DRUG COMPOSITIONS STABILIZED AGAINST OXIDATION AND DISCOLORATION

Abstract: The oxidation - and color-stability of certain ACE inhibitors is optimized when they are formulated with a stabilizer and at least one lubricant and/or excipient.

Description: Certain Angiotensin Converting Enzyme (ACE) inhibitors are highly susceptible to oxidative attack resulting in discoloration when they are formulated into pharmaceutical dosage forms. It is the conversion to unwanted colored substances which can lessen drug effectiveness in compositions containing this type of drug. It has been discovered that discoloration and degradation due to oxidation which have been common problems associated with dosage forms containing, eg., captopril, can be overcome via the use of ascorbic acid and/or sodium ascorbate as ingredient(s) in the formulation. The effect of the ascorbic acid is maximized when certain lubricants, eg., Sterotex ® , and/or talc, are used in combination therewith. Furthermore, the overall stability of the final pharmaceutical formulation is enhanced when specific types of excipients, such as mannitol and lactose are included therein. It is described in EP-A-99239 that ascorbic acid may be used as an antioxidant in connection with certain anti-glaucoma ACE-inhibitors. It is, however, not mentioned that ascorbic acid may be used to prevent the discoloration of the active ingredient containing drug in the amount of 0.5 to 15 weight percent of the composition. The compositions of the invention have several advantages over compositions which do not contain the stabilizing additive(s) in the amount discussed herein. Principally, the active ingredients or drug contained therein is initially preserved from oxidative attack. Furthermore, the discoloration which sometimes occurs when ACE inhibitors of this class are formulated and allowed to stand for significant periods of time, is minimized or eliminated completely. Thus, tabletted quinapril formulations can be produced which will undergo no detectable discoloration due to oxidation. In addition to their greater storage stability, the formulations of the invention are rendered more suitable for use in drug combinations. These and other advantages of the invention will become apparent from a consideration of the following description of the invention. The invention deals with: I. A pharmaceutical composition which contains: (a) a drug component which comprises an Angiotensin Converting Enzyme inhibitor of formula I wherein R₁ and R₂ are -H or -OC n H 2n+1 ; R₃ is -H or -C n H 2n+1 ; and n = 1 to 5, which is susceptible to discoloration, (b) one or more of ascorbic acid, and, sodium ascorbate at a color stabilizing amount of from 0.5% to 15% by weight of the composition and optionally, (c) one or more components which are compatible with the ascorbic acid stabilizer. II. A process for stabilizing an ACE inhibitor drug as defined above which comprises the steps of contacting the drug with: (a) one or more ascorbic acid, sodium ascorbate or mixture thereof at a color stabilizing amount of from 0.5 % to 15 % by weight of the composition to inhibit oxidation, and, optionally, (b) one or more components which are compatible with the ascorbic acid stabilizer. The compositions of the invention contain at least one ACE inhibitor of formula (I) and, optionally, one or more other medicament drugs or beneficial substances. In formula (I) preferably , R₁ and R₂ are the same. Most preferably, R₁ and R₂ are both CH₃O- or H-when R₃ is -H or -C₂H₅. Mixtures are operable. The production of compounds of formula (I) is disclosed in U. S. patent 4,344,949. One preferred ACE inhibitor is Quinapril. It has the structure: The total drug content of the final composition will be from 2 to 30%, preferably 3% to 20%. When one or more ACE inhibitor(s) is the only drug present, the total concentration of ACE inhibitors in the final dosage form will be 1% to 70% preferably 2% to 30%. All percentages stated herein are weight percentages based on total composition weight, unless otherwise stated. The daily dosages, of the pharmaceutical preparations to be used depend upon such factors as the nature of the dosage form, the nature of the drug(s) and the type and extent of any interaction(s) in drug combinations. Thus, the therapeutic needs of the individual patient and the desires of the prescribing physician will often dictate the dosage levels to be employed. In general, however, the manufacturer's specifications for any drug or drug combination are useful guides to administration. The Physician's Desk Reference or other competent publication can be consulted to ascertain appropriate dosage levels. Nonetheless, typical dosage levels for quinapril are 2 mg to 80 mg per dosage. Suitable categories of drugs that may be employed in addition to ACE inhibitors in the instant compositions may vary widely and generally represent any stable drug combination. Illustrative categories and specific examples include: (a) Antitussives, such as dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, and chlophedianol hydrochloride; (b) Antihistamines, such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, and phenyltoloxamine citrate, (c) Decongestants, such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine, hydrochloride ephedrine; and (d) Various alkaloids, such as codeine phosphate, codeine sulfate and morphine. (e) Mineral supplements such as potassium chloride and calcium carbonates. The medicaments and/or other beneficial substances to be used herein may be selected from a wide variety of substances and pharmaceutically acceptable forms thereof, eg., their acid addition salts. Both organic and inorganic salts may be used provided the drug maintains its medicament value. Exemplary acid salts include hydrochloride, hydrobromide, orthophosphate, benzoate, maleate, tartrate, succinate, citrate, salicylate, sulfate and acetate. Mixtures are operable. One preferred group of drugs to be used in combination with ACE inhibitors includes beta-blockers, diuretics and calcium blockers. The oxidative instability which is exhibited by some of the drugs discussed above can be overcome via the use of one or more of ascorbic acid and sodium ascorbate as stabilizer(s). While the use of ascorbic acid as an antioxidant for pharmaceuticals is known, its function as an oxidation inhibitor in stable ACE inhibitor formulations is not yet known. All or part of the ascorbic acid can be replaced with sodium ascorbate. Ascorbic acid itself is highly preferred. The quantity of ascorbic acid or sodium ascorbate to be used to stabilize the compositions of the invention will lie between 0.5% and 15%, preferably 1.0% to 10.0%. This amount will effectively retard or prevent oxidation and discoloration of the ACE inhibitor component(s). The phase "ascorbic acid component" is used herein to mean the acid and/or sodium ascorbate. Minor amounts of one or more other stabilizers can be tolerated in the instant formulations, but their use must not significantly interfere with the operation of the ascorbic stabilizer which is used. The optional lubricant component(s) to be used in the pharmaceutical products and methods of the invention are substances which are compatible with the ascorbic acid stabilizer. Generally, they are substances which do not contain groups which could significantly interfere with the function of either the ascorbic component or the drug component. One preferred group of lubricants include hydrogenated vegetable oils, eg., hydrogenated cottonseed oil, eg., sterotex ® and talc. Mixtures are operable. It is thought that the presence of readily ionizable moieties in the lubricant component adversely affects the action of the ascorbic stabilizer. Thus, stearic acid and conventional metal salts thereof are not operable lubricants in the instant formulations because they interfere with the ability of ascorbic acid to prevent oxidation. Generally, the quantity of lubricant present will be from 0.5% to 10%, preferably 1% to 5%. The optional excipients which can be used in the instant compositions are also substances which must be compatible with the ascorbic acid component so when resold, they do not interfere with its function in the composition. Generally, the excipients to be used herein include sugars such as mannitol, lactose, and other sweeteners and carriers which do not adversely affect the function of the other ingredients in the composition. Mannitol, lactose, and other sugars are preferred. Mixtures are operable. The compositions of the invention may contain carriers, diluents, pigments, binders, colorants, and other additives conventionally used in the production of pharmaceutical products. The method by which the ingredients are combined -- ie., the processing of the products of the invention -- is not critical. Any techniques which are appropriate according to the physical and chemical nature of the materials to be treated can be employed. The percentages in which excipients are used are not critical. In general, their quantities will be consistent with the amount given above for the drug, stabilizer, and lubricant components, ie., they make up the remainder of the composition. The final form of the pharmaceutical preparations made in accordance with the invention can vary greatly. Thus, tablets, capsules, sachets, sprinklers, pomades, transdermal compositions buccal preparations, candy compositions, nasal formulations, ocular compositions, are contemplated. Tablets, caplets, and capsules are preferred. Solid, semi-solid, and liquid formulations can be made, however, solids are highly preferred. The drug preparations can be adapted for immediate, slow, or sustained release profiles, or any combination of these. Thus a formulation adapted to give an initial loading dosage within 30 minutes followed by sustained release of the remaining drug over 4 to 12 hours is contemplated. Sustained and immediate release formulations are preferred.

Claims: A pharmaceutical composition which contains: (a) a drug component which comprises an Angiotensin Converting Enzyme inhibitor of formula I wherein R₁ and R₂ are -H or -OC n H 2n+1 ; R₃ is -H or -C n H 2n+1 ; and n = 1 to 5, which is susceptible to discoloration, (b) one or more of ascorbic acid and sodium ascorbate at a color stabilizing amount of from. 0.5% to 15% by weight of the composition and optionally, (c) one or more components which are compatible with the ascorbic acid stabilizer. The composition of Claim 1 wherein (c) is at least one material selected from excipients and lubricants. The composition of Claim 2 wherein (a) is quinapril and (c) contains a lubricant and an excipient. The composition of Claim 3 wherein the lubricant is selected from hydrogenated vegetable oil, talc, and mixtures thereof. The composition of Claim 4 wherein the excipient is selected from mannitol and lactose. The composition of Claim 5 wherein the lubricant is hydrogenated cottonseed oil. The composition of Claim 6 wherein (a) contains at least one additional drug. A tablet or candy containing the composition of Claim 1 to 7. A process for stabilizing an Angiotensin Converting Enzyme inhibitor drug as defined in Claim 1 which comprises the step of contacting the drug with: (a) one or more of ascorbic acid, and sodium ascorbate at a color stabilizing amount of from 0.5% to 15% by weight of the composition and optionally, (b) one or more components which are compatible with the ascorbic acid stabilizer. The process of claim 9 wherein R₁, and R₂ are -H and R₃ is -C₂H₅. The process of claim 9 wherein R₁ and R₂ are both -OCH₃ and R₃ is either -H or -C₂H₅.

Inventors: FAWZI, MAHDI BAKIR, HARRIS, MICHAEL RAY, HOKANSON, GERARD CLIFFORD, MURTHY, KUCHI SURY, REISCH, ROBERT GEORGE, JR., WALDMAN, FRANK STANLEY
Applicants: WARNER-LAMBERT COMPANY
Application year: 1987
Main classification: A61K31
IPC codes: A61K47, A61K31, A61P9, A61K45, A61P43