US 2004O197411A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0197411A1 Gao et al. (43) Pub. Date: Oct. 7, 2004

(54) ACCEPTABLY NON-HYGROSCOPIC Related U.S. Application Data FORMULATION INTERMEDIATE COMPRISINGA HYGROSCOPIC DRUG (60) Provisional application No. 60/435,147, filed on Dec. 19, 2002. Provisional application No. 60/435,022, (76) Inventors: Danchen Gao, Chicago, IL (US); Ann filed on Dec. 19, 2002. Provisional application No. M. Czyzewski, Grayslake, IL (US) 60/435,422, filed on Dec. 19, 2002. Correspondence Address: Publication Classification

PHARMACIA CORPORATION 7

GLOBAL PATENT DEPARTMENT 8. s ------Ales

POST OFFICE BOX 1027 Oa - 1 - O ------ST. LOUIS, MO 63006 (US) (57) ABSTRACT A Solid particulate composition is provided comprising a (21) Appl. No.: 10/741,530 hygroscopic and/or deliqueScent drug and at least one non hygroscopic polymer. The drug and the at least one polymer are in intimate association and the composition is acceptably (22) Filed: Dec. 18, 2003 non-hygroscopic. Patent Application Publication Oct. 7, 2004 Sheet 1 of 3 US 2004/0197411A1 FIG. 1 40

Mass Increase (%) 20 -- Compound 1

10

RH (%)

Mass Increase (%)

O 2O 40 60 80 1 OO 120 140 Time (h) Patent Application Publication Oct. 7, 2004 Sheet 2 of 3 US 2004/0197411A1

MaSS increase (%)

O 2O 40 60 80 1 OO 12O 140

Mass Increase (%)

O 1 OO 2OO 3OO 400 5 OO Patent Application Publication Oct. 7, 2004 Sheet 3 of 3 US 2004/0197411A1 F.G. 5

Mass Increase (%)

O 2O 40 6O 8O 1 OO 12O 140 160 US 2004/O1974 11 A1 Oct. 7, 2004

ACCEPTABLY NON-HYGROSCOPIC and are Said to absorb Significantly leSS moisture when FORMULATION INTERMEDIATE COMPRISINGA Subjected to humid conditions than unformulated clavulanic HYGROSCOPIC DRUG acid particles. Above-cited U.S. Pat. No. 4,223,006 teaches 0001. This application claims priority of U.S. Provisional that a disintegrant, Such as microcrystalline cellulose, can be Application Serial No. 60/435147 filed on 19 Dec. 2002, of blended with the particles after the dispersion has formed. U.S. Provisional Application Serial No. 60/435022 filed on 0008 U.S. Pat. No. 6,204.255 to Klokkers discloses 19 Dec. 2002, and U.S. Provisional Application Serial No. non-deliqueScent Solid dispersions consisting of the hygro 60/435422 filed on 19 Dec. 2002. Scopic and deliqueScent drug Sodium Valproate and expen sive cyclodextrins. While the disclosed dispersions, when FIELD OF THE INVENTION Subjected to humid conditions, absorbed leSS moisture than 0002 The present invention relates to pharmaceutical unformulated Sodium Valproate, the dispersions Still exhib compositions comprising a hygroscopic and/or deliqueScent ited significant moisture absorption at 75% relative humid drug, more particularly to Such compositions Suitable as ity. intermediates for further processing. The invention is illus 0009. Therefore, a need exists for acceptably non-hygro trated herein with particular reference to a hygroscopic drug Scopic Solid compositions comprising a hygroscopic and/or active as an inhibitor of inducible nitric oxide Synthase deliquescent drug that can readily be formulated as conve (iNOS). nient dosage forms and that are Suitable for large-scale manufacture. BACKGROUND OF THE INVENTION 0010 Illustratively, such a need exists where the drug is 0003. The sorption of moisture by drugs can create an inhibitor of inducible nitric oxide synthase (hereinafter Significant problems. In presence of moisture a Solid drug referred to as a “iNOS inhibitor”), a class of therapeutic Substance can become hydrated and/or convert to a new agents useful in treatment of a wide range of inflammatory crystal form. Moisture Sorption can also adversely affect conditions and other disorders mediated by iNOS. In par release rate of a Substance from formulation, shelf life of a ticular, Such a need exists where the drug is a preferential, formulation, and handling and processing properties of the Selective or Specific iNOS inhibitor, i.e., having Significantly Substance itself. Hygroscopic and/or deliqueScent drugs, by greater inhibitory effect on inducible forms of the nitric definition, are prone to experiencing these adverse effects oxide Synthase enzyme than on constitutive forms of the when exposed to environments with even moderate humid enzyme. ity. Thus, it is usually imperative to control moisture Sorp tion during formulation and Storage. SUMMARY OF THE INVENTION 0004. Manufacturing plant alterations, such as installa 0011. Accordingly, the present invention provides a solid tion of machinery to reduce humidity within a manufactur particulate composition comprising a hygroscopic and/or ing plant, have been used to limit exposure of hygroscopic deliquescent drug and at least one non-hygroscopic polymer and/or deliquescent drugs to humid conditions during pro wherein the drug and the polymer are in intimate association duction and packaging. However, Such alterations are dis and the composition is acceptably non-hygroscopic. advantageous in being costly and unreliable in effectiveness. Furthermore, alterations in manufacturing conditions do 0012 Preferably, the composition is flowable and/or very little to protect a hygroscopic and/or deliqueScent drug compressible. during Subsequent Storage and transport. 0013 Optionally, the composition comprises a filler 0005 Hygroscopic and/or deliquescent drugs also pose wherein the filler is preferably hygroscopic and/or deliques problems that do not directly result from interactions with cent. humid environments. For example, U.S. Pat. No. 5,037,698 0014) In a preferred embodiment, the drug is an iNOS to Brunel reports that when a hygroscopic and/or deliques inhibitor. cent drug is incorporated into a gelatin capsule, a commonly 0015. In one embodiment, the solid particulate composi used dosage form, the drug tends to absorb moisture from tion of the present invention may be prepared by Spray the capsule wall, leaving the capsule in a brittle or deformed drying an aqueous liquid having the drug and the at least one State, Susceptible to breakage and leakage. polymer dispersed therein. 0006 U.S. Pat. No. 5,225,204 to Chen et al., describes 0016. The term “hygroscopic” as used herein refers to compositions comprising a complex of the hygroscopic drug materials, Such as drugs or pharmaceutical excipients, that levothyroxine Sodium and a water Soluble polyvinylpyrroli absorb Significant amounts of atmospheric moisture when done which complex is adsorbed on a cellulose compound. exposed to conditions of normal ambient relative humidity Such compositions are Said to be stable in humid conditions. (RH), for example 10-50% RH. The term “deliquescent” 0007 U.S. Pat. No. 4,223,006 to Taskis discloses par refers to drugs or excipients that tend to undergo gradual ticles consisting of the hygroscopic compound clavulanic dissolution and/or liquefaction due to attraction and/or acid dispersed in a Solution of non-aqueous Solvent and absorption of moisture from air when exposed to these polymeric binder (e.g. ethylcellulose and polyvinyl acetate conditions. Those skilled in the art will appreciate that over phthalate of low water vapor permeability). Taskis teaches the usual range of ambient temperatures used in drug that the clavulanic acid must be anhydrous and that the formulation, hygroscopicity and the State of deliqueScence proceSS for making the particles of the invention are nor are largely temperature independent, and that there are mally kept as water-free as possible. The particles are varying degrees of hygroscopicity and deliqueScence. Thus, prepared by depositing a binder on the Salt of calvulanic acid for example, adverbs such as very, “slightly,” or “extremely' US 2004/O1974 11 A1 Oct. 7, 2004

Sometimes precede the words “hygroscopic' or “deliques prevent or cure a disease in a Subject, including but not cent' in descriptions of drugs or excipients in order to limited to therapeutic and diagnostic agents. indicate the amount of moisture a particular drug or excipi ent tends to absorb in humid climates or the degree to which 0026 Illustratively, suitable hygroscopic and/or deliques a particular drug or excipient tends to dissolve and/or liquefy cent drugs for use in the present invention include, without due to attraction and/or absorption of moisture from humid limitation, drugs from the following classes: abortifacients, air. AS used herein, "hygroscopic' refers to drugs or excipi ACE inhibitors, C- and B-adrenergic agonists, C- and B-adr ents that are at least slightly hygroscopic. Similarly, the term energic blockers, adrenocortical SuppreSSants, adrenocorti “deliqueScent herein refers to drugs or excipients that are at cotropic hormones, alcohol deterrents, aldose reductase inhibitors, aldosterone antagonists, anabolics, analgesics least Slightly deliqueScent. (including narcotic and non-narcotic analgesics), androgens, 0.017. The term “acceptably non-hygroscopic” with angiotensin II receptor antagonists, anorexics, antacids, respect to a Solid particulate composition of the invention anthelminthics, antiacne agents, antiallergics, antialopecia comprising an otherwise hygroscopic and/or deliqueScent agents, antiamebics, antiandrogens, antianginal agents, anti drug means that the composition does not absorb Substantial arrhythmics, antiarteriosclerotics, antiarthritic/antirheumatic amounts of moisture when Subjected to relatively humid agents (including selective COX-2 inhibitors), antiasthmat conditions, for example 40-70% RH. Consequently, shelf ics, antibacterials, antibacterial adjuncts, anticholinergics, life, flow, handling and processing properties of the com anticoagulants, anticonvulsants, antidepressants, antidiabet position are generally not Substantially affected by exposure ics, antidiarrheal agents, antidiuretics, antidotes to poison, to Such conditions. antidyskinetics, antieczematics, antiemetics, antieStrogens, 0.018 Compositions of the invention provide a surpris antifibrotics, antiflatulents, antifungals, antiglaucoma ingly effective Solution to the moisture Sorption problem agents, antigonadotropins, antigout agents, antihistaminics, asSociated with hygroscopic and/or deliqueScent drugs. It is antihyperactives, antihyperlipoproteinemics, antihyperphos particularly Surprising that Such hygroscopic and/or deli phatemics, antihypertensives, antihyperthyroid agents, anti quescent drugs can be prepared into acceptably non-hygro hypotensives, antihypothyroid agents, anti-inflammatories, Scopic formulation intermediates by an aqueous spray dry antimalarials, antimanics, antimethemoglobinemics, antimi ing process. Spray drying in and of itself is advantageous in graine agents, antimuscarinics, antimycobacterials, antine that it offers continuous processing and production condi oplastic agents and adjuncts, antineutropenics, antioS tions. Furthermore, Spray drying using an aqueous disper teoporotics, antipagetics, antiparkinsonian agents, Sion (as opposed to non-aqueous Solvents) is particularly antipheochromocytoma agents, antipneumocystis agents, advantageous in that it avoids potential chemical interaction antiprostatic hypertrophy agents, antiprotozoals, antiprurit between a non-aqueous Solvent and drug, and eliminates ics, antipsoriatics, antipsychotics, antipyretics, antirickettsi potential toxicities associated with many non-aqueous Sol als, antiseborrheics, antiseptics/disinfectants, antispasmod VentS. ics, antisyphylitics, antithrombocythemics, antithrombotics, antituSSives, antiulceratives, antiurolithics, antivenins, anti Viral agents, anxiolytics, aromatase inhibitors, astringents, BRIEF DESCRIPTION OF THE DRAWINGS benzodiazepine antagonists, bone resorption inhibitors, 0.019 FIG. 1 shows a moisture sorption isotherm of bradycardic agents, bradykinin antagonists, bronchodilators, hygroscopic Compound 1. calcium channel blockers, calcium regulators, carbonic 0020 FIG. 2 shows equilibrium water uptake (hygro anhydrase inhibitors, cardiotonics, CCKantagonists, chelat scopicity profile) by solid particulate compositions SP2-SP6 ing agents, cholelitholytic agents, choleretics, cholinergics, cholinesterase inhibitors, cholinesterase reactivators, CNS of Example 2 upon Storage in a humidity chamber for a Stimulants, contraceptives, debriding agents, decongestants, period of 120 hours. depigmentors, dermatitis herpetiformis SuppreSSants, diag 0021 FIG. 3 shows equilibrium water uptake by solid nostic agents, digestive aids, diuretics, dopamine receptor particulate compositions SP8 and SP10-SP14 of Example 2 agonists, dopamine receptor antagonists, ectoparasiticides, upon Storage in a humidity chamber for a period of 120 emetics, enkephalinase inhibitors, enzymes, enzyme cofac hours. tors, estrogens, expectorants, fibrinogen receptor antago 0022 FIG. 4 shows equilibrium water uptake by solid nists, fluoride Supplements, gastric and pancreatic Secretion particulate compositions SP15-SP17 of Example 5 and of Stimulants, gastric cytoprotectants, gastric proton pump inhibitors, gastric Secretion inhibitors, gastroprokinetics, matching placebo compositions P1-P3 of Example 5 upon glucocorticoids, a-glucosidase inhibitors, gonad-stimulating storage in a humidity chamber for a period of at least 400 principles, growth hormone inhibitors, growth hormone hours. releasing factors, growth Stimulants, hematinics, hematopoi 0023 FIG. 5 shows equilibrium water uptake by solid etics, hemolytics, hemostatics, heparin antagonists, hepatic particulate compositions SP18-SP22 of Example 6 upon enzyme inducers, hepatoprotectants, histamine H2 receptor Storage in a humidity chamber for a period of 120 hours. antagonists, HIV protease inhibitors, HMG CoA reductase inhibitors, immunomodulators, immunosuppressants, insu DETAILED DESCRIPTION OF THE lin Sensitizers, ion eXchange resins, keratolytics, lactation INVENTION Stimulating hormones, laxatives/catharitics, leukotriene antagonists, LH-RH agonists, lipotropics, 5-lipoxygenase 0024 Hygroscopic and/or Deliquescent Drug inhibitors, lupus erythematoSuS Suppressants, matrix metal 0.025 A composition of the invention comprises a hygro loproteinase inhibitors, mineralocorticoids, miotics, Scopic and/or deliqueScent drug. The term "drug” herein monoamine oxidase inhibitors, mucolytics, muscle relax refers to any compound or agent effective to treat, identify, ants, mydriatics, narcotic antagonists, neuroprotectives, US 2004/O1974 11 A1 Oct. 7, 2004 nootropics, nutraceuticals, ovarian hormones, oxytocics, Sodium phosphate, procainamide hydrochloride, procaine pepsin inhibitors, pigmentation agents, plasma Volume butyrate, L-proline, promazine hydrochloride, propamidine expanders, potassium channel activatorS/openers, progesto isethionate, proStacyclin Sodium, pyridoStigmine bromide, gens, prolactin inhibitors, prostaglandins, protease inhibi pyronaridine, quinacillin disodium, quinoline, radioactive tors, radio-pharmaceuticals, 5C-reductase inhibitors, respi Sodium iodide, reserpilic acid dimethylaminoethyl ester ratory Stimulants, reverse transcriptase inhibitors, Sedatives/ dihydrochloride, secobarbital sodium, silver fluoride, hypnotics, Serenics, Serotonin noradrenaline reuptake Sodium acetate, Sodium bromide, Sodium propionate, inhibitors, Serotonin receptor agonists, Serotonin receptor Sodium dibunate, Sodium dichromate(VI), Sodium nitrite, antagonists, Serotonin uptake inhibitors, Smoking cessation Sodium pentosan polysulfate, Sodium Valproate, Soluble Sul aids, Somatostatin analogs, thrombolytics, thromboxane A famerazine, Stibocaptate, Streptomycin, Succinylcholine bro receptor antagonists, thyroid hormones, thyrotropic hor mide, Succinylcholine iodide, Sulfaquinoxaline, Sulisatin mones, tocolytics, topoisomerase I and II inhibitors, urico disodium, Suramin Sodium, tamoxifen citrate, taurocholic Surics, vasomodulators including vasodilators and vasocon acid, teraZOsin hydrochloride, thiobutabarbital Sodium, thio Strictors, Vasoprotectants, Vitamins, Xanthine oxidase pental Sodium, ticarcillin disodium, 2,2,2-trichloroethanol, inhibitors, and combinations thereof. trientine, triethanolamine, triftazin, tolaZoline hydrochlo ride, Vinbarbital Sodium, Viomycin, Vitamin B, zinc iodide, 0.027 Non-limiting illustrative examples of hygroscopic and combinations, pharmaceutically acceptable hygroscopic and/or deliqueScent drugs Suitable for use in the present invention include acetylcholine chloride, acetylcarnitine, and/or deliqueScent Salts and variants thereof. actinobolin, aluminum methionate, aminopentamide, ami 0028 Preferred drugs include acetylcholine chloride, nopyrine hydrochloride, ammonium bromide, ammonium actinobolin, aminopentamide, aminopyrine hydrochloride, Valerate, amobarbital Sodium, anthiolimine, antimony ammonium Valerate, atropine N-oxide, avoparcin, betaine, Sodium tartrate, antimony Sodium thioglycollate, aprobar bupropion, calcium chloride, calcium iodide, carnitine, cho bital, arginine, aspirin, atropine N-oxide, avoparcin, azithro line alfoscerate, choline Salicylate, deaminooxytocin (L-iso mycin monohydrate, betahistine meSylate, betaine, mer, anhydrous), dimethyl Sulfoxidem, ergotamine, ferric bethanechol chloride, bismuth Subnitrate, bupropion, chloride, ferrous iodide, guanidine, heXobarbital Sodium, butamirate, buthalital Sodium, butoctamide, cacodylic acid, hyoscyamine hydrobromide, S-2-(1-iminoethyl)amino calcium chloride, calcium glycerophosphate, calcium ethyl-2-methyl-L-cysteine, imipramine N-oxide, iodide, carbachol, carnitine, carpronium chloride, caspofun isometheptene hydrochloride, magnesium chloride hexahy gin, ceruletide, chlorophyllin sodium-copper salt, choline drate, methantheline chloride, methitural Sodium, methyl alfoScerate, choline Salicylate, choline theophyllinate, cilas methionineSulfonium chloride, muscarine chloride, narce tatin, citicoline, cobalt dichloride, cromolyn disodium, ine, nicotine, nicotinyl alcohol, phySOStigmine Sulfate, cupric Sulfate pentahydrate, cyanocobalamin, cyclobutyrol, potassium iodide, pralidoxime meSylate, quinacillin diso cysteine hydrochloride, deaminooxytocin (L-isomer, anhy dium, Silver fluoride, Sodium propionate, Sodium dichromat drous), deanol hemisuccinate, demecarium bromide, dex e(VI), Sodium valproate, Streptomycin, taurocholic acid, amethaZone phosphate disodium Salt, DL-deXpanthenol, triethanolamine, and hygroscopic and/or deliqueScent Salts dibucaine hydrochloride, dichlorophenarsine hydrochloride, thereof. diclofenac Sodium, diethylcarbamazine citrate, dimethyl Sul 0029. In view of the Superior moisture protection quali foxidem, drotebanol, echinomycin, ephedrine (anhydrous), ties afforded by compositions described herein, the present ergotamine, ethanolamine, fencamine hydrochloride, ferric invention is particularly advantageous where the drug chloride, ferrous iodide, ficin, gadobenate dimeglumine, Selected for use in Such a composition is deliqueScent and/or gentamicin C complex Sulfate, guanidine, heparin, hexa has a hygroscopicity Such that when unformulated the drug dimethrine bromide, hexamethonium tartrate, hexobarbital exhibits at least about 15% mass increase at equilibrium Sodium, histamine, hydrastine hydrochloride, hyoscyamine when exposed to 60% relative humidity at ambient tempera hydrobromide, S-2-(1-iminoethyl)aminoethyl-2-methyl ture. L-cysteine, imipramine N-oxide, isometheptene hydrochlo ride, isosorbide, levothyroxine Sodium, licheniformins, 0030. In a preferred embodiment, the drug is nicotine. lobeline Sulfate, magnesium chloride hexahydrate, magne Nicotine is usefuil in pharmaceutical formulations as, for sium trisilicate, menadione, mercaptomerin Sodium, merSa example, an aid in Smoking cessation. In another preferred lyl, metaraminol, methacholine chloride, methantheline bro embodiment, S-2-(1-iminoethyl)aminoethyl-2-methyl mide, methantheline chloride, methitural Sodium, L-cysteine is the drug used in a composition of the inven L-methyldopa Sesquihydrate, methylmethionineSulfonium tion. This drug, disclosed in International Patent Publication chloride, mildiomycin, minocycline hydrochloride, mitox No. WO 01/72703, hereby incorporated herein by reference antrone dihydrochloride, morpholine, muscarine chloride, in its entirety, is a nitric oxide synthase (NOS) inhibitor, and nafronyl acid oxalate, narceline, nicotine, nicotinyl alcohol, is believed to have value in, for example, treating inflam nolatrexed dihydrochloride, omeprazole, oryzacidin, oxalic mation and other NOS-mediated disorders, Such as pain, acid, oxophenarsine hydrochloride, panthenol, pantothenic headache and fever. S-2-(1-iminoethyl)aminoethyl-2- acid (Sodium salt), papain, penicillamine hydrochloride, methyl-L-cysteine for use herein can be prepared by any penicillin G (potassium salt), pentamethonium bromide, Suitable means, including processes described in above-cited pentamidine isethionate, pepsin, perazine dihydrochloride, International Patent Publication No. WO O1/72703. This phenobarbital, Sodium 5,5-diphenyl hydantoinate, phetheny compound can be used in its free base form or as a late Sodium, phosphocreatine (calcium Salt tetrahydrate), pharmaceutically acceptable Salt, for example the dihydro phySOStigmine Sulfate, pilocarpine hydrochloride, pipemidic chloride salt. acid, podophyllotoxin-B-D-glucoside, potassium carbonate, 0031. It has now been found that S-2-(1-iminoethy potassium iodide, pralidoxime meSylate, prednisolone l)aminoethyl-2-methyl-L-cysteine and its dihydrochloride US 2004/O1974 11 A1 Oct. 7, 2004

Salt are extremely hygroscopic and deliqueScent. It is par Scopic polymer. AS used herein, the term “the intimate ticularly Surprising that Such a hygroscopic and deliqueScent asSociation' is the association that results from, by way of drug can be formulated in accordance with the present example, co-dispersing the drug and the polymer in an invention as an acceptably non-hygroscopic composition. aqueous liquid and then removing the liquid (e.g. by spray 0032. A hygroscopic drug, for example an iNOS inhibi drying, evaporation, lyophilization, etc.) to form a Solid tor, is preferably present in a composition of the invention in particulate composition. an amount of at least about 5%, more preferably at least 0041) Fillers about 10%, still more preferably at least about 15% and even 0042 Compositions of the invention optionally comprise more preferably at least about 20% by weight of the com one or more fillers. The term “filler,” as used herein, refers position. For example, a hygroscopic drug Such as an iNOS to inert materials that Serve to increase the mass and/or bulk inhibitor, is present in the instant composition at 10% to density of a composition of the invention, So that, for 80%, more preferably 15% to 60%, and still more preferably example, the composition can be relatively easily incorpo 20% to 40% by weight of the composition. rated into a conventional dosage form, e.g., a tablet or 0033) Non-Hygroscopic Polymer capsule. Preferably the filler used does not adversely affect 0034. The instant composition comprises at least one the Stability and/or dissolution performance of the disper non-hygroscopic polymer. The term “non-hygroscopic poly SO. mer herein means that the polymer exhibits an equilibrium 0043. The filler itself can be non-hygroscopic or hygro moisture uptake at 40% RH of not more than about 8%, Scopic and/or deliqueScent. Fillers of the present invention preferably not more than about 7%, and more preferably not can be cellulosic or noncellulosic. For the purpose of clarity, more than about 6%, for example about 1% to about 5%. The instant fillers can be (1) cellulosic and non-hygroscopic; (2) non-hygroscopic polymer can be cellulosic or non-cellulo non-cellulosic and non-hygroscopic; (3) non cellulosic and sic. In a preferred embodiment, the polymer is a cellulosic hygroscopic and/or deliquescent; or (4) cellulosic and polymer, for example, hydroxypropylmethylcellulose hygroscopic and/or deliqueScent. (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcel 0044) In one preferred embodiment, the filler is hygro lulose, methylcellulose and/or ethylcellulose. Scopic and/or deliqueScent. Hygroscopic and/or deliques 0035) Hydroxyethylcellulose is another preferred cellu cent fillers include for example microcystalline cellulose, losic polymer. Exemplary hydroxyethylcelluloses useful in tribasic calcium phosphate, anhydrous calcium Sulfate, car the invention include those having low dynamic Viscosity in boxymethylcellulose calcium, carboxymethylcellulose aqueous media, preferably below about 400 cps, e.g., below Sodium, anhydrous dextrose, fructose, anhydrous lactose, about 150 cps as measured in a 2% aqueous solution at 25 anhydrous magnesium Stearate, magnesium trisilicate, mal C. Hydroxyethylcellulose is available for example under the todextrin, methylcellulose, powdered cellulose, pregelati tradenames Cellosize TM (Amerchol) and NatrusolTM (Aqua nized Starch, Starch, Sterilizable maize Starch, compressible lon). Sugar, confectioner's Sugar and the like. 0.036 Preferably, the weight ratio of total polymer to 0045 Particularly preferably the filler is a hygroscopic drug, for example the weight ratio of a non-hygroscopic and/or deliqueScent cellulosic polymer, e.g., microcrystal polymer to an iNOS inhibitor, is about 1:5 to about 5:1, more line cellulose, carboxymethylcellulose Sodium, carboxym preferably about 1:3 to about 3:1,still more preferably about ethylcellulose calcium, methylcellulose or powdered cellu 1:2 to about 2:1, and yet more preferably about 1:1.5 to lose. Especially preferably the filler is microcrystalline about 1.5:1. An especially preferable polymer to drug weight cellulose, available for example under the tradename ratio is about 1:1 to about 1:1.5. AvicelTM (FMC) in various grades. 0037. In a preferred embodiment of the invention, the 0046 Fillers contemplated for use in the present inven non-hygroscopic polymer is present in the composition in a tion illustratively include microcrystalline cellulose, lactose, total amount of about 10% to about 85%, more preferably calcium carbonate, carboxymethylcellulose calcium, car about 30% to about 80%, and still more preferably about boxymethylcellulose Sodium, dibasic calcium phosphate 40% to about 75% by weight of the composition. dihydrate, tribasic calcium phosphate, calcium Sulfate, dex 0038 Hydroxypropylmethyl cellulose (HPMC) is an trose, ethyl cellulose, fructose, kaolin, magnesium carbon especially preferred cellulosic polymer. A preferred HPMC ate, magnesium Stearate, magnesium trisilicate, maltol, mal is one with a low apparent dynamic Viscosity, preferably todextrin, mannitol, methyl cellulose, powdered cellulose, below about 100 cps as measured at 20° C. for a 2% aqueous pregelatinized Starch, Starch, Sterilizable maize Starch, com solution, more preferably below about 50 cps, and still more pressible Sugar, confectioner's Sugar and the like. preferably below about 20 cps, for example 3 or 5 cps. 0047 The filler is preferably present in an amount Suf HPMC, including a grade having apparent dynamic ViscoS ficient to enable the composition, once formed, to be in a ity of 3 cps, is available for example under the tradename flowable State, Such as a powder, that can be easily incor PharmcoatTM 603 (Shin-Etsu). porated into conventional dosage forms, Such as tablets and 0039) Intimate ASSociation Between the Drug and the capsules. The filler is more preferably present in an amount Polymer. Sufficient to enable the composition, once formed, to be in both a flowable and compressible State, Such as a powder, 0040. Without being bound by theory, the composition of that can be easily incorporated into conventional dosage the present invention is Surprisingly non-hygroscopic due in forms, Such as tablets and capsules. Accordingly, the filler is part, to the intimate association between the hygroscopic generally present in an amount of about 1% to about 95%, and/or deliqueScent drug and the at least one non-hydro preferably about 5% to about 30% by weight of the com US 2004/O1974 11 A1 Oct. 7, 2004 position. The present inventors have found that hygroscopic invention will provide an advantage in inhibiting NOS and/or deliqueScent cellulosic polymers, Such as microcryS production from L-arginine include arthritic conditions. talline cellulose, in an amount of about 20% to about 30%, 0058 Such compositions are further useful in the treat by weight of the composition, are particularly well-Suited ment of asthma, bronchitis, menstrual cramps (e.g., dysmen for the present invention. orrhea), premature labor, tendonitis, bursitis, skin-related 0.048 Various methods are known to those skilled in the conditions Such as psoriasis, eczema, burns, Sunburn, der art for detecting or measuring moisture absorption by a matitis, pancreatitis, hepatitis, and from post-operative composition. An illustrative method that is convenient and inflammation including from ophthalmic Surgery Such as easy to apply in most situations is observation and/or cataract Surgery and refractive Surgery. Such compositions measurement of increase in mass of a composition upon are also useful to treat gastrointestinal conditions Such as exposure to humidity. A composition of the invention pref inflammatory bowel disease, Crohn's disease, gastritis, irri erably exhibits an increase in mass of not more than about table bowel Syndrome and ulcerative colitis. Such compo 10%, more preferably not more than about 7%, and even Sitions are useful for the prevention or treatment of cancer, more preferably not more than about 6%, when subjected to Such as colorectal cancer, and cancer of the breast, lung, conditions of 40% relative humidity and ambient tempera prostate, bladder, cervix and skin. Such compositions are tures (21-23 C.) for 24 hours and/or for a time sufficient to useful in treating inflammation and tissue damage in Such achieve Substantial equilibrium, i.e., a time after which no diseases as vascular diseases, migraine headaches, periar further Significant increase in mass is observed. teritis nodosa, thyroiditis, aplastic anemia, Hodgkin's dis ease, Sclerodoma, rheumatic fever, type I diabetes, neuro 0049 Moisture Sorption and Handling Properties muscular junction disease including myasthenia gravis, white matter disease including multiple Sclerosis, Sarcoido 0050 Additionally, a composition of the invention pref sis, nephrotic Syndrome, Behcet's Syndrome, polymyositis, erably will be in the form of a free-flowing powder when gingivitis, nephritis, hyperSensitivity, Swelling occurring maintained under conditions of 40% relative humidity and after injury, myocardial ischemia, and the like. Such com ambient temperature. positions are useful in the treatment of ophthalmic diseases, 0051 Particle Size Distribution Such as glaucoma, retinitis, retinopathies, uveitis, ocular photophobia, and of inflammation and pain associated with 0.052 A composition of the invention is preferably in the acute injury to the eye tissue. Of particular interest among form of a flowable powder comprising particles or granules. the uses of the present inventive compositions is the treat Preferably, Such particles or granules will have a Doo size, by ment of glaucoma, especially where Symptoms of glaucoma volume, of about 20 um to about 800 um, preferably about are caused by the production of nitric oxide, Such as in nitric 40 um to about 500 um, and more preferably about 50 lum oxide-mediated nerve damage. Such compositions are useful to about 300 lum. in the treatment of pulmonary inflammation, Such as that 0.053 Process for Preparing an Acceptably Non-Hygro asSociated with Viral infections and cystic fibrosis. Such Scopic Composition compositions are useful for the treatment of certain central nervous System disorders, Such as cortical dementias includ 0054. A composition of the invention can be prepared by ing Alzheimer's disease, and central nervous System damage any Suitable process for bringing into intimate association resulting from Stroke, ischemia and trauma. Such composi the drug and the non-hygroscopic polymer. A particularly tions are useful as anti-inflammatory agents, Such as for the preferred process for preparing a composition of the inven treatment of arthritis, with the additional benefit of having tion comprises co-dispersing the hygroscopic and/or deli Significantly leSS harmful side effects. These compositions quescent drug and the non-hygroscopic polymer in an aque are useful in the treatment of allergic rhinitis, respiratory ous liquid and then removing the liquid, for example by distress Syndrome, endotoxin Shock Syndrome, and athero Spray drying, evaporation, lyophilization, etc. In a particu Sclerosis. Such compositions are also useful in the treatment larly preferred embodiment, the liquid is removed by Spray of pain, but not limited to postoperative pain, dental pain, drying. muscular pain, and pain resulting from cancer. Such com positions are useful for the prevention of dementias, Such as 0055) Utility Alzheimer's disease. 0056 Compositions of the present invention are useful in 0059 Besides being useful for human treatment, these providing hygroscopic and/or deliqueScent drugs in a phar compositions are also useful for veterinary treatment of maceutically acceptable, non-hygroscopic formulation for companion animals, exotic animals, and farm animals, Subjects in need thereof. including mammals, rodents, and the like. More preferred 0057 Where the hygroscopic drug is an iNOS inhibitor, animals include horses, dogs, and cats. pharmaceutically acceptable compositions of the invention EXAMPLES are useful for treating, inter alia, inflammation in a Subject, 0060. The following examples illustrate aspects of the or for treating other nitric oxide Synthase-mediated disorders present invention but are not to be construed as limitations. Such as pain, headaches or fever. For example, Such com The invention is illustrated with particular reference to positions are useful to treat arthritis, including but not S-2-(1-iminoethyl)aminoethyl)-2-methyl-L-cysteine limited to rheumatoid arthritis, spondyloarthropathies, gouty dihydrochloride, herein identified as “Compound 1. arthritis, Osteoarthritis, Systemic lupus, erythematosus, juve nile arthritis, acute rheumatic arthritis, enteropathic arthritis, Example 1 neuropathic arthritis, psoriatic arthritis, and pyogenic arthri 0061 Compound 1 was prepared according to processes tis. Conditions in which the compositions of the present described in WO 01/72703. A sample of Compound 1 in US 2004/O1974 11 A1 Oct. 7, 2004

Substantially dry, amorphous form was Subjected to moisture SP4, SP7, SP8, SP13 and SP14 formed cake-like, sticky Sorption analysis. Dynamic vapor Sorption (DVS) was used masses within 12 hours of initiation of humidity treatment. to determine mass increase (relative to dry mass) was Compositions SP2, SP5, SP11, and SP12 remained free monitored over an adsorption range of 10-70% relative flowing powders throughout the Study. Example 4 humidity (RH) in increments of 10%. As shown by the 0064. The amount of drug present in each of composi moisture sorption isotherm represented in FIG. 1, Com tions SP2, SP5, SP6, SP10, SP12 and SP14 of Example 3 pound 1 is hygroscopic. was determined using high performance liquid chromatog Example 2 raphy (HPLC). Data, shown in Table 2, represents an aver age of 3 to 5 Samples, relative Standard deviation is also 0.062 Batches of fourteen solid particulate compositions, provided for each batch analyzed. SP1-SP14, each having a composition shown in Table 1, were prepared according to the following procedure. Several TABLE 2 intermediate Solutions were prepared by dissolving Com pound 1 in free base form in water at a concentration of Amount of drug present in SP2, SPS, SP6, SP10, SP12 and SP14 318.4 mg/ml. One or more excipients were added to each of Drug weight Number of Relative Standard the intermediate Solutions to form final Solutions. Each final Composition (%) Samples Deviation (%) Solution was then individually spray dried using a Yamato SP2 32.6 5 2 Pulvis Basic Unit, Model GB-21 (Yamato Scientific SP5 39.6 5 0.5 America, Inc.) spray dryer under the following condi SP6 26.0 3 3.5 tions: (a) Inlet temperature: 135 C.; (b) Outlet temperature: SP10 26.2 5 1.1 75° C.; (c) Atomizing air:0.75 Kg/cm ; (d) Drying air: 4 SP12 26.6 5 1.O gauge setting; (e) Feed Rate: 5-7 mL/min, (f) Feed total SP14 34.4 5 4.6 solids concentration: 15%-21% (wt), to form solid particu late compositions SP1-SP-14. 0065. These data show that each batch of composition tested exhibited relatively high drug loading and good TABLE 1. homogeneity (as shown by low standard deviation). Composition of solid particulate compositions SP1-SP14 Example 5 Composition Compound 1 (g) Excipient(s) (g) SP1 3 Microcrystalline cellulose (7) 0.066 Three solid particulate compositions, SP15-SP17, SP2 3 Microcrystalline cellulose (3): each having a composition shown in Table 2, were prepared Hydroxypropyl methylcellose (4) according to the following procedure. An intermediate Solu SP3 5 Microcrystalline cellulose (3): tion was prepared by dissolving Compound 1 (in free base Hydroxypropyl methylcellose (2) SP4 3 Microcrystalline cellulose (6.95); form) in water at a concentration of 318.4 mg/ml. One or Silicon dioxide (0.05) more excipients were added to aliquots of the intermediate SP5 3 Hydroxypropyl methylcellose (3) Solution to form Several final Solutions. Each final Solution SP6 3 Polyethylene glycol 8000 (5); was then individually spray dried using a Niro Mobile Minor Hydroxypropyl methylcellose (2) SP7 3 Lactose (7) spray dryer under the following conditions: (a) Inlet tem SP8 3 D-Trehalose dihydrate (7) perature: 135° C.; (b) Outlet temperature: 75 C.; (c) SP9 3 Mannitol (6); Atomizing air: 0.75 Kgt/cm; (d) Drying air: 4 gauge setting; Hydroxypropyl methylcellose (1) (e) Feed rate: 5-7 mL/min, (f) Feed total solids concentra SP10 3 Calcium phosphate tribasic (4) Hydroxypropyl methylcellose (3) tion: 15%-21% (wt) to form solid particulate compositions SP11 5 Calcium phosphate tribasic (3); SP15-SP17. Three matching placebo compositions, P1-P3, Hydroxypropyl methylcellose (2) were prepared according to a Substantially similar process. SP12 3 Calcium sulfate (4); Hydroxypropyl methylcellose (3) TABLE 3 SP13 3 Calcium sulfate (4) Silicon dioxide (0.05) SP14 3 Corn starch (7) Composition of solid particulate compositions SP15-SP17 Composition Compound 1 (g) Excipient(s) (g) SP15 3O Microcrystalline cellulose (40); Example 3 Hydroxypropyl methylcellose (30) SP16 35 Hydroxypropyl methylcellose (35) 0.063 Hygroscopicity of Solid particulate compositions SP17 3O Hydroxypropyl methylcellose (30); SP1-SP14 of Example 2 was assessed according to the Calcium phosphate tribasic (40) following procedure. Samples (40-60 mg) of each compo P1 O Microcrystalline cellulose (20); Hydroxypropyl methylcellose (15) Sition were Subjected to controlled environmental conditions P2 O Hydroxypropyl methylcellose (360) of 40% humidity (hygrometer measurement) and ambient P3 O Hydroxypropyl methylcellose (15); temperature (i.e. 21-23 °C.) using a sealed humidity cham Calcium phosphate tribasic (20) ber over a Saturated potassium carbonate Solution (theoreti cal RH-44%). At various time points during 120 hours of Storage, each Sample was weighed and water uptake was 0067. Hygroscopicity profiles for compositions SP15 determined as the measure of Sample mass gain (%). AS SP17 and matching placebo compositions P1-P3 were deter shown in FIGS. 1 and 2, equilibrium water uptake for all mined at 40% RH according to the procedure described in compositions tested ranged from 2%-8%. Compositions Example 3; data are shown in FIG. 4. While all three US 2004/O1974 11 A1 Oct. 7, 2004 placebo compositions exhibited lower equilibrium water uptake than did any of SP15-SP17, each of SP15-SP17 SP17 TABLE 5 exhibited less than 6% water uptake after 400 hours of Percent of Compound 1 dissolved from compositions humidity treatment. These data indicate that the hygroscop SP15-SP17 at various times icity problem associated with Compound 1 (as seen in Example 1 has been overcome to a Surprisingly effective Time (min.) SP15 SP16 SP17 eXtent. O O O O 15 60.66 91.3 45 3O 100.6 102 86.5 Example 6 45 102.3 102 102 60 102.3 102 102 0068 Five solid particulate compositions, SP18-SP22, each having a composition shown in Table 4, were prepared according to the following procedure. An intermediate Solu tion was prepared by dissolving Compound 1 (in free base What is claimed is: form) in water at a concentration of 318.4 mg/ml. One or 1. A Solid particulate composition comprising a drug and more excipients were added to aliquots of the intermediate at least one non-hygroscopic polymer, wherein: Solution to form Several final Solutions. Each final Solution i. the drug and Said at least one non-hygroscopic polymer was then individually spray dried using a Niro Utility are in intimate association, Production Minor spray dryer under the following condi ii. Said composition is acceptably non-hygroscopic, and tions: (a) Batch size: 220-420 g; (b) Inlet temperature: 112-138 C.; (c) Outlet temperature: 75 C.; (d) Atomizing iii. the drug is hygroscopic and/or deliqueScent. air: 300 Hz, (f) Feed rate: 100 mL/min; (g) Feed total solids 2. The composition of claim 1 wherein the drug is an concentration: 30% (wt), to form Solid particulate compo iNOS inhibitor. 3. The composition of claim 1 wherein the drug is Sitions SP18-SP22. S-2-(1-iminoethyl)aminoethyl)-2-methyl-L-cysteine or a TABLE 4 pharmaceutically acceptable Salt thereof. 4. The composition of claim 1 that exhibits a mass Composition of Solid particulate compositions SP18-SP23 increase of not more than about 10% when exposed to 40% Compound 1 Excipient(s) Batch Size relative humidity at 21-23 C. for a period of 24 hours or for Composition (g) (g) (g) a period of time Sufficient for the composition to reach equilibrium. SP18 55 HPMC (55); 22O Microcrystalline cellulose (73); 5. The composition of claim 1 wherein the at least one SP19 66 HPMC (66); 22O non-hygroscopic polymer is a cellulosic polymer. Microcrystalline cellulose (44) 6. The composition of claim 1 wherein the at least one SP2O 66 HPMC (33): 22O non-hygroscopic polymer and the drug are present in a Microcrystalline cellulose (77) SP21 66 HPMC (17); 22O weight ratio of about 1:2 to about 2:1. Microcrystalline cellulose (94) 7. The composition of claim 1 wherein the drug is present SP22 125 HPMC (31); 416 in an amount of about 10% to about 80%, by weight of the Microcrystalline cellulose (177) composition. 8. The composition of claim 1 wherein the at least one non-hygroscopic polymer is present in a total amount of 0069. Hygroscopicity profiles for compositions SP18 about 10% to about 85%, by weight of the composition. SP22 were determined at 40% RH according to the proce 9. The composition of claim 1 wherein the at least one dure described in Example 3. As shown in FIG. 5, all non-hygroscopic polymer exhibits a moisture content at compositions exhibited less than 6% mass increase through 40% relative humidity and 21-23 C. of not more than about out humidity treatment. Additionally, compositions SP18 6%. and SP19 remained flowable powders throughout humidity 10. The composition of claim 1 wherein the at least one treatment. Compositions SP20-SP22 exhibited some caking non-hygroscopic polymer is Selected from the group con by 24 hours. Sisting of hydroxypropylmethylcelluloses, hydroxypropyl celluloses, hydroxyethylcelluloses, methylcelluloses and Example 8 ethylcelluloses. 11. The composition of claim 1 further comprising a filler. 0070 Dissolution rate of drug from solid particulate 12. The composition of claim 11 wherein the filler is compositions SP15-SP17 of Example 5 was determined in hygroscopic and/or deliqueScent. vitro. An amount of composition sufficient to provide a 100 13. The composition of claim 11 wherein the filler is mg dose of drug was individually filled into a size 1 hard Selected from the group consisting of a tribasic calcium gelatin capsule and placed in 900 ml of 0.1 NHCl and was phosphate, an anhydrous calcium Sulfate, a carboxymethyl Stirred at 50 rpm using a Type II apparatus. Data are shown cellulose calcium, a carboxymethylcellulose Sodium, an in Table 5. Overall, all three compositions exhibited disso anhydrous dextrose, a fructose, an anhydrous lactose, an lution time Suitable for use of the compositions in preparing anhydrous magnesium Stearate, a magnesium trisilicate, a a pharmaceutical dosage form and, if desired, an immediate maltodextrin, a methylcellulose, a microcrystalline cellu release dosage form. lose, a powdered cellulose, a pregelatinized Starch, a Starch, US 2004/O1974 11 A1 Oct. 7, 2004 a sterilizable maize Starch, a compressible Sugar, a confec Second Step of removing the aqueous liquid from the dis tioner's Sugar, and combinations thereof. persion. 14. The composition of claim 1 in the form of a flowable 16. The process of claim 15 wherein said second step and/or compressible powder. comprises one or more Steps Selected from the group con 15. A process for preparing a composition of claim 1, the Sisting of Spray drying, lyophilizing, elevating temperature, proceSS comprising a first Step of dispersing a hygroscopic and vacuum filtering. and/or deliquescent drug and at least one non-hygroscopic polymer in an aqueous liquid to form a dispersion and a