The solution cyclosporine

 

The invention relates to the field of medicine and for the solution of cyclosporine. The invention lies in the fact that the proposed solution contains cyclosporine cyclosporine, dexpanthenol as the agent of dissolution, forming in water a stable colloidal solution, which is diluted with water in any proportion without deposition of cyclosporine. The invention provides good absorption of biologically active substances after oral administration. 2 C. and 14 C.p. f-crystals, 4 PL.

The present invention relates to a solution of cyclosporine. Cyclosporine is known cyclic group undecapeptide. Cyclosporine A (C62H111N11O12molecular weight 1202) is used as an immunosuppressive drug for the treatment of rejection reactions of the tissues or excessive immune response, which in the trade is available, for example, in the form of Sandimmunand Neoral. In addition to cyclosporine And well-known series of metabolites (cyclosporine B-Z), which are structurally and partly also by activity are characterized by a close relationship to cyclosporine A.

Locally, that cyclosporine a very poorly soluble in water. Hence the problem of forming a well and quickly absorbable pharmaceutical compositions of cyclosporine And as fast and complete or almost complete absorption of biologically active substances is a prerequisite for the reliable efficiency when vital evidence as to suppress tissue rejection after organ transplantation. Prior art many attempts have been made to get cyclosporin a, as well as the intake of the drug. Due to its high lipophilicity of cyclosporine a were prepared pharmaceutical compositions with conventional solid or liquid pharmaceutical carriers, which, however, often found deficiencies as lack of absorption (Cavanak und Sucker, Formulation of Dosage Forms, Prog. Allergy, 38, 65-72 (1986)), bad chemistry or physical instability as bicrystalline biologically active substances. The disadvantage is that the solubility of the biologically active substance in the composition will decrease considerably (about 3%) that at a daily dose of up to 1 g of cyclosporine a mean single dose up to 30 grams of the drug.

Patent DE 2907460 describes to improve storage is glyceride fatty acids and mono - or diglyceride. The product finds application in the form of a drinkable solution, solution for injection or in the form of capsules. To facilitate solubility can be added ethanol. Such a solution is relatively well absorbed, but with the disadvantage that the level in the blood can vary greatly and depends on the consumption of food. Improved the product described in the patent DE 3930928 in the form of so-called preconcentrate microemulsions, which consists of a hydrophilic phase, a lipophilic phase and an emulsifier. The hydrophilic component can be a simple C1-5- alkilany or simple tetrahydrofurfurylamine fluids, or incomplete simple ether of low molecular weight mono - or polyoxyalkylene, or 1,2-propylene glycol. Lipophilic component may be a medium chain triglyceride. As an emulsifier is provided, for example, polyethoxysiloxane vegetable oil.

In the comparative study of suction on hound dog shows 49% improvement suction compared to the preparation described in patent DE 2907460.

Patent DE 19521974 describes the solution of cyclosporine a in a mixture of emulsifying derivative of vitamin E, another emulsifier, as ester of polyoxyethylene, rastitel the and DE 3930928.

International application WO 97/35603 describes microdispersion comprising amorphous cyclosporine a, lower alkanols and polyoxyalkylene emulsifiers as co-solvent.

International application WO 97/07787 reveals the drug cyclosporine, which includes an alcohol solvent with 2 to 3 carbon atoms and an emulsifier selected from polyoxyethylene alcohols and monoamino fatty acids and ethoxylated With4-6polyols.

There is a need for an inexpensive, well tolerated and stable cyclosporine compositions, particularly easily manufactured, which is easily miscible with water and forms a stable solution of cyclosporine, which is for oral use provides good absorption of cyclosporine and may contain cyclosporine in high concentrations.

Thus, the present invention consists in obtaining cyclosporine composition, which is characterized by the above mentioned advantages.

Unexpectedly, it was shown that the solution of cyclosporine in the exclusively mix with water auxiliary substances only in combination with dexpanthenol, anionic surface-active agent and nonionic surface-active substance or which are water in any ratio without deposition of cyclosporine. Biological studies available showed good absorption of biologically active substances after oral administration.

The solution cyclosporine according to the invention may contain a greater amount of biologically active substance in ml than drugs cyclosporine known from the prior art.

Thus, the present invention relates to a solution of cyclosporine, including dexpanthenol, anionic surfactant and nonionic surfactant or mixture of nonionic surfactants.

Dexpanthenol is an abbreviated designation D - (+) -2,4-dihydroxy-N-(3-hydroxypropyl)-3,3-dimethylbutyramide.

Cyclosporine is preferably cyclosporin A.

The solution cyclosporine according to the invention may contain a biologically active substance, and also dexpanthenol, anionic surfactant and nonionic surfactant, and if necessary further pharmaceutically compatible auxiliary substances in any amount, because the number of dexpanthenol, anionic surfactants and nonionic surfactants sufficient which contains on a weight part of cyclosporine 0.2 to 2 weight parts of dexpanthenol, 0.2 to 1 weight part of the anionic surfactant and from 0.5 to 6 parts by weight of the nonionic surfactant or mixture of nonionic surfactants.

In General the solution of cyclosporine according to the invention contains on a weight part of cyclosporine 0.2 to 2, preferably 0.5 to 2, for example, of 0.7 to 1.3 weight parts of dexpanthenol, 0.2 to 1, preferably from 0.3 to 0.7 parts by weight of anionic surfactant and from 0.5 to 6, preferably 3-5 parts by weight of the nonionic surfactant or mixture of nonionic surfactants.

Preferably the solution of cyclosporine according to the invention may further comprise a diluent. Using the diluent reduces the viscosity of the solution. This is an advantage, as when filling solution, for example, megkozeliteni capsules, after taking the capsule with its contents very quickly out of the opened capsule, and thus provides good absorption of biologically active substances.

Drinking solution, before use, diluted with water, so that its viscosity is very minipedia, you can refuse to add a diluent.

If the solution according to the invention should stabeno about 20 weight. %. The preferred diluent is ethanol.

As the anionic surfactant to the solution according to the invention can be applied to any conventional pharmaceutically acceptable anionic surfactant. Can also be used one anionic surfactant or a mixture of two or more anionic surfactants. Examples used according to the invention, anionic surfactants are sulfates simple alilovic esters and alkanesulphonic. Preferred anionic surface-active agent is sodium lauryl sulfate.

As the nonionic surfactant to the solution according to the invention can be applied to any conventional pharmaceutically acceptable non-ionic surfactant. Also non-ionic surfactant may be used alone or in a mixture with other non-ionic surfactants, the mixture of nonionic surfactants is preferred. Examples used according to the invention the nonionic surfactants are glycerylmonostearate (Napolean, available under the trademark Tween 80. Preferred nonionic surfactants are Polysorbate 80 and glycerylmonostearate.

The preferred solution according to the invention consists of about 11 wt.% cyclosporin a, about 11 wt.% dexpanthenol, about 5.6 wt.% anionic surfactant, about 55,6% wt. a mixture of nonionic surfactants and about to 16.8 wt.% diluent, especially ethanol. This solution is particularly suitable for filling megkozeliteni capsules, as it due to its low viscosity very quickly released from the opened capsule and provides good absorption of biologically active substances. Another preferred solution according to the invention consists of about 19-26 weight. % cyclosporin a, about 8-10 wt.% dexpanthenol, about 8-10 wt.% anionic surfactant, about 44 to 50 wt.% nonionic surfactant and about 12-14% wt. diluent.

Thanks to the combination of dexpanthenol, anionic surfactants and non-ionic surfactant as a solvent to get cyclosporine solution of cyclosporine, which is easily miscible with water and with cyclosporine. The solution according to the invention does not constitute a microemulsion or microemulsion concentrate and consists exclusively of known pharmaceutical substances. It can rasfasovyvaetsya in capsules, and also be taken by patients in the form of a drinkable solution with good taste.

Compared with the prior art due to the combination of these compounds were able to abandon the lipophilic component that is needed for the formation of microemulsions. Here suddenly dexpanthenol, although it is not surface-active agent assumes the role of agent of dissolution, which primarily provides a stable colloidal solution of cyclosporine in solvents. Neither is contained in the composition of anionic and nonionic surface-active substances separately, or a combination of them is not able to dissolve the cyclosporin without precipitation.

Thanks to the unexpectedly good solvent properties of dexpanthenol the cyclosporine concentration in the solution according to the invention can be increased in comparison with the prior art, so that, for example, drugs can be achieved higher concentration of biologically active substances or can be reduced to accept the crystals.

Thus, the invention also applies to oral medications, which contains the above-described solution of cyclosporine.

Preferably it is of such a medicinal product in capsules, which is the solution. Especially preferred megkozeliteni capsules. When checking the speed of dissolution in media with different pH values, which is typical of the gastrointestinal tract, was found significant pH-independent release of biologically active substances from the capsules.

In another form of the drug, including the solution according to the invention, represented in the form of a drinkable solution, addition of a solution of cyclosporine may contain other conventional pharmaceutically compatible additives, as well as, for example, flavoring and coloring agents, and which prior to its reception may be diluted, for example, with water to the desired concentration. Thus, the solution of cyclosporine according to the invention is suitable also for simple obtain stable drinking water solution with good taste, which can be easily accepted by the patient.

After use of a medicinal product according to the invention very quickly and enjoy the applications available in the trade of the drug Neoral. The described solution can be applied in the form of a diluted aqueous solution for the reception or in separate dosage forms, for example, in the form of capsules. For example, the capsule may contain a single dose of 100 mg of cyclosporine.

In the preferred form of the medicinal product according to the invention it is, therefore, about megkozeliteni capsules, which, depending on the circumstances, contain the solution according to the invention from about 100 mg of cyclosporin a, about 100 mg of dexpanthenol, about 50 mg of lauryl sodium, about 100 g of Polysorbate 80, about 400 mg glycerol-polyethyleneterephtalate and about 150 mg of ethanol.

The drug according to the invention is suitable in particular for immunomodulary.

The following examples will better explain the invention.

Example 1.

This example shows getting the solution cyclosporine according to the invention and medicaments according to the invention in the form megkozeliteni capsules.

Megkozeliteni capsules were obtained by filling the composition given in table.1.

Cyclosporin a was dissolved in ethanol. Separately with light heating well the target is homogeneous mixed and then poured into megkozeliteni capsules.

Example 2.

With the capsules obtained in example 1 was conducted investigation of suction for six hounds dogs. The dog used capsule with 100 mg of cyclosporine a in the crossover study compared with Neoral(composition: cyclosporine a, ethanol, glycerol mono-di-tri-glycerides corn oil, propylene glycol, macrogol-glycerylhydrostearate, alpha-tocopherol) and 0.5, and 1.0, 1.5, 2.0 hours took blood samples. The level of cyclosporine in the first blood samples were determined by commercially available immunological analysis of enzymes. In table 2, as appropriate, average values obtained from the curves in blood levels with standard deviation.

The example shows that after applying the solution cyclosporine according to the invention in the form of a capsule very quickly and reliably achieved the required level in the blood, and the uniformity of the level in the blood is higher than after application of the comparison drug.

In table. 3 and 4 show variants of the mortar compositions of cyclosporine.

Claims

1. A solution of cyclosporine, comprising a surfactant and a dissolving agent, characterized in that on the surface-active substances, as an agent of the dissolution contains dexpanthenol.

2. A solution of cyclosporine on p. 1, wherein the cyclosporin is cyclosporin A.

3. The solution cyclosporine under item 1 or 2, characterized in that it comprises 1 weight. including cyclosporine 0.2 to 2 weight. hours of dexpanthenol, 0.2 to 1 weight. including anionic surfactant and from 0.5 to 6 weight. including non-ionic surfactant or mixture of nonionic surfactants.

4. A solution of cyclosporine on one of the PP. 1-3, characterized in that it further includes a diluent.

5. A solution of cyclosporine on p. 4, characterized in that the diluent is 10-40% of the total weight of the solution.

6. A solution of cyclosporine on p. 4 or 5, characterized in that the diluent is ethanol.

7. A solution of cyclosporine on one of the PP. 1-6, characterized in that the anionic surfactant is lauryl sulfate.

8. A solution of cyclosporine on one of the PP. 1-7, characterized in that the nonionic surfactants are Polysorbate 80 and glycerol-polietilenglikolmonostearat.

9. A solution of cyclosporine on one of the PP. 4-8, characterized in that it consists of 11 weight. % cyclosporine A, 11 weight. % dexpanthenol and 16.8 weight. % of solvent, especially ethanol.

10. A solution of cyclosporine on one of the PP. 4-8, characterized in that it consists of 19-26 weight. % cyclosporin a, 8-10 weight. % dexpanthenol, 8-10 weight. % anionic surfactants, 44-50 weight. % non-ionic surfactants and 12-14 weight. % diluent.

11. A solution of cyclosporine on one of the PP. 1-10, characterized in that it is suitable for obtaining a stable aqueous colloidal solution of cyclosporine.

12. A solution of cyclosporine on one of the PP. 1-10, characterized in that it is suitable for receiving immunosuppressive drugs for oral administration.

13. Immunosuppressive drug for oral administration, comprising a solution in one of the paragraphs. 1-10.

14. Drug under item 13, characterized in that the solution is filled into capsules.

15. Drug under item 14, characterized in that the capsules are megkozeliteni capsules.

16. Drug under item 13, characterized in that the solution is in the form of a drinkable solution.

 

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