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Definitions

• the invention relates to the solid-state crystalline acids of lipoxin A 4 analogs, their use in treating a disease-state characterized by inflammation, and pharmaceutical compositions containing the crystalline acids of the analogs and processes for their preparation.
• Lipoxins together with leukotrienes, prostaglandins, and thromboxanes, constitute a group of biologically active oxygenated fatty acids collectively referred to as the eicosanoids.
• Eicosanoids are all synthesized de novo from membrane phospholipid via the arachidonic acid cascade of enzymes. Since their initial discovery in 1984, it has become apparent that lipoxins, which are a structurally unique class of eicosanoids, possess potent anti-inflammatory properties that suggest they may have therapeutic potential (Serhan, C. N., Prostaglandins (1997), Vol. 53, pp. 107-137; O'Meara, Y.M. et al., Kidney Int.
• Lipoxins are thus potent anti-neutrophil agents which inhibit polymorphoneutrophil (PMN) chemotaxis, homotypic aggregation, adhesion, migration across endothelial and epithelial cells, margination/diapedesis and tissue infiltration (Lee, T. H., et al., Clin. Sci. (1989), Vol. 77, pp. 195-203; Fiore, S., et al., Biochemistry (1995), Vol. 34, pp. 16678-16686; Papyianni, A., et al., J. Immunol. (1996), Vol. 56, pp.
• PMN polymorphoneutrophil
• lipoxins are able to down-regulate endothelial P- selectin expression and adhesiveness for PMNs (Papyianni, A., ef al., J. Immunol. (1996), Vol. 56, pp. 2264-2272), bronchial and vascular smooth muscle contraction, mesangial cell contraction and adhesiveness (Dahle ⁇ , S.
• lipoxins particularly lipoxin A 4
• lipoxin A 4 This unique anti-inflammatory profile of lipoxins, particularly lipoxin A 4 , has prompted interest in exploiting their potential as therapeutics for the treatment of inflammatory or autoimmune disorders and pulmonary and respiratory tract inflammation.
• disorders and inflammations that exhibit a pronounced inflammatory infiltrate are of particular interest and include, but are not limited to, inflammatory bowel diseases such as Crohn's disease, dermatologic diseases (such as psoriasis), rheumatoid arthritis, and respiratory disorders (such as asthma).
• inflammatory bowel diseases such as Crohn's disease
• dermatologic diseases such as psoriasis
• rheumatoid arthritis and respiratory disorders (such as asthma).
• respiratory disorders such as asthma
• Naturally-occurring lipoxins are unstable products that are rapidly metabolized and inactivated (Serhan, CN. , Prostaglandins (1997), Vol. 53, pp. 107-137).
• Lipoxin A 4 analogs of interest to the invention are disclosed in U.S. Patent No. 6,831,186 and in U.S. Patent Application Publication No. 2004/0162433.
• a solid pharmaceutical substance is crystalline, rather than amorphous.
• a purification of the crystalline product is obtained.
• a crystalline solid state form can be very well characterized and usually shows a higher stability in comparison to an amorphous phase.
• a potential recrystallisation of the amorphous phase including the change of the characteristics of the drug substance or drug product, is avoided. Accordingly, there exists a need for a stable crystalline solid-state form of the lipoxin A 4 analogs disclosed in U.S. Patent No. 6,831 ,186 and in U.S. Patent Application Publication No. 2004/0162433.
• This invention is directed to a potent, selective and metabolically/chemically stable crystalline acid of a lipoxin A 4 analog and its use in treating disease-states characterized by inflammation, such as inflammatory or autoimmune disorders and pulmonary or respiratory tract inflammation in mammals, particularly in humans.
• this invention is directed to a crystalline free acid of a lipoxin A 4 analog of Formula (II):
• R 1 is -O-, -S(O) t ⁇ (where t is 0, 1 or 2), or a straight or branched alkylene chain; and R 2 is aryl (optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy); and wherein the compound of Formula (II) is a single stereoisomer or any mixture of stereoisomers.
• the present invention encompasses all of the crystalline forms of the free acid of
• this invention is directed to a method of preparing the crystalline form of the acid of Formula (II), the method comprising i) mixing an alkali hydroxide, in a suitable solvent, together with an ester corresponding to the acid of Formula (II), in a suitable solvent; ii) adjusting the pH of the resulting mixture to pH 3-4; iii) after crystals begin to form, further adjusting the pH of the mixture to pH 1-3; iv) isolating the resulting crystals from the resulting suspension; and v) drying the isolated crystals, to give the crystalline acid.
• this invention is directed to pharmaceutical compositions comprising a therapeutically effective amount of a crystalline acid of Formula (II), as set forth above, and a pharmaceutically acceptable excipient or mixture of excipients.
• this invention is directed to the use of a crystalline acid of Formula (II), as described above, for the manufacture of a medicament for treating a mammal having a disease-state characterized by inflammation, such as for example an inflammatory or autoimmune disorder or a pulmonary or respiratory tract inflammation.
• this invention is directed to methods of treating a disease-state in a mammal, such as a human, characterized by inflammation, wherein the method comprises administering to the mammal in need thereof a therapeutically effective amount of a crystalline acid of Formula (II) as described above.
• the disease-state may be, for example, an inflammatory or autoimmune disorder or a pulmonary or respiratory tract inflammation.
• Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1 ,1-dimethylethyl (f-butyl), and the like.
• Alkylene chain refers to a straight or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen, containing no unsaturation and having from one to eight carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like.
• Alkoxy refers to a radical of the formula -OR 3 where R 3 is an alkyl radical as defined above.
• Aryl refers to a phenyl or naphthyl radical. Unless stated otherwise, the aryl radical may be optionally substituted by one or more substituents selected from the group consisting of alkyl, alkoy, halo, haloalkyl or haloalkoxy. Unless stated otherwise specifically in the specification, it is understood that such substitution can occur on any carbon of the aryl radical.
• “Aralkyl” refers to a radical of the formula -R 3 Rb where R 3 is an alkyl radical as defined above and R b is an aryl radical as defined above, e.g., benzyl and the like. The aryl radical may be optionally substituted as described above.
• Halo refers to bromo, chloro, iodo or fluoro.
• Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 -fluoromethyl-2-fluoroethyl (1 ,3-difluoroisopropyl), 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl (1 ,3-dibromoisopropyl), and the like.
• Haloalkoxy refers to a radical of the formula -OR C where R 0 is an haloalkyl radical as defined above, e.g., trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy, 1-bromomethyl-2-bromoethoxy, and the like.
• “Clathrates” as used herein refers to substances which fix gases, liquids or compounds as inclusion complexes so that the complex may be handled in solid form and the included constituent (or "guest” molecule) is subsequently released by the action of a solvent or by melting.
• the term “clathrate” is used interchangeably herein with the phrase “inclusion molecule” or with the phrase “inclusion complex”.
• Clathrates used in the instant invention are prepared from cyclodextrins. Cyclodextrins are widely known as having the ability to form clathrates ⁇ i.e., inclusion compounds) with a variety of molecules. See, for example, Inclusion Compounds, edited by J. L. Atwood, J. E. D. Davies, and D. D.
• Cyclodextrin refers to cyclic oligosaccharides consisting of at least six glucopyranose units which are joined together by ⁇ (1-4) linkages.
• the oligosaccharide ring forms a torus with the primary hydroxyl groups of the glucose residues lying on the narrow end of the torus.
• the secondary glucopyranose hydroxyl groups are located on the wider end.
• Cyclodextrins have been shown to form inclusion complexes with hydrophobic molecules in aqueous solutions by binding the molecules into their cavities.
• Such complexes protects the "guest" molecule from loss of evaporation, from attack by oxygen, visible and ultraviolet light and from intra- and intermolecular reactions.
• Such complexes also serve to "fix" a volatile material until the complex encounters a warm moist environment, at which point the complex will dissolve and dissociate into the guest molecule and the cyclodextrin.
• the six-glucose unit containing cyclodextrin is specified as ⁇ -cyclodextrin, while the cyclodextrins with seven and eight glucose residues are designated as ⁇ -cyclodextrin and v- cyclodextrin, respectively.
• the most common alternative to the cyclodextrin nomenclature is the naming of these compounds as cycloamyloses.
• compounds which are "commercially available” may be obtained from standard chemical supply houses and other commercial sources including, but not limited to, Acros Organics (Pittsburgh PA), Aldrich Chemical (Milwaukee Wl, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.),Chemservice Inc. (West Chester PA), Crescent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), Fisher Scientific Co.
• “Mammal” includes humans and domesticated animals, such as cats, dogs, swine, cattle, sheep, goats, horses, rabbits, and the like.
• Optional or “optionally” or “may be” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
• optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
• Polymorphs refers to polymorphic forms of the acids of the invention. Solids exist in either amorphous or crystalline forms. In the case of crystalline forms, molecules are systematically positioned in 3-dimensional lattice sites. When a compound crystallizes from a solution or slurry, it may crystallize with different spatial lattice arrangements, a property referred to as "polymorphism,” with the different crystal forms individually being referred to as a "polymorph”. Different polymorphic forms of a given substance may differ from each other with respect to one or more physical properties, such as solubility and dissolution, true density, crystal shape, compaction behavior, flow properties, and/or solid state stability.
• thermodynamically stable forms In the case of a chemical substance that exists in two (or more) polymorphic forms, the unstable forms generally convert to the more thermodynamically stable forms at a given temperature after a sufficient period of time. When this transformation is not rapid, the thermodynamically unstable form is referred to as the "metastable" form. However, the metastable form may exhibit sufficient chemical and physical stability under normal storage conditions to permit its use in a commercial form. In this case, the metastable form, although less stable, may exhibit properties desirable over those of the stable form, such as enhanced solubility or better oral bioavailability.
• “Solvate” refers to an aggregate that comprises one or more molecules of a compound of the invention with one or more molecules of solvent or a non stoichiometric content of a solvent.
• the solvent may be water, in which case the solvate is called a hydrate.
• the solvent may be an organic solvent.
• the acids of lipoxin A 4 analogs of Formula (II) may exist as a hydrate, including a monohydrate, dihydrate, hemihydrate, sesquihydrate, trihydrate, tetrahydrate, the dehydrated hydrates with their non-stoichiometric water content, and the like, as well as the corresponding solvated forms.
• the acids of Formula (II) may be true solvates, while in other cases the salts may merely retain adventitious water or be a mixture of water plus some adventitious solvent. Additionally, the acids of Formula (II) may exist in a crystalline anhydrous form.
• suitable conditions for carrying out a synthetic step are explicitly provided herein or may be discerned by reference to publications directed to methods used in synthetic organic chemistry.
• Suitable solvent refers to any solvent that is compatible with the components of the reaction and the reaction conditions.
• the term encompasses one solvent or a mixture of solvents and includes, but is not limited to organic solvents and water. Suitable solvents are known to those of skill in the art or may be discerned by reference to publications directed to methods used in synthetic organic chemistry.
• Therapeutically effective amount refers to that amount of a acid of the invention which, when administered to a mammal, particularly a human, in need thereof, is sufficient to effect treatment, as defined below, for a disease-state characterized by inflammation.
• the amount of a acid of the invention which constitutes a "therapeutically effective amount” will vary depending on the salt, its solvated form, the disease-state to be treated and its severity, the age of the mammal to be treated, and the like, but can be determined routinely by one of ordinary skill in the art.
• Treating covers the treatment of a disease-state characterized by inflammation in a mammal, preferably a human, such as for example an inflammatory or autoimmune disorder or a pulmonary or respiratory tract inflammation, and includes:
• the acids of Formula (II) may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or as (D)- or (L)-.
• the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
• Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as HPLC using a chiral column.
• the compounds described herein contain olefinic double bonds or other centres of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
• stereoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
• the present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
• R 1 is -O-, -S(O)r (where t is O 1 1 or 2) or a straight or branched alkylene chain;
• R 2 is aryl (optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy) or aralkyl (optionally substituted by one or more substituents selected from alkyl, alkoxy, halo, haloalkyl and haloalkoxy); and wherein the compound of Formula (II) is a single stereoisomer or any mixtures of stereoisomers.
• the invention is directed to a crystalline acid of Formula (II) where R 1 is -O- and R 2 is phenyl optionally substituted by one or more substituents selected from fluoro, chloro and iodo.
• the compound of the invention is a crystalline acid of Formula (II) where R 1 is -O- and R 2 is 4-fluorophenyl.
• the compound is selected from the group consisting of the following: 2-((2S,3f?,4E,6E, 10E, 12S)-13-(4-fluorophenoxy)-2,3, 12-trihydroxytrideca-4,6, 10-trien-8- ynyloxy)acetic acid;
• the invention is directed to crystalline 2-((2S,3/?,4E,6E,10E,12S)- 13-(4-fluorophenoxy)-2,3, 12-trihydroxytrideca-4,6, 10-trien-8-ynyloxy)acetic acid:
• the methods of preparing the crystalline forms of 2-((2S,3R4E,6E,10E,12S)-13-(4- fluorophenoxy ⁇ .S. ⁇ -trihydroxytrideca ⁇ . ⁇ .iO-trien- ⁇ -ynyloxyJacetic acid also may be used to prepare crystalline acids of other compounds of Formula (II).
• the method of preparing the crystalline 2-((2S,3fl,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12- trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetic acid is based on the saponification of an ester having the following Formula (III):
• the ester of Formula (III) is dissolved in a suitable solvent, such as methanol, ethanol or tetrahydrofuran (THF), for example.
• a suitable solvent such as methanol, ethanol or tetrahydrofuran (THF)
• an alkali hydroxide base such as sodium hydroxide or potassium hydroxide for example
• a suitable solvent such as methanol, ethanol or water, for example, or mixtures of these solvents.
• the solution of the alkali hydroxide is added to the solution of the ester or vice versa. Additional water is added, if necessary, in an amount sufficient to effect suitable crystallization of the product upon acidification.
• the X-ray tube with copper anode was operated by 40 kV and 30 mA.
• the 2 ⁇ scans were performed using the small linear position sensitive detector with an angular resolution of 0 08° between 3° ⁇ 2 ⁇ ⁇ 35° and 2° ⁇ 2 ⁇ ⁇ 35° (stepwidth 0 5°) or 7° ⁇ 2 ⁇ ⁇ 35° (stepwidth 0.5°) if the wellplate was used
• the samples were enclosed between two polyacetate films held together by double-sided adhesive tape or between two aluminum foils to avoid the influence of the humidity during measurement.
• an X-ray diffraction pattern may be obtained with a measurement error that is dependent upon the measurement conditions employed.
• intensities in an X-ray diffraction pattern may fluctuate depending upon crystal habitus of the material and measurement conditions employed It is further understood that relative intensities may also vary depending upon experimental conditions and, accordingly, the exact order of intensity should not be taken into account
• a measurement error of diffraction angle Theta for a conventional X-ray diffraction pattern at a given temperature is typically about ⁇ 0.1 , and such degree of measurement error should be taken into account as pertaining to the aforementioned diffraction angles.
• the term "about" when used herein in reference to X-ray powder diffraction patterns means that the crystal forms of the instant invention are not limited to the crystal forms that provide X-ray diffraction patterns completely identical to the X-ray diffraction patterns depicted in the accompanying Figure disclosed herein. Any crystal form that provides X-ray diffraction patterns that is substantially identical to those disclosed in the accompanying FIGURES falls within the scope of the present invention.
• the ability to ascertain whether the polymorphic forms of a compound are the same albeit the X-ray diffraction patterns are not completely identical is within the purview of one of ordinary skill in the art.
• Polymorph I of the free acid is transformed above 60% relative humidity into the hydrate. It is hygroscopic and adsorbs at 80% relative humidity approx. 8% moisture, which corresponds to a dihydrate of the substance. The hydration is reversible. Below 40% relative humidity a transformation into polymorph I is observed. The sorption isotherm is given in
• the crystalline acids of Formula (II) have biological activity similar to that of natural lipoxin A 4 , but with an enhanced resistance to chemical and metabolic degradation. Accordingly, the crystalline acids of Formula (II) are useful in treating inflammatory or autoimmune disorders in mammals, such as, e.g., in humans.
• a crystalline acid of Formula (II) is useful in inhibiting acute or chronic inflammation or an inflammatory or autoimmune response that is mediated by neutrophils, eosinophils, T lymphocytes, NK cells or other immune cells that contribute to the pathogenesis of inflammatory, immune or autoimmune diseases.
• the crystalline acids of Formula (II) are also useful in the treatment of proliferative disorders including, but not limited to, those associated with derangements in the inflammatory or immune response, such as cancer.
• the crystalline acids of Formula (II) are also useful as an inhibitor of angiogenic responses in the pathogenesis of cancer.
• a crystalline acid of Formula (II) can be used to treat the following inflammatory or autoimmune disorders in mammals, particularly in humans: anaphylactic reactions, allergic reactions, allergic contact dermatitis, allergic rhinitis, chemical and non- specific irritant contact dermatitis, urticaria, atopic dermatitis, psoriasis, fistulas associated with Crohn's disease, pouchitis, septic or endotoxic shock, hemorrhagic shock, shock-like syndromes, capillary leak syndromes induced by immunotherapy of cancer, acute respiratory distress syndrome, traumatic shock, immune- and pathogen-induced pneumonias, immune complex-mediated pulmonary injury and chronic obstructive pulmonary disease, inflammatory bowel diseases (including ulcerative colitis, Crohn's disease and post-surgical trauma), gastrointestinal ulcers, diseases associated with ischemia-reperfusion injury (including acute myocardial ischemia and infarction, acute renal failure, ischemic bowel disease and acute hemorrhagic
• the crystalline acids of Formula (II) are also useful in treating folliculitis induced by inhibitors of epidermal growth factor (EGF) or epidermal growth factor receptor (EGFR) kinase used in the treatment of solid tumors.
• EGF epidermal growth factor
• EGFR epidermal growth factor receptor
• Clinical trials have revealed folliculitis (inflammation of the hair follicle manifested by severe acne-like skin rash on the face, chest and upper back) as a major dose-limiting side effect of such treatments.
• folliculitis is associated with an infiltration of neutrophils, suggesting products secreted by activated neutrophils to be the cause of the inflammation.
• the crystalline acids of Formula (II) inhibit neutrophil- or eosinophil- mediated inflammation, and are therefore useful in treating such folliculitis, thereby improving the quality of life of the treated cancer patients but also allowing for the increase of the dosage of the EGF inhibitor or EGFR kinase inhibitor or the extension of the duration of the treatment, resulting in improved efficacy of the desired inhibitor.
• the crystalline acids of Formula (II) are also useful in the treatment of pulmonary and respiratory inflammation, including, but not limited to, asthma, chronic bronchitis, bronchiolitis, bronchiolitis obliterans (including such with organizing pneumonia), allergic inflammation of the respiratory tract (including rhinitis and sinusitis), eosinophilic granuloma, pneumonias, pulmonary fibroses, pulmonary manifestations of connective tissue diseases, acute or chronic lung injury, chronic obstructive pulmonary diseases, adult respiratory distress syndrome, and other non-infectious inflammatory disorders of the lung characterized by eosinophil infiltration.
• pulmonary and respiratory inflammation including, but not limited to, asthma, chronic bronchitis, bronchiolitis, bronchiolitis obliterans (including such with organizing pneumonia), allergic inflammation of the respiratory tract (including rhinitis and sinusitis), eosinophilic granuloma, pneumonias, pulmonary fibroses, pulmonary manifestations of connective tissue
• a crystalline acid of Formula (II) is useful in the inhibition of: eosinophil-mediated inflammation of the lung or tissues; neutrophil-mediated inflammation of the lung; lymphocyte- mediated inflammation of the lung; cytokine and chemokine production, including interleukin-5, interleukin-13 and eotaxin; lipid mediator generation, including prostaglandin E 2 and cysteinyl leukotrienes; airway hyper-responsiveness; and airway and vascular inflammation.
• a hallmark of inflammation is the adhesion and transmigration across endothelium of neutrophils, eosinophils and other inflammatory cells.
• a similar process is observed for the migration of cells across polarized epithelial cells that occur in the lung, gastrointestinal tract and other organs.
• Cell culture models of these processes are available and have been used to show that lipoxin A 4 and stable lipoxin A 4 analogs inhibit the transmigration of human neutrophils across human endothelial cells and epithelial cells, including the human intestinal epithelial cell line T 84 .
• one of ordinary skill in the art can test a crystalline acid of Formula (II) for its ability to inhibit the transmigration of human neutrophils and eosinophils across human endothelial cells and epithelial cells by performing assays similar to those described in Colgan, S. P., et al., J. Clin. Invest. (1993), Vol. 92, No. 1 , pp. 75-82; and Serhan, C.N., et al., Biochemistry (1995), Vol. 34, No. 44, pp. 14609-14615.
• the air pouch model and/or the mouse zymosan-induced peritonitis model may be used to evaluate the in vivo efficacy of a crystalline acid of Formula (II) in treating an inflammatory response.
• These are acute experimental models of inflammation characterized by infiltration of inflammatory cells into a localized area. See, e.g., the in vivo assays described in Ajuebor, M. N., et al., Immunology (1998), Vol. 95, pp. 625-630; Gronert, K., et al., Am. J. Pathol. (2001), Vol. 158, pp. 3-9; Pouliot, M., et al., Biochemistry (2000), Vol. 39. pp.
• Animal models may also be utilized to determine the efficacy of the crystalline acids of Formula (II) in treating asthma and related disorders of the pulmonary and respiratory tract. See, e.g., the assays described in De Sanctis, GT. et al., Journal of Clinical Investigation (1999), Vol. 103, pp. 507-515; and Campbell, E.M., et al., J. Immunol. (1998), Vol.161 , No. 12, pp. 7047-7053.
• a crystalline acid of Formula (II) may be tested for its efficacy in the claimed methods of use by employing the assays described in U.S. Patent No. 6,831 ,186 and in U.S. Patent Application Publication No. 2004/0162433, the pertinent disclosures of which are incorporated in full in their entireties herein.
• a crystalline acid of Formula (II), as a single stereoisomer or any mixture of stereoisomers, or as a cyclodextrin clathrate thereof, or as a solvate or polymorph, in pure form or in an appropriate pharmaceutical composition can be earned out via any of the accepted modes of administration or agents for serving similar utilities.
• administration can be, for example, orally, nasally, parenterally, pulmonary, topically, transdermal ⁇ , or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, aerosols, patches, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.
• the compositions will include a crystalline acid of the invention as the/an active agent and a conventional pharmaceutical carrier or excipient and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc., as are generally known in the art.
• composition to be administered will, in any event, contain a therapeutically effective amount of a crystalline acid of Formula (II) for treatment of a disease-state characterized by inflammation in accordance with the teachings of this invention.
• the pharmaceutically acceptable compositions will contain about 0.1 % to about 99.9% by weight of a crystalline acid of Formula (II) and about 99.9% to about 0.1% by weight of a suitable pharmaceutical excipient.
• the preferred route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated.
• a pharmaceutically acceptable composition containing a crystalline acid of Formula (II) is formed by the incorporation of one or more of the normally employed pharmaceutically acceptable excipient(s).
• Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
• compositions will take the form of a capsule, caplet or tablet and therefore will also generally contain a diluent, a disintegrant, a lubricant, and a binder.
• a crystalline acid of Formula (II) may also be formulated into a suppository comprising the active ingredient disposed in a earner that slowly dissolves within the body, such as those normally employed in this capacity.
• Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., a acid of the invention and optional pharmaceutically acceptable adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
• a carrier such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.
• a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like.
• a crystalline acid of Formula (II) is administered in a therapeutically effective amount, which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the crystalline acid of Formula (II); the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disease-state(s) to be treated; and the host undergoing therapy.
• Example 1 Preparation of the anhydrous form of crystalline 2-((2S,3R,4E,6E,10E,12S)-13- (4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy) acetic acid
• 4,6,10-trien-8-yn-1-yl]oxy ⁇ acetate is dissolved in a toluene/methanol mixture and filtered over a plug of silica gel using mixtures of hexane and tert-butyl methyl ether as eluent. Fractions are collected and concentrated in vacuum.
• Example 2 Preparation of the hydrate form of the crystalline 2-((2S,3R,4E,6E,10E,12S)-13- (4-fluorophenoxy)-2,3, 12-trihydroxytrideca-4,6, 10-trien-8-ynyloxy) acetic acid
• the anhydrous crystalline free acid (15 mg) was dissolved in 0.1 mL hot acetonitrile.
• the solution was concentrated by slow evaporation of the solvent at room temperature.
• Example 4 Preparation of the hydrate form of the crystalline 2-((2S,3R,4E,6E,10E,12S)-13- (4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy) acetic acid

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