MX2008007291A - Pharmaceutical compositions comprising cyclosporin - Google Patents

Abstract

The invention relates to liquid pharmaceutical compositions containing:a) a therapeutically effective dose of a cyclosporin;b) an aqueous carrier liquid;c) a first solubilizing substance selected among the group of phospholipids;and d) a second solubilizing substance selected among the group of non-ionic surfactants. Preferably, the cyclosporin is liposome solubilized. The inventive composition is suitable for oral, parenteral, nasal, mucosal, topical, and particularly pulmonary application in the form of an aerosol.

Description

PHARMACEUTICAL COMPOSITIONS THAT COMPRISE CYCLOSPORINE FIELD OF THE INVENTION The invention concerns liquid pharmaceutical preparations containing cyclosporin as the active agent, as well as substances with similar physical, chemical and therapeutic properties and which are suitable for oral, parenteral, nasal, ocular, mucosal, topical and, in particular, for pulmonary application. Additional aspects of the invention pertain to containers for packaging and applying the preparations and concentrates thereof. In addition, the invention concerns the pharmaceutical uses of the preparations and their application for the treatment of specific diseases.

BACKGROUND OF THE INVENTION Ciclosporin is a cyclic oligopeptide with immunosuppressive and calcineurin inhibitory activity. It is characterized by a selective and reversible immunosuppression mechanism. It selectively blocks the activation of T lymphocytes by the production of certain cytokines that are involved in the regulation of these T cells. This involves, in particular, the inhibition of interleukin 2 synthesis, which, at the same time, suppresses the proliferation of cytotoxic T lymphocytes that are responsible, for example, for the rejection of foreign tissues. Cyclosporin acts intracellularly by binding to the so-called cyclophilins or immunophilins that belong to the family of proteins that bind cyclosporin with high affinity. The cyclosporin and cyclophilin complex subsequently blocks the serine-threonine phosphatase-calcineurin. Its activity state, in turn, controls the activation of transcription factors such as NF-Kappa-B or NFATp / c which play a decisive role in the activation of several cytokine genes that include interleukin 2. This results in the arrest of immunocompetent lymphocytes during the G0 or Gl phase of the cell cycle since proteins that are essential for cell division such as interleukin 2 can not be produced any longer. Auxiliary T cells that increase the activity of cytotoxic T cells, which are responsible for rejection, are the preferred site of cyclosporine attack. In addition, cyclosporine inhibits the synthesis and release of additional lymphokines that are responsible for the proliferation of T lymphocytes. mature cytotoxic and other functions of lymphocytes. The ability of cyclosporine to block interleukin 2 is critical for its clinical efficiency: transplant recipients who tolerate their transplants were well characterized by a low production of interleukin 2. Patients with overt rejection reactions, on the contrary, did not show inhibition of the interleukin production 2. The first and so far the only cyclosporin that has been placed on the market (in the 1980's) is cyclosporin A. Cyclosporin A is defined chemically as cycle - [[(E) - (2S, 3R, 4R) -3-hydroxy-4-methyl-2- (methylamino) -6-octenoyl] -L- 2-aminobutyryl-N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl-L - leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N-methyl-L-valyl]. Its availability initiated a new era in transplant medicine because, with its help, the proportion of transplanted organs that remain functional in the long term, could be substantially increased. The first cyclosporin medication (Sardimmun de Sandoz) could already increase the success rate in kidney transplants by a factor of approximately 2. A new oral preparation of ciclosporin (Neonal de Sandoz, this one from Novartis) with higher and more reliable bioavailability allowed better dosage and additional increase in the success rate since the 90s. Despite some new developments of active agents, cyclosporine is still an agent frequently used in transplant medicine. Currently, lung transplants can, in principle also be carried out successfully if patients are treated with cyclosporin A. Since the introduction of this active agent in clinical therapy, the number of lung transplants carried out worldwide has increased dramatically. This is true for both, single-lung transplants as well as for the transplantation of both lungs. Lung transplants are normally contemplated in the case of patients with a lung disease in the final stage where medicinal therapy has failed and life expectancy is short due to the disease. Single-lung transplants are indicated, for example, in the case of certain forms of emphysema and fibrosis, such as idiopathic pulmonary fibrosis. Both lungs are transplanted in cases of mucovisicidosis, primary pulmonary hypertension, emphysema with general insufficiency, frequent serious infections and as well as idiopathic pulmonary fibrosis with complication due to repeated infections. In the case of a successful lung transplant, the quality of life of patients can be increased again to an almost normal level. However, contrary to heart, kidney and liver transplants, the survival times after lung transplants are still relatively short and the amount at an average of only 5 years. This may be due, among other things, to the fact that the active agent ciclosporin can not be effectively dosed with all patients due to systemic side effects such as renal malfunction, increased serum levels of creatinine and urea, kidney damage with structural changes , for example, intestinal fibrosis, increasing serum levels of bilirubin and liver enzymes, hypertriquiosis, tremors, fatigue, headache, hypertrophic gingivitis, gastrointestinal irregularities such as anorexia, abdominal pain, nausea, vomiting, diarrhea, gastritis, gastroenteritis, paraesthesia, throbbing sensations in the hands and feet, high blood pressure, increased blood fat levels, acne, rash, allergic skin reactions, hyperglycemia, anemia, hyperuricemia, gout, increased body weight, edema, stomach ulcers, seizures, disorders menstrual, hyperkalemia, hypomagnesemia, flushes, erythema, itching, muscle cramps, muscle pain, myopathy, etc. Therefore, it would be desirable, if, for example, after a lung transplant or in cases of certain different indications, cyclosporin A could be administered in a specific tissue style and target and thus achieve a low systemic bioavailability of the active agent. in order to minimize the impact of the active agent on healthy tissue. A suitable dosage form could also be used for the treatment and prevention of diseases such as asthma, idiopathic pulmonary fibrosis, sarcoidosis, alveolitis, and parenchymal lung diseases (see: Drugs for the treatment of respiratory diseases, edited by Domenico Spina, Clive P. Page and collaborators, Cambridge University Press, 2003, ISBN 0521773210). New therapeutic aspects also resulted for the topical treatment of possible autoimmune diseases including diseases such as neurodermatitis, psoriasis, non-specific eczema, proliferations or mutations of the skin, and for treatment after skin transplantation. An area of application of interest is the field of ophthalmology, for example, for the treatment after transplants of cornea, kerato-conjunctivitis or other infectious diseases of the eye that respond in part insufficiently to anti-inflammatory therapy, for example with steroids. It is also useful for the treatment of ceratides in animals such as dogs. Indeed, attempts have been made to locally administer cyclosporin, for example, in the form of oily eye drops at 1% and 2% (formulation according to the German code of medicines using refined peanut oil as a solubilizer) or as an aerosol. However, this method usually fails, mainly due to the very low aqueous solubility of the active agent, which makes efficient administration considerably difficult. Accordingly, in the case of pulmonary application, certain adjuvants for solubilization that can be used in the case of oral administration can not be employed because they lack tolerance. For example, Sandimmun's Optoral capsules (Novartis) containing cephalosporin A, comprise a "microemulsion concentrated with ethanol, propylene glycol and significant amounts of surfactants and therefore constitutes a formulation that, if inhaled, would cause serious toxic effects.

Similarly, the concentrated infusion solution of Sandimmun® (Novartis), which is available for infusion, is also non-inhalable. The adjuvants only contained therein are ethanol and poly (oxyethylene) -40-ricino oil. It can be used for infusion only because it is previously diluted with 0.9% sodium chloride solution or a 5% glucose solution, at a ratio of 1:20 to 1: 100. This results in large volumes that can be administered by infusion, but not by inhalation. WO 00/45834 suggests the inhalation of aerosolized cyclosporin for the prevention or treatment of rejection reactions after lung transplants. It is recommended to give a dose of 15 to 30 mg of ciclosporin A to the lungs. The carrier to be used for the active agent is propylene glycol which, at a high concentration, results in considerable irritation, which is the reason why patients inhale a lidocaine solution for local anesthesia prior to administration of the cyclosporin preparation . New research (Akkar et al., Presentation of the poster in NACF 2005) shows that, depending on the concentration, propylene glycol destroys calu-3 cells which constitutes an established model for lung epithelial cells (Steimer and colleagues Jour Aerosol ed. 18 (2) page 137-182, 2205). Therefore, for physiological reasons, a predominantly aqueous preparation would be desirable. EP 0 294 239 A1, describes an aqueous preparation of cyclosporin for pulmonary application. In order to increase the solubility, the preparation contains an o-cyclodextrin. However, the solubilization effect is largely weak for efficient therapy by inhalation: achieved cyclosporin concentrations are only between 0.1 and 2.0 mg / ml, in particular, between 0.2 and 1.5 mg / ml. This means that the administration of a single dose of 20 mg to the lungs should take hours when using a conventional nebulizer. EP 0 504 760 A1, discloses a special orthorhombic crystalline form of cyclosporin A, which is said to be particularly suitable for inhalation. However, this would be relevant only for inhalation in the form of powder or for preparations with a dispersion of the active agent, but not for aqueous solutions for nebulization. Inhalers for dust, however, require a comparatively large breathable volume and are poorly suited for efficient treatment of patients with lung diseases. In addition, it is known that amounts of powder > 20 mg frequently results in cough and the respirable fraction of most powder mixtures decreases with increasing concentration of the carrier, such as lactose or trehalose. Furthermore, in view of all known in vitro data, it seems questionable whether the very poorly soluble active agent, if administered to the lungs in the form of suspended particles, will dissolve in the amount of mucus present in the lungs to a sufficient degree that would be a pre-condition for therapeutic efficiency. The same is true, in principle, for WO 99/42124 which describes an amorphous liquid crystalline cyclosporine. WO 95/24892, describes a preparation of cyclosporin with propellant gas which is to be applied in the form of an aerosol for dosage. However, aerosols for dosing have been criticized for years, since they contributed to global warming and it seems uncertain if the authorizations to market aerosols containing propellant gases were given in the medium term. Similar considerations apply to WO 98/01147. It is also known that the respirable fraction decreases when the active agents are applied at concentrations of > 1 mg / breath and that the precise dosage is subjected to great variation in vivo. Yet lung deposition of only 10% in the case of aerosols for dosing, it can be concluded that more than 50 breaths would be required in order to deposit therapeutically relevant cyclosporin concentrations in the peripheral regions of the lungs. WO 98/00111, proposes a liposomal dispersion of cyclosporin A for inhalation having a very high phospholipid concentration of up to 225 mg / ml. However, it has a high dynamic viscosity such that it can not be nebulized efficiently. A liposomal preparation of cyclosporin A is also known from US 2003/0215494. However, the invention described herein is based on the fact that such a preparation is to be used for the inhibition of pulmonary metastasis. This document does not provide a contribution to solve the technical problem of providing a preparation of the active agent that is most suitable for inhalation. The U.S. Patent 5,958,378, discloses liposomal preparations of cyclosporin for nebulization; however, the viscosity of these is so high that they can not be nebulized with an electronic vibrating membrane nebulizer. In addition, butanol organic solvent was used for the preparation of these, but in spite of a lyophilization process Subsequently, this can not be completely removed and produces liposomes of > 1 um, which can not be sterilized by filtration and have only a low ability to permeate epithelial cell membranes. Conventional non-liposomal topical preparations, for example, creams, ointments or lotions, do not show sufficient topical efficiency in the treatment of skin diseases such as neurodermatitis or psoriasis because the penetration effect is insufficient due to the desquamation and cornification of the epidermis. It is also known that in some cases of these diseases, equal liposomal preparations do not necessarily show improved skin permeation, but, depending on the specific composition and the size and nature of the liposomes, they produce only insignificant improvements.

SUMMARY OF THE INVENTION It is the object of the invention to provide a composition containing cyclosporin which overcomes the disadvantages found in the prior art. This object was achieved by providing the composition in accordance with claim 1. Solutions and further embodiments result from the other claims. The composition according to the invention is a liquid aqueous preparation containing a therapeutically effective dose of a cyclosporin, a solubility improving first substance, selected from the group of phospholipids and a second solubility enhancing substance, selected from the group of non-surfactants. ionic A particularly preferred cyclosporin is cyclosporin A.

DETAILED DESCRIPTION OF THE INVENTION The composition preferably contains the active agent cyclosporin in a solubilized liposomal form. The liposomes that were first formed by the phospholipids contained in the composition are preferably unilamellar liposomes. The liposomes preferably have an average diameter of at most about 100 nm measured as z-average using a Malvern Zeta Calibrator, and a polydispersity index of at most about 0.5, preferably at most about 0.4. The liposomes are preferably prepared with water as a carrier liquid and without using organic solvents. The preparation is preferably essential isotonic and has no negative effect on transepithelial electrical resistance (TEER, TransEpithelial Electrical Resistance) in a calu-3 pulmonary epithelial cell model, which is a measure of the tolerance of the active agent and the formulation in relation to the impact on vitality cellular, and, in human lung cells, the composition does not result in a significant increase in interleukin 8, a biomarker of inflammation. In the context of the present invention, a pharmaceutical composition is a preparation of at least one active agent and at least one adjuvant, which, in the simplest case, can be, for example, a carrier such as water. An active agent is a substance or a mixture of substance (s) that is / are suitable to directly or indirectly promote or support the health or well-being of a human or animal. An active agent can satisfy a diagnostic, prophylactic or therapeutic function, usually in or on the human or animal body, sometimes, however, in vitro, for example, in contact with isolated parts of the body such as cells or body fluids. In the present case, the preparation is preferably a colloidal aqueous solution without organic solvent consisting of unilamellar liposomes which have a diameter of at least 100 nm in which the active agent is at least predominantly dissolved. Preferably, water is the only liquid solvent contained in the preparation. In addition, it was preferred that the preparation be an aqueous solution or an aqueous colloidal solution, i.e., a single-phase liquid system. Such a system is essentially free of dispersed particles having a size greater than the size of colloidal particles. By convention, particles smaller than about 1 μm are considered as colloidal particles that do not constitute a separate phase and do not result in a limit of the physical phase. Sometimes, particles in a size range just above 1 um are still considered colloidal. Preferably, however, the invention is essentially free of particles that do not clearly belong to the colloidal spectrum, i.e., for example, particles having a diameter of 1 (Wi or more) The composition contains a therapeutically effective dose of a cyclosporin which is preferably cyclosporin A. Cyclosporin A is defined chemically as cyclo [[(E) - (2S, 3R, 4R) -3-hydroxy-4-methyl-2- (methylamino) -6-octenoyl] -L- 2-aminobutyryl- N-methylglycyl-N-methyl-L-leucyl-L-valyl-N-methyl- L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-Leucyl-N-methyl-L-valil] and is a cyclic peptide with immunosuppressive activity. In this context, the term "therapeutically effective" also includes prophylactic activity. The therapeutic dose is defined depending on the individual case of application. Depending on the nature and severity of the disease, route of application as well as height and condition of the patient, a therapeutic dose is determined in a manner known to the skilled person. Some common dosage advice is contained, for example, in the summary of characteristics for products marketed under the trademark of Sandimmun® by Novartis Pharma AG, which are also preparations containing cyclosporin A. However, the invention is also useful for administering cyclosporine via routes different from the application routes currently used, in particular by inhalation after nebulizing the preparation with a suitable nebulizer, and it will be necessary to adapt the dosage of the active agent in said applications in accordance with the common methods. In addition, the preparation according to the invention can at equal or lower concentrations, be applied topically or sprayed on the skin or it may be dripped into the eye or ear. Surprisingly, it has been found that, in an aqueous liquid preparation, cyclosporin can be effectively solubilized and its taste can be concealed at the same time by a phospholipid and a non-ionic surfactant and that, in certain cases, its stability can be improved . Accordingly, according to the invention, the preparation contains, apart from cyclosporin and water, phospholipids or a mixture of phospholipids such as, for example, Lipoid S 100 or Fosfolipon G90, and a nonionic surfactant, which is preferably a polysorbate , especially polysorbate 80. The second surfactant acts synergistically with the phospholipid and again increases the actual or colloidal aqueous solubility of the cyclosporin contained in the preparation to a statistically significant degree. A surfactant is a substance or mixture of amphiphilic or surfactant substances with surfactant properties. The surfactants have at least one very hydrophilic and at least one very lipophilic molecular region. There are low molecular weight, monomeric surfactants and surfactants that have an oligomeric or polymeric structure. In addition, a distinction is made between ionic and nonionic surfactants Examples of suitable surfactants in the meaning of the present invention are polyoxyethylene alkyl ethers, polyoxy ethylene sorbitan fatty acid esters such as, for example, polyoxyethylene sorbitan oleate, sorbitan fatty acid esters, poloxamers, vitamin E-TPGS (Da-tocopheryl polyethylene glycol 1000 succinate) and tyloxapol. Currently, preferred phospholipids are, in particular, mixtures of natural or enriched phospholipids, for example, lecithins such as those commercially available Fosfolipon G90, 100, or Lipoid 90, S 100. Among the nonionic surfactants polysorbates and vitamin E-TPGS are preferred especially polysorbate 80. Phospholipids are amphiphilic lipids containing phosphorus. They are also known as phosphatides, they play an important role in nature, especially as the constituents forming the double layer of biological membranes and are frequently used for pharmaceutical purposes are those phospholipids that are chemically derived from phosphatidic acid. This is a 3-acylated glycerol phosphate (usually in duplicate) in which the residues of Fatty acid can be of different lengths. Phosphatidic acid derivatives are, for example, phosphocholines or phosphatidylcholines, in which the phosphate group is additionally esterified with choline, as well as phosphatidylethanolamine, phosphatidylinositols, etc. Lecithins are natural mixtures of several phospholipids that usually contain a high proportion of phosphatidylcholines. The preferred phospholipids according to the invention are lecithins as well as also pure or enriched phosphatidylcholines, such as dimyristoylphosphatidylcholine, di-palmitoylphosphatidylcholine and di-stearoylphosphatidylcholine. In a further preferred embodiment of the invention, toxicologically acceptable antioxidants and stabilizers such as sodium ethylene diamine tetraacetic acid (Na-EDTA, tocopherols), isotonizing adjuvants such as sodium chloride, mannitol, trehalose or regulatory salts (citrate regulators, carbonate, phosphate, borate, etc.), flavor correction agents such as saccharin, aspartame or peppermint oil. The quantitative composition will usually depend on the medical indication. In general, the cyclosporin content selected will vary between 0.2 and 20 mg / ml, preferably between about 0.5 and 10 mg / ml, more preferably between about 1 and 5 mg / ml, prefers more between about 1 and 4.5 mg / ml. For the treatment of asthma, lower doses that can be in the range of 0.25 to 5 mg / ml are discussed. In order to preserve the nebulization time in a compressor, electronic or jet nebulizer such as, for example, AerX, AeroNeb Go, Omron U22 oder eFlow, as short as possible, it is advantageous to use small volumes of solutions (< 2 mi) at higher concentrations. In the especially preferred use of the preparation, ie, solutions for inhalation for the prophylaxis and therapy of rejection reactions in lung transplants, it is desirable and, in the interest of sufficient patient compliance, it is necessary that the content of cyclosporin be as high as possible and the inhalation time, therefore, be as short as possible. Preferably, the cyclosporin content - especially that of cyclosporin A - should be at least about 0.5 mg / ml, eg, between 0.5 and 10 mg / ml. A content of 1 to 5 mg / ml is even better and can be achieved using the aspects of the present invention. In a further preferred embodiment, the composition has a cyclosporin A content for topical application to the skin or to drip to the eyes or ears from 0.1 to 2% and for the prophylaxis and treatment of diseases respiratory levels of 1.5 - 5 mg / ml, for example, a content between about 5 to 10 mg / ml. The required content of surfactant adjuvants depends on the content of cyclosporin A. If lower concentrations of 0.5 to 1% of active agent are solubilized, the content of lecithin / surfactant can be reduced proportionally. In general, the content of phospholipids in the composition should be between about 0.2 and about 15% by weight, and preferably in the range of about 1 to about 8% by weight. The nonionic surfactant should be present in a concentration of about 0.01 to about 5% by weight and preferably the concentration thereof should be in the range of 0.1 to 2% by weight, especially in the case where a polysorbate, for example polysorbate 80.

The proportion by weight of phospholipids or of the phospholipid component to the nonionic surfactant is especially important in determining the amount of cyclosporin that can be solubilized per unit volume. A ratio of between about 15: 1 and 9: 1, especially between about 14: 1 and 12: 1, ie, for example, is preferred in the range of about 13: 1. These preferred ranges also they apply, in particular, in the case where a polysorbate such as polysorbate 80 is selected as a nonionic surfactant. The weight ratio selected between the two adjuvant components for solubilization, ie, the phospholipid and the nonionic surfactant on the one hand and the cyclosporin on the other hand is generally between about 5: 1 and about 20: 1. In presently preferred embodiments, the ratio is from about 8: 1 to about 12: 1, for example about 10: 1. In a particularly preferred composition, the ratio of cyclosporin A to the Lipoid S100 / surfactant mixture is 1: 9 and the solubilized cyclosporin A content is up to 0.5% by weight which results in the following proportion of mixture: cyclosporine: Lipoid S100: polysorbate 80 = 1: 9: 0.69, with which one obtains unilamellar liposomes with a cyclosporin content of, in total, about 4 to 6% by weight, for example, about 5% by weight. The following table shows some examples for proportions of amounts to which cyclosporin A can be optimally solubilized in liposomal form.

The composition according to the invention has the advantage that it can contain a relatively high content of a poorly soluble cyclosporin in solubilized form. At the same time, the taste of cyclosporine is masked, which is particularly advantageous in all oral, oromucosal, nasal and pulmonary uses, as well as in the particularly preferred use of preparation for the manufacture of a medicament for topical skin therapy, in the eyes, nose and ears and especially for the prophylaxis or treatment of rejection in lung transplants by inhalation. The composition may contain additional pharmaceutical adjuvants which are auxiliary and common in the intended application. Suitable adjuvants are known to the experts. For example, the composition may optionally contain pH correcting agents in order to adjust the pH, such as bases, acids or physiologically acceptable salts, optionally as regulatory mixtures. In this context, physiologically acceptable does not mean that one of the adjuvants should be tolerable by itself and in undiluted form, which would not be the case, for example, for sodium hydroxide solution, but it means that it should be tolerable to the concentration in which it is contained in the preparation. PH correcting agents suitable for adjusting the pH are selected, inter alia, with respect to the intended application route. Examples for potentially useful adjuvants of this group are sodium hydroxide solution, basic sodium, calcium or magnesium salts such as, for example, citrates, phosphates, acetates, tartrates, lactates, etc., amino acids, acid salts such as phosphates. of hydrogen or dihydrogenated phosphates, especially that of sodium, furthermore, organic and inorganic acids such as, for example, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, cromoglicinic acid, acetic acid, lactic acid, tartaric acid, succinic acid, fumaric acid, lysine, methionine, hydrogen phosphate, sodium or potassium acid, etc. In one of the advantageous embodiments of the invention, the preparation is adjusted - with or without pH-adjusting agent - to an acidic or neutral pH.

Preferably, the pH is in the range of at most 8.5 or in the range of about 2.5 to about 7.5. For pulmonary or parenteral application, a pH of from about 4 to about 7.5 is preferred, provided that it is compatible with other requirements of the formulation such as, for example, stability aspects. Particularly preferred is a composition that is regulated with a phosphate buffer at a pH in the range of 6.7 to 7.5, especially, a range of 6.7 to 7.3, with which the stability of the liposomal formulation can be markedly improved and the occurrence of Undesirable lysolecithin during storage can be effectively reduced (see Example 4). In addition, the preparation can contain osmotically active adjuvants in order to adjust it to a desired osmolality, which is important in certain applications such as, for parenteral injection or for inhalation or other topical applications, in order to achieve good tolerance. Said adjuvants are frequently mentioned as isotonizing agents even if their addition does not necessarily result in an isotonic composition, but in an isotonicity close to physiological osmolality in order to achieve the best possible physiological tolerance. Particularly, a frequently used isotonizing agent is sodium chloride, but this is not suitable in each case. In an advantageous embodiment of the invention, the preparation does not contain sodium chloride, except, of course, ubiquitous amounts of natural sodium chloride which may also be contained in pharmaceutical grade water. In another embodiment, the preparation contains an essentially neutral salt as an isotonizing agent that is not sodium chloride, but, for example, a sodium sulfate or sodium phosphate. In this case, however, different salts of sodium salts are even more preferable. Accordingly, it is known that certain calcium and magnesium salts have a positive or supportive effect on the inhalation of active agent solutions, possibly because they by themselves counteract the local irritations caused by the administration and because they have a bronchodilator effect which is currently postulated in the clinical literature (for example Gughes et al., Lancet 2003; 361 (9375); 2114-7) and / or because they inhibit the adhesion of germs to the proteoglycans of the mucosa of the respiratory tract so that mucociliary clearance when the natural defenses of the organism against pathogens are indirectly supported (K. Tsang et al., Eur Resp. 2003, 21, 932-938). It is advantageous, for example, magnesium sulfate, which has excellent lung tolerance and can be inhaled without consideration, as well as sodium chloride (1-10 mmol). As an alternative to neutral mineral salts, physiologically acceptable organic adjuvants can be used as isotonizing agents. Particularly suitable are water-soluble substances with relatively low molecular weights, for example, having a molecular mass of less than 300, or more preferably less than 200, and having a correspondingly high osmotic activity. Examples of said adjuvants are sugars and sugar alcohols, in particular, mannitol and sorbitol, xylitol, trehalose. The amount of isotonizing agent to be used can be adjusted so as to take into account the other components contained in the composition, an osmolality of at least 150 mosmol / l. Additionally an osmolality in the range of about 150 to 800 mosmol / l is preferred. In additional embodiments, the preparation has an osmolality of about 250 to about 600 mosmoles / liter.

If the cyclosporin content is as high as possible and if, therefore, a relatively high amount of solubility-enhancing adjuvants should be used, it can be assumed that, even without the addition of a separate isotonizing agent, the osmolality of the composition will be already located in the desired interval or above the desired range so that the use of an isotonizing agent will not be necessary. Since the composition contains surfactants as solubility-improving agents, this will of course have an effect on the surface tension of the preparation. This may be relevant especially for pulmonary application. In a preferred embodiment, the preparation has a surface tension, under standard conditions, i.e., at room temperature and under normal pressure, of about 25 to 75 mN / m, in order to allow efficient nebulization with a high fraction of respirable droplets that have a diameter of at most μ? when common nebulizers are used. However, if the preparation is adapted for use with specific types of nebulizers, the surface tension can be adjusted to specific values, for example, at about 30 to about 65 mN / m.

Normally, a surface tension of about 30 to about 45 mN / m is even more preferred, although this can not always be achieved if other parameters of the formulation are of primary relevance. On the other hand, the surface tension should not be less than about 25 mN / m. The reduced surface tension by means of a surfactant may be helpful in improving the aerosol spread in the lungs which may, in turn, have a positive effect on the efficiency of the administration. In the case of the application by inhalation, the viscosity of the composition may also be relevant. In a preferred embodiment for nebulization, the composition according to the invention has a dynamic viscosity under standard conditions of about 1.0 to 3.0 mPa. s. In a further embodiment, the viscosity is between 1.2 and 2 mPa. s. In addition, the preparation may contain additional common adjuvants such as stabilizers, antioxidants, flavor improving agents, flavors, sweeteners, colorants, etc. Which are available to experts for the formulation of preparations dependent on the intended application.

The liposomal preparation according to the invention can be prepared by high pressure homogenization. For example, the water soluble components can be provided in the form of an aqueous solution in which the cyclosporin is dispersed and subsequently the liposomes are formed by a high pressure homogenization process, wherein the size and the polydispersity index of the Liposomes can be adjusted by varying the pressure and the number of cycles. The composition or concentrate according to the invention is filled in single or multi-dose containers, preferably under specific conditions. Suitable primary packages are, for example, polypropylene or polyethylene bottles (PP-PE bottles) and cycloolefin copolymer vesicles (COC-vesicles) or polyterephthalate (PET-vesicles) vesicles. Alternatively, containers made of other polymers or copolymers can be used, which are suitable for a sealing process with filling by air insufflation or by a thermoplastic process. Plastic sealed containers such as PP- or PE bottles can be formed, filled and sealed, for example, in an integrated process comprising a sealed-filled-insufflated air procedure. The containers thus produced are especially suitable for liquid products having a volume of about 0.2 ml or more and small volumes are suitable for dripping into the eye and ear. For application in a nebulizer or for topical application to the skin where varying amounts of active agents are required, volumes of 0.2 to 5 ml, preferably 0.5 to 5 ml, are ideally filled in the container. For optimal patient acceptance, they can be formed with a closure that is removable by twisting or bending and that is formed to prevent sharp edges and allow a well dosable release by dripping fluid. Alternatively, the opening through which the liquid content can be removed can be designed in such a way as to suit a Luer connection or a Luer-Lock connection. Therefore, the opening can be round and have a diameter that corresponds essentially to the outlet diameter of a male Luer connection. In this way, a common syringe with a Luer connection must be connected hermetically to the container, for example, in order to capture the contents of the container and transfer it to a nebulizer, or in order to mix the contents of the container with the contents of the container. syringe and subsequently transfer it to a nebulizer. As an additional alternative, the The plastic container can be configured in such a way that, after the removal of the closure element, it can be essentially hermetically connected to the liquid inlet connector of a nebulizer adapted accordingly so as to allow direct transfer of the preparation to the reservoir of the container. inhaler. Plastic containers of this kind are also advantageous because they can be easily provided with engravings that will allow blind people to identify the product. This makes it possible to avoid the use of paper labels, or which is desirable to prevent the migration of adhesive components, paper or printing ink through the wall of the container in the preparation. In addition, through such an engraving, important information can be made available to visually impaired patients. The engraving may contain various information, for example, a batch number, a product identification, instructions for use or one or more volumes, instructions or dosage markings. Especially in the case of pediatric patients, where flexible dosing according to age and height is often desirable, a plurality of volume markings can serve to facilitate the extraction of a desired dose without require additional attachments, thus reducing the risk of dosing errors. In a further variant of the invention, multiple dose containers were provided which contain a preparation as described above and which are configured in such a way as to allow the aseptic extraction of an individual dose. Accordingly, the multi-dose container can be a plastic or glass container such as a vial or an infusion bottle having a closure made of an elastomer, which is pierceable with a cannula or can be a complex container comprising a extraction and dosing device of the kind used for preservative-free nasal nebulizers so that the preparation according to the invention need not contain a preservative and so that it can be sprayed into the nose or other body cavities or onto the skin as It is known in applications for the treatment of athlete's foot. A preservative-free pumping nebulizer has great advantages, especially in the treatment of psoriasis or neurodermatitis because the liposomes can thus be applied to the damaged or inflamed skin in a hygienic and homogeneous style.

One of the particular advantages of multi-dose containers in connection with the preparations for inhalation is the flexibility that makes it possible to individually adjust the dosage without problems and without having to discard substantial quantities of the preparation, as would be the case with individual dose containers, after these have been opened. In hospitals and care institutions, patients can thus be treated simultaneously and particularly efficiently and potentially at a reduced cost by individual dosage adjustment. Similarly, special requirements in the therapy of individual patients can thus be easily taken into account. If the composition can not be sterilized in the final container, it is preferably filled in the containers by the use of an aseptic method. For the preferred aerosolization of the preparation, in principle any nebulizer usable in therapy can be used. Well-established jet nebulizers are in principle as suitable as the most modern piezo-electric or ultrasonic nebulizers. The advantage of jet nebulizers is that they are already very common and can be obtained at a relatively low cost. Many patients are already familiar with the use of common jet nebulizers. Some new generation jet nebulizers (eg, PARI LC PLUS® and PARI LC SPRINT®) use mechanisms whereby nebulization is adjusted to the patient's respiratory rate so that as high a fraction as possible of the Generated spray is available for inhalation. Particularly preferred, however, the aerozolization of the preparation by means of a modern electronic or piezoelectric vibratory membrane nebulizer, in particular, with a nebulizer of the eFlow ™ of the PARI type. The special advantage for the patient using this device (or a similar device) is the marked reduction in inhalation time compared to alternative methods. The device not only aerozolizes a larger amount of liquid per unit of time, but also generates a particularly high quality aerosol having a high fraction of small respirable aerosol droplets with a narrow droplet size spectrum, typically with a deviation geometric standard <; 1.6. Other suitable vibratory membrane foggers are potentially, for example, the AeroNeb pro or -Go, ProDose or I-Neb devices.

The therapeutic success is critically dependent on the adequate and reliable availability of the active agent in the lungs. For the convenience of the patient, this would be achieved in an acceptable period of time. Patients will generally prefer short inhalation times and inhalation times of more than about 10 minutes may have a negative impact on patient compliance. It is also useful to conduct the inhalation either continuously or by means of a respiration trigger or a guided breathing pattern, which is possible, for example, when an eFlow type nebulizer is used in connection with a device for inhalation of Akita (from InaMed). Particularly preferred is a respiratory maneuver comprising a slow deep inhalation for 4-10 seconds, a breath hold for up to 10 seconds followed by rapid inhalation. As can be seen in Example 4 and in Figure 1, the active agent is distributed very uniformly in the lungs with peripheral and central reservoir each quantifying to approximately 50%, which is therapeutically useful. Excessive peripheral deposits would result in increased generalized absorption, which is known, at high concentrations, to result in kidney damage. Ideally, the proportion from central storage to serious peripheral, depending on the nature of the disease, for example, for the prevention of bronchitis obliterans and subsequent rejection of transplanted lungs, the amount at a peripheral to central deposition ratio of 30:70 or 50: 50 or 70:30. However, the nasal, oral, ophthalmic, mucosal, parenteral or topical application of the composition according to the invention can, in individual cases, also be advantageous. The administration can be affected by drip application, nebulization on or in the body, which in initial tests in humans, proved to be particularly well tolerated. Due to its immunosuppressive activity, cyclosporine can be used for a variety of medical indications, for example, for the prophylaxis and therapy of transplant rejections after several transplants (kidney, liver, heart, heart and lungs, pancreas, bone marrow, etc.). .), prophylaxis and therapy of host disease versus graft, endogenous uveitis therapy, manifest non-infectious intermediate or posterior uveitis, behcet-uveitis, serious and resistant psoriasis, especially of the plaque type, nephritis syndrome due to glomerular diseases such as Minimal glomerular change, segmental glomerulosclerosis focal or membranous glomerulonephritis, serious active rheumatoid arthritis, forms resistant to long-term atopic dermatitis therapy as well as other diseases that will require generalized or local immune suppression, such as for the treatment of asthma or eye diseases. In accordance with new findings, cyclosporine also acts as an inhibitor of pump efflux and thus prevents cancer cells from cytostatically expelling active drugs. An additional use of the composition according to the invention is in the prophylaxis or treatment of skin diseases, especially of psoriasis, neurodermatitis, eczema or rejection reactions after skin transplantation. The treatment can be carried out, for example, in the form of a pumping nebulizer that is sprayed on the affected skin parts. As described above, a particularly preferred use of the composition according to the invention is the prophylaxis and rejection therapy of lung transplantation as well as the prevention or delay of bronchiolitis obliterans. This disease occurs in many cases also after bone marrow transplantation or germ cell transplantation. which is because inhalation is considered particularly suitable for preventing or treating diseases such as for example, bronchiolitis obliterans. For this application, the composition is to be inhaled in the form of an aerosol. Compared to generalized therapy (for example, by oral administration), local therapy has the advantage that the active agent is applied directly to the site of action which, on the one hand, increases the therapeutic efficiency and, on the other hand, reduces the generalized effort on the organism and improves tolerance to therapy. due to the liposomal encapsulation of the active agent and the size of the liposomes of, on average, at most 100 nm, the active agent can permeate particularly well from the respiratory tract through the lung epithelial cell layer in the lung tissue and exert the effects there. In a further variant, liposomes with an average diameter of 30 to 80 nm are preferred. In order to achieve lung therapy by efficient local inhalation, the preferred aspects discussed above should be selected with respect to the nebulizer used for administration, in such a way that preparation of an aerosol with as large a fraction as possible is preferred. droplets In particular, the fraction of droplets lower from 2 to 4 μ ?? in diameter will be as large as possible. Particularly preferred is an electronic vibratory membrane nebulizer having a perforated stainless steel membrane comprising approximately 4000 pores of a defined size by which an aerosol with a defined particle spectrum can be rapidly and efficiently generated (Martin Knoch &Manfred Keller). The usual electronic nebulizer: a new category of liquid aerosol drug delivery systems. Expert Opin. Drug Deliv. (2005) 2 (2) .377-390). The liposomal preparation according to the invention can thus be inhaled, without destruction of the liposomes either in a guided or breathing-activated aerosol generation mode or via a breathing machine so that a high fraction of the active agent can be deposited in a selected form in the lungs in a short period of time. The advantage of this inhalation system is, in particular, that the dose that can be inhaled from the mouth piece is greater than 50% and up to 98% of the generated droplets have a diameter of less than 5 μ? and that up to 80% have an average geometric diameter of less than 3.5 um so that the active agent can be deposited, in a manner selected, in the distal region of the lungs at higher efficiency than with compression jet nebulizers. The composition may comprise one or more additional active agents. An additional active agent can be selected, for example from the group of immunomodulators, interferons, steroidal, nonsteroidal and anti-inflammatory agents, heparinoids, beta-agonists, anti-cholinergics, endothelin inhibitors and phosphodiestearase, antibiotic, anti-fungal substances , antiviral and cytostatic.

Alternatively, a combination therapy can be achieved if the composition according to the invention contains only cyclosporin as an active agent, but is administered in combination with another preparation containing another active agent. The administration of the composition according to the invention, in particular, the administration by inhalation, can be carried out without pre-medication. In particular, the administration can be carried out without pre-medication with local anesthetics such as, for example, lidocaine and / or without pre-medication with bronchodilators ("Bronchodilators") such as, for example, salbutamol. Preferably, the composition is sterile, especially when it is intended to be used for pulmonary, parenteral or ophthalmic application. In addition, it is preferably essentially free of solid particles having a size of more than about 3 μp ?. It is advantageous if, for example, the entire active agent contained in the composition is present in solubilized liposomal form. Accordingly, solid particles of active agent should be essentially absent, especially solid particles of active agent having a diameter of more than about 500 nm. Preference is given to compositions that are essentially free of solid particles of any substance having a diameter of more than 500 nm. As indicated above, the composition can be used as a medicament, for example for the prophylaxis and treatment of autoimmune diseases, skin diseases, after transplants or diseases of the sense organs (eyes, nose, ears) discomforts and pulmonary diseases, for example, asthma, chronic obstructive bronchitis, parenchymal, fibrotic and interstitial pulmonary diseases or inflammations, lung cancer, and preferably for the prevention and treatment of chronic or acute transplant rejection reactions and diseases that results thereof such as bronchiolitis obliterans, especially after transplantation of lung, heart, bone marrow or germ cells, especially after lung transplantation is preferred. Additionally it can be used to increase the efficiency of other particulate drugs, of cytostatics, where an additive or synergistic effect can be achieved with cyclosporine through the inhibitory effect of the efflux pump. The pharmaceutical composition according to the present invention provides, inter alia, the following advantages: - It is possible to prepare the liposomes in a single stage process, even on a large scale of up to 1000 kg, to be carried out by means of of high pressure homogenization and sterilization by sterile filtration subsequent to a pore diameter of 0.22 μ. - Liposomes can diffuse well from the respiratory tract into the lung tissue. In order to achieve a therapeutic effect, only 1-3 are needed, more preferably 1-2 inhalations per day.

- The composition shows a deposit effect on the target organ and, in certain cases, it must be inhaled only 1-4 times per week, and is particularly preferred only every second day. - The composition can be stored in the refrigerator (4-8 ° C for at least 12 months and particularly preferred for up to 36 months) The composition can also be used in breathing machines or in connection with systems for controlled breathing maneuvers, such as the eFlow-Akita device Important aspects and embodiments of the invention will now be illustrated by way of the following examples: Additional modalities are available to the experts with reference to the description and patent claims Example 1: Solution for treatment Topical to spray on the skin The water-soluble adjuvants (sodium chloride, sodium citrate, citric acid and Tween 80) listed in the table above are weighed into a 1 liter Erlen Meyer flask and dissolved in water with agitation. Then, the lecithin (Fosfolipon G90), dexpanthenol, tocopherol acetate and the active agent (cyclosporin A) are added and dispersed with agitation. Afterwards, the mixture is homogenized for approximately 10 minutes in a Ultraturax and is transferred to a high pressure homogenizer. At approximately 1500 bar, the mixture is homogenized until a colloidal preparation is obtained whose droplets or particle size in a Malvern ZetaSizer has a diameter of < 100 nm and a polydispersity index of < 0.4. The colloidal preparation is subsequently sterile filtered and 20 ml thereof is filled into previously sterilized brown glass bottles which are closed with a pump spray cap which allows multiple sterile extractions of the composition. Example 2: Colloidal solution for inhalation A colloidal preparation was prepared which consisted of the components listed in the following table, as described above and after sterile filtration of 4 ml of it was filled into 6 ml brown glass bottles, the which were closed. The content of these is then transferred as necessary to the drug reservoir of a sterile nebulizer such as, for example, the PARI eFlow device, and the resulting aerosol can then be inhaled in order to avoid, for example, rejection reactions. after lung transplants or the formation of a bronchiolitis obliterans.

The pH of the clear, slightly opalescent liposomal solution at 20 ° C was 4.5, the osmolality was 0.32 osmoles / kg. The dynamic viscosity was measured, it was 1.35 mPa.s, the surface tension was 36 mN / m. The colloidal solution was nebulized with a vibrating membrane nebulizer adapted especially from the eFlow type of PARI and the aerosols were characterized by means of the PARI breathing simulator. This test involved two different inhalation maneuvers, ie that of a child, 16 breaths per minute at a volume of 225 ml each, with an inhalation ratio of 40: 60) and that of an adult (15 breaths per minute a a volume of 500 ml each, with an inhalation ratio of 1: 1). The characteristics of the aerosol are given in the following table: Breathing pattern of adult breathing pattern (15 child breaths (16 to 500 ml, inhalation: breaths to 225 ml, exhalation = 50:50 inhalation: exhalation = 40:60 Average Deviation Average Standard standard deviation Aerosol dose 9577.1 745.1 895. 1085.8 from the mouthpiece. { μg) Residue from 1606.8 559.2 2123.9 352.8 nebulizer (μg) Losses from 2872.5 255.9 2763.3 376.2 aerosol (μ ^) Time from 9.5 0.6 11.6 1.4 nebulization (min) Aerosol dose 66.5 4.5 62.9 8.4 (% full dose) Residue from 11.2 3.9 15.0 2.5 nebulizer (% full dose) Losses of 20.0 2.0 19.4 2.5 aerosol (%) Recovery (% 97.7 5.0 97.3 7.1 full dose) In addition to using the same inhalation solution, fractions of particle size, which are relevant for pulmonary administration, were determined by laser beam diffraction measurements at various speeds of aerosol release (see next table). You are shown spray release and simulated deposit of particularly high efficiency, the which allowed short inhalation time and which are widely independent of the inhalation maneuver.

L / min 20 L / min 28.3 L / min P D.E. P D. E. P D.E. A 2.8 0.1 2.9 0.1 2.7 0.1 B 1.5 0.0 1.5 0.0 1.5 0 C 63.5 1.7 61.5 4.1 66.0 3.4 D 89.4 1.1 89.2 2.1 91.2 1.6 E 289.0 10.8 258.3 40.3 282. 5 28.0 P = Average FROM. = standard deviation A = Diameter representing the average mass (μp?) B = geometric standard deviation C = breathable fraction < 3.3 μ?) D = breathable fraction < 5 μ?) E = aerosol release rate [mg / min] The effect of the inhalation solution was investigated described in Example 12 on calu-3 cells (monolayer For this purpose, calu-3 cells (HTB-55, ATCC, Manassas, VA, USA) were cultured in Minimum Culture Medium (MEM) with Earl salts, supplemented by L-glutamine (PAA Laboratories GmbH, Pasching, Austria), 10% fetal bovine serum, 1% non-essential amino acid solution, and 55 mg / 500 ml of sodium pyruvate. The formation of confluent monolayers with hermetic junctions was confirmed by measuring the trans-epithelial electrical resistance (TEER) using a suitable voltmeter (EVOM, World Precision Instruments, Berlin, Germany) and an STX-2 electrode. The age of the cell monolayer for at least cyclosporin solution was 14 days. First, the culture medium was removed, the monolayer was washed and pre-incubated with Ringer's bicarbonate buffer for 20-30 minutes. Subsequently, the liposomal solution was added by means of a pipette. The TEER was measured immediately after application and 120 minutes later. Then, the cells were washed and incubated with culture medium for 24 hours. Then, the TEER was measured again. For comparison, Ringer's bicarbonate buffer (KRB), propylene glycol, a solution of cyclosporin A in propylene glycol (62.5 mg / ml) and an aqueous solution of sodium dodecyl sulfate (SDS) (0.1%) were used for comparison. The following table shows the TEER values measured as percentages of the initial values after of addition of the Ringer's bicarbonate buffer solution.

(Continuation) (Continuation) P = Average D.E. = standard deviation SDS = sodium dodecyl sulfate The measured TEER values showed that the composition according to the present invention does not have or has only a small, widely reversible effect on the integrity of the calu-3 monolayer. Sodium dodecyl sulfate (SDS, synonym: sodium lauryl sulfate), propylene glycol and cyclosporin A dissolved in propylene glycol, on the other hand, produces significant and largely non-reversible damage to the monolayer of calu-3 cells. From this, it can be concluded, among other things, that propylene glycol is probably it is not a suitable carrier for cyclosporin A for application by inhalation.

Example 3: Colloidal solution The following Formulations A and B (see following tables) were prepared in a style similar to that described in Example 1 and filled in brown glass bottles under sterile conditions.

Colloidal solutions are suitable, in particular, for inhalation. In addition, they can be used for topical and ophthalmic applications.

Example 4: Colloidal solution The following formulation (see the table below) was prepared in a style analogous to that described in Example 1 and the filling procedure was carried out under sterile conditions.

The slightly opalescent solution was subsequently characterized; The results are shown in the following table.

In addition, the current content of CsA was measured and was 4.83 mg / ml. The content of impurities was 0.81 mg / ml. After storage at 5 ° C for three months, all parameters were essentially unchanged, including, for example, the CsA content (4.93 mg / ml), the impurity content (0.36 mg / ml) as well as the diameter medium of the liposome (36.6 nm). After storage at 25 ° C and 60% relative humidity for three months, the preparation still proved to be remarkably stable, in particular, the content of CsA and impurities remained essentially constant. The average diameter of the liposome was slightly increased to 44.4 nm, however this would have no impact on the operation of the composition. 3.2 ml (corresponding to 15 mg of CsA) of the colloidal solution were aerosolized by means of the specially adapted electronic vibratory membrane nebulizer or the PARI type 30 L eFlow having a mixing chamber and respiratory inlet / outlet valves and the droplet size distribution of the aerosol thus produced was characterized by laser diffraction using a Malvern MasterSizerX at an expense of 20 1 / min. The diameter representing the average particle mass thus determined was 2.8 um to a geometric standard deviation of 1.5. The particle fraction < 5 um (respirable fraction) was 89.4%, the fraction having a particle size < 3.3 um was 63.5%. The total exit velocity was 289 mg / ml. In addition, the aerosol was characterized in a breathing simulation test using a PARI breathing simulator using the typical inhalation pattern in an adult (see Example 2) as well as a cascade impactor of the following type of impactor. generation at an expense of 15 1 / min, a temperature of 23 ° C and a relative humidity of 50%. The The aerosol characteristics thus determined are shown in the following table. The inhalation time was 11 minutes. The determination of the CsA fractions was made after the determination of the active agent content by HPLC. In an additional test, the inhalation solution was radio-labeled with "mTc-DTPA, subjected to the same experimental setting and the characteristics of the aerosol were determined from the radioactivity of the deposited fractions." The results of both experiments were essentially identical. Figure 3 shows the distribution of the aerosol fractions during the individual impactor stages (based on the radioactivity and HPLC measurements), the values on the abscissa are shown in units of μ ??.

Using the composition a gamma scintigraphy study was also carried out to determine the Lung deposition of CsA in vivo. For this purpose, 12 patients with lung transplants (7 with double-sided transplants [DLTx] and 5 with single-sided transplants [SLTx]) were treated with 2 ml (approximately 10 mg CsA) of the inhalation solution . Each dose of inhaled solution administered was previously radiolabelled with 4 MBq88mTc-DTPA (Pentacis, CIS-Diagnostik) and subsequently filled in an electronic vibration membrane nebulizer of the type 30 L eFlow of PARI. Patients were instructed to inhale slowly and deeply. After the nebulizer reservoir was emptied, the head and heart region of the patients were subjected to imaging using a gamma camera of the Siemens Diacam type. Figure 1 shows a typical image of a patient treated with double-sided lung transplantation, Figure 2 shows the image of a patient with a single-sided lung transplant. The image shows the uniform deposit of fine aerosol in the lungs. Inhalation was well tolerated by all patients, pre-medication as used according to literature in the inhalation of known CsA preparations, where the active agent was dissolved in propylene glycol, was not necessary.

In a further experiment with the same patients, a dose of 4 ml was administered at the same concentration of active agent. This dose, too, was tolerated with-without pre-medication. The qualitative determination of radioactivity showed an average deposition in lung of 36% of the dose of CsA filled in the nebulizer. The relative deposition in the lungs was slightly higher in the case of the lower dose of 2 ml than in the higher dose of 4 ml.

In addition, the pharmacokinetic parameters for the administration of 10 mg or 20 mg of CsA by inhalation are determined by blood tests. The results thus obtained are given in the following table.

MRT = Average residence time Surprisingly it was found that only a small proportion of the liposomal CsA inhalation solution was found in the blood and that the half-life is very short at 5.2 and 6.1 hours, respectively. Previously published data (Corocran TE et al .: Preservation of Post-transplant lung function with aerosol cyclosporin, Eur. Respir J., 23 (3), 378-83 (2004)) mentioned a half-life of approximately 40 hours after inhalation of 300 mg of the CsA / propylene glycol inhalation solution. The advantage of short half-lives lies in the possibility for frequent administration, for example, once or twice a day. In this way, it will be possible to achieve uniform therapeutic levels in the lungs and this will result in a reliable therapy.

In addition, it was found that there is a correlation between the dose of peripherally deposited CsA and the pharmacological parameters AUC (area under the curve) and Cmax (maximum concentration) for liposomal CsA therapy: this makes it possible to provide an estimate of the active concentration of CsA in the target area of the target organ, that is, in the periphery of the lungs, by simply measuring the serum levels of the patient in question. This allows simple monitoring of therapy.

Example 5: Colloidal solution for dripping into the eye A colloidal preparation of the ingredients listed in the following table was prepared as described above and, after sterile filtration, 0.25 ml of it was filled, under aseptic conditions and laminar air flow , in sealed, filled-in-the-box, sterile, 0.5-mil polyethylene (PE) filled flasks, formed with sterile nitrogen and subsequently sealed in aluminum bladders under nitrogen gas. From these sterile unit dose vials that allow the product to be drip-dried, the colloidal solution can be dripped into the eye in order to treat, for example, rejection reactions after corneal transplants and other inflammatory processes.

Example 6: 0.2 g of given one of cyclosporin A and tacrolimus were dispersed in a liposomal isotonic placebo solution containing lecithin and polysorbate 80 in a weight ratio of 10: 1 in an isotonic solution of sodium chloride by means of an Ultraturax and Subsequently homogenized under high pressure in a microfluidizer at 1500 bar so that, in a Malvern ZetaSizer, a colloidal preparation with a diameter of less than 80 nm and a polydispersity index < 0.35. After sterile filtration, portions of 2 ml were filled, under aseptic conditions and laminar air flow in sealed, insufflation filled flasks, of 0.5 ml polyethylene (PE) shaped, sterile, formed with sterile nitrogen and subsequently sealed ( "eingeschwe t") in aluminum bladders under nitrogen gas. From these sterile unit dose vials that allow the product to be drip-dried, the colloidal solution can be used for pulmonary, nasal or topical application in order to treat undesirable autoimmune diseases. Example 7: Liposomal solution for inhalation or for application to the eye. ears In a dispersed-colloidal, isotonic placebo solution prepared by high pressure homogenization and consisting of 10% Lipoid S100, 0.7% polysorbate 80, 0.8% sodium chloride and 0.01% sodium EDTA and tocopheryl acetate, respectively , 0.4% of cyclosporin A and 0.04% of budenoside were dispersed in it and these were incorporated in colloidal form dispersed so that a liposome preparation having a diameter < 75 nm, a polydispersity index < 0.3. Under a transmission electron microscope, spherical unilamellar liposomal structures of 55-75 nm can be seen, which correlate well with the results of 40-55 nm determined by photon correlation spectroscopy (PSC). After sterile filtration, portions of 0.25 ml for eye and ear treatment and 2 ml portions for use in nebulizers were filled in polypropylene vials filled with nitrogen gas and, for storage stability, they were sealed separately in aluminum bladders. full of nitrogen gas. After nebulization with an electronic eFlow nebulizer, the product is inhaled for the treatment of lung diseases such as, for example, asthma and COPD. Example 8: In a dispersed, isotonic colloidal placebo solution prepared by high pressure homogenization, consisting of 40% Lipoid S100 and 2% each of polysorbate 80 and vitamin E-TPGS, 0.8% sodium chloride and 0.2 % of sodium EDTA, 1.5% of cyclosporin A and sirolimus (rapamycin) were dispersed therein, respectively, and were incorporated in colloidal-dispersed form so that a liposomal preparation was obtained which had a diameter < 100 nm and a polydispersity index < 3. After sterile filtration, 2 ml portions were filled in polyethylene flasks filled with nitrogen gas and, for storage stability, were sealed separately in aluminum bladders filled with nitrogen gas. The product is used for inhalation to treat interstitial lung diseases such as sarcoidosis and pulmonary fibrosis. Alternatively, it can be used to drip into the eye after corneal transplants. Example 9: Colloidal solution for topical treatment of the skin, eye and ears The water-soluble adjuvants listed in the table above are weighed into 1-liter Erlen Meyer flask and dissolved in water with stirring, then the lecithin (Lipoid S100 or Fosfolipon G90) and the active agent (cyclosporin) were added and dispersed with agitation. Subsequently, the mixture is homogenized for 10 minutes in the Ultraturax and transferred to a high pressure homogenizer. At about 1500 bar, this mixture is homogenized until a colloidal preparation was obtained whose droplets or particle size in a ZetaZiser from Malvern had a diameter of < 100 nm and a polydispersity index of < 0.4. The colloidal preparation is subsequently sterile filtered under clean bench and filled in previously sterilized brown glass bottles that had a volume of 5-50 ml which were subsequently closed with a sterile pumping metering lid that allows multiple droplets to be removed. Of content . Example 10: In a colloidal-dispersed, isotonic placebo solution prepared by high pressure homogenization and consisting of 40% Phospholipon and 2% each of polysorbate 80 and vitamin E-TPGS, 0.8% sodium chloride and 0.02% of sodium EDTA, 3% of dexpanthenol and 1% cyclosporin A, amphotericin B and were incorporated in colloidal-dispersed form so that a liposome preparation having a diameter <1 was obtained. 100 nm and a polydispersity index < 0.3. After sterile filtration, portions of 2 ml were filled into polyethylene flasks filled with nitrogen gas and, for storage stability, were sealed separately in aluminum vesicles filled with nitrogen gas. The product is used for the prevention and treatment by inhalation of possible rejection reactions after transplantation of organs or parts of organs such as the lungs, nose, skin, cornea, ear and diseases resulting therefrom. Example 11: In a colloidal-dispersed, isotonic placebo solution prepared by high pressure homogenization and consisting of 20% Fosfolipon and 1% each of polysorbate 80 and vitamin E-TPGS, 0.8% sodium chloride and 0.02% of sodium EDTA, 2% of each of hyaluronic acid as well as sodium cromoglycate and 1% of cyclosporin A were dispersed and incorporated in colloidal-dispersed form so that a colloidal-dispersed preparation having a diameter <lt was obtained.; 100 nm and a polydispersity index < 0.3. After sterile filtration, 2 ml portions were filled in polyethylene flasks filled with nitrogen gas and, for greater storage stability, were sealed separately in aluminum vesicles filled with nitrogen gas. The product is used for the prevention and treatment by inhalation of chronic obstructive bronchitis, interstitial and fribotic pulmonary diseases or inflammations, parenchymal as well as topically for the suppression of autoimmune diseases and for wound healing of the skin, nose and heard. Example 12: In a style analogous to that of Example 2, a liposome solution for inhalation containing cyclosporin A (4.5 mg / ml), phospholipids (Lipoid S100, 40 mg / ml), polysorbate 80 (Tween 80, 3 mg / ml), sodium chloride (8.5 mg / ml) and disodium edetate (0.5 mg / ml). Homogenization was carried out by means of a high pressure homogenizer at 1500 bar and 2 cycles. The average particle size of the liposomes was 50 nm (measured as z-average) at a polydispersity index of about 0.25. The liposomes (2 ml portions) were, after sterile filtration under aseptic conditions, filled into specially formed 3 ml vials which could be hermetically connected to the twist cap and push of an eFlow. When the closure device of the medication container, the membrane of the PE vial is rotated so that the contents can be inhaled without filling them manually in the nebulizer.

Example 13 The liposomal formulation can also be combined with water-soluble active agents as can be seen from the following example. The water-soluble adjuvants are weighed in a 200 liter container. according to the composition in weight percent according to the composition in percent by weight given in the following tables and dissolved with agitation in water for injections. Water-soluble active agents such as, for example, sodium heparin (Formulation A) or salbutamol sulfate (Formulation B) are then dissolved there, lecithin and lipophilic cyclosporin A are added and dispersed with agitation and the mixture is subsequently homogenized by 10 minutes in an Ultraturans and transferred to a pressure can homogenizer. This mixture is homogenized in 5 cycles under high pressure of approximately 1000 bar. After that, a sample is taken out and the specification is verified according to the "in process" control. When the droplets or particle size, measured in a ZetaSizer, is < 100 and had a polydispersity index of < 0.35, the colloidal preparation is filtered sterile. Portions of 2 ml of this were filled in polyethylene vials using an aseptic filling process in a sterile room according to an insufflation filling process and 5 pieces of these are sealed in aluminum bladders filled with nitrogen gas.

Claims (51)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as novelty, and therefore the content of the following is claimed as property: CLAIMS 1. - A liquid pharmaceutical composition, characterized in that it comprises: (a) a therapeutically effective dose of cyclosporin; (b) an aqueous carrier liquid; (c) a first solubility enhancing substance selected from the group of phospholipids and (d) a second solubility enhancing substance selected from the group of nonionic surfactants.
2. 2. The composition according to claim 1, characterized in that it contains cyclosporin in a liposomally solubilized form.
3. 3. The composition according to claim 1 or 2, characterized in that the cyclosporin is cyclosporin A.
4. 4. The composition according to claim 3, characterized in that the content of Cyclosporin A is from about 0.2 to about 20 mg / ml. 5. - The composition according to claim 4, characterized in that the cyclosporin content is from about 0.
5. 5 to about 10 mg / ml and preferably from about 1 to about 5 mg / ml.
6. 6. - The composition according to any of the preceding claims, characterized in that the phospholipid is a mixture of natural phospholipids and is preferably a lecithin containing unsaturated fatty acids, for example, Lipoid S100, Fosfolipon G90, 100 or a comparable lecithin.
7. 7. - The composition according to any of the preceding claims, characterized in that the content of phospholipids is from about 0.2 to about 15% by weight and preferably from about 1 to about 8% by weight.
8. 8. - The composition according to any of the preceding claims, characterized in that the content of nonionic surfactant is from about 0.01 to about 5% by weight, preferably from 0.1 to 2% by weight.
9. 9. - The composition according to any of the preceding claims, characterized in that the nonionic surfactant is selected from the group of polysorbates, preferably it is polysorbate 80.
10. 10. The composition according to claim 9, characterized in that the weight ratio of phospholipids to polysorbate is between 15: 1 and 9: 1, preferably between about 14: 1 and about 12: 1, for example, about 13: 1.
11. 11. - The composition according to any of the preceding claims, characterized in that the weight ratio between the phospholipid and the nonionic surfactant on the one hand and the cyclosporin on the other hand is between 5: 1 and 20: 1, preferably between approximately 8: 1 and 12: 1 and more preferably of about 9: 1.
12. The composition according to any of the preceding claims, characterized in that the weight ratio between lecithin, nonionic surfactant and cyclosporin is between about 15: 1: 1.5 and 5: 0.3: 0.5, and preferably about 9 : 0.7: 1
13. 13. The composition according to any of the preceding claims, characterized in that the composition contains liposomes with an average diameter of at most 100 nm, and / or a polydispersity index of at most 0.5.
14. 14. - The composition according to any of the preceding claims, characterized in that the composition contains at least one additional active agent.
15. 15. - The composition according to any of the preceding claims, characterized in that the composition contains one or more additional pharmaceutical adjuvants such as, for example, stabilizers, regulating agents, salts, substances for the adjustment of tonicity, antioxidants, flavors, improving agents of taste or sweetening agents.
16. 16. - The composition according to any of the preceding claims, characterized in that the composition is sterile and essentially free of solid particles with a particle diameter of more than 3 μp? and is preferably free of solid particles of active agent having a particle diameter of more than 500 nm.
17. 17. - The composition according to any of the preceding claims, characterized in that the composition is essentially free of organic solvents.
18. 18. The composition according to any one of the preceding claims, characterized in that the composition has a dynamic viscosity of from about 1 to about 3 mPa.s.
19. 19. - The composition according to any of the preceding claims, characterized in that the composition has an osmolality of about 150 to about 800 mosmoles / 1, preferably 250 to 600 mosmoles / 1.
20. 20. - The composition according to any of the preceding claims, characterized in that the composition has a pH of less than about 8.5, preferably from about 2.5 to about 7.5.
21. 21. The composition according to claim 20, characterized in that the composition is regulated with a phosphate regulator and has a pH in the range of 6.7 to 7.5.
22. 22. - A method for the preparation of a composition according to any of the preceding claims, characterized in that the method comprises a step of homogenization at high pressure.
23. 23. The use of a composition according to any of claims 1 to 21 for the preparation of a medicament for oral, nasal, ophthalmic, pulmonary, topical or mucosal parenteral application.
24. 24. - The use according to claim 23, characterized in that the pulmonary or nasal application is carried out after conversion of the composition into an aerosol.
25. 25. The use according to claim 24, characterized in that the composition is intended for inhalation by means of an electronic or ultrasonic, compressor / jet vibrating membrane nebulizer, preferably by means of a vibrating membrane nebulizer such as, for example, example, an eFlow ™, AeroNeb Pro or -Go or I-Neb type device.
26. 26. Use according to claim 23, characterized in that the topical application is carried out by spraying the composition on the skin by means of a pump atomizer.
27. 27. Use according to claim 23, characterized in that the nasal, mucosal or ophthalmic application is carried out by means of the application, dripping or spraying of the composition.
28. 28. The use of a composition according to any of claims 1 to 21 for the preparation of a medicament for the prophylaxis and treatment of autoimmune diseases, skin diseases, diseases of the sensory organs (eyes, nose, ears) ), discomfort and lung diseases, in particular; asthma, persistent asthma, chronic obstructive bronchitis, parenchymal, interstitial and fibrotic lung diseases and inflammations, lung cancer, and preferably for the prevention and treatment of acute and chronic organ transplant rejection reactions after lung transplantation, cells germinal, bone marrow, heart or other organs and diseases resulting from these such as bronchiolitis obliterans.
29. 29. The use of a composition according to any of claims 1 to 21 for the preparation of a medicament for the prophylaxis or treatment of skin diseases, in particular, psoriasis, neurodermatitis, eczema, or rejection reactions after of skin transplant.
30. 30. The use according to any of claims 23 to 29, characterized in that the administration of the drug is carried out without pre-medication.
31. 31. The use according to claim 30, characterized in that the administration of the drug is carried out without pre-medication with a local anesthetic.
32. 32. - The use according to claim 31, characterized in that the local anesthetic is lidocaine.
33. 33. - The use according to any one of claims 30 to 32, characterized in that the administration of the drug is carried out without pre-medication with a bronchodilator.
34. 34. The use according to claim 33, characterized in that the bronchodilator is salbutamol.
35. 35. - The use of a composition according to any of claims 1 to 21 to improve the efficiency of other medications, whereby an additive or synergistic effect can be achieved.
36. 36. The use according to claim 29 as a pump flow inhibitor to improve the efficiency of cytostatics and other drugs for the treatment of diseases of the lungs, skin and sensory organs.
37. 37. The use according to claim 23, characterized in that the composition is administered as part of a therapy in combination with at least one additional medicament and because the additional medicament preferably comprises an active agent from the group of immunomodulators, interferons, anti-inflammatory agents steroidal and non-spheroidal, heparinoids, beta agonists, anticholinergics, endothelin and phosphodiesterase inhibitors, antifungals, antiviral and cytostatic substances.
38. 38. - A container containing a composition according to any one of claims 1 to 21, characterized in that the container consists predominantly of plastic, has a volume of 0.2 -5 ml and has a removable closure element.
39. 39. - The container according to claim 38, characterized in that the container after removal of the closure element can be connected to the connection element for liquid intake of a nebulizer in an essentially adapted form and to the style of liquid tightness .
40. 40. The container according to claim 38 or 39, characterized in that the container is provided with at least one engraving representing a product identification, a batch code, an expiration date, and / or a volume mark or dosage.
41. 41. - The container according to claim 38 to 40, characterized in that the container is a container for multiple doses consisting of glass or plastic and because the composition contained therein is intended for topical or generalized application.
42. 42. - The process for filling a container with a composition in accordance with any of the claims 1 to 21 characterized in that the process comprises an aseptic filling.
43. 43. - The process for generating an aerosol by means of a nebulizer by nebulization of a pharmaceutical composition according to any one of claims 1 to 21.
44. 44. - The process according to claim 43, characterized in that the nebulization of 4 mg of ciclosporin in < 5 μ ?? It requires less than 10 minutes.
45. 45. - The process according to claim 43, characterized in that the rate at which the cyclosporin is inhaled from the mouthpiece is 0.2-4 mg / min and more preferably 0.5-1.5 mg / min.
46. 46.- The process in accordance with the claim 43, characterized in that the percentage of droplets of < 5 μ ?? is between 50% and 98% and more preferably 60-90% and the distribution of droplets has a geometric standard deviation < 2.2 and preferably < 1.8.
47. 47.- The process in accordance with the claim 43, characterized in that the percentage of droplets of < 3.5 μp? it is between 40% and 95% and more preferably between 50-85%.
48. 48. - The process according to claim 43, characterized in that the lung deposit is at least 30% and the central to peripheral deposition ratio is from 30:70 - 70:30. 49.- The process in accordance with the claim 43, characterized in that the inhalable dose by means of a mouth piece is > 40% of the dose of active agent filled in the nebulizer. 50. - The process according to claim 43, characterized in that the residue of active agent remaining in the nebulizer is < 20% and more preferably < 10% 51. - The process according to claim 43, characterized in that the nebulization time is < 15 minutes and more preferably < 10 minutes. SUMMARY OF THE INVENTION The invention concerns liquid pharmaceutical compositions containing a) a therapeutically effective dose of a cyclosporin, b) an aqueous carrier liquid; c) a first solubilizing substance selected from the group of phospholipids, and d) a second solubilizing substance selected from the group of nonionic surfactants. Essentially, cyclosporine is a solubilized liposome. The composition of the invention is suitable for oral, parenteral, nasa, mucosal, topical, and particularly pulmonary application in the form of an aerosol.