Pharmaceutical compositions

 

(57) Abstract:

The invention can be used in pharmacy for the manufacture of preparations of cyclosporine, used in medicine. The claimed preparation containing cyclosporin, propylene carbonate, surfactant, with the amount of hydrophilic-lipofilno balance 8-17, and at least one compound selected from the group consisting of ester of fatty acid and primary alcohol, a triglyceride of fatty acids with medium chain length and a monoglyceride of a fatty acid as lubricant. The second variant of the preparation contains cyclosporine and propylene carbonate. The invention allows to obtain a dosage form of cyclosporine that remain stable during the entire period of their retention. They do not alter the bioavailability, and therefore the effect of cyclosporine may be maintained at a constant level. 2 C. and 8 C.p. f-crystals, 8 PL.

The invention relates to the preparation, for example, in the form of capsules, soft coated, containing as active ingredient cyclosporine. In particular, the present invention relates to the preparation in the form of capsules, soft coated, containing cyclosporin as active ingredient, propylene carbonate or polietilene ester of fatty acid and primary alcohol, the triglyceride fatty acids with medium chain length and a monoglyceride of a fatty acid as a lubricant and a surfactant having the products HLB value (hydrophilic-lipophilic balance) ranging from 8 to 17.

Cyclosporine is a certain macromolecular (molecular weight 1202,64) cyclic peptide compound consisting of 11 amino acids and having a wide spectrum of pharmacological actions, in particular immunosuppressive activity and anti-inflammatory activity. Therefore, cyclosporine was used to suppress innate immunological responses of a living organism caused by the transplantation of tissue and organ, for example, transplantation of heart, lung, liver, kidney, pancreatic, bone marrow, skin and cornea, and first of all transplanted foreign tissues and organs. In addition, cyclosporine suitable for the treatment of hematological disorders such as anemia, various autoimmune diseases such as systemic lupus erythematosus, idiopathic malabsorption syndrome, and so on, and inflammatory diseases such as arthritis, rheumatoid diseases, etc. Cyclosporine useful for treatment of diseases caused by protozoa, such as illusory is highly lipophilic and hydrophobic compound. Therefore, cyclosporine poorly soluble in water and soluble in organic solvents, such as methanol, ethanol, acetone, simple, ether, chloroform, etc. because cyclosporine has the above characteristics of low water solubility, bioavailability of cyclosporine in the introduction oral route is extremely low, and it can exert a strong influence of the individual characteristics of the patient. Therefore, it is very difficult to maintain effective therapeutic against concentration. In addition, cyclosporine can have significant side effects, such as nephrotoxicity. Due to the low solubility of cyclosporin in water is very difficult to produce on the basis of preparations for oral administration. In this regard, we conducted extensive research aimed at establishing suitable for the effective introduction of cyclosporine oral route of drug that could provide an acceptable standard dose and appropriate bioavailability.

According to the known prior art solutions preparations suitable for oral administration of poorly water-soluble cyclosporine, usually produced in the form of pre is idlogin in patent US 4388307, issued June 14, 1983, this patent describes a liquid composition on the basis of cyclosporine with ethanol. According to the method described in this patent, to obtain a liquid composition cyclosporine combined with the medium containing ethanol as a secondary surfactant, olive oil as the vegetable oil and the product of the interesterification of triglycerides of natural vegetable oils and polyalkyleneglycol as surface-active substances.

However, the resulting liquid composition is administered in the form of aqueous dilute solutions, which greatly complicates the adaptation of the individual to its introduction and preparation of standard doses for oral administration.

To reduce the inconvenience associated with the dissolution liquid compositions on the basis of cyclosporine in the water before oral introduction of liquid composition in the form of pre-prepared emulsion concentrate was introduced into the capsule with a soft floor, and this drug is currently sold under the name Sandimmune (registered trademark). In this case, the composition containing cyclosporine capsules, soft coated include ethanol, because of the requirement is th shell capsules, as it is volatile even at normal temperature, to prevent evaporation of ethanol from the compositions in the form of capsules with a soft covering for storage and sale of such compositions in the form of capsules, soft coated can be enclosed in a shell made of special packaging material, for example, in blister packing type aluminum-aluminum.

Recently it was possible to create a drug on the basis of cyclosporine, which is stable during the whole period of storage and, in addition, practically does not alter the bioavailability, which is the same for individual patients, resulting biological effect of cyclosporine may be maintained at a constant level. One of the drugs developed for this purpose, is described in Korean laid out the application 93-113. This drug is sold under the trademark Sandimmun Neoral. However, because this drug is also used ethanol, it may have some drawbacks in terms of stability during storage and may change the content of ethanol, which is typical for containing ethanol product prototypes.

Therefore, the authors of the invention was studied large colechester etc. with the aim of creating a composition based on cyclosporine, which would be stable from the point of view of their pharmacokinetic characteristics would provide a higher bioavailability and less difference between the concentrations in blood of individual patients than drugs-prototypes based on cyclosporine. In the result it was found that a composition based on cyclosporine, comprising the following components, can satisfy the above requirements, and thus decides to put in a basis of the present invention the task.

Thus, an object of the present invention is a composition suitable for preparation of capsules with soft coating, comprising cyclosporin as active ingredient, a hydrophilic substance is polyethylene glycol or nigerienne substance propylene carbonate or a mixture thereof, sizing, as defined below, and surfactant.

The next object of the present invention is the preparation of capsules with a soft coating that contains a composition that includes a cyclosporin as active ingredient, a hydrophilic substance is polyethylene glycol, nigerienne substance propylene the FYR of fatty acid and primary alcohol, the triglyceride fatty acids with medium chain length (if necessary) and a monoglyceride of a fatty acid as a lubricant and a surfactant having the products HLB value (hydrophilic-lipophilic balance) ranging from 8 to 17.

Another object of the present invention is a method of manufacturing the above product in the form of gelatin capsules, soft coated.

Although the present invention is described with reference to gelatin capsules, soft coated, it should be noted that in its volume and the composition itself, which can be used, for example, in the form of a solution for drinking, for example, as Sandimmun Neoral, or other standard dosage forms.

One of the objects of the present invention relates to containing cyclosporine capsule, which has a high storage stability, so that over time there is only a slight change in composition, and increased bioavailability and which contains a composition comprising a cyclosporin as active ingredient, a hydrophilic substance is polyethylene glycol or nigerienne substance propylene carbonate or a mixture thereof as a second component, the sizing, as he crystals with a soft covering, containing composition on the basis of cyclosporine, it is necessary to use a gelatin shell. However, if the capsule with a soft coating is manufactured using a conventional capsule shell containing as plasticizer glycerol, the product in the form of capsules with a soft coating has certain drawbacks related to the fact that the emulsion state of the previously prepared emulsion concentrate may be altered due to the penetration of glycerol into the emulsion, which leads to a considerable reduction in the solubility of cyclosporine, resulting in the deposition of cyclosporine from the emulsion.

Therefore, in the present invention as shell capsules, soft coated preferably choose the gelatinous shell, in which the plasticizer is a mixture of propylene glycol and polyethylene glycol, but not glycerol, which allows to solve the problem of penetration of glycerol.

However, if the tape shells of capsules containing propylene glycol and polyethylene glycol according to the present invention manufactured by the method of water cooling, which is usually used for drum refrigerators, it is difficult to remove from the drum. Tannage refrigerator with continuous water circulation for lowering the temperature of the tape to approximately 17oC. However, the tape shells of capsules, cooled to a lower temperature, may have a poor ability to hermetic sealed in the encapsulation process, which can lead to performance degradation.

Therefore, in the method of manufacturing the tape does not contain glycerin plasticizer shells of capsules of the present invention instead used in the prototype method cooling method used air cooling, in which the tape shells of capsules is cooled to the optimum temperature by supplying air from the fan, allowing you to easily remove it from the drum of the refrigerator, and wherein the tape further incubated at the optimum temperature of approximately 21oWith to improve the ability hermetically sealed in the encapsulation process, which ensures high performance.

As indicated above, the products of the present invention can be fabricated using do not contain glycerin gelatin shell of the capsule and using the method of air cooling composition that does not contain ethanol, which is a volatile solvent with a low boiling point, and therefore it has a high, and increased bioavailability.

More specifically the present invention relates to the preparation on the basis of cyclosporine containing composition which includes

1) a cyclosporin as active ingredient,

2) a polyethylene glycol or propylene carbonate or a mixture thereof,

3) one combination or mixture of two or more selected connection(s) from the group comprising the ester of fatty acid and primary alcohol, a triglyceride of fatty acids with medium chain length (if necessary) and a monoglyceride of a fatty acid as lubricant and

4) surface-active substance, relevant products HLB (hydrophilic-lipophilic balance) ranging from 8 to 17, and, for example, contained within a gelatin shell containing as plasticizer polyethylene glycol or propylene glycol. Another object of the present invention is the preparation on the basis of cyclosporine, which contains a composition including

1) a cyclosporin as active ingredient and

2) propylene carbonate.

Another object of the present invention is specified composition that does not contain polyethylene glycol.

This composition, which composition according to the invention may n the improvement in quantities mentioned in the present description.

Cyclosporine used as pharmaceutically active substances in the composition of the present invention, is a cyclic peptide compound having the above-described valuable immunosuppressive and anti-inflammatory activity. Although as cyclosporine component of the present invention can also be used cyclosporine a, b, C, D, G, etc., the most preferred is cyclosporine And, because of its clinical efficacy and pharmacological properties are well known in this field.

As the second component of the composition of the present invention, which can act as a secondary surfactant can be applied propylene carbonate or ethylene glycol or mixtures thereof.

As negidrirovannogo substances can be used propylene carbonate, which has a high boiling point (approximately 242o(C) is non-volatile, has low hygroscopicity and permeability through the shell and in which it is soluble cyclosporine.

Alternatively, as hydrophilic substances can also use the gelatin shell of the capsule with a soft covering and in which it is soluble cyclosporine. Although the composition of the present invention can be applied to any polyethylene glycol, which may be liquefied, preferably should be used polyethylene glycol (PEG) with a molecular mass of from 200 to 600 (in particular PEG 200).

In the present invention can also be used a mixture of negidrirovannogo substance and a hydrophilic substance, as defined above. If as a component of the present invention using a mixture of polyethylene glycol and propylene carbonate, they can usually be combined in a mass ratio of 1: 0.1 to 5, preferably 1:0.1 to 3, most preferably 1:0.2 to 2.

In the present invention due to the use of polyethylene glycol and propylene carbonate are achieved certain advantages. So, for example, improves the storage stability of the composition containing cyclosporine, and therefore, the content of the components is maintained almost at a constant level. In addition, the use of propylene carbonate can even increase the solubility of cyclosporin as active ingredient and to inhibit the penetration of water from the shell gelatin capsules in the composition, thereby increasing the stability of the composition.

In the composition according to edocfile from 0.5 to 8 wt. parts and most preferably from 1 to 5 wt.parts in terms of 1 wt.part of cyclosporine.

The third component used in the previously prepared emulsion concentrate according to the present invention is the sizing. As lubricant of the present invention can be applied to a single connection or a mixture of two or more selected connection(s) from the group comprising the ester of fatty acid and primary alcohol, triglycerides of fatty acids with medium chain length (if present) and monoglycerides of fatty acids. Ester of fatty acid and primary alcohol, which can be used according to the present invention, may include an ester of a fatty acid with 8 to 20 carbon atoms and a primary alcohol with 2-3 carbon atoms, for example, isopropylmyristate, isopropyl, ethyllinoleate, etiloleat and so on, it is particularly preferred is an ester of linoleic acid and ethanol. In addition, as the triglyceride fatty acids with medium chain length (if present) can be applied triglyceride of saturated fatty acid having from 8 to 10 carbon atoms, most preferably be used as the triglyceride of saturated fatty the output can also be used as lubricant according to the present invention, includes a monoglyceride of a fatty acid having from 18 to 20 carbon atoms, in particular the monoglyceride of oleic acid.

In a pre-prepared emulsion concentrate according to the present invention, the lubricant can be applied in a ratio of from 1 to 10 wt. parts, preferably from 2 to 6 wt.parts 1 wt.part of cyclosporine.

Preferably as lubricant a monoglyceride of a fatty acid and fatty acid ester are present, for example, in a ratio of from 1:1 to 1:2, for example, from 1:1 to 1:1,2.

Optional is also present triglyceride Caprylic/capric acids, for example, in a ratio of from 1:0.1 to 1:0.2 to ethyllinoleate.

In the oil mixture used as lubricant of the present invention, the mass ratio in a mixture of a monoglyceride of a fatty acid/ester of fatty acid and primary alcohol/triglyceride fatty acids with medium chain length (if present) can typically be in the range 1: 0,1-5:0,1-10, preferably 1:0,1-3,0:0,1-3,0.

The fourth component used in the compositions of the present invention is a surfactant. Suitable for use according to the present invention p is Uchenie products HLB (hydrophilic-lipophilic balance) ranging from 8 to 17 and which have the ability to stably emulsify lipophilic part of the composition, including containing cyclosporine samelevel, and a hydrophilic part, including secondary surfactant in water to form a stable microemulsion. Examples of preferred surfactants but the present invention include polyoxyethylene products of hydrogenated vegetable oils, esters of polyoxyethylenesorbitan and fatty acids, etc., for example, NIKKOL HCO-50, NIKKOL HCO-40, NIKKOL HCO-60, TWEEN 20, TWEEN 21, WEEN 40, TWEEN 60, TWEEN 80, TWEEN 81, and so on, In particular, preferably the use of hydrogenated castor oil with a content of ethylenoxide links 50 moles, marketed under the trademark NIKKOL HCO-50, NIKKO Chemical Co., Ltd), and sorbitanoleat content ethylenoxide links to 20 moles, marketed under the trademark TWEEN 20 (firm ICI Chemicals) and having an acid number of approximately 48-56, a hydroxyl number of 45 to 55 and the pH value (5%) of 4,5-7,0.

Surfactant may include one or any of the foregoing surfactants, or preferably a combination of two or more surfactants selected from the above-mentioned surfactants. In the composition of the present invention stand the AI from 2 to 8 wt.parts 1 wt.part of cyclosporine.

In addition, if the composition of the present invention uses a mixture of two surfactants, for example, hydrogenated castor oil, containing 50 moles ethyleneoxide links, and sorbitanoleat containing 20 ethylenoxide links made mass ratio of hydrogenated castor oil containing 50 moles ethyleneoxide links, and sorbitanoleat containing 20 moles ethyleneoxide links, preferably is in the range of 1:0.1 to 5, more preferably in the range of 1:0.5 to 4.

In the composition of the present invention four component is preferably present in a weight ratio of cyclosporin/second component/lubricant/surfactant 1:0,1-10:1 -10:1 -10, more preferably 1:0,5-8:2-6:2-8.

In addition to this composition, as a further preferred compositions of the present invention may be noted the composition shown in the following examples.

For oral administration composition of the present invention, containing the above components, can be made in the form of capsules with soft coating. Because the drug is in the form of capsules, soft coated on nya, this drug is stable from a pharmaceutical point of view and can meet requirements for improved performance, including improved bioavailability.

However, it may be that this goal is difficult to achieve using conventional shell capsules, soft coated using conventional methods of producing capsules with soft coating. If the capsule with a soft coating is manufactured using a conventional shell, containing as plasticizer glycerin, made so capsule with a soft coating may have certain disadvantages, namely, the emulsion state of the previously prepared emulsion concentrate may be altered due to the penetration of the emulsion of glycerol and, as a consequence, a significant decrease in the solubility of cyclosporine, which can lead to the deposition of cyclosporine from the emulsion.

Therefore, according to the invention provides that, if the shell of a capsule made, using as a plasticizer mixture of polyethylene glycol and propylene glycol, but not glycerol, can be obtained in the preparation of capsules with a soft coating that has been applied any glycol, which may be liquefied, it is preferable to use a polyethylene glycol having a molecular weight of from 200 to 600.

In particular, it is preferable to use polyethylene glycol 200. Shell capsules, soft coated according to the present invention preferably use a mixture of polyethylene glycol and propylene glycol in a ratio of from 0.1 to 0.5. parts, more preferably from 0.1 to 0.4 wt.parts and most preferably from 0.2 to 0.3 wt.parts 1 wt.part of the gelatin used to manufacture shell capsules. In a mixture of polyethylene glycol and propylene glycol, used as a plasticizer, propylene glycol is preferably in the ratio from 1 to 10 wt.parts, more preferably in a ratio of from 3 to 8 wt.parts and most preferably in a ratio of from 3 to 6 wt.parts 1 wt.part of polyethylene glycol.

To improve the extraction of the tape for shells of capsules of the drum fridge in the method of manufacturing a tape gelatin shells of the capsules of the present invention use a method of air cooling method instead of water cooling. In this method, air cooling, because the tape shells of capsules not peregrevat approximately 21oWith the ability hermetically sealed in the encapsulation process is high, which ensures high performance, and, consequently, the effectiveness of the proposed method is quite high.

In the manufacture of capsules with a soft coating of the present invention is acceptable volumetric flow rate of air in the drum refrigerator for cooling the shell of the capsule is preferably from 5 to 15 m3/min, most preferably approximately 10 m3/min.

Because the second component of the present invention the propylene carbonate can be used individually or as its main component, in the manufacture containing cyclosporine drug in the form of capsules with a soft coating that remain stable over a long period of time, do not want to use a specific plasticizer for gelatin shell.

In such gelatinous membranes can be used without any limitation, one or more plasticizers selected from the group comprising glycerin, sorbitol, hexanetriol, propylene carbonate, hexandiol, sorbitane, simple ether tetrahydropyrrolo alcohol , the fact plasticizers that can be used according to the present invention is not limited to the above.

In the manufacture of capsules with soft coating containing composition of the present invention, the drug is in the form of capsules, if necessary, may additionally contain pharmaceutically acceptable additives commonly used in the manufacture of capsules with soft coating. Such additives include, for example, lecithin, viscosity regulator, flavouring (for example, peppermint oil, and so on), antioxidants (for example tocopherol, vitamin E and so on), a preservative (for example, paraben, and so on), dye, amino acids, etc.

The drug is in the form of capsules, soft coated according to the present invention can be produced by thoroughly mixing the secondary surfactant, lubricant and surfactant, dissolving under stirring this mixture of cyclosporine and careful heating to a temperature of approximately 60oAnd then fill in a machine for making capsules, soft coated using the method of air cooling cooked concentrate with the above-mentioned pharmaceutically acceptable additives, usually Mgr with soft coating, gelatin shell containing as plasticizer polyethylene glycol and propylene glycol.

Compositions and formulations of the present invention are suitable under such conditions and can be entered in the same way and in the same dose range that is known compositions containing cyclosporine, using if necessary a dose adjustment on the basis of standard experiments for assessing bioavailability in animals, for example dogs, or people, for example, as described below.

If the composition of any of the excipients or components not represented specifically in the present description, the list can be found in the literature, for example, at N.R. Fiedler in Lexikon der Hilfsstoffe, published by Edito Cantor, Aulendorf, Germany, 4th ed., 1996, Handbook of Pharmaceutical Excipients, American Pharmaceutical Association, Washington, and The Pharmaceutical Society, London, 2nd ed., 1994, as well as in the application to the Korean patent 94-29208 filed 9.11.94.

The present invention is illustrated in more detail by the following examples. However, it should be emphasized that these examples in no way limit the scope of the invention.

Examples 1-5 are shown in table.1A.

Example 6

The drug is in the form of capsules, soft coated, containing any visually observed the change of the characteristics and condition content as a result of penetration of glycerol.

6.1 (Control group)

The component - Mass ratio

gelatin - 20

purified water - 16

glycerin - 9

6.2. (The test group)

The component - Mass ratio

gelatin - 20

purified water - 16

propylene glycol - 4

polyethylene glycol 200 - 1

The results obtained are presented in table 1.

As follows from the results presented in table 1, the product in the form of capsules, manufactured using the composition 6.1 (control group), containing as plasticizer glycerol, has certain disadvantages, including the formation of a precipitate due to the penetration of glycerol, while the drug is in the form of capsules, manufactured using the composition 6.2 (test group), containing as plasticizer polyethylene glycol and propylene glycol, maintains a stable condition.

Example 7

The drug is in the form of capsules, soft coated, containing the composition of example 1 was produced using the compositions 6.2 (test group) for the shell of the capsules shown in the above example 6, using respectively the method of water cooling (water temperature approximately 12oC) and what you learn has been evaluated and compared the extraction of the tape shells of capsules of the drum fridge. The results obtained are presented in table 2.

As follows from the results presented in table 2, the drug in the form of capsules, soft coated, fabricated using the method of air cooling according to the present invention has significantly better extraction of drum fridge compared with that produced using the method of water cooling. In particular, it is generally considered that if the angle required to eject the tape gelatin shells of the drum fridge is approximately 70oor more, the extraction is bad, and if the angle required to eject the tape gelatin shells of the drum of the refrigerator is less than approximately 70othe extraction is good. The drug is in the form of capsules with soft coating obtained by the method of water cooling, the poor were extracted from the drum of the refrigerator, even if the composition was removed at an angle 100oor more.

In contrast, the drug in the form of capsules, soft coated, fabricated using the method of air cooling according to the present invention, can be easily rocheste hermetic sealing and high performance.

Example 8

The bioavailability of the test formulation, manufactured by encapsulation compositions of example 1 in the gelatinous shell, the composition of which is specified in section 6.2, compared with the biological availability of marketed product SANDIMMUN Capsule containing ethanol, which was used as a control drug to assess the impact of the drug on the basis of cyclosporine in the present invention the bioavailability of cyclosporine and its difference to individual patients.

In this experiment as the test drug and the control drug was administered at the rate of 300 mg of cyclosporine per 1 kg of body weight of the rabbit.

Rabbits were kept for 4 days or more in the same conditions in wire cages on the same stern, composed of solid nutritional composition for rabbits. When conducting experiments on oral drug rabbits were fixed for 48 h in a steel cage, restricting movement, and during this time the rabbits had free access to water.

The nasogastric tube with a diameter of 5 mm, the surface of which has been pre-lubricated with vaseline to reduce friction, was introduced into the esophagus to the depth of the Lee in the syringe, attached to the nasogastric tube. Ear veins of rabbits has expanded with the use of xylene and then processed using heparin disposable syringe taking samples of blood from the ear vein of each rabbit prior experience and through 0,5, 1, 1,5, 2, 3, 4, 6, 10 24 hours To 1 ml of the thus obtained blood was added 0.5 ml of aqueous saturated solution of sodium chloride and 2 ml of a simple ester, and then the mixture was shaken for 5 min and centrifuged for 10 min at 5000 rpm to separate the supernatant fluid (ether layer). Selected 1 ml of supernatant and subjected to treatment using activated silica type sep-pak(firm Waters). The processed product sep-pakwashed with 5 ml n-hexane and suirable 2 ml of methanol. The eluate was evaporated to dryness in a nitrogen atmosphere under reduced pressure. The residue was analyzed using GHUR (liquid chromatography high resolution) [conditions GHUR: column-BondpakC18(firm Waters), mobile phase CH2CN:Meon:H2O in the ratio of 55:15:30, detection at 210 nm, flow rate 1.0 ml/min, column temperature 70oWith a sensitivity of 0.01 units of absorbance, the amount of injection of 100 ál].

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As follows from table 3, the test drug has a large value ACC-score andmaxthat exceed about 4 times and about 7 times those for control of the drug. Therefore, we can assume that the bioavailability of the test drug significantly higher biological availability of the control drug. In addition, the test drug of the present invention results in the reduction of differences in the value of CPD is approximately 2 times or more and the value ofmaxapproximately 1.5 times between the respective experimental animals (COST, %) compared with the control drug.

Therefore, we can assume that the introduction of the drug in the form of capsules, soft coated according to the present invention through the mouth it has approximately 4 times greater bioavailability of cyclosporine in accordance with known marketed product SANDIMMUNCapsule containing ethanol, it also reduces the difference between the bioavailability of cyclosporine for different individuals and at the same time remains stable without any changes for a long period of storage is substantial the best characteristics among known in the field of preparations containing cyclosporine capsules with a soft covering.

Example 9

Made of soft gels with the composition presented in table.3A.

Examples 10-14 (see tab. 3b).

Examples 15-18 (see tab. 3b).

Example 19

The bioavailability of the test product, made on the basis of the composition of example 10 was compared with the biological availability of marketed product containing ethanol, namely, SANDIUN Capsule, which was used as a control drug to assess the impact of containing cyclosporin drug of the present invention on the bioavailability of cyclosporine and its difference to individuals.

The Protocol of the experiment was the same as described in example 8.

The results obtained for the test drug and the control drug, is given in table 4.

As can be seen from table 4, the test drug has a large value ACC-score andmaxthat exceed about 4 times and about 7 times or more than those for control of the drug. Therefore, we can assume that the bioavailability of the test drug significantly higher biological availability control prepac about 2 times or more and the value ofmaxapproximately 1.5 times between the respective experimental animals (COST, %) compared with the control drug.

Therefore, we can assume that with the introduction of oral medication in the form of capsules, soft coated according to the present invention it has approximately 4 times greater bioavailability of cyclosporine compared with the known marketed product SANDIMMUNCapsule containing ethanol, and gives the decrease in the differences between the bioavailability of cyclosporine for different individuals, and at the same time remains stable without any changes for a long period of storage. Thus, it is obvious that the drug in the form of capsules, soft coated according to the present invention has significantly better performance among known in the field of preparations containing cyclosporine capsules with soft coating.

1. Preparation containing cyclosporin as active ingredient, propylene carbonate, at least one compound selected from the group consisting of ester of fatty acid and primary alcohol, a triglyceride of fatty acids with medium chain length and the fatty monoglyceride it is about balance from 8 to 17.

2. The drug under item 1, in which the triglyceride fatty acids with medium chain length is a triglyceride Caprylic/capric acid.

3. The drug PCP. 1 or 2, in which the monoglyceride of a fatty acid is a monoglyceride of oleic acid.

4. The drug according to any one of paragraphs. 1-3, in which the surfactant is polyoxyethylene product of hydrogenated vegetable oil or ether of polyoxyethylenesorbitan and fatty acids.

5. The drug under item 1 made in the form of capsules with a soft covering and containing as a surfactant mixture of surfactants comprising hydrogenated castor oil containing 50 moles ethyleneoxide links, and sorbitanoleat containing 20 moles ethyleneoxide links, in a mass ratio of 1: 0.1 to 5.

6. The drug according to any one of paragraphs. 1-5, made in the form of capsules, soft coated, containing cyclosporine, propylene carbonate, lubricant and surfactant mass ratio, respectively 1: 0,1-10: 1-10: 1-10.

7. The drug under item 6, in which the specified mass ratio is 1: 0,5-8: 2-6: 2-8.

10. The drug under item 9 that does not contain as an additional component of the glycol.

 

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