Solid lipid compositions

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition for oral administration in treatment or prophylaxis of obesity or hyperlipidemia. The composition comprises orlistat and at least one ester of fatty acids and polyols. Melting point of fatty acid ester exceeds the body temperature and polyol is taken among group including glycerol, sugars, derivatives of sugars and their mixtures. Also, invention relates to a method for preparing above described composition and to a method for treatment or prophylaxis of obesity. Invention enhances effectiveness and activity of orlistat by reducing variability of effectiveness and/or activity of orlistat between patients and frequency and severity of adverse effects.

EFFECT: improved and valuable pharmaceutical properties of compositions.

24 cl, 1 tbl, 10 ex

 

The present invention relates to pharmaceutical compositions containing at least one inhibitor of lipases.

Examples of such inhibitors of lipases are lipstatin and orlistat. The latter is also well known as tetrahydrolipstatin or THL, and it is a derivative of a natural product secreted by Streptomyces toxytricini. We found that this class of compounds exhibits both in vitro and in vivo activity against various lipases, such as lingual lipase, pancreatic lipase, gastric lipase and carboxylate-lipase. The use of this compound for the treatment or prevention of obesity and hyperlipidemia are described, for example, in patent US 4598089.

Orlistat is usually used in doses of 120 mg per meal, and this dose does not depend on the body weight of the patient. Orlistat has a local action in the gastrointestinal tract (LCD), and prevents the cleavage of the triglyceride lipase and thus inhibits formation of absorbable products of cleavage of lipids. For this purpose does not require the presence of systemic availability of lipase inhibitors, on the contrary, it is preferable their local presence in the gastrointestinal tract.

Accepted including inhibitors of lipase composition of about 30% inhibit the absorption of fat after ingestion of a mixed meal; increasing the concentration inhibit the s lipases in the pharmaceutical composition does not increase its clinical efficacy and/or activity, while the intensity of side effects increases.

Anal after oil (oily spots) is a side effect that is sometimes seen in patients during treatment with inhibitors of lipases. This phenomenon reflects the physical separation of some part of the liquid unabsorbed absorbed with dietary fat from the mass of solids in the lower part of the colon.

Thus, the present invention is the creation of containing inhibitors of lipase compositions, improving clinical effectiveness and/or activity of the inhibitor, which minimized or which are completely devoid of the above disadvantages.

This task is solved by a pharmaceutical composition comprising at least one lipase inhibitor and at least one ester of fatty acids and polyols, which differs in that the melting point of the fatty acid ester exceeds body temperature, ie >37°and the polyol is chosen from the group comprising glycerol, sugars, derivatives of sugars and mixtures thereof.

With the invention it has been unexpectedly found that the introduction of a lipase inhibitor in a composition that includes at least one of the above esters of fatty acids, significantly increases the efficiency and activity of the lipase inhibitor. To the ome, reduced variability of efficiency and/or activity between patients, and the frequency of occurrence and severity of side effects.

It was found that the pharmaceutical compositions according to the invention have the most beneficial effect when administered orally during eating man. With the invention it has been unexpectedly found that their effectiveness and activity higher than that of already existing songs. This is unexpected due to the fact that the composition of the invention remain solid in the body and as a result, they need badly to dispergirujutsja among oil particles of food in the stomach.

In addition, the composition of the invention when evaluated using the same test Breakfast reduce unpleasant side effects compared to existing compositions, despite the fact that more fat remains unabsorbed. In experiments on humans using a single trial of Breakfast, it was found that in stool obtained after absorption of the compositions according to the invention, the detected lower degree of separation of the oil from the main mass of stool compared to conventional compositions. This is unexpected, because in the collected stool samples is the same or greater amount of fat.

In the context of the present description for the enterprise "lipase inhibitor" and "lipase inhibitor" refers to compounds that which have the ability to inhibit the action of lipases, such as gastric and pancreatic lipases. For example, orlistat and lipstatin described in U.S. patent 4598089, are effective inhibitors of lipases. Lipstatin is a natural product of microbial origin, and orlistat is obtained by hydrogenation of lipstatin. Other inhibitors of lipases include the class of compounds, analogues of orlistat, which is usually called policyname (Mutoh and others, 1994). The term "lipase inhibitor" also refers to a polymer that is associated with inhibitors of lipases, for example, described in international patent application WO 99/34786 (name of firm Geltex Pharmaceuticals Inc.). These polymers are characterized in that they are substituted by at least one or more groups, any abscopal lipase. The term "lipase inhibitor" also includes pharmaceutically acceptable salts of these compounds. Preferably the term "lipase inhibitor" refers to orlistat.

Orlistat is a known compound, which is used for the treatment or prevention of obesity and hyperlipidemia (see patent US 4598089, issued July 1, 1986, which also describes methods of obtaining orlistat, and the US patent 6004996, which describes the corresponding pharmaceutical compositions). Other acceptable pharmaceutical compositions are described, for example, in international applications in atent WO 00/09122 and WO 00/09123. Additional methods of obtaining orlistat described in the publication of European patent applications 185359, 189577, 443449 and 524495.

Orlistat is administered preferably by mouth in amounts of from 60 to 720 mg per day in divided doses 2-3 times a day. Preferably the patient from 180 to 360 mg, most preferably 360 mg per day of a lipase inhibitor, preferably in divided doses 2 or particularly preferably 3 times a day. The patient preferably is a person who is obese or overweight, i.e. the person from whom the index weight is 25 or more. Generally, it is preferable to apply the inhibitor of lipases in the process of absorption of food containing fat. Typically, a lipase inhibitor, as defined above, preferably used for the treatment of a person with a severe family history from the point of view of obesity and having an index of body weight of 25 or more.

Thus, the present invention relates to compositions containing at least one lipase inhibitor and at least one ester of fatty acids and polyols, which differs in that the fatty acid ester has a temperature greater than body temperature, and the polyols are selected from the group comprising glycerol, sugars, derivatives of sugars and mixtures thereof.

The polyols can be independently from each other selected from the group including glycerol, sugars, derivatives of sugars and their mixtures. This group, in particular, includes sucrose, glycerin and sugar alcohols, and most preferably glycerol, i.e. compositions according to the invention is most preferably applied esters, representing glycerides.

The term "sugar alcohols" refers to compounds, including mono-, oligo - and polysaccharides and their reduced products, such as mannitol.

The concept of "ether, representing the glycerides" refers to an ester of glycerol. According to the present invention, the ether may include 1-3, preferably 1 or 3 fragments of fatty C12-C20 acid fragment of glycerin, or they can represent the failure of a phospholipid, preferably lecithin, or mixtures thereof. For example, glycerides can be selected from the group consisting of one or more triglycerides, one or more monoglycerides, one or more phospholipids and their mixtures.

Preferably the fragments of fatty acids in the fatty acid esters and polyols independently from each other have 12 or more carbon atoms, preferably 12-20 carbon atoms. Most preferably the fragments of fatty acids in the fatty acid esters and polyols have 12-20 carbon atoms and are saturated.

According to a preferred variant of the invention, the acceptable triglycerides Triowin, trimyristin, tripalmitin, tristearin and mixtures thereof. The most preferred triglycerides are trimyristin and Triowin.

Monoglycerides can be selected from the group comprising monocaprin, monolaurin, monomerization and monopolisation and mixtures thereof.

According to a preferred variant of the invention, the phospholipid is preferably a lecithin, for example, dehydrogenation, partially or fully hydrogenated lecithin, and mixtures thereof. The term "lecithin" in the context of the present description refers to esters formed by glycerol, two fatty acids and a movie phosphorylcholine. Lecithin has the following structure:

where R1-COO -, and R2-COO - represent fragments of fatty acids, as described above.

Phospholipids, such as lecithins, can be selected from the group comprising natural lecithin, synthetic lecithin, soy lecithin, egg lecithin, synthetic dipalmitoyl, partially or fully hydrogenated lecithin, and mixtures thereof.

Esters of fatty acids and polyols known in this field and are commercially available.

Preferably ether, representing the glycerides present in an amount of from 0.5 to 90%, calculated on the total weight of the composition.

It is advisable to pharmaceutical compositions p the invention additionally include at least one pharmaceutically acceptable excipient. Additional excipient can improve the dispersive ability of the pigment and distribution in the stomach. Excipient can be selected from the group including leavening agents, effervescent mixtures, and their mixtures. You can also add other excipients such as carbohydrates, starch and/or its derivatives, maltodextrins, cellulose, cellulose derivatives, sugar, fillers, antioxidants, anionic and nonionic surfactants, such as sodium dodecyl sulphate, salts of fatty acids such as Na stearate, complex poly(oksietilenom)alkalemia esters, simple poly(oksietilenom)alkalemia esters and mixtures thereof. Examples of additional excipients are glucose, lactose, sorbitol, maltodextrin, talc, magnesium stearate, mannitol, sodium bicarbonate, crosspovidone, glycoluril, tartaric acid and mixtures thereof.

According to the invention can be applied to any inhibitor of lipases, but the most preferred active substances are inhibitors of gastric and pancreatic lipases and in particular orlistat.

According to the invention the lipase inhibitor is present in an amount of from 1 to 50%, preferably from 5 to 30% based on the total weight of the composition.

In a preferred embodiment of the present invention described above, the composition may include

a) from 1 to 50% of the lipase inhibitor in terms of the total weight is the composition;

b) from 0.5 to 90% of at least one ester of fatty acids and polyols, calculated on the total weight of the composition; and optionally, the composition includes one or more pharmaceutically acceptable excipients.

The composition of the invention can be entered using the conventional dosage forms, such as hydroxypropylmethylcellulose (HPMC) capsules, hard gelatin capsules, starch capsules, tablets, chewable tablets and capsules, powders, pellets, granules, etc.

The present invention also relates to a method for the preparation of the above-described pharmaceutical compositions, which involves mixing at least one lipase inhibitor and at least one ester of fatty acids and polyols in the solid or molten state, and the fatty acid ester has a temperature greater than body temperature, and the polyols are selected from the group comprising glycerol, sugars, derivatives of sugars and mixtures thereof.

Another object of the invention is a method of treating or preventing obesity, comprising the stage of introduction of the patient the above pharmaceutical compositions.

The invention also relates to the use of the above-described composition for preparing a medicinal product intended for the prevention and treatment of obesity.

Below the invention more podrobnosti.ua with examples.

Performance data regarding the excretion of fat compositions on the basis of orlistat from examples 1-10 and Xenical® as a benchmark are shown in table 1.

EXAMPLES

Example 1

10 g of molten trimyristin (Dynasan 114, the firm Hiils AG) was mixed for 30 min at a temperature 57-63°With 20 g of orlistat. To the thus obtained combined melt (coreplay) was added 20 g of glucose and mixed at room temperature until hardened. The thus obtained solid product was kept for 1 h at room temperature, were crushed with a mixer for dry food and then sieved through sieves with openings of 1.6 mm, the Formed particles are kept at 39°C for 4.5 hours in an atmosphere of inert gas, subjected to cryogenic grinding with dry ice and then mixed with lactose (the ratio of lactose and the resulting particles 100:15 wt./wt.). Finally, the thus obtained mixture is extruded with getting chewable tablets with a diameter of 16 mm, a weight of 1.15 g, each of which consisted of 60 mg of orlistat, 30 mg trimyristin, 60 mg of glucose and 1000 mg of lactose.

Thus obtained chewable tablets were given to volunteers during one of the test Breakfast. People received food, consisting of 130 g of ground beef, 10 g butter 100 g of French fries (fried in peanut oil), Ls is the fat which was about 35, Collected stool samples, starting from day -1 (the day before the start of the experiment) before the fifth day after the test Breakfast. The first and the last stool samples were used to evaluate the baseline level of excretion of fat. Stool samples were stored in a frozen state and carried out the extraction of total lipids according to the method of Bligh and Dyer (Bligh, E.G. and W.J. Dyer, Can. J. Biochem. Physiol., 37, 911 (1959)). Subtract the value of the background level of excretion, getting fat, which was excretions during treatment with orlistat. The amount of excreted fat was estimated gravimetrically and expressed as percentage of the fat content in the test Breakfast.

Example 2

100 g trimyristin (Dynasan 114, the company Huls AG) is melted at 65°in a suitable mixer with a high shear forces. In the mixer were introduced 200 g of orlistat and melted by careful mixing (mix is sorepla). The molten phase was stirred for 2 minutes was Added with stirring in the form of two portions of 1800 g of maltodextrin DE21 (ratio sorepla and maltodextrine 1:6 wt./wt.) and mixed before curing at room temperature, receiving flowable granulate. The granulate was sieved through sieves with openings of 0.85 mm Separately 4950 g of sorbitol were sieved through sieves with openings of 0.85 mm and mixed with coreplugins granulate for 3 minutes Add the eno external phase (375 g of talc and 75 g of magnesium stearate) were screened manually through sieves with openings of 0.5 mm and mixed with the granules for 3 minutes Finally, the thus obtained mixture is extruded with getting chewable tablets with a diameter of 20 mm, weight 1.5 g, each of which consisted of 40 mg of orlistat 20 mg trimyristin, 360 mg maltodextrin, 960 mg of sorbitol, 75 mg of talc and 15 mg of magnesium stearate.

Thus obtained chewable tablets was tested on human volunteers according to the method described in example 1.

Example 3

1,25 g HPMC (Pharmacoat 603, the company Shin-Etsu Chemocal Co) was dissolved in 39.5 g of water at a temperature of about 75°C. the Solution was cooled to room temperature (25° (C), and adding a solution of 5 g of mannitol, 2.5 g of sodium bicarbonate and 1 g of crosspovidone, receiving the variance. 0.75 g Kryosome 1703H (hydrogenated lecithin, firm Lipoid AG) was dispersively 7.5 g of water using a homogenizer (transmitter station) for 30 s and then mixed with the above dispersion. The resulting aqueous system used to prepare the emulsion by emulsification of 4.5 g of melted oil mixture, obtained by joint fusion of 3.15 g trimyristin (Dynasan 114, the company Huls AG) and 6.3 g of orlistat at 65°using homogenizer type transmitter station for 1.5 min at 65°C. This emulsion was frozen at -80°in rotating round bottom flask of 250 ml in a mixture of dry ice-ethanol and then liofilizirovanny. Then lyophilized grinded at room temperature and 3 g of this productivemail and sieved through sieves with openings of 0.5 mm 1.3 g of the mixture extruded to obtain chewable tablets with a diameter of 16 mm, weight 1.3 g, each of which consisted of 60 mg of orlistat, 30 mg trimyristin, 15 mg Kryosome, 25 mg HPMC, 20 mg of crosspovidone, 100 mg of mannitol, 50 mg of sodium bicarbonate and 1000 mg of lactose.

Thus obtained chewable tablets was tested on human volunteers according to the method described in example 1.

Example 4

30 g of orlistat and 15 g trimyristin (Dynasan 114, the company Huls AG) was passed through sieves with openings of 0.9 mm and was stirred for 10 minutes the Mixture is again sieved through sieves with openings of 0.9 mm and was stirred for 10 minutes the resulting mixture of (portions) was subjected to coarse grinding in the mill for dry products for 0.5 min, adding three times the amount of dry ice. This cooled mixture is then subjected to cryogenic grinding in the mill with pins, getting small particles. The obtained particles were dried for 15 minutes in a high vacuum and then mixed with 2/3 (wt./wt.) of glucose. 15 g of this dry mixture was mixed with 100 g of lactose within 10 min and was then screened through a sieve with openings of 0.5 mm Finally, the thus obtained milled and mixed in a mill granulate is extruded with getting chewable tablets with a diameter of 16 mm, a weight of 1.15 g, each of which consisted of 60 mg of orlistat, 30 mg trimyristin, 60 mg Glu is eskers and 1000 mg of lactose.

Thus obtained chewable tablets was tested on human volunteers according to the method described in example 1.

Example 5

1.2 g of orlistat and 1.8 g of glucose was sifted through a sieve with openings of 0.9 mm and was stirred for 2 minutes and then 4.0 g Kryosome 1702 (the ratio of soy lecithin and sucrose, 1:2, the firm Lipoid AG) was also sieved through sieves with openings of 0.9 mm and mixed with the first mixture for 2 minutes Combined mixture is then subjected to cryogenic grinding in vostokstrojj mill using for cooling dry ice. The resulting particles were dried for 15 minutes in a high vacuum. 3.5 g of the dried particles were mixed with 10 g of lactose within 15 minutes Finally, the thus obtained powdery mixture was extruded to obtain chewable tablets with a diameter of 16 mm, weight : 1.35 g, each of which consisted of 60 mg of orlistat, 90 mg of glucose, 200 mg Kryosome and 1000 mg of lactose.

Thus obtained chewable tablets was tested on human volunteers according to the method described in example 1.

Example 6

4,24 g of soya lecithin and 4,24 g orlistat consistently was dissolved in 31,52 g glucotrol 75 (firm Roche). Empty solid gelatinolytic apsule was sealed using a 25%aqueous solution of gelatin in water and allowed to dry. In a sealed hard gelatin capsules punched hole and ZAT is m filled 565 mg solution orlistat/lecithin/glucotrol. The holes were sealed using the above solution of gelatin and closed capsule was allowed to dry for at least 15 minutes Each capsule contains 60 mg of orlistat, 60 mg of soy lecithin and 445 mg of glucotrol.

Thus obtained capsules were tested on human volunteers according to the method described in example 1.

Example 7

10 g of molten trimyristin (Dynasan 114, firm Hills AG) was mixed for 30 min at a temperature 57-63°With 20 g of orlistat. To the thus obtained to coreplay was added 20 g of glucose and mixed at room temperature until hardened, were crushed with a mixer for dry food and then sieved through sieves with openings of 1.6 mm, 48 g of the obtained particles was kept at 39°C for 4.5 h in a closed vessel in an atmosphere of inert gas, subjected to cryogenic grinding with dry ice in the mill with the pins. Then 15 g of the obtained particles was mixed for 30 min with 10 g Kryosome 1702 (firm Lipoid AG) and 100 g of lactose. The mixture was sifted through a sieve with openings of 0.5 mm and extruded with getting chewable tablets with a diameter of 16 mm, weight of 1.25 g, each of which consisted of 60 mg of orlistat, 30 mg trimyristin, 60 mg of glucose, 100 mg Kryosome and 1000 mg of lactose.

Thus obtained capsules were tested on human volunteers according to the method described in example 1.

When is EP 8

0.75 g melted together and subjected to cryogenic grinding product (orlistat-trimyristin-glucose 2:1:2)obtained according to the process described in example 7, 0.5 g Kryosome 1702 sieved through sieves with openings of 0.5 mm and was stirred for 10 minutes, 3.0 g of sodium bicarbonate and 1.5 g of tartaric acid grinded at room temperature in a laboratory blade mill, sieved through sieves with openings of 0.5 mm and was stirred for 10 minutes 2.7 g of this effervescent mixture was added to the first mixture and again stirred for 10 minutes 0,395 g this mixture was filled in capsules GPMC size 0, containing 30 mg of orlistat, 15 mg trimyristin, 30 mg of glucose, 50 mg Kryosome, 180 mg of sodium bicarbonate and 90 mg of tartaric acid.

Thus obtained capsules were tested on human volunteers according to the method described in example 1.

Example 9

20 g of orlistat and 10 g tilouine (Dynasan 112, the firm Hiils AG) was sifted through a sieve with openings of 0.5 mm and mixed. This mixture was subjected to cryogenic grinding with dry ice in the mill with pins and then dried in vacuum for 15 min to 10 g of this mixture was mixed with 15 g of glucose. 3 g of this mixture and 2 g Kryosome 1702 (firm Lipoid AG) were subjected to joint cryogenic grinding with dry ice in a laboratory blade mill and dried overnight in a vacuum former is cator. 1,25 g of the obtained powder was pressed with getting chewable tablets with a diameter of 16 mm, weight of 1.25 g, each of which consisted of 60 mg of orlistat, 30 g tilouine, 60 mg of glucose, 100 mg Kryosome and 1000 mg of lactose.

Thus obtained chewable tablets was tested on human volunteers according to the method described in example 1.

Example 10

16 g monolaurin (Rylo MG12, firm Danisco Ingregient AG) and 4 g of emulsifier monocaprin TS-PH003 (firm Danisco Ingregient AG) is melted together at a temperature of about 70°C, cooled to room temperature (25° (C) and thereby completely utverjdali. After 1 day from the walls scraped film with a spatula, portions subjected to rough grinding in the mixer for dry products at low temperature when adding dry ice (three-fold volume relative to the milled product) for about 0.5 min and then subjected to thin cryogenic grinding in the mill with pins and dried in vacuum for 15 minutes Mixing 15 g of this mixture and 15 g of orlistat. Added 50 g of dry ice and the mixture portions subjected to rough grinding, every time 0.5 minutes After drying in vacuo the resulting powder was sieved through sieves with openings of 0.9 mm and subjected to thin cryogenic grinding in the mill with pins, receiving a fine powdery mixture orlistat-monocaprin-monolaurin(50:10:40). 2,4G jointly milled mixture, containing approximately 2.16 g of tartaric acid and 4,56 g of sodium bicarbonate was added to 5.6 g of the above powder mixture and 2 g of anhydrous lactose was stirred for 5 min and sieved through sieves with openings of 0.5 mm and was again mixed. 500 mg of the resulting powder was filled in hard gelatin capsules containing 60 mg of orlistat, 48 mg monolaurin, 12 mg monocaprin, 100 mg of lactose, 190 mg of sodium bicarbonate and 90 mg of tartaric acid.

Thus obtained capsules were tested on human volunteers according to the method described in example 1.

Table 1

The results of the experiments in vivo
ExampleThe dose of orlistat (mg)Excretion config fat(1)n(2)Free oil in stool samples(3)
Standard120 (Xenical®)41,8±11,5189/18
16048,1±3,931/3
24037,6±17,150/5
36050,2±13,431/3
46043,1±the 15.650/5
56064,8±14,350/5
66047,2±to 12.05N/O
76082,0±5.560/6
86040,6±10,650/5
96060,6±13,352/5
106054,2±10,951/5

(1)excreted fat in the percentage of ingested fat

(2)the number of volunteers participating in the experiment

(3)the number of stool samples containing free oil/number of volunteers

As can be seen from table 1, the efficiency and/or activity of the compositions according to the invention is significantly higher than conventional compositions.

The composition of the invention containing only half or even a quarter of that amount of lipase inhibitor, which is used in known compositions had similar or even higher efficiency and/or activity. Using the present invention it is possible, while maintaining the same level of inhibition of lipases, significantly reduce the amount of active substance in the composition, minimizer whom I thus undesirable side effects.

In table 1 for each of the above compositions also shows the number of stool samples, which included free oil. In stool samples obtained after absorption of the compositions according to the invention is found very rarely or not found quite the separation of oil from the main mass of the chair. Thus, compositions according to the invention have the ability to minimize or completely suppress anal after oil, which is one of the most undesirable side effects known in the field of compositions.

1. Pharmaceutical composition for oral administration in the treatment or prevention of obesity or hyperlipidemia comprising orlistat and at least one ester of fatty acids and polyols, which differs in that the melting point of the fatty acid ester exceeds body temperature and the polyols are selected from the group comprising glycerol, sugars, derivatives of sugars and mixtures thereof.

2. The pharmaceutical composition according to claim 1, where the polyols independently from each other selected from the group comprising sucrose, glycerin and sugar alcohols.

3. The pharmaceutical composition according to claim 1 or 2, where the polyol is a glycerol.

4. The pharmaceutical composition according to any one of claims 1 to 3, where the fatty acid ester is an glycerides and it is chosen from the group consisting of one or a few is to triglycerides, one or more monoglycerides, one or more phospholipids and their mixtures.

5. The pharmaceutical composition according to any one of claims 1 to 4, where fragments of fatty acids in the fatty acid ester and polyol independently from each contain 12 or more carbon atoms and fragments of fatty acids in the fatty acid ester and polyol are saturated.

6. The pharmaceutical composition according to claim 5, where the fragments of fatty acids in the fatty acid ester and polyol independently of one another contain 12-20 carbon atoms.

7. The pharmaceutical composition according to any one of claims 4 to 6, where the triglycerides are selected from the group comprising Triowin, trimyristin, tripalmitin, tristearin and mixtures thereof.

8. The pharmaceutical composition according to claim 7, where the triglyceride is trimyristin or Triowin or mixtures thereof.

9. The pharmaceutical composition according to any one of claims 4 to 6, where monoglycerides selected from the group comprising monocaprin, monolaurin, monomerization, monopalmitate and mixtures thereof.

10. The pharmaceutical composition according to any one of claims 4 to 6, where the phospholipid is a lecithin.

11. The pharmaceutical composition of claim 10, where the phospholipid is dehydrogenation, partially or fully hydrogenated lecithin, and mixtures thereof.

12. The pharmaceutical composition of claim 10 or 11, where the phospholipids are selected from the group including the cabbage soup natural lecithin, synthetic lecithin, soy lecithin, egg lecithin, synthetic dipalmitoyl, partially or fully hydrogenated lecithin, and mixtures thereof.

13. The pharmaceutical composition according to any one of claims 1 to 12, where the ether of fatty acids and polyols are present in an amount of from 0.5 to 90%, calculated on the total weight of the composition.

14. The pharmaceutical composition according to any one of claims 1 to 13, further comprising at least one pharmaceutically acceptable excipient.

15. The pharmaceutical composition according to 14, where excipient chosen from the group comprising carbohydrates, starch and/or its derivatives, maltodextrins, cellulose, cellulose derivatives, sugar, fillers, disintegrating agents, effervescent mixtures, antioxidants, anionic surfactants, nonionic surfactants and mixtures thereof.

16. The pharmaceutical composition according to item 15, where the surfactant is chosen from the group comprising sodium dodecyl sulphate, salts of fatty acids, complex poly(oksietilenom)alkalemia esters and simple poly(oksietilenom)alkalemia esters and mixtures thereof.

17. The pharmaceutical composition according to any one of p-16, including excipient selected from the group comprising glucose, lactose, sorbitol, maltodextrin, talc, magnesium stearate, mannitol, sodium bicarbonate, crosspovidone, glycoluril, tartaric acid and mixtures thereof./p>

18. The pharmaceutical composition according to any one of claims 1 to 17, where the lipase inhibitor is an inhibitor of gastrointestinal lenses.

19. The pharmaceutical composition according p, where the inhibitor of gastrointestinal lipases represents orlistat.

20. The pharmaceutical composition according to any one of claims 1 to 19, where the inhibitor of lipase is present in an amount of from 1 to 50% based on the total weight of the composition.

21. The pharmaceutical composition according to claim 20, where the lipase inhibitor is present in an amount of 5 to 30% based on the total weight of the composition.

22. The pharmaceutical composition according to any one of claims 1 to 21, including

a) from 1 to 50% based on the total weight of the composition of at least one inhibitor of lipases;

b) from 0.5 to 90%, calculated on the total weight of the composition of at least one ester of fatty acids and polyols; and optional

C) one or more pharmaceutically acceptable excipients.

23. The method of preparation of the pharmaceutical composition according to any one of claims 1 to 22, providing a mixture of at least one lipase inhibitor and at least one ester of fatty acids and polyols and ether fatty acids and of polyols has a temperature greater than body temperature, and the polyols are selected from the group comprising glycerol, sugars, derivatives of sugars and mixtures thereof.

24. The method of treatment or prevention is Denia obesity, introducing a patient the pharmaceutical composition according to any one of claims 1 to 22.



 

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FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

eliciting inhibitory effect on activity of HMG-CoA-reductase and, therefore, can be used for preparing pharmaceutical agents for treatment, for example, hypercholesterolemia, hyperproteinemia and atherosclerosis. Also, invention relates to a method for preparing indicated intermediate compound by reaction of the new parent compound - diphenyl-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-ylmethyl]phosphine oxide with tert.-butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxane-4-yl]acetate in the presence of a strong base in simple ether or aromatic solvents or their mixtures at temperature in the range from -200C to -900C. Also, invention relates to a method for preparing of compound of the formula (IV) wherein R1 means hydrogen atom or pharmaceutically acceptable cation and to a method for preparing intermediate compounds of the formula (VI):

wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

and wherein P3 represents (C1-C8)-alkyl. Applying new intermediate compounds and proposed methods provide enhancing quality and yield of compounds.

EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex

The invention relates to medical and pharmaceutical industry, namely the use of homogenate and freeze-dried from drone larvae, can be used as sources of highly effective medicinal and therapeutic tools

The invention relates to pharmaceutical industry and relates to the creation of medical-prophylactic vegetable-based with a wide spectrum of pharmacological action

The invention relates to pharmacology

Chewing gum // 2180561
Chewing gum // 2141217
The invention relates to the food industry and can also be used in medicine for diagnostic purposes
Chewing gum // 2118157
The invention relates to medicine, in particular to anesthesiology, and can be used for pain control in dental practice in the treatment of uncomplicated caries), surgery (with dressings), ENT, endoscopy, etc

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a medicinal agent made as a gelatin capsule. A medicinal agent as gelatin capsule consists of cycloserine and accessory additives wherein calcium phosphate dihydrate, aerosil and calcium stearate taken in the definite components are used as accessory additives. Also, gelatin capsule comprises additionally glutamic acid, gelatin and water, Invention provides rapid and complete release of agent in intake and the development of a medicinal formulation reducing toxicity of an active substance and eliciting stability in storage.

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

1 tbl, 1 ex

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