The present invention is directed to ACE inhibitor-containing compositions stabilized by the presence of magnesium oxide. Preferably, the ACE inhibitor, quinapril, is protected from certain forms of degradation when prepared in a pharmaceutical composition consisting essentially of magnesium oxide as the stabilizing agent. The presence of magnesium oxide also lends itself to favorable processing conditions during the manufacture of ACE inhibitor-containing compositions, especially processing by wet granulation.

DETAILED DESCRIPTION OF THE INVENTION

The invention deals with:

• (a) Diuretics, such as hydrochlorothiazide,
• (b) Antitussives, such as dextromethorphan, dextromethorphan hydrobromide, noscapine, carbetapentane citrate, and chlophedianol hydrochloride,
• (c) Antihistamines, such as chlorpheniramine maleate, phenindamine tartrate, pyrilamine maleate, doxylamine succinate, and phenyltoloxamine citrate,
• (d) Decongestants, such as phenylephedrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, and ephedrine,
• (e) Various alkaloids, such as codeine phosphate, codeine sulfate, and morphine,
• (f) Mineral supplements such as potassium chloride and the like.

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, e.g., their acid addition salts. Both organic and inorganic salts may be used provided the drug maintains its medicament value. Exemplary acid salts include, but are not limited to, hydrochloride, hydrobromide, orthophosphate, benzoate, maleate, tartrate, succinate, citrate, salicylate, sulfate, acetate, and the like. Mixtures are operable.

One preferred group of drugs to be used in combination with ACE inhibitors includes: betablockers, diuretics, calcium blockers, and the like.

Stabilizer(s)

The cyclization and hydrolytic instability which are exhibited by certain of the drugs discussed above can be overcome via the use of a suitable quantity, i.e., an effective amount of magnesium oxide together with a an agent that minimizes the hydrolysis of the ACE inhibitor, such as saccharides. While additional stabilizers may be present in the present invention, their cyclization stabilizing effects on the ACE inhibitor formulations are minimal in comparison to the stabilizing effects of the magnesium oxide. Even small amounts of magnesium carbonate, which can result from the exposure of magnesium oxide to water and air, will have a minimal stabilizing effect on the ACE inhibitor formulations when compared to the stabilizing effect of the magnesium oxide present in the formulation.

Magnesium oxide, or calcined magnesia, is commercially available from such companies as Dead Sea Periclase of Israel, Lohmann of Germany or Morton International. This compound occurs in nature as the mineral periclase. Commercial preparation of magnesium oxide from magnesite ores is described in U.S. Pat. No. 3,320,029.

Magnesium oxide is available in many commercial grades, all of which are within the scope of the present invention. Two preferred forms of magnesium oxide are a very bulky form termed "Light" and a dense form termed "Heavy."

In the preferred embodiment of the invention, the stabilized ACE-inhibitor compositions consist essentially of magnesium oxide as the cyclization stabilizer. The quantity of the magnesium oxide to be used will lie between about 1% and 90%, preferably about 1% to about 50%, and most preferably about 1% to about 10% of the total composition. In general, any amount which will effectively retard or prevent cyclization degradation of the ACE inhibitor component(s) can be used.

Hydrolysis-Minimizing Agent

The hydrolysis-minimizing agents of the present invention act to protect the ACE inhibitor from hydrolytic degradation. The hydrolysis-minimizing agent(s) to be used in the pharmaceutical products and methods of the invention are substances which are compatible with magnesium oxide so that they do not interfere with magnesium oxide's function in the composition. Generally, they are substances which do not contain groups which could significantly interfere with the function of either the metal-containing component or the drug component. Preferred hydrolysis-minimizing agents of the present invention are saccharides such as mannitol, lactose, and other sugars, diuretics, dicalcium phosphate, hydrochloro thiazide, and known fillers that have a hydrolysis-minimizing effect on the ACE inhibitors. Saccharides are most preferred and mixtures are operable.

Generally, the quantity of the hydrolysis-minimizing agent present will be from about 10% to about 95%, preferably about 50% to about 95%, and most preferably from about 70% to about 90% of the total composition.

Dosage Forms

The compositions of the present invention can be administered to a patient alone or as part of a composition that contains other components such as excipients, diluents, and carriers, all of which are well-known in the art. The compositions can be administered to humans and animals either orally, rectally, parenterally (intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments, or drops), or as a buccal or nasal spray.

The final form of the pharmaceutical preparations made in accordance with the invention can vary greatly. Orally administrable forms, i.e., tablets, caplets, and capsules, are preferred. Solid, semi-solid, and liquid formulations can be made. However, solids are highly preferred. The optional excipients which can be used in the instant compositions are also substances which must be compatible with magnesium oxide so that it does not interfere with its function in the composition.

Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, or emulsions and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents, or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), Cremophor EL (a derivative of castor oil and ethylene oxide; purchased from Sigma Chemical Co., St. Louis, Mo.) and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, as for example, carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as for example, glycerol; (d) disintegrating agents, as for example, agar-agar, potato or tapioca starch, alginic acid, certain complex silicates, modified starch, polyvinylpyrrolidone (cross- or uncross-linked), and modified cellulose derivatives, (e) solution retarders, as for example paraffin; (f) absorption accelerators, as for example, quaternary ammonium compounds; (g) wetting agents, as for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, as for example, kaolin and bentonite; (i) lubricants, as for example, talc, hydrogenated vegetable oil, zinc stearate, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate; (j) pigments; and (k) colorants or mixtures thereof. In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethyleneglycols and the like.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and others well-known in the art. They may contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions which can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide, oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, Cremophor EL (a derivative of castor oil and ethylene oxide; purchased from Sigma Chemical Co., St. Louis, Mo.), polyethyleneglycols and fatty acid esters of sorbitan or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

Compositions for rectal administrations are preferably suppositories which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and, therefore, melt in the rectum or vaginal cavity and release the active component.

Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants. The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

The above ACE inhibitor-containing compositions set forth above will be used in therapeutic amounts as indicated in the Physicians' Desk Reference (PDR) 47^th Edition (1993), which is incorporated herein by reference, or such therapeutically useful amounts as would be known to one of ordinary skill in the art.

The compositions can be administered at the recommended maximum clinical dosage or at lower doses. Dosage levels of the active compounds in the compositions of the invention may be varied so as to obtain a desired therapeutic response depending on the route of administration, severity of the disease, and the response of the patient. The determination of optimum dosages for a particular patient is well known to those skilled in the art.

Processing

The present invention is directed to a process for stabilizing an ACE inhibitor drug which comprises the step of contacting an effective amount of the drug with an effective amount of magnesium oxide and a hydrolysis-minimizing agent suitable to retard cyclization, hydrolysis, and/or discoloration, wherein the magnesium oxide is the principal cyclization stabilizer component of the composition. While any techniques known to those of skill in the art for contacting the drug and the magnesium oxide, and which are appropriate, can be employed, a wet granulation process is preferred. The presence of magnesium oxide lends itself to improved wet granulation processing of ACE inhibitor-containing compositions, the advantages of which are discussed below in detail in Example 6 (see Original Patent) where a comparison is made of previously known magnesium carbonate hydroxide formulations and the magnesium oxide formulations of the present invention. A summary of these advantages is as follows:
 

• (1) magnesium oxide formulations are dense and can allow an increase in batch sizes using current equipment;
• (2) a decrease in granulation times, the granulation times ranging from about 4.5 to about 5 minutes or less;
• (3) a decrease in the variability in granulation times, the variability ranging from about 0.5 to about 1 minute when using different lots of magnesium oxide;
• (4) a decrease in the amounts of water required to achieve granulation end points and potentially shorter drying times, the amounts of water required is from about 50% or less and drying times of about 7 minutes;
• (5) initial LODs in the range of 5 to 8%;
• (6) an improvement in the flowability or angle of repose test where magnesium oxide formulations had a flowability or angle of repose of 32°.

In a preferred embodiment, the present invention is directed to a process for preparing a stabilized pharmaceutical composition comprising an effective amount of an ACE inhibitor and a hydrolysis-minimizing agent and consisting essentially of an effective amount of magnesium oxide as the cyclization stabilizing agent, wherein the process comprises:

• (1) blending together a suitable amount of an ACE inhibitor, a hydrolysis-minimizing agent and magnesium oxide;
• (2) adding a granulating fluid to the blend to form a moist mass;
• (3) drying the granules; and
• (4) blending the granules with pharmaceutically inactive excipients.

The process further comprises the optional steps of screening the dried granules before addition of the pharmaceutically inactive excipients. The granulation medicament so formed may then be subjected to further conventional processing to form various solid dosage forms. The solid dosage forms may then be processed into final dosage forms by conventional techniques.

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 and stabilizer components (disintegrant about 1% to about 15% of the total composition; lubricant about 0.1% to about 5% of the total composition; and binder about 1% to about 10% of the total composition), i.e., they make up the remainder of the composition.

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. Reasonable variations, such as those which would occur to a skilled artisan, can be made herein without departing from the scope of the invention.
 

Claim 1 of 2 Claims

1. A pharmaceutical composition which contains:

(a) quinapril hydrochloride;

(b) a suitable amount of a stabilizer to retard cyclization and discoloration of quinapril, the stabilizer consisting essentially of magnesium oxide;

(c) a suitable amount of a hydrolysis-minimizing agent to inhibit hydrolysis, the hydrolysis minimizing agent consisting of lactose;

(d) gelatin;

(e) polyplasdone; and

(f) magnesium stearate.

____________________________________________
If you want to learn more about this patent, please go directly to the U.S. Patent and Trademark Office Web site to access the full patent.