Oral compositions cyclosporine

 

(57) Abstract:

Oral cyclosporiasis composition contains cyclosporine, arcanely solvent containing from 2 to 3 carbon atoms and the nonionic polyoxyalkylene surfactant. Specified surfactant selected from the group consisting of polyoxyethylenated alcohols and complex monoamino fatty acids ethoxylated polyols containing from 4 to 6 carbon atoms. Preferably used cyclosporin a at a concentration of from 50 to 150 mg/ml, arcanely solvent is ethanol or propylene glycol at a concentration of from 5 to 75% (o/o) of the specified composition and complex monoether ethoxylated sorbitane in a concentration of from 10 to 50% (o/o) of the specified structure. Oral cyclosporiasis composition is in the form of hard capsules. Also described aqueous dispersion of nanoparticles of cyclosporine for administration to the patient. At least 50 wt.% cyclosporine in the dispersion is present in the form of particles less than 1 micron. New cyclosporine compositions have a high biological value and are suitable for introduction into hard capsules or nanoparticles. The compositions are stable in a wide temperature range, no crystallization of the active agent is cyclosporine. 7 C. and 12 C.p. f-crystals, 6 ill., table 1.

Cyclosporine are a class of cyclic polypeptides consisting of eleven amino acids which are produced as a metabolite of the fungi species Tolypocladium inflatum Gams. It was found that cyclosporine reversibly inhibit immunocompetent lymphocytes, especially T lymphocytes, G0or G1phases of the cell cycle. It was also shown that cyclosporine reversibly inhibit the production and release of lymphokines. Although there are a large number of cyclosporine, the most widely used is cyclosporine A.

It is believed that the use of cyclosporine a in the small intestine and lungs. It was shown that cyclosporin a suppresses humoral immunity and, to a greater extent, immune response cell-mediated immunity, including allograft rejection, delayed hypersensitivity, experimental allergic encephalomyelitis, arthritis, caused by the adjuvant's adjuvant, graft-versus-host. Although the success achieved with the use of cyclosporine A, the introduction of the agent after transplantation should be continued, as the success of cyclosporine therapy is reversible and graft rejection occurs as soon as the introduction of cyclosporine And stops.

Despite the fact that the developed formulations of cyclosporine for oral, intravenous, oral introduction is preferred because of the ease of administration and greater endorsement of patients. Moreover, intravenous administration of cyclosporine may cause anaphylactic reactions, side effects were not observed in oral compositions. Oral cyclosporine structures that are designed and are currently for sale, and include soft gelatin capsules and soluble compounds, each of which is sold under the trade names SANDIMMUNEand NEORAL.

Thus, the desired oral formulations of cyclosporine should be compositions that solve at least some of the above problems. Ideally, the oral compositions should provide a high biological value, to contain the other Reference for Practitioners (1994), pp. 2071-2074, describes oral cyclosporine formulations currently marketed under the trademark SANDIMMUNE< / BR>
Oral immune compositions are also described in the liner for packaging NEORAL(1995) (Sandoz Pharmaceutical Corporation, East Hanover, New Jersey, 07936).

U.S. patents on the subject, describing the cyclosporine and their derivatives include: 4,220,641; 4,639,434; 4,289,851 and 4,384,996. U.S. patent N 5.047.396 describes the preparation for intravenous cyclosporine. U.S. patent N 4.388.307; 4,970,076 and 4,990,337 describe the preparations of oral formulations of cyclosporine.

Drugs in solid capsules for oral delivery of pharmaceutical compositions is described in U.S. patent N 4,822,618; 4,576,284; 5,120,710 and 4,894,235.

Presents oral cyclosporine compositions and methods of their use in immunosuppressive therapy. The compositions object of the cyclosporine is present in an orally acceptable carrier containing at least one arcanely solvent containing from 2 to 3 carbon atoms in combination with at least one non-ionic surface-active agent (surfactant). The composition of the object may further contain one or more co-solvent, and are interested in co-solvents are esters ironicheski valuable nanoparticles of cyclosporine, including polyoxyalkylene surfactant, forming a stable dispersion upon dilution in liquid medium.

Fig. 1 shows the peak concentration of cyclosporine (Cmax), achieved in mice for various oral compositions in accordance with the subject invention, where Cmaxshown as a relative value compared with Cmaxreached for the composition of SANDIMMUNEORAL (SO).

Fig. 2 shows the time that is Cmax(Tmaxfor each of the compositions shown in Fig. 1, where Tmaxshown as a relative value in comparison with TmaxSANDIMMUNEORAL(SO).

Fig. 3 shows the relative area under the curve "concentration of blood - time" (AUC) for each of the compositions shown in Fig. 1, where AUC is represented as a relative value compared with the value of the AUC for the composition of SANDIMMUNEORAL(SO).

Fig. 4 shows peak concentrations of cyclosporine Cmaxmade in patients for several oral formulations in accordance with the subject invention, as for SANDIMMUNE solutionORAL(of Fig. 4 "Sand").

Fig. 5 shows the time for which Cmax

Provided oral cyclosporine compounds that increase the biological value and can be formulated in the form of capsules, especially of hard capsules. The compositions object of the cyclosporine is present in an orally acceptable carrier containing at least one arcanely solvent containing from 2 to 3 carbon atoms in combination with at least one non-ionic surface-active agent (surfactant). The composition of the object may further contain one or more co-solvent, and are interested in co-solvents are esters of fatty acids and diols. Each of the components of the compositions object is pharmaceutically acceptable. In addition, to ensure a high biological value structures object to provide a reproducible from one batch to another adsorption of cyclosporine a specific composition. The structures of the object are used in immunosuppressive therapy.

In the area there are a large number of cyclosporine, showing immunosuppressive activity, and can be attributed to the object of oral compositions. Cyclosporine, which can be introduced into the compositions of the object, vkluchaut. Cm. Merck Index (1989) 2759. Oral formulations of the object are particularly suitable for delivery of cyclosporine A. Upon delivery of the compositions object of cyclosporine And will be present in concentrations ranging from 50 to 150 mg/ml, usually from 100 to 150 mg/ml, based on the amount of the component carrier composition.

Component carrier of the compositions will include arcanely solvent component, and arcanely solvent component will contain at least one alkanol and usually not more than three different alkanol, most typically, no more than two different alkanol, where the alkanols are, typically, carbon atoms in an amount of from 2 to 3 and from 1 to 2 hydroxy groups, so that there is not more than 1 hydroxy group at 1.5 carbon atoms. Suitable alkanols include ethanol and propylene glycol. The total number balkanologie solvent in the composition is at least about 1% (o/o), usually at least about 3% (o/o) and can be as high as 95% (o/o), but will usually be in the range of from about 5 to 75% (o/o), usually from about 5 to 60% (o/o), and most typically from about 10 to 60% (on/about) composition. As balkanologie solvent in the composition is ethanol, the amount of ethanol can is present as balkanologie solvent, the amount of propylene glycol in the composition of the object may be in the range of from about 5 to 90% (o/o), usually from about 5 to 85% (o/o), most typically from about 10 to 50% (o/o) composition.

Also in the orally acceptable carrier is present, at least one nonionic polyoxyalkylene surfactant, usually not more than two polyoxyalkylene non-ionic surfactant. Polyoxyalkylene surfactants will have a hydrophobic-lipophilic balance (HLB) from about 5 to 20: usually from about 8 to 16. Preferably, polyoxyalkylene surfactants used in the compositions of the object will be polyoxyethylene components. Interested polyoxyethylene connections include: ethoxylated alcohol, i.e. polyoxyethylene alcohols or ethoxylated fatty alcohols where the alcohol motives, usually in the range from 10 to 18, usually, from 10 to 14 carbon atoms as well as esters and substitutes esters, and polyoxyethylene derivatives of partial esters of fatty acids, usually monetary of polyols in an amount of from 4 to 6 carbon atoms, usually 6 carbon atoms, where the polyols may be anhydrides, polyols, i.e., sorbitan. Motives fatty acid surfactant of the object will be, typically, is about, in the range of from about 2 to 25. The preferred surfactants are polyoxyethylene (4) lauric ether (BRIJ 30) and polyoxyethylene (20) mono sorbitan mono-oleate (TWEEN 80). The total amount of nonionic surfactant represented in the composition of the object will be in the range from 5 to 65%, usually from about 5 to 60% (o/o) composition. Where TWEEN 80is present in the composition, it is usually presented in amounts range from 5 to 60%, most typically from about 10 to 50% (o/o) composition. When BRIJ 30is present in the composition of the object, it will usually be present in amounts range from 10 to 45%, most typically, from about 15 to 40% (o/o) composition.

The composition of the object may further contain one or more co-solvents, usually no more than three different co-solvent, most typically, no more than two different co-solvent, where suitable co-solvents include esters of fatty acids and diols, where the co-solvent may be 100% complex fatty acid ester, 100% diola or their combination. The total number of co-solvent represented in the composition may be in the range of from about 20 to 80% (o/o) and is usually in the range from approximately 25 to be in the range of, about 1:1 to 15:1, but will usually be in the range of from about 1:1 to 13: 1.

Esters of fatty acids can serve as co-solvents in the compositions object such esters of fatty acids, which gidrocarbonata chain fatty acids ranging in length from 12 to 18, usually from 14 to 18 carbon atoms, where an ester of a fatty acid is a mono-ether of the lower alkanol. Suitable esters of fatty acids will mostly contain similar number chain fatty acids, where gidrocarbonata the chain may be saturated or unsaturated, usually having not more than a two-site saturation. Interested fatty acids are normally of plant or animal origin and include palmitate, stearate, palmitoleate, linoleate, linolenate and the like, especially, monistat and oleate. Alcohol mono-ester of the fatty acid will lower alkanol in length from 2 to 4 carbon atoms, usually 2 to 3 carbon atoms in length, with or without branches. Particularly interested in complex fatty acid esters are isopropyl myristate and ethyl oleate. Isopropyl myristate, if present, will be in the range of from about 55 to 75% (o/o), and ethyl oleate, if present, will be in the range of from about 35 to 75% (o/o) of the total composition. About the 8 times larger than the amount of the surfactant in the composition is usually not more than 5 times the amount of the surfactant in the composition (o/o).

Diols can also be represented in the composition of the object, and diols may be present in addition to, or instead of a co-solvent of ester fatty acids. Interested dialami as a co-solvent are usually lipids at physiological temperature and include diols of from 8 to 28 carbon atoms, usually from 16 to 20 carbon atoms, where diola can be polyoxyalkylene diol, where alkylene contains from 2 to 3 carbon atoms. Suitable diols for use as co-solvents can be in the range of from about 200 to 800 daltons, typically from about 200 to 650 daltons. Particularly interested diols include polyethylene glycols, especially polyethylene glycol 200 (PEG200), polyethylene glycol 400 (PEG400), polyethylene glycol 600 (PEG600) and the like, with the most preferred PEG400. Being presented as a co-solvent in the composition of the object, diols will be in the range of from about 5 to 60% (o/o), usually from 5 to 55% (o/o) composition.

For the formation of amorphous nanoparticles are desired in the composition, the total number of lower alkanol is usually in the range is the number of alkylene connection(s) is typically in the range about 20-50 weight percent, most typically in the range of about 25-40 weight percent. Where there are combinations polyoxyalkylene compounds, a number of esters of fatty acids is usually in the range of from about 25 to 100% polyoxyalkylene connections.

In the object co-solvents may themselves give the composition the desired physical characteristics such as viscosity, stability and the like. Preferably, the composition may further contain additional agents, which give the composition the desired physical characteristics, such as thickening agents, suspendresume agents, curing agents and the like, where such agents include acacia, carboxymethyl-cellulose, hydroxypropyl-cellulose, lecithin, methyl cellulose, polyethylene glycol of high molecular weight, i.e., polyethylene glycols with molecular weights in the range from about 1000 to 6000, usually from 1000 to 5000 daltons, povidone, sodium alginate, tragakant and the like. Also in the composition of the object may be a number of minor components that provide various functions, such as enzyme inhibitors, preservance, antioxidants, antimicrobial agents, stabilizers and under the em, OK, not more than 5 weight percent, usually 2 weight percent, most typically 1 weight percent of the composition. As is known in the field, excipients can also be represented in the composition of the object.

The composition of the object is stable under a wide range of temperatures, and under stable is meant that the physical integrity of the composition is not violated, i.e. there is no crystallization of the active agent is cyclosporine. Included in the range of temperatures at which the compositions of the stable object are reduced temperatures, such as are used in cold storage, where such low temperatures are usually in the range from about 0 to 15oC, more typically, from about 2 to 8oC.

The composition of the object suitable for administration in capsule form, i.e., hard and soft capsules. Methods for the manufacture of hard capsules containing liquid compositions known in the field and are described in U.S. Patent N 4,822,618 and 4,576,284, disclosure of which is made here in the links. Usually, hard capsules, which are used with the compositions object will contain two parts: the shell component and the component cover. The components of the shell and cap are the same together to form a nested cavity defined is received from a hydrophilic polymer, such as starch or gelatin. In the preparation of hard capsules, the liquid composition will be poured into the shell and then the capsule will be sealed by placing the component cover on top of the shell component. Isolation between the two components can be strengthened, thereby preventing leakage from the capsule placed composition, by using the insulator as described in EP 116744, the disclosure of which is included here in the links. To prevent destruction in the stomach capsules containing the composition of the object can be covered with intestinal membrane, which inhibits the degradation of the capsules in the acid environment of the stomach. In the area there are many intestinal membranes. See, for example, U.S. Patent N 5,206,219, the disclosure of which is included here in the link.

The compositions, especially the compositions of producing nanoparticles, can be prepared initially by dissolving the cyclosporin in the lower alkanol, which may also be included a small proportion of polyoxyalkylene connection, usually less than about 50 weight percent of the composition used for the dissolution of cyclosporine. Can be used elevated temperature, typically in the range of from about 60 to 90oC. After dissolve the den to the desired ratio by adding suitable compounds. As a rule, cyclosporine can be dissolved in the lower alkanol (optimally, including the portion of polyalkylene connections) in a weight ratio of about 1:1.5-5, most usually 1:2-4.

The structures of the object are used in immunosuppressive therapy. Immunosuppressive therapy is indicated for a number of different diseases, including idiopathy nephrotic syndrome, insulin-dependent type I diabetes, syndrome Waseca, active Crohn's disease, aplastic anemia, severe corticosteroid-dependent asthma, psoriasis, rheumatoid arthritis and other diseases in which the immune system may play a pathogenic role. Particularly interesting is the use of the compositions of the object in situations with transplants, including allogenic, and xenogenic organs, transplantation of tissues or cells, when the desired immunosuppression to ensure the viability of the transplanted organ or tissue, or cells after transplantation, i.e., to prevent transplant rejection or to prevent graft versus host, for example after bone marrow transplantation.

If using the object to provide immunosuppressive therapy in Hosa is pressie the owner, depending on the specific treatment condition. At transplantation, typically, the initial dose of cyclosporine will be introduced before the operation. After transplantation of a donor organ, the owner of cyclosporine will be introduced to the owner again, i.e. permanently, for maintenance immunosuppression. The initial dose should be administered for 4 to 12 hours before transplantation and may vary from 10 to 18 mg/kg, usually from 10 to 15 mg/kg of host. After surgery, the initial dose will usually continue on a daily basis for the period from 1 to 3 weeks, usually, from 1 to 2 weeks. The dose may then be gradually reduced to a maintenance dose of 3 to 10 mg/kg / day, usually from 3 to 6 mg/kg / day. The level at which the dose is gradually attenuated to support level is in the range from 3 to 8% per week and will be, typically, about 5% per week. The dose may be generally selected based on the levels of blood in the cavities to maintain a concentration of from 150 to 250 ng/ml, as calculated using liquid chromatography under high pressure, radioimmunoassay, enzyme-linked immunosorbent or TDx analysis. The composition of the object can be introduced in combination with additional agents, when recommended by dopolnitelnyefunktsii, azathioprine and such.

Introduction compounds in combination with transplantation of a donor organ, the master leads to the lengthening of the viability of the donor organ in the host as a result of suppressing the immune response of the host to the presence of the donor organ. Under "extension viability" means that the donor organ remains viable in the host for a longer period of time than if immunosuppressive therapy was not used in combination with transplantation. Thus, lengthening the viability includes maintaining the viability for an indefinite period of time. Donor organ is considered viable until it supports the functionality in the environment of the host.

For the convenience of the user can be provided in kits, with a suitable quantity of cyclosporine, one or two levels of dose and co-solvent, namely low alkanol(s), polyalkylene compound(I), i.e., at least one of ethanol and propylene glycol, and at least one Polysorbate 80 and PEG400.

The following examples are offered with illustrations and without restrictions.

It was cooked a few oral ciclosporin the prepared compounds was further evaluated in rats and patients.

I. Oral zakopalova compounds

Were prepared following oral formulations of cyclosporine A. In each case in a measuring vessel with a volume of 1.0 ml were added 100 mg of CsA, the amount of surfactant and a specified amount of ethanol or propylene glycol, and the final volume of 1.0 ml was achieved by adding a suitable amount of ester of fatty acid and/or diol.

II. Studies of biological values in vivo to compounds of 19-24 and 33-42

The biological value of the compositions 19-24 and 33-42 cyclosporine studied as follows. To measure the biological value was determined by the following pharmacokinetic parameters: (a) the peak concentration of cyclosporine in the blood (Cmax); (b) the time required to achieve a Cmax(Tmax), and area under the curve "concentration of blood - time curve" (AUC). In addition to the compositions 19-24 and 33-42 were evaluated to compare biocenose cyclosporine SANDIMMUNEOral Solution (SO) under similar conditions. For each of the above composition in rats CsA-naive Sprague Dawley weighing 250-350 g were fed with standard food in pills Agway3000, Granville Mill, Greensboro, NC) and water ad libitum. One day before the experiment in the right neck and right badrena was introduced CsA via a stomach tube.

After the introduction of the cervical veins were sampled blood 200 ál in 0.5 ml polypropylene tubes containing 0.3 mg of lyophilized EDTA-Na, and immediately mixed for 10 sec. The time of sampling in animals that received oral formulations was 0, 0.5, 1, 2, 4, 8, 12, 24, 36, 48 and 72 hours after injection.

CsA, including some of its metabolites, were measured in blood in fluorescence polarization immunoassay (FPI)(Tdx, Abbot Lab.). Briefly, 150 μl of the sample are full of blood quantitatively transferred into a microcentrifuge tube with a volume of 1.5 ml of Cells were literally and dissolved in 50 μl of surfactant containing a dissolving agent. Further wizardly proteins 300 μl of acetonitrile. After centrifugation supernatant was subjected to FPI analysis in the Tdx auto-analyzer, following the procedure recommended by Abbott Diagnostics. Because Tdx assay was originally developed for human blood, some of the recommended procedures were modified as follows. There were prepared a series of standard solutions with known concentrations of CsA by adding a known quantity of CsA to the blood of rats treated with EDTA. When it was expected that the concentration of CsA in the sample is higher than 1.0 mg/ml, the blood sample was diluted 10 times with 0.1 M forandring solutions containing a known quantity of CsA, an equal volume of 10% in the blood of rats and 90% phosphate buffer.

From compartmental analysis were obtained descriptive pharmacokinetic parameters. Peak concentrations (Cmax) and the time at which appeared the peak concentration (Tmax) was evaluated by checking the profile of the undiluted concentration - time for each rat. The area under the curve "concentration of blood - time" (AUC) from time 0 to the last data point (AUC0t) was calculated according to the linear trapezoidal procedure. The residual area under the tail of the curve "concentration of blood - time" (AUC0) was estimated as the ratio of the last observed concentration (C*) with the initial rate constant associated with the terminal phase of elimination profile "concentration - time" (z). The rate constantzwas determined by log-linear regression data "concentration - time" in the visible terminal log-linear phase profile "concentration - time" (i.e., the latest data from 3 to 5 points, depending on the analyzed profile). The total value of AUC (AUC0t) was obtained as the sum of AUC0tand AUC0.

The results for each composition were compared with the results obtained for the bioavailability of cyclosporine with that of the object compared to SANDIMMUNEOral Solution (SO), as shown by higher values of AUC composition of the object.

III. Biocenose compounds 35, 43-46 and 48-52 in humans in vivo

48 healthy men aged between 19 and 55, with the deviation from ideal weight is not more than 20% were used for the test. Conducted single dose, fasting, randomized, double-blind, triple cross-sectional study. 48 patients were randomly allocated to 6 groups of 8 patients. Each group received one dose of 300 mg cyclosporine of the above compositions or SANDIMMUNEOral Solution (SO) in three different ways, each introduction was separated by a 7-day washout period.

Patients were required to fast for 10 hours before and 4 hours after dose. During the study, were allowed to take water ad lib, except for the one-hour period before, during and 2 hours after a dose. Before the introduction of the doses were selected 15 ml blood samples. For introductions combined 3 ml aliquot of the compound (300 mg) with 200 ml of chocolate milk and was administered orally. Were collected 10 ml of blood samples at time t=0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 16, 20 and 24 hours. After the study was also selected 15 ml blood samples.

The concentration of cyclosporine in the appropriate fields.

Compartmentize pharmacokinetics were taken using standard methods. The maximum concentration of full blood (Cmaxand the time of its occurrence (Tmax) were collected from the data "concentration - time". The area under the curve "concentration of blood - time" (AUC) was calculated by linear trapezoidal rule for the last of the blood concentration above the limit of sensitivity (25 ng/ml) and extrapolated to infinity.

The obtained values of Cmac, Tmaxand AUC for each composition was average. Average values for each composition is shown in Fig. 4-6. The results demonstrate that each tested composition Cmaxappeared at least two times faster than SANDIMMUNEOral Solution (SO) under the same conditions. Moreover, the AUC value obtained in tests of the compounds was at least 2000 GCAS/ml greater than that obtained for SANDIMMUNEOral Solution (SO) under the same conditions. Based on these results, compounds 35, 43-46 and 48-52 provide more biocenose than SANDIMMUNEOral Solution (SO).

The compositions were prepared for the formation of amorphous nanoparticles upon dilution in water.

IV. The compositions of n is sporine A. To the resulting solution were added 25 g of Polysorbate 80 and brought volume up to 50 ml 1,2-propylene glycol. The mixture was stirred at room temperature is sufficient for the formation of a homogeneous solution.

B. 5 g of cyclosporin a was added to 5 ml of ethanol. The mixture was stirred until complete dissolution of cyclosporine A. To the resulting solution was added 15 g of Polysorbate 80 and brought volume up to 50 ml with a mixture of 1,2-propylene glycol and polyethylene glycol 400. The mixture was stirred at room temperature is sufficient for the formation of a homogeneous solution.

C. 1 ml of the solution obtained in Example 1 was added to 50 ml of water glass syringe, as recommended for oral administration of concentrated emulsions or microemulsions person. After adding the solution was followed by rapid dissolution and obtain a white suspension of small particles, with a blue glow, as a colloidal suspension (effect of Tindale). After centrifugation at 26.000 g for 5 hours, the precipitate was washed with water and then centrifuged at 26.000 g within 24 hours. The processes of washing and centrifugation was repeated twice under the same conditions. After drying conducted a chart of x-ray powder. The solid was exclusively in Amorin eticheskikh nanoparticles with a diameter between 200 and 400 nm with the presence of some aggregates.

, 2 ml of the solution obtained in Example 1 was added 100 ml of water and investigated the colloidal suspension 10 minutes and 1 hour after the dissolution diffraction/diffusion laser granulometer (Malvern SB.OD.

After 1 hour was observed two populations of particles: one represented 70% of the weight of cyclosporin a with a mean diameter of 300 nm and the second represented 30% of the weight of cyclosporin a with an average diameter of 20 μm, possibly containing aggregates of nanoparticles.

D. 1 ml of the solution obtained in Example 1 was added 50 ml of water and stirred colloidal suspension within 10 minutes. Then the suspension was added to 200 ml of artificial gastric acid juice and heated at 37oC. a Homogeneous colloidal suspension was analyzed diffraction/diffusion laser grain size distribution (Malvern SB.OD). The suspension consisted solely of nanoparticles with an average diameter of 600 nm.

That is, 1 ml of the solution obtained in Example 1 was added directly to 200 ml of artificial gastric acid juice.

A homogeneous suspension was heated at 37oC and quickly analyzed diffraction/diffusion laser grain size distribution (Malvern SB.OD). The suspension consisted solely of nanoparticles with an average diameter of 350 nm.

All publications and patent applications that are marked in this specification are incorporated herein as references, as each individual publication or patent applications, are specifically and individually marked, included in the references.

Although the above invention has been described in some detail by way of illustration and example for purposes of clarity of perception, for working in the field will be readily apparent in light of the teachings of the present invention that it can be made certain changes and modifications without changing ideas and leaving the framework of the attached claims.

1. Oral cyclosporiasis composition containing cyclosporin, at least one arcanely dissolve the specified eat surfactant selected from the group consisting of polyoxyethylenated alcohols and complex monoamino fatty acids ethoxylated polyols containing from 4 to 6 carbon atoms.

2. Oral cyclosporiasis composition under item 1, additionally comprising at least one co-solvent selected from the group consisting of complex monoamino lower alcohol and a fatty acid containing from 14 to 18 carbon atoms and diols containing from 8 to 28 carbon atoms.

3. The composition according to p. 2, wherein said arcanely solvent is from 5 to 75% (o/o) of the composition of at least one specified nonionic polyoxyalkylene surfactant is from 5 to 65% (o/o) of the composition, and at least one designated co-solvent is from 20 to 80% (o/o) of the specified structure.

4. Cyclosporiasis composition containing cyclosporin a, at least one arcanely solvent selected from the group consisting of ethanol and propylene glycol, and specified arcanely solvent is from 5 to 75% (o/o) of the composition of at least one nonionic polyoxyethylene surfactant, and specified non-ionic polyoxyethylene surfactant selected from the group consisting of polyoxyethylenated spirea least one co-solvent, and at least one of these co-solvents is difficult monoufia lower alcohol containing from 2 to 4 carbon atoms, and a fatty acid containing from 14 to 18 carbon atoms, and said co-solvent is from 20 to 80% (o/o) of the specified structure.

5. The composition according to p. 4, wherein said non-ionic surfactant selected from the group consisting of polyoxyethylene (4) lauric ether and polyoxyethylene (20) monocarbide of monooleate, and specified complex monoether lower alcohol and a fatty acid selected from the group consisting of isopropylmyristate and ethyloleate, and the composition contains a co-solvent, and one of the co-solvent is diola containing from 8 to 28 carbon atoms.

6. Oral cyclosporiasis composition containing cyclosporin a at a concentration of from 50 to 150 mg/ml, arcanely solvent consisting of ethanol and propylene glycol, and specified arcanely solvent is from 5 to 75% (o/o) of the specified structure, and complex monoether ethoxylated sorbitan, which is 10 to 50% (o/o) of the specified structure.

7. The composition according to p. 6, in which the ethanol content is from 5 to 20% (V/o) ukazannogo composition.

9. Solid capsule-containing oral composition under item 1.

10. Water dispersion of nanoparticles of cyclosporine for administration to a patient, including cyclosporine, at least one arcanely solvent containing from 2 to 3 carbon atoms, and at least one non-ionic polyoxyalkylene surfactant selected from the group consisting of polyoxyethylenated alcohols and complex monoamino fatty acids ethoxylated polyols containing from 4 to 6 carbon atoms, and at least 50 wt.% cyclosporine specified in cyclosporine dispersion are present in the form of particles less than 1 μm, and the specified cyclosporine is amorphous.

11. Dispersion under item 10, in which the specified nonionic polyoxyalkylene surfactant selected from the group consisting of polyoxyethylenated alcohols and complex monoamino of ethoxylated sorbitans, and ranges from 5 to 65% (o/o) specified cyclosporine composition.

12. Dispersion under item 11, in which the specified nonionic polyoxyalkylene surfactant is Polysorbate 80.

13. Dispersion under item 10, in which the specified arcanely solvent selected from the group consisting of ethanol and propylene glycol, and ranges from 5 to 75% (on/about) pointed to by described in paragraph 10, includes mixing cyclosporine with at least one alkanols solvent containing from 2 to 3 carbon atoms, and at least one non-ionic polyoxyalkylene a surfactant to obtain a solution at a dilution which an aqueous medium is formed of amorphous nanoparticles of cyclosporine a size less than 1 micron.

15. The method according to p. 14, wherein said non-ionic polyoxyalkylene surfactant selected from the group consisting of polyoxyethylenated alcohols and complex monoamino of ethoxylated sorbitans, and ranges from 5 to 65% (o/o) specified cyclosporine composition.

16. The method according to p. 15, wherein said non-ionic polyoxyalkylene surfactant is Polysorbate 80.

17. The method according to p. 14, wherein said arcanely solvent selected from the group consisting of ethanol and propylene glycol, and ranges from 5 to 75% (about/on) specified cyclosporine composition.

18. The method according to p. 14, further comprising the stage of adding a co-solvent to the specified solution before dilution of this solution in an aqueous medium, with specified co-solvent selected from the group consisting of complex monoamino lower alcohol and a fatty acid containing from 14 to 18 canal and/or propylene glycol, and Polysorbate 80 and/or polyethylene glycol 400.

Priority points:

25.08.1995 on PP. 1, 7 and 9;

21.03.1996 on PP. 2 - 6 and 8;

25.03.1996 on PP. 10 - 19.

 

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