10:1, and the drug, raloxifene hydrochloride and a Surfactant Selected polyethylene glycol has a melting point of at least 37 C., from a Sorbitan fatty acid ester or a polyoxyethylene Sorbitan Said method comprising: fatty acid ester, polyvinylpyrrolidone and a water-Soluble 0017 (a") combining a drug with melted polyethyl diluent Selected from a polyol or Sugar. ene glycol and optionally a Surfactant to form a 0005. It would be desirable to develop a pharmaceutical Slurry, and composition having enhanced Solubility, especially for hydrophobic drugs. In addition, the pharmaceutical compo 0018 (b") cooling the slurry formed in Step (a") to sition should be Suitable for tablet formulations. form a Solid; 0.019 (c") milling the solid formed in Step (b") to SUMMARY OF THE INVENTION form granules, and 0006 The invention provides a pharmaceutical compo Sition having enhanced Solubility comprising a drug and 0020 (d") mixing at least one excipient with the polyethylene glycol, wherein the ratio of polyethylene gly granules to form a pharmaceutical composition col to drug by weight is from about 0.2:1 to about 10:1, and which is encapsulated or tableted. the polyethylene glycol has a melting point of at least 37 C. 0021. The pharmaceutical compositions having enhanced 0007 According to another aspect, the invention pro solubility of the invention exhibit rapid dissolution upon vides a tablet having enhanced Solubility comprising a contact with physiological Solvents, Such as water, Saliva or hydrophobic drug and polyethylene glycol, wherein the ratio gastrointestinal fluids, due to the presence of a critical type of polyethylene glycol to drug by weight is from about 0.2:1 and amount of polyethylene glycol, as compared to phar to about 10:1, and the polyethylene glycol has a melting maceutical compositions which do not contain Such poly point of at least 37° C. ethylene glycol. US 2005/OOO8704 A1 Jan. 13, 2005 BRIEF DESCRIPTION OF THE DRAWINGS 0028 Preferably, the pharmaceutically acceptable salt of raloxifene is raloxifene hydrochloride. Preferably, the phar 0022 FIG. 1 is a dissolution profile of five anagrelide maceutically acceptable Salt of paroxetine is paroxetine Samples. hydrochloride. Preferably, the pharmaceutically acceptable 0023 FIG. 2 is a dissolution profile of three modafinil salt of glimepiride is glimepiride hydrochloride. Preferably, Samples. the pharmaceutically acceptable Salt of anagrelide is 0024 FIG. 3 is a dissolution profile of five raloxifene anagrelide hydrochloride. Samples. 0029. The amount of drug in the pharmaceutical compo 0025 FIG. 4 is a dissolution profile of five raloxifene sitions is preferably from about 20 mg to about 2000 mg. Samples. More preferably, the amount of drug in the pharmaceutical compositions is from about 60 mg to about 200 mg. DESCRIPTION OF THE INVENTION 0030 Polyethylene glycol is a condensation polymer of 0026. The pharmaceutical compositions of the invention ethylene glycol having the formula comprise a drug, preferably a hydrophobic drug, and poly HOCH (CHOCH), CH-OH, wherein n is the average ethylene glycol (PEG). Examples of hydrophobic drugs number of oxyethylene groups. Preferably, n is from 20-204. include, but are not limited to, raloxifene, paroxetine, glime The PEG should have a m.p. of at least about 37° C. In piride, anagrelide, modafinil, paroxetine, cabergoline, addition, the PEG preferably has an average molecular replaginide, glipizide, benzodiazepines, clofibrate, chlor weight (m.w.) from about 950 to about 20,000, more pref pheniramine, dinitirate, digoxin, digitoxin, ergotamin tar erably from about 2700 to about 9000. A combination of tate, estradiol, fenofibrate, griseofulvin, hydrochlorothiaz ide, hydrocortisone, isosorbide, medrogeston, PEGs may also be used. Thus, grades of PEG 1000 and OxyphenbutaZone, prednisolone, prednisone, polythiazide, upwards are Suitable for use in the present invention. The progensterone, Spironolactone, tolbutamide, 10,11-dihydro average m.W.
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