Indian Patents. 213682:A PROCESS FOR PREPARING PHARMACEUTICAL COMPOSITIONS CONTAINING 4-AMINOQUINOLINE COMPOUNDS FOR TREATMENT OF INFLAMMATORY DISORDERS OF THE EYE AND COMPOSITIONS RESULTING THEREFROM

Title of Invention	A PROCESS FOR PREPARING PHARMACEUTICAL COMPOSITIONS CONTAINING 4-AMINOQUINOLINE COMPOUNDS FOR TREATMENT OF INFLAMMATORY DISORDERS OF THE EYE AND COMPOSITIONS RESULTING THEREFROM
Abstract	The present invention relates to novel process for preparing ophthalmic pharmaceutical compositions comprising an inflammation-treating amount of a 4-aminoquinoline compound, derivative, isomers, or chemical skts, compositions resulting therefrom and methods for using these compositions for the tratment of ocular inflammatory by topical administration directly to the eye.

Full Text	FORM 2 THE PATENTS ACT, 1970 (39 of 1970) COMPLETE SPECIFICATION (Section 10) "A PROCESS FOR PREPARING PHARMACEUTICAL COMPOSITIONS CONTAINING 4rAMlNOQUlNOLlNE COMPOUNDS FOR TREATMENT OF INFLAMMATORY DISORDERS OF THE .EYE AND COMPOSITIONS RESULTING THEREFROM" RAUT RAJEEV 27, Manisha, 2A Moledina road Pune 411 001, Maharashtra State, India An Indian National, The following specification particularly describes the nature of this invention and the manner in which it is to be performed: TITLE OF INVENTION A PROCESS FOR PREPARING PHARMACEUTICAL COMPOSITIONS CONTAINING 4-AMINOQUINQLlNES COMPOUNDS FOR TREATMENT OF INFLAMMATORY DISORDERS OF THE EYE, COMPOSITIONS RESULTING THEREFROM AND METHOD OF TREATING SUCH DISORDERS WITHTHESE COMPOSITIONS. This application claims the benefit of U.S. Provisional Application No. 60/380926 fliea May 17,2002. FIELD OF THE INVENTION This invention is a process for preparing pharmaceutical compositions containing 4-aminoqunulines compounds for treatment of ocular inflammation of varied etiology such as immune disease factors, surgery* chemical or mechanical injury, injury due to exposure to radiation, infrared or ultra-violet rays, degenerative changes or dystrophies, allergic or infective etiology, compositions resulting from the said process and treatment of ocular inflammation with the said compositions. The said ocular inflammation may also present as dry eye or ocular surface disorder. More particularly, this invention relates to ophthalmic pharmaceutical compositions comprising a 4-aminoquinolme compounds, used for the treatment of malaria and rheumatoid arthritis, and methods for treating ocular inflammation with said compositions. This invention relates to a method of administration of 4-aminoquinolines as ophthalmic pharmaceutical compositions that permits administration of 4-amwoquinolmes directly to the eye, through corneal conjunctival, subconjunctival and intravitreal routes for attaining sustained ocular levels of the active agent, without oral or parenteral administratioa Ocular administration avoids the severe side effects of systemicaUy administered 4- aminoquinolones while attaining effective dosage levels in the eye. Chloroquine, a representative generic drug, faas never been used to treat the eye by die composition and method described herein. BACKGROUND OF THE INVENTION Inflammatory disorders of the eye have historically been recognized as complex and vision threatening. Although numerous pharmaceutical agents and compositions exist far its treatment, their site efforts proffle aitf effectiveness are less than desired The side effects may not be acceptable in a particular patient, or if prolonged use is required. The current invention provides a new and original method for treatmeot of CKtflarmtiaiimiatm Inflammation of the eye may be localized to the eye* the eyes, or may be part of more generalized inflammatory process. Its etiology may be infection, aUergy,mmraiK>logical reactions, or as a respcrase to other causes. The ocular inflammation causes pain, irritation, watering, threatens visual function of the eye and may also change optical properties of the eye. Inflammation may be seen as uveitis or keratoconjunctivitis. Inflammation may also be seen as dry eye" or as ocular surface disorder. Uveitis is an inflammation of the uvea, the middle layer of tissue behind the white of the eye. The cause of uveitis is poorly understood, but a variety of systemic diseases are associated with it. Uveitis has been treated by various classes of compounds including steroids and nonsteroidal amMnflatnmatoty agents such as dexamethasone, ftarometbokme, prednisolone, indomethacin, aspirin, flubiprofen and diclofenac. However, a number of uveitic cases are not responsive to or become refractory to these drugs. Kulkarni, P., 17(2) JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS 181-7 (2001). Serious side effects including cataract, glaucoma, delayed wound healing, and altered prostaglandin production, Id, at 181, and corneal complications including ulceration, perforation, and corneal and scleral melts have been reported with the use of topical nonsteroidal anti-inflammatory drugs. Giridera, AC, Luchs, JI, Udell, IT, 108 OPHTHALMOLOGY 936-944 (2001). Steroids are known to cause increased ocular pressure, cataracts, superinfections, and reduced immunity to infectioa Olsen, EG & Davanger M, 62(6) ACTA OPHTALMOL 893-9 (1984). A newer immunosuppressive, Tacrolimus, is used orally in uveitis, but may cause severe side effects similar to those seen with cyclosporin including renal dysfunction, and neurological disorders. Kiilkaroi, at 183. The use of Cyclosporin A is further limited by its low penetration into the eye. Van der Bijl, P, van Eyk, AD & Meyer, D 20(5) CCVPROGKAM RLESYMY DOCUMENTOR RAUIPCT I»AFT.DOCORNEA 505-8,505 (2001). Aldose reductase inhibitors have also been used, especially in diabetics. U.S. Patent No. 4,600,717, to York. Fibronectin has also been tried to improve healing, but the defect closure rate was unaltered in the treated group. Phan, TM 30(3) Invest Ophthamol Vis Sci 377-385,381 (1989). Mast cell stabilizers such as topical Lodoxamide and Cromolyn Sodium have been used to treat vernal keratoconjunctivitis. Avunduk, AM, et al, 107 OPHTHALMOLOGY 1333-1337 (2000). Nedrocromil sodium has a safety profile similar to cromolyn sodium. Verin PJ, Dicker ID, Mortemousque B, 29(4) CuN EXP ALLERGY 529-36 (1999). Vernal keratoconjunctivits is often controlled with topical steroids, but the vision threatening side effects are worse than the underlying disease, which usually is self-limiting and resolves as the patient grows up. Verin, 28(S6) ALLERGY 44 - (1998) Immunosuppressives such as topical Cyclosporin A have been used in the treatment of Mooren"s ulcer, vernal keratoconjunctivitis, ulcerative keratitis associated with rheumatoid arthrttis, anterior uveitis, and Thygeson"s punctate keratitis. Kulkanri, P., 109 QMBHAIAKHJOGY 845-850 (2002). Recurrence may occur in some patients. Field, AJ, Gottsch, JD, 23(4) Ausr N ZEALAND J OnnHALMOLOGY 333-334 (1995). Cidofovir 1% has been used in acute adenoviral keratoconjunctivits but is limited by local toxicity including conjunctival injection chermosis and punctate epithelial keratitis during the course of treatment and subepithelial infiltrates. It may cause an atypical and uncomfortable erythema of the skin of the eyelids and pronounced conjunctival injection mat could be differentiated from adenoviral conjunctival inflammation alone. Hillenkamp, et al 109 OPOTHALMOLOGY 845-850,847 (2002). Researchers have studied the use of human epidermal growth factor on postkeratoplasty re-eprthetiahsation without success, in spite of promising earlier animal data no benefit on epithelial healing. DeOaert MJ, et al, 81 BR J QpfflHALMOL 391-395 (1997). Accordingly, a need exists tor novel ophthalmic pharmaceutical compositions which safely and effectively treat oxailar iinlainmation conditions. It was disclosed tbat tte 4-aminoquinolines have strong anti-inflammatory action and are useful for treatment of inflammatory diseases. Rynes, RI, 36 BR J RHEUMATOL 799-805 (1997). However, mere has been no report or study in ophthalmologic field. The anti¬inflammatory properties of the anti-malarial 4-amhu>qumolone pharmaceuticals are well known. They have not been used to treat inflammation of the eye because their systemic use in high doses has been associated with a rare, but serious, incidence of ocular toxicity including corneal deposits known as verticiUata, loss of foveal reflex, impairment of accommodatiori, maculopatby and retinopathy. These effects may be reversible or irreversible. Retinopathy is the major and potentially most serious as it is irreversible. Jones, SK, 140(1) BRIT J DERMATOL 3-7, (1999). Ocular toxicity, however, is believed to occur only when doses exceed 6.5 mg/kg/day fix- a minimum of five 5) years. Cordes, MG, 2000 Southern J Optometry, Poster (2000). www.optcom3.com/sio/cordes htmThe dosageof cMoroqurae appears to be the most fundamentally important factor in determining the risk of development of retinopathy. In general, it appears that serious retinopathy m nearly all instances is caused by taking more than 250 mg of cbloroquine diphosphate or 200 mg of cbloroquine sulfate per day to a total amount greater than 100 gms. By not exceeding this daily dosage, it has been found possible for patients to take chloroquine for as long as nine years without developing clinically evident retinopathy. In most cases in which dosage slightly greater than 250 mg cbloroquine diphosphate per day has been administered, the onset of definite retinopathy has taken one to three years. According to Nyiander, most patients who have developed retinopathy have received nearly a total of 300 gms for three or more years. TOXBDOLOOY OF THE EYE, Vol. 1, 272 (Grant, M, ed, 2" Edition). This inventor has discovered that when used directly in the eye, the 4-aminoquinolone compounds are non-toxic and highly effective in a wide variety of ocular inflammatory disorders. The 4-arninoquinoline compounds used here in novel ophthalmic pharmaceutical compositions have been previously reported to be useful as therapeutics m the treatment of malaria and riieumatoid artliritis. See, for example, U.S. Pat Nos. 4,421,920 to Baudouin, 5,596,002, to Bfaffaeinz, 5,948,791, also to Hbfheinz. It has now been found that certaio 4 ammoquiaeteB^ ^4-ammoq^iinoline compounds are useful for preventing and treating ocular inflammation by application of the compositions to the eye prior to, during and after an inflammatory disorder, especially inflammation of the outer and middle coats of the eye, such as dry eye, conjunctivitis, scleritis, keratitis, and uveitis. The first object of the invention is to provide a novel method by way of "process of composition", route and concentration for the delivery of 4-aminoquinolme drugs directly to the eye for improved effectiveness to treat inflammatory disorders of the eye. Another object of the invention is to provide prolonged stable intraocular levels of 4- aminoquinolkes. A mrtl^oi^oftbe invention is to provide Biirtamed intraocular levels of 4-^aminoquinolines without having to increase their plasma levels. Yet another object of the invention is to provide an unproved long term administration method for delivering 4- aminoquinohnes to patients suffering from inflammatory disorders of the eye. The objects of the invention are met and the problems and shortcomings associated with systemic administration are overcome by the in Compounds suitable for delivery using this method include ditoroquine, amodiaquine, an isomer or a salt thereof, and structurally similar compounds. As used above, the term "salt thereof is meant to include any nontoxic pharmaceuticaUy suitable salt of a compound described above with the desired pharmacological properties in mammals. Preparation of such a salt is well-known to those skilled in pharmaceutical science. This inventor has discovered that the 4-aminoquinoHne compounds are no«-toxic to tlw eye when administered directly to the eye. Ocular administration permits the compound to be administered in adequate ocular doses and to maintain intraocular levels of the compound for prolonged periods. The 4-anunoquinolone compounds, when used in ophthalmic pharmaceutical compositions, are effective in treating ocular inflammation of varied etiology such as immune disease actors, surgery, chemical or mechanical injury, injury due to exposure to radiation, infrared or ultraviolet rays, degenerative changes or dystrophies; urticaria, allergic conjunctivitis, vernal conjunctivitis, allergic responses in the eye, iritis, iridocyclitis, sclerals, episcleritis, choroiditis, optic neuritis, Mooren"s ulcer, ulcerative keratitis associated with rheumatoid arthritis, anterior uveitis, Thygeson"s punctate keratitis, or other inimunological reactions; chlamydia, amoeba, adenovirus, cytomegalovirus, toxoplasmosis, tuberculosis, or syphilis; uveitis due to Behcet"s disease, pars planitis, idiopathic uveitis, ocular sarcoid, sympathetic ophthalmia, idiopathic vHritis, vitritis, or uveitis resulting from trauma. 4-armnoquinolines and their derivatives which are particularly suitable for the method of the present invention and processes for preparing these compositions are disclosed in U.S. Patent No. 4,421,920 to Baudouin, U.S. Patent No. 5,596,002, to Hbfheinz, and U.S. Patent No. 5,948,791, to Hbfhemz. To the extent these applications and patents disclose 4-eminoquinoune compounds and their derivatives which are usefiil in the practice of the present invention, they are incorporated herein by reference. Detailed descriptions of the preferred embodiment are provided herein; however, it is to be understood that the present invention may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in virtually any appropriately detailed system, structure or manner. As discussed above, the ophthalmic pharmaceutical compositions of this invention contain one or more 4-anrinoquinoline compounds as the active components). Prior to describing this invention in further detail, the following terms will first be defined. The term "lower-alky!" used in the present description denotes straight-chain or branched saturated hydrocarbon residues such as methyl, ethyl, n-propyl, isopropyl, n-butyL, isobutyl, s-butyl, t-butyl and the like. "Halogen" is chorine, bromine, fluorine or iodine. When A in formula I is an aliphatic hydrocarbon chain, branched chains, for example -CH(CH.sub.3)-CH.sub.2 -, -CH.sub.2 CH(CH.sub.3}- or -CH.sub.2 C(CH.sub.3).sub.2 -, are especially preferred The term "cyctoalkylene" embraces preferably cydopentyl or cydohexyl. The term "aryl" embraces conveniently phenyl or substituted phenyl, with the number of substituents preferably being 1-3 and the substhuents being selected from a group consisting of halogen, hydroxy, lower-alkyl, tower-alkoxy, CF.sub.3, cyano, di-lower-alkylamino or their N-oxides, phenyloxy, phenyl or methylsulphanyl. Furthermore, the term "aryl" conveniently embraces naphthyl, benzo)l73!dioxol or mono- or bicyclic aromatic heterocydes with 1 or 2 betero atoms, especially N and/or O, for example pyridyl, quinolyl or ftnyl. Rings such as phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, naphthalen-1-yl, naphthalen-2-yi, furan-2-yl, furan-3-yl or quinolin-4-yl are preferred. Preferred compounds of general formula I are especially those in which R.sup.9 is chlorine, R.sup.10 is hydrogen, p is 1, A is -CH.sub.2 -C(CH.sub.3).sub.2 ~ and B is a benzene ring which is unsubstituted, mono-substituted or di-substhuted. "Pharmaceutically acceptable salt" refers to phannaceutically acceptable salts which are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkyl-anunonium, and die like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, tartrate, mesylate, acetate, maleate, bitartarate, lactate, phosphate, malate, maleate, fumarate, succinate, acetate, pahnoate, oxalate and the like. Among the conventional salts which can be utilized there are the base salt, for example, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or alkyl ammonium salts. Thus, according to this invention, the process of the invention consists of mixing between O.Opl nanograms per ml. to l.OOmg. per ml. of 4-aminoquinolines compounds such as amodiaquine, chloroquine or its derivatives, its salts and isomers such as but not restricted to Hydroxychloroquine sulphate, Chloroquine phosphate with known phannaceutically acceptable carrier s for example, bat not restricted to sterile water and if desired, father mixing acids and bases to adjust the pH, tonicity imparting agents, antimicrobial preservatives, other viscosity imparting agents, suitable absorption enhancers such as surfactants and stabilizing agents. According to the present invention a process for preparing a novel pharmaceutical composition for external application in mflammatory disorder of eye as eye drops, eye ointments or directly subconjunctivally or directly intravitreally is described. This new process of preparation, treatment technique and delivery method unexpectedly results in a prolonged and sustained intraocular levels of the active drug in mammals using formulations that not necessarily increase drug plasma levels, and therefore avoid hazards associated with raised plasma levels and implications thereof, like drug toxicity. Compounds suitable for delivery using this method include chloroquine, amodiaquine, an isomer or a sah thereof, and structurally similar compounds. As used above, the term "sah thereof5 is meant to include any nontoxic pbarmaceutically suitable salt of a compound described above with the desired pharmacological properties in mammals. Preparation of such a salt is well known to those skilled in pharmaceutical science. Phannaceutically acceptable salts of the above compounds include : hydrochloride, hydrobromide, hydroiodide, sulfite, bisulfite, nitrate, salicylate, citrate, tartarate, bitartarate, lactate, phosphate, malate, maleate, fiiymarate, succinate, acetate and pamoate, acid forms thereof. A better and more complete understanding of the invention may be garnered from the detailed description of the preferred embodiment of the best mode of the invention as contemplated by the inventor. Detailed descriptions of the preferred embodiment are provided herein; however, it is to be understood that the present invention may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in virtually any appropriately detailed system, structure or matter. The compositions disclosed herein is a preparation of the active ingredient, namely a 4-ammoquinoline, in a concentration between .001 nanogram per ml to 1 mg. Per ml in a phannaceutically acceptable carrier. The composition disclosed now will be applied directly to the eye 1 to 10 times a day. The active ingredients can be administered in the conjunctival sack as eye drops, ointments, gels, sustained release carriers, slow dissolving capsules placed in the conjunctival sack, via release from a contact lens. The composition of this invention may be prepared to include: 1. acids and bases to adjust the pH; 2. tonicity imparting agents such as sorbitol, glycerin and dextrose; 3. antimicrobial preservatives, to inhibit microbial contamination, such as other parahydroxybenzoic acid esters (sorbate, benzoate, propionate), chlorobutanol, benzyl alcohol, benzalkonium chloride, and mercurials; 4. Other viscosity imparting agents such as sodium carboxymethylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, polyvinyl alcohol and other gums; 5. suitable absorption enhancers, such as surfactants, bile acids; 6. stabilizing agents such as antioxidants, like bisulfttes and ascorbates, metal chelating agents, such as sodium edetate; and drug solubility enhancers, such as polyethylene glycols. These additional ingredients help make commercial solutions with adequate stability so that they need not be compounded on demand. The other synonyms of chloroquine and related compounds, as per the invention include 7- CUoro^(4HliethyiaoiiiK^l-methyllHitylaimno)quinoline Chingamin Chmgarnin phosphate Chlorochin Chloroquin diphosphate Chloroquina Chloroquine diphosphate Chloroquine hydrochloride Chloroquine phosphate Chloroquine sulfate Chloroquine sulphate Chloroquinum Cholarquine Cboroquin sulfate Quinagamin Accordingly, in one of its composition aspects, this invention is directed to an ophthalmic pharmaceutical composition comprising a pharmaceutically acceptable ophtnalmic carrier and an ocular inflammation-treating amount ofa4- aminoquinolinc compound of formula t 7 \ "wherein and R.sup. 1 to R.sup.6 are hydrogen or in which one or two of Rsup. 1 to R.sup.6 are independently selected from alkyl and the other substituents are hydrogen; R.sup.7 and R.sup.8 are independently selected from alkyl, alkenyl or aralkyl, or together with the N atom signify pyrrolidine or piperidine, either or both of which may be substituted by alkyl; and n=0 or 1; or wherein R.sup. 1 and Rsup.3 are tri- or tetramethylene; R.sup.2 and R.sup.4 to R.sup.6 are hydrogen; n=0, and R.sup.7 and R.sup.8 are defined as above; or wherein R.sup.1 and R.sup.7 are methylene or dimethylene and n=l, or R.sup.3 and R.sup.7 are di- or trimethylene and 0=0, or R.sup.3 and R.sup.7 are di- or trimethylene and n=l, or R.sup.3 and R.sup.7 are tri- or tetramethylene and n=0, or R.sup.5 and R.sup.7 are tri- or tetramethylene and n-1, or Rsup. 1 and R.sup.5 are di- or tri-methylene and n=l, and the remaining substituents are hydrogen, except R.sup.8 which is selected from alkyl, alkenyl or alkynyl; or wherein R.sup.3 and R.sup.5 are tri-or tetramethylene and n=l; Rsup. 1, R.sup.2, R.sup.4 and R.sup.6 are hydrogen; and R.sup.7 and R.sup.8 are selected from alkyl, alkenyl or aralkyl or together with the N atom are pyrrolidine or piperidine, either or both of which may be substituted by alkyl; R.sup.9 is hydrogen or halogen; and Rsup. 10 is halogen or trifluoromemyl; Rsup. 11 is a hydrogen atom or an alkyl radical (1-5 carbon atoms); Tn another of its composition aspects, the 4-aniinoquinoline compound of Formula 1. VS(M?JL* ^ A is or (C.sub.5 -C.sub.6)-cycloalkylene; n is 1-4; n or Rsup.7 is hydrogen and R.sup.8 is (CH.sub.2)sub.p-B and p 10 is 1-3 and B is aryl selected from phenyl, phenyl mono-, dt~, m tri-gubsthuted by substituent from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, cyano, di-lower alkylamino or their N-oxides, phenyloxy, phenyl, and methylsuphanyl, napbthyl, benzo>l,3!dioxol, or monocyclic aromatic heterocycle with 1 or 2 heteroatoms selected from N and O; and R.sup.9 is hydrogen or halogen; and Rsup. 10 is halogen or trifluoromethyl; as well as pharmaceuticaUy acceptable salts of basic compounds of formula L In the third of its composition aspects, the 4-aminoqurooline Of Formula I isi wherein A is an alkyl of 1 through 5 carbon atoms substituted by a diaikylamino group of which each alkyl radical contains 1 through 4 carbon atoms, phenyl, or phenyl substituted by one or more radicals selected from carboxy and hydroxy and alkyl radicals of 1 through 4 carbon atoms and R.sup.9 is hydrogen or halogen; and R.sup. 10 is halogen or trifluoromethyl. Compounds of general formula I in which R.sup.9 is hydrogen, R.sup.10 is chlorine are preferred embodiments: diamine,Compounds of general formula I in which R.sup.9 is hydrogen, R sup. 10 is chlorine, p is 1, A is cyclohexane-l,2-diyl or cyclohexane-l,4-diyl and B is a benzene ring which is unsubstituted or mono- or di-substituted are also preferred: (lS,2S>N.sub.l-(7-Chloro-quinolin-4-yl>N.sub.2 -{benzyl)-cyclohexane-l> diamine, (lS,2S}-N.sub.l -(7-chloro quinolm-4-yl)-N.sub.2 -(4-chloro-beazyl)- cyclobexane-l,2-diamine, (lS,2S)-N.sub.l-(7-cbloro-quinolm-4-yi)-N.sub.2 - cyclo-hexane-I,2-dianiine, cis-N.sub.l -(7-chloro-quinolk-4-yl)-N.sub.4 -(4-dimethylamino-ben2yi)- cyclohexane-l,4rdiamine, cis-N.sub.l -(7-chloro-qiitaohn-4-yl)-N.sub.4 -(ben2yl>cyclohearane-lJ4^iiamine, cis-N.sub.l -{7-chloro-quinDUn-4-yl)-N.sub.4 -(3-chloro-benzyl)-cyclohexane- l,4H3iamineJ cis-N.sub.l -(7-chloro-quinolin-4-yl)-N.sub.4 -(2-hydroxy-4^nethoxy-benzyl)- cyclohexane-l,4-diamine, cis-N.sub.l -(7-chloro-quinolin-4-yl)-N.sub.4 -(3,5-dimetboxy~benzyl)- cyclohexane-l,4-diamine, cis-N.sub.l -(7-chloro-quhiolm-4-yl)-N.sub.4-(4-methylsulphanyl-b^ cyclohexane-l,4-diamine, cis-N.sub.l -(7-chJoro-quinolin-4-yl)-N.sub.4 ^4-diethylamuio-benzyI)- cyclohexane-1,4-diamine, cis-N.sub.l -(7-chloro-quinolin-4-yl)-N.sub.4 -(biphenyl-4-ylmethyl)- cyclohexane-l,4-diamine, trans-N.sub.l -(7-chlorc-quinolin-4-yl)-N.sub.4 ->2-(3,5-dimethoxy-phenyl)- ethyl!-cyclohexane-l,4-d%iiine, ds-N.sub.l -(7-chloro-quinoIin-4-yl)-N.8ub.4 -(4-methoxy-benzyl)-cyclohexane- 1,4-diamine, trans-N.sub.l-(-(choro-quiiK)lin-4-yl)-N.sub.4-(4-dimethylamiao-bcnzyl)- cyclohexane-l,4-diamine and trans-N.sub.l -(7-dilon)-quinolin-4-yl)-N.sub.4 - (2,6-difluoro-benzyl)-cyclohexane-l,4-diamine. Most preferably, the 4-anunoquinoline compound in the ophthalmic pharmaceutical composition is: Chloroquine phosphate Quinoline, 7-chloro-4-(4-(dlethylauimio)-l-methbutyl)amino)-, suliate, Qufnoline,4-(4-(bis(2-chloroe4hyl)aminol-methlbutyl)amino)-, suliate dihydrochloride N,N-Dideethylchloroquine, Quinoline, 4-(2-s(2-chloroethyl)amino)«hylaraino)-7-chloro-, dihydrochloride, monohydrate, Quinoline, 7choro-4-(4-(diethylaniuM))-l-methylbutyl)amino)-, diphosphate, (- Quinoline, 4-(p4Hs(2-choroethyl)amin0phenylethylamino)-7-chloro-, monohydrochloride Chloroquine 3-Methylchloroquine Salicylic acid, 4-acetamido-, compd. with 7-chloro-4-(4-(dieutylamino)-l- methyIbutyl)amino)quinoline, Hydroxychloroquine Quinoline, 7^oro-4-((4-(d1ethylammo)-l-memylbutyl)amino)-, mixed with sodium nitrite Hydroxychloroquine sulfate, Quinoline, 7-(choro-4-(4-dietliylaniino)-l-methylbutyl)aniino)-J diphosphate, Quinoline, 7-choro-(4-dietiylamino)-l-methylbutyl)aniino>-, phosphate, Desethylchloroquine. Chloroquine hydrochloride, L-Ascorbic acid, compd. withN(sup 4)-(7-chloro-4-quinolinyl)-N(sup l),N(sup l)-diethyl-l,4-pentanediamine, N,N-Dideethylchloroquhie Amodiaquine In another embodiment, the 4-aminoquinoline compound in the ophthalmic pharmaceutical composition is mefloquine, quinacrine (mepacrine), pyrimethamine, and cletoquine. General Synthetic Procedures The 4-aminoquinoline compounds and their derivatives employed in this invention are either commercially available or can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (Le., reaction temperatures, times, mote ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protecting and deprotectmg various functional groups are well known in the art For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. In a preferred method of synthesis, the novel compounds of formula I can be manufactured in accordance with the invention by reacting appropriate quinoline derivatives of the general formula with appropriate amino compounds or reacting alkylanunchquinoline derivatives with amines according to the process of Hofheinz, U.S. Patent No. 5,596,002. Tn another preferred method of synthesis, the novel compounds of formula I can be manufactured by a) reducing an appropriate Schiff s base or b) reacting an appropriate amine with a compound of the formula X~(CH.sub.2).sub.p -BIV wherein X is a leaving group and the other substttuents have the significance described in the process taught by Hofheinz, U.S. Patent No. 5,948,791. In yet another preferred method of synthesis the products of the general formula (I) can be obtained, with good yields and virtually free of dechlorinated product, by condensing an appropriate amine with a chloro-1,2,3,4-tetrahydroquinolin-4-one, the reaction being carried out in the presence of a ruthenium based catalyst on a support and preferably in the absence of oxygen, according to the method of Baudouin, U.S. Patent No. 4,421,920. The following formulation examples illustrate representative pharmaceutical compositions suitable for ophthalmic delivery of the 4-aminoquinoline compounds used in this invention. The present invention, however, is not limited to the following exemplified pharmaceutical compositions. Formulation The ophthalmic pharmaceutical composition of the invention includes one or more additional ophthalmic pharmaceutical compositions including buffers, surfactants, stabilizers, preservatives, ophthalmic wetting agents, ophthalmic diluting agents. Wetting agents commonly used in ophthalmic solutions include carboxymethylcellulose, hydroxypropyl methylcellulose, glycerin, mannitol, polyvinyl alcohol or hydroxyethylcellulose and the diluting agent may be water, distilled water, sterile water, or artificial tears, wherein the wetting agent is present in an amount of about 0.001% to about 10%. In another embodiment, the ophthalmic pharmaceutical composition further comprises one or more additional pharmaceutically active ophthalmic pharmaceutical compositions such as anti inflammatory agents, antibiotics, and fungals, anti virals, ocular hypotensive agents, local anaesthetic agents, cyclopiegics, or pupillary dilators used in the treatment of diseases of the eye. Examples of ophthalmic solutions and opthalmic ointments can be formulated into such preparations utilizing a number of widely-used methods well known to those of ordinary skill in the art. In the case of ophthalmic solutions, for example, they can be prepared using distilled water, an aqueous base, or any other acceptable base; tonicity agents such as sodium chloride and concentrated glycerol; butters such as sodium phosphate and sodium acetate; surfactants such as poryoxyethylenc sorbhan monooleate, stearic polyoxyl 40, and polyoxyethylene hydrogenated castor oil; stabilizers such as sodium citrate and sodium edetate; preservatives such as benzalkonium chloride, thimerosal, chlorobutanol, sodium chloride, boric acid, parahydroxybenzoic acid esters (sorbate, benzoate, propionate), chlorobutanol, benzyl alcohol, mercurials, paraben; etc., and mixtures thereof if necessary. Benzalkonium chloride and thimerosal are the preferred preservatives. The formulation of this invention may be varied to include acids and bases to adjust the pH; tonicity imparting agents such as sorbitol, glycerin and dextrose; other viscosity imparting agents such as sodium carboxymethylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, polyvinyl alcohol and other gums; suitable absorption enhancers, such as surfactants, bile acids; stabilizing agents such as antioxidants, like bisulfites and ascorbates; metal chelating agents, such as sodium edetate; and drug solubility enhancers, such as polyethylene glycols. These additional ingredients help make commercial solutions with adequate stability so that they need not be compounded on demand. In a preferred embodiment, benzalkonium chloride is added as an antimicrobial preservative in an amount ranging from about 0.001 to about 0.02 weight percent, preferably 0.01 weight percent. In another preferred embodiment, thimerosal is added as an antimicrobial preservative in an amount ranging from about 0.005 to about 0.02 weight percent. In another embodiment of the invention, the ophthalmic carrier is a surfactant such as » poryoxyethylene fatty acid ester, polyoxyethylcnc aflcylphenyl ether, and polyoxyethylene alkyl ether, or mixtures thereof or a thickening agent such as a carboxyvinyl polymer, polyvinyl polymer, and polyvinylpyrrolidones, as taught by U.S. Patent No. 5,951,971, to Kawashima. In the ophthalmic pharmaceutical composition of this invention, the ophthalmic carrier is preferably a sterile aqueous carrier or a salve or ointment carrier. Such salves or ointments typically comprise one or more 4-aflnnoquinoline compounds dissolved or suspended in a sterile pharmaceuacally acceptable salve of ointment base, such as a mineral ou-whto petrolatum base. In salve or ointment compositions, anhydrous lanolin may also be included in the formulation. Thimerosal or chlorobutanol are also preferably added to such ointment compositions as antimicrobial agents. hi yet another embodiment of the invention, the ophthalmic carrier may be olive oil, arachis oil, castor oil, polyoxyethylated castor oil, mineral oil, petroleum jelly, dimethyl sulphoxide, an alcohol, liposome, silicone fluid and mixtures thereof as taught by U.S. Patent No. 6,254,860, to Garst. Preferably, the active ingredient, namely a 4 aminoquinoline, is found in a concentration between .001nanogram per millilitre to 10 rag per milijlitre, in a pharmaceuticajly acceptable carrier. The ophthalmic 4-aminoquinoline compositions may be incorporated into liposomes. The use of liposomes as drug delivery systems has been known for some tune, and comprehensive review articles on their properties and clinical applications are available; see, e.g., Barenholz and Amselem, in "Liposome Technology", 2nd ed., G. Gregoriadis, ed., CRC press, 1992; Lichtenberg and Barenholz, in Methods for Biochemical Analysis, 33, D. Ghck, ed., 1988. A liposome is defined as a structure consisting of one or more concentric lipid bilayers separated by water or aqueous buffer compartments. These hollow structures, which have an internal aqueous compartment, can be prepared with diameters ranging from 20 ran to 10 .mu.m. U.S. Patent No. 5,576,016, to Amselem. The compositions may be incorporated in nanoemulsions of particles comprising a lipid core composed of lipid which is in a solid or liquid crystalline phase at at least 25degree. C, stabilized by at least one phospholipid envelope, for the parenteral, oral, rectal, intranasal, or topical delivery of both fat-soluble and water-soluble drugs according to the method of U.S. Patent No. 5,576,016, to Amselem. The dose can be appropriately selected depending upon symptom, age, dosage form, etc. and, in the ophthalmic solutions, contain between about 0.001 nanograms per milliliter and 10.00 milligrams per milliliter of a 4-aminoquinoline derivative., preferably between 0.001 nanograms per milliliter and 1.00 milligram per milliliter and most preferably about .3 milligrams per milliliter of a 4-anujooquinoline derivative or a salt or isomer of a 4-aminoquinoline derivative in a pharmaccutically acceptable ophthalmic carrier. The pH can be within a range which is acceptable to ophthalmic preparations and, preferably within a range from4to8. Any of the disclosed 4-aminoquinoline derivatives may be incorporated into chitosan nanoparticles to improve the delivery of the 4-aminoquinoline derivatives to the ocular mucosa, as described by Dc Campos, Am, Sanchez, A and Atonso MJ 224 (1-2) Jm J PHARM 159-68,161 (2001). In one example, the solution is prepared by adding a variable volume of a 4-anrinoquinolone compound solution in an acetonhrile/water mixture is incorporated into to Chitosan SeaCure 123, purchased from Pronova Biopolymer AS of Norway (4 mg, 0.2 or 0.5% w/v). Nano particles are formed upon the addition of Sodium tripolyphosphate aqueous solution (0.5 ml, 0.2%w/v) under magnetic stirring at room temperature, purified by centrifugation at 900 x g in a glucose bed for 30 minues. Supernatants are discarded and nanoparticles are resuspended in pure water. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington"s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa., and International Programme on Chemical Safety (IPCS), and ideological information may be found at bitp://www.inchem.oig/documents/pims/pharm/chlorogu,htm, both of which are incorporated herein by reference. Mixtures of two or more 4-aminoquinoline compounds may be employed, if desired, in the pharmaceutical compositions and methods of this invention. Examples Representative examples for preparing ophthalmic solutions and ophthalmic ointment of 4-aminoquinolone compounds are shown as follows. The drops may be combined with other anti inflammatory agents , and biotics, anti fiingals, anti virals, ocular hypotensive agents. The drops may be combined with topical ophthalmic steroids, antimetabolites. The drops may be combined with artificial tears and ocular lubricants. The drops may be combined with buffers, surface tension lowering agents, local anaesthetic agents, cycloplegics, pupillary dilators, eyedrop formulations used in treatment of eye diseases. The generally used range of pH can be used for this preparation, but a preferable range is 4-8. Depending on the salt of chloroquine used, the Ph of the solution may be adjusted by using hydrochloric acid or sodium hydroxide, between 4 and 8. Chloroquine phosphate and chloroquine sulphate, for example, are sensitive to light, and may be dispensed in opaque bottles. Example 1. A 4-anunoquinoline compound, such as Chloroquine phosphate equivalent to chloroquine 30mg. Sodium chloride 0.9 gms, Benzalkonium chloride S mg, are mixed to dissolve in purified sterile water. Purified sterile water is then added to produce a total volume of 100 mL. Example 2 A 4-aminoquinoline compound, such as Chloroquine phosphate equivalent to chloroquine 100 mg, Sodium chloride 0.9 gms, Benzalkonium chloride 5 mg, are mixed to dissolve in purified sterile water. Purified sterile water is then added to produce a total volume of 100 mL. Example 3 A 4-aminoquinoline compound, such as Chloroquine phosphate equivalent to chloroquine 1 mg, Sodium chloride 0.9 gms, Benzalkonium chloride 5 mg are mixed to dissolve in purified sterile water. Purified sterile water is then added to produce a total volume of 100 mL. Example 4 - Ophthalmic Ointment A 4-minoquinoline compound such as Chloroquine phosphate is admixed with mineral oil and white petrolatum to form an ointment containing 0.05 weight percent active 4-armnoquinoline compound. It will be appreciated that any of the 4-aminoquinoline compounds described herein could be employed in any of these representative formulations taking into account solubility, dispersability and the like, and that any of these formulations could be administered in any of the above described manners so as to treat ocular inflammation-Method of Drag Delivery Any of the 4-aminoquinoline compounds (including salts thereof) employed in this invention may be formulated into ophthalmic pharmaceutical compositions suitable for topical administration. The active ingredients can be administered in the conjunctival Back as eye drops, ointments, gels, sustained release carriers, slow dissolving capsules placed in the conjunctival sack, via release from a contact lens, subconjunctivally by injection, or intravftreally by injection, by preparing a suitable formulation of the active ingredient and utilizing procedures well known to those skilled in the art. Preferably, the formulations are prepared with suitable nontoxic phannaceutically acceptable ingredients. These ingredients are known to those skilled in the preparation of eyedrops, ointments, subconjunctival and intravitreal injections. Some of these ingredients can be found in Remington"s Pharmaceutical Sciences, 17th edition, 1985, a standard reference in the field. The choice of suitable carriers is highly dependent upon the exact nature of the eyedrops, eyeointments, subconjunctival, intravitreal dosage form desired, e.g. solutions, sprays, drops, gels, pastes, patches. The 4-aininoquinoline derivatives may be administered via a biocompatible and implantable controUed-release drug delivery device as taught in U.S. Patent No. 6,331,313, to Wong. The 4-amuKxjuinoline compounds employed in tins invention can also be administered in sustained release forms or from sustained release drug delrvery systems which can be found in Remington"s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa., and International Programme on Chemical Safety (IPCS). In one of the more preferred embodiments, the ophthalmic carrier is a conjunctival insert. Preparation of said inserts is taught by U.S. Patent No. 6,217,896 to Benjamin and other methods are well known in the art Method of Treating Ocular Inflammation One object of the invention is to provide a method for treating ocular inflammation comprising topically applying to the eye an ophthalmic pharmaceutical composition comprising a phannaceuticaUy acceptable ophthalmic carrier and an ocular inflammation-treating amount of one or more 4-aminoquinoline compounds, or one of their pharmaceutically acceptable analogues or sabs. The inventor has discovered unexpectedly that by administering a 4-ammoquinoline compound topically directly into the eye, the much feared ocular toxicity is avoided rather than enhanced. Any of the formulations and methods of drug delivery disclosed in this invention may be used to treat ocular inflammation by direct application of a 4-aminoquinoline compound to the eye. The conditions treated with the ophthalmic pharmaceutical compositions of this invention generally include ocular inflammation and the various symptoms which fall within the ocular inflammation definition. These include, for example, uveitis. The 4-amhioquinoline formulations provided by this invention can be administered to achieve an inflammation reducing effect in the eye. To achieve tins effect, a topical preparation is administered directly to the inflamed eye by instilling adequate topical solution or salve or ointment to the inflamed eye to reduce the inflammation. Typically, the concentration will range from about 0.001 nanograms per milliliter and 10.00 milligrams and the dose will range from two to twelve drops per day, administered at intervals throughout the day. Ophthalmic pharmaceutical compositions comprising a pharmaceutically acceptable ophthalmic carrier and an ocular inflammation-treating amount of one or mote 4-aminoquinoline compounds are effective in preventing and treating ocular inflammation of any etiology. Said opthalmic pharmaceutical compositions are also effective in treating retinitis pigmentosa. Non-limiting examples include I) Ocular inflammation related to allergy, infection, pain in the eye, non-infectious inflammation triggered by immunological factors, surgery, chemical or mechanical injury, injury due to exposure to radiation, infrared or ultraviolet rays, degenerative changes or dystrophies; 2) Ocular inflammation related urticaria, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, uveitis, iritis, iridocyclitis, scleritis, episcleritis, choroiditis, optic neuritis, Mooren"s ulcer, ulcerative keratitis associated with rheumatoid arthritis, anterior uveitis, Thygeson"s punctate keratitis, or other immunological reactions; 3) Ocular inflammation related to an infection of the eye by any one or more infective agents such as bacteria, viruses including adenovirus and cytomegalovirus, fungi including toxoplasmosis, bacteria including tuberculosis and syphilis, chlamydia, and amoeba; 4) Ocular inflammation related to uveitis such as Behcet"s disease, pars planhis, idiopathic uveitis, ocular sarcoid, sympathetic ophthalmia, idiopathic vitritis, vitritis, or uveitis resulting from trauma; 5) Retinitis pigmentosa.6. Ocular inflammation that causes dry eye or ocular surface disorders. In any treatment regimen, a health care professional should assess the patient"s condition and determine whether or not the patient would benefit from 4-aminoquinoline treatment. Some routine dosage adjustments may be necessary to achieve an optimal dosage level and pattern. The compounds of this invention can be administered as the sole active agent or they can be administered in combination with other agents, including other active 4-aminoquinoline compounds. In one preferred embodiment of the invention, said ophthalmic pharmaceutical composition is administered as ophthalmic drops, ophthalmic salve, ophthalmic suspension, opthalnric ointment, ophthalmic spray, subconjunctival injection, or intravitreal injection or via a contact lens, ocular time release insert, liposomal composition, or sustained relase implant. In another embodiment, it is delivered in a conjunctival insert according the U.S. Patent No. 6,217,896 to Benjamin. In one of its method aspects, this invention is directed to a method for treating a mammal with ocular inflammation which method comprises administering to said mammal a pharmaceutical composition comprising a phannaceutically acceptable ophthalmic carrier and an ocular inflammation-treating amount of a 4-aminoquinoline compound of formula I as described above, and in U.S. Patent No. 4,421,920 to Baudoum, U.S. Patent No. 5,596,002, to Hofheinz, and U.S. Patent No. 5,948,791, to Hofheinz. In another of its method aspects, this invention is directed to a method for treating a mammal with inflammation which method comprises administering to said mammal a pharmaceutical composition comprising a phannaceutically acceptable ophthalmic carrier and an inflammation-treating amount of a compound selected from die group consisting of Amodlaquine, Chloroquine, and Hydroxychloroquine, and die derivatives, salts and isomers of Amodiaquinc, Chloroquine, and Hydnjxychloroqume. In another memod, ophthalmic pharmaceutical composition comprising a phannaceutically acceptable ophthalmic carrier and an ocular inflammation-treating an ocular inflammation-treating amount of cletoquine, quinacrine (mepacrine), pyrimethamine, or mefloquine is topically applied to the eye. In another preferred embodiment of the invention, said ophthalmic pharmaceutical composition is administered as ophthalmic drops in a dose of one to ten drops to the eye per day at intervals of one (1) to ten (10) times per day, one (1) drop on alternative days or one (1) drop per week. The concentration of the 4-ammoquinolme compound or a salt or isomer of a 4-aminoquinoline derivative in said ophthalmic pharmaceutical composition is preferably about 0.001 nanograms per milliliter and 10.00 milligrams per milliliter. Most preferably, the 4-aminoquinoline derivative is selected from the group consisting of Amodiaquine, Chloroquine, and HydroxycMoroquine, and the derivatives, salts and isomers of Amodiaquine, Chloroquine, and Hydroxychloroquine. Cletoquine, mefloquine, quinacrine (mepacrine), or pyrimethamine may also be used. The invention will be further illustrated by the following non-limiting examples: From the foregoing description, various modifications and changes in the compositions and methods of this invention will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein. Those skilled in the art will find"tt apparent that various modifications and variations can be made to the formulations of this invention. Thus, the present invention is intended to cover such modifications and variations, provided that they come within the scope of the appended claims and their equivalents. The disclosures of all publications cited above are expressly incorporated by reference in their entireties to the same extent as if each were incorporated by reference individually. I claim 1. An ophthalmic pharmaceutical composition comprising a pharmaceutical^ acceptable ophthalmic carrier and 0.001 nanograms per milliliter to 1.0 milligrams per milliliter of a 4-aminoquinoline compound of formula I: wherein A is (C(R3)(R4))„; or A is or (C5 C6)-cycloalkylene; n is 1 4; or A is an alkyl of 1 through 5 carbon atoms substituted by a dialkylamino group of which each alkyl radical contains 1 through 4 carbon atoms, phenyl, or phenyl substituted by one or more radicals selected from carboxy and hydroxy and alkyl radicals of 1 through 4 carbon atoms and R9 is hydrogen or halogen; and R10 is halogen or trifluoromethyl; and R.1 to R6 are hydrogen or in which one or two of R1 to R6 are independently selected from alkyl and the other substituents are hydrogen; R7 and R8 are independently selected from alkyl, alkenyl or aralkyl, or together with the N atom signify pyrrolidine or piperidine, either or both of which may be substituted by alkyl; and n=0 or 1; or wherein R1 and R3 are tri- or tetramethylene; R2 and R4 to R6 are hydrogen; n=0; and R7 and R8 are defined as above; or wherein R1 and R7 are methylene or dimethylene and n=l, or R3 and R7 are di- or trimethylene and n=0, or R3 and R7 are di- or trimethylene and n=l, or R and R are tri- or tetramethylene and n=0, or R5 and R7 are tri- or tetramethylene and n=l, or Ri and R5 are di- or tri-methylene and n=l, and the remaining substituents are hydrogen, except R8 which is selected from alkyl, alkenyl or alkynyl; or wherein R3 and R5 are tri- or tetramethylene and n=l; R1, R2, R4 and R6 are hydrogen; and R7 and R8 are selected from alkyl, alkenyl or aralkyl or together with the N atom are pyrrolidine or piperidine, either or both of which may be substituted by alkyl; R9 is hydrogen or halogen; and R10 is halogen or trifluoromethyl; R11 is a hydrogen atom or an alkyl radical (1-5 carbon atoms); or R7 is hydrogen and R8 is (CH2)P-B and p is 1 - 3; B is aryl selected from phenyl, phenyl mono-, di-, or tri-substituted by substituent from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, cyano, di-lower alkylamino or their N-oxides, phenyloxy, phenyl, and methylsuphanyl, naphthyl, benzo[l,3]dioxol, or monocyclic aromatic heterocycle with 1 or 2 heteroatoms selected from N and O; and R9 is hydrogen or halogen; and R10 is halogen or trifluoromethyl; and pharmaceutically acceptable salts of basic compounds of formula I. Dated this 13th day of December 2004 (Raut Rajeev) Applicant

Full Text

FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION (Section 10)
"A PROCESS FOR PREPARING PHARMACEUTICAL
COMPOSITIONS CONTAINING 4rAMlNOQUlNOLlNE
COMPOUNDS FOR TREATMENT OF INFLAMMATORY DISORDERS OF THE .EYE AND COMPOSITIONS RESULTING THEREFROM"
RAUT RAJEEV
27, Manisha,
2A Moledina road
Pune 411 001, Maharashtra State, India
An Indian National,
The following specification particularly describes the nature of this invention and the manner in which it is to be performed:

TITLE OF INVENTION A PROCESS FOR PREPARING PHARMACEUTICAL COMPOSITIONS CONTAINING 4-AMINOQUINQLlNES COMPOUNDS FOR TREATMENT OF INFLAMMATORY DISORDERS OF THE EYE, COMPOSITIONS RESULTING THEREFROM AND METHOD OF TREATING SUCH DISORDERS WITHTHESE COMPOSITIONS.
This application claims the benefit of U.S. Provisional Application No. 60/380926 fliea May 17,2002.
FIELD OF THE INVENTION
This invention is a process for preparing pharmaceutical compositions containing 4-aminoqunulines compounds for treatment of ocular inflammation of varied etiology such as immune disease factors, surgery* chemical or mechanical injury, injury due to exposure to radiation, infrared or ultra-violet rays, degenerative changes or dystrophies, allergic or infective etiology, compositions resulting from the said process and treatment of ocular inflammation with the said compositions. The said ocular inflammation may also present as dry eye or ocular surface disorder.
More particularly, this invention relates to ophthalmic pharmaceutical compositions comprising a 4-aminoquinolme compounds, used for the treatment of malaria and rheumatoid arthritis, and methods for treating ocular inflammation with said compositions. This invention relates to a method of administration of 4-aminoquinolines as ophthalmic pharmaceutical compositions that permits administration of 4-amwoquinolmes directly to the eye, through corneal conjunctival, subconjunctival and intravitreal routes for attaining sustained ocular levels of the active agent, without oral or parenteral administratioa Ocular administration avoids the severe side effects of systemicaUy administered 4-

aminoquinolones while attaining effective dosage levels in the eye. Chloroquine, a representative generic drug, faas never been used to treat the eye by die composition and method described herein.
BACKGROUND OF THE INVENTION
Inflammatory disorders of the eye have historically been recognized as complex and vision threatening. Although numerous pharmaceutical agents and compositions exist far its treatment, their site efforts proffle aitf effectiveness are less than desired The side effects may not be acceptable in a particular patient, or if prolonged use is required. The current invention provides a new and original method for treatmeot of CKtflarmtiaiimiatm
Inflammation of the eye may be localized to the eye* the eyes, or may be part of more generalized inflammatory process. Its etiology may be infection, aUergy,mmraiK>logical reactions, or as a respcrase to
other causes. The ocular inflammation causes pain, irritation, watering, threatens visual function of the eye and may also change optical properties of the eye. Inflammation may be seen as uveitis or keratoconjunctivitis. Inflammation may also be seen as *dry eye" or as ocular surface disorder.
Uveitis is an inflammation of the uvea, the middle layer of tissue behind the white of the eye. The cause of uveitis is poorly understood, but a variety of systemic diseases are associated with it. Uveitis has been treated by various classes of compounds including steroids and nonsteroidal amMnflatnmatoty agents such as dexamethasone, ftarometbokme, prednisolone, indomethacin, aspirin, flubiprofen and diclofenac. However, a number of uveitic cases are not responsive to or become refractory to these drugs. Kulkarni, P., 17(2) JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS 181-7 (2001). Serious side effects including cataract, glaucoma, delayed wound healing, and altered

prostaglandin production, Id, at 181, and corneal complications including ulceration, perforation, and corneal and scleral melts have been reported with the use of topical nonsteroidal anti-inflammatory drugs. Giridera, AC, Luchs, JI, Udell, IT, 108 OPHTHALMOLOGY 936-944 (2001). Steroids are known to cause increased ocular pressure, cataracts, superinfections, and reduced immunity to infectioa Olsen, EG & Davanger M, 62(6) ACTA OPHTALMOL 893-9 (1984).
A newer immunosuppressive, Tacrolimus, is used orally in uveitis, but may cause severe side effects similar to those seen with cyclosporin including renal dysfunction, and neurological disorders. Kiilkaroi, at 183. The use of Cyclosporin A is further limited by its low penetration into the eye. Van der Bijl, P, van Eyk, AD & Meyer, D 20(5) CCVPROGKAM RLESYMY DOCUMENTOR RAUIPCT I»AFT.DOCORNEA 505-8,505 (2001). Aldose reductase inhibitors have also been used, especially in diabetics. U.S. Patent No. 4,600,717, to York. Fibronectin has also been tried to improve healing, but the defect closure rate was unaltered in the treated group. Phan, TM 30(3) Invest Ophthamol Vis Sci 377-385,381 (1989).
Mast cell stabilizers such as topical Lodoxamide and Cromolyn Sodium have been used to treat vernal keratoconjunctivitis. Avunduk, AM, et al, 107 OPHTHALMOLOGY 1333-1337 (2000). Nedrocromil sodium has a safety profile similar to cromolyn sodium. Verin PJ, Dicker ID, Mortemousque B, 29(4) CuN EXP ALLERGY 529-36 (1999). Vernal keratoconjunctivits is often controlled with topical steroids, but the vision threatening side effects are worse than the underlying disease, which usually is self-limiting and resolves as the patient grows up. Verin, 28(S6) ALLERGY 44 - (1998)
Immunosuppressives such as topical Cyclosporin A have been used in the treatment of Mooren"s ulcer, vernal keratoconjunctivitis, ulcerative keratitis

associated with rheumatoid arthrttis, anterior uveitis, and Thygeson"s punctate keratitis. Kulkanri, P., 109 QMBHAIAKHJOGY 845-850 (2002). Recurrence may occur in some patients. Field, AJ, Gottsch, JD, 23(4) Ausr N ZEALAND J OnnHALMOLOGY 333-334 (1995). Cidofovir 1% has been used in acute adenoviral keratoconjunctivits but is limited by local toxicity including conjunctival injection chermosis and punctate epithelial keratitis during the course of treatment and subepithelial infiltrates. It may cause an atypical and uncomfortable erythema of the skin of the eyelids and pronounced conjunctival injection mat could be differentiated from adenoviral conjunctival inflammation alone. Hillenkamp, et al 109 OPOTHALMOLOGY 845-850,847 (2002).
Researchers have studied the use of human epidermal growth factor on postkeratoplasty re-eprthetiahsation without success, in spite of promising earlier animal data no benefit on epithelial healing. DeOaert MJ, et al, 81 BR J QpfflHALMOL 391-395 (1997).
Accordingly, a need exists tor novel ophthalmic pharmaceutical compositions which safely and effectively treat oxailar iinlainmation conditions.
It was disclosed tbat tte 4-aminoquinolines have strong anti-inflammatory
action and are useful for treatment of inflammatory diseases. Rynes, RI, 36 BR J
RHEUMATOL 799-805 (1997).
However, mere has been no report or study in ophthalmologic field. The anti¬inflammatory properties of the anti-malarial 4-amhu>qumolone pharmaceuticals are well known. They have not been used to treat inflammation of the eye because their systemic use in high doses has been associated with a rare, but serious, incidence of ocular toxicity including corneal deposits known as verticiUata, loss of foveal reflex, impairment of accommodatiori, maculopatby and retinopathy. These effects may be reversible or irreversible.

Retinopathy is the major and potentially most serious as it is irreversible. Jones, SK, 140(1) BRIT J DERMATOL 3-7, (1999). Ocular toxicity, however, is believed to occur only when doses exceed 6.5 mg/kg/day fix- a minimum of five 5) years. Cordes, MG, 2000 Southern J Optometry, Poster (2000). www.optcom3.com/sio/cordes htmThe dosageof cMoroqurae appears to be the most fundamentally important factor in determining the risk of development of retinopathy. In general, it appears that serious retinopathy m nearly all instances is caused by taking more than 250 mg of cbloroquine diphosphate or 200 mg of cbloroquine sulfate per day to a total amount greater than 100 gms. By not exceeding this daily dosage, it has been found possible for patients to take chloroquine for as long as nine years without developing clinically evident retinopathy. In most cases in which dosage slightly greater than 250 mg cbloroquine diphosphate per day has been administered, the onset of definite retinopathy has taken one to three years. According to Nyiander, most patients who have developed retinopathy have received nearly a total of 300 gms for three or more years. TOXBDOLOOY OF THE EYE, Vol. 1, 272 (Grant, M, ed, 2"* Edition).
This inventor has discovered that when used directly in the eye, the 4-aminoquinolone compounds are non-toxic and highly effective in a wide variety of ocular inflammatory disorders. The 4-arninoquinoline compounds used here in novel ophthalmic pharmaceutical compositions have been previously reported to be useful as therapeutics m the treatment of malaria and riieumatoid artliritis. See, for example, U.S. Pat Nos. 4,421,920 to Baudouin, 5,596,002, to Bfaffaeinz, 5,948,791, also to Hbfheinz.
It has now been found that certaio 4 ammoquiaeteB^ ^4-ammoq^iinoline compounds are useful for preventing and treating ocular inflammation by

application of the compositions to the eye prior to, during and after an inflammatory disorder, especially inflammation of the outer and middle coats of the eye, such as dry eye, conjunctivitis, scleritis, keratitis, and uveitis.
The first object of the invention is to provide a novel method by way of "process of composition", route and concentration for the delivery of 4-aminoquinolme drugs directly to the eye for improved effectiveness to treat inflammatory disorders of the eye.
Another object of the invention is to provide prolonged stable intraocular levels of 4- aminoquinolkes.
A mrtl^oi^oftbe invention is to provide Biirtamed intraocular levels of 4-^aminoquinolines without having to increase their plasma levels.
Yet another object of the invention is to provide an unproved long term administration method for delivering 4- aminoquinohnes to patients suffering from inflammatory disorders of the eye.
The objects of the invention are met and the problems and shortcomings associated with systemic administration are overcome by the in Compounds suitable for delivery using this method include ditoroquine, amodiaquine, an isomer or a salt thereof, and structurally similar compounds. As

used above, the term "salt thereof is meant to include any nontoxic pharmaceuticaUy suitable salt of a compound described above with the desired pharmacological properties in mammals. Preparation of such a salt is well-known to those skilled in pharmaceutical science.
This inventor has discovered that the 4-aminoquinoHne compounds are no«-toxic to tlw eye when administered directly to the eye. Ocular administration permits the compound to be administered in adequate ocular doses and to maintain intraocular levels of the compound for prolonged periods. The 4-anunoquinolone compounds, when used in ophthalmic pharmaceutical compositions, are effective in treating ocular inflammation of varied etiology such as immune disease actors, surgery, chemical or mechanical injury, injury due to exposure to radiation, infrared or ultraviolet rays, degenerative changes or dystrophies; urticaria, allergic conjunctivitis, vernal conjunctivitis, allergic responses in the eye, iritis, iridocyclitis, sclerals, episcleritis, choroiditis, optic neuritis, Mooren"s ulcer, ulcerative keratitis associated with rheumatoid arthritis, anterior uveitis, Thygeson"s punctate keratitis, or other inimunological reactions; chlamydia, amoeba, adenovirus, cytomegalovirus, toxoplasmosis, tuberculosis, or syphilis; uveitis due to Behcet"s disease, pars planitis, idiopathic uveitis, ocular sarcoid, sympathetic ophthalmia, idiopathic vHritis, vitritis, or uveitis resulting from trauma.
4-armnoquinolines and their derivatives which are particularly suitable for the method of the present invention and processes for preparing these compositions are disclosed in U.S. Patent No. 4,421,920 to Baudouin, U.S. Patent No. 5,596,002, to Hbfheinz, and U.S. Patent No. 5,948,791, to Hbfhemz. To the extent these applications and patents disclose 4-eminoquinoune compounds and their derivatives which are usefiil in the practice of the present invention, they are

incorporated herein by reference.
Detailed descriptions of the preferred embodiment are provided herein; however, it is to be understood that the present invention may be embodied in various forms. Therefore, specific details disclosed herein are not to be interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in virtually any appropriately detailed system, structure or manner.
As discussed above, the ophthalmic pharmaceutical compositions of this
invention contain one or more 4-anrinoquinoline compounds as the active components). Prior to describing this invention in further detail, the following terms will first be defined.
The term "lower-alky!" used in the present description denotes straight-chain or branched saturated hydrocarbon residues such as methyl, ethyl, n-propyl, isopropyl, n-butyL, isobutyl, s-butyl, t-butyl and the like. "Halogen" is chorine, bromine, fluorine or iodine. When A in formula I is an aliphatic hydrocarbon chain, branched chains, for example -CH(CH.sub.3)-CH.sub.2 -, -CH.sub.2 CH(CH.sub.3}- or -CH.sub.2 C(CH.sub.3).sub.2 -, are especially preferred
The term "cyctoalkylene" embraces preferably cydopentyl or cydohexyl.
The term "aryl" embraces conveniently phenyl or substituted phenyl, with the number of substituents preferably being 1-3 and the substhuents being selected from a group consisting of halogen, hydroxy, lower-alkyl, tower-alkoxy, CF.sub.3, cyano, di-lower-alkylamino or their N-oxides, phenyloxy, phenyl or methylsulphanyl.
Furthermore, the term "aryl" conveniently embraces naphthyl, benzo)l73!dioxol or mono- or bicyclic aromatic heterocydes with 1 or 2 betero

atoms, especially N and/or O, for example pyridyl, quinolyl or ftnyl. Rings such as phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, naphthalen-1-yl, naphthalen-2-yi, furan-2-yl, furan-3-yl or quinolin-4-yl are preferred.
Preferred compounds of general formula I are especially those in which R.sup.9 is chlorine, R.sup.10 is hydrogen, p is 1, A is -CH.sub.2 -C(CH.sub.3).sub.2 ~ and B is a benzene ring which is unsubstituted, mono-substituted or di-substhuted.
"Pharmaceutically acceptable salt" refers to phannaceutically acceptable salts which are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkyl-anunonium, and die like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, hydroiodide, tartrate, mesylate, acetate, maleate, bitartarate, lactate, phosphate, malate, maleate, fumarate, succinate, acetate, pahnoate, oxalate and the like. Among the conventional salts which can be utilized there are the base salt, for example, alkali metal salts such as sodium or potassium, alkaline earth metal salts such as sodium or potassium, alkaline earth metal salts such as calcium or magnesium, and ammonium or alkyl ammonium salts.
Thus, according to this invention, the process of the invention consists of mixing between O.Opl nanograms per ml. to l.OOmg. per ml. of 4-aminoquinolines compounds such as amodiaquine, chloroquine or its derivatives, its salts and isomers such as but not restricted to Hydroxychloroquine sulphate, Chloroquine phosphate with known phannaceutically acceptable carrier s for example, bat not restricted to sterile water and if desired, father mixing acids and bases to adjust the pH, tonicity imparting agents, antimicrobial preservatives,

other viscosity imparting agents, suitable absorption enhancers such as surfactants and stabilizing agents.
According to the present invention a process for preparing a novel pharmaceutical composition for external application in mflammatory disorder of eye as eye drops, eye ointments or directly subconjunctivally or directly intravitreally is described. This new process of preparation, treatment technique and delivery method unexpectedly results in a prolonged and sustained intraocular levels of the active drug in mammals using formulations that not necessarily increase drug plasma levels, and therefore avoid hazards associated with raised plasma levels and implications thereof, like drug toxicity.
Compounds suitable for delivery using this method include chloroquine, amodiaquine, an isomer or a sah thereof, and structurally similar compounds. As used above, the term "sah thereof5 is meant to include any nontoxic pbarmaceutically suitable salt of a compound described above with the desired pharmacological properties in mammals. Preparation of such a salt is well known to those skilled in pharmaceutical science. Phannaceutically acceptable salts of the above compounds include : hydrochloride, hydrobromide, hydroiodide, sulfite, bisulfite, nitrate, salicylate, citrate, tartarate, bitartarate, lactate, phosphate, malate, maleate, fiiymarate, succinate, acetate and pamoate, acid forms thereof.
A better and more complete understanding of the invention may be garnered from the detailed description of the preferred embodiment of the best mode of the invention as contemplated by the inventor.
Detailed descriptions of the preferred embodiment are provided herein; however, it is to be understood that the present invention may be embodied in various forms. Therefore, specific details disclosed herein are not to be

interpreted as limiting, but rather as a basis for the claims and as a representative basis for teaching one skilled in the art to employ the present invention in virtually any appropriately detailed system, structure or matter. The compositions disclosed herein is a preparation of the active ingredient, namely a 4-ammoquinoline, in a concentration between .001 nanogram per ml to 1 mg. Per ml in a phannaceutically acceptable carrier. The composition disclosed now will be applied directly to the eye 1 to 10 times a day. The active ingredients can be administered in the conjunctival sack as eye drops, ointments, gels, sustained release carriers, slow dissolving capsules placed in the conjunctival sack, via release from a contact lens.
The composition of this invention may be prepared to include:
1. acids and bases to adjust the pH;
2. tonicity imparting agents such as sorbitol, glycerin and dextrose;
3. antimicrobial preservatives, to inhibit microbial contamination, such as other parahydroxybenzoic acid esters (sorbate, benzoate, propionate), chlorobutanol, benzyl alcohol, benzalkonium chloride, and mercurials;
4. Other viscosity imparting agents such as sodium carboxymethylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, polyvinyl alcohol and other gums;
5. suitable absorption enhancers, such as surfactants, bile acids;
6. stabilizing agents such as antioxidants, like bisulfttes and ascorbates, metal chelating agents, such as sodium edetate; and drug solubility enhancers, such as polyethylene glycols. These additional ingredients help make commercial solutions with adequate stability so that they need not be compounded on demand. The other synonyms of chloroquine and related compounds, as per the invention include 7-

CUoro^(4HliethyiaoiiiK^l-methyllHitylaimno)quinoline Chingamin
Chmgarnin phosphate Chlorochin Chloroquin diphosphate
Chloroquina Chloroquine diphosphate Chloroquine hydrochloride
Chloroquine phosphate Chloroquine sulfate Chloroquine sulphate
Chloroquinum Cholarquine Cboroquin sulfate Quinagamin
Accordingly, in one of its composition aspects, this invention is directed to an
ophthalmic pharmaceutical composition comprising a pharmaceutically
acceptable ophtnalmic carrier and an ocular inflammation-treating amount ofa4-
aminoquinolinc compound of formula t
7
\ "wherein

and
R.sup. 1 to R.sup.6 are hydrogen or in which one or two of Rsup. 1 to R.sup.6 are
independently selected from alkyl and the other substituents are hydrogen;
R.sup.7 and R.sup.8 are independently selected from alkyl, alkenyl or aralkyl, or
together with the N atom signify pyrrolidine or piperidine, either or both of which
may be substituted by alkyl; and n=0 or 1; or
wherein R.sup. 1 and Rsup.3 are tri- or tetramethylene; R.sup.2 and R.sup.4 to
R.sup.6 are hydrogen; n=0, and R.sup.7 and R.sup.8 are defined as above; or
wherein R.sup.1 and R.sup.7 are methylene or dimethylene and n=l, or
R.sup.3 and R.sup.7 are di- or trimethylene and 0=0, or
R.sup.3 and R.sup.7 are di- or trimethylene and n=l, or
R.sup.3 and R.sup.7 are tri- or tetramethylene and n=0, or
R.sup.5 and R.sup.7 are tri- or tetramethylene and n-1, or
Rsup. 1 and R.sup.5 are di- or tri-methylene and n=l, and the
remaining substituents are hydrogen, except R.sup.8 which is selected from alkyl,
alkenyl or alkynyl; or
wherein R.sup.3 and R.sup.5 are tri-or tetramethylene and n=l; Rsup. 1, R.sup.2,
R.sup.4 and R.sup.6 are hydrogen; and R.sup.7 and R.sup.8 are selected from
alkyl, alkenyl or aralkyl or together with the N atom are pyrrolidine or piperidine,
either or both of which may be substituted by alkyl;
R.sup.9 is hydrogen or halogen; and Rsup. 10 is halogen or trifluoromemyl;
Rsup. 11 is a hydrogen atom or an alkyl radical (1-5 carbon atoms);
Tn another of its composition aspects, the 4-aniinoquinoline compound of
Formula 1. VS(M?JL* ^
A is or (C.sub.5 -C.sub.6)-cycloalkylene; n is 1-4;

n
or
Rsup.7 is hydrogen and R.sup.8 is (CH.sub.2)sub.p-B and p
10 is 1-3 and
B is aryl selected from phenyl, phenyl mono-, dt~, m tri-gubsthuted by substituent from the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl, cyano, di-lower alkylamino or their N-oxides, phenyloxy, phenyl, and methylsuphanyl, napbthyl, benzo>l,3!dioxol, or monocyclic aromatic heterocycle with 1 or 2 heteroatoms selected from N and O; and
R.sup.9 is hydrogen or halogen; and Rsup. 10 is halogen or trifluoromethyl; as well as pharmaceuticaUy acceptable salts of basic compounds of formula L
In the third of its composition aspects, the 4-aminoqurooline Of Formula I
isi wherein A is an alkyl of 1 through 5 carbon atoms substituted by a
diaikylamino group of which each alkyl radical contains 1 through 4 carbon atoms, phenyl, or phenyl substituted by one or more radicals selected from carboxy and hydroxy and alkyl radicals of 1 through 4 carbon atoms and R.sup.9 is hydrogen or halogen; and R.sup. 10 is halogen or trifluoromethyl.
Compounds of general formula I in which R.sup.9 is hydrogen, R.sup.10 is chlorine are preferred embodiments:

diamine,Compounds of general formula I in which R.sup.9 is hydrogen, R sup. 10
is chlorine, p is 1, A is cyclohexane-l,2-diyl or cyclohexane-l,4-diyl and B is a
benzene ring which is unsubstituted or mono- or di-substituted are also preferred:
(lS,2S>N.sub.l-(7-Chloro-quinolin-4-yl>N.sub.2 -{benzyl)-cyclohexane-l>
diamine,
(lS,2S}-N.sub.l -(7-chloro quinolm-4-yl)-N.sub.2 -(4-chloro-beazyl)-
cyclobexane-l,2-diamine,
(lS,2S)-N.sub.l-(7-cbloro-quinolm-4-yi)-N.sub.2 -
cyclo-hexane-I,2-dianiine,
cis-N.sub.l -(7-chloro-quinolk-4-yl)-N.sub.4 -(4-dimethylamino-ben2yi)-
cyclohexane-l,4rdiamine,
cis-N.sub.l -(7-chloro-qiitaohn-4-yl)-N.sub.4 -(ben2yl>cyclohearane-lJ4^iiamine,
cis-N.sub.l -{7-chloro-quinDUn-4-yl)-N.sub.4 -(3-chloro-benzyl)-cyclohexane-
l,4H3iamineJ
cis-N.sub.l -(7-chloro-quinolin-4-yl)-N.sub.4 -(2-hydroxy-4^nethoxy-benzyl)-
cyclohexane-l,4-diamine,
cis-N.sub.l -(7-chloro-quinolin-4-yl)-N.sub.4 -(3,5-dimetboxy~benzyl)-
cyclohexane-l,4-diamine,
cis-N.sub.l -(7-chloro-quhiolm-4-yl)-N.sub.4-(4-methylsulphanyl-b^
cyclohexane-l,4-diamine,
cis-N.sub.l -(7-chJoro-quinolin-4-yl)-N.sub.4 ^4-diethylamuio-benzyI)-
cyclohexane-1,4-diamine,
cis-N.sub.l -(7-chloro-quinolin-4-yl)-N.sub.4 -(biphenyl-4-ylmethyl)-
cyclohexane-l,4-diamine,
trans-N.sub.l -(7-chlorc-quinolin-4-yl)-N.sub.4 ->2-(3,5-dimethoxy-phenyl)-
ethyl!-cyclohexane-l,4-d%iiine,

ds-N.sub.l -(7-chloro-quinoIin-4-yl)-N.8ub.4 -(4-methoxy-benzyl)-cyclohexane-
1,4-diamine,
trans-N.sub.l-(-(choro-quiiK)lin-4-yl)-N.sub.4-(4-dimethylamiao-bcnzyl)-
cyclohexane-l,4-diamine and trans-N.sub.l -(7-dilon)-quinolin-4-yl)-N.sub.4 -
(2,6-difluoro-benzyl)-cyclohexane-l,4-diamine.
Most preferably, the 4-anunoquinoline compound in the ophthalmic pharmaceutical composition is: Chloroquine phosphate
Quinoline, 7-chloro-4-(4-(dlethylauimio)-l-methbutyl)amino)-, suliate, Qufnoline,4-(4-(bis(2-chloroe4hyl)aminol-methlbutyl)amino)-, suliate dihydrochloride N,N-Dideethylchloroquine,
Quinoline, 4-(2-s(2-chloroethyl)amino)«hylaraino)-7-chloro-, dihydrochloride, monohydrate, Quinoline, 7choro-4-(4-(diethylaniuM))-l-methylbutyl)amino)-, diphosphate, (-

Quinoline, 4-(p4Hs(2-choroethyl)amin0phenylethylamino)-7-chloro-,
monohydrochloride
Chloroquine
3-Methylchloroquine
Salicylic acid, 4-acetamido-, compd. with 7-chloro-4-(4-(dieutylamino)-l-
methyIbutyl)amino)quinoline,
Hydroxychloroquine
Quinoline, 7^oro-4-((4-(d1ethylammo)-l-memylbutyl)amino)-, mixed with
sodium nitrite
Hydroxychloroquine sulfate,

Quinoline, 7-(choro-4-(4-dietliylaniino)-l-methylbutyl)aniino)-J diphosphate,
Quinoline, 7-choro-(4-dietiylamino)-l-methylbutyl)aniino>-, phosphate,
Desethylchloroquine.
Chloroquine hydrochloride,
L-Ascorbic acid, compd. withN(sup 4)-(7-chloro-4-quinolinyl)-N(sup l),N(sup
l)-diethyl-l,4-pentanediamine,
N,N-Dideethylchloroquhie
Amodiaquine
In another embodiment, the 4-aminoquinoline compound in the ophthalmic pharmaceutical composition is mefloquine, quinacrine (mepacrine), pyrimethamine, and cletoquine.
General Synthetic Procedures
The 4-aminoquinoline compounds and their derivatives employed in this invention are either commercially available or can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (Le., reaction temperatures, times, mote ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protecting and deprotectmg various functional groups are well known in the art For example,

numerous protecting groups, and their introduction and removal, are described in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.
In a preferred method of synthesis, the novel compounds of formula I can be manufactured in accordance with the invention by reacting appropriate quinoline derivatives of the general formula with appropriate amino compounds or reacting alkylanunchquinoline derivatives with amines according to the process of Hofheinz, U.S. Patent No. 5,596,002.
Tn another preferred method of synthesis, the novel compounds of formula I can be manufactured by a) reducing an appropriate Schiff s base or b) reacting an appropriate amine with a compound of the formula X~(CH.sub.2).sub.p -BIV wherein X is a leaving group and the other substttuents have the significance described in the process taught by Hofheinz, U.S. Patent No. 5,948,791.
In yet another preferred method of synthesis the products of the general formula (I) can be obtained, with good yields and virtually free of dechlorinated product, by condensing an appropriate amine with a chloro-1,2,3,4-tetrahydroquinolin-4-one, the reaction being carried out in the presence of a ruthenium based catalyst on a support and preferably in the absence of oxygen, according to the method of Baudouin, U.S. Patent No. 4,421,920.
The following formulation examples illustrate representative pharmaceutical compositions suitable for ophthalmic delivery of the 4-aminoquinoline compounds used in this invention. The present invention, however, is not limited to the following exemplified pharmaceutical compositions.
Formulation
The ophthalmic pharmaceutical composition of the invention includes one

or more additional ophthalmic pharmaceutical compositions including buffers, surfactants, stabilizers, preservatives, ophthalmic wetting agents, ophthalmic diluting agents.
Wetting agents commonly used in ophthalmic solutions include carboxymethylcellulose, hydroxypropyl methylcellulose, glycerin, mannitol, polyvinyl alcohol or hydroxyethylcellulose and the diluting agent may be water, distilled water, sterile water, or artificial tears, wherein the wetting agent is present in an amount of about 0.001% to about 10%.
In another embodiment, the ophthalmic pharmaceutical composition further comprises one or more additional pharmaceutically active ophthalmic pharmaceutical compositions such as anti inflammatory agents, antibiotics, and fungals, anti virals, ocular hypotensive agents, local anaesthetic agents, cyclopiegics, or pupillary dilators used in the treatment of diseases of the eye.
Examples of ophthalmic solutions and opthalmic ointments can be formulated into such preparations utilizing a number of widely-used methods well known to those of ordinary skill in the art. In the case of ophthalmic solutions, for example, they can be prepared using distilled water, an aqueous base, or any other acceptable base; tonicity agents such as sodium chloride and concentrated glycerol; butters such as sodium phosphate and sodium acetate; surfactants such as poryoxyethylenc sorbhan monooleate, stearic polyoxyl 40, and polyoxyethylene hydrogenated castor oil; stabilizers such as sodium citrate and sodium edetate; preservatives such as benzalkonium chloride, thimerosal, chlorobutanol, sodium chloride, boric acid, parahydroxybenzoic acid esters (sorbate, benzoate, propionate), chlorobutanol, benzyl alcohol, mercurials, paraben; etc., and mixtures thereof if necessary. Benzalkonium chloride and thimerosal are the preferred preservatives.

The formulation of this invention may be varied to include acids and bases to adjust the pH; tonicity imparting agents such as sorbitol, glycerin and dextrose; other viscosity imparting agents such as sodium carboxymethylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, polyvinyl alcohol and other gums; suitable absorption enhancers, such as surfactants, bile acids; stabilizing agents such as antioxidants, like bisulfites and ascorbates; metal chelating agents, such as sodium edetate; and drug solubility enhancers, such as polyethylene glycols. These additional ingredients help make commercial solutions with adequate stability so that they need not be compounded on demand.
In a preferred embodiment, benzalkonium chloride is added as an antimicrobial preservative in an amount ranging from about 0.001 to about 0.02 weight percent, preferably 0.01 weight percent. In another preferred embodiment, thimerosal is added as an antimicrobial preservative in an amount ranging from about 0.005 to about 0.02 weight percent.
In another embodiment of the invention, the ophthalmic carrier is a surfactant such as » poryoxyethylene fatty acid ester, polyoxyethylcnc aflcylphenyl ether, and polyoxyethylene alkyl ether, or mixtures thereof or a thickening agent such as a carboxyvinyl polymer, polyvinyl polymer, and polyvinylpyrrolidones, as taught by U.S. Patent No. 5,951,971, to Kawashima.
In the ophthalmic pharmaceutical composition of this invention, the ophthalmic carrier is preferably a sterile aqueous carrier or a salve or ointment carrier. Such salves or ointments typically comprise one or more 4-aflnnoquinoline compounds dissolved or suspended in a sterile pharmaceuacally acceptable salve of ointment base, such as a mineral ou-whto petrolatum base. In salve or ointment compositions, anhydrous lanolin may also be included in the formulation. Thimerosal or chlorobutanol are also preferably added to such

ointment compositions as antimicrobial agents.
hi yet another embodiment of the invention, the ophthalmic carrier may be olive oil, arachis oil, castor oil, polyoxyethylated castor oil, mineral oil, petroleum jelly, dimethyl sulphoxide, an alcohol, liposome, silicone fluid and mixtures thereof as taught by U.S. Patent No. 6,254,860, to Garst.
Preferably, the active ingredient, namely a 4 aminoquinoline, is found in a concentration between .001nanogram per millilitre to 10 rag per milijlitre, in a pharmaceuticajly acceptable carrier.
The ophthalmic 4-aminoquinoline compositions may be incorporated into liposomes. The use of liposomes as drug delivery systems has been known for some tune, and comprehensive review articles on their properties and clinical applications are available; see, e.g., Barenholz and Amselem, in "Liposome Technology", 2nd ed., G. Gregoriadis, ed., CRC press, 1992; Lichtenberg and Barenholz, in Methods for Biochemical Analysis, 33, D. Ghck, ed., 1988. A liposome is defined as a structure consisting of one or more concentric lipid bilayers separated by water or aqueous buffer compartments. These hollow structures, which have an internal aqueous compartment, can be prepared with diameters ranging from 20 ran to 10 .mu.m. U.S. Patent No. 5,576,016, to Amselem. The compositions may be incorporated in nanoemulsions of particles comprising a lipid core composed of lipid which is in a solid or liquid crystalline phase at at least 25degree. C, stabilized by at least one phospholipid envelope, for the parenteral, oral, rectal, intranasal, or topical delivery of both fat-soluble and water-soluble drugs according to the method of U.S. Patent No. 5,576,016, to Amselem.
The dose can be appropriately selected depending upon symptom, age, dosage form, etc. and, in the ophthalmic solutions, contain between about 0.001

nanograms per milliliter and 10.00 milligrams per milliliter of a 4-aminoquinoline derivative., preferably between 0.001 nanograms per milliliter and 1.00 milligram per milliliter and most preferably about .3 milligrams per milliliter of a 4-anujooquinoline derivative or a salt or isomer of a 4-aminoquinoline derivative in a pharmaccutically acceptable ophthalmic carrier. The pH can be within a range which is acceptable to ophthalmic preparations and, preferably within a range from4to8.
Any of the disclosed 4-aminoquinoline derivatives may be incorporated into chitosan nanoparticles to improve the delivery of the 4-aminoquinoline derivatives to the ocular mucosa, as described by Dc Campos, Am, Sanchez, A and Atonso MJ 224 (1-2) Jm J PHARM 159-68,161 (2001). In one example, the solution is prepared by adding a variable volume of a 4-anrinoquinolone compound solution in an acetonhrile/water mixture is incorporated into to Chitosan SeaCure 123, purchased from Pronova Biopolymer AS of Norway (4 mg, 0.2 or 0.5% w/v). Nano particles are formed upon the addition of Sodium tripolyphosphate aqueous solution (0.5 ml, 0.2%w/v) under magnetic stirring at room temperature, purified by centrifugation at 900 x g in a glucose bed for 30 minues. Supernatants are discarded and nanoparticles are resuspended in pure water.
Other materials as well as processing techniques and the like are set forth in Part 8 of Remington"s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa., and International Programme on Chemical Safety (IPCS), and ideological information may be found at bitp://www.inchem.oig/documents/pims/pharm/chlorogu,htm, both of which are incorporated herein by reference.
Mixtures of two or more 4-aminoquinoline compounds may be employed,

if desired, in the pharmaceutical compositions and methods of this invention.
Examples
Representative examples for preparing ophthalmic solutions and ophthalmic ointment of 4-aminoquinolone compounds are shown as follows.
The drops may be combined with other anti inflammatory agents , and biotics, anti fiingals, anti virals, ocular hypotensive agents. The drops may be combined with topical ophthalmic steroids, antimetabolites.
The drops may be combined with artificial tears and ocular lubricants. The drops may be combined with buffers, surface tension lowering agents, local anaesthetic agents, cycloplegics, pupillary dilators, eyedrop formulations used in treatment of eye diseases. The generally used range of pH can be used for this preparation, but a preferable range is 4-8. Depending on the salt of chloroquine used, the Ph of the solution may be adjusted by using hydrochloric acid or sodium hydroxide, between 4 and 8. Chloroquine phosphate and chloroquine sulphate, for example, are sensitive to light, and may be dispensed in opaque bottles.
Example 1. A 4-anunoquinoline compound, such as Chloroquine phosphate equivalent to chloroquine 30mg.
Sodium chloride 0.9 gms, Benzalkonium chloride S mg, are mixed to dissolve in purified sterile water. Purified sterile water is then added to produce a total volume of 100 mL.
Example 2 A 4-aminoquinoline compound, such as Chloroquine phosphate equivalent to chloroquine 100 mg, Sodium chloride 0.9 gms, Benzalkonium chloride 5 mg, are mixed to dissolve in purified sterile water. Purified sterile water is then added to produce a total volume of 100 mL.

Example 3 A 4-aminoquinoline compound, such as Chloroquine phosphate equivalent to chloroquine 1 mg,
Sodium chloride 0.9 gms, Benzalkonium chloride 5 mg are mixed to dissolve in purified sterile water. Purified sterile water is then added to produce a total volume of 100 mL.
Example 4 - Ophthalmic Ointment
A 4-minoquinoline compound such as Chloroquine phosphate is admixed with mineral oil and white petrolatum to form an ointment containing 0.05 weight percent active 4-armnoquinoline compound.
It will be appreciated that any of the 4-aminoquinoline compounds described herein could be employed in any of these representative formulations taking into account solubility, dispersability and the like, and that any of these formulations could be administered in any of the above described manners so as to treat ocular inflammation-Method of Drag Delivery
Any of the 4-aminoquinoline compounds (including salts thereof) employed in this invention may be formulated into ophthalmic pharmaceutical compositions suitable for topical administration.
The active ingredients can be administered in the conjunctival Back as eye drops, ointments, gels, sustained release carriers, slow dissolving capsules placed in the conjunctival sack, via release from a contact lens, subconjunctivally by injection, or intravftreally by injection, by preparing a suitable formulation of the active ingredient and utilizing procedures well known to those skilled in the art. Preferably, the formulations are prepared with suitable nontoxic phannaceutically acceptable ingredients. These ingredients are known to those skilled in the

preparation of eyedrops, ointments, subconjunctival and intravitreal injections. Some of these ingredients can be found in Remington"s Pharmaceutical Sciences, 17th edition, 1985, a standard reference in the field. The choice of suitable carriers is highly dependent upon the exact nature of the eyedrops, eyeointments, subconjunctival, intravitreal dosage form desired, e.g. solutions, sprays, drops, gels, pastes, patches.
The 4-aininoquinoline derivatives may be administered via a biocompatible and implantable controUed-release drug delivery device as taught in U.S. Patent No. 6,331,313, to Wong. The 4-amuKxjuinoline compounds employed in tins invention can also be administered in sustained release forms or from sustained release drug delrvery systems which can be found in Remington"s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pa., and International Programme on Chemical Safety (IPCS).
In one of the more preferred embodiments, the ophthalmic carrier is a conjunctival insert. Preparation of said inserts is taught by U.S. Patent No. 6,217,896 to Benjamin and other methods are well known in the art
Method of Treating Ocular Inflammation
One object of the invention is to provide a method for treating ocular inflammation comprising topically applying to the eye an ophthalmic pharmaceutical composition comprising a phannaceuticaUy acceptable ophthalmic carrier and an ocular inflammation-treating amount of one or more 4-aminoquinoline compounds, or one of their pharmaceutically acceptable analogues or sabs.
The inventor has discovered unexpectedly that by administering a 4-ammoquinoline compound topically directly into the eye, the much feared ocular toxicity is avoided rather than enhanced.

Any of the formulations and methods of drug delivery disclosed in this invention may be used to treat ocular inflammation by direct application of a 4-aminoquinoline compound to the eye.
The conditions treated with the ophthalmic pharmaceutical compositions of this invention generally include ocular inflammation and the various symptoms which fall within the ocular inflammation definition. These include, for example, uveitis. The 4-amhioquinoline formulations provided by this invention can be administered to achieve an inflammation reducing effect in the eye. To achieve tins effect, a topical preparation is administered directly to the inflamed eye by instilling adequate topical solution or salve or ointment to the inflamed eye to reduce the inflammation. Typically, the concentration will range from about 0.001 nanograms per milliliter and 10.00 milligrams and the dose will range from two to twelve drops per day, administered at intervals throughout the day.
Ophthalmic pharmaceutical compositions comprising a pharmaceutically acceptable ophthalmic carrier and an ocular inflammation-treating amount of one or mote 4-aminoquinoline compounds are effective in preventing and treating ocular inflammation of any etiology. Said opthalmic pharmaceutical compositions are also effective in treating retinitis pigmentosa.
Non-limiting examples include I) Ocular inflammation related to allergy, infection, pain in the eye, non-infectious inflammation triggered by immunological factors, surgery, chemical or mechanical injury, injury due to exposure to radiation, infrared or ultraviolet rays, degenerative changes or dystrophies; 2) Ocular inflammation related urticaria, allergic conjunctivitis, vernal conjunctivitis, inflammation of the eye, allergic responses in the eye, uveitis, iritis, iridocyclitis, scleritis, episcleritis, choroiditis, optic neuritis, Mooren"s ulcer, ulcerative keratitis associated with rheumatoid arthritis, anterior

uveitis, Thygeson"s punctate keratitis, or other immunological reactions; 3) Ocular inflammation related to an infection of the eye by any one or more infective agents such as bacteria, viruses including adenovirus and cytomegalovirus, fungi including toxoplasmosis, bacteria including tuberculosis and syphilis, chlamydia, and amoeba; 4) Ocular inflammation related to uveitis such as Behcet"s disease, pars planhis, idiopathic uveitis, ocular sarcoid, sympathetic ophthalmia, idiopathic vitritis, vitritis, or uveitis resulting from trauma; 5) Retinitis pigmentosa.6. Ocular inflammation that causes dry eye or ocular surface disorders.
In any treatment regimen, a health care professional should assess the patient"s condition and determine whether or not the patient would benefit from 4-aminoquinoline treatment. Some routine dosage adjustments may be necessary to achieve an optimal dosage level and pattern.
The compounds of this invention can be administered as the sole active agent or they can be administered in combination with other agents, including other active 4-aminoquinoline compounds.
In one preferred embodiment of the invention, said ophthalmic pharmaceutical composition is administered as ophthalmic drops, ophthalmic salve, ophthalmic suspension, opthalnric ointment, ophthalmic spray, subconjunctival injection, or intravitreal injection or via a contact lens, ocular time release insert, liposomal composition, or sustained relase implant. In another embodiment, it is delivered in a conjunctival insert according the U.S. Patent No. 6,217,896 to Benjamin.
In one of its method aspects, this invention is directed to a method for treating a mammal with ocular inflammation which method comprises administering to said mammal a pharmaceutical composition comprising a

phannaceutically acceptable ophthalmic carrier and an ocular inflammation-treating amount of a 4-aminoquinoline compound of formula I as described above, and in U.S. Patent No. 4,421,920 to Baudoum, U.S. Patent No. 5,596,002, to Hofheinz, and U.S. Patent No. 5,948,791, to Hofheinz.
In another of its method aspects, this invention is directed to a method for treating a mammal with inflammation which method comprises administering to said mammal a pharmaceutical composition comprising a phannaceutically acceptable ophthalmic carrier and an inflammation-treating amount of a compound selected from die group consisting of Amodlaquine, Chloroquine, and Hydroxychloroquine, and die derivatives, salts and isomers of Amodiaquinc, Chloroquine, and Hydnjxychloroqume. In another memod, ophthalmic pharmaceutical composition comprising a phannaceutically acceptable ophthalmic carrier and an ocular inflammation-treating an ocular inflammation-treating amount of cletoquine, quinacrine (mepacrine), pyrimethamine, or mefloquine is topically applied to the eye.
In another preferred embodiment of the invention, said ophthalmic pharmaceutical composition is administered as ophthalmic drops in a dose of one to ten drops to the eye per day at intervals of one (1) to ten (10) times per day, one (1) drop on alternative days or one (1) drop per week.
The concentration of the 4-ammoquinolme compound or a salt or isomer of a 4-aminoquinoline derivative in said ophthalmic pharmaceutical composition is preferably about 0.001 nanograms per milliliter and 10.00 milligrams per milliliter.
Most preferably, the 4-aminoquinoline derivative is selected from the group consisting of Amodiaquine, Chloroquine, and HydroxycMoroquine, and the derivatives, salts and isomers of Amodiaquine, Chloroquine, and

Hydroxychloroquine. Cletoquine, mefloquine, quinacrine (mepacrine), or pyrimethamine may also be used.
The invention will be further illustrated by the following non-limiting examples:
From the foregoing description, various modifications and changes in the compositions and methods of this invention will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein. Those skilled in the art will find"tt apparent that various modifications and variations can be made to the formulations of this invention. Thus, the present invention is intended to cover such modifications and variations, provided that they come within the scope of the appended claims and their equivalents.
The disclosures of all publications cited above are expressly incorporated by reference in their entireties to the same extent as if each were incorporated by reference individually.

I claim
1. An ophthalmic pharmaceutical composition comprising a pharmaceutical^ acceptable ophthalmic carrier and 0.001 nanograms per milliliter to 1.0 milligrams per milliliter of a 4-aminoquinoline compound of formula I:

wherein A is

(C(R3)(R4))„;
or A is
or (C5 C6)-cycloalkylene; n is 1 4;
or A is an alkyl of 1 through 5 carbon atoms substituted by a dialkylamino group of which each alkyl radical contains 1 through 4 carbon atoms, phenyl, or phenyl substituted by one or more radicals selected from carboxy and hydroxy and alkyl radicals of 1 through 4 carbon atoms and R9 is hydrogen or halogen; and R10 is halogen or trifluoromethyl; and

R.1 to R6 are hydrogen or in which one or two of R1 to R6 are independently selected from
alkyl and the other substituents are hydrogen; R7 and R8 are independently selected from
alkyl, alkenyl or aralkyl, or together with the N atom signify pyrrolidine or piperidine,
either or both of which may be substituted by alkyl; and n=0 or 1; or
wherein R1 and R3 are tri- or tetramethylene; R2 and R4 to R6 are hydrogen; n=0; and R7
and R8 are defined as above; or
wherein R1 and R7 are methylene or dimethylene and n=l, or
R3 and R7 are di- or trimethylene and n=0, or
R3 and R7 are di- or trimethylene and n=l, or
R and R are tri- or tetramethylene and n=0, or
R5 and R7 are tri- or tetramethylene and n=l, or
Ri and R5 are di- or tri-methylene and n=l, and the remaining substituents are hydrogen,
except R8 which is selected from alkyl, alkenyl or alkynyl; or
wherein R3 and R5 are tri- or tetramethylene and n=l; R1, R2, R4 and R6 are hydrogen; and
R7 and R8 are selected from alkyl, alkenyl or aralkyl or together with the N atom are
pyrrolidine or piperidine, either or both of which may be substituted by alkyl;
R9 is hydrogen or halogen; and R10 is halogen or trifluoromethyl;
R11 is a hydrogen atom or an alkyl radical (1-5 carbon atoms); or
R7 is hydrogen and R8 is (CH2)P-B and p is 1 - 3;
B is aryl selected from phenyl, phenyl mono-, di-, or tri-substituted by substituent from
the group consisting of halogen, hydroxy, lower alkyl, lower alkoxy, trifluoromethyl,
cyano, di-lower alkylamino or their N-oxides, phenyloxy, phenyl, and methylsuphanyl,
naphthyl, benzo[l,3]dioxol, or monocyclic aromatic heterocycle with 1 or 2 heteroatoms
selected from N and O; and
R9 is hydrogen or halogen; and R10 is halogen or trifluoromethyl; and
pharmaceutically acceptable salts of basic compounds of formula I.
Dated this 13th day of December 2004
(Raut Rajeev) Applicant

Documents:

716-mumnp-2004-cancelled pages(14-9-2007).pdf

716-mumnp-2004-claims(granted)-(14-9-2007).doc

716-mumnp-2004-claims(granted)-(14-9-2007).pdf

716-mumnp-2004-correspondence(14-9-2007).pdf

716-mumnp-2004-correspondence(ipo)-(25-9-2007).pdf

716-mumnp-2004-form 19(13-12-2004).pdf

716-mumnp-2004-form 1a(13-12-2004).pdf

716-mumnp-2004-form 2(granted)-(14-9-2007).doc

716-mumnp-2004-form 2(granted)-(14-9-2007).pdf

716-mumnp-2004-form 3(13-12-2004).pdf

716-mumnp-2004-form-pct-ipea-409(21-9-2006).pdf

716-mumnp-2004-form-pct-isa-210(21-9-2006).pdf

« Previous Patent

Next Patent »

Patent Number

213682

Indian Patent Application Number

716/MUMNP/2004

PG Journal Number

12/2008

Publication Date

21-Mar-2008

Grant Date

10-Jan-2008

Date of Filing

13-Dec-2004

Name of Patentee

RAUT RAJEEV

Applicant Address

27, MANISHA, 2A MOLEDINA ROAD, PUNE 411 001

Inventors:

#	Inventor's Name	Inventor's Address
1	RAUT RAJEEV	27, MANISHA, 2A MOLEDINA ROAD, PUNE 411 001

PCT International Classification Number

A61K31/00

PCT International Application Number

PCT/IN03/00189

PCT International Filing date

2003-05-14

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/380,926	2002-05-17	U.S.A.