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

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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

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 -

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. and m.p. of preferred PEGs are typically as 5H-dibenzoa, dicyclo-heptene-5-carboxamide; 5H-dibenzo follows: PEG 1000: m.w. 950-1050, m.p. 37-40° C.; PEG a, dicycloheptene-5-carboxamide, fish oil and the like, 1500: m.w. 1400-1600, m.p. 44-48 C.; PEG 1540: m.w. including pharmaceutical acceptable Salts thereof. Prefer 1300-1600, m.p. 40-48° C.; PEG 2000: m.w. 1800-2200, ably, the hydrophobic drug is selected from raloxifene, m.p. 45-50° C.; PEG 3000: m.w. 2700-3300, m.p. 48-54°C.; paroxetine, glimepiride, anagrelide and modafinil, including PEG 4000: m.w.. 3000-4800, m.p. 50-58° C.; PEG 6000: pharmaceutical acceptable Salts thereof. A combination of m.w. 5400-6600, m.p. 55-63° C.; PEG 8000: m.w. 7000 drugs may also be used. While the invention is illustrated 9000, m.p. 60-63° C.; and PEG 20000: m.w. 15000-20000, with particularly hydrophobic drugs, the pharmaceutical m.p. 60-63 C. composition of the invention is also applicable to more Soluble drugs in need of enhanced dissolution and bioavail 0031. The ratio of polyethylene glycol to drug by weight ability. is from about 0.2:1 to about 10:1. Preferably, the ratio of polyethylene glycol to drug by weight is from about 0.5:1 to 0027. The term “pharmaceutically acceptable salt” refers about 5:1. More preferably the ratio of polyethylene glycol to those Salts of the above described drugs that are not to drug by weight is from about 0.7:1 to about 2:1, most Substantially toxic at the dosage administered to achieve the preferably the ratio is 1:1. desired effect and do not independently possess significant pharmacological activity. The Salts included within the 0032. The pharmaceutical compositions of the invention Scope of this term are pharmaceutically acceptable acid may additionally include a Surfactant or a combination of addition Salts of a Suitable inorganic or organic acid. Suitable Surfactants. Preferred Surfactants include: polyoxyethylene inorganic acids are, e.g., hydrochloric, hydrobromic, Sulfu Sorbitan-fatty acid esters, also called polySorbates, e.g., ric and phosphoric acids. Suitable organic acids include mono- and tri-lauryl, palmityl, Stearyl and oleyl esters of the carboxylic acids, Such as acetic, propionic, glycolic, lactic, type known and commercially-available under the trade pyruvic, malonic, Succinic, fumaric, malic, tartaric, citric, mark TWEEN including the following products: cyclamic, ascorbic, maleic, hydroxymaleic, dihydroxyma leic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxyben 0033) Tween 2O Zoic, anthranillic, cinnamic, Salicylic, 4-aminoSalicyclic, polyoxyethylene(20)Sorbitanmonolaurate 2-phenoxybenzoic, 2-acetoxybenzoic and mandelic acid; Sulfonic acids, Such as methaneSulfonic, ethaneSulfonic and 0034) Tween 21 B-hydroxyethaneSulfonic acid. In addition, “pharmaceuti polyoxyethylene(4)Sorbitanmonolaurate cally acceptable Salts' include those Salts of the above described drugs formed with inorganic and organic bases, 0035) Tween 40 Such as those of alkali metals, e.g., Sodium, potassium and polyoxyethylene(20)Sorbitanmonopalmitate lithium; alkaline earth metals, e.g., calcium and magnesium; light metals of group IIIA, e.g., aluminum; organic amines, 0.036 Tween 60 e.g., primary, Secondary or tertiary amines, Such as cyclo polyoxyethylene(20)SorbitanmonoStearate hexylamine, ethylamine, pyridine, methylaminoethanol and 0037 Tween 65 piperazine. The Salts are prepared by conventional means by polyoxyethylene(20)sorbitantristearate one of ordinary skill in the art as, e.g., by treating a compound with an appropriate acid or base. Such Salts can 0.038 Tween 8O exist in either a hydrated or Substantially anhydrous form. polyoxyethylene(20)sorbitanmonooleate US 2005/OOO8704 A1 Jan. 13, 2005

0.039 Tween 81 0050 Examples of solubilizers and/or emulsifiers include polyoxyethylene(5)Sorbitanmonooleate Sorbitan fatty acid esters, Such as Sorbitan trioleate; phos 0040) Tween 85 phatides, Such as lecithin, acacia, tragacanth, polyoxyethy polyoxyethylene(20)sorbitantrioleate lated Sorbitan monooleate and other ethoxylated fatty acid esters of Sorbitan, polyoxyethylated fats, polyoxyethylated 0041) More preferably, the surfactant is TWEEN 80 oleotriglycerides, linolizated oleotriglycerides, polyethylene polyoxyethylene(20)Sorbitanmonooleate. oxide condensation products of fatty alcohols, alkylphenols 0042. The surfactant is preferably present in an amount of or fatty acids or also 1-methyl-3-(2-hydroxyethyl)imidazoli from about 0.01 weight percent (wt %) to about 20 wt %, done-(2). In this context, polyoxyethylated means that the based on the total weight of the pharmaceutical composition. Substances in question contain polyoxyethylene chains, the More preferably, the Surfactant is present in an amount of degree of polymerization of which generally lies between 2 from about 1 wt % to about 5 wt %, based on the total weight and 40 and in particular between 10 and 20. of the composition. 0051 Examples of disintegrants include: 0043. It is within the scope of the invention for the 0.052 (i) natural starches, such as maize starch, pharmaceutical compositions, in addition to the hydrophobic potato Starch and the like, directly compressible drug, PEG and optionally a Surfactant, to include one or Starches, e.g., Sta-rX(R) 1500; modified Starches, e.g., more pharmaceutically acceptable excipients. Examples of carboxymethyl Starches and Sodium Starch glycolate, Such excipients are enteric-coating agents, diluents, binders, available as Primoje1(R), Explotab(F), Explosol(R); anti-caking agents, amino acids, fibers, Solubilizers, disin tegrants, fillers, lubricants, emulsifiers, flavorants, Solvents, 0053 and starch derivatives, such as amylose; buffers, Stabilizers, colorants, dyes, anti-oxidants, anti-ad herents, preservatives, electrolytes, glidants and carrier 0054 (ii) cross-linked polyvinylpyrrolidones, e.g., materials. A combination of excipients may also be used. croSpoVidones, Such as Polyplasdonee XL and Kol Such excipients are known to those skilled in the art, and lidon(R) CL; thus, only a limited number will be specifically referenced. 0055 (iii) alginic acid and sodium alginate; 0044) Examples of fillers include lactose anhydrous, 0056 (iv) methacrylic acid-divinylbenzene co-poly microcrystalline cellulose, Starch, pregelatinized Starch, mer salts, e.g., Amberlite(E) IRP-88; and modified Starch, dibasic calcium phosphate dihydrate, cal cium Sulfate trihydrate, calcium Sulfate dihydrate, calcium 0057 (v) cross-linked sodium carboxymethylcellu carbonate, lactose, dextrose, Sucrose, mannitol and Sorbitol. lose, available as, e.g., Ac-di-Sol E), PrimelloSe(E), A combination of fillers may also be used. Preferred fillers Pharmacel(R) XL, Explocel(R) and Nymcel(R) ZSX. are mannitol and lactose monohydrate. Additional disintegrants also include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, croScar 0.045 Examples of solvents include water, acetonitrile, melloSe Sodium, Sodium Starch glycolate, polacrillin ethyl acetate, acetone, benzene, toluene, dioxane, dimethyl potassium, polyacrylates, Such as Carbopolf, mag formamide, chloroform, methylene chloride, ethylene chlo nesium aluminium Silicate and bentonite. ride, carbon tetrachloride, chlorobenzene, acetone, metha nol, ethanol, isopropanol and butanol. A combination of 0058 Examples of carrier materials include cross-linked solvents may also be used. Preferably, the solvent is water. polyvinyl pyrrollidone, carboxymethylamide, potassium methacrylatedivi nylbenzene co-polymer, high-molecular 0.046 Examples of lubricants include magnesium stear weight polyvinylacohols, low-molecular weight polyvinyla ate, calcium Stearate, Zinc Stearate, talc, propylene glycol, lcohols, medium-Viscosity polyvinylalcohols, polyoxyethyl PEG, Stearic acid, vegetable oil, Sodium benzoate, Sodium eneglycols, non-cross-linked polyvinylpyrrollidone, PEG, lauryl Sulfate, magnesium lauryl Sulfate, mineral oil and Sodium alginate, galactomannone, carboxypolymethylene, polyoxyethylene monoStearate. A combination of lubricants Sodium carboxymethyl Starch, Sodium carboxymethyl cel may also be used. A preferred lubricant is magnesium lulose or microcrystalline cellulose; polymerizates, as well Stearate. as co-polymerizates of acrylic acid and/or methacrylic acid 0047 Examples of enteric-coating agents include and/or their esters, such as, but not limited to, poly(methyl hydroxypropylmethylcellulose phthalate, methacrylic acid methacrylate), poly(ethyl methacrylate), poly(butyl meth methacrylic acid copolymer, methyl methacrylate-meth acylate), poly(isobutyl methacrylate), poly(hexyl methacry acrylic acid copolymer, polyvinyl acetate-phthalate and cel late), poly(isodecyl methacrylate), poly(lauryl methacry lulose acetate phthalate. late), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate) or poly(oc 0.048 Examples of binders include starches, e.g., potato tadecyl acrylate); co-polymerizates of acrylic and meth Starch, wheat Starch, corn Starch; gums, Such as gum traga acrylic acid esters with a lower ammonium group content, canth, acacia gum and gelatin; microcrystalline cellulose, e.g., EudragitTM RS, available from Rohm; co-polymerizates e.g., products known under the registered trademarks AVicel, of acrylic and methacrylic acid esters and trimethyl ammo Filtrak, Heweten or Pharmacel, hydroxypropyl cellulose, nium methacrylate, e.g., Eudragit" RL, available from hydroxyethyl cellulose and hydroxypropylmethyl cellulose; Rohm, polyvinyl acetate; fats, oils, waxes, fatty alcohols; and polyvinyl pyrrollidone, e.g., PoVidone. hydroxypropyl methyl cellulose phthalate or acetate Succi 0049. Examples of glidants include silica, magnesium nate, cellulose acetate phthalate, Starch acetate phthalate, as trisilicate, powdered cellulose, Starch, talc and tribasic cal well as polyvinyl acetate phthalate, carboxy methyl cellu cium phosphate. Colloidal Silica, e.g., Aerosil, is particularly lose, methyl cellulose phthalate, methyl cellulose Succinate, preferred. -phthalate Succinate, as well as methyl cellulose phthalic US 2005/OOO8704 A1 Jan. 13, 2005

acid half ester, Zein, ethyl cellulose, as well as ethyl cellu ing, tray drying, Vacuum drying, radio-frequency drying, lose Succinate; shellac, gluten; ethylcarboxyethyl cellulose; microwave drying, and lyophilizing. ethylacrylate-maleic acid anhydride co-polymer; maleic acid anhydride-vinyl methyl ether co-polymer; Styrol-maleic 0074 The pharmaceutical compositions of the invention acid co-polymerizate, 2-ethyl-hexyl-acrylate maleic acid may be in the form of a capsule, caplet, powder, disc or anhydride; crotonic acid-Vinyl acetate co-polymer; tablet. In a preferred embodiment, the pharmaceutical com glutaminic acid/glutamic acid ester co-polymer; carboxym positions are in the form of a tablet. ethylethylcellulose glycerol monooctanoate; cellulose 0075 Referring to the drawings, FIG. 1 is a graph acetate Succinate; polyarginine; poly(ethylene), poly(ethyl illustrating the average dissolved anagrelide during a period ene) low-density, poly(ethylene) high-density, poly(propy of 70 minutes from five different samples containing lene), poly(ethylene oxide), poly(ethylene terephthalate), anagrelide. A USP Apparatus I dissolution apparatus was poly(vinyl isobutyl ether), poly(vinyl chloride) or polyure used at 100 rpm which containing 900 mL of 0.1 NHCL at thane. 37 C. Each sample was tested three times and the average 0059. In one embodiment of the invention, the pharma was plotted: ceutical composition of the invention is prepared by a 0.076 Sample A contained 0.5 mg of PEG 4500, 1 process comprising: mg of anagrelide and 0.03 mg of polysorbate 80. 0060 (a) combining polyethylene glycol with a drug 0.077 Sample B contained 1 mg of PEG 4500, 1 mg and optionally one or more excipients to form a of anagrelide and 0.04 mg of polysorbate 80. premix, 0078 Sample C contained 0.5 mg of PEG 4500 and 0061 (b) adding a solvent and optionally a surfac 1 mg of anagrelide. tant to the premix formed in Step (a) to form a wet granulation; 0079 Sample D contained 1 mg of PEG 4500 and 1 mg of anagrelide. OO62 c) drvingdrying ththe wet granulationlati to fform drieddrie granules, and optionally milling the dried granules, 0080 Sample E contained 1 mg of anagrelide. and 0081 FIG. 1 clearly shows that a 1:1 ratio of PEG 4500 0063 (d) optionally mixing at least one excipient to anagrelide increases the Solubility of anagrelide with or with the granules to form a pharmaceutical compo without the presence of a surfactant. Sample D which Sition which is encapsulated or tableted. contained a 1:1 ratio of PEG 4500 to anagrelide without a surfactant dissolved faster than Sample B which contained a 0064. In another embodiment of the invention, the phar maceutical composition of the invention is prepared by a 1:1 ratio of PEG 4500 to anagrelide and a surfactant. process comprising: 0082 Referring to the drawings, FIG. 2 is a graph illustrating the average dissolved modafinil during a period 0065 (a) combining a drug and optionally one or of 70 minutes from two different samples containing more excipients to form a premix, modafinil. A USP Apparatus II dissolution apparatus was 0066 (b") adding a mixture comprising a solvent and used at 50 rpm containing 900 mL of 0.1 NHCL at 37° C. polyethylene glycol to the premix formed in Step (a") Each Sample was tested three times and the average was to form a wet granulation; plotted. 0067 (c) drying the wet granulation to form dried 0083) Sample A contained 200 mg of PEG 4500 and granules, and optionally milling the dried granules, 200 mg of modafinil. and 0084 Sample B contained 200 mg of PEG 3350 and 0068 (d) optionally mixing at least one excipient 200 mg of modafinil. with the granules to form a pharmaceutical compo 0085) Sample C contained 200 mg of modafinil. Sition which is encapsulated or tableted. 0.086 FIG. 2 clearly shows that different PEG's can be 0069. In an additional embodiment of the invention, the used to increase the Solubility of hydrophilic drugs provided pharmaceutical composition of the invention is prepared by the PEG is a solid at room temperature (about 25 C.). In a process comprising: addition, FIG. 2 shows that the presence of PEG 4500 and 0070 (a") combining a drug with melted polyethyl PEG 3350 significantly increases the dissolution or solubil ene glycol and optionally a Surfactant to form a ity of modafinil. Slurry, and 0087 Referring to the drawings, FIG. 3 is a graph illustrating the average dissolved raloxifene during a period 0071 (b") cooling the slurry formed in Step (a") to of 50 minutes from four different Samples containing ralox form a Solid; ifene. A USP Apparatus II dissolution apparatus was used at 0.072 (c") milling the solid formed in Step (b") to 50 rpm which containing 900 mL of sodium acetate buffer form granules, and (d") mixing at least one excipient pH 4.5, at 37 C. Each sample was tested three times and the with the granules to form a pharmaceutical compo average was plotted. The only difference in the Samples was Sition which is encapsulated or tableted. the amount of PEG 4500. 0.073 Drying techniques useful for drying the granulation 0088 Sample A contained 12 mg of PEG 4500, 60 include spray-drying, flash drying, ring drying, micron dry mg of raloxifene and 7.2 mg of polysorbate 80. US 2005/OOO8704 A1 Jan. 13, 2005

0089 Sample B contained 30 mg of PEG 4500, 60 EXAMPLE 3 mg of raloxifene and 7.2 mg of polysorbate 80. 0105 Preparation of Raloxifene HCl-PEG Solid Disper 0090 Sample C contained 60 mg of PEG 4500, 60 Sion without Surfactant. mg of raloxifene and 7.2 mg of polysorbate 80. 0106 PEG 4500, 2.5g, was placed in a 50 mL beaker with a magnetic Stirrer and melted to liquid over hot plate. 0091 Sample D contained 120 mg of PEG 4500, 60 Isopropyl alcohol, 5 mL, was added to the beaker and mixed. mg of raloxifene and 7.2 mg of polysorbate 80. The mixture was stirred vigorously and to it was dispersed 2.5 g raloxifene HC1. A uniform mixing was done at room 0092 FIG. 3 clearly shows that when the ratio of PEG temperature before cooling the mixture. The Solid obtained 4500 to raloxifene by weight is from 0.5:1 to 2:1, the was milled, and dried overnight under Vacuum at room Solubility of raloxifene is significantly increased. temperature. 0.093 Referring to the drawings, FIG. 4 is a graph EXAMPLE 4 illustrating the average dissolved raloxifene during a period of 60 minutes from three different Samples containing ral 0107 Preparation of Paroxetine HCl-PEG Solid Disper OXifene. A USPApparatus II dissolution apparatus was used Sion with Surfactant. at 50 rpm which containing 900 mL of sodium acetate buffer 0108 PEG 4500, 2.5g, was placed in a 50 mL beaker pH 4.5, at 37 C. Each sample was tested three times and the with a magnetic Stirrer and melted to liquid over hot plate. average was plotted. Polysorbate 80, 5 drops (about 2%) was added to the beaker and mixed. The mixture was stirred vigorously and to it was 0094 Sample A contained 60 mg of PEG 4500, 60 dispersed 2.5g paroxetine HC1. A uniform mixing was done mg of raloxifene and 7.2 mg of polysorbate 80. at room temperature to cool the mixture. The Solid obtained was milled, and dried overnight under Vacuum at room 0.095 Sample B contained 60 mg of PEG 4500 and temperature. 60 mg of raloxifene. EXAMPLE 5 0096 Sample C contained 60 mg of PEG 8000, 60 mg of raloxifene, and 7.2 mg of polyoxyethylene 0109 Preparation of Paroxetine HCl-PEG Solid Disper polyoxypropylene copolymer (Poloxamer 188). Sion with Surfactant. 0110. The procedure set forth in Example 4 was followed 0097 Sample D contained 60 mg of raloxifene and except that PEG 4500 was replaced with PEG 8000 and the other excipients. amount of PEG 8000 to paroxetine HCl was varied from 0.2:1 to 5:1 and the amount of polysorbate 80 varied from 0098 Sample E contained 60 mg of raloxifene. 1-5%. 0099 FIG. 4 clearly shows that the solubility of ralox EXAMPLE 6 ifene is increased in the presence of a Surfactant, provided that a polyethylene glycol is also used. 0111 Preparation of Paroxetine HC1-PEG Solid Disper Sion without Surfactant. 0100. The following non-limiting examples illustrate fur 0112 PEG 4500, 2.5 g, was placed in a 50 mL beaker ther aspects of the invention. with a magnetic Stirrer and melted to liquid over hot plate. Isopropyl alcohol, 5 mL, was added to the beaker and mixed. EXAMPLE 1. The mixture was stirred vigorously and 2.5g paroxetine HCl was added. A uniform mixing was done at room temperature 0101 Preparation of Raloxifene HCl-PEG Solid Disper to cool the mixture. The Solid obtained was milled, and dried Sion with Surfactant. overnight under vacuum at room temperature. 0102 PEG 4500, 2.5g, was placed in a 50 mL beaker EXAMPLE 7 with a magnetic Stirrer and melted to liquid over hot plate. Polysorbate 80, 5 drops (about 2%) was added to the beaker 0113 Preparation of Glimepiride HCl-PEG Solid Disper and mixed. The mixture was Stirred vigorously and to this Sion with Surfactant. mixture was added 2.5 g of raloxifene HCl to form a 0114 PEG 4500, 2.5 g, was placed in a 50 mL beaker dispersion. A uniform mixing was done at room temperature with a magnetic Stirrer and melted to liquid over hot plate. before cooling the mixture. The solid obtained was milled Polysorbate 80, 5 drops (about 2%) was added to the beaker and dried overnight under Vacuum at room temperature. and mixed. The mixture was stirred vigorously and 2.5 g. glimepiride HCl was added. A uniform mixing was done at Example 2 room temperature to cool the mixture. The solid obtained was milled, and dried overnight under Vacuum at room 0103) Preparation of Raloxifene HCl-PEG Solid Disper temperature. Sion with Surfactant. EXAMPLE 8 0104. The procedure set forth in Example 1 was followed 0115 Preparation of Glimepiride HCl-PEG Solid Disper except that PEG 4500 was replaced with PEG 8000 and the Sion with Surfactant. amount of PEG 8000 to Raloxifene HCl was varied from 0.2:1 to 5:1 and the amount of polysorbate 80 varied from 0116. The procedure set forth in Example 7 was followed 1-5%. except that PEG 4500 was replaced with PEG 8000 and the US 2005/OOO8704 A1 Jan. 13, 2005

amount of PEG 8000 to glimepiride HCl was varied from EXAMPLE 1.4 0.2:1 to 5:1 and the amount of polysorbate 80 varied from 0127 Preparation of Modafinil-PEG Solid Dispersion 1-5%. without Surfactant. EXAMPLE 9 0128 PEG 4500, 2.5g, was placed in a 50 mL beaker 0117 Preparation of Glimepiride HCl-PEG Solid Disper with a magnetic Stirrer and melted to liquid over hot plate. Sion without Surfactant. Isopropyl alcohol, 5 mL, was added to the beaker and mixed. The mixture was stirred vigorously and 2.5 g modafinil was 0118 PEG 4500, 2.5 g, was placed in a 50 mL beaker added. A uniform mixing was done at room temperature to with a magnetic Stirrer and melted to liquid over hot plate. cool the mixture. The Solid obtained was milled, and dried Isopropyl alcohol, 5 mL, was added to the beaker and mixed. overnight under vacuum at room temperature. The mixture was Stirred vigorously and 2.5 g glimepiride HCl was added. A uniform mixing was done at room EXAMPLE 1.5 temperature to cool the mixture. The Solid obtained was milled, and dried overnight under vacuum at room tempera 0129 ture.

EXAMPLE 10 Preparation of Raloxifene Tablet Composition. 0119 Preparation of Anagrelide HCl Monohydrate-PEG Solid Dispersion with Surfactant. Item # Ingredients mg/unit % 1. Raloxifene HCI 60 23.62 0120 PEG 4500, 2.5g, was placed in a 50 mL beaker 2 Lactose Anhydrous 12O 47.24 with a magnetic Stirrer and melted to liquid over hot plate. 3 Lactose Hydrous 3O 11.81 4 PEG 45OO 26 10.24 Polysorbate 80, 5 drops (about 2%) was added to the beaker 5 Polysorbate 80 2.4 O.94 and mixed. The mixture was stirred vigorously and 2.5 g. 6 Crospovidone 6 2.36 anagrelide HCl monohydrate was added. A uniform mixing 7 Purified Water C.S. was done at room temperature to cool the mixture. The Solid 8 Crospovidone 8.4 3.31 obtained was milled, and dried overnight under vacuum at 9 Magnesium Stearate 1.2 O.47 room temperature. Total 254 1OO EXAMPLE 11 0121 Preparation of Anagrelide HCl Monohydrate-PEG 0.130. The tablet composition was prepared by weighing Solid Dispersion with Surfactant. items 1-6. The PEG 4500 was crushed and added to a mixture of raloxifene, lactose anhydrous and lactose 0122) The procedure set forth in Example 10 was fol hydrous. The crospovidone (item 6) was added to the lowed except that PEG 4500 was replaced with PEG 8000 mixture. A granulating Solution containing 2.5 g of water and the amount of PEG 8000 to anagrelide HCl monohy and polysorbate 80 (Tween 80) was prepared and added to drate was varied from 0.2:1 to 5:1 and the amount of the mixture to form a wet granulation. The wet granulation polysorbate 80 varied from 1-5%. was dried in an oven at 55 C. to form dried granules. The granules were Sieved through a Screen if20. CrospoVidone EXAMPLE 12 (item #8) was mixed with the granules for one minute. 0123 Preparation of Anagrelide HCl Monohydrate-PEG Magnesium Stearate was mixed with the granules for one Solid Dispersion without Surfactant. minute. 0124 PEG 4500, 2.5g, was placed in a 50 mL beaker with a magnetic Stirrer and melted to liquid over hot plate. EXAMPLE 16 Isopropyl alcohol, 5 mL, was added to the beaker and mixed. 0131 Preparation of Raloxifene Tablet Formulation. The mixture was stirred vigorously and 2.5g anagrelide HCl 0132) The ingredients and procedure set forth in Example monohydrate was added. A uniform mixing was done at 15 was followed except that the PEG 4500 was mixed with room temperature to cool the mixture. The solid obtained the water and polySorbate 80 to form a granulating Solution was milled, and dried overnight under Vacuum at room which was added to the premix containing raloxifene, lac temperature. tose anhydrous, lactose hydrous and crospoVidone (item 6). EXAMPLE 13 0.133 While the invention has been described with par ticular reference to certain embodiments thereof, it will be 0125 Preparation of Modafinil-PEG Solid Dispersion understood that changes and modifications may be made by with Surfactant. those of ordinary skill within the scope and spirit of the 0126 PEG 4500, 2.5g, was placed in a 50 mL beaker following claims: with a magnetic Stirrer and melted to liquid over hot plate. Polysorbate 80, 5 drops (about 2%) was added to the beaker What is claimed is: and mixed. The mixture was stirred vigorously and 2.5 g. 1. A pharmaceutical composition having enhanced Solu modafinil was added. A uniform mixing was done at room bility comprising a drug and polyethylene glycol, wherein temperature to cool the mixture. The Solid obtained was the ratio of polyethylene glycol to drug by weight is from milled, and dried overnight under vacuum at room tempera about 0.2:1 to about 10:1, and the polyethylene glycol has a ture. melting point of at least 37 C. US 2005/OOO8704 A1 Jan. 13, 2005

2. A pharmaceutical composition having enhanced Solu 16. The composition according to claim 15, wherein the bility comprising a drug and polyethylene glycol, wherein Surfactant is a polyoxyethylene-Sorbitan-fatty acid ester. the ratio of polyethylene glycol to drug by weight is from 17. The composition according to claim 16, wherein the about 0.5:1 to about 5:1, and the polyethylene glycol has a polyoxyethylene-Sorbitan-fatty acid ester is Selected from melting point of at least 37 C. the group consisting of 3. A pharmaceutical composition having enhanced Solu polyoxyethylene(20)Sorbitanmonolaurate, bility comprising a drug and polyethylene glycol, wherein polyoxyethylene(4)Sorbita nmonolaurate, the ratio of polyethylene glycol to drug by weight is from polyoxyethylene(20)Sorbitanmonopalmitate, about 0.7:1 to about 2:1, and the polyethylene glycol has a polyoxyethylene(20)Sorbitanmonostearate, melting point of at least 37 C. polyoxyethylene(20)Sorbitantristearate, 4. The composition according to claim 3, wherein the polyoxyethylene(20)Sorbitanmonooleate, weight ratio of polyethylene glycol to drug is about 1:1. polyoxyethylene(5)Sorbitanmonooleate, and 5. The composition according to claim 1, wherein the polyoxyethylene(20)sorbitantrioleate. polyethylene glycol has a melting point of at least 50 C. 18. The composition according to claim 17, wherein the 6. The composition according to claim 1, wherein the drug polyoxyethylene-Sorbitan-fatty acid eSter is is a hydrophobic drug. polyoxyethylene(20)Sorbitanmonooleate. 7. The composition according to claim 6, wherein the 19. The composition according to claim 14, wherein the hydrophobic drug is Selected from the group consisting of surfactant is present in an amount of from about 0.01 wt % raloxifene, paroxetine, glimepiride, anagrelide, modafinil, to about 20 wt %, based on the total weight of the compo cabergoline, replaginide, glipizide, benzodiazepines, clofi Sition. brate, chlorpheniramine, dinitirate, digoxin, digitoxin, 20. The composition according to claim 19, wherein the ergotamin tartate, estradiol, fenofibrate, griseofulvin, hydro Surfactant is present in an amount of from about 1 wt % to chlorothiazide, hydrocortisone, isosorbide, medrogeston, about 5 wt %, based on the total weight of the composition. OxyphenbutaZone, prednisolone, prednisone, polythiazide, 21. The composition according to claim 1, which addi progensterone, Spironolactone, tolbutamide, 10,11-dihydro tionally comprises at least one excipient. 5H-dibenzoa, dicyclo-heptene-5-carboxamide; 5H-dibenzo 22. The composition according to claim 21, wherein the a,dcycloheptene-5-carboxamide, fish oil and combinations excipient is selected from the group consisting of enteric thereof. coating agents, diluents, binders, anti caking agents, amino 8. The composition according to claim 7, wherein the acids, fibers, Solubilizers, disintegrants, fillers, lubricants, hydrophobic drug is Selected from the group consisting of emulsifiers, flavorants, Solvents, buffers, Stabilizers, colo raloxifene, paroxetine, glimepiride, anagrelide and modafi rants, dyes, anti-oxidants, anti-adherents, preservatives, nil. electrolytes, glidants, carrier materials and combinations 9. The composition according to claim 1, wherein the thereof. polyethylene glycol has the formula 23. The composition according to claim 1, which is in the HOCH-(CHOCH2)CHOH, wherein n is from 20-204. form Selected from the group consisting of a tablet, granules, 10. The composition according to claim 9, wherein the bar, block, disc, capsule, caplet and powder. polyethylene glycol has an average molecular weight from 24. A method of preparing a pharmaceutical composition about 950 to about 20,000. having enhanced Solubility comprising a drug and polyeth 11. The composition according to claim 10, wherein the ylene glycol, wherein the ratio of polyethylene glycol to polyethylene glycol has an average molecular weight from drug by weight is from about 0.2:1 to about 10:1, and the about 2700 to about 9000. polyethylene glycol has a melting point of at least 37 C., 12. The composition according to claim 9, wherein the Said method comprising: polyethylene glycol is Selected from the group consisting of PEG 1000, PEG 1500, PEG 1540, PEG 2000, PEG 3000, (a) combining polyethylene glycol with a drug and PEG 4000, PEG 4500, PEG 6000, PEG 8000 and PEG optionally one or more excipients to form a premix, 2OOOO. (b) adding a Solvent and optionally a Surfactant to the 13. The composition according to claim 1, which is premix formed in Step (a) to form a wet granulation; essentially free of a Surfactant. and 14. The composition according to claim 1, which addi tionally comprises a Surfactant. (c) drying the wet granulation to form a pharmaceutical 15. The composition according to claim 14, wherein the composition. Surfactant is Selected from the group consisting of reaction 25. A method of preparing a pharmaceutical composition products of a natural or hydrogenated castor oil and ethylene having enhanced Solubility comprising a drug and polyeth oxide, polyoxyethylene-Sorbitan-fatty acid esters, polyoxy ylene glycol, wherein the ratio of polyethylene glycol to ethylene fatty acid esters, polyoxyethylene-polyoxypropy drug by weight is from about 0.2:1 to about 10:1, and the lene co-polymers and block co-polymers, dioctylsulfoSuc polyethylene glycol has a melting point of at least 37 C., cinate or di-2-ethylhexyl-Succinate, phospholipids, Said method comprising: propylene glycol mono- and di-fatty acid esters, polyoxy ethylene alkyl ethers, tocopherol esters, docusate Salts and a') combining9. a drug9. and optionallvp y one or more excipip combinations thereof. ents to form a premix, US 2005/OOO8704 A1 Jan. 13, 2005

(b) adding a mixture comprising a Solvent and polyeth (a") combining a drug with melted polyethylene glycol ylene glycol to the premix formed in Step (a) to form and optionally a Surfactant to form a Slurry; and a wet granulation; and (c) drying the wet granulation to form a pharmaceutical (b") cooling the slurry formed in Step (a") to form a solid; composition. (c") milling the solid formed in Step (b") to form granules, 26. A method of preparing a pharmaceutical composition and having enhanced Solubility comprising a drug and polyeth ylene glycol, wherein the ratio of polyethylene glycol to (d") mixing at least one excipient with the granules to drug by weight is from about 0.2:1 to about 10:1, and the form a pharmaceutical composition. polyethylene glycol has a melting point of at least 37 C., Said method comprising: k k k k k