CA2332270A1

CA2332270A1 - Cyclosporin preparations

Info

Publication number: CA2332270A1
Application number: CA002332270A
Authority: CA
Inventors: Robert Heger; Helmut Auweter; Peter Pfluger; Jorg Breitenbach; Rudolf Binder; Jurgen Zeidler; Gunther Berndl
Original assignee: Individual
Current assignee: BASF SE
Priority date: 1998-05-15
Filing date: 1999-05-04
Publication date: 1999-11-25
Also published as: WO1999059541A3; JP2002515415A; NO20005769L; AU3930399A; NO20005769D0; CN1301171A; WO1999059541A2; EP1077676A2; DE19821951A1

Abstract

The invention relates to solid or liquid cyclosporin preparations for oral administration in which the cyclosporin is presented in the form of solid X-amorphous particles embedded in a coating matrix in a colloidally dispersed manner.

Description

Cyclosporin preparations The present invention relates to cyclosporin preparations in which the cyclosporin is present colloidally in the form of solid, X-ray-amorphous particles.
Cyclosporins, a series of nonpolar, cyclic oligopeptides, are distinguished by their immunosuppressive action. Among them, cyclosporin A, obtained by fermentation and consisting of 11 amino acids, has especially gained therapeutic importance.
Although cyclosporin formulations have been developed both for oral and for intravenous administration, the oral administration of cyclosporin is preferred, as it guarantees better patient compliance.
However, the quite large cyclosporin A, with a molecular weight of 1202 g/mol, has a high lipophilicity, which is simultaneously manifested by a very low water solubility (< 0.004% m/V). Owing to a certain solubility in oils such as olive oil as well as in ethanol, it has been possible to develop emulsion concentrates which lead, on peroral administration, to a bioavailability, even if relatively variable, of about 30% (cf. ~.H. Muller et al. in "Pharmazeutische Technologies Moderne Arzneiformen"
[Pharmaceutical Technology: Modern Pharmaceutical Forms], Wissenschaftliche Verlagsgesellschaft, Stuttgart, 1997, pp. 118-125).
Peroral forms which can be obtained at present on the market are accordingly either emulsion concentrates for administration as solutions or microemulsions filled into capsules. In both cases, solvents such as ethanol and/or oil are employed for the solubilization of the cyclosporin.
In these cases, the bioavailability, however, can be subject to great variations in the range from 10 to 60%. These variations are connected with the pharmaceutical form. and the state of the preparation in the gastrointestinal tract. Furthermore, the natural fat digestion has a significant influence on the absorption of the perorally administered cyclosporin.
WO 97/07787 also describes cyclosporin formulations which in addition to the active compound contain an alkanolic solvent such as ethanol or propylene glycol and also a nonionic polyoxyalkylene derivative as a surface-active substance.

A disadvantage of such forms, however, is on the one hand that they contain solvents, especially ethanol, and on the other hand that the cyclosporin tends to recrystallize at low temperatures, which is problematical with respect to the storage stability. As a matter of fact, such precipitates are largely unabsorbed, so that uniform bioavailability is not guaranteed under certain circumstances.
EP-A 425 892 discloses a process for improving the bioavailability of pharmaceutical active compounds having peptide bonds, in which a solution of the active compound is rapidly mixed with an aqueous colloid in a water-miscible organic solvent such that the active compound precipitates in colloidally disperse form.
WO 93/10767 describes peroral administration forms for peptide drugs in which the drug is incorporated into a gelatin matrix in such a way that the colloidal particles formed are present in uncharged form. A disadvantage of such forms, however, is their tendency to flocculate.
It is an object of the present invention to find administration forms of cyclosporin suitable for oral administration, which are free of solvents and are comparable with the microemulsions with respect to their bioavailability.
Accordingly, we have found that this object is achieved by solid cyclosporin preparations in which the cyclosporin is present in the form of solid, X-ray-amorphous particles distributed in colloidally disperse form in a matrix of a polymeric encasing material.
All cyclosporins can be processed according to the invention, but cyclosporin A is preferred. Cyclosporin A has a melting point of 148-151°C and is employed as a colorless crystalline substance.
In the preparations according to the invention, the cyclosporin is embedded in particulate form in an encasing matrix consisting of one or more polymeric stabilizers.
Polymeric stabilizers which are suitable according to the invention are swellable protective colloids such as, for example, bovine, porcine or fish gelatin, starch, dextrin, pectin, gum arabic, lignosulfonates, chitosan, polystyrene sulfonates, alginates, casein, caseinate, methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, milk powder, dextran, whole milk or skimmed milk or mixtures of these protective colloids. Furthermore, homo- and copolymers based on the following monomers are suitable: ethylene oxide, propylene oxide, acrylic acid, malefic anhydride, lactic acid, N-vinylpyrrolidone, vinyl acetate, a- and ~-aspartic acid.
Particularly preferably, one of the gelatin types mentioned is employed, in particular gelatin subjected to acidic or basic degradation and having bloom numbers in the range from 0 to 250, very particularly preferably gelatin A 100, A 200, B 100 and B 200 and also low-molecular weight, enzymatically degraded gelatin types having the bloom number 0 and molecular weights of 3000 to 30,000 D such as, for example, Collagel A and Gelitasol P
(Stoess, Eberbach) or chemically modified gelatin, such as, for example, Gelafundin (B. Braun, Melsungen), and mixtures of these gelatin types.
The preparations furthermore contain low-molecular weight surface-active compounds. Those suitable are especially amphiphilic compounds or mixtures of such compounds. Basically, all surfactants having an HLB of 5 to 20 are suitable. Suitable appropriate surface-active substances are, for example: esters of long-chain fatty acids containing ascorbic acid, mono- and -diglycerides of fatty acids and their ethoxylation products, esters of monofatty acid glycerides with acetic acid, citric acid, lactic acid or diacetyltartaric acid, polyglycerol fatty acid esters such as, for example, the monostearate of triglycerol, sorbitan fatty acid esters, propylene glycol fatty acid esters, 2-(2'-stearoyllactyl)lactic acid salts and lecithin.
Ascorbyl palmitate is preferably employed.
The amounts of the various components are chosen according to the invention such that the preparations contain 0.1 to 70% by weight, preferably 1 to 40% by weight, of cyclosporin, 1 to 80%
by weight, preferably 10 to 60% by weight, of one or more polymeric stabilizers and 0 to 50% by weight, preferably 0.5 to 20% by weight, of one or more low-molecular weight stabilizers.
The percentages by weight relate to a dry powder.
In addition, the preparations can also contain antioxidants and/or preservatives for the protection of the cyclosporin.
Suitable antioxidants or preservatives are, for example, a-tocopherol, t-butylhydroxytoluene, t-butylhydroxyanisole, lecithin, ethoxyquin, methylparaben, propylparaben, sorbic acid, sodium benzoate or ascorbyl palmitate. The antioxidants or preservatives can be present in amounts of from 0 to 10% by weight, based on the total amount of the preparation. It can also be recommended to add to the preparations lipoprotein blockers to improve the absorption of the cyclosporin, for example polyoxyethylene cholesterol ethers.
Furthermore, the preparations can also contain plasticizers for increasing the stability of the final product. Suitable plasticizers are, for example, sugars and sugar alcohols such as sucrose, glucose, lactose, invert sugar, sorbitol, mannitol, xylitol or glycerol. Lactose is preferably employed as a plasticizes. The plasticizers can be present in amounts of from 0 IO to 50% by weight.
Furthermore, the preparations can also contain edible oils and/or fats to increase the colloidal stability of the preparation according to the invention. Suitable oils and fats are, for example, of vegetable origin such as sunflower oil, groundnut oil, corn oil, linseed oil, olive oil, poppyseed oil, rapeseed oil, castor oil, coconut oil, peanut oil, soybean oil, palm oil or cottonseed oil. Other suitable oils or fats are fish oils, neatsfoot oil, lard, beef tallow and butterfat. The oils and fats can be present in the preparation according to the invention in the range from 0-50% by weight, based on cyclosporin. In the -formulation, the oil or fat is embodied in the colloidal particles containing solid cyclosporin. It is crucial in the choice of the nature and amount of the oil or fat that the colloidal particles containing cyclosporin are furthermore present as solid particles at administration temperatures (T < 40~C).
Further pharmaceutical excipients such as binders, disintegrants, flavorings, vitamins, colorants, wetting agents, additives affecting the pH (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart 1978) can also be incorporated via the organic solvent or the aqueous phase.
For carrying out the process according to the invention, a solution of the cyclosporin in a suitable solvent is first prepared, solution in this connection meaning a true molecularly disperse solution or a melt emulsion. Suitable solvents are organic, water-miscible solvents which are volatile and thermally stable and only contain carbon, hydrogen and oxygen. Expediently, they are miscible to at least 10% by weight with water and have a boiling point of below 200°C and/or have less than 10 carbon atoms. Appropriate alcohols, esters, ketones and acetals are preferred. In particular, ethanol, n-propanol, isopropan-1-ol, 1,2-butanediol 1-methyl ether, 1,2-propanediol 1-n-propyl ether or acetone is used.

According to one embodiment of the process, a molecularly disperse solution of the cyclosporin is dissolved in the chosen solvent at temperatures in the range from preferably 20 to 150°C, within a period of time of less than 120 seconds, it optionally 5 being possible to work at an overpressure of up to 100 bar, preferably 30 bar.
According to a further preferred embodiment, the cyclosporin solution is prepared such that the mixture of cyclosporin and solvent is heated above the melting point of the cyclosporin to 150 to 240°C within a period of time of less than 10 seconds, it optionally being possible to work at an overpressure of up to 100 bar, preferably 30 bar.
The concentration of the cyclosporin solution prepared in this way is in general 10 to 500 g of cyclosporin per 1 kg of solvent.
In a preferred embodiment of the process, the low-molecular weight stabilizer is added directly to the cyclosporin solution.
In a process step connected thereto, the cyclosporin solution is mixed with an aqueous solution of the polymeric encasing -material. The concentration of the solution of the polymeric encasing material is 0.1 to 200 g/1, preferably 1 to 100 g/1.
In order to obtain particle sizes which are as small as possible in the mixing process, a high mechanical energy input is recommended when mixing the cyclosporin solution with the solution of the encasing material. Such an energy input can be effected, for example, by vigorous stirring or shaking in a suitable apparatus, or by injecting the two components into a mixing chamber using a powerful jet, so that vigorous mixing occurs.
The mixing process can be carried out batchwise or, preferably, continuously. As a result of the mixing process, precipitation of the cyclosporin occurs in the form of solid, X-ray-amorphous particles. The suspension or the colloid thus obtained can then be converted into a dry powder in a manner known per se, for example by spray-drying, freeze-drying or drying in a fluidized bed.
A procedure is used in the production of the preparations according to the invention in which the pH of the solution of the encasing material, in particular of gelatin, and a solution of the cyclosporin is adjusted such that no neutral charge occurs in the cyclosporin particles formed, i.e. the pH of the gelatin solution does not have to be adjusted to such a value that a charge-neutral state is established on formation of the particles.
The mean particle diameter of the solid cyclosporin particles in the matrix of the polymeric encasing material is 20 to 1000 nm, preferably 100 to 600 nm. Surprisingly, the spherical cyclosporin particles are completely X-ray-amorphous. X-ray-amorphous in this connection means the absence of crystal interferences in X-ray powder diagrams (cf. H.P. Klug, L.E. Alexander, "X-Ray Diffraction procedures for Polycristalline and Amorphous Materials, John Wiley, New York, 1959).
The dry powders obtained according to the invention can be employed in all customary oral pharmaceutical forms. It is thus possible, for example, to fill the powders into hard or soft gelatin capsules or to compress them to give tablets using the excipients customary therefor.
Furthermore, the powders, on account of their good redispersibility in water, are suitable for use as beverage forms, for example as beverage granules, in effervescent tablets, -juices, syrup forms or in sachets and for parenteral administrations. Even after redispersion, uniform finely divided suspensions (hydrosols) or colloids are obtained.
The preparations according to the invention not only offer the advantage that they are completely free of solvents such as ethanol, but also have a good bioavailability, which is perfectly comparable to that of the microemulsions. kith respect to the prior art, such a good bioavailability was not to be expected for a preparation which contains cyclosporin in solid form.
The results of a canine study confirm the good bioavailability of the preparation in comparison to a commercially available product.
Production Example 1 Production of a cyclosporin dry powder having an active compound content in the range of 10~ by weight a) Production of the micronizate 3 g of cyclosporin A were stirred into a solution of 0.6 g of ascorbyl palmitate in 36 g of isopropanol at 25°C, a clear solution resulting.

For the precipitation of the cyclosporin A in colloidally disperse form, this molecularly disperse solution was fed into a mixing chamber at 25°C. Mixing with 537 g of an aqueous solution of 14.4 g of gelatin B 100 bloom and 12.6 g of lactose in completely deionized water adjusted to pH 9.2 by means of 1 N NaOH was carried out therein. The entire process was carried out with pressure restriction to 30 bar.
After mixing, a colloidally disperse cyclosporin A dispersion having a cloudy white color shade was obtained.
By means of quasi-elastic light scattering, the mean particle size was determined to be 256 nm with a variance of 31%. By means of Fraunhofer diffraction, the mean value of the volume distribution was determined to be D(4,3) = 0.62 Eun with a I5 fine component of the distribution of 99.2 < 1.22 Eun.
b) Drying of the dispersion a) to give a nanoparticulate dry powder Spray-drying of the product la) afforded a nanoparticulate dry powder. The active compound content in the powder was determined to be 9.95% by weight by chromatography. The dry powder dissolves in drinking water with formation of a cloudy white dispersion (hydrosol).
c) X-ray wide-angle scattering Figure 1 illustrates the scattering curves of active compound (above) and dry powder according to lb) (below). The cyclosporin starting material is crystalline, as the X-ray diagram, which is distinguished by a number of sharp interferences, confirms. In contrast to this, the scattering curve of the dry powder exhibits only diffuse, broad interference maxima, such as are typical of an amorphous material. The active compound is accordingly present in X-ray amorphous form in the dry powder produced according to lb).
This also applies to the otherwise crystalline excipients lactose and ascorbyl palmitate.
d) Cryo-replica transmission electron microscopy (Cryo-TEM) Figure 5 shows a Cryo-TEM photograph of the dry powder according to lb) redispersed in tap water. The spherical nanoparticulate cyclosporin particles having a mean diameter of D = 500 nm can be readily detected. This illustration confirms that after the redispersion of the dry powder a colloidally disperse cyclosporin solution again forms in which the individual colloid particles are present in nonaggregated form.
Production Example 2 Production of a cyclosporin dry powder having an active compound content in the range of 15% by weight a) Production of the micronizate 3 g of cyclosporin A were stirred into a solution of 0.6 g of ascorbyl palmitate in 18 g of isopropanol and 18 g of completely deionized water at 25°C. This solution was converted into the molecularly dissolved state by heating in a heat exchanger. The residence time of the cyclosporin solution in the heat exchanger was 90 min, a temperature of at most 135°C not being exceeded.
For the precipitation of the cyclosporin A in colloidally disperse form, this molecularly disperse solution was fed into a mixing chamber at 135°C. Mixing with 393.9 g of an aqueous solution of 9.2 g of gelatin A 100 bloom and 6.1 g of lactose in completely deionized water adjusted to pH 9.2 by means of 1 N NaOH was carried out therein. The process was carried out with pressure restriction to 30 bar in order to prevent evaporation of the water. After mixing, a colloidally disperse cyclosporin A dispersion having a cloudy white color shade was obtained.
By means of quasi-elastic light scattering, the mean particle size was determined to be 285 nm with a variance of 48%. By means of Fraunhofer diffraction, the mean value of the volume distribution was determined to be D(4,3) = 0.62 ~.m with a fine component of the distribution of 99.8% < 1.22 Vim.
b) Drying of the dispersion 2a) to give a dry powder Spray-drying of the dispersion led to a nanoparticulate dry powder. The active compound content in the dry powder was determined to be 15.9% by weight by chromatography. The dry powder dissolved in drinking water with formation of a cloudy white dispersion.
By means of quasi-elastic light scattering, the mean particle size immediately after redispersion was determined to be 376 nm with a variance of 38%. By means of Fraunhofer diffraction, the mean value of the volume distribution was determined to be D(4,3) = 0.77 Eun with a fine component of the distribution of 84.7% < 1.22 Eun.
Freeze-drying of the product led to a nanoparticulate dry powder. The active compound content in the powder was determined to be 16.1% by weight of cyclosporin by chromatography. The dry powder dissolved in drinking water to give a cloudy white hydrosol.
By means of quasi-elastic light scattering, the mean particle size immediately after redispersion was determined to be 388 nm with a variance of 32%. By means of Fraunhofer diffraction, the mean value of the volume distribution was determined to be D(4,3) = 0.79 N.m with a fine component of the distribution of 82.4% < 1.22 N,m.
c) Microelectrophoresis Figure 3 illustrates the pH-dependent mobility curves of an aqueous dispersion of active compound, gelatin and dry powder according to 2b) (spray-drying). The mobility curve of the crystalline cyclosporin A employed as starting material differs markedly in the height of the mobilities and the position of the isoelectric point from that of the micronized dry powder according to 2b). The isoelectric point of the redispersed dry powder coincides with the gelatin used. This shows that the nanoparticulate cyclosporin particles are embedded by a gelatin casing.
Production Example 3 Analogously to Example 2a), a colloidally disperse cyclosporin A
dispersion was produced from 4.5 g of cyclosporin A, 0.9 g of ascorbyl palmitate, 9.6 g of gelatin A 100 bloom and 7.2 g of lactose.
By means of quasi-elastic light scattering, the mean particle size was determined to be 280 nm with a variance of 21%. By means of Fraunhofer diffraction, the mean value of the volume distribution was determined to be D(3,4) -- 0.62 N.m with a fine component of the distribution of 99.2% < 1.2 Vim.
b) Drying of the dispersion 3a) to give a nanoparticulate dry powder By means of spray-drying, a nanoparticulate dry powder having a cyclosporin A content (determined by chromatography) of 19.9% by weight was obtained. The dry powder dissolved in drinking water with formation of a cloudy white dispersion 5 (hydrosol).
By means of quasi-elastic light scattering, the mean particle size immediately after redispersion was determined to be 377 nm with a variance of 45%. By means of Fraunhofer 10 diffraction, the mean value of the volume distribution was determined to be D(4,3) = 0.62 N.m with a fine component of the distribution of 83.3% < 1.2 N.m.
Figure 3: X-ray wide-angle scattering of dry powders 2b) and 3b) Figure 3 presents the scattering curves of the dry powders according to 2b) (upper curve) and 3b) (lower curve) obtained in each case by spray-drying. In contrast to the scattering curve of the crystalline cyclosporin starting material, which contains sharp interferences, contained in Figure 1, the scattering curves of the dry powders exhibit only diffuse, broad interference maxima, such as are typical of amorphous materials.
Production Example 4 Analogously to Production Example 3, a preparation was produced in which the encasing matrix material was fish gelatin having molecular weight components of 103 to 10~ D.
Pharmacokinetic properties of the dry powders Blood level kinetics in the dog: general method Cyclosporin was administered either orally as a solid form or by means of stomach tube in liquid form in the appropriate preparation to beagle dogs having a weight in the range from 8 to 12 kg. Liquid forms were given in 50 ml of water and washed down with a further 50 ml of water. Solid forms were administered without water. The animals were not fed for 16 h before substance administration; feeding continued 4 h after substance administration. Blood was taken in heparinized vessels from the jugular vein or the antebrachial cephalic vein of the dogs before substance administration and at intervals up to 32 h after substance administration. The blood was deep-frozen and stored at -20°C until the analytical work-up. The blood levels were determined by a validated, internally standardized GC-MS method.

Form 1 (for comparison): Sandimmun~ Optoral, capsule, 100 mg of active compound Form 2: dry powder according to Production Example 1, active compound dose 100 mg; administration as a hydrosol Form 3: dry powder according to Production Example 3, active compound dose 100 mg; administration as a hydrosol Figure 4 indicates the medians of the corresponding blood levels.
It can be clearly discerned that with the forms F2 and F3 according to the invention at the start a more rapid increase in the blood level values is achieved than with the comparison form F1.
Areas under the blood level curves and relative bioavailability Table Form 1 (Sandimmun Optoral) Para- Animal)Animal AnimalAnimal Animal AnimalMean Median meter 1 2 3 4 5 6 tmax 2 2 2 1 2 2 2 Cmax 1030.01062.0 865.0 387.0 1799.0 869.0 1002.0 949.5 AUC 5781.86487.8 6497.02403.6 7892.2 7047.86018.4 6492.4 AUC/ 734.7 855.9 759.9 288.5 947.4 846.1 738.8 803.0 dose BA$ 99 116 103 39 128 114 100 100 AUC: Area under the curve BA: Bioavailability tmax: [h]
Cmax: [ng/ml]

Form 2 Para- Animal AnimalAnimal Animal AnimalAnimal Mean Median meter 1 2 3 4 5 6 tmax 0.5 1 2 1 0.5 1 1 Cmax 3529.0 718.0 676.0 459.0 853.0 580.0 1135.8 697.0 AUC 123x9.74410.13889.5 2727.2 5049.74251.3 5452.9 4330.7 AUC/ 1574.3 581.8 454.9 327.4 606.2 510.4 675.8 546.1 dose BA% 213 79 62 44 82 69 91 74 Form 3 para- Animal Animal AnimalAnimal AnimalAnimal Mean Median meter 1 2 3 4 5 6 tmax 0.5 2 0.5 2 2 0.5 1.25 Cmax 4208.0 567.0 829.0 439.0 956.0 4086.0 1847.5 892.5 AUC 17049.34565.2 3889.82849.6 5222.51s7o3.o8379.9 4893.9 AUC/ 2166.4 602.3 454.9 342.1 627.0 2005.2 1003.0 614.6 dose BA$ 293 81 62 46 85 271 140 83 production Example 4 Production of a cyclosporin dry powder having an active compound content in the region of 15% by weight a~ production of the micronizate 3 g of cyclosporin A were stirred into a solution of 0.6 g of ascorbyl palmitate and 0.3 g of soybean oil in 18 g of isopropanol and 18 g of completely deionized water at 25°C
such that a cloudy, coarsely disperse solution resulted. This solution was converted into the molecularly dissolved state by heating in a heat exchanger. The residence time of the cyclosporin solution in the heat exchanger was about 90 min, a temperature of at most 135°C not being exceeded.
For the precipitation of the cyclosporin A in colloidally disperse form, this molecularly disperse solution was fed into a mixing chamber at 135°C. Mixing with 412.3 g of an aqueous solution of 8.9 g of gelatin A 100 bloom and 6.5 g of lactose in completely deionized water, adjusted to pH 9.2 by means of 1 N NaOH, was carried out therein. The entire process was carried out with pressure restriction to 30 bar in order to prevent evaporation of the solvent. After mixing, a colloidally disperse cyclosporin A dispersion having a cloudy white color shade was obtained.
By means of quasi-elastic light scattering, the mean particle size was determined to be 273 nm with a distribution breadth of t 37%. By means of Fraunhofer diffraction, the mean value of the volume distribution was determined to be D(4,3) _ 0.62 N.m with a fine component of the distribution of 99.8% <
1.22 Nm.
b) Drying of the dispersion from a) to give a nanoparticulate dry powder Spray-drying of the product from Production Example [lacuna]
led to a nanoparticulate dry powder. The active compound content in the powder was determined to be 15.21% by weight of cyclosporin A (theoretical value: 15.54% by weight) by chromatography. The dry powder dissolves in drinking water with formation of a cloudy white dispersion (hydrosol).
By means of quasi-elastic light scattering, the mean particle size immediately after redispersion was determined to be 352 nm with a distribution breadth of ~ 42%. By means of Fraunhofer diffraction, the mean value of the volume distribution was determined to be D(4,3) = 0.73 ~.m with a fine component of the distribution of 86.3% < 1.22 Vim.

Claims

We claim:

1. A solid or liquid cyclosporin preparation for oral administration, in which the cyclosporin is present in the form of solid, X-ray-amorphous particles embedded in colloidally disperse form in an encasing matrix.

2. A cyclosporin preparation as claimed in claim 1, having a mean particle diameter of the cyclosporin particles in the range from 20 to 1000 nm.

3. A cyclosporin preparation as claimed in claim 1 or 2, comprising one or more edible oils or fats or mixtures of such oils and fats.

4. A cyclosporin preparation as claimed in one of claims 1 to 3, comprising one or more low-molecular-weight surface-active compounds.

5. A cyclosporin preparation as claimed in one of claims 1 to 4, comprising casein or caseinate as a polymeric encasing matrix.

6. A cyclosporin preparation as claimed in one of claims 1 to 4, comprising gelatin as a polymeric encasing matrix.

7. A cyclosporin preparation as claimed in one of claims 1 to 6, comprising ascorbyl palmitate as the low-molecular-weight surface-active substance.

8. A process for the production of preparations as claimed in one of claims 1 to 7, which comprises bringing about precipitation of the cyclosporin particles by mixing a solution of the cyclosporin in water or a water-miscible organic solvent with an aqueous solution of a polymeric protective colloid with introduction of mechanical energy.