Preparation containing cyclosporin (options), and method thereof

 

(57) Abstract:

The invention can be used in medicine to suppress innate immunological responses of a living organism, the cause of which is the transplantation of tissues and organs. The product contains: 1) a cyclosporin as active ingredient, 2) a polyethylene glycol or propylene carbonate, or a mixture thereof, 3) a mixture of esterified compounds of fatty acid and primary alcohol with a monoglyceride of a fatty acid as lubricant and 4) surfactant, the HLB value of which is equal to 8-17. Variant product contains a composition that includes a cyclosporin as active ingredient, propylene carbonate and a mixture of triglycerides of fatty acids with medium chain length and monoglyceride fatty acids. The preparation can be enclosed in a gelatin shell and be a capsule. The drug is produced by homogeneous mixing of the components, 2), 3) and 4), dissolving them under stirring cyclosporine and the mixture heated to 60oC. Preparation can be enclosed in gelatin shell in a machine for making capsules with soft coating. The invention allows to reduce the inconvenience associated with the adaptation of the patient to PR the tx2">

The present invention relates to the preparation, for example, in the form of capsules, soft coated, containing as the active ingredient, ciclosporin. In particular, the invention relates to the preparation in the form of capsules, soft coated, containing a stable composition based on cyclosporine, an encapsulated with gelatin coating, which includes a specific plasticizer, and method of its manufacture.

Cyclosporine is a known macromolecular (molecular weight 1202,64) cyclic peptide compound consisting of 11 amino acids and has a wide range of useful pharmacological properties, in particular immunosuppressive activity and anti-inflammatory action. Consequently, cyclosporine is used to suppress innate immunological responses of a living organism, the cause of which is the transplantation of tissues and organs, such as heart transplantation, lung, liver, kidney, pancreas, bone marrow, skin and cornea, and primarily transplantation alien tissues and organs. In addition, cyclosporine is used in the treatment of hematological disorders such as anemia, various autoimmune-related disease the disease, such as arthritis, rheumatoid disorders, etc. Cyclosporine is used in the treatment of diseases caused by protozoa such as malaria, schistosomiasis, and so on, and, in addition, he currently is also used in chemotherapy.

Cyclosporine is vysokopitatelny and a hydrophobic compound. Therefore, cyclosporine poorly soluble in water and at the same time it is soluble in organic solvents, such as methanol, ethanol, acetone, simple, ether, chloroform, etc., Because, as stated above, cyclosporine has a low solubility in water, in the case when cyclosporine is administered orally, its bioavailability is very low, and it can largely depend on the characteristics of each individual patient. As a result, it is difficult to maintain effective therapeutic against concentration. Moreover, cyclosporine can have a pronounced adverse 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. Therefore, we carried out extensive numerous studies aimed at razbaby to provide an acceptable standard dose and appropriate bioavailability.

Known preparations suitable for oral administration of poorly water-soluble cyclosporine, usually produced in the form of pre-prepared emulsion concentrate.

One of the most common methods of using such composition is described in U.S. patent 4388307, issued June 14, 1983, this patent describes a liquid composition on the basis of cyclosporine with ethanol. In accordance with the method according to this U.S. patent, to obtain a liquid composition cyclosporine combined with a carrier consisting of ethanol as a secondary surfactant, olive oil as vegetable oils and products of the transesterification of triglycerides of natural vegetable oils and polyalkyleneglycol as surface-active substances.

However, the resulting liquid composition is injected into the aqueous solution, which is very difficult to adapt to its introduction and establishment 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, the liquid composition in the form of pre-prepared emulsion concentrate NR is Sandimmune (registered trademark). In this case, the composition containing cyclosporine capsules, soft coated include ethanol, due to the requirements related to the solubility of cyclosporine. However, since ethanol due to its volatility can penetrate the gelatin shell of the capsule even at normal temperature, to prevent evaporation of ethanol from the preparations in the form of capsules with a soft covering for storage and sale of drugs in the form of capsules, soft coated can be enclosed in a shell made of special packaging material, for example, in blister packaging aluminum-aluminum.

Recently it has become possible to create a drug on the basis of cyclosporine, which is stable throughout the intended shelf life, and further retains its biological availability, which does not depend on the individual characteristics of individual patients, so the biological effect of cyclosporine can be maintained at the same level. One of the drugs developed for this purpose, is described in published lined Korean patent 93-113. This drug is sold under the trademark Sandimmun Neoral. However, since this drug is also used ethanol * ethanol and characterized for known drugs, contains ethanol.

Therefore, when creating the present invention examined a large number of combinations of various surfactants, sizing, secondary surfactants, etc. with the purpose to find the song on the basis of cyclosporine, which is stable from the point of view of their pharmacokinetic characteristics has a higher bioavailability and the level of content in the blood to a lesser extent depends on the individual characteristics of individual patients in comparison with the known compounds based on cyclosporine. In the result it was found that a composition based on cyclosporine, consisting of the following components that can satisfy the above requirements, which was the object of the present invention.

Therefore, the present invention was based on the task to create a suitable for introduction into capsules with a soft coating composition containing cyclosporin as an active ingredient, a hydrophilic substance is polyethylene glycol or nigerienne substance propylene carbonate or a mixture thereof, sizing, as defined below, and surface-active veytia, containing composition, which comprises cyclosporin as active ingredient, a hydrophilic substance is polyethylene glycol or nigerienne substance propylene carbonate or a mixture, the mixture is esterified compounds of fatty acid and primary alcohol, triglyceride fatty acids with medium chain length (if necessary) and monoglyceride fatty acids as lubricant and surfactant, the HLB value (hydrophilic-lipophilic balance) of which is from 8 to 17.

The present invention is to develop a method of manufacture of the above product in the form of capsules, soft gelatin coating as defined above.

Although this invention is described capsules soft gelatin coating, it is obvious that the invention includes the composition itself, which can be used, for example, in the form of a solution for drinking, such as Sandimmun Neoral, or other conventional dosage forms.

According to the present invention is proposed containing cyclosporine capsule, which has a high storage stability, i.e., it is characterized by a slight change in composition over time, and este active ingredient, the hydrophilic substance is polyethylene glycol or nigerienne substance propylene carbonate or a mixture thereof as a second component, the sizing, as defined below, and surfactant.

For the manufacture of such a product in the form of capsules with soft coating 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 glycerin, a substance in the capsule with a soft coating has certain drawbacks related to the fact that the stability 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 and, as a consequence, the deposition of cyclosporine from the emulsion.

Therefore, in the present invention to shell capsules, soft coated preferably choose the gelatinous shell, in which the plasticizer is a mixture of polypropylenglycol and polyethylene glycol, instead of glycerin that helps to solve the problem associated with the penetration of the gli is openinglabel and polyethylene glycol, manufactured using the method of water cooling, which is usually used for drum refrigerators, it is difficult to remove from the drum. This feature extracted tape shells of capsules from the drum of the refrigerator can be improved by cooling drum fridge with continuous circulation of cooling water to reduce the temperature of the tape to approximately 17oC. However, the tape shells of capsules, cooled to a lower temperature, may have a reduced ability to hermetic sealed in the encapsulation process, which can lead to performance degradation.

Thus, in the method of manufacturing a tape gelatinous membranes not containing as plasticizer glycerin, instead of the previously known method of water cooling in accordance with the present invention uses a method of air cooling, whereby the tape shells of capsules can be cooled to an optimum temperature by means of air flow from the fan and could therefore be easily removed from the drum fridge, followed by keeping it at the optimum temperature of approximately 21o the th performance.

As indicated above, the products of the present invention can be manufactured using does not contain glycerin gelatin shell of the capsule and using the method of air cooling composition that does not contain ethanol, which is a solvent with a low boiling point, and therefore, has high storage stability, i.e., the composition varies little over time and is characterized by high biological availability.

In particular, according to the invention is proposed based drug cyclosporine containing composition, which includes

1) a cyclosporin as active ingredient,

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

3) a mixture of esterified compounds of fatty acid and primary alcohol and monoglyceride fatty acid and optionally a triglyceride of fatty acids with medium chain length as lubricant and

4) surfactant, the HLB value (hydrophilic-lipophilic balance) of which is from 8 to 17, and which, for example, enclosed in a gelatin shell containing as plasticizer polyethylene glycol and propylene glycol. Further, according to izobreten as the active ingredient and

2) propylene carbonate.

This composition, which is also a composition according to the invention can optionally further comprise any other component presented in the present description, in the amounts, specified in the present description.

Cyclosporine, which is used as a pharmaceutically active ingredient proposed composition, is a cyclic peptide compounds having immunosuppressive activity and anti-inflammatory action, as described above. Although as cyclosporine component according to the present invention can be applied cyclosporine a, b, C, D, G, etc., cyclosporine a is the most preferred because of its clinical efficacy and pharmacological properties, well known in this field.

As a hydrophilic substance, which is the second component in the proposed composition, it is possible to use polyethylene, which may function as a secondary surfactant has a high boiling point, is non-volatile, does not penetrate through the gelatinous shell capsules, soft coated, and in which well restorany may be liquefied, it is preferable to use polyethylene glycol (PEG) having a molecular weight of from 200 to 600, in particular PEG 200.

Alternatively, as negidrirovannogo component can also be applied propylene carbonate (tKipapproximately 242oC). According to the invention can also be applied mixture negidrirovannogo substance and a hydrophilic substance, as defined above. When 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.

The use of polyethylene glycol and propylene carbonate according to the present invention provides certain advantages. So, for example, improves the storage stability of the composition containing cyclosporine, and therefore, practically at a constant level supported by the content of its components. In addition, the use of propylene carbonate can even increase the solubility of an active ingredient of cyclosporine and to inhibit the penetration of water from the gelatin shell of the capsule in the composition, making the composition more stabilnyi from 0.1 to 10 mass parts, more preferably from 0.5 to 8 mass parts, and most preferably from 1 to 5 mass parts per 1 mass part of cyclosporine.

The third component used in the previously prepared emulsion concentrate according to the present invention is the sizing. As lubricant according to the invention can be applied to the mixture of esterified compounds of fatty acid and primary alcohol, triglyceride (when they are present) fatty acids with medium chain length and monoglycerides of fatty acids. Esterified compound of fatty acid and primary alcohol, which can be used according to the invention, may be an esterified compound of fatty acid having 8-20 carbon atoms, and primary alcohol having 2-3 carbon atoms, for example, isopropylmyristate, isopropyl, ethyllinoleate, etiloleat and so on, and particularly preferred is esterified compound of linoleic acid and ethanol. In addition, as the triglyceride (when present) fatty acids with medium chain length can be used triglyceride of saturated fatty acids having 8-10 carbon atoms, and most preferably is prelovac/capric acid. The monoglyceride of a fatty acid, which can also be used as lubricant of 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 microemulsion concentrate according to the present invention, the lubricant can be applied in a ratio of from 1 to 10 mass parts, preferably from 2 to 6 mass parts per 1 mass part of cyclosporine.

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

Optional may also be present triglyceride Caprylic/capric acids, for example, in relation to ethyllinoleate from 1:0.1 to 1:0,2.

In the mixture of oils used as lubricant of the present invention, the mass ratio of the monoglyceride of fatty acid esterified compound of fatty acid and primary alcohol/triglyceride (when present) fatty acids with medium chain length can typically be in the range from 1:0.1 to 5:0.1 to 10, preferably from 1:0.1 to 3,0:0,1--3,0.

Fourth compleme for use in the present invention, surfactants are any pharmaceutically acceptable surfactants, the HLB value (hydrophilic-lipophilic balance) ranging from 8 to 17 and which can stably emulsify lipophilic part of the composition, including sizing. containing cyclosporine, and a hydrophilic part, including secondary surfactant in water, which leads to the formation of stable micro-emulsions. Examples of preferred surfactants of the present invention include polyoxyethylene products hydrogenated vegetable oils, polyoxyethylene esters of anotherservice and fatty acids, etc., for example, NIKKOL HCO-50, NIKKOL HCO-40, NIKKOL HCO-60, TWEEN 20. TWEEN 21, TWEEN 40, TWEEN 60, TWEEN 80, TWEEN 81, etc., In particular, can preferably be used polyoxyethylene gidrirovannoe castor oil containing 50 moles ethyleneoxide links that sold under the trade name NIKKOL HCO-50, NIKKO Chemical Co., Ltd.) and polyoxyethylene sorbitanoleat containing 20 moles ethyleneoxide links that sold under the trade name TWEEN 20 (firm ICI Chemicals), having an acid number below 1, a saponification number of approximately 48-56, a hydroxyl number of approximately 45-55 and pH (5% solution) 4,5-7,0.

Surface-or preferably a combination of two or more surfactants, selected from the above-mentioned surfactants. In the composition according to the present invention, surfactants can be used in a ratio of from 1 to 10 mass parts, preferably in the ratio from 2 to 8 mass parts per 1 mass part of cyclosporine.

In addition, when the composition of the present invention using a mixture of two surfactants, i.e. polyoxyethylene hydrogenated castor oil containing 50 moles ethyleneoxide links, and polyoxyethylene of sorbitanoleat containing 20 moles ethyleneoxide links made mass ratio polyoxyethylene hydrogenated castor oil containing 50 moles ethyleneoxide links, and polyoxyethylene of sorbitanoleat containing 20 moles ethyleneoxide units, is preferably 1:0.1 to 5, more preferably 1: 0.5 to 4.

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

In addition to this composition as extra the following examples.

For oral administration composition of the present invention, containing the above components can be manufactured in the form of capsules with soft coating. Because the drug is in the form of capsules, soft coated in accordance with the present invention is not used ethanol as a volatile solvent with a low boiling point, this drug is a pharmaceutically stable and can meet the necessary 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 a conventional method of manufacturing capsules with soft coating. When they produce a capsule, soft coated using conventional capsule shell containing as plasticizer glycerin produced thereby capsule with a soft coating may have a number of disadvantages, namely that the stability of the previously prepared emulsion concentrate may be altered due to the penetration of glycerol into the emulsion and, as a consequence, a significant decrease in the solubility of cyclosporine, which can lead to outabout, using as a plasticizer mixture of polyethylene glycol and propylene glycol, but not glycerol, the resulting product in the form of capsules with a soft coating is stable over a long period of time, which in turn is yet another object of the present invention. Although the plasticizer may be any polyethylene 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 in accordance with the present invention, a mixture of polyethylene glycol and propylene glycol, preferably in a ratio of from 0.1 to 0.5 mass parts, more preferably from 0.1 to 0.4 mass parts, and most preferably from 0.2 to 0.3 mass parts of one mass part of the gelatin used for negativley shell capsules. Used as a plasticizer mixture of polyethylene glycol and propylene glycol latter of which is preferably in the ratio from 1 to 10 mass parts, more preferably 3 to 8 mass parts, and most preferably from 3 to 6 mass parts per od is their cover of the drum fridge in the method of manufacturing such a tape shell gelatin capsules of the present invention use a method of air cooling method instead of water cooling. Using this method of air cooling, because the tape shells of capsules not overheat and easily removed from the drum fridge, which supported the optimum temperature is approximately 21oWith the ability hermetically sealed in the encapsulation process is quite high, which ensures high productivity and, consequently, the effective implementation of the method.

In the manufacture of capsules, soft coated in accordance with the present invention acceptable volumetric air flow drum in the refrigerator to cool the shells of the capsules is preferably from 5 to 15 m3/min, most preferably approximately 10 m /min.

In the manufacture of compositions according to the present invention enclosed in a capsule with a soft coating, the drug in the form of a capsule may further comprise, if necessary, pharmaceutically acceptable additives, which are usually used for such preparations in the form of capsules with soft coating. Such additives include, for example, lecithin, viscosity regulator, the odorant (e.g., peppermint oil, and so on), antioxidants (for example tocopherol, vitamin E and so on), preservative (nepristojnu invention can be produced by homogeneous mixing of the secondary surfactant, sizing and surfactants, dissolving under stirring them cyclosporine and careful heating to a temperature of approximately 60oWith the integration of the obtained concentrate with the above-mentioned pharmaceutically acceptable additives commonly used in preparations in the form of capsules, soft coated or without them in the gelatinous shell, containing as plasticizer polyethylene glycol and propylene glycol, in a machine for making capsules, soft coated using the method of air cooling.

Compositions and preparations according to the present invention are suitable under such conditions and can be applied in the same way and in the same dose range that is known compositions on the basis of cyclosporine using, if necessary, dose adjustment based on standard experiments to study the biological availability of animals, such as dogs or people, in particular, according to the present description.

Although the compositions of any of the excipients or components not represented specifically in the present description, they are known from the literature, see, for example, H. P. Fiedler, Lexikon der Hilfsstoffe, Edito Cantor Verlag, Aulendorf, Germany, 4th edition, 1996, Handbook of Pharmaceutical Excip is this 9.11.94.

The present invention is illustrated in more detail by the following examples. However, it is obvious that the invention is not limited to these examples.

Example 1

Component Content (mg/capsule)

Cyclosporine - 25

Polyethylene glycol 200 - 45

Propylene carbonate - 25

Polyoxyethylene gidrirovannoe castor oil containing 50 moles ethyleneoxide links - 35

Polyoxyethylene sorbitanoleat containing 20 moles ethyleneoxide links - 85

The ethyllinoleate - 40

Triglyceride Caprylic/capric acid - 5

The monoglyceride of oleic acid - 35

Only 295 mg

Example 2

Component Content (mg/capsule)

Cyclosporine - 25

Polyethylene glycol 200 - 70

Polyoxyethylene gidrirovannoe castor oil containing 50 moles ethyleneoxide links - 35

Polyoxyethylene sorbitanoleat containing 20 moles ethyleneoxide links - 85

The ethyllinoleate - 40

Triglyceride Caprylic/capric acid - 5

The monoglyceride of oleic acid - 35

Only 295 mg

Example 3

Component Content (mg/capsule)

Cyclosporine - 25

Polyethylene glycol 200 - 100

Propylene carbonate - 5BR>
Polyoxyethylene sorbitanoleat containing 20 moles ethyleneoxide links - 85

The ethyllinoleate - 40

Triglyceride Caprylic/capric acid - 5

The monoglyceride of oleic acid - 35

Only 375 mg

Example 4

Component Content (mg/capsule)

Cyclosporine - 25

Polyethylene glycol 200 - 45

Propylene carbonate - 25

Polyoxyethylene gidrirovannoe castor oil containing 50 moles ethyleneoxide links - 50

Polyoxyethylene sorbitanoleat containing 20 moles ethyleneoxide links - 100

The ethyllinoleate - 40

Triglyceride Caprylic/capric acid - 5

The monoglyceride of oleic acid - 35

Just - 325 mg

Example 5

Component Content (mg/capsule)

Cyclosporine - 25

Polyethylene glycol 200 - 45

Propylene carbonate - 25

Polyoxyethylene gidrirovannoe castor oil containing 50 moles ethyleneoxide links - 35

Polyoxyethylene sorbitanoleat containing 20 moles ethyleneoxide links - 85

The ethyllinoleate - 80

Triglyceride Caprylic/capric acid - 10

The monoglyceride of oleic acid - 70

Only 375 mg

Example 6

The drug in the composition for the shell of the capsule, and then visually observed for changes in properties and States 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 (Experimental 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 can be seen from the results shown in table. 1, the drug is in the form of capsules, manufactured using the composition 6.1 (control group), containing as plasticizer glycerol, has some disadvantages, including the sediment as a result of penetration of glycerol, while the drug is in the form of capsules, manufactured using the composition 6.2 (experimental 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 obtained using the composition for shell capsules, as specified above in section 6.2 (experimental group) of example 6, using with the statement (volumetric air flow rate of approximately 10 m3/min).

Each case was evaluated and compared the extraction of the tape shells of capsules of the drum fridge. The results obtained are presented in table. 2.

As can be seen from the results shown in table. 2, the drug in the form of capsules with soft coating, obtained by the method of air cooling in accordance with the present invention has significantly better extraction of drum fridge compared with those obtained 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, approximately 70oor higher, then the extraction is bad, and if the angle required to eject the tape shells of the drum fridge, less than approximately 70othe extraction is good. The drug is in the form of capsules, soft coated, obtained using the method of water cooling, the poor were extracted from the drum of the refrigerator even when the tape was removed at an angle 100oor more.

In contrast, in the preparation of the kapsa what Subramaniam, can be easily removed from the drum fridge angle of 50oand smaller, which allows to provide good strength hermetic sealing and high performance.

Example 8

The bioavailability of the drug obtained by encapsulation of the composition of example 1 in the gelatinous shell, having specified in section 6.2 of example 6 (experimental group) composition, compared with the biological availability of commercially available containing ethanol product Sandimmun Capsule, 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 to change this parameter in different patients.

In this experiment, as an experienced 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. For experiments on oral drug rabbits were fixed for 48 hours in limiting the movement of the cage is made of SIC with a diameter of 5 mm, the surface which has been pre-lubricated with vaseline to reduce friction, was injected at a depth of 30 cm through the esophagus. Each of the experimental drug and the control drug was emulsiable with 50 ml of water and then introduced into a syringe attached to notogastral probe. The ear vein of the rabbit has expanded with the help of xylene and then took blood samples from each vein of the rabbit to experience and through 0,5, 1, 1,5, 2, 3, 4, 6, 10 and 24 hours using a disposable syringe treated with heparin. 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 minutes and centrifuged at 5000 rpm for 10 minutes to separate supernatant (ether layer). Selected 1 ml of supernatant and subjected to treatment using activated silica on sep-pak(firm Waters). Processed sep-pak was washed in 5 ml of 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 type-BondapakC18(firm Waters), mobile phase CH3CN:MeOH:H2O in the ratio 55 of 0.01 Aufs., the amount of injection of 100 ál].

The results obtained using the experimental drug and the control drug, is given in table. 3.

As you can see from the table that the experimental drug is found to increase the value of CPD andmaxthat about 4 times or more and about 7 times or more greater than those for control of the drug. Thus, we can conclude that the biological availability of the experimental drug is significantly higher than that of the control drug. In addition, an experienced drug of the present invention is characterized by the ability to reduce the difference between the respective indicators (CV%) for experimental animals. For example, the difference values of CPD is reduced about 2 times or more, and the difference values WITHmaxdecreases approximately 1.5 times compared to the control drug.

Consequently, the use of the drug in the form of capsules, soft coated in accordance with the present invention, which is administered by oral, bioavailability of cyclosporine increased approximately 4-fold compared with the known product containing ethanol, SANDIMMUMtime 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 in accordance with the present invention has a significant advantage among known in the field of drugs on the basis of cyclosporine in the form of capsules with a soft covering.

Example 9

Make preparations in the form of capsules, soft gel coatings, which contain the components shown in table. 4.

1. Preparation on the basis of cyclosporine containing composition that includes 1) a cyclosporin as active ingredient, 2) a polyethylene glycol or propylene carbonate, or a mixture thereof, 3) a mixture of esterified compounds of fatty acid and primary alcohol with a monoglyceride of a fatty acid as lubricant, and (4) surface-active substance is hydrophilic-lipophilic balance (HLB) which ranges from 8 to 17.

2. The drug under item 1, which contains cyclosporine a and is enclosed in a gelatin shell containing as plasticizer polyethylene glycol and propylene glycol.

3. Preparation on the basis of cyclosporine under item 1 or 2, where the polyethylene glycol is a polyethylene glycol having a molecular weight of from 200 to 600.

4. The drug on the basis of the percent weight of 200.

5. Preparation on the basis of cyclosporine on PP. 1, 2, 3 or 4, wherein component 2) is a mixture of polyethylene glycol and propylene carbonate in a ratio of 1: 0.1 to 5, respectively.

6. Preparation on the basis of cyclosporine on p. 5, where component 2) is a mixture of polyethylene glycol and propylene carbonate in a ratio of 1: 0.2 to 2, respectively.

7. Preparation on the basis of cyclosporine according to any one of the preceding paragraphs, where the esterified compound of fatty acid and primary alcohol composition of the sizing is a ethyllinoleate.

8. The drug according to any one of the preceding paragraphs, in which the lubricant additionally contains triglyceride fatty acids with medium chain length.

9. The drug under item 8, in which the triglyceride fatty acid is a triglyceride Caprylic/capric acid.

10. Preparation on the basis of cyclosporine according to any one of the preceding paragraphs, where the monoglyceride of a fatty acid is a monoglyceride of oleic acid.

11. Preparation on the basis of cyclosporine according to any one of the preceding paragraphs, where the sizing composition mass ratio monoglyceride fatty acids and a complex ester of fatty acid and particination surfactant is polyoxyethylene product hydrogenated vegetable oil or polyoxyethylene ether anhydromannitol and fatty acids, when this drug is made in the form of capsules, soft gelatin coating.

13. The drug under item 12 in which the surfactant is a mixture consisting of polyoxyethylene hydrogenated castor oil containing 50 moles ethyleneoxide links, and polyoxyethylene of sorbitanoleat containing 20 moles ethyleneoxide units, at a ratio of 1: 0.1 to 5, when this drug is made in the form of capsules, soft gelatin coating.

14. The drug according to any one of the preceding paragraphs, in which the mass ratio of the components 1): 2): 3): 4) equal respectively 1: 0,1-10: 1-10: 1-10, when this drug is made in the form of capsules, soft gelatin coating.

15. The drug under item 14, in which the mass ratio of the components 1): 2): 3): 4) well 1: 0,5-8: 2-6: 2-8.

16. Preparation on the basis of cyclosporine according to any one of the preceding paragraphs, where the plasticizer is a mixture of polyethylene glycol and propylene glycol in a ratio of from 0.1 to 0.5. hours per wt. including gelatin.

17. Preparation on the basis of cyclosporine according to any one of the preceding paragraphs, where the plasticizer is a mixture of propylene glycol with ethylene glycol in a ratio of 1-10 wt. including Purina according to any one of paragraphs. 1-16, which includes a homogeneous mixture of polyethylene glycol, or propylenecarbonate, or mixtures thereof, lubricant and surfactant, dissolving them under stirring cyclosporine and careful heating to a temperature of approximately 60oWith and, if necessary, encapsulation concentrate in a gelatin shell containing as plasticizer polyethylene glycol and propylene glycol, in a machine for making capsules with soft coating with subsequent cooling capsules made with soft coating drum in the refrigerator using the method of air cooling.

19. The method according to p. 18, where the cooling method air cooling is carried out at a volumetric flow of air from 5 to 15 m3/min.

20. Preparation on the basis of cyclosporine containing composition, which includes: 1) a cyclosporin as active ingredient, 2) propylene carbonate, and optionally contains 3) a mixture of triglycerides of fatty acids with medium chain length and monoglyceride fatty acids.

21. The drug under item 20, optionally containing polyethylene glycol and a surfactant, is hydrophilic-lipophilic balance (HLB) of coordinare fatty acid and primary alcohol with a monoglyceride of a fatty acid as lubricant, when this drug is made in the form of capsules, soft gelatin coating.

23. The drug under item 20, further containing a mixture of triglycerides of fatty acids with medium chain length and monoglyceride fatty acid and surfactant, is hydrophilic-lipophilic balance (HLB) which ranges from 8 to 17, the drug is made in the form of capsules, soft gelatin coating.

Priority points:

19.06.1996 on PP. 1-18;

19.06.1997 on PP. 19-22;

14.03.1997 on p. 23.

 

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The invention relates to the field of medicine and relates to a drug for treatment of allergic diseases

The invention relates to pharmacology and medicine, in particular to the preparation of solid dosage forms of the drug rapamycin, which includes a core and a sugar coating

The invention relates to purine derivative of L-nucleoside of the formula (I), where R1, R2', R3' and R4- N; R2, R3and R5- HE; Z1- N; Z2selected from N and CH; Z3- NR-, -C(R)2, -S-, where R, same or different, selected from H, Br, NH2, alkyl and alkenyl; Z4selected from C=O, -NR-, -C(R)2- where R, same or different, selected from H and Br; Z5Is N; X is selected from H, HE, SH, -SNH2, -S(O)NH2, -S(O)2NH2Y from H and NH2; W is O, and Y represents NH2then Z3is not a-S-

The invention relates to veterinary science and medicine, in particular to methods for increasing the resistance of the organism of animals and humans through the use of prophylactic drug of natural origin

The invention relates to a method for cyclosporine And high purity by purification of the crude product containing cyclosporiasis complex by multi-step chromatography on silica gel at high load columns from 10 to 52%, using as eluent a mixture of toluene with acetone in an amount of from 10 to 30 vol.% or toluene with ethyl acetate in an amount of from 10 to 35 vol.%, cyclosporine And high purity with content cyclosporine L, U and D less than 0.05% and the content of cyclosporine and < 0,02% vol., industrial method of purification of cyclosporin a from a crude product containing complex cyclosporiasis

The invention relates to new derivatives of benzimidazole of formula 1, where R1represents hydrogen or hydrocarbon group with a short chain, R2- CH2HE, COOH, СООR34,4-dimethyl-2-oxazoline

The invention relates to the field of medicine and for the application of muteena interleukin-6 (IL-6) of a person to prevent pathological conditions caused by excessive production of IL-6
The invention relates to medicine, specifically to pharmaceutical compositions comprising as active ingredient an effective amount of lincomycin hydrochloride and targeted supplements, which are used starch and powdered sugar
The invention relates to medicine and medical industry and relates to a pharmaceutical composition having analgesic, anti-inflammatory, antipyretic, antispasmodic effect
The invention relates to medicine, specifically to a pharmaceutical composition for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, acute gout, back pain, neuralgia, myalgia, traumatic inflammation of soft tissues and musculoskeletal system, acute infectious-inflammatory diseases of the upper respiratory tract, dysmenorrhea
The invention relates to medicine, specifically to medicines, analgesic action

The invention relates to compositions intended for parenteral or oral administration

The invention relates to the field of pharmaceutical industry
The invention relates to medicine and concerns capsules (tablets) with radon
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