GB2031917A - Graft copolymers of cellulose for use as a pharmaceutical adjuvant - Google Patents

Abstract

A pharmaceutical adjuvant comprises a graft polymer of cellulose and at least one polymerisable monomer, e.g. styrene. The process for the production of this adjuvant and also pharmaceutical compositions containing this adjuvant are described.

Description

SPECIFICATION A pharmaceutical adjuvant, process for the production thereof and pharmaceutical compsotion containing the adjuvant The present invention is concerned with a novel pharmaceutical adjuvant, with the preparation thereof and with pharmaceutical compositions containing it.

For the production of tablets and dragee cores, the materials used must be easily compressible, i.e. they should have good flowing properties and form relatively solid, compact bodies under a pressure of from 5 to 30 kN/cm2; and should release active material present therein to the organism at a given rate, i.e. they should dissolve or disintegrate more or less rapidly in water and be extractible.

Active materials a lone generally do not satisfy these requirements. Hence for working up active materials into tablets, dragees and other solid pharmaceutical compositions, as a matter of principle, several pharmaceutical adjuvants are required which not only increase the weight but also provide the required properties in the heterogeneous solid system. It is especially favourable when the same adjuvant influences several factors in the desired manner.

Few substances are known which approach the ideal properties for tabletting adjuvants mentioned above.

Preferred, known adjuvants include cellulose powders which are commercially available as so-called micro-crystalline celluloses. These substances have good flow properties so that they can be pressed directly without granulating. Furthermore, even when using relatively low pressures, they give mechanically resistant compressed bodies which easily disintegrate in water. Hence, the use of cellulose has been closely investigated and is used worldwide in the pharmaceutical industry.

However, a disadvantage of microcrystalline cellulose is that it is only suitable for tablets which are to disintegrate rapidly in water, When manufacturing solid pharmaceutical compositions, it is usually highly desirable to make the active substances applicable in such a manner that, dependent upon their behaviour in the organism, they will display certain rates, durations and strengths of activity. At the moment, numerous galentical methods are known which enable the availability of the active materials to be influenced and the activity parameters dependentthereon. By means of such methods, an accelerated, delayed, sudden or uniform effect can be achieved. The conventional processes used for this purpose can be subdivided into those for influencing the dissolution rate and those for changing the rate of diffusion or permeation.A faster liberation of the active agent can, for example, be obtained by enlarging the surface area (comminution), rendering amorphous or adding solubilisers. A retarded liberation can be achieved by embedding into or coating with sparingly soluble substances.

The known methods include, for example, those in which the particles of the active material or the whole compressed body (tablet or capsule) is coated with a film, those in which the active material is embedded in an erodable hard fat, those in which the active material is polymerised into a synthetic resin, those in which the active material is pressed with a synthetic resin and those in which the active material is bound to an insoluble carrier, such as an ion exchange resin. In all of these known cases, the procedure either is not capable of very much variation or requires an additional operational step. The use of certain matrix-forming agents largely determines the properties of the pharmaceutical compositions produced therewith. Coating processes and other specific operations necessitate the use of special techniques.

It is an object of the present invention to provide a novel pharmaceutical adjuvant which can be processed easily and directly, as well as a process for producing pharmaceutical compositions with desirable dissolution, disintegration and liberation properties.

A further object of the present invention is to utilise the excellent properties which cellulose possesses because of its chemical composition and fibrous structure and to combine these properties with those of synthetic resins, such cellulose-synthetic resin combinations having characteristics which are dependent upon the nature and amount of the synthetic resin component.

For chemically changing cellulose, graft copolymerisation could be considered which, unlike forming derivatives of cellulose, permits the basic structure of the cellulose molecule to be retained.

Cellulose grafting is, in principle, well known although hitherto it has only been used for finishing cotton and for treating wood. The materials obtained by these processes have had no relation whatsoever to the manufacture of pharmaceutical compositions and are not suitable for that purpose. Neither the processes of the textile industry nor those of wood precessing can be utilised by the pharmaceutical industry.

We have now found that a flowable, cellulose graft copolymer of excellent suitability for the manufacturing of solid pharmaceutical compositions is obtained when microcrystalline cellulose or, generally, cellulose powders are used as starting material.

The graft polymerisation can be directed in such a manner that either only the surface or all of the cellulose particles is subject to reaction, the properties of the resulting products being correspondingly different.

Monomers which an be used include methacrylic acid esters, acrylonitrile, acrylic acid esters, styrene, vinyl derivatives and silicones. The reaction can be induced by high-energy irradiation. In addition to graft copolymers, the polymerisation mainly results in the formation of homopolymers which are embedded into the pores of the cellulose matrix and serve to improve the properties of the product. The degree of grafting and the extent of the homopolymerisation are dependent, interalia, upon the radiation dosage.

Consequentiy, "tailor-made" adjuvants can be obtained by selection of the monomers, combination ratios and polymerisation conditions. The loose powders prove to be very useful for the production of granulates, tablets, dragee cores and dragees, as well as for filling of hard gelatine capsules and other solid pharmaceutical compositions. In most cases, it is sufficient to mix the active materials with the novel cellulose graft copolymers. Thus, for example, in the case of tabletting, such mixtures can be compressed directly without further additives and/or without granulation being necessary.

As the preliminary step for tabletting, only a mixing step or a spraying on the active substance is necessary. Liberation of active material from the compressed composition is delayed by the cellulose graft copolymers. The adjuvant surface, which has been made more or less marked hydrophobic, changes the wettability and the diffusion behaviour of the pharmaceutical compsotion. This effect is manifest not only in hard gelatine capsules but also in tablets and in dragee cores. If a further modificaton or reduction of the effect is desired, a mixture of different graft copolymers or a mixture with cellulose powder or other adjuvants can be employed. In no case is a special technique required.

The acute toxicity testing of the novel cellulose graft copolymer shows that rats with an average body weight of 200 g. tolerate the cellulose graft copolymer up to a dosage of 3.0 g. in a 30% by weight solution.

Up to an observation time of 8 days p.i., no reduction in food intake and weight was observed.

The following Examples are given for the purpose of illustrating the present invention: Example 1 100.0 g. Cellulose powder are impregnated with a mixture of 50.0 g. styrene, 35.0 g. acrylonitrile and 5.0 g.

carbon tetrachloride and subjected to gamma irradiation of 2.5 Mrad. Subsequently, the treated powder is washed out with carbon tetrachloride and ethanol and then dried.

Example 2 The process described in Example 1 is repeated but using a mixing ratio of cellulose powder: styrene: acrylonitrile : carbon tetrachloride of 100:10 : 7 :1 or 100 : 25 :17 : 2.5, similar products being obtained.

Example3 Cellulose powder is impregnated with methyl methacrylate and carbon tetrachioride and then further treated as described in Example 1, a similar product again being obtained.

Example 4 Cellulose graft copolymer is mixed with 1% by weight of active substance and processed at a pressure of 15 kM/cm2 to give tablets of 11 mm. diameter and 200 mg. weight. Dependent upon the individual degree of grafting, the tablets have the following properties: sample cellulose graft copolymer ultimate crushing rate of of parts by weight strength disinte gration cellu- styrene acrylo lose nitrile 0 100 - - more than 15 kp 15 sec.

1 100 10 7 3.8 kp 90 min.

2 100 25 17 4.9 kp 180 min.

3 100 50 33 4.8 kp 150 min.

Example 5 The cellulose graft copolymer of sample 3 of the Table given in Example 4 is mixed with active material and with different amounts of cellulose powder and processed into tablets in the manner described in Example 1. The tablets obtained have the following properties: weight ratio of cellulose ultimate rate of graft copolymer of sample crushing disintegration 3: cellulose powder strength 1:9 10.0kp 54sec.

2:8 9.4 kp 61 sec.

3:7 8.0 kp 74 sec.

5:5 6.4 kp 78 sec.

6:4 5.1 kp 100sec.

Example 6 The cellulose graft copolymer of sample 3 of the Table given in Example 4 is mixed with cellulose powder in a weight ratio of 3 : 7 and thereafter with 1% by weight of active material and subsequently processed into tablets under varying pressures (see Example 1). The tablets have the following properties: pressure ultimate rate of used crushing strength disintegration (kN/cm2) (kp) (sec.) 5 2.8 21 10 5.5 49 15 8.1 78 20 9.4 100 This cellulose graft copolymer can also be used for manufcturing granulates and coated tablets.

Example 7 50 kg. Phenformin hydrochloride (phenylethyl biguanide) are mixed with 199.5 kg. cellulose-styrene graft copolymer and 0.5 kg. magnesium stearate and subsequently pressed to give tablets of 12 mm. diameter and 250 mg. weight.

Example 8 15 kg. Pindolol are mixed with 184.6 kg. cellulose-polymethacrylate graft copolymer and 0.4 kg.

magnesium stearate and subsequently pressed to give tablets of 11 mm. diameter and 200 mg. weight.

Example 9 6 kg. Fluphenazine hydrochloride are mixed with 93.8 kg. cellulose-styrene graft copolymer and 0.2 kg.

magnesium stearate and pressed to give tablets of 6 mm. diameter and 100 mg. weight.

Claims (12)

1. A pharmaceutical adjuvant comprising a graft polymer of cellulose and at least one polymerisable monomer.

2. An adjuvant according to claim 1, wherein the polymerisable monomer is a methacrylic acid ester, an acrylic acid ester, acrylonitrile, styrene, a vinyl derivative and/or a silicone.

3. An adjuvant according to claim 1 or 2, wherein the pores of the cellulose matrix contain a homopolymer of the polymerisable monomer.

4. An adjuvant according to any of the preceding claims, wherein the cellulose is microcrystalline cellulose.

5. A pharmaceutical adjuvant according to claim 1, substantially as herein before described and exemplified.

6. A process for the production of an adjuvant according to claim 1, wherein cellulose is graft polymerised with a polymerisable monomer.

7. A process according to claim 6, wherein the polymerisation is induced by high-energy irradiation.

8. A process for the production of an adjuvant according to claim 1, substantially as hereinbefore described and exemplified.

9. An adjuvant according to claim 1, whenever produced by the process according to any of claims 6 to 8.

10. A pharmaceutical composition comprising an adjuvant according to any of claims 1 to 5 and 9.

11. A pharmaceutical composition according to claim 10 in the form of a granulate, tablet, dragee or dragee core.

12. A pharmaceutical composition according to claim 10, substantially as hereinbefore described and exemplified.