US 20080188539A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0188539 A1 Harrison et al. (43) Pub. Date: Aug. 7, 2008

54) RAMPRL-AMNO ACID SALTS 3O Foreigngn AppApplication PrioritVty Data

(75) Inventors: Paul Jonathan Harrison, Dublin Dec. 1. 2006 (GB) ------O624084.O (IE); Anna Marie Elizabeth Power, Dublin (IE): Deirdre Publication Classification O'Keeffe, London (GB) (51) Int. Cl. A63L/403 (2006.01) Correspondence Address: C07D 209/02 (2006.01) WILSON SONSIN GOODRCH & ROSAT A6IP3/10 (2006.01) 650 PAGE MILL ROAD A6IP 9/00 (2006.01) PALO ALTO, CA 94304-1050 (US) A6IPI3/2 (2006.01) (52) U.S. Cl...... 514/412: 548/452 (73) Assignee: Selamine Limited, Dublin (IE) (57) ABSTRACT (21) Appl. No.: 11/948,057 The present invention relates to ramipril-amino acid salts, Such as, naturally occurring, basic amino acid salts of rami (22) Filed: Nov.30, 2007 pril.

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RAMPRL-AMNO ACID SALTS 0010. In yet another embodiment, the invention relates to methods for treating or preventing a Condition, comprising FIELD OF THE INVENTION administering to a subject in need thereofatherapeutically or prophylactically effective amount of a ramipril-amino acid 0001. The present invention relates to ramipril-amino acid salt. salts, such as, naturally occurring, basic amino acid salts of 0011. In still yet another embodiment, the invention ramipril. relates to methods for reducing the incidence of recurrence or severity of a symptom of a Condition, comprising adminis INCORPORATION BY REFERENCE tering to a subject in need thereof a therapeutically or pro 0002 Each of the references cited is hereby expressly phylactically effective amount of a ramipril-amino acid salt. incorporated herein by reference. BRIEF DESCRIPTION OF THE DRAWINGS BACKGROUND OF THE INVENTION 0012 FIG. 1 is an X-Ray Powder diffractogram of a rami 0003 Ramipril, the United States Adopted Name (USAN) pril-(L)-arginine salt. for (2S,3aS,6aS)-1 (S)- N—(S)-1-carboxy-3-phenylpro pylalanyloctahydrocyclopentablpyrrole-2-carboxylic 0013 FIG. 2 is an FTIR spectrum of a ramipril-(L)-argi acid, 1-ethyl ester (CAS Number 087333-19-5) is an angio nine salt. tensin converting enzyme (ACE) inhibitor having the chemi I0014 FIG. 3 is a 'H-NMR spectrum of ramipril-(L)-argi cal structure shown below (I). nine salt in d-DMSO. (0015 FIG. 4 is a TGA and DSC scan of a ramipril-(L)- arginine salt. (I) O Ho–4 DETAILED DESCRIPTION N-19 O H 0016. According to the invention there is provided amino acid salts of ramipril. In one embodiment, the amino acid is a naturally occurring, basic amino acid. In another embodi N H ment, the amino acid is an L-amino acid. In still another O H embodiment, the amino acid is a D-amino acid. In certain C 1, embodiments, the ramipril-amino acid salt is a ramipril lysine salt, a ramipril-arginine salt or a ramipril-histidine salt. 0004 Ramipril has been used for the treatment of hyper 0017. In other embodiments, the ramipril-amino acid salt tension, heart failure, stroke, myocardial infarction, diabetes is not a ramipril-arginine salt or a ramipril-lysine salt. and cardiovascular disease. It is commercially available at 0018. In one embodiment, the ramipril-amino acid salt is 1.25 mg, 2.5 mg, 5 mg, 10 mg and 15 mg strengths. substantially free of ramipril (free acid) or amino acid that is 0005 Degradation of pharmaceutically active compounds not associated with ramipril (conjugate base). In this context, is of concern to both medical practitioners and to the com the term “substantially free” means that the ramipril-amino munity at large. If significant degradation takes place acid salt comprises no more than 5% by weight of ramipril between manufacture and administration of an active then (free acid) or amino acid that is not associated with ramipril Suboptimal dosing is highly likely. For actives used in the (conjugate base); in another embodiment, no more than 2% treatment of hypertension and cardiovascular disease dosing by weight of ramipril (free acid) or amino acid that is not accuracy is of tantamount importance as ineffective treatment associated with ramipril (conjugate base); in still another is likely to result in life-threatening complications. embodiment, no more than 1% by weight of ramipril (free 0006. It would be useful to provide a form of ramipril, that acid) or amino acid that is not associated with ramipril (con provides benefits over current formulations of ramipril, for jugate base); in yet another embodiment no more than 0.5% example, a form of ramipril that avoids significant degrada by weight of ramipril (free acid) or amino acid that is not tion to inactive impurities. associated with ramipril (conjugate base); in still yet another 0007 An object of the present invention is to provide a embodiment no more than 0.1% by weight of ramipril (free form of ramipril, that avoids significant degradation to inac acid) or amino acid that is not associated with ramipril (con tive impurities. jugate base). In another embodiment, the ramipril-amino acid salt is substantially free of ramipril (free acid) and amino acid SUMMARY OF THE INVENTION that is not associated with ramipril (conjugate base). In this context, the term “substantially free” means that the ramipril 0008. The present invention relates to ramipril-amino acid amino acid salt comprises no more than 5% by weight of salts. A ramipril-amino acid salt is useful for the treatment or ramipril (free acid) and amino acid that is not associated with prevention of a cardiovascular disorder, renal failure, an ramipril (conjugate base); in another embodiment, no more ischemic condition, diabetes mellitus or a diabetic complica than 2% by weight of ramipril (free acid) and amino acid that tion, or stroke (each being a “Condition') is not associated with ramipril (conjugate base); in still 0009. In another embodiment, the present invention another embodiment, no more than 1% by weight of ramipril relates to compositions comprising a therapeutically or pro (free acid) and amino acid that is not associated with ramipril phylactically effective amount of a ramipril-amino acid salt (conjugate base); in yet another embodiment no more than and a pharmaceutically acceptable carrier. The compositions 0.5% by weight of ramipril (free acid) and amino acid that is are useful for treating or preventing a Condition. not associated with ramipril (conjugate base); in still yet US 2008/O 188539 A1 Aug. 7, 2008

another embodiment no more than 0.11% by weight of rami embodiments to about 5° C. to. The precipitate is filtered pril (free acid) and amino acid that is not associated with (optionally under vacuum), washed, and dried (either air ramipril (conjugate base). dried, oven dried at ambient pressure or oven dried under 0019. A ramipril-amino acid salt of is believed to offer the reduced pressure). potential for alternatives to existing ramipril formulations and 0029. In certain aspects of the invention the ramipril potential benefits include, but are not limited to improved amino acid salt is provided in non-crystalline form, taking the solubility, dissolution and/or hygroscopicity. Physical and/or form e.g. of a solid or oil. As an oil, a ramipril-amino acid salt chemical stability may be improved, and a ramipril-amino can be adsorbed onto or admixed with a pharmaceutically acid salt may have improved flowability and/or improved acceptable carrier for use in a pharmaceutical composition. In compressibility—relevant in tablet manufacture. further aspects of the invention, a ramipril-amino acid salt is provided in crystalline form. DEFINITIONS 0030 Treatment or Prevention of a Condition 0020. In order that the invention may be more readily 0031. In accordance with the invention, a ramipril-amino understood, certain terms are first defined and collected here acid salt is useful for the treatment or prevention of a Condi for convenience. Other definitions appear in context through tion as set forth below. out the application. 0032 Treatment or Prevention of a Cardiovascular Disor 0021. A “therapeutically effective amount of a ramipril der amino acid salt is an amount that is effective to treat a Con 0033. A ramipril-amino acid salt is useful for treating or dition. preventing a cardiovascular disorder. Examples of cardiovas 0022 A“prophylactically effective amount of a ramipril cular disorder include, but are not limited to, hypertension, amino acid salt is an amount that is effective to prevent a congestive heart failure (such as chronic or acute heart fail Condition. ure), atherosclerosis, hypercholesterolemia, circulatory 0023 The term “subject” refers to an animal such as a shock, cardiomyopathy, cardiac transplant, myocardial inf mammal, including, but not limited to, a primate (e.g., a arction, and a cardiac arrhythmia, Such as atrial fibrillation, human), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, Supraventricular tachycardia, atrial flutter, and paroxysmal a rat, a mouse and the like. In certain embodiments, the atrial tachycardia. Subject is a human. 0034. In one embodiment, the cardiovascular disorder is 0024. It is also to be understood that the terminology used chronic heart failure. herein is for purposes of describing particular embodiments 0035. In another embodiment, the cardiovascular disorder only, and is not intended to be limiting. As used in the speci is acute heart failure. fication and the appended claims, the singular forms 'a', 0036. In yet another embodiment, the cardiovascular dis “an', and “the include plural referents unless the context order is cardiac arrhythmia. In still another embodiment, the clearly indicates otherwise. cardiac arrhythmia is atrial fibrillation, supraventricular 0025 Synthesis OF Ramipril–Amino Acid Salt tachycardia, atrial flutter or paroxysmal atrial tachycardia. 0026. To provide ramipril-amino acid salts of the inven 0037. In one embodiment, the cardiovascular disorder is tion, ramipril (free acid) and a solvent are mixed, optionally chronic heart failure, atrial fibrillation, supraventricular with heating, until all solids have been Suspended or dis tachycardia, atrial flutter or paroxysmal atrial tachycardia. solved. Ramipril (free acid) is commercially available or can 0038 Treatment or Prevention of an Ischemic Condition be prepared by the methods described in U.S. Pat. No. 4,587. 0039. A ramipril-amino acid salt is useful for treating or 258; 5,061,772 or 6.407.262. Solvents which may be utilized preventing an ischemic condition. Examples of ischemic con include, but are not limited to, toluene; alcohols such as ditions include, but are not limited to, stable angina, unstable methanol, ethanol, propan-2-ol and propanol; esters such as angina, myocardial ischemia, hepatic ischemia, mesenteric ethyl acetate, ketones Such as acetone and butanone; haloge artery ischemia, ischemic heart disease, intestinal ischemia, nated hydrocarbons such as dichloromethane; and ethers such critical limb ischemia, chronic critical limb ischemia, cere as tetrahydrofuran (THF) and diethyl ether. The suspension or bral ischemia, acute cardiac ischemia, and an ischemic dis solution is generally heated with stirring from about 30°C. to ease of the central nervous system, such as stroke or cerebral about 75° C. (depending on the solvent employed) for ischemia. approximately 1-60 minutes; in Some embodiments from 0040. In one embodiment, the ischemic condition is myo 15-45 minutes; in other embodiments from 25-35 minutes. cardial ischemia, stable angina, unstable angina, stroke, 0027. After this time the suspension, if any, is heated again ischemic heart disease or cerebral ischemia. to about 30° C. to about 90° C. (depending on the solvent 0041 Treatment or Prevention of Renal Failure employed) until all solids dissolve. After about 5 minutes, an 0042 A ramipril-amino acid salt is useful for treating or amino acid is added (from about 1.0 equivalents to about 5.0 preventing renal failure. equivalents; in Some embodiments from about 1.0 equiva 0043. In one embodiment, the renal failure is chronic renal lents to about 2.5 equivalents; in still other embodiments from failure. In another embodiment, the renal failure is acute renal about 1.0 equivalents to about 1.5 equivalents; in some other failure. embodiments from about 0.5 equivalents to about 1.0 equiva 0044 Treatment or Prevention of Diabetes Mellitus or a lents; and in still other embodiments from about 0.75 equiva Diabetic Complication lents to about 1.0 equivalents) was added, optionally in a 0045. A ramipril-amino acid salt is useful for treating or solvent which may be the same as or different than the initial preventing diabetes mellitus or one or more of its complica Solvent employed in the Suspension or solution. tions. Examples of diabetes mellitus include, but are not 0028. After formation of a precipitate, the mixture is gen limited to, Type I diabetes (Insulin Dependent Diabetes Mel erally cooled to about 25°C.; in some embodiments to about litus), Type II diabetes (Non-Insulin Dependent Diabetes 15°C.; instill other embodiments to about 10°C.; and in other Mellitus), gestational diabetes, autoimmune diabetes, insuli US 2008/O 188539 A1 Aug. 7, 2008

nopathies, diabetes due to pancreatic disease, diabetes asso temic or local. Various delivery systems are known, e.g., ciated with other endocrine diseases (such as Cushing's Syn encapsulation in liposomes, microparticles, microcapsules drome, acromegaly, pheochromocytoma, glucagonoma, and capsules. primary aldosteronism or somatostatinoma). Type A insulin 0055 Methods of administration include, but are not lim resistance syndrome, Type B insulin resistance syndrome, ited to, intradermal, intramuscular, intraperitoneal, intrave lipatrophic diabetes, and diabetes induced by beta-cell tox nous, Subcutaneous, intranasal, epidural, oral, Sublingual, ins. A ramipril-amino acid salt is also useful for treating or intracerebral, intravaginal, transdermal, rectal, by inhalation, preventing a complication of diabetes mellitus. Examples of or topical, specifically to the ears, nose, eyes, or skin. In some complications of diabetes mellitus include, but are not limited instances, administration will result in the release of a rami to, diabetic cataract, glaucoma, retinopathy, nephropathy pril-amino acid salt into the bloodstream. (such as microalbuminuria or progressive diabetic nephropa 0056. In one embodiment, a ramipril-amino acid salt is thy), polyneuropathy, gangrene of the feet, immune-complex administered orally. In other embodiments, it can be desirable to administer a ramipril-amino acid salt locally. This can be vasculitis, systemic lupus erythematosus (SLE), atheroscle achieved, for example, and not by way of limitation, by local rotic coronary arterial disease, peripheral arterial disease, infusion during Surgery, topical application, e.g., in conjunc nonketotic hyperglycemic-hyperoSmolar coma, mononeuro tion with a wound dressing after Surgery, by injection, by pathies, autonomic neuropathy, foot ulcers, joint problems, means of a catheter, by means of a Suppository or enema, or and a skin or mucous membrane complication (such as an by means of an implant, said implant being of a porous, infection, a shin spot, a candidal infection or necrobiosis non-porous, or gelatinous material, including membranes, lipoidica diabeticorumobesity), hyperlipidemia, hyperten Such as Sialastic membranes, or fibers. Sion, syndrome of insulin resistance, coronary artery disease, 0057. In certain embodiments, it can be desirable to intro retinopathy, neuropathy (Such as diabetic neuropathy, poly duce a ramipril-amino acid salt into the central nervous sys neuropathy or mononeuropathy), autonomic neuropathy, a tem or gastrointestinal tract by any Suitable route, including foot ulcer, a joint problem, a fungal infection, cardiomyopa intraventricular, intrathecal, and epidural injection, and thy, and a bacterial infection. In one embodiment diabetes enema. Intraventricular injection can be facilitated by an mellitus is Type I diabetes mellitus or Type II diabetes mel intraventricular catheter, for example, attached to a reservoir, litus. Such as an Ommaya reservoir. 0046 Reduction of Incidence of Recurrence or Severity of 0.058 Pulmonary administration can also be employed, Symptoms Associated with a Condition e.g., by use of an inhaler of nebulizer, and formulation with an 0047 Aramipril-amino acid salt is useful for the reduction aerosolizing agent, or via perfusion in a fluorocarbon oar, of the incidence of recurrence or the severity of symptoms synthetic pulmonary Surfactant. In certain embodiments, a associated with a Condition. ramipril-amino acid salt can be formulated as a Suppository, 0048. In certain embodiments, a ramipril-amino acid salt with traditional binders and excipients such as triglycerides. is useful for the reduction of the incidence of recurrence of 0059. In another embodiment a ramipril-amino acid salt heart attack. can be delivered in a vesicle, specifically a liposome (see 0049. In certain embodiments, a ramipril-amino acid salt Langer, Science 249:1527-1533 (1990) and Treat or prevent is useful for the reduction of the incidence of recurrence of etal, Liposomes in Therapy of Infectious Disease and Cancer hypertension. In other embodiments, a ramipril-amino acid 317-327 and 353–365 (1989)). salt is useful for the reduction of the severity of symptoms 0060. In yet another embodiment, a ramipril-amino acid associated with hypertension. salt can be delivered in a controlled-release system or Sus 0050. In certain embodiments, a ramipril-amino acid salt tained-release system (see, e.g., Goodson, in Medical Appli is useful for the reduction of the incidence of recurrence of cations of Controlled Release, supra, vol. 2, pp. 115-138 stroke. In still other embodiments, a ramipril-amino acid salt (1984)). Other controlled or sustained-release systems dis is useful for the reduction of cognitive impairment associated cussed in the review by Langer, Science 249: 1527-1533 with stroke. (1990) can be used. In one embodiment a pump can be used (Langer, Science 249: 1527-1533 (1990); Sefton, CRC Crit. 0051 Formulation and Administration Ref. Biomed. Eng. 14:201 (1987); Buchwald et al. Surgery 0052. Due to their activity, a ramipril-amino acid salt is 88:507 (1980); and Saudek et al., N. Engl. J. Med. 321:574 advantageously useful in Veterinary or human medicine. As (1989)). In another embodiment polymeric materials can be described above, a ramipril-amino acid salt is useful for treat used (see Medical Applications of Controlled Release ing or preventing a Condition in a Subject in need thereof. (Langer and Wise eds., 1974); Controlled Drug Bioavailabil 0053 Aramipril-amino acid salt can be administered in an ity, Drug Product Design and Performance (Smolen and Ball amount that is effective to treat or prevent a Condition in a eds., 1984); Ranger and Peppas, J. Macromol. Sd. Rev. Mac subject in need thereof. romol. Chem. 2:61 (1983); Levy et al. Science 228:190 0054 When administered to a subject, a ramipril-amino (1935): During et al. Ann. Neural. 25:351 (1989); and acid salt can be administered as a component of a composition Howard et al., J. Neurosurg. 71:105 (1989)). that comprises a pharmaceutically acceptable carrier. The 0061 Dosage Regimen present compositions, which comprise a ramipril-amino acid 0062 Suitable dosages and formulations of a ramipril salt, can be administered orally. A ramipril-amino acid salt amino acid salt can be empirically determined those of skill in can also be administered by any other convenient route, for the art. Standard texts, such as Remington: The Science and example, by infusion or bolus injection, by absorption Practice of Pharmacy, 17th edition, Mack Publishing Com through epithelial or mucocutaneous linings (e.g., oral, rectal, pany, and the Physician's Desk Reference, each of which are or intestinal mucosa) and can be administered together with incorporated herein by reference, can be consulted to prepare another biologically active agent. Administration can be sys Suitable compositions and doses for administration. A deter US 2008/O 188539 A1 Aug. 7, 2008

mination of the appropriate dosage is within the skill of one in carrier. In certain embodiments, the ramipril-amino acid salt the art given the parameters for use described herein. is administered to the Subject in a pharmaceutically accept 0063 Standard texts, such as Remington: The Science and able formulation. In certain embodiments, the pharmaceuti Practice of Pharmacy, 17th edition, Mack Publishing Com cal compositions are Suitable for topical, intravenous, paren pany, incorporated herein by reference, can be consulted to tal, or oral administration. The methods of the invention prepare Suitable compositions and formulations for adminis further include administering to a subject an effective amount tration, without undue experimentation. Suitable dosages can of a ramipril-amino acid salt in combination with another also be based upon the text and documents cited herein. A pharmaceutically active compound. Pharmaceutically active determination of the appropriate dosages is within the skill of compounds that may be used can be found in Harrison's one in the art given the parameters herein. Principles of Internal Medicine. Thirteenth Edition, Eds. T. R. 0064. The dosage regimen utilizing a ramipril-amino acid Harrison et al. McGraw-Hill N.Y., NY; and the Physicians salt can be selected in accordance with a variety of factors Desk Reference 50th Edition 1997, Oradell New Jersey, including type, species, age, weight, sex and medical condi Medical Economics Co., the complete contents of which are tion of the subject; the severity of the Condition to be treated: expressly incorporated herein by reference. the route of administration; the renal or hepatic function of the 0068 Methods of preparing these compositions can Subject; and the specific ramipril-amino acid salt employed. A include the step of bringing into association a ramipril-amino ramipril-amino acid salt can be administered in a single daily acid salt with the carrier and, optionally, one or more acces dose, or the total daily dosage can be administered in divided sory ingredients. These compositions may also contain adju doses of two, three or four times daily. Furthermore, a rami vants such as preservatives, wetting agents, emulsifying pril-amino acid salt can be administered in intranasal form via agents and dispersing agents. topical use of Suitable intranasal carriers, or via transdermal 0069 Oral Dosage Forms routes, using those forms of transdermal skin patches known 0070 Ramipril-amino acid salts and compositions com to those of ordinary skill in that art. To be administered in the prising them that are suitable for oral administration can be form of a transdermal delivery system, the dosage adminis presented as discrete dosage forms, such as, but are not lim tration can be continuous rather than intermittent throughout ited to, tablets (e.g., chewable tablets), caplets, capsules, and the dosage regimen. Other illustrative topical preparations liquids (e.g., flavored syrups). Such dosage forms contain include creams, ointments, lotions, aerosol sprays and gels, predetermined amounts of a ramipril-amino acid salt or wherein the concentration of a ramipril-amino acid salt another therapeutic or prophylactic agent, and may be pre ranges from about 0.1% to about 15%, wfw or w/v. A rami pared by methods of pharmacy well known to those skilled in pril-amino acid salt can be assayed in vitro or in vivo for the the art. Seegenerally, Remington's Pharmaceutical Sciences, desired therapeutic or prophylactic activity prior to use in 18th ed., Mack Publishing, Easton Pa. (1990). humans. Animal model systems can be used to demonstrate 0071 Typical oral dosage forms of the invention can be safety and efficacy in humans. prepared by combining a ramipril-amino acid salt or another 0065. The amount of a ramipril-amino acid salt that is therapeutic or prophylactic agent(s) in an intimate admixture effective in the treatment or prevention of a Condition can be with at least one excipient according to conventional pharma determined using standard clinical techniques. In addition, in ceutical compounding techniques. Excipients can take a wide vitro or in vivo assays can optionally be employed to help variety of forms depending on the form of preparation desired identify optimal dosage ranges. The precise dose to be for administration. For example, excipients Suitable for use in employed can also depend on the route of administration, and oral liquid or aerosol dosage forms include, but are not limited the seriousness of the Condition being treated and can be to, water, glycols, oils, alcohols, flavoring agents, preserva decided according to the judgment of the practitioner and tives, and coloring agents. Examples of excipients suitable for each Subject's circumstances in view of, e.g., published clini use in Solid oral dosage forms (e.g., powders, tablets, cap cal studies. Suitable effective dosage amounts, however, Sules, and caplets) include, but are not limited to, starches, range from about 1 mg to about 15,000 mg per day; about Sugars, micro-crystalline cellulose, diluents, granulating 1000 mg to about 10,000 mg per day; or about 2,500 mg to agents, lubricants, binders, and disintegrating agents. about 5,000 mg per day. The dosage of ramipril salts can 0072 Because of their ease of administration, tablets and range from about 150 to 1500 mg/kg of body weight. Such capsules can be advantageous oral dosage unit forms, in dosages may vary, for example, depending on whether mul which case Solid excipients can be employed. If desired, tiple administrations are given, tissue type and route of tablets can be coated by standard aqueous or nonaqueous administration, the Condition of the individual, the desired techniques. Such dosage forms can be prepared by any of the objective and any other factors known to those of skill in the methods of pharmacy. In general, pharmaceutical composi art. Administrations can be conducted infrequently, or on a tions and dosage forms can be prepared by uniformly and regular weekly basis until a desired, measurable parameter is intimately admixing a ramipril-amino acid salt or another detected, such as diminution of disease symptoms. Adminis therapeutic or prophylactic agent with liquid carriers, finely tration can then be diminished, such as to a biweekly or divided solid carriers, or both, and then shaping the product monthly basis, as appropriate. The effective dosage amounts into the desired presentation if necessary. described herein refer to total amounts administered; that is, 0073 For example, a tablet can be prepared by compres if more than one dose of a ramipril-amino acid salt is admin sion or molding. Compressed tablets can be prepared by istered, the effective dosage amounts correspond to the total compressing in a suitable machine a ramipril-amino acid salt amount administered. or another therapeutic or prophylactic agent in a free-flowing 0066 Compositions and Dosage Forms form Such as powder or granules, optionally mixed with an 0067. The invention also provides a composition, com excipient. Molded tablets can be made by molding in a suit prising an effective amount a ramipril-amino acid salt able machine a mixture of the powdered compound moist described hereinanda pharmaceutically acceptable diluent or ened with an inert liquid diluent. US 2008/O 188539 A1 Aug. 7, 2008

0074 Examples of excipients that can be used in oral Grace Co. of Baltimore, Md.), a coagulated aerosol of syn dosage forms of the invention include, but are not limited to, thetic silica (marketed by Degussa Co. of Plano, Tex.), CAB binders, fillers, disintegrants, and lubricants. Binders suitable O-SIL (a pyrogenic silicon dioxide product sold by Cabot Co. for use in pharmaceutical compositions and dosage forms of Boston, Mass.), and mixtures thereof. If used at all, lubri include, but are not limited to, corn starch, potato starch, or cants are typically used in an amount of less than about 1 other starches, gelatin, natural and synthetic gums such as weight percent of the pharmaceutical compositions or dosage acacia, Sodium alginate, alginic acid, other alginates, pow forms into which they are incorporated. dered tragacanth, guar gum, cellulose and its derivatives (e.g., 0080 Parenteral and Intravascular Dosage Forms ethyl cellulose, cellulose acetate, carboxymethyl cellulose I0081. A parenteral or intravascular dosage form can be calcium, Sodium carboxymethyl cellulose), polyvinyl pyr administered to a subject via various routes including, but not rolidone, methyl cellulose, pre-gelatinized starch, hydrox limited to, Subcutaneous, intravenous (including bolus injec ypropyl methyl cellulose, (e.g., nos. 2208, 2906, 2910), tion and constant infusion), intramuscular, and intraarterial. microcrystalline cellulose, and mixtures thereof. Because their administration can bypass a Subject's natural 0075 Examples of fillers suitable for use in the pharma defenses against contaminants, parenteral and intravascular ceutical compositions and dosage forms disclosed herein dosage forms can be, in general, sterile or capable of being include, but are not limited to, talc, calcium carbonate (e.g., sterilized prior to administration to a subject. Examples of granules or powder), microcrystalline cellulose, powdered parenteral dosage forms include, but are not limited to, solu cellulose, dextrates, kaolin, mannitol, silicic acid, Sorbitol, tions ready for injection, dry products (including, but not starch, pre-gelatinized starch, and mixtures thereof. The limited to lyophilized powders, pellets, and tablets) ready to binder or filler in pharmaceutical compositions of the inven be dissolved or Suspended in a pharmaceutically acceptable tion is typically present in from about 50 to about 99 weight carrier for injection, Suspensions ready for injection, and percent of the pharmaceutical composition or dosage form. emulsions. 0076 Suitable forms of microcrystalline cellulose I0082 Suitable carriers that can be used to provide include, but are not limited to, the materials sold as AVICEL parenteral dosage forms of the invention are known to those PH-101, AVICEL-PH-103 AVICEL RC-581, AVICEL-PH skilled in the art. Examples include, but are not limited to: 105 (available from FMC Corporation, American Viscose Water for Injection USP; aqueous carriers such as, but not Division, Avicel Sales, Marcus Hook, Pa.), and mixtures limited to, Sodium Chloride Injection, Ringer's Injection, thereof. A specific binder is a mixture of microcrystalline Dextrose ejection, Dextrose and Sodium Chloride Injection, cellulose and sodium carboxymethyl cellulose sold as and Lactated Ringer's Injection; water-miscible carriers such AVICEL RC-581. Suitable anhydrous or low moisture as, but not limited to, ethyl alcohol, polyethylene glycol, and excipients or additives include AVICEL-PH-103TM and polypropylene glycol; and non-aqueous carriers such as, but Starch 1500 LM. not limited to, corn oil, cottonseed oil, peanut oil, Sesame oil, 0077 Disintegrants can be used in the compositions of the ethyl oleate, isopropyl myristate, and benzyl benzoate. invention to provide tablets that disintegrate when exposed to I0083 Compounds that increase the solubility of a rami an aqueous environment. Tablets that contain too much dis pril-amino acid salt or of another therapeutic or prophylactic integrant may disintegrate in Storage, while those that contain agent disclosed herein can also be incorporated into the too little may not disintegrate at a desired rate or under the parenteral dosage forms of the invention. desired conditions. Thus, a Sufficient amount of disintegrant I0084. For intravascular administration, for instance by that is neither too much nor too little to detrimentally alter the direct injection into the blood vessel, or Surrounding area, it release of a ramipril-amino acid salt or another therapeutic or may be desirable to administer the compositions locally to the prophylactic agent can be used to form Solid oral dosage area in need of treatment. This can be achieved, for example, forms of the invention. The amount of disintegrant used, if by local infusion during Surgery, by injection, by means of a any, varies based upon the type of formulation, and is readily catheter, or by means of an implant, said implant being of a discernible to those of ordinary skill in the art. Typical phar porous, non-porous, or gelatinous material, including mem maceutical compositions comprise from about 0.5 to about 15 branes, such as Silastic membranes, or fibers. weight percent of disintegrant, specifically from about 1 to about 5 weight percent of disintegrant. Transdermal, Topical, and Mucosal Dosage Forms 0078 Disintegrants that can be used in pharmaceutical I0085 Transdermal, topical, and mucosal dosage forms of compositions and dosage forms of the invention include, but the invention include, but are not limited to, ophthalmic solu are not limited to, agar-agar, alginic acid, calcium carbonate, tions, sprays, aerosols, creams, lotions, ointments, gels, solu microcrystalline cellulose, croScarmellose sodium, crospovi tions, emulsions, Suspensions, or otherforms known to one of done, polacrilin potassium, sodium starch glycolate, potato or skill in the art. See, e.g., Remington's Pharmaceutical Sci tapioca starch, pre-gelatinized starch, other starches, clays, ences, 16th and 18th eds., Mack Publishing, Easton Pa. (1980 otheralgins, other celluloses, gums, and mixtures thereof. & 1990); and Introduction to Pharmaceutical Dosage Forms, 0079 Lubricants that can be used in pharmaceutical com 4th ed., Lea & Febiger, Philadelphia (1985). Dosage forms positions and dosage forms of the invention include, but are Suitable for treating mucosal tissues within the oral cavity can not limited to, calcium Stearate, magnesium Stearate, mineral be formulated as mouthwashes or as oral gels. Further, trans oil, light mineral oil, glycerin, Sorbitol, mannitol, polyethyl dermal dosage forms include “reservoir type' or “matrix ene glycol, other glycols, Stearic acid, Sodium lauryl Sulfate, type' patches, which can be applied to the skin and worn for talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed a specific period of time to permit the penetration of a desired oil, Sunflower oil, sesame oil, olive oil, corn oil, and soybean amount of a ramipril-amino acid salt or another therapeutic or oil), Zinc Stearate, ethyl oleate, ethyl laureate, agar, and mix prophylactic agent. tures thereof. Additional lubricants include, for example, a I0086) Suitable excipients (e.g., carriers and diluents) and syloid silica gel (AEROSIL 200, manufactured by W. R. other materials that can be used to provide transdermal, topi US 2008/O 188539 A1 Aug. 7, 2008

cal, and mucosal dosage forms encompassed by this invention lations known to those skilled in the art, including those are known to those skilled in the art, and depend on the described herein, can be readily selected for use with a rami particular tissue to which a given pharmaceutical composi pril-amino acid salt or one or more other therapeutic or pro tion or dosage form will be applied. With that fact in mind, phylactic agents of the invention. The invention thus encom typical excipients include, but are not limited to, water, passes single unit dosage forms Suitable for oral acetone, ethanol, ethylene glycol, propylene glycol, butane administration Such as, but not limited to, tablets, capsules, 1,3-diol, isopropyl myristate, isopropyl palmitate, mineral gelcaps, and caplets that are adapted for controlled- or Sus oil, and mixtures thereof to form lotions, tinctures, creams, tained-release. emulsions, gels or ointments, which are non-toxic and phar 0090. In one embodiment a controlled- or sustained-re maceutically acceptable. Moisturizers or humectants can also lease composition comprises a minimal amount of a ramipril be added to pharmaceutical compositions and dosage forms if amino acid salt to treat or prevent a Condition over a period of desired. Examples of Such additional ingredients are known time. Advantages of controlled- or Sustained-release compo in the art. See, e.g., Remington's Pharmaceutical Sciences, sitions include extended activity of the ramipril-amino acid 16th and 18th eds., Mack Publishing, Easton Pa. (1980 & salt, reduced dosage frequency, and increased Subject com 1990). pliance. In addition, controlled- or Sustained-release compo 0087 Additional components may be used prior to, in sitions can favorably affect the time of onset of action or other conjunction with, or Subsequent to treatment with a ramipril characteristics, such as blood levels of a ramipril-amino acid amino acid salt or another therapeutic or prophylactic agent of salt, and can thus reduce the occurrence of adverse side the invention. For example, penetration enhancers can be effects, if any. Controlled- or Sustained-release compositions used to assist in delivering a ramipril-amino acid salt or can initially release an amount of a ramipril-amino acid salt another therapeutic or prophylactic agent to the tissue. Suit that promptly produces the desired therapeutic or prophylac able penetration enhancers include, but are not limited to: tic effect, and gradually and continually release other acetone; various alcohols such as ethanol, oleyl, and tetrahy amounts of a ramipril-amino acid salt to maintain this level of drofuryl; alkyl sulfoxides such as dimethyl sulfoxide; dim therapeutic or prophylactic effect over an extended period of ethyl acetamide; dimethyl formamide; polyethylene glycol; time. To maintain a relatively constant level of a ramipril pyrrolidones such as polyvinylpyrrolidone; Kollidon grades amino acid salt in the body, a ramipril-amino acid salt can be (Povidone, Polyvidone); urea; and various water-soluble or released from the dosage form at a rate that will replace the insoluble sugar esters such as Tween 80 polysorbate 80) and amount of a ramipril-amino acid salt being metabolized and Span 60 (sorbitan monostearate). excreted from the body. 0088. The pH of a pharmaceutical composition or dosage 0091 Controlled- or sustained-release of an a ramipril form, or of the tissue to which the pharmaceutical composi amino acid salt or one or more other therapeutic or prophy tion or dosage form is administered, may also be adjusted to lactic agents can be stimulated by various conditions, includ improve delivery of a ramipril-amino acid salt or one or more ing but not limited to, changes in pH, changes in temperature, other therapeutic or prophylactic agents. Similarly, the polar concentration or availability of enzymes, concentration or ity of a solvent carrier, its ionic strength, or tonicity can be availability of water, or other physiological conditions or adjusted to improve delivery. Compounds such as Stearates compounds. can also be added to pharmaceutical compositions or dosage forms to advantageously alter the hydrophilicity or lipophi Combination Therapy licity of a ramipril-amino acid salt or one or more other 0092. In certain embodiments, a ramipril-amino acid salt therapeutic or prophylactic agents so as to improve delivery. is administered to a subject concurrently with one or more In this regard, Stearates can serve as a lipid carrier for the other therapeutic or prophylactic agents. For example, each formulation, as an emulsifying agent or Surfactant, and as a component may be administered at about the same time or delivery-enhancing or penetration-enhancing agent. Differ sequentially in any order at different points in time; however, ent salts, hydrates or Solvates of a ramipril-amino acid salt or if not administered at about the same time, they should be one or more other therapeutic or prophylactic agents to fur administered sufficiently closely in time so as to provide the ther adjust the properties of the resultant composition. desired treatment or preventative effect. In one embodiment, all components are administered at about the same time, and Controlled-Release Dosage Forms if not administered at about the same time, they are all admin 0089. A ramipril-amino acid salt can be administered by istered on the same day, or within 1 hour, 2 hours, 6 hours, 12 controlled-release or Sustained-release means or by delivery hours, 48 hours or 72 hours of one another. devices that are well known to those of skill in the art. 0093. When used in combination with one or more other Examples include, but are not limited to, those described in therapeutic or prophylactic agents, a ramipril-amino acid salt U.S. Pat. Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; and the therapeutic or prophylactic agent can act additively 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; or, in certain embodiments, synergistically. In one embodi 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of ment, a ramipril-amino acid salt or a composition of the which is incorporated herein by reference in its entirety. Such invention is administered concurrently with another thera dosage forms can be useful for providing controlled- or Sus peutic or prophylactic agent in the same pharmaceutical com tained-release of a ramipril-amino acid salt or one or more position. In another embodiment, a ramipril-amino acid salt other therapeutic or prophylactic agents using, for example, or a composition of the invention is administered concur hydropropylmethyl cellulose, other polymer matrices, gels, rently with another therapeutic or prophylactic agent in sepa permeable membranes, osmotic systems, multilayer coat rate pharmaceutical compositions. In still another embodi ings, microparticles, liposomes, microspheres, or a combina ment, a ramipril-amino acid salt or a composition of the tion thereof to provide the desired release profile in varying invention is administered prior or Subsequent to administra proportions. Suitable controlled- or sustained-release formu tion of another therapeutic or prophylactic agent. As some of US 2008/O 188539 A1 Aug. 7, 2008 the Conditions for which the compounds and compositions of acetate, prednisolone, prednisolone acetate, prednisolone the invention are useful in treating are chronic disorders, in Sodium phosphate, prednisolone tebuatate, prednisone, tri one embodiment combination therapy involves alternating amcinolone, triamcinolone acetonide, triamcinolone diac between administering a ramipril-amino acid salt or a com etate, and triamcinolone hexacetonide; and other anti-inflam position of the invention and a pharmaceutical composition matory agents including, but not limited to, methotrexate, comprising another therapeutic or prophylactic agent, e.g., to colchicine, allopurinol, probenecid, Sulfinpyrazone and ben minimize the toxicity associated with a particular drug. In Zbromarone. certain embodiments, when a composition of the invention is 0098. In one embodiment, the other therapeutic or prophy administered concurrently with another therapeutic or pro lactic agent is an anti-renal failure agent. Anti-renal failure phylactic agent that potentially produces adverse side effects agents useful in the compositions and methods of the present including, but not limited to toxicity, the therapeutic or pro invention include, but are not limited to, ACE (angiotensin phylactic agent can advantageously be administered at a dose converting enzyme) inhibitors, such as captopril, enalaprilat, that falls below the threshold that the adverse side effect is lisinopril, benazepril, fosinopril, trandolapril, quinapril, and elicited. ramipril; diuretics, such as mannitol, glycerin, furosemide, 0094. In one embodiment, the other therapeutic or prophy toresemide, tripamide, chlorothiazide, methyclothiazide, lactic agent is a diuretic agent. Diuretic agents useful in the indapamide, amiloride, and spironolactone; and fibric acid compositions and methods of the present invention include, agents, such as clofibrate, gemfibrozil, fenofibrate, ciprofi but are not limited to, piretanide, amiloride, amiloride/HCTZ brate, and bezafibrate. chlorothiazide (Diuril R. Oral Susp), bumetanide, clonidine/ 0099. In one embodiment, the other therapeutic or prophy chlorthalidone (Clorpres(R), chlorothalidone, deserpidine/ lactic agent is an anti-diabetic agent. Anti-diabetic agents methyclothiazide (Enduronyl-ForteR), chlorothiazide, useful in the methods and compositions of the present inven ethacrynic acid (EdecrinR), furosemide, hydroflumethiazide tion include include but are not limited to glucagons; Soma (Saluron(R), hydrochlorothiazide, polythiazide (Renese(R). to statin; diaZOxide; Sulfonylureas, such as tolbutamide, indapamide, prazosin/polythiazide (Minizide(R), methy acetohexamide, tolaZamide, chloropropamide, glybencla clothiazide, reserpine/methyclothiazide (Diutensin-R(R), mide, glipizide, gliclazide, and glimepiride; insulin secreta metolazone, spironolactone/hctz (Aldactazide 50/50R), gogues. Such as repaglinide, and nateglinide; biguanides, torsemide, trichlormethazide (NaquaR), triamterene or tri Such as metformin and phenformin; thiazolidinediones, such amterenefCTZ. as pioglitaZone, rosiglitaZone, and troglitaZone; and alpha 0095. In one embodiment, the other therapeutic or prophy glucosidase inhibitors, such as acarbose and miglitol. lactic agent is a statin. Statins useful in the compositions and 0100. In one embodiment, the other therapeutic or prophy methods of the present invention include, but are not limited lactic agent is an anti-cardiovascular disease agent. Anti to, atorvastatin, cerivastatin, fluvastatin, lovastatin, pravasta cardiovascular disease agents useful in the methods and com tin, rosuvastatin, or simvastatin. positions of the present invention include include but are not 0096. In one embodiment, the other therapeutic or prophy limited to carnitine; thiamine; and muscarinic receptor lactic agent is a calcium channel blocker. Calcium channel antagonists, such as atropine, Scopolamine, homatropine, blockers useful in the compositions and methods of the tropicamide, pirenzipine, ipratropium, tiotropium, and present invention include, but are not limited to, amlodipine, tolterodine. bepridil, diltiazem, felodipine, isradipine, nicardipine, nife 0101. In one embodiment, the other therapeutic or prophy dipine, nimodipine, niSoldipine, or Verapamil. lactic agent is an antiemetic agent. Antiemetic agents useful 0097. In one embodiment, the other therapeutic or prophy in the methods and compositions of the present invention lactic agent is an antiinflammatory agent. Anti-inflammatory include include, but are not limited to, metoclopromide, dom agents useful in the compositions and methods of the present perildone, prochlorperazine, promethazine, chlorpromazine, invention include but are not limited to non-steroidal anti trimethobenzamide, ondansetron, granisetron, hydroxy Zine, inflammatory agents (NSAIDs). Such as Salicylic acid, ace acetylleucine monoethanolamine, aliZapride, aZasetron, ben tylsalicylic acid, methyl salicylate, diflunisal, Salsalate, Zquinamide, bietanautine, bromopride, buclizine, clebopride, olsalazine, SulfaSalazine, acetaminophen, indomethacin, cyclizine, dimenhydrinate, diphenidol, dolasetron, mecliz Sulindac, etodolac, mefenamic acid, meclofenamate Sodium, ine, methallatal, metopimazine, nabilone, oxyperndyl. tolimetin, ketorolac, dichlofenac, ibuprofen, naproxen, pipamazine, Scopolamine, Sulpiride, tetrahydrocannabinol, naproxen Sodium, fenoprofen, ketoprofen, flurbinprofen, thiethylperazine, thioproperazine, tropisetron, and mixtures oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, thereof. pivoxicam, tenoxicam, nabumetome, phenylbutaZone, 0102. In one embodiment, the other therapeutic or prophy oxyphenbutaZone, antipyrine, aminopyrine, apaZone and lactic agent is an opioid analgesic agent. Opioid analgesic nimeSulide; leukotriene antagonists including, but not limited agents useful in the methods and compositions of the present to, Zileuton, aurothioglucose, gold sodium thiomalate and invention include, but are not limited to, morphine, heroin, auranofin, Steroids including, but not limited to, alclometa hydromorphone, hydrocodone, oxymorphone, oxycodone, Sone diproprionate, amcinonide, beclomethasone dipropi metopon, apomorphine, normorphine, etorphine, buprenor onate, betametasone, betamethasone benzoate, betametha phine, meperidine, lopermide, anilleridine, ethoheptazine, Sone diproprionate, betamethasone sodium phosphate, piminidine, betaprodine, diphenoxylate, fentanil, Sufentanil, betamethasone Valerate, clobetasol proprionate, clocortolone alfentanil, remifentanil, levorplianol, dextromethorphan, pivalate, hydrocortisone, hydrocortisone derivatives, des phenazocine, pentazocine, cyclazocine, methadone, onide, desoximataSone, dexamethasone, flunisolide, flucoxi isomethadone and propoxyphene. nolide, flurandrenolide, halcinocide, medrysone, methyl 0103) In one embodiment, the other therapeutic or prophy prednisolone, methprednisolone acetate, methylprednisolone lactic agent is a non-opioid analgesic agent. Non-opioid anal Sodium Succinate, mometaSone firoate, paramethasone gesic agents useful in the methods and compositions of the US 2008/O 188539 A1 Aug. 7, 2008

present invention include, but are not limited to, aspirin, cele drol, dulloxetine, etoperidone, febarbamate, femoxetine, fen coxib, rofecoxib, diclofenac, diflusinal, etodolac, fenoprofen, pentadiol, fluoxetine, fluvoxamine, hematoporphyrin, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, hypericin, levophacetoperane, medifoxamine, milnacipran, meclofenamate, mefanamic acid, nabumetone, naproxen, minaprine, moclobemide, nefazodone, oxafloZane, pibera piroXicam and Sulindac. line, prolintane, pyriSuccideanol, ritanserin, roXindole, 0104. In one embodiment, the other therapeutic or prophy rubidium chloride, Sulpiride, tandospirone, thoZalinone, lactic agent is an antibiotic. Antibiotics useful in the methods tofenacin, toloxatone, tranylcypromine, L-tryptophan, Ven and compositions of the present invention include, but are not lafaxine, Viloxazine, and Zimeldine. limited to, a macrollide (e.g., tobramycin (TobiR)), a cepha 0106. In one embodiment, the other therapeutic or prophy losporin (e.g., cephalexin (Keflex(R), cephradine (VelosefR), lactic agentis, an antifungal agent. Suitable antifungal agents cefuroxime (CeftinR), cefprozil (Cefail(R), cefaclor (Ce useful useful in the compositions and methods of the inven clorR), cefixime (Suprax(R) or cefadroxil (DuricefR)), a tion in the compositions and methods of the invention include clarithromycin (e.g., clarithromycin (BiaxinR)), an erythro but are not limited to amphotericin B, itraconazole, ketocona mycin (e.g., erythromycin (EMycin R)), a penicillin (e.g., Zole, fluconazole, intrathecal, flucytosine, miconazole, buto penicillin V (V-Cillin KCR) or Pen Vee K(R)) or a quinolone conazole, clotrimazole, nystatin, terconazole, tioconazole, (e.g., ofloxacin (Floxin R), ciprofloxacin (CiproR) or nor ciclopiroX, econazole, haloprogrin, naftifine, terbinafine, floxacin (NoroXin R)), aminoglycoside antibiotics (e.g., apra undecylenate, and griseofildin. mycin, arbekacin, bambermycins, butirosin, dibekacin, neo 0107. In one embodiment, the other therapeutic or prophy mycin, neomycin, undecylenate, netilmicin, paromomycin, lactic agent is an immunomodulatory agent. Immunomodu ribostamycin, Sisomicin, and spectinomycin), amphenicol latory agents useful in the compositions and methods of the antibiotics (e.g., azidamfenicol, chloramphenicol, florfeni invention include, but are not limited to, methothrexate, col, and thiamphenicol), ansamycin antibiotics (e.g., rifamide leflunomide, cyclophosphamide, cyclosporine A, mycophe and rifampin), carbacephems (e.g., loracarbef), carbapenems nolate mofetil, rapamycin (sirolimus), mizoribine, deox (e.g., biapenem and imipenem), cephalosporins (e.g., cefa yspergualin, brequinar, malononitriloamindes (e.g., lefluna clor, cefadroxil, cefamandole, cefatrizine, cefazedone, cefo mide), T cell receptor modulators, and cytokine receptor Zopran, cefipmizole, cefpiramide, and ce?pirome), cephamy modulators, peptide mimetics, and antibodies (e.g., human, cins (e.g., cefbuperaZone, cefimetazole, and cefiminox), humanized, chimeric, monoclonal, polyclonal, Fvs, ScPVS, monobactams (e.g., aztreonam, carumonam, and tige Fab or F(ab')2 fragments or epitope binding fragments), monam), oxacephems (e.g., flomoxef, and moxalactam), nucleic acid molecules (e.g., antisense nucleic acid molecules penicillins (e.g., amdinocillin, amdinocillin pivoxil, amox and triple helices), Small molecules, organic compounds, and icillin, bacampicillin, benzylpenicillinic acid, benzylpenicil inorganic compounds. Examples of T cell receptor modula lin Sodium, epicillin, fenbenicillin, floxacillin, penamccillin, tors include, but are not limited to, anti-T cell receptor anti penethamate hydriodide, penicillino-benethamine, penicillin bodies (e.g., anti-CD4 antibodies (e.g., cM-T412 0, penicillin V, penicillin V benzathine, penicillin V hydrab (Boeringer), IDEC-CE9.1 (IDEC and SKB), mAB amine, penimepicycline, and phencihicillin potassium), lin 4162W94, Orthoclone and OKTcdraa (Janssen-Cillag)), anti cosamides (e.g., clindamycin, and lincomycin), amphomy CD3 antibodies (e.g., Nuvion (Product Design Labs), OKT3 cin, bacitracin, capreomycin, colistin, enduracidin, (Johnson & Johnson), or Rituxan (IDEC)), anti-CD5 antibod enviomycin, tetracyclines (e.g., apicycline, chlortetracycline, ies (e.g., an anti-CD5 ricin-linked immunoramipril salt), anti clomocycline, and demeclocycline), 2,4-diaminopyrimidines CD7 antibodies (e.g., CHH-380 (Novartis)), anti-CDS anti (e.g., brodimoprim), nitrofurans (e.g., furaltadone, and fura bodies, anti-CD40 ligand monoclonal antibodies (e.g., IDEC Zolium chloride), quinolones and analogs thereof (e.g., cino 131 (IDEC)), anti-CD52 antibodies (e.g., CAMPATH 1H Xacin, clinafloxacin, flumequine, and grepagloxacin), Sul (Ilex)), anti-CD2 antibodies, anti-CD11a antibodies (e.g., fonamides (e.g., acetyl Sulfamethoxypyrazine, Xanelim (Genentech)), and anti-B7 antibodies (e.g., IDEC benzylsulfamide, noprylsulfamide, phthalylsulfacetamide, 114 (IDEC)) and CTLA4-immunoglobulin. Examples of Sulfachrysoidine, and Sulfacytine), Sulfones (e.g., diathymo cytokine receptor modulators include, but are not limited to, Sulfone, glucosulfone sodium, and Solasulfone), cycloserine, soluble cytokine receptors (e.g., the extracellular domain of a mupirocin and tuberin. TNF-alpha. receptor or a fragment thereof, the extracellular 0105. In one embodiment, the other therapeutic or prophy domain of an IL-1.beta. receptor or a fragment thereof, and lactic agent is an antidepressant. Suitable antidepressants the extracellular domain of an IL-6 receptor or a fragment useful in the compositions and methods of the invention thereof), cytokines or fragments thereof (e.g., interleukin include, but are not limited to, binedaline, caroXaZone, citalo (IL)-2, IL-3, IL-4, IL-S, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, pram, dimethazan, fencamine, indalpine, indeloxazine IL-12, IL-15, TNF-alpha., interferon (IFN)-alpha. IFN-. hydrocholoride, nefopam, nomifensine, oxitriptan, oxyper beta. IFN-gamma., and GM-CSF), anti-cytokine receptor tine, paroxetine, Sertraline, thiaZesim, traZodone, benmoxine, antibodies (e.g., anti-IFN receptor antibodies, anti-IL-2 iproclozide, iproniazid, isocarboxazid, nialamide, octa receptor antibodies (e.g., Zenapax (Protein Design Labs)), moxin, phenelZine, cotinine, rolicyprine, rolipram, mapro anti-IL-4 receptor antibodies, anti-IL-6 receptor antibodies, tiline, metralindole, mianserin, mirtazepine, adinazolam, anti-IL-10 receptor antibodies, and anti-IL-12 receptor anti amitriptyline, amitriptylinoxide, amoxapine, butriptyline, bodies), anti-cytokine antibodies (e.g., anti-IFN antibodies, clomipramine, demexiptiline, desipramine, dibenzepin, anti-TNF-alpha. antibodies, anti-IL-1.beta. antibodies, anti dimetacrine, dothiepin, doxepin, fluacizine, imipramine, imi IL-6 antibodies, anti-IL-8 antibodies (e.g., ABX-IL-8 (Ab pramine N-oxide, iprindole, lofepramine, melitracen, metap genix)), and anti-IL-12 antibodies). ramine, nortriptyline, noxiptilin, opipramol, pizotyline, 0108. In one embodiment, the other therapeutic or prophy propizepine, protriptyline, quinupramine, tianeptine, trimi lactic agent is a cytokine. Examples of cytokines useful in the pramine, adrafinil, benactyzine, bupropion, butacetin, dioxa compositions and methods of the invention include, but are US 2008/O 188539 A1 Aug. 7, 2008

not limited to, interleukin-2 (IL-2), interleukin-3 (IL-3), of pharmaceutically acceptable carriers include, but are not interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-6 (IL limited to: Water for Injection USP; aqueous carriers such as, 6), interleukin-7 (IL-7), interleukin-9 (IL-9), interleukin-10 but not limited to, Sodium Chloride Injection, Ringer's Injec (IL-10), interleukin-12 (IL-12), interleukin 15 (IL-15), inter tion, Dextrose Injection, Dextrose and Sodium Chloride leukin 18 (IL-18), platelet derived growth factor PDGF), Injection, and Lactated Ringer's Injection; water-miscible eryropoietin (Epo), epidermal growth factor (EGF), fibro carriers such as, but not limited to, ethyl alcohol, polyethyl blast growth factor (FGF), granulocyte macrophage stimulat ene glycol, and polypropylene glycol; and non-aqueous car ing factor (GM-CSF), granulocyte colony stimulating factor riers such as, but not limited to, corn oil, cottonseed oil, (G-CSF), macrophage colony stimulating factor (M-CSF), peanut oil, Sesame oil, ethyl oleate, isopropyl myristate, and prolactin, and interferon (IFN), e.g., IFN-alpha, and IFN benzyl benzoate. gamma). The invention is further described by way of the following 0109. In one embodiment, the other therapeutic or prophy non-limiting examples. lactic agentis a hormone. Examples of hormones useful in the compositions and methods of the invention include, but are EXAMPLES not limited to, luteinizing hormone releasing hormone 0116. In order that the invention may be more fully under (LHRH), growth hormone (GH), growth hormone releasing stood, the following examples are provided. It should be hormone, ACTH, somatostatin, Somatotropin, Somatomedin, understood that these examples are for illustrative purposes parathyroid hormone, hypothalamic releasing factors, insu only and are not to be construed as limiting the invention in lin, glucagon, enkephalins, vasopressin, calcitonin, heparin, any way. low molecular weight heparins, heparinoids, synthetic and 0117 Analytical Methods: natural opioids, insulin thyroid stimulating hormones, and 0118 X-Ray Powder Diffraction endorphins. 0119 X-Ray Powder Diffraction patterns were collected 0110. In one embodiment, the other therapeutic or prophy using a Bruker AXS C2 GADDS diffractometer using Cu KC. lactic agent is a B-interferon which include, but are not limited radiation (40 kV. 40 mA), automated XYZ stage, laser video to, interferon B-1a and interferon B-1b. microscope for auto-sample positioning and a HiStar 2-di 011 1 Kits mensional area detector. X-ray optics include a single Göbel 0112 This invention encompasses kits which, when used multilayer mirror coupled with a pinhole collimator of 0.3 by, for example, a medical practitioner or Subject, can sim . plify the administration of appropriate amounts of ramipril I0120. The beam divergence, i.e., the effective size of the amino acid salt to a subject. X-ray beam on the sample, was approximately 4 mm. A 0-0 0113 A typical kit of the invention comprises one or more continuous scan mode was employed with a sample—detec unit dosage forms of a ramipril-amino acid salt. In one tor distance of 20 cm which gives an effective 20 range of embodiment, the kit comprises is a container, which can be 3.2°-29.7°. Typically the sample was exposed to the X-ray sterile, containing an effective amount of a ramipril-amino beam for 120 seconds. acid salt and a physiologically acceptable carrier. The kit can I0121 Samples run under ambient conditions were pre further comprise a label or printed instructions instructing the pared as flat plate specimens using powder as received with use of a ramipril-amino acid salt to treat or prevent a Condi outgrinding. Approximately 1-2 mg of the sample was lightly tion. The kit can also further comprise a unit dosage form of pressed on a glass slide to obtain a flat surface. another prophylactic or therapeutic agent, for example, a I0122) Nuclear Magnetic Resonance container containing an effective amount of the other prophy (0123 NMR spectra were collected using a Bruker 400 lactic or therapeutic agent. In one embodiment, the kit com MHZ instrument equipped with an auto-sampler and con prises a container containing an effective amount of a rami trolled by a DRX400 console. Automated experiments were pril-amino acid salt and an effective amount of another acquired using ICON-NMR v4.0.4 (build 1) running with prophylactic ortherapeutic agent. Examples of other prophy Topspin v 1.3 (patch level 8) using the standard Brukerloaded lactic or therapeutic agents include, but are not limited to, experiments. For non-routine spectroscopy, data were those listed above. acquired through the use of Topspin alone. 0114 Kits of the invention can further comprise one or 0.124 Samples were prepared in d-DMSO, unless other more devices that are useful to administer a ramipril-amino wise stated. Off-line analysis was carried out using ACD acid salt and/or another prophylactic or therapeutic agent. SpecManager v. 9.09 (build 7703). Examples of such devices include, but are not limited to, 0.125. Differential Scanning Calorimetry intravenous cannulation devices, Syringes, drip bags, patches, 0126. DSC data were collected on a Mettler DSC 823e topical gels, pumps, containers that provide protection from equipped with a 50 position auto-sampler. The instrument photodegredation, autoinjectors, and inhalers. was calibrated for energy and temperature using certified 0115 Kits of the invention can further comprise one or indium. Typically 0.5-3 mg of each sample, in a pin-holed more pharmaceutically acceptable carriers that can be used to aluminium pan, was heated at 10°C/minute from 25°C. to administer a ramipril-amino acid salt or another therapeutic 300° C. A nitrogen purge at 50 mL/minute was maintained or prophylactic agent. For example, if an a ramipril-amino over the sample. acid salt or another therapeutic or prophylactic agent is pro I0127. The instrument control and data analysis software vided in a solid form that must be reconstituted for parenteral was STARe v9.01. administration, the kit can comprise a sealed container of a I0128. Thermogravimetric Analysis Suitable carrier in which a ramipril-amino acid salt or another I0129. TGA data were collected using a Mettler TGA/ therapeutic or prophylactic agent can be dissolved or Sus SDTA 851e equipped with a 34 position auto-sampler. The pended to form a particulate-free sterile Solution or Suspen instrument was temperature calibrated using certified indium. sion that is suitable for parenteral administration. Examples Typically 5-50 mg of each sample was loaded onto a pre US 2008/O 188539 A1 Aug. 7, 2008

weighed aluminium crucible and was heated at 10°C.min-1 acetate (10 mL) was added, and the distillation was repeated from ambient temperature to 350° C. A nitrogen purge at 50 to provide a ramipril-(L)-arginine salt. mL/minute was maintained over the sample. 0141 Biological Assays 0130. The instrument control and data analysis software 0142. Determination of the Effect of a Ramipril-Amino was STARe v9.01. Acid Salt on In Vivo Models of Reperfusion Injury 0131 Fourier Transform Infrared Spectroscopy 0143. The efficacy of a ramipril-amino acid salt in amouse 0132 FT-IR data were collected using a Perkin-Elmer model of ischemic and reperfused gut can be determined Spectrum One fitted with a Universal ATR sampling acces according to the method described in Liaudet et al., Shock sory. 2000, 14(2): 134-41. 0133. The data were collected and analysed using Spec 0144. In another set of experiments, the effect of a rami trum V5.0.1 software. pril-amino acid salt in a rat model of middle cerebral artery occlusion/reperfusion can be assayed as described in Synthetic Examples Abdelkarimetal, Int. J. Mol Med. 2001, 7(3):255-60. 0134 Ramipril-(L)-Arginine Salt 0145 Determination of the Effect of a Ramipril-Amino 0135 Method A. Ramipril (15.06 g) and L-arginine were Acid Salt on In Vivo Models of Hypertension added to a 1 L round bottomed flask, and a solution of 1:1 0146 The efficacy of a ramipril-amino acid salt in amouse water/Isopropyl alcohol was added (320 mL). The resultant model of hypertension can be determined according to the solution was stirred at room temperature, and after 30 minutes methods described in Badyal et al. Indian J. of Pharmacol all of the solid dissolved. The solution was frozen using an ogy, 2003, 35:349-362. acetone/dry ice bath. The frozen solution was freeze dried for 0147 Determination of the Effect of a Ramipril-Amino 60 hours to provide 20.9 g (98%) of a ramipril-(L)-arginine Acid Salt on In Vivo Models of Cardiovascular Disease salt whose X-ray powder) diffraction pattern is depicted in 0.148. The efficacy of a ramipril-amino acid salt in amouse FIG. 1, IR spectrum is depicted in FIG. 2 (see peak summary model of cardiovascular disease can be determined according below), 'H-NMR (DMSO-d) spectrum is depicted in FIG.3 to the methods described in Rusell et al. Cardiovasc Pathol. and thermographic gravimetric analysis (TGA) (upper plot) 2006, 15(6):318-30. and differential scanning calorimetry scan (DSC) (lower plot) 0149 Determination of the Effect of a Ramipril-Amino are depicted in FIG. 4. Acid Salt in an In Vivo Model of Diabetes Mellitus 0150. The anti-diabetic effect of a ramipril-amino acid salt 0.136 IR Summary can be determined using a single high-dose streptozotocin model of diabetes mellitus, which can be used as conducted as described in Mabley et al., Br. J. Pharmacol. 2001, 133(6): Peak (cm) 96 T 909-9; and Soriano et al., Nat. Med. 2001, 7(1): 108-13. 3062 82.9 We claim: 3027 82.5 1. A ramipril-amino acid salt. 2940 77.2 2. The salt of claim 1, wherein the amino acid is not argi 2868 82.2 1728 75.3 nine or lysine. 1603 52.5 3. The salt of claim 1, wherein the salt is substantially free 1497 72.2 of ramipril (free acid) and amino acid that is not associated 1453 66.9 with ramipril (conjugate base). 1384 62.2 1349 69.0 4. The salt of claim 1, wherein the amino acid is histidine. 1294 71.3 5. The salt of claim 1, in crystalline form. 118O 65.5 6. The salt of claim 1, in non-crystalline form. 1029 75.4 7. A composition comprising a therapeutically effective 979 87.O 954 86.9 amount of the ramipril-amino acid salt of claim 1 and a 831 79.7 pharmaceutically acceptable carrier. 747 64.5 8. The composition of claim 7, further comprising another 699 54.6 therapeutic agent. 9. The composition of claim8, wherein the other therapeu 0.137 Generation of Ramipri-(L)-lysine Salt tic is a diuretic, an antiinflammatory agent, an anti-renal 0138 Ramipril (1.10 g) was added to butanone (10 mL), failure agent, an anti-diabetic agent, an anti-cardiovascular and the resultant solution was brought to reflux. To this clear disease agent, an opioid analgesic agent, a non-opioid anal solution was added L-lysine (0.35 g), portionwise. The solu gesic agent, an antibiotic, an antiemetic, an antifungal agent, tion was stirred at reflux for 30 minutes and allowed to cool to an antidepressant, an immunomodulatory agent, a cytokine, a room temperature overnight. The solvents were removed by hormone, or a B-interferon. distillation at reduced pressure. Ethyl acetate (10 mL) was 10. A method for treating a cardiovascular disorder, com added and the distillation was repeated to afford a ramipril prising administering to a Subject in need thereofatherapeu (L)-Lysine salt. tically effective amount of the ramipril-amino acid salt of 0139 Ramipri-(L)-Arginine Salt claim 1. 0140 Method B. Ramipril (0.51 g) was added to butanone 11. The method of claim 10, further comprising adminis (15 mL), and the resultant solution was brought to reflux. To tering another therapeutic agent. this clear Solution was added L-arginine (0.21 g), portion 12. A method for treating an ischemic condition, compris wise. The solution was stirred at reflux for 30 minutes and ing administering to a subject in need thereof a therapeuti allowed to cool to room temperature overnight. The solvents cally effective amount of the ramipril-amino acid salt of claim were removed by distillation at reduced pressure. Ethyl 1. US 2008/O 188539 A1 Aug. 7, 2008

13. The method of claim 12, further comprising adminis 17. The method of claim 16, further comprising adminis tering another therapeutic agent. tering another therapeutic agent. 14. A method for treating renal failure, comprising admin 18. A method for reducing the incidence of recurrence or istering to a subject in need thereofatherapeutically effective severity of a symptom of a cardiovascular disorder, an ischemic condition, renal failure, diabetes mellitus or a dia amount of the ramipril-amino acid salt of claim 1. betic condition, comprising administering to a subject in need 15. The method of claim 14, further comprising adminis thereof a therapeutically effective amount of the ramipril tering another therapeutic agent. amino acid salt of claim 1. 16. A method for treating diabetes mellitus or a diabetic 19. The method of claim 18, further comprising adminis condition comprising administering to a subject in need tering another therapeutic agent. thereof a therapeutically effective amount of the ramipril amino acid salt of claim 1. c c c c c