Nateglynide-containing preparation

FIELD: medicine, endocrinology, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to nateglynide-containing preparation used in treatment of diabetes mellitus that comprises nateglynide as an active component and a carrier wherein nateglynide in amorphous form and indicated carrier represents hydrophilic material. Amorphous property of crystalline nateglynide is provided by the following methods: 1) by dissolving nateglynide crystals in pharmacologically acceptable solvent in common with hydrophilic materials taken among the group consisting of water-soluble polymers, water-swelling polymers, sugar alcohols and salts followed by granulation in fluidized layer, granulation by stirring at high rate, drying by spraying and process for coat applying for granulation of amorphous nateglynide; 2) by mixing nateglynide crystals with hydrophilic materials taken among the group of water-soluble polymers, water-swelling polymers, sugar alcohols and salts and the following application of the high shift force to the prepared mixture; 3) by mixing nateglynide crystals with hydrophilic materials taken among the group of water-soluble polymers, water-swelling polymers, sugar alcohols and salts and the following plasticizing the prepared mixture in melt by heating and milling at cooling; 4) by dissolving nateglynide crystals in pharmacologically acceptable liquid additives wherein liquid additives represent water-soluble polymers that are liquid at 37°C. Using amorphous nateglynide allows preparing the nateglynide preparation with immediate release wherein the dissolving rate of medicinal agents is high and without crystalline transition during preparing or preserving preparations.

EFFECT: valuable pharmaceutical properties of preparation.

6 cl, 3 tbl, 9 dwg

 

Technical field of invention

The present invention relates to the preparation of nateglinide, which is suitable as antidiabetic agents, more specifically to the preparation of nateglinide immediate-release.

Background of the invention

It is known that nateglinide [connection name: N-(TRANS-4-isopropylcyclohexane)-D-phenylalanine] has an excellent effect of reducing glucose in the blood after oral administration and, therefore, is suitable as a therapeutic agent for diabetes (patent publication Japan No. Hei 4-15221).

On the other hand, nateglinide is a substance that is poorly soluble in water, and therefore, capsules filled with powdered medicinal substance by nateglinide, or conventional tablets containing nateglinide, do not dissolve after oral administration, due to the poor ability to disintegration. As a result of such preparations containing nateglinide may not have a quick and short in duration lowering the level of glucose in the blood (fast-acting hypoglycemic agent), which is typical for nateglinide. In order to show the characteristic efficiency of nateglinide, the drug must quickly escape from the drugs, and thus the time there is a need to improve these drugs.

As a way of solving this problem was created the product, which as affinity was included nizkozameshhennoj hydroxypropylcellulose (Japan patent No. 2508949).

Meanwhile, nateglinide has a crystalline polymorphs. Similar to the way in which the drug include baking powder, effectively enhances the ability of the drug containing nateglinide in a stable crystalline form of N-type and polystable crystalline form, disintegrants and to increase the degree of dissolution. However, it cannot be considered as effective when all crystalline forms of nateglinide.

In addition, when nateglinide used in other crystalline forms, but the most stable crystalline forms of N-type and polystability crystalline forms, it is known that during the manufacture or preservation of drugs is crystalline transition. Usually it is preferable that the crystalline transition of the drug did not occur during the manufacture or preservation of pharmaceutical products.

Description of the invention

The purpose of this invention is the provision in the quality of the drug containing nateglinide, a pharmaceutical preparation containing amorphous nateglinide is, in which the dissolution rate of drugs would be high, and at the time of manufacture or preservation of drugs would not happen crystalline transition.

To solve these problems were conducted intensive studies and found that the properties of solubility can be improved by the use of drugs nateglinide in amorphous form. The present invention was made on the basis of this discovery. According to the method of the present invention may create nateglinide in the form of any crystalline polymorph drug nateglinide immediate-release, in which the dissolution rate of drugs is high, and during the production or preservation of drugs does not occur crystalline transition. The present invention mainly relates to the preparation containing nateglinide as an active ingredient, in which nateglinide is amorphous. The present invention includes each of the following inventions:

(1) Preparation containing nateglinide, including nateglinide as an active ingredient, in which nateglinide is amorphous.

(2) Preparation containing nateglinide, according to (1), in which the amorphous nateglinide get through the process of removing solvent from a solution of nateglinide in races is varicela.

(3) Preparation containing nateglinide, according to (2), in which the solvent used in the process of removing the solvent is a mixture of ethanol and water.

(4) Preparation containing nateglinide, according to (1), in which the amorphous nateglinide get through the application of high shearing forces.

(5) Preparation containing nateglinide, according to (1), in which the amorphous nateglinide get through the process of granulation of the melt.

(6) Preparation containing nateglinide, according to (2), which includes hydrophilic materials as carriers.

(7) Preparation containing nateglinide, according to (6), in which hydrophilic materials selected from the group consisting of water-soluble polymers, swelling in water of the polymers, sugar alcohols and salts.

(8) Preparation containing nateglinide, according to (7), in which water-soluble polymers or swelling in water of the polymers selected from the group consisting of polyvinylpyrrolidone derivatives, polysaccharide derivatives, derivatives of polyacrylic acid derivatives, polylactic acid derivatives, polyoxyethylene derivatives of polyvinyl alcohol and surfactant.

(9) Preparation containing nateglinide, according to (8), in which the polysaccharide derivative selected from the group consisting of methylcellulose SM-4, hydroxypropylcellulose SL and Hydra is xiphopenaeus SSL.

(10) Preparation containing nateglinide, according to (8), in which the derivatives of polyoxyethylene represent glycol.

(11) Preparation containing nateglinide, according to (7), in which the sugar alcohols are selected from the group consisting of sorbitol, xylitol and mannitol.

(12) Preparation containing nateglinide, according to (7), in which swelling in water, the polymers are crosspovidone (COLIDONE CL-M).

(13) Preparation containing nateglinide, according to (1), which is a tablet containing amorphous nateglinide.

(14) Preparation containing nateglinide, according to (1), which is a product in the form of capsules filled with liquid in which is dissolved nateglinide.

(15) Preparation containing nateglinide, according to (14), in which the liquid in which is dissolved nateglinide, is a water-soluble polymer or a surfactant.

(16) Preparation containing nateglinide, according to (15), in which water-soluble polymers or surfactants, solvent nateglinide represent derivatives of polyoxyethylene.

(17) a method of manufacturing a drug containing amorphous nateglinide, which includes a step of dissolving crystals nateglinide in a pharmacologically acceptable solvent together with hydrophilic materials selected from the group SOS is oasa of water-soluble polymers, swelling in water of the polymers, sugar alcohols and salts, and the stage of exposure to the resulting solution process selected from the group consisting of a process of granulation in the fluidized bed, the process of granulation using mixing with a high speed the drying process by spraying and coating process for granulating amorphous nateglinide.

(18) the Method for producing the drug containing amorphous nateglinide, which includes a step of mixing the crystals nateglinide with hydrophilic materials selected from the group consisting of water-soluble polymers, swelling in water of the polymers, sugar alcohols and salts, and the stage of application to the obtained mixture to shearing forces.

(19) the Method of manufacturing a drug containing amorphous nateglinide, which includes a step of mixing the crystals nateglinide with hydrophilic materials selected from the group consisting of water-soluble polymers, swelling in water of the polymers, sugar alcohols and salts, and the stage of exposure of the mixture to plastilinovaya melt with heating and grinding when cooled.

(20) the Method of manufacturing a drug containing amorphous nateglinide, which includes a step of dissolving crystals nateglinide a pharmacologically acceptable liquid supplements.

Brief description of drawings

<> Figure 1 shows the results of DSC (differential scanning calorimetry) tablets amorphous nateglinide.

Figure 2 shows a picture of a DSC drug nateglinide in crystalline form In type.

Figure 3 shows a picture of a DSC drug nateglinide in crystalline form N-type.

Figure 4 shows a picture of a DSC tablets amorphous nateglinide after one week of canned, Packed in an aluminum bag with 50°C.

Figure 5 shows a picture of a DSC tablets amorphous nateglinide after one month preservation, Packed in an aluminum bag with 40°C, 75% RH).

Figure 6 shows a comparative chart of dissolution profiles of each drug of examples 2 and 3 and comparative examples 1-3.

Figure 7 shows the change of concentration of nateglinide in plasma after administration of tablets nateglinide dog breed Beagle for 5 minutes before feeding. Average ± WITH n = 3.

Figure 8 shows the change of the glucose level in the blood after administration of tablets nateglinide dog breed Beagle for 5 minutes before feeding. Average ± WITH n = 3.

Figure 9 shows a picture of a DSC tablets amorphous nateglinide after six months of conservation, Packed in an aluminum bag with 40°C, 75% RH).

The best option is the implementation of the present invention

Nateg the INID, which is a source material of amorphous nateglinide contained in the pharmaceutical preparation of the present invention, can be synthesized by a method described, for example, in patent publication Japan No. Hei 4-15221, and its crystalline forms are not specifically limited.

Methods of obtaining amorphous nateglinide include, for example, the process of solvent removal, the process of application of high shearing forces, the process of granulation of the melt and the process of dissolution in a pharmaceutically acceptable solvent. Other methods are also acceptable if they can give nateglinide amorphous. Among these methods, preferred is the process of removing the solvent and the dissolution process in a pharmaceutically acceptable solvent from the standpoint of ease of manufacture, etc. of Obtaining the amorphous state can be performed without the media.

The hydrophilic material is preferred as the carrier, which makes nateglinide amorphous. Examples include water-soluble polymers, swelling in water, polymers, sugar alcohols and salts. The media can be any agent that can make nateglinide amorphous and rapidly dissolve or swell in water. The added amount is preferably 0.1 or more wt. parts what about the relation to medicines. More preferably it is from 0.1 to 100 wt. parts and even more preferably from 0.1 to 50 wt. parts in relation to nateglinide.

The solvent for dissolving nateglinide preferably is a pharmaceutically acceptable liquid at a temperature of about 37°C. Examples are water-soluble polymers and surfactants. The solvent is added in an amount of preferably 0.1 or more wt. parts in relation to medicines. More preferably from 0.1 to 1000 wt. parts in relation to nateglinide and even more preferably from 0.1 to 100 wt. parts in relation to nateglinide. It is preferable to add it in an amount of from 0 to 100 wt. parts and more preferably from 0 to 50 wt. parts in relation to the media, which makes nateglinide amorphous.

The process of removing the solvent to obtain amorphous nateglinide used in the pharmaceutical preparations of the present invention, is a technique in which the drug and the carrier to give the amorphous state is dissolved in a solvent and then the solvent is removed to give medicines amorphous. The solvent can be any solvent water type, organic type or mixed type of water and organic solvent, if only medicines and media can be dissolved. Specifically, it includes alcohols such as methanol, ethanol and isopropyl alcohol, ketones such as acetone and methyl ethyl ketone, cyclic ethers such as dioxane and tetrahydrofuran, and acetonitrile. Among them, preferred is ethanol. When using the mixed water and organic solvent, the ratio (mass ratio) is preferably water: organic solvent = 99:1 to 1:99, and more preferably from 90:10 to 10:90.

An example of a process of removal of the solvent include a method in which a drug and a carrier, which makes nateglinide amorphous, such as water-soluble polymers are dissolved in a solvent such as ethanol, and then the solution is dried under vacuum, evaporated or use any other method to remove solvent. Conditions of removal of the solvent is not specifically limited if only the amorphous nateglinide can exist in a stable form. The operation can be performed using nateglinide and without solvent medium to give the amorphous state. Amorphous nateglinide can be subjected to the process of granulation in the fluidized bed, the process of granulation by mixing with a high speed, the process of spray drying, the coating process and the like, to obtain pellets, with the holding of an amorphous nateglinide. Without removing the solvents from the solution in which the dissolved nateglinide and the media, which gives nateglinide amorphous, the solution can directly be subjected to the process of granulation in the fluidized bed, the process of granulation by mixing with a high speed, the process of spray drying, the coating process and the like, to obtain a granulated product containing nateglinide. Conditions of granulation in the fluidized bed and other processes not specifically limited, unless they provide amorphous nateglinide stable existence. The operation can be performed with only one nateglinide. The resulting granules can be used as dosage forms, pellets or they can then be compressed into tablets. The drug dosage form containing nateglinide, according to the present invention is not specifically limited.

Method of preparation by applying a high shearing forces is a way in which to the mixture of drug and carrier to make nateglinide amorphous state attached a high shearing force using a suitable method, giving medicines amorphous. The applied shearing force are not specifically limited, if it can provide amorphous NAT is glinide stable existence. The operation can be performed with only one nateglinide.

For example, there is a way in which medicines and water-soluble polymers are mixed, and the mixture is then crushed together on ultracentrifugal mill, or a high shearing force supplied to the mixture by using an extrusion granulator to obtain granules containing amorphous drug. The resulting granules can be used as dosage forms, pellets or they can be pressed into tablets. The drug dosage form containing nateglinide, according to the present invention is not specifically limited.

The process of granulation of the melt method is a method in which a mixture of drug and carrier to give the amorphous state is heated and melted, and then cooled and utverjdayut to make medicines amorphous.

For example, medicines and water-soluble polymers are placed in a heat-resistant multi-purpose mixer or similar device, plasticity melt with the heat and chop when cooled to obtain granules containing amorphous drug. The resulting granules can be used as dosage forms, pellets, or remains in the amorphous state, the drug dosage form containing n is taglined, according to the present invention are not specifically limited. The operation can be performed with only one nateglinide.

The method of dissolution in a pharmaceutically acceptable liquid supplements is a technique in which the drug is dissolved in a pharmaceutically acceptable liquid additive for giving medicines vagueness. For example, this can be a technique in which the drug is dissolved in water-soluble polymers which are liquid at 37°C, to obtain a solution. This solution fills the shell gelatin capsules, or fill, the soft shell gelatin capsules, receiving capsules filled with liquid.

The product containing amorphous nateglinide of the present invention, may further include hydrophilic materials. Hydrophilic materials include water-soluble polymers, swelling in water, polymers, sugar alcohols, salts and other Hydrophilic materials, as such, can be used as a carrier, which gives nateglinide amorphous, or you can also use other materials.

Examples of water-soluble polymers or swelling in water of the polymers are polyvinylpyrrolidone derivatives, polysaccharide derivatives, derivatives of polyacrylic acid, derivatives of Polym lacnych acids, derivatives of polyoxyethylene derivatives of polyvinyl alcohol and a surfactant.

Derivatives include polyvinylpyrrolidone cross-linked polyvinylpyrrolidone, more specifically crosspovidone (COLIDONE CL-M, BASF).

Polysaccharide derivatives as hydrophilic materials include cellulose derivatives, etc. are Examples of these include methylcellulose, hydroxypropylcellulose and carboxymethylcellulose. More specifically, they include methylcellulose SM-4, hydroxypropylcellulose SL and hydroxypropylcellulose SSL. Derivatives of polyacrylic acids include methacrylic acid copolymer L, methacrylic acid copolymer S and methacrylic acid copolymer LD (Rohm).

Derived polylactic acid include a copolymer of lactic acid and glycolic acid (1:1), having a molecular weight of 17,000 to 24,000.

As an example, derivatives of polyoxyethylene preferred is polyethylene glycol. In particular, its molecular weight is preferably from 200 to 20,000 and more preferably from 200 to 6000. Specifically, it includes macrogol 300, 400, 600, 1000, 1500, 4000, 6000 or other

Derivatives of polyvinyl alcohol include polyvinyl alcohol (completely saponified substances), polyvinyl alcohol (partially saponified substances), etc.

Surfactants include policy shall rbat 80, sodium lauryl sulfate, etc.

As the swelling in water of the polymers is preferred crosspovidone (COLIDONE CL-M).

Sugar alcohols include sorbitol, xylitol, mannitol and the like, Among them, preferred is mannitol.

Salts include chloride, phosphates, citrates of sodium, etc.

Examples

The following examples, which in no way limit the invention, will further illustrate the present invention.

Example 1: Obtaining amorphous nateglinide

4 g of nateglinide in crystalline form b-type and 32 g of polyvinylpyrrolidone was dissolved in ethanol. The ethanol was removed by evaporation (60° (C) and the mixture was dried under vacuum at 60°C for 3 hours or more. The solid material was ground in a mortar to obtain 36 g of nateglinide in the form of a solid dispersion.

Example 2: Production of tablets containing amorphous nateglinide

60 g of nateglinide (crystal type), 4 g hydroxypropylcellulose and 60 g of crosspovidone (COLIDONE CL-M, BASF) was dissolved and suspended in 160 g of ethanol to obtain a binder solution. 180 g of crosspovidone (COLIDONE CL-M, BASF) and 96 g of crystalline cellulose were placed in a granulator fluidized bed (type FLO-1, Freund Industrial Co., Ltd.) and stirred. Then the binder solution was sprayed on the granules in the fluidized bed (inlet temperature: 80°, spraying speed: 4.9 g/min, pressure raspy is possible: 1.8 kg-force/cm 2).

250 g of the obtained granules and 3.8 g of magnesium stearate were mixed in a mixer, V-type with obtaining granules for tableting. Used rotary tablet press machine (HT-AP15ssII, Hata Factory stamped 8 mm ⊘ - 14R2r obtaining 253,8 g nuclei tablets (weight of the core tablet 203,1 mg).

80 g hydroxypropylmethylcellulose, 15 g of macrogol 6000, 24 g of talc and 5 g of titanium oxide was dissolved and suspended in 876 g of water to obtain the liquid to cover. 300 g of the core tablets were placed in a device for coating tablets ("High Coater Mini, Freund Industrial Co., Ltd.). On the tablet was coated so that one engine had to 2.54 g hydroxypropylmethylcellulose obtaining 303,8 g tablets coated.

Manufactured tablets were Packed in an aluminum bag and perform a stability test at 50°C for one week or 40°C, 75% RH for one month.

Example 3: Production of capsules filled with liquid

186 mg of nateglinide, 1456 mg of macrogol 400 and 1456 mg of Polysorbate 80 was stirred in a stirrer at room temperature until dissolution and obtain a clear solution nateglinide. 500 mg of a solution of a medicinal product filled capsules 0 size to receive capsules containing liquid (nateglinide: 30 mg).

Comparative example 1: Preparation of 1 capsule filled with powder, in addition to the promote tool

300 mg of powdered drug nateglinide (crystal type) filled gelatin capsule (size 2) to obtain the capsules filled with powdered drug - nateglinide in the form of b-type.

Comparative example 2: Preparation of 2 capsules filled with powdered medicine

30 mg of powdered drug nateglinide (crystal N-type) filled gelatin capsule (size 2) to obtain the capsules filled with powdered drug - nateglinide in the form of N-type.

Comparative example 3: preparation of tablets using nateglinide in the form of crystals of N-type

The core tablets (weight: 120 mg), 7 mm ⊘ - 9R2r received using nateglinide (crystal N-type) according to example 1 of the patent publication Japan No. Hei 10-194969. Then it was coated with getting coated tablets containing nateglinide in the form of crystals of N-type.

Example 4: Measurement of DSC

Tablets produced in example 2 was ground in an agate mortar and approximately 10 mg of powder was placed on a silver tray and sealed with a silver lid. Then was measured by DSC using a tool SII-DSC with increasing temperature from 25°, 250°C, with a heating rate: 5°C/min, the Results are presented at the Phi is ur 1. They were compared to the results obtained with the powdered drug by nateglinide in the form of b-type (figure 2) and the results obtained with the powdered drug by nateglinide in the form of N-type (figure 3). As can be seen from figures 1-3, it was confirmed that the tablets produced in example 2, contained amorphous nateglinide, because they showed no absorption, which is typical for crystals nateglinide.

Meanwhile, produced canned test sample preparations of example 2 using the same procedure. The received picture DSC (figure 4 and figure 5) were the same as those that were obtained to test for conservation. Therefore, it was confirmed that nateglinide not crystallised and was amorphous (not observed transition of the crystalline forms).

Example 5: Measurement of the rate of dissolution

Properties on dissolution of drugs manufactured in example 2 and example 3 was measured in 900 ml of the second fluid test and the disintegration of the Japanese Pharmacopoeia, in accordance with the Japanese Pharmacopoeia (hereinafter referred to as JP), Chapter 13, the method of compacting (50 rpm). The results are presented in figure 6. The products manufactured in comparative examples 1 to 3 was measured in the same way mentioned above. The results are presented in figure 6.

As can be seen from figure 6, / min net and dissolution of tablets manufactured in example 2, and fluid-filled capsules produced in example 3, in which nateglinide was in amorphous state, is improved in comparison with the same indicators for capsules filled with powdered medicinal product manufactured in comparative example 1 and comparative example 2. The average dissolution rate of tablets containing amorphous nateglinide, and fluid-filled capsules in each moment of time was confirmed as corresponding to the same indicators of dissolution for tablets nateglinide (tablets using crystal N-type) of comparative example 3.

Meanwhile, the dissolution properties of the products manufactured in example 2, and after the test on the preservation was measured in 500 ml of the second fluid test and the disintegration of the Japanese Pharmacopoeia, in accordance with JP, Chapter 13, the method of compacting (50 rpm, 30 minutes later). The results are presented in table 1. As can be seen from table 1, no change in the degree of dissolution was not observed either before or after the test on the enclosure.

Table 1
The tested samplesTo conservation50°C, after one week40°C, RH 75%, one month
The degree of dissolution (%) 939591

Example 6: Evaluation of absorption after oral administration to dogs breed Beagle

The concentration profile of nateglinide in plasma, the change of the glucose level in the blood plasma and pharmacokinetic parameter was evaluated after the introduction of the breed Beagle for five minutes before feeding tablets amorphous nateglinide obtained in example 2, and tablets nateglinide in crystalline form N-type obtained in comparative example 3. The results are presented in figure 7, figure 8 and in table 2.

It was found that tablets amorphous nateglinide demonstrate equivalent or better absorption capacity when administered orally and efficiency compared to tablets nateglinide in crystalline form N-type.

Table 2: Pharmacokinetic parameter after the introduction of tablets nateglinide dog breed Beagle for five minutes before feeding (n=3)

Table 2
AUC[mg/ml per hour]Cmax[ág/ml]Tmax [hours]
Tablet nateglinide in crystalline form N-type20,538,930,38
Tablets amorphous nateglinide22,299,46 0,38

Example 7: evaluation of the stability of tablets amorphous nateglinide storage

Tablets amorphous nateglinide obtained in example 2 was Packed in an aluminum bag and kept at 40°C, 75% RH for six months. The dissolution properties were evaluated in 500 ml of the second fluid test disintegration JP, in accordance with JP, Chapter 13, the method of compacting (50 rpm, 30 minutes later). The results are presented in table 3, and the picture DSC are shown in figure 9.

Both before and after storage no change in the dissolution rate and the nature of the DSC was observed. This shows that tablets amorphous nateglinide are a preparation having a high storage stability.

Table 3: Comparison of solubility before and after storage

Table 3
TabletsThe degree of dissolution
The initial stage40°C, 75% RH, 6 months.
Tablets amorphous nateglinide93(93-94)101(99-104)

As can be seen from each figure and table 1, the amorphous nateglinide used in the preparation of the present invention, does not come in crystalline form during its manufacture and storage. According to this the invention, which refers to the drug using amorphous nateglinide because it contains nateglinide, suitable as anti-diabetic agent, a non-crystalline form, it is possible to manufacture drugs, having good dissolution properties, equivalent to the specified properties of preparations containing crystalline nateglinide.

1. Drug containing nateglinide, for the treatment of diabetes, including nateglinide as an active ingredient and a carrier, where nateglinide is amorphous and the specified carrier is a hydrophilic material.

2. Drug containing nateglinide, according to claim 1, in which the amorphous nateglinide get through the process of removing solvent from a solution of nateglinide in the solvent.

3. Drug containing nateglinide, according to claim 2, in which the solvent used in the process of removing the solvent is a mixture of ethanol and water.

4. Drug containing nateglinide, according to claim 1, in which the amorphous nateglinide get through the application of high shearing forces.

5. Drug containing nateglinide, according to claim 1, in which the amorphous nateglinide obtained using the process of granulation of the melt.

6. Drug containing nateglinide, according to claim 2, in which the hydrophilic material is selected from the group consisting of water-soluble polymers, naujausi the polymers in water, sugar alcohols and salts.

7. Drug containing nateglinide, according to claim 6, in which water-soluble polymers or swelling in water of the polymers selected from the group consisting of polyvinylpyrrolidone derivatives, polysaccharide derivatives, derivatives of polyacrylic acid derivatives, polylactic acid derivatives, polyoxyethylene derivatives of polyvinyl alcohol and surfactant.

8. Drug containing nateglinide, according to claim 7, in which the polysaccharide derivative selected from the group consisting of methylcellulose SM-4, hydroxypropylcellulose SL and hydroxypropylcellulose SSL.

9. Drug containing nateglinide, according to claim 7, in which the derivative is a polyoxyethylene glycol.

10. Drug containing nateglinide, according to claim 6, in which the sugar alcohols are selected from the group consisting of sorbitol, xylitol and mannitol.

11. Drug containing nateglinide, according to claim 6, in which swelling in water, the polymers are crosspovidone (COLIDONE CL-M).

12. Drug containing nateglinide, according to claim 1, in which the drug is a pill containing amorphous nateglinide.

13. Drug containing nateglinide, for the treatment of diabetes containing nateglinide as the active ingredient, where nateglinide is amorphous and where the product is a capsule, napolnyaemostyu, in which is dissolved nateglinide.

14. Drug containing nateglinide, item 13, in which the liquid in which is dissolved nateglinide, is a water-soluble polymer or a surfactant.

15. Drug containing nateglinide, 14, in which water-soluble polymers or surfactants, solvent nateglinide represent derivatives of polyoxyethylene.

16. The method of preparation of drug containing amorphous nateglinide, which includes a step of dissolving crystals nateglinide in a pharmacologically acceptable solvent together with hydrophilic materials selected from the group consisting of water-soluble polymers, swelling in water of the polymers, sugar alcohols and salts, and the stage of exposure to the resulting solution process selected from the group consisting of a process of granulation in the fluidized bed, the process of granulation using mixing with a high speed the drying process by spraying and coating process for granulating amorphous nateglinide.

17. The method of preparation of drug containing amorphous nateglinide, which includes a step of mixing the crystals nateglinide with hydrophilic materials selected from the group consisting of water-soluble polymers, swelling in water of the polymers, sugar alcohols and salts, and the stage of application to the mixture of high shearing forces.

18. The method according to 17, in which a high shearing force is attached using ultracentrifugal mill or extrusion granulator.

19. The method of preparation of drug containing amorphous nateglinide, which includes a step of mixing the crystals nateglinide with hydrophilic materials selected from the group consisting of water-soluble polymers, swelling in water of the polymers, sugar alcohols and salts, and the stage of exposure of the mixture to plastilinovaya melt with heating and grinding when cooled.

20. The method of preparation of drug containing amorphous nateglinide, which includes a step of dissolving crystals nateglinide a pharmacologically acceptable liquid additives, where the liquid additives are water-soluble polymers that are liquid at 37°C.

21. The method according to claim 20, in which the pharmacologically acceptable liquid additives are macrogol 300 or 400 or Polysorbate 80.



 

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1 tbl, 1 ex

FIELD: medicine, gastroenterology, phytotherapy, pharmacy.

SUBSTANCE: invention relates to solid medicinal formulations, namely capsules "Gastrobiol-TSD". Gelatin capsule contain the natural pharmacologically active component - sea-buckthorn oil concentrate, cyclodextrin, vitamin U and magnesium oxide taken in the definite ratio of components given in the invention description. Invention provides preparing a medicinal formulation eliciting an anti-ulcer, analgetic and protective effect on mucosa effect being with minimal risk for development of adverse effect.

EFFECT: valuable medicinal properties of preparation.

1 tbl, 1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition as a capsule for oral administration that comprises testosterone undecanoate as an active component dissolved in pharmaceutically acceptable liquid carrier wherein liquid carrier involves at least 50 wt.-% of castor oil. Using castor oil as a liquid carrier in combination with testosterone undecanoate as androgen provides preparing a solution that can contain about 200-250 mg of testosterone undecanoate/ml that represents the new achievement for testosterone solution for oral administration. Solution can contain lipophilic surface-active substance, such as lauryl glycol also. The composition shows good absorption in human body and elicits higher activity as compared with the known composition of undecanoate.

EFFECT: improved and valuable properties of composition.

7 cl, 1 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention discloses compositions with sustained-release of active component and masking taste that comprise one of more active components included in tricomponent matrix structure as a globule. This structure is formed successively by amphiphilic, lipophilic or inert matrices and included as globule or dispersed in hydrophilic matrix. Applying large amount of systems for regulation of dissolving active component provides modulating the dissolving rate of active component in aqueous and/or biological fluids by regulating thus kinetics in releasing active component in digestive tract.

EFFECT: valuable pharmaceutical properties of compositions.

14 cl, 14 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to the medicinal preparation zolpidem. Pharmaceutical composition comprises zolpidem hemitartrate as active substance taken in the effective dose and ludipress, aerosil and stearate as special additives. Pharmaceutical composition is made preferably as a tablet covered by envelope. Invention solves the problem for the development of the nonprolonged soporofic medicinal agent based on zolpidem corresponding to all requirements of the State Pharmacopoeia of XI Edition. Proposed nonprolonged formulation of zolpidem is suitable for workers contingent suffering with insomnia, especially, in professions requiring attention and concentration.

EFFECT: improved and valuable medicinal properties of composition.

6 cl, 2 tbl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a combined medicinal agent used in treatment of arterial hypertension. The proposed agent comprises the combination of enalapril maleate and hydrochlorothiazide as an active component, and also sodium hydrocarbonate, starch, lactose, iron oxide and stearate as accessory substances. The proposed agent is stable in storage and releases the active component easily.

EFFECT: improved and valuable properties of agent.

8 cl, 1 tbl, 5 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a ketoconazole-base antifungal pharmaceutical composition. The composition is prepared as a solid medicinal formulation. The composition comprises the following components, wt.-%: ketoconazole, 50.5-75.0; lactose, 1.0-12.0; starch, 5.0-25.0; polyvinylpyrrolidone, 2.0-12.0; stearic acid or calcium, magnesium or zinc stearate or mixture of indicated compounds, 0.2-1.2; aerosil and/or talc, 0.5-10.0. The novel antifungal composition comprises ketoconazole in the amount 50 wt.-%, not less, and it satisfies Pharmacopoeia requirements, stable in storage for 2 years, not less, and shows high therapeutic activity.

EFFECT: improved and valuable medicinal and pharmaceutical properties of composition.

3 cl, 2 tbl, 6 ex

FIELD: pharmaceutics.

SUBSTANCE: the suggested preparation consists of basic bismuth nitrate, basic magnesium carbonate, sweet flag rhizome, buckthorn bark as water-soluble extract, water-soluble extracts of licorice root and birch leaves taken at a certain ratio. It is designed in tableted form.

EFFECT: higher efficiency of application.

1 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: the present innovation deals with applying antihistamine preparation named mebhydrolin. It is suggested to apply pharmaceutical composition that includes therapeutically efficient quantity of mebhydrolin and target additives as sugar, starch, polyvinyl pyrrolidone and salt of stearic acid. Pharmaceutical composition is designed in tableted form. The innovation provides correspondence of mebhydrolin tablets against all the standards of State pharmacopoeia XI, decreased quantity of additional substances and expiry period of 3 yr, not less.

EFFECT: higher efficiency of application.

5 cl, 3 ex, 2 tbl

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-methyl-[(methylsulfonyl)amino]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid as an active component or its pharmaceutically acceptable salt and inorganic salt with polyvalent cation also. Also, invention proposes a method for preparing the stabilized pharmaceutical composition. Invention provides preparing the stabilized pharmaceutical composition.

EFFECT: valuable medicinal properties of composition.

25 cl, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention concerns a new oral formulation of the galenic preparation molsidomine with prolonged releasing an active substance and designated in treatment of stenocardia attack in all its variations (stress stenocardia, spastic stenocardia, nonstable stenocardia). This novel formulation of galenic preparation comprises the therapeutically effective dose of molsidomine or one of its active metabolites and shows the following dissolving rate values in vitro [measured by spectrophotometry method at wavelength 286 or 311 nm according to a method reported in Pharmacopee Europeene, 3-d edition (or U. S. P. XXIV) at 50 rev./min in 500 ml of medium consisting of 0.1 N HCl at 37°C]: 15-25% of molsidomine released in 1 h; 20-35% of molsidomine released in 2 h; 50-65% of molsidomine released in 6 h; 75-95% of molsidomine released in 12 h; >85% of molsidomine released in 18 h, and >90% of molsidomine released in 24 h wherein the maximal blood plasma concentration of molsidomine in vivo appears in 2.5-5 h but preferably in 3-4 h after intake of abovementioned formulation and has value from 25 to 50 ng/ml of blood plasma. Invention provides reducing amount of doses of drug per a day that is more suitable for a patient.

EFFECT: improved and valuable pharmaceutical properties of preparation.

14 cl, 5 dwg, 2 tbl, 7 ex

FIELD: medicine, therapy, gastroenterology, pharmacy.

SUBSTANCE: method involves oral intake of solid medicinal formulation at vertical position of patient and change of medicinal formulation position into stomach is carried out in each 5 min, not rare. Change of medicinal formulation position is carried out by pressing on epigastrium region by hand or by cyclic change of position of patient body from its vertical position to horizontal position and back. Method provides enhancing safety in enteral using a solid medicinal formulation due to diminishing its ulcerogenic effect. Invention can be used in enteral using solid medicinal formulations.

EFFECT: improved method for diminishing ulcerogenic effect.

2 ex

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a method for pressing in preparing a medicinal formulation of phenytoin sodium, method for pressing in rollers and preparing a pharmaceutical composition involves stages of addition of phenytoin sodium into a mixer receiver and addition of at least one excipient into indicated mixer. Mixture is stirred and transferred into roller thickener wherein pressure is applied on the mixture of phenytoin sodium and excipient. The prepared compact-(briquette) is ground and prepared granulate is mixed repeatedly that is suitable from further processing to a medicinal formulation. Excipients involve magnesium stearate, sugar, lactose monohydrate and talc, or talc is added directly before the second mixing the granulate.

EFFECT: improved pressing method.

15 cl, 10 tbl, 2 dwg, 4 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to agents stimulating the central nervous system, i. e. psychomotor stimulators. Invention proposes combination of sydnocarbum with ladastenum taken in the ratio = 1:(0.4-2) as an agent. Invention provides enhancing physical working ability, prevents the development of acute physical fatigue and exceeds effect of sydnocarbum and ladastenum by 2.7 and 1.6 times, respectively.

EFFECT: enhanced effectiveness and valuable medicinal properties of agent.

4 cl, 13 tbl

FIELD: pharmacy.

SUBSTANCE: invention relates to a granulated pharmaceutical composition comprising granulated material and erythritol. Granulated material comprises a medicinal substance of unpleasant taste and wax. Also, invention relates to a pharmaceutical product for oral using that comprises the indicated granulated composition. The composition masks unpleasant taste of a medicinal agent and provides good feeling in oral using. The granulated composition can be swallowed easily by elderly humans, children and patients suffering with dysphagia. Except for, the product is useful for administration by using a tube.

EFFECT: improved and valuable properties of composition.

15 cl, 5 tbl, 6 ex

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