RU2301679C2 - Ciclosporin-containing pharmaceutical preparation and its using - Google Patents

Abstract

FIELD: chemical-pharmaceutical industry, medicine.

SUBSTANCE: invention relates to a pharmaceutical preparation comprising a lipophilic phase in the amount 1-10% by mass, mixture of a surface-active substance and an accessory surface-active substance wherein a surface-active substance is chosen from polyoxyethylene glycerol esters and fatty acids and polyoxyethylene sorbitan esters and fatty acids, and an accessory surface-active substance is chosen from poloxamers, block-copolymers of polyoxyethylene and polyoxypropylene in the amount 1-50% by mass, hydrophilic phase in the amount 40-80% by mass, and ciclosporin or its derivatives as an active component in the concentration 0.1-20% by mass. Proposed pharmaceutical preparation is made in colloidal formulation for topical using and designated for treatment and prophylaxis of skin pathological alterations, and/or skin adventitious, and/or mucous envelopes including mucous envelopes in digestive tract, urogenital ways and bronchial system, and/or conjunctives.

EFFECT: valuable medicinal properties of pharmaceutical preparation.

17 cl, 5 tbl, 11 dwg

Description

This invention relates to colloidal carrier systems for a pharmaceutical agent containing cyclosporine for topical application to the skin and mucous membrane, comprising a surfactant / auxiliary surfactant mixture (polyoxyethylene glycerol monooleate / poloxamers), a hydrophilic phase, for example mixtures propylene glycol / water, lipophilic phase (isopropyl palmitate or oleic acid) and penetration enhancing agents.

This invention relates, in particular, to pharmaceutical preparations containing cyclosporin A (CsA), for topical use in the treatment of pathological changes in the skin, skin appendages or mucous membranes, in particular atopic dermatitis and psoriasis, to the use of these preparations and the method for their preparation.

CsA is known to be a cyclic peptide of 11 amino acids, with a molar mass of 1202 g / mol, which is produced by the soil fungus Tolypocladium inflatum. CSA is very difficult to dissolve in water (<0.04 mg / ml at 25 ° C), at the same time it is easily soluble in oils and alcohols. Its immunomodulatory effect is based on inhibiting the release of interleukin-1 from macrophages and interleukin-2 from T helper cells, which, in turn, activate the cytotoxic precursors of T cells from which cytotoxic T cells originate. Thus, the transcription of genes encoding said cytokines is inhibited. In this case, CSA affects only to a small extent the naturally occurring defense of the body. From the point of view of galenic agents, a pharmaceutical agent is a substance which, in particular, is not suitable for topical treatment, since high lipophilicity makes penetration through the epidermal lipid barrier almost impossible. As a reason for the failure of previous attempts to obtain and use various lipophilic, hydrophilic and liposome preparations for local application, as a rule, inadequate penetration of the pharmaceutical agent is indicated.

In dermatology, CSA, as it turned out, is especially suitable for systemic use for the treatment of severe psoriasis and atopic dermatitis. In addition, there are reports and studies of efficacy after systemic use in the case of many other inflammatory dermatoses (for example, ulcerative dermatitis, lichen planus, actinic reticuloid, disseminated annular granuloma).

WO 9302664 describes W / O microemulsions that contain a lipophilic phase (medium chain triglycerides and a surfactant with a low hydrophilic lipophilic balance (HLB) ratio of 5: 1 to 1.5: 1), an aqueous hydrophilic phase, surface - an active substance with a high HLB value and a water-soluble therapeutic agent.

GB 2222770 includes microemulsion preconcentrates including CSA, hydrophilic phase (propylene glycol or partial ester of low molecular weight mono- or polyoxyalkanediols) (transcutol / glycofurol), lipophilic phase (medium chain triglycerides) and surfactant R 40 (Cre). These systems are suitable for oral use and improve bioavailability compared to existing systems.

EP 760237 describes O / W microemulsions for water-insoluble pharmaceutically active substances, such as CsA, which are completely soluble in dispersed oil droplets. These systems include C ₈ -C ₂₀ substituted plant triglycerides, lecithin, as well as another surfactant and a lipophilic phase containing propylene glycol.

WO 97/22358 includes microemulsion pre-concentrates with CSA, the pharmaceutical agent being dissolved in a system comprising hydrophobic (tocopherols or tocopherol derivatives) and hydrophilic components (propylene carbonate and polyethylene glycol with a molecular weight <1000), as well as a surfactant.

WO 94/08603, WO 94/08605 and WO 99/39700 describe pharmaceutical preparations in which cyclosporin and its derivatives are listed as a possible active ingredient in the colloidal system.

In Tran HS et al, Site-specific immunosuppression using a new formulation of topical cyclosporine A with polyethylene glycol-8 glyceryl caprylate / caprate // J Surg Res. 1999, 83 (2), p.136-40, which is the closest analogue of the claimed invention, a topical preparation is disclosed containing cyclosporin A and a penetration enhancer of polyethylene glycol-8-glyceryl caprylate / caprate.

However, the previously described systems have some significant drawbacks. Partial organic solvents are used for dissolution, which must then be removed again from the preparation without any residue. Often, surfactant / adjuvant surfactant combinations are used in too high concentrations (more than 20% w / w) to improve the solubility of the pharmaceutical preparation. Some publications mention systems that are not exclusively composed of skin compatible ingredients. Some microemulsion preconcentrates are described, the actual structure of which is believed to be formed in situ only after application. In addition, existing systems have significantly larger particle diameters.

Thus, it is an object of the present invention to provide a new colloidal carrier system for a pharmaceutical agent, which essentially includes dermatologically acceptable ingredients, which carrier system for a pharmaceutical agent should at the same time have a relatively low surface- active substance / auxiliary surfactant.

This problem is solved by the distinguishing features according to claim 1. With respect to use, this invention is defined by the features of paragraphs 14-20 of the claims.

In accordance with this invention, therefore, it is proposed that the pharmaceutical preparation in colloidal form includes four essential components. The pharmaceutical preparation of this invention therefore includes a lipophilic phase, a mixture of a surfactant and an auxiliary surfactant, a hydrophilic phase and cyclosporin as the active ingredient at the concentrations indicated in claim 1.

The advantage of colloidal carrier systems for a pharmaceutical agent according to this invention can be seen, in particular, in the composition of exclusively dermatologically acceptable ingredients with a relatively low content of surfactant / auxiliary surfactant, as well as a small particle size dispersion.

From the point of view of materials, in particular, oils, waxes or fats are particularly suitable for the lipophilic phase for the pharmaceutical preparation of this invention. With respect to the lipophilic phase, all lipophilic phases that are known per se today from the prior art can be used. Especially preferred are triglycerides, isopropyl myristate, 2-octyldodecanol, isopropyl palmitate or oleic acid. The lipophilic phase is contained in the preparation in an amount of 1-10% by weight.

An essential component of the pharmaceutical preparation of this invention is a mixture of a surfactant and an auxiliary surfactant, which is used in an amount of 1-50% by weight, preferably 20-30% by weight. From the point of view of materials, surfactants selected from polyoxyethylene glycerol fatty acid esters and polyoxyethylene sorbitan fatty acid esters are preferred. Examples of auxiliary surfactants are poloxamers, block copolymers of polyoxyethylene and polyoxypropylene.

A particularly preferred mixture ratio is a mass ratio of from 1.5 to 2.5 for a surfactant and from 2.5 to 3.5 for an auxiliary surfactant. The authors of this invention were able to prove that, in particular, maintaining this ratio in a mixture of surfactant / auxiliary surfactant is important for the stability and suitability of the pharmaceutical preparation (Fig.9-11).

If the surfactant / auxiliary surfactant mixture comprises polyoxyethylene glycerol fatty acid esters and poloxamers in a 2: 3 weight ratio, particularly good results can be achieved.

The preparation according to this invention contains, in addition, a hydrophilic phase, which, as is known per se from the prior art, may include polyols, water or a polyol, or a polyol-buffer mixture, or only a buffer. The concentration of this component is 40-80% by weight, preferably 60-75% by weight.

In another preferred embodiment of the present invention, it is proposed, in the case of a hydrophilic phase, that a mixture of propylene glycol and water is used in a ratio of from 1:10 to 10: 1. The most preferred ratio of the mixture is 2: 1.

In accordance with this invention, the pharmaceutical preparation contains as an active ingredient cyclosporine and / or its derivative in a concentration of 0.1-20% by weight. It is particularly preferred that the pharmaceutical preparation contains cyclosporin A and / or its derivatives. The preferred concentration is in the range of 0.01-10% by weight, most preferably 0.5-5% by weight.

Of course, it is also possible that, in addition to cyclosporin A and / or its derivative, an additional active ingredient is contained in the pharmaceutical preparation. Examples of active ingredients of this type are corticosteroids, antibiotics, antifungal agents and / or virostatic agents.

As is known per se from the prior art, conventional additives such as penetration enhancing agents can also be added to the pharmaceutical preparation of this invention. If penetration enhancing agents are added, dimethyl sulfoxide or short chain alcohols in a concentration of 5-10% by weight are preferred.

The pharmaceutical preparation of this invention exists in colloidal form. It is preferable that the dispersed phase has a particle diameter in the range from 5 to 200 nm. Particularly preferably, the particle diameter is in the range from 5 to 100 nm.

The pharmaceutical preparation according to this invention is particularly suitable for the prevention of inflammatory diseases of the skin and mucous membrane, for the treatment and prevention of atopic dermatitis, for the treatment and prevention of psoriasis.

Other suitable uses are the treatment and prevention of collagenoses, chronic wounds, burns and / or chronic inflammatory diseases of the skin and mucous membrane, as well as the treatment and prevention of chronic inflammatory bowel diseases and the treatment and prevention of inflammatory eye diseases, as well as after transplantation.

The invention is described below in more detail using various compositions and test results.

Composition and preparation of solvent systems

Three colloidal carrier systems for a pharmaceutical agent have been developed, the composition of which follows from Table 1.

Isopropyl Palmitate System (IPP) m [g] % [wt./wt.] Cyclosporin A 2.0% (w / w) Cyclosporin A 0.2 2.0 Tagat® O2 / Synperonic® PE / L 101 2: 3 Tagat® O2 0.8 8.0 20.0% (w / w) Synperonic® PE / L 101 1,2 12.0 Isopropyl palmitate (IPP) 5.0% (w / w) Isopropyl palmitate 0.5 5,0 Propylene glycol / water 2: 1 73.0% (w / w) Propylene glycol 4.87 48.7 Water Ext. 10.0 24.3 DMSO system Cyclosporin A 2.0% (w / w) Cyclosporin A 0.2 2.0 Tagat® O2 / Synperonic® PE / L 121 2: 3 Tagat® O2 0.8 8.0 20.0% (w / w) Synperonic® PE / L 121 1,2 12.0 Oleic acid 5.0% (w / w) Oleic acid 0.5 5,0 Dimethyl sulfoxide (DMSO) 5.0% Dimethyl sulfoxide 0.5 5,0 (w / w) Propylene glycol / water 2: 1 68.0% (w / w) Propylene glycol 4,53 45.3 Water ext. 10.0 22.7 Oleic Acid System (OK) Cyclosporin A 1.5% (w / w) Cyclosporin A 0.15 1,5 Tagat® O2 / Synperonic® PE / L 121 2: 3 Tagat® O2 0.8 8.0 20.0% (w / w) Synperonic® PE / L 121 1,2 12.0 Oleic acid 5.0% (w / w) Oleic acid 0.5 5,0 Propylene glycol / water 2: 1 73.5% (w / w) Propylene glycol 4.9 49.0 Water ext. 10.0 24.5 Table 1: Developed colloidal carrier systems for pharmaceuticals

The preparation of systems was carried out according to a specific sequence of the following stages:

- weighing the pharmaceutical product,

- adding a mixture of surfactant / auxiliary surfactant,

- thorough grinding,

- adding the required number of IPPs,

- thorough mixing

- adding the prepared mixture of propylene glycol and water,

- mixing until then, until it becomes transparent, possibly a short-term treatment of the colloidal system with ultrasound.

Polyoxyethylene glycerol monooleate (Tagat® O2) and poloxamers (Synperonic® PE / L 101 or 121) were selected as emulsifiers. It is shown that for the preparation of a carrier system, a combination of both components in a mass ratio of 2: 3 is particularly suitable.

Mixtures of two surfactants and propylene glycol / water were prepared in advance. First, the powdered pharmaceutical was carefully triturated with a surfactant mixture, and then the lipophilic phase (isopropyl palmitate or oleic acid) was added. Subsequently, a hydrophilic phase (propylene glycol / water mixture) was added and stirring until the mixture became clear. At the end, DMSO was added. If required, the system was left for several minutes in an ultrasonic bath.

Isopropyl palmitate or oleic acid, both of which act as solvents of CSA, was used as lipophilic components. In addition, oleic acid functions as a penetration enhancing agent in order to facilitate the penetration of CsA through the stratum corneum. Dimethyl sulfoxide was added to improve the solubility of CSA in the carrier and in view of its penetration enhancing properties. As a mixture of a surfactant / auxiliary surfactant, polyoxyethylene glycerol monooleate was selected, which is transferred by human skin without any reaction at a 100% concentration and is well tolerated by the mucous membrane, as well as poloxamers that are allowed for intravenous administration.

Characteristics of carrier systems

Carrier systems for a pharmaceutical are characterized, inter alia, by dynamic scattering of laser light. This method is suitable for determining the size of colloidal particles in a liquid medium. Particle diameters of approximately 20 nm were determined for pharmaceutical-free preparations.

Analysis

The determination of CsA was carried out by high performance liquid chromatography (HPLC) (modified according to Merck KgA - Darmstadt). Technical data is presented in Table 2.

HPLC Block Merck-hitachi L-4250 UV-VIS detector AS-4000A Programmable Auto Sampler D-6000A Interface L-6200A Programmable Pump Fixed phase Lichrospher® RP select B (Merck), 125 × 4 mm inner diameter, 5 μm Mobile phase Acetonitrile / Water 70/30 (V / V) Flow 1 ml / min, isocratic Temperature 60 ° C Detection UV 210 nm Tab. 2: Analytical data

Release tests

The in vitro release of a pharmaceutical agent from the aforementioned preparations was tested with time using a multilayer membrane model system.

The individual cells of this model include, respectively, the base and the covering disk, between which the membrane layers are located. Through a hole in the integumentary disc (4 cm ² ) a certain amount of the preparation (10-20 mg) was applied to the membrane. Dodecanol colloidal membranes with a dodecanol content of 2%, which were prepared using an apparatus for applying a film, served as an acceptor. The acceptor absorption capacity was determined by determining the saturating solubility of CsA in dodecanol. This is important to ensure that achieving saturating solubility of the pharmaceutical in membranes is not a limiting factor for release. By using three membranes located one above the other, absorption conditions in the acceptor were achieved.

During the test (30, 100, 300 and 1000 minutes), the model was at a temperature of 32 ± 1 ° C. After the test time, the excess drug was carefully removed, the membranes were separated, extracted with ethanol-water (80/20; v / v) and subjected to determination of the content by HPLC. The determination was carried out five times during the testing time.

From FIG. 1, it can be determined that all three drugs release approximately 25% of the contained CSA after 30 minutes. The released amount of the pharmaceutical agent increases with longer testing times. In figure 2, for better comparison of carriers with different concentrations, the released amount of the pharmaceutical product is given per 10 mg of the drug used.

These tests were carried out in order to make sure that there is a sufficient release of CsA from the carriers and, therefore, the condition of penetration into human skin is fulfilled.

Penetration tests

Used the skin of the human chest obtained by surgical plastic surgery to reduce breast. Sliced skin pieces were stored at -3 ° C. After thawing, the liquid remaining on the surface was removed with a cotton swab and a defined surface of 3.14 cm ^{2 was} stamped. Approximately 6 mg of the radiolabelled test preparation per cm ^{2 was} applied to this surface so that as uniform a film as possible was formed on the skin surface. Then, a piece of skin lying on gauze was pulled onto a Franz diffusion cell, which was stored at 32 ° C. The same was done before the test started in the filled state to the equilibrium phase at 30 minutes. The acceptor medium, which was constantly stirred to reduce the thickness of the diffusion layer, directly adjoined to the inner surface of the skin or gauze. An isotonic NaCl solution was used as an acceptor fluid to simulate physiological conditions. Tests were carried out respectively on 3 different operating preparations for triple determination. After exposure, skin pieces were removed and fixed on a polystyrene foam box covered with aluminum foil using needles. Then the test drugs were wiped with a gauze swab.

Removal of the stratum corneum was carried out through a matrix containing a circular recess (diameter = 16 mm). Through this recess, 20 strips of Tesa film (Tesa Film® 4 204, 33 m × 19 mm; Co. Beiersdorf AG, Hamburg) were removed from 2.0106 cm ^{2 of} the skin surface. Two consecutively obtained strips, respectively, were measured together.

3 cylinders with a total surface of 0.848 cm ^{2 were} stamped from the remaining piece of leather using a Cromeyer stamp (diameter 6 mm; Stiefel Laboratorium GmbH, Offenbach) from approximately the central area of the skin. Using a freezing microtome, the thus obtained tissue cylinders were subsequently deep-frozen to -40 ° C and cut horizontally with respect to the skin surface. Sections of 10 × 20 μm were then removed to remove the components of the living epidermis, and sections of 15 × 18 μm were taken to treat the dermis. After this, a residue and an acceptor medium remained.

From Fig.3-5 it follows that in the case of all three preparations, after 30 minutes> 25% (PPI 35%, OA 32%, DMSO 27%) of the contained CsA penetrates the acceptor. In the case of a longer test time, the penetrating amount of the pharmaceutical agent increases slightly. 6-8, for a better comparison of carriers with different concentrations, the amount of penetrating pharmaceutical agent is given in micrograms.

Previously published data on galenic preparations for topical preparations containing cyclosporine have revealed inadequate release and / or penetration of the active substance. In this case, hydrophilic and lipophilic standard systems or liposomal preparations were tested. In many cases, the publications did not provide any precise indications regarding the contents of the preparations used, type of preparation or medical data. Two reasons are indicated regarding the lack of clinical effect. Firstly, due to the strong lipophilicity of CsA, the release and / or penetration of the active ingredient into the dermal layers of the skin is too low. Secondly, at a high molar mass, a factor significantly inhibiting penetration was detected. These results first revealed the release and penetration rates of approximately 25-30% of the applied concentration of the active ingredient during the first 30-100 minutes into healthy, i.e. ex vivo intact barrier skin. It is significant that if the skin is damaged (for example, plaques in psoriasis), more favorable conditions for penetration can be achieved compared to healthy skin.

Topical application of CSA compared with systemic treatment provides significant advantages. In case of local application, even during treatment over a large area, only minimal and not clinically significant systemic side effects should be taken into account. Known undesirable effects of pharmaceuticals, in particular, impaired renal function and arterial hypertension, are either not expected at all, or are expected to a lower degree. Application is possible even for patients who already have developed side effects as a result of systemic treatment and who therefore are no longer treated with CSA. In addition, through topical application, an increased spectrum of efficacy is obtained. In many inflammatory dermatoses, the formation and action of nitrogen monoxide (NO), which is formed from L-arginine through the enzyme NO synthase, is central to pathogenesis. The most recent studies have revealed that the induction and maintenance of inflammation in the case of psoriasis is essentially mediated by NO. CSA is known to be a sufficient blocker of NO synthase (NOS), which is also present in dermal microvascular endothelial cells due to eNOS and iNOS isoenzymes, and is inhibited by a high concentration of CSA in tissue after topical application to a greater extent than after systemic use. In addition, CSA also has a proliferation-inhibitory effect on keratinocytes, which act synergistically on psoriatic skin when applied topically. Reducing the cost of treatment per patient due to the lower amount of CSA required is also beneficial.

The disadvantages of local application and the associated lower systemic concentration are observed primarily in the absence of an effect on the lymph nodes, in which there is a significant activation process at the level of T cells. In addition, a therapeutic effect against arthropathic psoriasis should not be expected.

The presented tests, firstly, showed that it is possible to develop a medical system that satisfies the conditions for the penetration of CSA in sufficient concentration into the upper dermal layers. Stable carrier systems are presented in which CSA can be introduced in sufficient quantities. The loading of the system was deliberately chosen to be very high in order to fully utilize the medical properties of the systems and to provide favorable conditions for clinical use. Smaller concentrations of CSA can be achieved without difficulty with sufficient clinical efficacy. Tests for release revealed that amounts of the pharmaceutical agent from 25 to 40% are released at the relevant time and are available for penetration into the skin.

Ex vivo penetration tests have shown significant importance for preclinical development. They make it clear that after an appropriate duration of use (30-100 min), the concentration of the active ingredient of about 25-30% penetrates into the dermal layers or, respectively, through them, and thereby the ingredient becomes available at the desired site of action.

The components of the preparations were selected in accordance with the dermatological point of view. No potent sensitizing substances are contained, and the tests themselves have shown good tolerance, which makes the appearance of an irritant or toxic effect very unlikely, even in case of impaired barrier function in various dermatoses. The main area of evidence is psoriasis of a chronic stationary type or atopic dermatitis. In addition, there are many possible indications in connection with systemic treatment. Possible applications include collagenoses, burns, transplantations of skin or mucous membranes, and chronic ulcers.

The use of systems is proposed not only in relation to the outer part of the skin. In principle, it is possible to use the eyes after corneal transplantation, either for treating cicatricial pemphigoid mucous membrane, or use it in the area of the oral mucosa in case of red lichen mucosa or as an enema in case of chronic inflammatory bowel disease (e.g. M. Crohn, ulcerative colitis), if necessary, also in the form of an intraluminal foam.

The composition of microemulsions (ME) containing iiclosporin (CsA) and hydrocortisone (NS) Isopropyl palmitate microemulsion (IPP-ME) m [g] % [wt./wt.] Cyclosporin A 2.0% (w / w) Cyclosporin A 0.2 2.0 Hydrocortisone Hydrocortisone 0.2 2.0 Tagat® O2 / Synperonic® PE / L 101 2: 3 Tagat® O2 0.8 8.0 20.0% (w / w) Synperonic® PE / L 101 1,2 12,, 0 Isopropyl palmitate (IPP) 5.0% (w / w) Isopropyl palmitate 0.3 0 3 Propylene glycol / water 2: 1 73.0% (w / w) Propylene glycol 4.87 48.7 Water ext. 10.0 24.3 Microemulsion with DMSO (DMSO-ME) Cyclosporin A 2.0% (w / w) Cyclosporin A 0.2 2.0 Hydrocortisone Hydrocortisone 0.2 2.0 Tagat® O2 / Synperonic® PE / L 121 2: 3 Tagat® O2 0.8 8.0 20.0% (w / w) Synperonic® PE / L 121 1,2 12.0 Oleic acid 5.0% (w / w) Oleic acid 0.3 3.0 Dimethyl sulfoxide (DMSO) 5.0% (w / w) Dimethyl sulfoxide 0.5 5,0 Propylene glycol / water 2: 1 68.0% (w / w) Propylene glycol 4,53 45.3 Water ext. 10.0 22.7 Microemulsion with oleic acid (OK-ME) Cyclosporin A 1.5% (w / w) Cyclosporin A 0.15 1,5 Hydrocortisone Hydrocortisone 0.2 2.0 Tagat® O2 / Synperonic® PE / L 121 2: 3 Tagat® O2 0.8 8.0 20.0% (w / w) Synperonic® PE / L 121 1,2 12.0 Oleic acid 5.0% (w / w) Oleic acid 0.3 3.0 Propylene glycol / water 2: 1 73.5% (w / w) Propylene glycol 4.9 49.0 Water ext. 10.0 24.5

To prepare microemulsions (ME) containing hydrocortisone, the method described above was used to prepare microemulsions in the absence of hydrocortisone. Hydrocortisone was added immediately after cyclosporin was added to the lipophilic phase, namely, the corresponding amount of microcrystalline hydrocortisone was dissolved in the lipophilic phase at room temperature. All other stages of preparation correspond to the preparation of microemulsions in the absence of hydrocortisone.

Claims (17)

1. A pharmaceutical preparation in colloidal form for topical use in the treatment and prevention of pathological changes in the skin and / or appendages of the skin and / or mucous membranes, including the mucous membranes of the gastrointestinal tract, genitourinary tract and bronchial system, and / or conjunctiva, containing a) lipophilic phase in an amount of 1-10% by weight, b) a mixture of a surfactant and an auxiliary surfactant in an amount of 1-50% by weight, the mixture of a surfactant / auxiliary surfactant is used in a mass ratio of from 1.5 to 2.5 for a surfactant substances and from 2.5 to 3.5 for auxiliary surfactant, where the surfactant is selected from polyoxyethylene glycerol fatty acid esters and polyoxyethylene sorbitan fatty acid esters, and the auxiliary surfactant is selected from poloxamers, block copolymers of polyoxyethylene and polyoxypropylene, c) a hydrophilic phase in an amount of 40-80% by weight, and g) as an active ingredient, cyclosporine and / or its derivatives in a concentration of 0.1-20% by weight. 2. The pharmaceutical preparation according to claim 1, characterized in that the lipophilic phase is selected from pharmaceutical oils, waxes or fats. 3. The pharmaceutical preparation according to claim 2, characterized in that the lipophilic phase is selected from triglycerides, isopropyl myristate, 2-octyldodecanol, isopropyl palmitate or oleic acid. 4. The pharmaceutical preparation according to claim 1, characterized in that the mixture of surfactant / auxiliary surfactant includes an ether of polyoxyethylene glycerol and fatty acids and poloxamers in a mass ratio of 2: 3. 5. The pharmaceutical preparation according to claim 1, characterized in that the hydrophilic phase is selected from polyols, water or polyol-buffer mixtures. 6. The pharmaceutical preparation according to claim 5, characterized in that the hydrophilic phase is a mixture of propylene glycol and water in a ratio of from 1:10 to 10: 1, preferably 2: 1. 7. The pharmaceutical preparation according to claim 1, characterized in that cyclosporin A and / or its derivatives are contained in a concentration of 0.01-10% by weight, preferably 0.5-5% by weight. 8. The pharmaceutical preparation according to claim 1, characterized in that at least one additional active ingredient, for example a corticosteroid, is contained in addition to cyclosporin A and / or its derivatives. 9. The pharmaceutical preparation according to claim 1, characterized in that it additionally contains penetration enhancing agents, such as, for example, dimethyl sulfoxide or short chain alcohols, in a concentration of 5-10% by weight. 10. The pharmaceutical preparation according to claim 1, characterized in that the dispersed phase has particle diameters in the range from 5 to 200 nm. 11. The use of the pharmaceutical preparation according to any one of claims 1 to 10 for the treatment and prevention of inflammatory diseases of the skin and mucous membranes. 12. The use of the pharmaceutical preparation according to any one of claims 1 to 10 for the treatment and prevention of atopic dermatitis. 13. The use of the pharmaceutical preparation according to any one of claims 1 to 10 for the treatment and prevention of psoriasis. 14. The use of the pharmaceutical preparation according to any one of claims 1 to 10 for the treatment and prevention of collagenoses, chronic wounds, burns and / or chronic inflammatory diseases of the skin and mucous membranes. 15. The use of the pharmaceutical preparation according to any one of claims 1 to 10 for the treatment and prevention of chronic inflammatory bowel diseases. 16. The use of the pharmaceutical preparation according to any one of claims 1 to 10 for the treatment and prevention of inflammatory eye diseases. 17. The use of the pharmaceutical preparation according to any one of claims 1 to 10 for the treatment and prevention of rejection reactions after transplantation.

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