WO2005027881A2

WO2005027881A2 - Stable quinapril compositions

Info

Publication number: WO2005027881A2
Application number: PCT/EP2003/010569
Authority: WO
Inventors: Antoni Santamaria
Original assignee: Texcontor Etablissement
Priority date: 2003-09-23
Filing date: 2003-09-23
Publication date: 2005-03-31
Also published as: AU2003270245A8; WO2005027881A3; AU2003270245A1

Abstract

The invention describes stabilised compositions comprising quinapril or a salt thereof, an alkali metal or alkaline earth metal carbonate, preferably magnesium carbonate, a first disintegrant, preferably hydroxypropylcellulose, a second disintegrant, preferably crosspovidone, and a lubricant, preferably magnesium stearate.

Description

Quinapril

The present invention relates to stabilised compositions comprising angiotensin converting enzyme inhibitors, in particular to compositions comprising quinapril or a salt thereof and at least two disintegrants . Angiotensin converting enzyme (ACE) inhibitors are drugs useful in the treatment of cardiovascular disorders, especially hypertension. Various specific ACE inhibitors are known in the art including the compounds enalapril, moexipril, spirapil, indolapril and quinapril, the latter compound being of the following formula:

Certain angiotensin converting enzyme inhibitors are unstable in that they are highly susceptible to decomposition by cyclisation, hydrolysis and/or oxidative attack. It is believed that this type of decomposition causes the discolouration which results when these compounds are formulated in pharmaceutical dosage forms . Quinapril and structurally related drugs can degrade via cyclisation via internal nucleophilic attack to form substituted diketopiperazines . Moreover, they may hydrolyse by losing the side chain ester group or oxidise to form products having unwanted colouration. Breakdown of ACE inhibitors has been found to occur both in solid and in liquid states and as breakdown of inhibitor increases, the concentration of available, functional ACE inhibitor decreases. Also, at least some degradation products may well be deleterious. There has therefore been much research into providing stable pharmaceutical compositions for the delivery of ACE inhibitors . Within the group of ACE inhibitors it is also known that certain compounds are easier to stabilise than others. For example, enalapril and its acid addition salts are more easily stabilised than quinapril and its acid addition 'salts. There are, in fact, known methods for stabilising enalapril which are not suitable for stabilising quinapril. Quinapril therefore provides a particular challenge for the skilled pharmaceutical composition formulator. Various solutions to the problem of ACE inhibitor stabilisation have been proposed in the prior art . WO00/34314 (Sherman) suggests the use of a magnesium salt of quinapril in a stable solid composition. The compositions are said to be stable even in the absence of an alkaline stabilising compound and can be simply formed from the reaction of a quinaparil salt or free base with an alkaline magnesium compound. In EP-A-264888 (Warner-Lambert) it is suggested that the use of quantities of ascorbic acid alone or in combination with fumaric acid, citric acid or rnaleic acid helps prevent cyclisation and hydrolysis of dosage forms containing quinapril. The ascorbic acid needs to be present in an amount from 10 to 20% by weight of the composition. An alternative stabilising system for ACE inhibitors, described in EP-A-280999 (also of Warner- Lambert) involves the use of an alkali or alkaline earth metal carbonate and a saccharide as a stabilising mixture. Magnesium carbonate is said to be a preferred alkaline metal carbonate and lactose a preferred sugar. EP-A-468929 (Sandoz Ltd.) suggests that stable pharmaceutical compositions comprising ACE inhibitors can be provided by the use of a hydrochloric acid donor that releases hydrochloric acid, said donor being for example an amino acid hydrochloride such as glycine hydrochloride. The more volatile hydrochloric acid is said to be an improvement over previously used acid stabilisers such as ascorbic acid. More recently, Warner-Lambert have suggested in WO 99/62560 that magnesium oxide is a suitable stabilising agent for ACE inhibitor compositions. Magnesium oxide is also said to aid formulation of the dosage form by wet granulation. WO01/15724 (Mutual Pharmaceutical Company) describes a method for formulating a stable composition of enalapril maleate which involves the mixing of an alcoholic enalapril maleate dispersion with a metal compound dispersion, e.g. a clea.tr sodium bicarbonate dispersion. There still remains however a long standing need for stable formulations of ACE inhibitors and for methods of preparing such stabilised compositions. There is also a need for formulations of ACE inhibitors, that minimise breakdown of the inhibitor, that are inexpensive and can be produced in a time efficient manner in readily available equipment. Additionally, the compositions should have i p-troved uniformity from batch to batch. It is has now been surprisingly found that a particular combination of components gives rise to a composition in which quinapril oar a pharmaceutically acceptable salt thereof is exceptionally stable. The composition of the invention has surprisingly found to be stable despite the absence of any magnesium oxide, ascorbic acid, hydrochloric acid donor or even a saccharide . Thus, viewed from one aspect, the invention provides a pharmaceutical composition comprising: quinapril or a pharmaceutically acceptable salt thereof ; an alkali metal or alkaline earth metal carbonate, preferably magnesium carbonate; a first disintegrant, preferably hydroxypropylcellulose; a second disintegrant, preferably crosspovidone; and a lubricant, preferably magnesium steaxate. Viewed from another aspect the invention provides a process for the preparation of a pharmaceutical composition comprising quinapril or a pharmaceutically acceptable salt thereof comprising the steps of: 1. mixing a first disintegrant, quinapril or a pharmaceutically acceptable salt thereof and an alkali or alkaline earth metal carbonate; • 2. adding water to the resulting mixture; 3. granulating the resulting slurry; 4. drying the resulting granules; 5. adding a second disintegrant to said granules and mixing; -6. adding a lubricant and mixing; 7. compressing to form tablets. The quinapril employed in the compositions of the invention may be in its free base form but is preferably formulated as an acid addition salt such as the hydrochloride, hydrobromide, orthophosphate , benzoate, maleate, tartrate, succinate, citrate, salicylate, sulfate or acetate. In a preferred embodiment, the quinapril is in its hydrochloride form, i.e. quinapril hydrochloride. Whilst the invention is described in relation to quinapril, it is envisaged that the composition described herein will also be suitable for the stabilisation of other ACE inhibitors such as enalapril, indolapril, moexipril and spirapil. The amount of quinapril present in a composition of the invention can, of course, vary depending on the intended use of the composition and the age, sex etc of the patient. Conveniently however, the quinapril forms between 1 to 20% of the composition, preferably 5 to 15%, e.g. approximately 10% of the composition. Where the composition is in the form of a tablet for example, the tablet may comprise between 1-100 mg, e.g. 5, 10, 20 or 40 mg of quinapril. The alkali or alkaline earth metal carbonate used in the stabilised compositions of the invention is a carbonate of a group I or group II metal. Hence, suitable carbonates include those of magnesium, calcium and sodium of which magnesium carbonate is most preferred. The carbonate may make up 5-80% by weight of the pharmaceutical composition, preferably 30-70% by weight e.g. approximately 50% by weight. In addition to carbonates, it is contemplated that alkali and alkaline earth metal borates and silicates may be alternatively employed. The compositions of the invention should contain a number of conventional excipients which must be compatible with the other ingredients listed and which do not interfere with the function of the composition. These may include, inter alia, carriers, diluents, pigments, binders, colorants, lubricants, plasticisers, film coatings and colour film coatings. In addition, the composition should also contain a combination of disintegrants. It is the particular combination of components as claimed which yield quinapril compositions of exceptional stability. Suitable disintegrants include modified starch, modified cellulose derivatives and polyvinylpyrrolidone . A particularly preferred first disintegrating agent is a modified cellulose derivative such as hydroxypropylcellulose, hydroxymethylcellulose or hydroxyethylcellulose . A preferred second disintegrant is crosspovidone (cross-linked polyvinylpyrrolidone ( VP ) ) . The amount of disintegrant in the compositions of the invention may range from 10-50% by weight, preferably 20-40% by weight. Where a modified cellulose disintegrant is present, it is preferred if the modified cellulose disintegrant component forms the greater part of the disintegrant components present. Preferably, there should be at least 2 times, preferably at least 5 times the amount of modified cellulose disintegr-ant than other disintegrant, e.g. crosspovidone. In an especially preferred embodiment the disintegrants are hydroxypropylcellulose and crosspovidone and the amount of crosspovidone is between 2-5%, e.g. 4% and the amount of modified cellulose derivative is between 20-40% e.g. 30-35% by weight. Useful lubricants include those generally used in pharmaceutical formulations to assist in the processing of one or more materials during the preparation of a final dosage form. Particularly preferred lubricants are stearates of magnesium, calcium or zinc as well as hydrogenated vegetable oils. Magnesium stearate is a highly preferred lubricant . The amount of lubricant in the compositions of the invention may range from 0.1-5% by weight, especially approximately 1% by weight . If the composition of the invention is to comprise a binder, suitable compounds are gelatin or PVP. In a preferred embodiment crosspovidone acts as both a binder and as a disintegrant. The weight of the entire composition may vary also but is conveniently between 50 mg and 1000 mg, e.g. 100 mg, 200 mg or 400 mg. The final form of the pharmaceutical compositions of the invention can vary greatly. Thus, tablets, capsules, sachets, sprinklers, pomades, transderτnal compositions, buccal preparations, sugar compositions, nasal formulations, ocular compositions and the like are all contemplated. Orally administrable forms such as tablets and capsules are however, preferred. Solid, semi-solid or liquid formulations may be manufactured of which solids are the most preferred. If necessary, the formulations of the invention may be adapted for sustained release. The compositions of the invention may be made by standard formulation processes well known to the person skilled in the art. For example, if the composition is to take the form of a tablet, a direct compression, dry granulation or wet granulation process may be used. Preferably however, a standard wet granulation process is employed. In such a wet granulation process, initially, the active pharmaceutical ingredient (API) i.e. quinapril hydrochloride, the carbonate and the first disintegrant, e.g. hydroxypropylcellulose are individually screened to ensure a uniform particle size. Once these ingredients have been screened they are all mixed using, for example, a standard powder mixer to produce a uniform dispersion of components. , This mixture is then wetted using purified water and the subsequent slurry again mixed to ensure uniformity. The resulting damp mass is granulated by being passed through a coarse sieve yielding roughly spherical particles or granules. The sieving procedure is usually achieved mechanically often by means of an oscillating granulator in which a rotor oscillating about its horizontal axis passes the damp material through the screen. The granulated mixture is then dried using, for example, either a tray drier or a fluidized bed drier to yield a coarse free flowing solid. These granules are then sized to ensure that the particle sizes are uniform and that the particles are of a suitable size for tableting. At this stage a second blend is required to add further important additives including further disintegrants such as crosspovidone. Subsequently, a lubricant such as magnesium stearate is then added with further blending. The lubricant is preferably prescreened to ensure particle size uniformity. The resulting mixture is then compressed, e.g. using a single punch tableting machine to give the pharmaceutical composition normally in the form of a tablet. The invention will now be described further with reference to the following non-limiting Example.

Example 1

A pharmaceutical composition comprising quinapril hydrochloride was manufactured as follows:

1. Hydroxypropylcellulose LH21, quinapril hydrochloride and magnesium carbonate were separately screened using a mesh size of 1-2 mm.

2. The hydroxypropylcellulose LH21, quinapril hydrochloride and magnesium carbonate were then mixed and purified water added. The resulting slurry was stirred for a further 5 minutes before the damp mass- was granulated using a conventional coarse sieve having a mesh size of 1-3 mm.

3. The granulated product was then dried using a fluidised bed drier and screened using a sieve of mesh size 0.5-2 mm. The sieved material was mixed with crosspovidone and subsequently mixed with magnesium stearate which had been prescreened on a mesh of 0.2-1.5 mm.

4. The final hydroxypropylcellulose LH21, quinapril hydrochloride, magnesium carbonate, magnesium stearate and crosspovidone mixture was then compressed to form tablets .

rne oiiowmg compositions were maαe-as shown in Table 1 below.

* plasticisers, film-coating, colourfilm coating.

Claims

1. A pharmaceutical composition comprising: quinapril or a pharmaceutically acceptable salt thereof; an alkali metal or alkaline earth metal carbonate; a first disintegrant; a second disintegrant ; and a lubricant.

2. A composition as claimed in claim 1 comprising quinapril hydrochloride.

3. A composition as claimed in claim 1 or 2 wherein said carbonate is magnesium carbonate.

4. A composition as claimed in any one of claims 1 to

3 wherein said first disintegrant is a modified cellulose derivative.

5. A composition as claimed in claim 4, wherein said modified cellulose derivative is hydroxypropylcellulose, hydroxymethylcellulose or riydroxyethylcellulose.

6. A composition as claimed in claim 5 wherein said second disintegrant is cross povidone.

7. A composition as claimed in claim 6 wherein said lubricant is magnesium stearate.

8. A composition as claimed in claim 7 wherein composition does not comprise magnesium oxide, ascorbic acid, a hydrochloric acid donor or a saccharide.

9. A composition as claimed in any one of claims 1 to 8 wherein said composition comprises: 5 to 15% quinapril or pharmaceutically acceptable salt thereof; 30 to 70% carbonate; 20 to 40% disintegrant; 0.1 to 5% lubricant.

10. A composition as claimed in claim 9 wherein there is at least 5 times more first disintegrant than second disintegrant .

11. A composition as claimed in any one of claims 1 to 10 suitable for oral administration.

12. A process for the preparation of a pharmaceutical composition as claimed in any one of claims 1 to 11 comprising quinapril or a pharmaceutically acceptable salt thereof comprising the steps of: 1. mixing a first disintegrant, quinapril or a pharmaceutically acceptable salt thereof and an alkali or alkaline earth metal carbonate;

2. adding water to the resulting mixture;

3. granulating the resulting slurry;

4. drying the resulting granules;

5. adding a second disintegrant to said granules and mixing;

6. adding a lubricant and mixing;

7. compressing to form tablets .