GB2119648A

GB2119648A - Anorexogenic pharmaceutical composition

Info

Publication number: GB2119648A
Application number: GB08213162A
Authority: GB
Inventors: Joseph Hodgson Briggs
Original assignee: Individual
Current assignee: Individual
Priority date: 1982-05-06
Filing date: 1982-05-06
Publication date: 1983-11-23

Abstract

An anorexogenic pharmaceutical composition comprises phentermine and diazepam, the diazepam at least being in slow-release form. The diazepam is present in an amount effective to eliminate the stimulating effect of the phentermine. Preferred ratios of diazepam to phenteramine are from 20:80 to 40:60. A preferred slow-release matrix for the diazepam is a cross-linked polystyrene-divinylbenzene ion- exchange resin having active sulphuric acid groups.

Description

SPECIFICATION Anorexogenic pharmaceutical composition This invention relates to a pharmaceutical composition comprising a special combination of cooperating agents, especially a medicament comprising such a composition in dosage unit form.

In recent years medical and social factors have caused attention to be focussed on methods of achieving control of obesity. One of the methods to which greatest attention has been given is the partial suppression of appetite, whereby a person who is obese or who has a tendency to obesity is assisted in combating such obesity by a relatively effortless reduction in the consumption of food.

Various anorexogenic agents have been developed, which, when administered orally or otherwise to a patient, result in partial suppression of appetite and a reduction in food consumption. Some of the agents which have been in use for several years have proved to be very effective.

Nevertheless, the use of such agents has not been free from difficulties. These difficulties often arise from undesirable side-effects produced by these agents.

It has been discovered that a particular undesirable side-effect of several such agents is an excessive stimulation of the nervous system. In attempting to combat this disadvantage, recourse has been had to the administration of known sedative preparations. Analysis of the results of such courses of treatment has shown that such methods are an inadequate solution of the problem. The neutralisation of the stimulating effect of the anorexogenic agent by the sedative effect of the sedative preparation which had been hoped for has not taken place effectively; the two contrary effects did occur, with different intensities at different times.

Attempts have been made to overcome this problem by the administration of an anorexogenic agent in conjunction with a sedative in slowrelease form. Such attempts have met with extremely limited success, however. Indeed, while certain commercial preparations which contained an anorexogenic agent and a sedative in slowrelease form were introduced, they have had to be withdrawn.

Meanwhile attention has been focussed on attempts to find new appetite suppressants which would not have the disadvantage of the known agents, especially their strong stimulant effects.

The present invention provides a means of avoiding the need to seek for and develop wholly new and untried agents which would require a long series of test of their effectiveness and of their safety.

We have identified a particular anorexogenic agent and sedative which can be combined to form a highly effective anorexogenic composition, without the disadvantages of the prior compositions.

The present invention is a pharmaceutical composition which comprises Phentermine and Diazepam, the Diazepam being in a delay release form and in an amount effective to eliminate the stimulating effect of the Phentermine substantially through the period of activity of the Phentermine.

In principle both Phentermine and Diazepam may be incorporated into a single siow-release matrix, for example a resin carrier. However, it has been found that this may, in many cases, be inconvenient or impractical, by reason, for example, of the limited number of binding sites in the resin. Accordingly, the two agents may be separately incorporated into two matrices, and appropriate portions of the resulting matrix-bound agents may be incorporated into the composition.

The proportions of the Phentermine and the Diazepam are selected so as to ensure that the amount of Diazepam is such that it will eliminate the stimulating effect of the Phentermine.

Usually, the proportion of Diazepam to Phentermine will be within the range from 20:80 to 40:60 by weight.

The composition may be formulated to contain any appropriate diluents. These may include any of the conventional pharmaceutical fillers and extenders.

It is especially preferred that the compositions should be in the form of medicaments in dosage unit form. By this is meant separate discrete portions which are appropriate for medical administration. Each portion contains either a daily dose or a multiple or sub-multiple of a daily dose. If the portion contains a multiple of a daily dose this may be up to five times the daily dose and in such a case the medicament should be formed in such a way that it can be readily divided into individual doses. If the medicament contains a sub-multiple of a daily dose, this may generally be from a half of a thirtieth of a daily dose, preferably a half or a third or a quarter or a fifth of a daily dose.

The medicament will normally be in the form of a capsule containing the appropriate amount of the composition of the invention, but it may alternatively be in other forms, such as tablets or pills or dragees. Such tablets, dragees or pills may, of course, contain conventional constituents such as binding agents or disintegrating agents.

Delay-release tablets may be formed in any of a number of ways. For example, they may be formed by the addition of large amounts of waxy solids (e.g. stearic acid) to the active ingredients, so that the active ingredients dissolve only slowly.

Alternatively, granules of the active ingredients may be coated with shellac or other waterimpervious substances. A particularly preferred way of forming delay-release tablets is to add powdered plastics, for example derivatives of polyvinyl chloride, to a mixture of the active ingredients. As the plastics-containing composition is compressed during the tabletforming operation, the plastics material melts. On release of the pressure on the tablet, the plastics material re-hardens, forming a porous plastics matrix from which the active ingredients can be leached out only slowly.

Delay-release capsules according to the invention may be filled with delay-release pellets.

Such pellets may, for example, be formed by coprecipitating a wateF-insoluble material such as ethyl cellulose onto crystals of the active ingredients. An alternative method of forming delay-release pellets is to spray onto a non-pareil (i.e. a very small lactose or sugar pellet) a mixture of the active ingredients with a delay-release agent which may be non pH-dependent. Examples of such delay-release agents are shellac and polymers such as cellulose acetate phthalate and polyvinylacetate phthalate.

A particularly advantageous delay-release composition according to the present invention involves the incorporation of Diazepam into an ion-exchange resin which results in the slow and controlled release of the sedative from the resin in the digestive system. One method of effecting such incorporation is described below, by way of Example.

Example 10 mg of Phentermine was dissolved in 500 ml of water. 40 g of Zerolit 225 (H-form) resin was then added and the mixture was stirred for 2-2+ hours. (Zerolit 225 resin is a cross-linked polystyrene-divinylbenzene resin with active sulphuric acid groups). The resin mixture was then filtered and dried at 450C and assayed at 24.6% Phentermine. 5 mg of Diazepam was dissolved in a mixture of 500 ml industrial methylated spirits and 500 ml water. 25 g of Zerolit 225 (H-form) resin was then added, and the mixture was stirred for 2 2 hours. After filtering and drying at 450C, the resin mixture was assayed at 20.6% Diazepam.

Capsules containing resin-bound Phentermine and resin-bound Diazepam were administered to adult humans over a period of 8 weeks. Each capsule contained 20 mg of Phentermine and 7.5 mg of Diazepam. The Diazepam and Phentermine were incorporated in a resin in a manner described above. One capsule was administered to each adult each day.

Clinical observation showed that the Phenterm ine satisfactorily performed its own anorexogenic function, but that is stimulating function on the nervous system was effectively eliminated throughout the period of activity.

Claims (Filed on 3 May 83) 1. A pharmaceutical composition comprising phentermine and diazepam, the diazepam being in a delay-release form and in an amount effective to eliminate the stimulating effect of the phentermine substantially throughout the period of activity of the phentermine.

2. A composition according to claim 1 wherein the ratio of diazepam to phentermine is from 20:80 to 40:60 by weight.

3. A composition according to claim 2 wherein said ratio is from 25:75 to 30:70 by weight.

4. A composition according to any preceding claim wherein the diazepam and the phentermine are incorporated into separate slow-release matrices.

5. A composition according to any preceding claim wherein the diazepam is incorporated in an ion-exchange resin.

6. A composition according to claim 5 wherein said resin is a cross-linked polystyrene-divinylbenzene resin having active sulphuric acid groups.

7. A pharmaceutical composition comprising phentermine and diazepam substantially as hereinbefore described with reference to the Example.

8. A composition according to any preceding claim in dosage unit form.

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Claims

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matrix from which the active ingredients can be leached out only slowly.

Delay-release capsules according to the invention may be filled with delay-release pellets.

Such pellets may, for example, be formed by coprecipitating a wateF-insoluble material such as ethyl cellulose onto crystals of the active ingredients. An alternative method of forming delay-release pellets is to spray onto a non-pareil (i.e. a very small lactose or sugar pellet) a mixture of the active ingredients with a delay-release agent which may be non pH-dependent. Examples of such delay-release agents are shellac and polymers such as cellulose acetate phthalate and polyvinylacetate phthalate.

A particularly advantageous delay-release composition according to the present invention involves the incorporation of Diazepam into an ion-exchange resin which results in the slow and controlled release of the sedative from the resin in the digestive system. One method of effecting such incorporation is described below, by way of Example.

Example

10 mg of Phentermine was dissolved in 500 ml of water. 40 g of Zerolit 225 (H-form) resin was then added and the mixture was stirred for 2-2+ hours. (Zerolit 225 resin is a cross-linked polystyrene-divinylbenzene resin with active sulphuric acid groups). The resin mixture was then filtered and dried at 450C and assayed at 24.6% Phentermine. 5 mg of Diazepam was dissolved in a mixture of 500 ml industrial methylated spirits and 500 ml water. 25 g of Zerolit 225 (H-form) resin was then added, and the mixture was stirred for 2 2 hours. After filtering and drying at 450C, the resin mixture was assayed at 20.6% Diazepam.

Capsules containing resin-bound Phentermine and resin-bound Diazepam were administered to adult humans over a period of 8 weeks. Each capsule contained 20 mg of Phentermine and 7.5 mg of Diazepam. The Diazepam and Phentermine were incorporated in a resin in a manner described above. One capsule was administered to each adult each day.

Clinical observation showed that the Phenterm ine satisfactorily performed its own anorexogenic function, but that is stimulating function on the nervous system was effectively eliminated throughout the period of activity.

Claims (Filed on 3 May 83) 1. A pharmaceutical composition comprising phentermine and diazepam, the diazepam being in a delay-release form and in an amount effective to eliminate the stimulating effect of the phentermine substantially throughout the period of activity of the phentermine.
2. A composition according to claim 1 wherein the ratio of diazepam to phentermine is from 20:80 to 40:60 by weight.
3. A composition according to claim 2 wherein said ratio is from 25:75 to 30:70 by weight.
4. A composition according to any preceding claim wherein the diazepam and the phentermine are incorporated into separate slow-release matrices.
5. A composition according to any preceding claim wherein the diazepam is incorporated in an ion-exchange resin.
6. A composition according to claim 5 wherein said resin is a cross-linked polystyrene-divinylbenzene resin having active sulphuric acid groups.
7. A pharmaceutical composition comprising phentermine and diazepam substantially as hereinbefore described with reference to the Example.
8. A composition according to any preceding claim in dosage unit form.