WO2011041870A1

WO2011041870A1 - Non-steroidal anti-inflammatory drugs coadministered with nitric oxide amino acid ester compounds as prophylaxis in hypertensive patients

Info

Publication number: WO2011041870A1
Application number: PCT/CA2009/001427
Authority: WO
Inventors: Michael Farber
Original assignee: Nitrogenix Inc.
Priority date: 2009-10-07
Filing date: 2009-10-07
Publication date: 2011-04-14

Abstract

There is provided a novel pharmaceutical composition containing amino acid ester compounds comprising at least one nitric oxide releasing group and pharmaceutical salts thereof, for the boosting nitric oxide levels. There is also provided a novel pharmaceutical composition containing amino acid ester compounds comprising at least one nitric oxide releasing group and pharmaceutical salts thereof, in combination with non-stereoidal anti-inflammatory drug (NSAID) and/or a cyclooxygenase-2 (COX-2) selective inhibitor, for the relief of pain.

Description

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS COADMINISTERED WITH NITRIC OXIDE AMINO ACID ESTER COMPOUNDS AS PROPHYLAXIS IN HYPERTENSIVE PATIENTS

BACKGROUND

(a) Field

[0001] The subject matter disclosed generally relates to the prophylaxis of inflammation and/or pain in hypertensive patient. More specifically, the subject matter disclosed generally relates to the prophylaxis of inflammation and/or pain in hypertensive patient using nitric oxide amino acid ester compounds.

(b) Related Prior Art

[0002] Non-Steroidal Anti-inflammatory Drugs (NSAIDS) are still one of the first choices in the prophylaxis of inflammatory conditions and among the most commonly prescribed drugs worldwide. However they are not devoid of adverse effects. In fact they are associated with high levels of gastrointestinal ulceration, renal damage and hypertensive effects among others, and sometimes these effects are life threatening.

[0003] Several strategies have been followed to reduce these adverse effects, including enteric coating, parenteral administration, formulation of prodrugs that require hepatic metabolism for the unmasking of effects and coadministration of either suppressors of gastric acid secretion or exogenous prostaglandins without the desired results.

[0004] Another more recent approach to reduce the toxicity of NSAIDS is the linking of a nitric Oxide releasing moiety to these compounds, thus creating a new category of anti-inflammatory agent NO-NSAIDS. Again the results have been disappointing in that bioavailability of the drug has been reduced and the anti-hypertensive effects have fallen short of expectations due to limitations in the amount of nitric oxide producing intermediate that can enter the physiological system.

[0005] Nitric Oxide is a small diatomic radical that plays an important physiological role in nervous, cardiovascular and immune system function. Its generation is controlled by three isoforms of NO synthetase which are constitutive and produce nanomolar amounts of NO important for normal cell function and tissue protection. The endogenous tissue NO generated constitutively by gastrointestinal eNOS and nNOS appears to play a key role in the chronic maintenance of gastrointestinal tissue integrity and in adaptive cytoprotection to injurious stimuli, perhaps acting synergistically with other cytoprotective prostaglandins. NO promotes several gastric defense mechanisms by increasing mucus and bicarbonate secretion in the Gl tract, increasing mucosal blood flow and inhibiting pro-inflammatory activities of neutrophils and platelets.

[0006] Several NO-NSAIDS have already been synthesized and have shown protective activity against acute mycocardial infarction and have demonstrated safe Gl profiles. However as already mentioned their effects as Nitric Oxide donator have been limited by the presence of a direct bond between the parent compound and the Nitric Oxide donator, thus limiting the amount of NO donated to a direct stoichiometric relationship.

[0007] Therefore there still exists the necessity for a more flexible approach to nitric oxide donation with NSAIDS. By connecting the nitric oxide moiety through an aliphatic linkage such as an ethyl or butyl linkage to an inert carrier, an amino acid, by an ester bond the limitations of a direct connection between the parent compound and the nitric oxide moiety are overcome. This is to say that the parent NSAID, such as naproxen, is dosed concurrently with a nitric oxide donating amino acid ester such that the amount of nitric oxide effects a reduction in inflammation and ulceration and also produces a significant and timely drop in blood pressure that would otherwise be elevated through administration of the NSAID. The toxicity of the aliphatic linkages has been shown to be nil or minor in fact to reduce the toxicity of the parent compound. In this case, since the novel nitric oxide donating amino acid esters are themselves natural constituents of the human or mammalian physiology, toxicity should be nil or minimal. [0008] Therefore the efficacy of the dosing of the parent NSAID concurrently with an nitric oxide donating amino acid ester can overcome any of the current shortfalls in performance of the NO-NSAIDS heretofore synthesized and can offer increased flexibility as to release profiles, dosing regimen, and anti-hypertensive effects.

SUMMARY

[0009] In a first embodiment there is disclosed a composition for use with a NSAID or a COX-2 inhibitor, which comprises a therapeutically effective amount of a nitric oxide releasing compound of formula (I):

(I)

[0010] wherein Ri may be CH₂-CH₃ and (CH₃)₂, R₂ may be a hydrogen atom, an amino acid (D or L configuration) and derivatives thereof, forming a peptide bond; or any pharmaceutically acceptable salts thereof; in association with a pharmaceutically acceptable carrier, in an enteric coating.

[0011] The R₂ m ay also be an amino acid of formula (II) (D or L configuration) and derivatives thereof, forming a peptide bond:

H H O H N C C— O H

[0012] ^Rx (II), and R_x is chosen from

H H

CH₃ CH₃

CH₃

(CH₃)₂ CH

The compound of formula (I) may be valine butylene glycol

[0014] or any pharmaceutically acceptable salts thereof.

[0015] The compound of formula (I) may be norvaline butylene glycol nitrate:

[0016] or any pharmaceutically acceptable salts thereof.

[0017] The compound of formula (I) may be:

[0018] wherein R₃ may be an amino acid side chain group (D or L configuration) and derivatives thereof; or any pharmaceutically acceptable salts thereof. The R₃ may also be chosen from:

[0019] The pharmaceutically acceptable salt may be valine butylene glycol nitrate tartrate:

[0020] The pharmaceutically acceptable salt may be norvaline butylene glycol nitrate tartrate:

[0021] The composition may further contain at least one non-steroidal anti-inflammatory drug (NSAID).

[0022] The at least one non-steroidal anti-inflammatory drug (NSAID) may be acetaminophen, acemetacin, aceclofenac, alminoprofen, arnfenac, bendazac, benoxaprofen, bromfenac, bucloxic acid, butibufen, carprofen, cinmetacin, clopirac, diclofenac, etodolac, felbinac, fenclozic acid, fenbufen, fenoprofen, fentiazac, flunoxaprofen, flurbiprofen, ibufenac, ibuprofen, indomethacin, isofezolac, isoxepac, indoprofen, ketoprofen, lonazolac, loxoprofen, metiazinic acid, mofezolac, miroprofen, naproxen, oxaprozin, pirozolac, pirprofen, pranoprofen, protizinic acid, salicylamide, sulindac, suprofen, suxibuzone, tiaprofenic acid, tolmetin, xenbucin, ximoprofen, zaitoprofen, zomepirac, aspirin, acemetcin, bumadizon, carprofenac, clidanac, diflunisal, enfenamic acid, fendosal, flufenamic acid, flunixin, gentisic acid, ketorolac, meclofenamic acid, mefenamic acid, mesalamine, and prodrugs thereof. [0023] The composition may contain at least one cyclooxygenase-2 (COX-2) selective inhibitor.

[0024] The at least one cyclooxygenase-2 (COX-2) selective inhibitor may be nimesulide, celecoxib, etoricoxib, flosulide, lumiracoxib, parecoxib, rofecoxib, tiracoxib, valdecoxib, ABT 963, BMS 347070, CS 502, DuP 697, GW-406381 , NS-386, SC-57666, SC-58125, and SC-58635.

[0025] In a second embodiment there is disclosed a method of boosting NO levels in a patient in need thereof by administering a therapeutically effective amount of the composition of the present invention.

[0026] In another embodiment, there is disclosed a method of relieving pain in a patient in need thereof comprising administering a therapeutically effective amount of the composition of the present invention in combination with at least one NSAID and COX-2 inhibitor, wherein said composition comprises a nitric oxide releasing compound. The nitric oxide releasing compound helps to counter ulcerative effects and hypertensive effects of NSAID or COX-2 inhibitor especially in hypertensive patients.

[0027] In another embodiment, there is disclosed a method of relieving pain in a patient in need thereof comprising administering a therapeutically effective amount of the composition of the present invention further containing at least one non-steroidal anti-inflammatory drug (NSAID).

[0028] In another embodiment, there is disclosed a method of relieving pain in a patient in need thereof by administering a therapeutically effective amount of the composition of the present invention prior to, during, or after administration of at least one non-steroidal anti-inflammatory drug (NSAID).

[0029] In yet another embodiment, there is disclosed a method of relieving pain in a patient in need thereof by administering a therapeutically effective amount of the composition of the present invention prior to, during, or after administration of at least one cyclooxygenase-2 (COX-2) selective inhibitor. [0030] In yet another embodiment, the administration is peroral, transdermal, intranasal, and/or sublingual.

[0031] The amount may be a daily total dosage of about 25 to 200 mg, and the daily total dosage may be divided at least in two equal dosages to be administered at twelve hours intervals. The daily total dosage may also be divided at least in three equal dosages to be administered at eight hours intervals.

[0032] The following terms are defined below.

[0033] "Amino acid ester compound" is intended to mean the condensation product of an amino acid with mononitrated alkane ou alkene diol. As will be evident to those familiar to the art, the condensation reaction could also involve, but not limited to, dipeptides or tripeptides, nitrated alcohols containing aliphatic, alkyl or aromatic moieties, as well as other nitric oxide groups attached to the alkane or alkene diols. Amino acid or dipeptide reactions are preferred as well as the condensation reaction with short chain mononitrated alkane diols such as 1 ,3 propanediol or 1 ,4 butanediol.

[0034] "Therapeutically effective amount" is intended to mean the amount of the compound and/or composition that is effective to achieve its intended purpose.

[0035] "Transdermal" is intended to mean the delivery of a compound by passage through the skin and into the blood stream.

[0036] "Transmucosal" is intended to mean the delivery of a compound by passage of the compound through the mucosal tissue and into the blood stream.

[0037] "Carriers" or "vehicles" are intended to mean carrier materials suitable for compound administration and include any such material known in the art such as, for example, any liquid, gel, solvent, liquid diluent, solubilizer, or the like, which is non-toxic and which does not interact with any components of the composition in a deleterious manner. [0038] The term "enteric coating" is intended to mean a barrier applied to oral medication to control the location in the digestive system where the oral medication released and absorbed. Enteric coatings prevent release of medication before it reaches the small intestine.

[0039] "Alkyl" is intended to mean a lower alkyl group, a substituted lower alkyl group, a haloalkyl group, a hydroxyalkyl group, an alkenyl group, a substituted alkenyl group, an alkynyl group, a bridged cycloalkyl group, a cycloalkyl group or a heterocyclic ring, as defined herein. An alkyl group may also comprise one or more radical species, such as, for example a cycloalkylalkyl group or a heterocyclicallyl group.

[0040] "Nitric oxide adduct" or "NO adduct" is intended to mean compounds and functional groups which, under physiological conditions, can donate, release and/or directly or indirectly transfer any of the three redox forms of nitrogen monoxide (NO⁺, NO^", NO^"), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action.

[0041] "Nitric oxide releasing" or "nitric oxide donating" is intended to mean methods of donating, releasing and/or directly or indirectly transferring any of the three redox forms of nitrogen monoxide (NO+, NO-, NO^'), such that the biological activity of the nitrogen monoxide species is expressed at the intended site of action. The nitric oxide releasing groups are preferably nitro groups (i.e. N0₂), nitroso groups (i.e. NO) and/or heterocyclic nitric oxide donor groups that are linked to the amino acid ester compounds through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen. The heterocyclic nitric oxide donor groups are preferably furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5- imines.

[0042] "Nitric oxide donor" or "NO donor" is intended to mean compounds that donate, release and/or directly or indirectly transfer a nitrogen monoxide species, and/or stimulate the endogenous production of nitric oxide or endothelium-derived relaxing factor (EDRF) in vivo and/or elevate endogenous levels of nitric oxide or EDRF in vivo and/or are oxidized to produce nitric oxide and/or are substrates for nitric oxide synthase and/or cytochrome P450. "NO donor" also includes compounds that are precursors of L-arginine, inhibitors of the enzyme arginase and nitric oxide mediators.

[0043] The term "pharmaceutical acceptable carrier" is intended to mean a preservative solution, a saline solution, an isotonic (about 0.9%) saline solution, or about a 5% albumin solution, suspension, sterile water, phosphate buffered saline, and the like. Other buffering agents, dispersing agents, and inert non-toxic substances suitable for delivery to a patient may be included in the compositions of the present invention. The compositions may be solutions, suspensions or any appropriate formulation suitable for administration, and are typically sterile and free of undesirable particulate matter. The compositions may be sterilized by conventional sterilization techniques.

[0044] "NSAID" is intended to mean a nonsteroidal anti-inflammatory compound or a nonsteroidal anti-inflammatory drug. NSAIDs inhibit cyclooxygenase, the enzyme responsible for the biosyntheses of the prostaglandins and certain autocoid inhibitors, including inhibitors of the various isozymes of cyclooxygenase (including but not limited to cyclooxygenase-1 and-2), and as inhibitors of both cyclooxygenase and lipoxygenase.

[0045] "Cyclooxygenase-2 (COX-2) selective inhibitor" is intended to mean a compound that selectively inhibits the cyclooxygenase-2 enzyme over the cyclooxygenase-1 enzyme. In one embodiment, the compound has a cyclooxygenase-2 IC₅o of less than about 2 μΜ and a cyclooxygenase-1 IC₅₀ of greater than about 5μΜ, in the human whole blood COX-2 assay (as described in Brideau et al., Inflamm Res., 45: 68-74 (1996)) and also has a selectivity ratio of cyclooxygenase-2 inhibition over cyclooxygenase-1 inhibition of at least 10, and preferably of at least 40. In another embodiment, the compound has a cyclooxygenase-1 IC₅₀ of greater than about 1 μΜ, and preferably of greater than 20μΜ. The compound can also inhibit the enzyme, lipoxygenase. Such selectivity may indicate an ability to reduce the incidence of common NSAT-induced side effects.

[0046] Features and advantages of the subject matter hereof will become more apparent in light of the following detailed description of selected embodiments, as illustrated in the accompanying figures. As will be realized, the subject matter disclosed and claimed is capable of modifications in various respects, all without departing from the scope of the claims. Accordingly, the drawings and the description are to be regarded as illustrative in nature, and not as restrictive and the full scope of the subject matter is set forth in the claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] In embodiments there is disclosed a composition for boosting nitric oxide co ntaining a therapeutically effective amount of a nitric oxide amino acid ester compound in association with a pharmaceutically acceptable carrier, in an enteric coating.

[0048] In another embodiment, there is disclosed a method of boosting NO levels in a patient in need thereof by administering a therapeutically effective amount of a composition of the present invention.

[0049] In another embodiment, there is disclosed a method of relieving pain in a patient in need thereof by administering a therapeutically effective amount of a composition of the present invention.

[0050] The nitric oxide amino acid ester compounds of the present invention possess many of the required characteristics necessary to fulfill the role of a primary boosting of NO levels. The compounds easily dissociate in water into the amino acid derivative and associated ion forming the pharmaceutical salt. The compounds of the present invention are extremely stable in the form of the salts, and thus possess long shelf lives and stability. The compounds are readily absorbed sublingually and this absorption factor may be enhanced through the use of inclusion in a liposome for faster and more efficient transmucosal uptake across the mucosal membrane. Administration can be accomplished through fast disintegrating sublingual tablet, sublingual spray, lozenge or other vehicle whether in solution or in a liposomal delivery system.

[0051] The nitric oxide releasing groups of the compounds of the present invention are preferably nitro groups (i.e. N0₂), nitroso groups (i.e. NO) and/or heterocyclic nitric oxide donor groups that are linked to the amino acid ester compounds through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen. The heterocyclic nitric oxide donor groups are preferably furoxans, sydnonimines, oxatriazole-5-ones and/or oxatriazole-5-imines.

[0052] The preferred compound of the present invention is the valine derivative of the nitric oxide amino acid ester of the present invention. It is also known as valine nitrooxy butyl ester or valine butylene glycol nitrate. Valine butylenes glycol nitrate and more specifically its tartrate salt possess many of the required characteristics necessary to fulfill the role of boosting NO levels. The compound easily dissociates in water into the valine derivative valine butylenes glycol nitrate and tartaric acid (H0₂CCH(OH)CH(OH)C0₂H). The compound is extremely stable in the form of the salt and thus possesses a long shelf life.

[0053] The compounds of the present invention, because of the small size of the molecule, can be other choices of linkages and/or amino acids or their derivatives. For example, as alternatives to the above choices, propyl, butyl, or longer chains may be linked to any amino acid. Other salts such as chloride salts may be used. Other amino acid derivatives may also be chosen. Derivatives of the base amino acids whether they are in the L or D configuration of these amino acids can be chosen. Non standard amino acids, or synthetic derivative of standard and non-standard amino acids may be elected, such as those containing acetyl groups attached to the amide of the molecule or nor derivatives of the amino acids, when such derivatives can be achieved. [0054] The amino acid esters compounds may be based on natural, non-standard or even modified amino acids, with the basic structure as depicted below, where the R_x represents the side chain of the amino acid (wherein R_x may be R-i , R₂ or R₃, as applicable to the specific molecule described herein):

Basic amino acid structure

[0055] Natural Amino Acids

^* essential amino acids [0056] Modified Amino Acids

[0057] The nitric oxide amino acid ester compounds of the present invention are not limited to a single amino acid molecule. The compounds of the present invention may be dipeptide or even tripeptide molecules, with the general formula depicted below and where R_x and R_y independently are any of the amino acid side chains described herein.

[0058] The composition containing a compound as defined in the present invention may include a wide variety of additional components, including, for example, one or more of gases, gaseous precursors, liquids, oils, stabilizing materials, diagnostic agents, pharmaceutical acceptable carriers, photoactive agents, bioactive agents and/or a targeting agent.

[0059] The invention provides methods for boosting NO levels by administering to the patient in need thereof a therapeutically effective amount of the compounds and/or compositions described herein. For example, the patient can be administered a therapeutically effective amount of at least one amino acid ester compound of the present invention comprising a nitric oxide releasing group, In another embodiment, the patient can be administered a therapeutically effective amount of at least one amino acid ester compound comprising a nitric oxide releasing group, and at least one nitric oxide donor compound. In yet another embodiment, the patient can be administered a therapeutically effective amount of at least one amino acid ester compound comprising a nitric oxide releasing group, and, at least one therapeutic agent, including but not limited to, such as, for example, nonsteroidal antiinflammatory compounds (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, and combinations of the two thereof. In another embodiment, the patient can be administered a therapeutically effective amount of at least one amino acid ester compound comprising a nitric oxide releasing group, and, at least one therapeutic agent, and, at least one nitric oxide donor compound. The amino acid ester compounds comprising a nitric oxide releasing group, nitric oxide donors, and/or therapeutic agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.

[0060] Suitable NSAIDs include, but are not limited to, acetaminophen, acemetacin, aceclofenac, alminoprofen, arnfenac, bendazac, benoxaprofen, bromfenac, bucloxic acid, butibufen, carprofen, cinmetacin, clopirac, diclofenac, etodolac, felbinac, fenclozic acid, fenbufen, fenoprofen, fentiazac, flunoxaprofen, flurbiprofen, ibufenac, ibuprofen, indomethacin, isofezolac, isoxepac, indoprofen, ketoprofen, lonazolac, loxoprofen, metiazinic acid, mofezolac, miroprofen, naproxen, oxaprozin, pirozolac, pirprofen, pranoprofen, protizinic acid, salicylamide, sulindac, suprofen, suxibuzone, tiaprofenic acid, tolmetin, xenbucin, ximoprofen, zaltoprofen, zomepirac, aspirin, acemetcin, bumadizon, carprofenac, clidanac, diflunisal, enfenamic acid, fendosal, flufenamic acid, flunixin, gentisic acid, ketorolac, meclofenamic acid, mefenamic acid, mesalamine, prodrugs thereof, and the like.

[0061] Suitable NSAIDs are described more fully in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995, Pgs. 617-657; the Merck Index on CD-ROM, 13th Edition ; and in U.S. Patents Nos. 6,057,347 and 6,297,260 assigned to NitroMed Inc.

[0062] In some embodiments the NSAIDs are acetaminophen, diclofenac, flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen or aspirin. In more particular embodiments the acetaminophen is administered in an amount of about 325 milligrams to about 4 grams as a single dose or as multiple doses per day ; the diclofenac is administered in an amount of about 50 milligrams to about 250 milligrams as a single does or as multiple doses per day; the flurbiprofen is administered in an amount of about 100 milligrams to about 300 milligrams as a single does or as multiple doses per day; the ibuprofen is administered in an amount of about 400 milligrams to about 3.2 grams as a single does or as multiple doses per day; the indomethacin is administered in an amount of about 25 milligrams to about 200 milligrams as a single does or as multiple doses per day; the ketoprofen is administered in an amount of about 50 milligrams to about 300 milligrams as a single does or as multiple doses per day; the naproxen is administered in an amount of about 250 milligrams to about 15 grams as a single does or as multiple doses per day ; the aspirin is administered in an amount of about 10 milligrams to about 2 grams as a single does or as multiple doses per day.

[0063] Suitable COX-2 inhibitors include, but are not limited to, nimesulide, celecoxib (CELEBREX®), etoricoxib (ARCOXIA®), flosulide, lumiracoxib (PREXIG®, COX-189), parecoxib (DYNSTAT®), rofecoxib (VIOXX®), tiracoxib (JTE-522), valdecoxib (BEXTRA®), ABT 963, BMS 347070, CS 502, DuP 697, GW-406381 , NS-386, SC-57666, SC-58125, SC- 58635, and the like, and mixtures of two or more thereof. Suitable COX-2 inhibitors are in U.S. Patents Nos. 5,344,991 , 5,380,738, 5,393,790, 5,409,944, 5,434,178, 5,436,265, 5,466,823, 5,474,995, 5,510,368, 5,536,752, 5,550,142, 5,552,422, 5,604,253, 5,604,260, 5,639,780, 5,932,598 and 6,633,272, and in WO 94/03387, WO 94/15723, WO 94/20480, WO 94/26731 , WO 94/27980, WO 95/00501 , WO 95/15316, WO 96/03387, WO 96/03388, WO 96/06840, WO 96/21667, WO 96/31509, WO 96/36623, WO 97/14691 , WO 97/16435, WO 01/45703 and WO 01/87343; and in the literature, such as in Goodman and Gilman, The Pharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1995; and the Merck Index on CD- ROM, Thirteenth Edition; and on STN Express, file phar and file registry.

[0064] When administered separately, the amino acid ester compound comprising a nitric oxide releasing group, nitric oxide donor and/or therapeutic agent can be administered about the same time as part of the overall treatment regimen, i.e., as a combination therapy. "About the same time" includes administering the one amino acid ester compound comprising a nitric oxide releasing group, simultaneously, sequentially, at the same time, at different times on the same day, or on different days, as long as they are administered as part of an overall treatment regimen, i.e., combination therapy or a therapeutic cocktail. [0065] When administered in vivo, the compounds and compositions of the invention can be administered in combination with pharmaceutically acceptable carriers and in dosages described herein. When the compounds and compositions of the invention are administered as a combination of at least one amino acid ester compound comprising a nitric oxide releasing group and/or at least one nitric oxide donor and/or therapeutic agent, they can also be used in combination with one or more additional compounds which are known to be effective against the specific disease state targeted for treatment. The nitric oxide donors, therapeutic agents and/or other additional compounds can be administered simultaneously with, subsequently to, or prior to administration of the amino acid ester compound comprising a nitric oxide releasing group.

[0066] The compounds and compositions of the invention can be administered by any available and effective delivery system including, but not limited to, orally, bucally, parenterally, by inhalation, by topical application, by injection, transdermal^, or rectally (e.g. , by the use of suppositories) in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles, as desired. Parenteral includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques. In one embodiment of the invention the amino acid ester compound comprising at least one nitric oxide releasing group is administered orally, parentally or by inhalation.

[0067] Solid dosage forms for oral administration can include capsules, sustained-release capsules, tablets, sustained release tablets, chewable tablets, sublingual tablets, effervescent tablets, pills, powders, granules and gels. In such solid dosage forms, the active compounds can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms can also comprise, as in normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets, effervescent tablets, and pills, the dosage forms can also comprise buffering agents. Soft gelatin capsules can be prepared to contain a mixture of the active compounds or compositions of the invention and vegetable oil. Hard gelatin capsules can contain granules of the active compound in combination with a solid, pulverulent carrier such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives of gelatin. Tablets and pills can be prepared with enteric coatings.

[0068] The compounds and compositions of the invention can include an enteric coating to prevent release of the amino acid ester compound before it reaches the small intestine. Enteric coatings are often used to prevent stomach irritation caused by some medicine or to safeguard the medicine or compounds against the stomach acids or enzymes of the gastric environment. Therefore, an enteric coating will control the location in the digestive system where it is absorbed.

[0069] Enteric coatings are selectively insoluble substances that will not dissolve in the acidic juices (pH ~3) of the stomach, but upon reaching the relatively higher pH (pH >5.5) environment of the small intestine will readily dissolve. Materials used for enteric coatings include fatty acids, waxes, and shellac as well as plastics. Suitable materials used for enteric coatings include but are not limited to: methacrylic acid copolymers, cellulose acetate (including succinate and phthalate versions), styrol maleic acid co-polymers, polymethacrylic acid/acrylic acid copolymer, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate phthalate, hydroxyethyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, cellulose acetate tetrahydrophtalate, acrylic resin, timellitate, shellac, alginic acid, medium chain triglycerides, oleic acid, stearic acid.

[0070] The compositions of this invention can further include conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral application which do not deleteriously react with the active compounds. Suitable pharmaceutically acceptable carriers include, for example, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, surfactants, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethyl- cellulose, polyvinylpyrrolidone, and the like. The pharmaceutical preparations can be sterilized and if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavoring and/or aromatic substances and the like which do not deleteriously react with the active compounds. For parenteral application, particularly suitable vehicles consist of solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants. Aqueous suspensions may contain substances which increase the viscosity of the suspension and include, for example, sodium carboxymethyl cellulose, sorbitol and/or dextran. Optionally, the suspension may also contain stabilizers.

[0071] Various delivery systems are known and can be used to administer the compounds or compositions of the invention, including, for example, encapsulation in liposomes, microbubbles, emulsions, microparticles, microcapsules and the like. The required dosage can be administered as a single unit or in a sustained release form.

[0072] The bioavailability of the compositions can be enhanced by micronization of the formulations using conventional techniques such as grinding, milling, spray drying and the like in the presence of suitable excipients or agents such as phospholipids or surfactants.

[0073] Sustained release dosage forms of the invention may comprise microparticles and/or nanoparticles having a therapeutic agent dispersed therein or may comprise the therapeutic agent in pure, preferably crystalline, solid form. For sustained release administration, microparticle dosage forms comprising pure, preferably crystalline, therapeutic agents are preferred. The therapeutic dosage forms of this aspect of the invention may be of any configuration suitable for sustained release.

[0074] Microparticles, (also called microgranules neutral pellets, nonpareil seeds, sugar spheres or sugar beads) are inert spherical granules often composed of sucrose and/or maize (corn) starch, or other ingredients which are pharmacologically indifferent, digestible excipients, frequently present in the normal diet. Microgranules are often produced using a layered sugar-coating structure. The result is microparticles with sufficient mechanical stability for further processing. The ideally rounded microparticles classed in closely graduated particle sizes are then coated with active substance(s) and/or sustained release additives. The core of the finished pellet contains no active substance itself so that this solution is used for low-dose substances or substances with a high effect/dose relation. But the use of small sugar spheres and corresponding procedures also makes it possible to use this method to produce pellets containing more than 75% active substance. Microparticles may be used as excipients in the capsule and tablet formulation of the present invention, particularly in multiparticulate formulations. They are the core upon which a Amino acid ester compounds are coated, usually used for controlled or sustained release drug delivery technologies. The microparticles may be coated with the Amino acid ester compound, which are then coated with a film, such as an enteric coating or any other suitable film. Subsequently, a secondary or even a tertiary layer of sugar may be added and coated with the active Amino acid ester compounds for release of the molecules in two or even three bursts of Amino acid ester compounds or Amino acid ester compounds and other NSAID or COX-2 inhibitor included in the formulation of the present invention.

[0075] One important requirement for uniform application of the active substance(s) in subsequent coating is the particle size of the microgranules. Calculating the surface-per-input quantity also depends on a uniform particle size, as well as a spherical shape. The particle size is defined in micrometer (μΓη) and according to the international sieve series, whereby the partly uneven numbers of the nominal mesh widths come from conversion from the still common ASTM standard sieves.

Table 1 : μηι limits and corresponding ASTM mesh values.

[0076] Nanoparticle sustained release therapeutic dosage forms are preferably biodegradable and, optionally, bind to the vascular smooth muscle cells and enter those cells, primarily by endocytosis. The biodegradation of the nanoparticles occurs over time (e.g., 30 to 120 days; or 10 to 21 days) in prelysosomic vesicles and lysosomes. Preferred larger microparticle therapeutic dosage forms of the invention release the therapeutic agents for subsequent target cell uptake with only a few of the smaller microparticles entering the cell by phagocytosis. A practitioner in the art will appreciate that the precise mechanism by which a target cell assimilates and metabolizes a dosage form of the invention depends on the morphology, physiology and metabolic processes of those cells. The size of the particle sustained release therapeutic dosage forms is also important with respect to the mode of cellular assimilation. For example, the smaller nanoparticles can flow with the interstitial fluid between cells and penetrate the infused tissue. The larger microparticles tend to be more easily trapped interstitiall-y in the infused primary tissue, and thus are useful to deliver anti-proliferative therapeutic agents.

[0077] Particular sustained release dosage forms of the invention comprise biodegradable microparticles or nanoparticles. More particularly, biodegradable microparticles or nanoparticles are formed of a polymer containing matrix that biodegrades by random, nonenzymatic, hydrolytic scissioning to release therapeutic agent, thereby forming pores within the particulate structure. [0078] In a particular embodiment, the compositions of the invention are administered parenterally or orally as a sustained release tablet or a sustained release capsule. For example, the parental or sustained release formulations can comprise a therapeutically effective amount of at least one amino acid ester compound comprising a nitric oxide releasing group or a pharmaceutically acceptable salt thereof, and, optionally at least one nitric oxide donor, or the parental or sustained release formulations can comprise a therapeutically effective amount of at least one amino acid ester compound comprising a nitric oxide releasing group or a pharmaceutically acceptable salt thereof, and at least one nitric oxide donor, and, optionally at least one therapeutic agent

[0079] The compounds and compositions of the invention can be formulated as pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts include, for example, alkali metal salts and addition salts of free acids or free bases. The nature of the salt is not critical, provided that it is pharmaceutically-acceptable. Suitable pharmaceutically- acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid and the like. Appropriate organic acids include, but are not limited to, aliphatic, cycloaliphatic, aromatic, heterocyclic, carboxylic and sulfonic classes of organic acids, such as, for example, formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, salicylic, p- hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2- hydroxyethanesulfonic, sulfanilic, stearic, algenic, β-hydroxybutyric, cyclohexylaminosulfonic, galactaric and galacturonic acid and the like. Suitable pharmaceutically-acceptable base addition salts include, but are not limited to, metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from primary, secondary and tertiary amines, cyclic amines, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N- methylglucamine) and procaine and the like. All of these salts may be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. In one embodiment, the pharmaceutically acceptable salts of the compounds of the invention include the nitrate salts. In another embodiment, the pharmaceutically acceptable salts of the compounds of the invention are heterocyclic compounds such as, furoxan, a sydnonimine, an oxatriazole-5- one and/or an oxatriazole-5-imine.

[0080] While individual needs may vary, determination of optimal ranges for effective amounts of the compounds and/or compositions is within the skill of the art. Generally, the dosage required to provide an effective amount of the compounds and compositions, which can be adjusted by one of ordinary skill in the art, will vary depending on the age, health, physical condition, sex, diet, weight, extent of the dysfunction of the recipient, frequency of treatment and the nature and scope of the dysfunction or disease, medical condition of the patient, the route of administration, pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular compound used, whether a drug delivery system is used, and whether the compound is administered as part of a drug combination.

[0081] The amount of a given amino acid ester compound comprising a nitric oxide releasing group of the invention that will be effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques, including reference to Goodman and Gilman, supra; The Physician's Desk Reference, Medical Economics Company, Inc., Oradell, N. J., 1995; and Drug Facts and Comparisons, Inc., St. Louis, MO, 1993. The precise dose to be used in the formulation will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided by the physician and the patient's circumstances.

[0082] In one embodiment of the invention the amino acid ester compound comprising a nitric oxide releasing group is administered as a daily dose of about 1 mg to about 100 mg, preferably at a daily dose of about 5 mg to 50 mg and even more preferably at a daily dose of about 10 to 30 mg. The administration may be as a single dose or as a divided dose in infusion.

Alternative embodiments

[0083] EXAMPLE I

[0084] Exemplary method of preparation of the compounds of the present invention

[0085] The compounds of the present invention may be prepared through production of an intermediate 2-nitrooxy alkyl alcohol. For example, such intermediate may be obtained by reaction of ethylene glycol with glacial acetic acid, acetic anhydride and nitric acid.

butylene glycol (a.k.a. butanediol) NOBA

Intermediate 2

[0086] This intermediate butyl alcohol is then reacted with valine attached through the amino group to a BOC column to render the amino group inert and non-reactive. This forms the product valine nitrooxy butylester or Valine butylene Glycol Nitrate which is then precipitated and purified as a tartrate salt.

[0087] The synthetic route (DCC or EDC) involves the key intermediates 2 and 4. The quality of the intermediate 2 must be controlled, and methods of purification of the intermediate 2, such as high vacuum distillation may be used to purify and isolate high quality intermediate 2. Intermediate 3 is obtained by the condensation reaction of intermediate 2 and valine derivative (identified as 1) in ethyl acetate.

[0088] The hydrolysis (deprotection) reaction of compound 3 will then lead to the key intermediate 4 that is then combined with tartaric acid in order to yield the final product of valine butylene glycol nitrate tartrate.

[0089] EXAMPLE 2

[0090] Intermediate 2 prepared as above is reacted with norvaline (identified as intermediate 5) instead of valine, to yield the compound of the present invention norvaline butylene glycol nitrate, and the tartrate salt of the same.

norvaline butylene glycol nitrate tartrate

[0091] EXAMPLE 3

[0092] The compounds of the present invention may also take the form of dipeptides which may be synthesized from similar reactions, such as that de icted below.

[0093] The embodiments and examples presented herein are illustrative of the general nature of the subject matter claimed and are not limiting. It will be understood by those skilled in the art how these embodiments can be readily modified and/or adapted for various applications and in various ways without departing from the spirit and scope of the subject matter disclosed claimed. The claims hereof are to be understood to include without limitation all alternative embodiments and equivalents of the subject matter hereof. Phrases, words and terms employed herein are illustrative and are not limiting. Where permissible by law, all references cited herein are incorporated by reference in their entirety. It will be appreciated that any aspects of the different embodiments disclosed herein may be combined in a range of possible alternative embodiments, and alternative combinations of features, all of which varied combinations of features are to be understood to form a part of the subject matter claimed.

Claims

CLAIMS:

1. A composition for use with a NSAID or a COX-2 inhibitor, which comprises a therapeutically effective amount of a nitric oxide releasing compound of formula (I):

(I) wherein Ri is chosen from CH₂-CH₃ and (CH₃)₂,

wherein R₂ is chosen from a hydrogen atom, an amino acid (D or L configuration) and derivatives thereof, forming a peptide bond;

or any pharmaceutically acceptable salts thereof; in association with a pharmaceutically acceptable carrier, in an enteric coating.

2. The composition according to claim 1 , wherein said compound of formula (I) is valine butylene glycol nitrate:

or any pharmaceutically acceptable salts thereof.

3. The composition according to claim 1 , wherein said compound of formula (I) is norvaline butylene glycol nitrate:

or any pharmaceutically acceptable salts thereof.

4. The composition according to claim 1 , wherein said compound of formula (I) is:

wherein R₃ is an amino acid side chain group (D or L configuration) and derivatives thereof;

or any pharmaceutically acceptable salts thereof.

5. The composition according to claim 1 , wherein said pharmaceutically acceptable salt is valine butylene glycol nitrate tartrate:

6. The composition according to claim 1 , wherein said pharmaceutically acceptable salt is norvaline butylene glycol nitrate tartrate:

7. The composition according to claim 1 , wherein said R₂ is an amino acid of formula (II) (D or L configuration) and derivatives thereof, forming a peptide bond:

H H O

H N- -O H

(Π)

wherein R_x is chosen from

8. The composition according to claim 4, wherein R₃ chosen from:

H H

CH₃ CH₃

CH₃

(CH₃)₂ CH

CH₃

9. The composition according to any one of claims 1 to claim 8, further comprising at least one non-steroidal anti-inflammatory drug (NSAID).

10. The composition according to claim 9, wherein said at least one nonsteroidal anti-inflammatory drug (NSAID) is chosen from acetaminophen, acemetacin, aceclofenac, alminoprofen, arnfenac, bendazac, benoxaprofen, bromfenac, bucloxic acid, butibufen, carprofen, cinmetacin, clopirac, diclofenac, etodolac, felbinac, fenclozic acid, fenbufen, fenoprofen, fentiazac, flunoxaprofen, flurbiprofen, ibufenac, ibuprofen, indomethacin, isofezolac, isoxepac, indoprofen, ketoprofen, lonazolac, loxoprofen, metiazinic acid, mofezolac, miroprofen, naproxen, oxaprozin, pirozolac, pirprofen, pranoprofen, protizinic acid, salicylamide, sulindac, suprofen, suxibuzone, tiaprofenic acid, tolmetin, xenbucin, ximoprofen, zaltoprofen, zomepirac, aspirin, acemetcin, bumadizon, carprofenac, clidanac, diflunisal, enfenamic acid, fendosal, flufenamic acid, flunixin, gentisic acid, ketorolac, meclofenamic acid, mefenamic acid, mesalamine, and prodrugs thereof.

1 1. The composition of claim 9, wherein said at least one non-steroidal anti-inflammatory drug (NSAID) is naproxen.

12. The composition according to any one of claims 1 to 5, further comprising at least one cyclooxygenase-2 (COX-2) selective inhibitor.

13. The composition according to claim 12, wherein said at least one cyclooxygenase-2 (COX-2) selective inhibitor is chosen from nimesulide, celecoxib, etoricoxib, flosulide, lumiracoxib, parecoxib, rofecoxib, tiracoxib, valdecoxib, ABT 963, BMS 347070, CS 502, DuP 697, GW-406381 , NS-386, SC-57666, SC-58125, and SC-58635.

14. A method of boosting NO levels in a patient in need thereof comprising administering a therapeutically effective amount of the composition of any one of claims 1 to .13

15. A method of relieving pain in a patient in need thereof comprising administering a therapeutically effective amount of the composition of any one of claims 1 to 13 in combination with at least one of NSAID and COX-2 inhibitor, wherein said composition comprises a nitric oxide releasing compound.

16. A method of relieving pain in a patient in need thereof comprising administering a therapeutically effective amount of the composition of any one - of claims 1 to 8 prior to, during, or after administration of at least one nonsteroidal anti-inflammatory drug (NSAID).

17. A method of relieving pain in a patient in need thereof comprising administering a therapeutically effective amount of the composition of any one of claims 1 to 8 prior to, during, or after administration of at least one cyclooxygenase-2 (COX-2) selective inhibitor.

18. The method according to any one of claims 14 to 17, wherein said administration is peroral.

19. The method according to any one of claims 14 to 17, wherein said administration is chosen from transdermal, intranasal, and sublingual.

20. The method according to any one of claims 14 to 19, wherein said amount is a daily total dosage of about 25 to 200 mg.

21. The method according to claim 20, wherein said daily total dosage is divided at least in two equal dosages to be administered at twelve hours intervals.

22. The method according to claim 20, wherein said daily total dosage is divided at least in three equal dosages to be administered at eight hours intervals.