GB2246072A - Pharmaceutical compositions stabilised against light - Google Patents

Abstract

Compositions, e.g. soft gelatin capsules. contain a light-sensitive active ingredient optionally sparingly soluble in water, e.g. nifedipine and also contain a vegetable dye. The dye ensures reliable light protection during manufacturing operations and improves the solubility of nifedipine in certain carriers. The dye may be included also in the capsule wall and is e.g. chlorophyll, caramel, saffron yellow or beetroot dye. <IMAGE>

Description

SOLID PHARMACEUTICAL COMPOSITIONS This invention relates to solid pharmaceutical compositions and a process for the preparation thereof. More particularly it is concerned with solid pharmaceutical compositions comprising a light -sensitive active ingredient optionally being soluble in water, furthermore with a process for the preparation of such compositions.

It is known that the preparation of pharmaceutical compositions comprising as active ingredient a light -sensitive substance involves serious difficulties.

Under effect of light,decomposition products are formed which may be inactive or even harmful from therapeutical point of view. At the same time there are more and more severe pharmacopoeial requirements concerning the quantity of the decomposition products. It is also known that active ingredients which do not dissolve readily in water can be formulated only by overcoming great difficulties. On the one hand, the sparingly water -soluble ingredients are barely soluble in the carriers and additives used for the preparation of pharmaceutical compositions and, on the other hand, owing to the poor water-solubility of the molecule, the release of the active ingredient is of slight degree.

From the above facts it follows that formulation of light-sensitive and hardly water-soluble active ingredi- ents into solid pharmaceutical compositions is a hard task for skilled artisans which, at the same time, is a more and more urgent demand for the pharmaceutical industry.

The above problems arise especially when making pharmaceutical preparations from dihydropyridine derivatives which are both light-sensitive and barely soluble in water. One of the most important representative of these compounds is nifedipine [4-(2'-nitro phenyl)-2,6-dimethyl-3,5-dimethoxycarbonyl-1,4-di- hydropyridine], a widely used calcium antagonist, which is highly useful in the treatment of acute and chronic ischemic heart diseases, hypertension, cerebral and peripheral circulation disorders.

It is known that nifedipine is highly light -sensitive and does not readily dissolve in water (British patent specification No. 1,362,627). Owing to the high light-sensitivity of the molecule, decomposition products, especially nitro and nitroso derivatives, are formed very readily. The allowable maximum amount of the decomposition products is determined by severe pharmacopoeial regulations. Thus, according to the requirements specified in USP XXII the allowable maximum amount of the nitro compound may not exceed 2.0 % by mass, while in case of the nitroso decomposition product this value may not exceed 0.5 % by mass.

Furthermore, owing to its hard solubility in water, nifedipine does not readily dissolve in the carriers and auxiliary agents usually applied in the pharmaceutical industry for the preparation of solid pharmaceutical compositions; at the same time, due to its bare solubility in water, the release of the active ingredient is of very slight degree whereby the proper absorption is hindered.

Preferred representatives of the pharmaceutical compositions comprising nifedipine are soft gelatin capsules, but the preparation thereof gives rise to difficulties because of the light-sensitivity and slight water-solubility of the active ingredient.

Several methods have been published for the preparation of soft gelatin capsules of such a kind. Accordding to British patent specification No. 1,362,627 one or more opacifier(s) (e.g. titanium dioxide or calcium carbonate) and optionally a synthetic dye absorbing light in a certain wavelength range (e.g.

Gelborange, Erythrosin) are incorporated into the gelatin shell of the capsule. The presence of the opacifier is obligatory, while that of the synthetic dye is only preferable. Coloured opacifiers, e.g.

iron oxide pigments, give an aesthetic exterior and colour to the capsule shell. Said coloured pigments are incorporated into the gelatin shell of the capsule in an amount of 2 to 3 % by mass to ensure the desired anti-fading effect. The amount of the opacifier can be reduced to about 0.5 to 1.5 % by mass by adding a dye to the composition, but the addition thereof can not be omitted. Synthetic dyes by themselves can not ensure an infallible antifading effect, only when applied with an opacifier.

However, light protection ensured by the capsule wall involves serious drawbacks. Namely, the antifading effect is provided only by the ready-to-use capsule which involves already the filling solution containing the active ingredient. This latter is completely unprotected against light during the manufacturing and filling processes, consequently expensive and cumbersome precautionary measures requiring strict technological and labour disciplines have to be effectuated to avoid decomposition caused by light (e.g. the operations have to be carried out under indifferent red lighting etc.). The protection of the filling solution from the effect of light is particularly important when filtering the ready solution. Light protection has to be ensured during each of the encapsulating operations (e.g. black foil, special devices to exclude light, light filters etc.).

A further drawback of the light protection ensured by the capsule wall is that the incorporation of the finely dispersed solid opacifier into the capsule wall requires a separate operation and separate instruments. The finely powdered opacifier has to be smoothly suspended in the viscous gelatin mass constituting the capsule wall, which is a lengthy and cumbersome process. During the manufacturing process the possibility of an accidental inhomogeneity can not be precluded, the gelatin mass may become bubbled upon stirring, which may lead to the formation of inclusions, and these latter may cause inhomogeneity and desortment inside the capsule wall.

The published European patent application No.

143,857 discloses soft gelatin capsules comprising nifedipine as active ingredient. The capsule wall consists of glycerol, one or more dye(s) absorbing light in the desired wavelength range and an opacifier, while the mixture constituting the filling of the capsule contains a solution of nifedipine in an organic solvent. A characteristic feature of this patent application is that the filling of the capsule contains nifedipine and polyvinylpyrrolidone (PVP) dissolved in a solution of a polyetheralcohol in tetrahydrofurfurylalcohol, and it does not contain glycerol at all, this latter being present only in the capsule wall. This method also involves the disadvantages specified above.Namely, the opacifying agent is admixed exclusively to the material of the capsule wall, consequently the filling of the capsule is unprotected against light during the manufacturing and filling operations, furthermore the abovespecified difficulties arising when incorporating the opacifier into the capsule wall have to be surmounted, too.

The aim of the present invention is to elaborate a simple manufacturing process for the preparation of solid pharmaceutical compositions comprising as active ingredient a light-sensitive substance optionally being hardly soluble in water which ensures reliable light-protection and eliminates the drawbacks of the hitherto known processes.

The aim of the present invention is especially to provide an easily feasible process, ensuring reliable light protection, for the preparation of solid pharmaceutical compositions, particularly soft gelatin capsules, containing light-sensitive and slightly water-soluble nifedipine as active ingredient.

The invention is based on the recognition that vegetable dyes in themselves, that is without the presence of opacifying components, are able to prevent the photolysis of light-sensitive active ingredients.

According to an aspect of the present invention there is provided a process for the preparation of solid pharmaceutical compositions comprising a lightsensitive and optionally hardly water-soluble active ingredient together with conventional carriers and/or auxiliary agents, which comprises incorporating a vegetable dye into the composition.

As vegetable dyes preferably chlorophyll, caramel, saffron yellow or beetroot dye (Rote Beete, Dragocoo) can be used. According to a preferred form or realization of the process of the present invention, chlorophyll, the natural dye of green plants, is applied.

Both the lipophilic and hydrophilic forms of chlorophyll are suitable for accomplishing the process according to the invention with the desired result. The lipophilic form of chlorophyll is extracted from nettle with an organic solvent. The lipophilic form of chlorophyll is a dark-green honey-like product. The hydrophilic chlorophyll is a dye of natural origin, wherein the central magnesium atom of the molecule is exchanged for a copper atom, and the water-soluble sodium salt is obtained with sodium hydroxide. The potassium salt can be prepared in an analogous manner with potassium hydroxide. The hydrophilic chlorophyll is a finely dispersed green powder.

The vegetable dye can be used in an amount of 0.1 to 10 % by mass related to the total mass of the product.

According to our investigations the following light-sensitive compounds optionally sparingly soluble in water can be used as active ingredients for the solid pharmaceutical compositions according to the invention: vitamins D, preferably colecalciferol; vitamin A; imidazoline derivatives, preferably methynazol; piperazine derivatives, preferably tripolydine hydrazine hydrochloride; ergot and indole alkaloids, preferably dihydroergo toxin methanesulfonate or ergotamine tartrate; butyrophenone derivatives, preferably haloperidol, droperidol or benperidol; nitroglycerin; dihydropyridine derivatives, preferably nifedipine, nirudipine, nitrendipine, nisoldipine, nimodipine, nicarbipine or phenodipine; anabolic steroids, preferably phenoxymesteron; thyroid hormones, preferably levothyroxine; folic acid analogue antimetabolites, preferably methotrexate; purine-analogue antimetabolites, preferably azathoprine; nitrofuran derivatives, preferably nitrofurantoin; antineoplastic methylhydroxines, preferably pro carbazine; corticosteroids, preferably betamethasone; sodium nitroprusside; morphine derivatives, preferably morphine sulfate or papaverine hydrochloride; catecholamines, preferably dopamine or isoprenaline; estrogens, preferably hexosterol; sulfadiazine; alkaloids, preferably colchicine; profen derivatives, preferably ketoprofen; antibiotics, preferably mitomycin or bacitracin; tricyclic antidepressants, preferably carbamazepine; phenthiazines, preferably hibernal or trifluoperazine; mustardnitrogens; ***e hydrochloride; ethylenediamine derivatives, preferably tripelenamine; or aminoquinoline derivatives, preferably chloroquine.

According to a particularly preferred embodiment of the present invention a light-sensitive dihydropyridine derivative hardly soluble in water such as vitamin A or nitroglycerin is used as active ingredient.

According to an other particularly preferred embodiment of the present invention dihydropyridine derivatives showing a water-solubility not exceeding 20 g/l at 25 OC are used as active ingredients. Thus nifedipine, niludipine, nitrendipine, nisoldipine, nimodipine, nicardipine and felodipine have prooved to be particularly preferred as active ingredients.

According to the process of the present invention light-sensitive and optionally hardly water-soluble active ingredients can be formulated preferably into soft gelatin capsules, tablets, drags or hard gelatin capsules, particularly into soft gelatin capsules.

When preparing soft gelatin capsules a vegetable dye, especially chlorophyll, is incorporated into the filling of the capsule. Consequently, the filling containing the light-sensitive active ingredient is already protected from light during the manufacturing and filling processes, and not only after having been enclosed into the capsules. By this means expensive and cumbersome measures ensuring light-protection during the working up of the filling, which encloses the light-sensitive active ingredient, can be eliminated.

The lipophilic form of chlorophyll is admixed to the filling in an amount of 1 to 10 % by mass, preferably 1 to 5 % by mass, particularly preferably 1.5 to 3.5 % by mass. The hydrophilic colloid content of the filling may vary between 0.5 and 10 t by mass, preferably 1 to 7 % by mass, particularly preferably 1.5 to 5 % by mass. If nifedipine is used as active ingredient, the active ingredient content of the filling may vary between 0.5 and 7 % by mass, preferably 1 to 5 t by mass, particularly preferably 1.5 to 3 % by mass.

As a further component, the filling contains also a solvent suitable for oral administration and compatible with the wall material of the soft gelatin capsule. For this purpose the following solvents can be used: vegetable and aromatic oils (such as sunflower oil, calabash oil, olive oil, lemon oil etc.), non-ionic surfactants [e.g. poly(ethylene oxide) -sorbitan fatty acid esters, preferably poly(ethylene oxide)-sorbitan monooleate], lecithin or polyethylene glycols (e.g. Carbowax 300). The filling of the capsulemay optionally contain flavouring agents (e.g.

flavourings or essential oils), too.

When using lipophilic chlorophyll, the filling of the capsule may contain as solvent preferably a poly(ethylene oxide)-sorbitan fatty acid ester, particularly poly(ethylene oxide)-sorbitan monooleate.

When applying hydrophilic chlorophyll, preferably polyethylene glycols (e.g. Carbowaw 300) are used as solvent.

The preparation of the capsule filling is carried out by conventional methods of the pharmaceutical industry. One proceeds preferably by dissolving the active ingredient in a solvent heated to the appropriate temperature. The lipophilic or hydrophilic chlorophyll and the other components are added to this solution either while it is still warm or after cooling it and, if necessary, the solution thus obtained is filtered on a sieve.

The filling prepared as specified above containing a vegetable dye is then filled into soft gelatin capsules. The wall of the capsule may contain plasticizers of gelatin base (e.g. glycerin or sorbite) and a conserver (e.g. Nipagin). One may also proceed by adding a vegetable eXye, preferably chlorophyll, to the material of the capsule wall, too. In this case the chlorophyll content of the capsule wall is 0.1 to 5 % by mass, preferably 0.2 to 3 % by mass, particularly preferably 0.3 to 1.5 % by mass. The capsule wall may contain the hydrophilic form of chlorophyll.

The preparation of the capsule wall containing a vegetable dye is carried out as follows: the plasticizer (e.g. glycerol or sorbitol) and the optionally applied further component(s) (e.g. polyvinylpyrrolidone or a conserver) are dissolved in warm (70 to 90 OC) water and gelatin is added to the solution. The mass thus obtained is treated in vacuo under continuous vigorous stirring until a translucid, honey-like mass has been formed. Chlorophyll is dissolved separately in a small portion of water and then admixed to the ready, cooled mass.

Encapsulation is carried out mechanically by methods known i)er se. The tablets, drags and hard gelatin capsules may contain the following conventional carriers and/or auxiliary agents: Disintegrants such as starch, modified starch, cellulose, cellulose derivatives, cross-linked PVP (PVPP), sodium alginate and colloidal silicon dioxide; binding materials such as gelatin, tragacanth, glucose syrup, starch, PVP, cellulose derivatives, polyethylene glycols (PEG 1000-5000) and alginates; lubricants such as magnesium stearate, stearic acid, paraffin, talc, vegetable or animal fats, oils and waxes, silicones, polyethylene glycols (e.g.PEG 1000-5000); carriers and fillers such as starch, cellulose, PVP, PVPP, colloidal silicon dioxide, lactose, magnesium stearate, calcium stearate; diluents such as lactose, mannitol, starch, microcrystalline cellulose; colouring and flavouring agents and conventional coatings.

The pellet of the above-listed solid pharmaceutical compositions may contain 0.1 to 5 % by mass, preferably 0.5 to 3 % by mass of a vegetable dye, while the coating thereof may incorporate 0.1 to 1 % by mass, preferably 0.3 to 0.7 % by mass of the same substance.

The preparation of the tablets, drags and hard gelatin capsules according to the invention is carried out by methods known per se.

According to a further aspect of the present invention there are provided solid pharmaceutical compositions comprising a light-sensitive active ingredient optionally being hardly soluble in water together with conventional carriers and/or auxiliary agents, wherein said composition comprises a vegetable dye.

The preferred forms of the solid pharmaceutical compositions according to the invention, the vegetable dyes, furthermore the light-sensitive and hardly water -soluble active ingredients preferably used for the solid pharmaceutical compositions according to the invention have already been specified above.

According to a preferred aspect of the present invention there are provided solid pharmaceutical compositions, particularly soft gelatin capsules, comprising nifedipine as active ingredients.

According to a still further aspect of the present invention there are provided soft gelatin capsules comprising nifedipine as active ingredient, wherein the filling and/or the capsule wall incorporate(s) a vegetable dye, preferably chlorophyll, in an amount of 0.1 to 10 % by mass.

The photolytic decomposition of the active ingredient of the soft gelatin capsules according to the present invention was investigated by the so-called "sun test" during 4 hours. The results are given in Table I.

Table I Photolytic decomposition Sample used Concentration Concentration of Example No. of the initial the decomposition active ingre- products (% by dient mass) (t bv mass) nitro nitroso other Filling solution: Example 2 98.50 1.00 0.23 0.27 Capsule wall: Example 4 Filling solution: Example 1 98.00 0.90 0.24 0.86 Capsule wall: Example 5 According to USP XXII the amount of the nitro decomposition product may not exceed 2.0 % by mass, while that of the nitroso compound may not be more than 0.5 % by mass. From the data of Table I it can be established that the soft gelatin capsules prepared according to the present invention contain the decomposition products in a considerably lower amount than the allowed one.It is highly remarkable that even in case of soft gelatin capsules containing a vegetable dye only in the filling a light protection satisfying the requirements of USP XXII has been achieved without the incorporation of a colouring agent into the capsule wall. On the other hand, the capsule wall does not contain any opacifier.

Surprisingly it has been found that not only a proper light protection can be achieved by the process according to the invention but the vegetable dyes improve the solubility of nifedipine in certain carriers (e.g. in vegetable oils). It is known that nifedipine is barely soluble in vegetable oils.

At the same time the latter are, owing to their compatibility with the gelatin capsule wall, excellent carriers, but their applicability is hindered by the slight solubility of nifedipine.

The following experiment proves that under effect of vegetable dyes both the solubility of nifedipine in different vegetable oils and its release are improved.

The drug release from the capsules was determined in a rotating paddle equipment according to USP XXII by using distilled water as dissolving medium within 15 minutes, at a temperature of 37 + 0.5 OC (revolutions per minute = 50). The results are summarized in Table II.

Table II Release of the active ingredient Vegetable oil Chlorophyll content Release of the used as solvent of the filling active ingre solution dient from the (% by mass) capsule within 15 minutes (% by mass) (demand: 80 %) Calabash oil - 82.30 Calabash oil 1.5 92.40 Calabash oil 3.0 97.02 Lemon oil - 90.76 Lemon oil 1.5 95.37 Lemon oil 3.0 100.14 Olive oil - 86.38 Olive oil 1.5 90.50 Olive oil 3.0 96.40 According to the requirements specified is USP XXII the degree of the release of nifedipine has to amount at least to 80 %. From the data of Table II it can be seen that the release of nifedipine from the vegetable oils used as solvent (calabash oil, lemon oil, olive oil) considerably exceeds this value.Furthermore it is remarkable that in the presence of chlorophyll the release of nifedipine is significantly better than in case of using basically the same carrier but without any vegetable dye. The recognition that vegetable dyes promote drug release could not be aforeseen and so it is fully surprising.

Further details of the present invention are to be found in the following Examples, without limiting the scope of protection to these Examples.

Example 1 A capsule filling having the following composition is prepared: Component Amount. % bv mass Nifedipine 3.00 Poly(ethylene oxide)-sorbitan monooleate 22.85 Lemon oil 14.65 Lecithin 57.00 Chlorophyll (lipophilic) 2.50 100.00 Preparation: poly(ethylene oxide)-sorbitan monooleate is warmed to about 70 OC and nifedipine is dissolved in it. When the dissolution has been completed, lecithin and lipophilic chlorophyll are added to the solution while it is still warm, then the mixture is cooled to room temperature and lemon oil is introduced to it. If necessary, the solution is filtered through a plastic sieve (pore size: 120 mesh).

Example 2 A capsule filling having the following composition is prepared: Component Amount. % by mass Nifedipine 2.80 Poly(ethylene oxide)-sorbitan monooleate 82.50 Calabash oil 11.50 Chlorophyll (lipophilic) 3.20 100.00 Preparation: poly (ethylene oxide)-sorbitan monooleate is warmed toabout 70 OC and nifedipine is dissolved in it. When the dissolution has been completed, the solution is cooled to about 45 OC and calabash oil and lipophilic chlorophyll are added to it. If necessary, the solution is filtered through a plastic sieve (pore size: 120 mesh).

Example 3 A capsule filling having the following composition is prepared: Component Amount. % bv mass Nifedipine 4.00 Carbowax 300 88.00 Lemon oil 3.00 Chlorophyll (hidrophilic) 5.00 100.00 Preparation: Carbowax 300 is warmed to 60 OC and nifedipine is dissolved in it. When the dissolution has been completed, the solution is cooled to 25-30 OC and hydrophilic chlorophyll and lemon oil are added to it. If necessary, the solution is filtered through a plastic sieve (pore size: 120 mesh).

Example 4 A capsule wall having the following composition is prepared: ComPonent Amount, % bv mass Gelatin 50.00 Glycerin 27.00 Sorbitol 70 % 6.00 Distilled water 17.00 100.00 Preparation: water is warmed to 80 OC and sorbitol and glycerol are added to it. Then gelatin is introduced to the mixture under vigorous stirring and the stirring is continued under vacuum until the mixture has turned into a translucid, honey-like mass. This latter is covered into capsules mechanically by methods known per se.

Example 5 A capsule wall having the following composition is prepared: Component Amount, % by mass Gelatin 45.00 Glycerin 36.30 Conserver 0.20 Chlorophyll (hydrophilic) 0.50 Distilled water 18.00 100.00 Preparation: water is warmed to 80 OC and a conserver is dissolved in it. Then glycerol is added to the solution, and gelatin is introduced to it under vigorous stirring. The stirring is continued under vacuum until the mixture has turned into a translucid, honey-like mass. Chlorophyll is dissolved separately in a small portion of water and the aqueous solution is admixed with the above-specified mass cooled to 60 OC. This latter is converted into capsules mechanically by methods known per se.

Example 6 A capsule wall having the following composition is prepared: Component Amount, % bv mass Gelatin 45.00 Glycerin 37.00 Polyvinylpyrrolidone 5.00 Chlorophyll (hydrophilic) 1.00 Distilled water 12.00 100.00 Preparation: water is warmed to 80 OC, polyvinylpyrrolidone is dissolved in it and glycerol is added to the solution. Then gelatin is introduced to the mixture under continuous vigorous stirring. The mass is stirred under vacuum until it has turned into a translucid, honey-like product. Chlorophyll is dissolved separately in a small portion of water, and the aqueous solution is admixed with the above-specified mass cooled to 60 OC. This latter is converted into capsules mechanically by methods known per se.

Claims (21)

1. A solid pharmaceutical composition comprising a light-sensitive and optionally hardly water-soluble active ingredient together with conventional carriers and/or auxiliary agents, wherein said composition incorporates a vegetable dye.

2. A solid pharmaceutical composition according to claim 1, prepared in the form of a soft gelatin capsule.

3. A soft gelatin capsule according to claim 2, comprising as active ingredient nifedipine and containing chlorophyll in the filling solution and optionally in the capsule wall.

4. A process for the preparation of a solid pharmaceutical composition as claimed in claim 1, w h i c h c o m p r i s e s incorporating a vegetable dye into the composition.

5. A process according to claim 4, w h i c h c o m p r i s e s using chlorophyll, caramel, saffron yellow or beetroot dye as vegetable dye.

6. A process according to claim 4 or 5, w h i c h c o m p r i s e s using chlorophyll in an amount of 0.1 to 10 % by mass related to the total mass of the composition.

7. A process according to any of claims 4 to 6, w h i c h c o m p r i s e s using as hardly water-soluble and/or light-sensitive active ingredient a compound selected from the group consisting of vitamins D, preferably colecalciferol; vitamin A; imidazoline derivatives, preferably methynazol; piperazine derivatives, preferably tripolydine hydrazine hydrochloride; ergot and indole alkaloids, preferably dihydroergo toxin methanesulfonate or ergotamine tartrate; butyrophenone derivatives, preferably haloperidol, droperidol or benperidol; nitroglycerin; dihydropyridine derivatives, preferably nifedipine, nirudipine, nitrendipine, nisoldipine, nimodipine, nicarbipine or phenodipine; anabolic steroids, preferably phenoxymesteron; thyroid hormones, preferably levothyroxine; folic acid analogue antimetabolites, preferably methotrexate; purine-analogue antimetabolites, preferably azathoprine; nitrofuran derivatives, preferably nitrofurantoin; antineoplastic methylhydroxines, preferably pro carbazine; corticosteroids, preferably betamethasone; sodium nitroprusside; morphine derivatives, preferably morphine sulfate or papaverine hydrochloride; catecholamines, preferably dopamine or isoprenaline; estrogens, preferably hexosterol; sulfadiazine; alkaloids, preferably colchicine; profen derivatives, preferably ketoprofen; antibiotics, preferably mitomycin or bacitracin; tricyclic antidepressants, preferably carbamazepine; phenthiazines, preferably hibernal or trifluoperazine; mustardnitrogens; ***e hydrochloride; ethylenediamine derivatives, preferably tripelenamine; or aminoquinoline derivatives, preferably chloroquine.

8. A process according to claim 7, w h i c h c o m p r i s e s using a dihydropyridine derivative, nitroglycerin or vitamin A as light-sensitive and optionally hardly water-soluble active ingredient.

9. A process according to claim 8, w h i c h c o m p r i s e s using nifedipine as light-sensitive and optionally hardly water-soluble active ingredient.

10. A process according to any of claims 4 to 9, w h i c h c o m p r i s e s preparing soft gelatin capsules, tablets, dragees or hard gelatin capsules as solid pharmaceutical composition.

11. A process according to claim 10, w h i c h c o m p r i s e s preparing soft gelatin capsules as solid pharmaceutical composition.

12. A process according to claim 9 or 11 for the preparation of soft gelatin capsules comprising nifedipine as active ingredient, w h i c h c o m p r i s e s incorporating into the filling and/or wall of the capsule a vegetable dye in an amount of 0.1 to 10 % by mass.

13. A process according to claim 12, w h i c h c o m p r i s e s using chlorophyll as vegetable dye.

14. A process according to any of claims 11 to 13, w h i c h c o m p r i s e s incorporating 1 to 10 % by mass, preferably 1 to 5 % by mass, particularly preferably 1.5 to 3.5 % by mass, of lipophilic chlorophyll into the filling of the soft gelatin capsule.

15. A process according to any of claims 11 to 13, w h i c h c o m p r i s e s incorporating 0.5 to 10 % by mass, preferably 1 to 7 % by mass, particularly preferably 1.5 to 5 % by mass, of hydrophilic chlorophyll into the filling of the soft gelatin capsule.

16. A process according to any of claims 11 to 15, w h i c h c o m p r i s e s using 1 to 7 % by mass, preferably 1.5 to 5 % by mass, of chlorophyll and conventional carriers and auxiliary agents, preferably vegetable and aromatic oils or non-ionic surfactants and flavouring agents, for the preparation of the filling of the soft gelatin capsules.

17. A process according to claim 12, w h i c h c o m p r i s e s incorporating 0.1 to 5 % by mass, preferably 0.2 to 3 % by mass, particularly preferably 0.3 to 1.5 % by mass of chlorophyll into the capsule wall.

18. A process according to claim 11 for the preparation of soft gelatin capsules comprising nifedipine as active ingredient, w h i c h c o m p r i s e s filling a composition containing 2 to 5 % by mass of nifedipine, a vegetable dye or a non-ionic surfactant and 0.5 to 10 % by mass, preferably 1 to 7 % by mass, particularly preferably 1.5 to 5 % by mass, of chlorophyll into a capsule having a wall enclosing a plasticizer of gelatin base, preferably glycerol or sorbitol, and optionally a conserver and optionally 0.1 to 5 % by mass, preferably 0.2 to 3 % by mass, particularly preferably 0.3 to 1.5 % by mass of chlorophyll.

19. A process according to claim 18, w h i c h c o m p r i s e s filling a composition containing 2 to 5 % by mass of nifedipine, an oil selected from the group consisting of sunflower oil, calabash oil, olive oil and lemon oil, a poly(ethylene oxide) -sorbitan fatty acid ester, preferably poly(ethylene oxide)-sorbitan monooleate, or polyethylene glycol and 1.5 to 3.5 % by mass of chlorophyll into a capsule having a wall of gelatin base comprising glycerol and optionally 0.3 to 1.5 % by mass of chlorophyll.

20. A solid pharmaceutical composition comprising a filling substantially as hereinbefore described in any one of Examples 1 to 3 encapsulated within a capsule substantially as hereinbefore described in any one of Examples 4 to 6.

21. A pharmaceutical composition produced by a process as claimed in any one of claims 4 to 19.