Pharmaceutical composition comprising lipase inhibitor and sucrose fatty acid ester

FIELD: medicine, pharmacology, biochemistry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition that comprises a medicine orlistat and sucrose fatty acid ester wherein fatty acid moiety in fatty acid di-, tri- or tetra-ester means a mixture of two or some fatty acids. Also, invention relates to a method for treatment of obesity by using the claimed composition. Invention provides enhancing effectiveness of treatment.

EFFECT: enhanced and valuable properties of composition.

36 cl, 5 dwg, 7 tbl, 19 ex

 

The present invention relates to a pharmaceutical composition comprising a lipase inhibitor, preferably orlistat, having a melting point of ≥37°C, fatty acid ester of sucrose where the above-mentioned ester is a mono-, di-, tri - or tetraform, and optionally one or more pharmaceutically acceptable excipients.

Examples of such lipase inhibitors are lipstatin and orlistat. The latter is also known as tetrahydrolipstatin or THL and is derived from a natural product secreted Streptomyces toxytricini. It was found that this class of compounds have activity in vitro and in vivo against various lipases, such as lingual lipase, pancreatic lipase, gastric lipase and carboxylesterase. Its application for the control or prevention of obesity and hyperlipemia described, for example, in patent US 4598089.

Currently, orlistat is administered at a dose of 120 mg per meal, and the dose is administered independently of the mass of the body. Orlistat acts locally in the gastrointestinal (GI) tract and prevents the breakdown of triglycerides by lipase and, therefore, suppresses the formation of degradation products are absorbed lipids. For this reason, inhibitors of lipase is not required system availability, and instead preferred is a local finding what begins in the gastrointestinal tract.

Currently imposed compositions of lipase inhibitors suppress about 30% absorption of fat after consuming mixed meals; increase in the concentration of lipase inhibitors in the pharmaceutical composition does not increase its clinical efficacy and/or effectiveness, while the intensity of local side effects increases.

Anal expiration butter (butyric spots) is an undesired effect that sometimes occurs in patients taking inhibitors of lipase. This phenomenon reflects the physical separation of a quantity of liquid unabsorbed fat coming from food, from a large number of solids in the lower part of the colon.

In the patent US 5447953 it is shown that the combination of lipase inhibitor with significant amounts of insoluble crude fiber inhibitory effect on fat absorption can be enhanced. In WO 00/09123 demonstrated that the combination of a lipase inhibitor, such as orlistat, with small amounts of chitosan or its derivative, or salt phenomenon anal expiration oils may be impaired.

WO 01/19378 discloses solid lipid composition for lipase inhibitors, applicable to reduce or prevent the excretion of fat and undesirable formation of free oil. It was found that bol is e high efficiency (high excretion of fat) may be combined with a reduction in undesirable side effects, for example, the formation of free oil. Recently it was found that the efficiency of lipase inhibitors may significantly depend on the type of digestible food. High efficiency was found when eating, consisting of potato chips, fried in butter, hotdogs and hamburgers, while the lowest efficiency was observed when consuming cheese and other dairy products. A strong dependence of the efficiency of the composition from the power supply is an undesirable phenomenon because or when susceptible diets composition overdose (and consequently the formation of free oil), or inactive when less susceptible diets. Therefore, the reduction of dependence on power is a prerequisite for the implementation of the action plan with a low dose of the inhibitor, high efficiency and minimal side effects.

It has been unexpectedly found that a subgroup of some fatty acid esters of sucrose may enhance the activity of lipase inhibitors, to reduce dependence on power and reduce the formation of free oil.

Drawings

Figure 1 shows that compositions based on esters of sucrose, are approximately 1.7 times higher efficiency with 240 mg of ester of sucrose R, component of 67.4 (±5,3%, n=5), 30 mg of ester Saha is eskers R, component of 66.6% (±13%, n=4), compared with xenicalcom, the efficiency of which is 39,7% (±8,1%, n=5), in the experiment of double ingestion, conducted on human volunteers.

Figure 2 shows that the effectiveness of xenical less digestible food was only 48.4 percent compared with digestible, while the composition is 30 mg of ester of sucrose R reached 73,9% (experiment double meal on volunteers).

Figure 3 shows the studied emulsions Surfhope SE Pharma D-1811 after centrifugation at 3100g for 1 min (a) and 300 min (b), respectively. Emulsion containing a 2.0% (wt./wt.) complex ester of sucrose, remains stable even after centrifugation for 300 min ((b), the right capillary). Left to right: standard (a mixture of soybean oil/buffer); C=0,01%; C=0,1%; C=0,5%; C=1,0%; C=1,5%; C=2,0% (wt./wt.).

Figure 4 shows the studied emulsions Surfhope SE Pharma D-1811 after centrifugation at 3100 g for 1 min (a) and 300 min (b), respectively. Emulsions stabilized with 1% of ester of sucrose at different pH values. While the emulsion at pH≤7 clearly demonstrate the separation of the phases after centrifugation for 300 min, the emulsion at pH>7 emit significantly less free oil.

The present invention relates to a pharmaceutical composition comprising a lipase inhibitor, preferably orlistat, available the melting point ≥ 37°C, fatty acid ester of sucrose where the above-mentioned ester means a mono-, di-, tri - or tetraethyl, and optionally one or more pharmaceutically acceptable excipients.

Fatty acid esters of sucrose are nonionic surfactants consisting of sucrose as hydrophilic part and one or more fatty acid residue as lipophilic groups. They are obtained from purified sugar and vegetable oils. As sucrose contains 8 hydroxyl groups, it is possible to obtain derivatives that make up the range from mono - to Octavio sucrose with fatty acids. The following formula shows the example of the chemical structure of sucrose monostearate

The term "fatty acid ester of sucrose" includes one fatty acid ester of sucrose and a mixture of two or more esters of sucrose with fatty acids, as defined below. In a preferred variant embodiment of the present invention, the degree of substitution of ester of sucrose varies between 1 and 4; for example mono-, di-, tri-, tetraethyl fatty acids with sucrose. The term includes pure esters of sucrose, and mixtures of esters of sucrose, where ester of sucrose can be etherified the van of different fatty acids and can have multiple degrees of substitution, for example mono-, di-, tri - or Tetra-substituted.

Fatty acid esters of sucrose, mixtures thereof and the drug is known in the art and are commercially available (Mitsubishi-Called Foods Corp., Montello Inc., Multi-Kem Corp., and so on; see also Garti N.; Clement V.; Leser, M.; Aserin, A.; M. Fanun "Microemulsions esters of sucrose". J. Mol. Liq. (1999), 80(2,3), 253-296; "Ugleobogatitelnye ester derivatives as surface-bioactive substances". Allen D.K.; Tao B.Y., J. Surfactants Deterg. (1999), 2(3), 383-390).

The term "lipase inhibitor" refers to compounds that are able to suppress the action of lipases, such as gastric and pancreatic lipases. For example, orlistat and lipstatin, as described in patent US 4598089, are strong inhibitors of lipases. Lipstatin is a natural product of microbial origin, and orlistat is formed by the hydrogenation of lipstatin. Other lipase inhibitors include the class of compounds commonly referred to as anglicani. Anglicani are analogues of orlistat (Mutoh etc., J. Antibiot. (1994), 47(12), 1369-1375). The term "lipase inhibitor" also refers to synthetic inhibitors of lipase, for example, described in WO 99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized in that they are substituted by one or more groups which inhibit the lipase. The term "lipase inhibitor" also includes pharmaceutically acceptable salts of these compounds. In addition, the term "inhibitor does the basics" also applies to 2-oxy-4H-3,1-benzoxazin-4-Onam, described in WO 00/40569 (Alizyme Therapeutics Ltd.), for example, 2-decyloxy-6-methyl-4H-3,1-benzoxazin-4-one, 6-methyl-2-tetradecenoic-4H-3,1-benzoxazin-4-one and 2-hexadecylamine-6-methyl-4H-3,1-benzoxazin-4-one and other oxetanone described, for example, in WO 01/32616, WO 01/32669 and WO 01/32670. Most preferably, the term "lipase inhibitor" refers to orlistat.

In the patent DE 1965133 (Merck) describes some of the polymers based on polystyrene, which have the property of direct inhibition of lipase after binding of bile acids and triglycerides.

Orlistat is a known compound (formula I), applicable to the regulation or prevention of obesity and hyperlipemia.

See US patent 4598089, published July 1, 1986, which discloses how to get orlistat, and the US patent 6004996, which opens the corresponding pharmaceutical compositions. Other relevant pharmaceutical compositions are described, for example, in WO 00/09122, WO 00/09123, WO 01/19340 and WO 01/19378. Additional ways to get orlistat disclosed in European applications 185359, 189577, 443449 and 524495.

In a preferred variant embodiment of the present invention, the complex molecules of sucrose esters are mono-, di - and treatery. More preferably, the complex molecules of sucrose esters are mono - and diesters and most preferably is an ester of sucrose is monoform.

In di-, tri - or therefore residues of fatty acids can be identical or different (for example, palmitostearate sucrose), preferably identical.

The preferred ratio (wt./wt.) between the lipase inhibitor and complex fatty acid ester of sucrose following. The composition may include from 0.05 to 20 mg of a complex of fatty acid ester of sucrose, 1 mg lipase inhibitor, preferably 0.1 to 10 mg of a complex of fatty acid ester of sucrose, 1 mg lipase inhibitor, more preferably 0.1 to 2 mg of complex fatty acid ester of sucrose, 1 mg lipase inhibitor and most preferably 0.15 to 1 mg of complex fatty acid ester of sucrose, 1 mg lipase inhibitor.

Preferably, the lipase inhibitor is a lipophilic compound. Most preferably, the lipase inhibitor is orlistat.

In an additional preferred variant of embodiment of the present invention, the residue of a fatty acid complex of fatty acid ester of sucrose means (C8-C24)fatty acid, saturated or partially unsaturated. Preferably the residue of a fatty acid complex of fatty acid ester of sucrose means rich (C12-C18)fatty acid, such as sucrose laurate, myristate sucrose, sucrose palmitate, sucrose stearate, arachidonate sucrose and beenout sugar is SHL, preferably sucrose laurate, myristate sucrose, sucrose palmitate, sucrose stearate, more preferably sucrose palmitate or stearate sucrose.

In an additional preferred variant of embodiment of the present invention fatty acid complex of sucrose esters may be selected from (C8-C24), preferably (C12-C18)fatty acids, mono-or polyunsaturated, for example, selected from the group consisting of palmitoleic acid, oleic acid, elaidic acid, erucic acid, linoleic acid, γ-linolenic acid, α-linolenic acid and arachidonic acid, the most preferred oleic acid, i.e. a complex fatty acid sucrose esters may be sucrose oleate.

Fatty acid part in di-, tri - or tetrafino sucrose can be a mixture of residues of two or more fatty acids, such as palmitostearate sucrose.

For lipase inhibitors, as described above, such as orlistat, preferred compositions include 10-240 mg, more preferably 30-120 mg, for example 30, 40, 60, 80, 100 or 120 mg. Especially preferred compositions consist of 60 to 120 mg of orlistat and 20-100 mg of fatty acid complex ester of sucrose.

For example, the composition as defined above, may include 120 mg orlistat 60 mg of ester of sucrose or 120 mg of the Lestat and 30 mg of fatty acid complex ester of sucrose. Another composition may include 80-120 mg of orlistat and 10-40 mg fatty acid complex ester of sucrose or 20 to 60 mg of orlistat and 5-15 mg fatty acid ester of sucrose. Each standard dose of the above-mentioned pharmaceutical compositions can contain daily dose of pharmaceutically active compounds or may contain part of the daily dose, such as one third of the dose. Alternate each standard dose can contain all the dose of one of the compounds and of the doses of other compounds. In this case, the patient every day would take one of the combined standard doses and one or more standard doses containing only another connection. Orlistat in the number of 30-800 mg per day, preferably administered orally in divided doses two to three times a day (see above). Other preferred daily dose can be in the range between 120 and 360 mg, more preferred are a daily dose of between 180 and 270 mg, and most preferred 180 mg. Preferably the daily dose is divided and administered twice or particularly three times a day. Generally, it is preferable that the lipase inhibitor must be entered within approximately one to two hours of digestion of food containing fat. As a rule, for the introduction of a lipase inhibitor, as defined above, it is preferable that the treatment had been the b man which has a compelling family history of obesity or reached a body mass index of 25 or more.

The compositions of the present invention can be administered to the people in the form of traditional oral dosage forms such as tablets, tablets coated, hard and soft gelatine capsules, emulsions, suspensions, dry powders, wafers or crackers. Examples of media that can be used for tablets, tablets coated, coated tablets, hard gelatin capsules and dry powders are pharmaceutically acceptable excipients as lactose or other carbohydrates and carbohydrate alcohols like sorbitol, mannitol, maltodextrin, or other fillers; surfactants like sodium lauryl sulfate, simple alerby ether of polyethylene glycol (Brij 96), tween 80; disintegrators, as modified by glycolate sodium starch, corn starch or derivatives thereof; polymers such as povidone, crosspovidone, moving substances as talc; stearic acid or its salt and the like. Moreover, the pharmaceutical compositions can contain preservatives, substances that contribute to the dissolution, stabilizers, wetting agents, binding agents, emulsifiers, sweeteners, colorants, flavoring agents, salts for modifying the osmotic pressure, buffers, enrobing is the means and antioxidants. They may also contain other valuable substances. The composition may for convenience be presented in a standard dosage form and obtained by any means known in the field of pharmacy.

In particular, the above-mentioned composition can include one or more fillers selected from the group consisting of mannitol, lactose, hydroxypropylmethylcellulose (receiver array), lecithin, sorbitol, talc, polyvinylpyrrolidone, polyethylene glycol, Polysorbate, polyoxyethylenated and Dimethicone, preferably lactose.

Oral dosage forms are preferred compounds for use according to the present invention, and they are the known pharmaceutical forms for such administration, for example tablets, capsules or dry powders. Pharmaceutically acceptable fillers (diluents and carriers) are known to pharmacists. Tablets can be formed from a mixture of active compounds with extenders, such as calcium phosphate; with disintegrators, such as corn starch, sliding agents, such as magnesium stearate; binders, such as microcrystalline cellulose or polyvinylpyrrolidone, and other optional ingredients known in the field to allow tableting the mixture by known methods. Like about the time capsule, for example hard or soft gelatin capsules, containing the active compound with added fillers or without them, can be obtained by known methods. The contents of the capsules can be prepared using known methods in such a way as to provide slow release of the active compounds. For example, tablets and capsules for convenience may contain each of a number of pharmaceutically active compounds and a complex ester of sucrose, as described above.

The term "pharmaceutically acceptable"as used in the context, means that the corresponding connection is acceptable from the point of view of toxicity.

Oral dosage form can be a chewable tablet comprising 10-240 mg of orlistat, 0.5 to 1000 mg of fatty acid complex ester of sucrose and, in addition, fillers such as maltodextrin, lactose or cellulose, for example 120 mg of orlistat, 30 mg of sucrose palmitate, such as sucrose palmitate R, 960 mg of maltodextrin, 360 mg cellactose and 15 mg of talc.

In the compositions of the present invention the active compounds optionally may be combined with other compatible pharmacologically active ingredients. Vitamin supplements may not necessarily introduced with the compounds of the present invention.

The invention relates also to FPIC is Boo obtain compositions as described above, comprising mixing pharmaceutically active compounds with fatty acid complex ester of sucrose and one or more pharmaceutically acceptable diluents and/or carriers.

The invention also provides use of the above-mentioned combinations of the compounds in the manufacture of a medicinal product for the treatment or prevention of obesity. In addition, it provides the above-mentioned composition for use in the treatment and prevention of obesity.

In addition, the present invention relates to a method of treating obesity in a human in need of such treatment, which includes the introduction of man pharmaceutically active compound, as defined above, and fatty acid complex ester of sucrose and optional additional pharmaceutically acceptable excipients.

The invention relates also to the use of a composition as defined above for use in the treatment and prevention of obesity.

Another variant of the embodiment of the present invention relates to a method for obtaining a composition, as defined above, comprising mixing the pharmaceutically active compound as defined in claim 1 of the claims, with a complex ester of sucrose and optionally even with a pharmaceutically acceptable diluent and/or carrier.

Further, the invention from OSISA to set for the treatment of obesity, said set including a first component which is a lipase inhibitor and a second component, which is a fatty acid ester of sucrose in standard dosage form.

Another variant embodiment of the invention relates to the use of a composition as defined above in the manufacture of drugs used for the treatment and prevention of obesity, and to a method of treating obesity in a human in need of such treatment, which comprises administration to a human a therapeutically effective amount of a lipase inhibitor and a complex of sucrose esters defined above. The invention relates also to the lipase inhibitor and complex ether of sucrose, as defined above, for the treatment and prevention of obesity.

The invention will be better understood by the following examples which illustrate, but not limit the invention described in the context.

Examples

General note: all of the connections used in the examples are commercially available.

Example 1. The transfer of orlistat in oil in vitro

td align="left"> Xenical
CompositionTransfer to cream (%)Migration in olive oil (%)
after 10'after 60'after 10'after 60'
5103570
L-169555655580
R-167025455080
S-167010256090
O-157055654580

Suspension orlistat (4 mg), stable esters of sucrose (2 mg)was transferred into 5 ml of emulsion, 10% oil in water (pH value of 4.5; oil ingredients: olive oil and cream, respectively). The dispersion was subjected to constant stirring for the desired period of time. The oil phase was separated by centrifugation in the cold and the contents of orlistat in the oil phase was determined by HPLC. For adequate comparison experiment was also conducted with the suspension xenical®. L-1695, P-1670, S-1670, O-1570 are commercially available esters of saccharose (sucrose laurate, sucrose palmitate, sucrose stearate, sucrose oleate) from Mitsubishi-Called Foods, Japan.

The results show that the ester of sucrose is more effective when the transfer of orlistat in oil compared with xenicalcom®. In addition to the overall higher transfer efficiency and in contrast to xenica what we® orlistat is transferred to various types of oils (cream: emulsified and covered with casein oil drops; olive oil: unprotected oil) when more comparable speeds. The high dependence of orlistat from food is reflected in the fact that migration in olive oil after 10 minutes seven times more efficient than transfer to cream. Ester of sucrose shows less dependence on food. Consequently, it is possible to expect reduction of dose and weakened side effects.

Example 2. The composition tablets

Were made chewable tablets of the following composition.

Composition 1
Orlistat120 g
Sucrose palmitate R30 g
Maltodextrin960 g
Cellactose360 g
Talc15 g

Orlistat, palmitate sucrose and maltodextrin were mixed to a homogeneous state and portions were added 350 g of water with continuous stirring.

With a syringe homogeneous dispersion was distributed on the sieve (hole size 0.5 mm) in Truckee. The sieve was put in a vacuum drying oven (Heraeus VT 5050 EC), which raised the temperature to 25°C. the chamber Pressure was reduced to 30 mm Hg (Leybold Heraeus TRIVAC D8B; COMAT AG DP 700). After 5 min the creation of the foam structure was completed. The foam was dried in vacuum for several hours. Carefully controlled so that the temperature of the foam does not exceed 35°C. the Resulting foam was ground and sieved to achieve a homogeneous free flowing powder. Added cellactose and talc distributed to homogeneity by dry mixing. From the resulting composition produced tablets containing 120 mg of orlistat, 30 mg of sucrose palmitate, 960 mg of maltodextrin, 360 mg cellactose and 15 mg of talc.

Example 3. The composition chews

Were made chewable tablets of the following composition.

Composition 2
Orlistat120 g
Sucrose palmitate R240 g
Maltodextrin750 g
Cellactose375 g
Talc15 g

Tablets produced in the same manner as described in example 2.

Example 4. The composition chews

Were made chewable tablets of the following composition.

Composition 3
Orlistat60 g
Sucrose palmitate R 60 g
Maltodextrin750 g
Cellactose375 g
Talc15 g

Tablets produced in the same manner as described in example 2.

Example 5. The composition chews

Were made chewable tablets of the following composition.

Composition 4
Orlistat60 g
Sucrose stearate S181160 g
Maltodextrin750 g
Cellactose375 g
Talc15 g

Tablets produced in the same manner as described in example 2.

Example 6. The composition chews

Were made chewable tablets of the following composition.

Composition 5
Orlistat60 g
Sucrose myristate M169560 g
Maltodextrin750 g
Cellactose375 g
Talc15 g

Tablets produced in the same manner as described in example 2.

Example 7. The composition chews

Were the projectors is prepared since the chewable tablets of the following composition.

Composition 6
Orlistat60 g
Sucrose stearate S181660 g
Maltodextrin750 g
Cellactose375 g
Talc15 g

Tablets produced in the same manner as described in example 2.

Example 8. The composition of the granules

Composition 7
Orlistat240 g
Sucrose palmitate R60 g
Avicel PH-10535 g
Starch-modified glycolate sodium60 g
Povidone K30 g

The ingredients were mixed in a dry form in a high speed mixer Diosna P450. Added portions 240 g of water and continued procedure mixing for about 5 minutes this material fills the extruder (NICA lab E-140; mesh hole size 0.8 mm, 1.0 mm thick mesh surrounded by a cooling device). The material was extrudible in the form of small tubes of appropriate length. The temperature of the extrudate does not exceed 35°C. the Extrudate was transferred into spheronization (NICA lab S320) and processed for pridani the spherical shape for 0.5-3 min at 700 rpm The wet granules were dried in the apparatus for drying in pseudouridine layer (Aeromatic MP-1) at temperatures below 35°C. the Dried granules were sifted through a sieve with inserts with hole sizes of sieves of 0.5 and 1.25 mm, and fractions less than and greater than the specified size are discarded. The granules were filled package of the normal dose of 106 mg (corresponding to 60 mg of orlistat).

Example 9. The capsules composition

The above pellets were filled in a gelatin capsule of size I at a dose of 106 mg (corresponding to 60 mg of orlistat).

Example 10. The composition tablets

Was added magnesium stearate to the granules described in example 8, in the amount of 1% (wt./wt.) and distributed to a homogeneous state by appropriate mixing. The mixture was pressed into tablets of 107 mg, which corresponded to 60 mg of orlistat.

Example 11. The efficiency of in vitro

Table: reduced dependent on food efficiency compositions based on a complex ester of sucrose in the analysis of inhibition in vitro lipase with digestible and resistant to the absorption of fat. Researched granules xenical and tablets from example 2 and example 3. Added water to the crushed tablet to obtain a concentration of orlistat 6,64 mg/ml Sample was stirred for 15 min and was preparing a series of dilutions in a geometrical progression. Aliquot part of each stage of the dilution was mixed with substrate and on univali inhibition of lipase. The final emulsion contained a 2.5% (wt./about.) fat and 10 mg/ml of Pancreatin on the US Pharmacopoeia (USP).

Analysis of the inhibition of lipase in vitro simulates the digestion of fat in the gastrointestinal tract and evaluates dependent on the composition of the food suppression of lipolysis. In this experiment the substrate lipase (cream and coarse hamburger/potato crisps, fried in oil, representing resistant to digestion and digestible fat, respectively) were preincubated composition of tetrahydrolipstatin (THL) in simulated gastric conditions (i.e. at pH 4.5 in the presence of 20% human gastric fluid). During inactivated in the song, you can enter the oil droplets with THL. Then adding artificial intestinal fluid containing bile salts, phospholipids and hydrolytic enzymes (Pancreatin), began lipolysis. After 1 h was added organic solvent, to stop the reaction, and determined the amount of free fatty acids. The shape of the curve dose-response depended on the composition and on the type of substrate used.

The value of the IC50means the concentration at which the cleavage of the triglyceride inhibited by 50%. Higher dependence on food observed for xenical, IC50increased by a factor of 20. Dependence on food in vitro compositions based on other attributes of the aqueous sucrose esters was approximately 6 times less than xenicalcom.

Example 12. Efficiency in vivo.

Tablets containing 120 mg of orlistat, which is described in example 2 (30 mg sucrose palmitate) and example 3 (240 mg sucrose palmitate), and xenical tested on volunteers through the test double of the meal, which was of digestible fat (lunch: hamburger, fried in oil potato chips) and less digestible fat (lunch: cheese food). Unabsorbed fat was determined by Bligh and Dyer (Bligh E.G.; Dyer W.J. Can. J. Biochem. Physiol. 37 (1959) 911). The results show (1)that the compositions based on esters of sucrose, are approximately 1.7 times higher efficiency with 240 mg of ester of sucrose R, component of 67.4 (±5,3%, n=5), 30 mg of ester of sucrose R, component 66,6% (±13%, n=4), compared with xenicalcom, the efficiency of which is 39,7% (±8,1%, n=5).

Example 13.

Dependence on food in vivo.

Specific analysis of the fatty acids of chair allows you to selectively determine the absorption of fat from food, adopted during lunch and dinner respectively. The results show that the effectiveness of xenical less digestible food was only 48.4 percent compared with digestible, while the composition is 30 mg of ester of sucrose R reached 73,9%. Based on these data we can conclude that the dependence of the efficiency of orlistat from piximage to be essentially minimized by using compositions based on esters of sucrose.

Example 14. Side effect of in vitro studies.

Among various other control strategies anal expiration of education in the colon stable emulsion of dietary fat is of extreme importance. For this reason, using the technique of centrifugation was investigated emulsifying properties of esters of sucrose, covering a wide range of hydrophilic-lipophilic balance (HLB). This in vitro method made it possible to investigate how the concentration and pH-dependent stability of emulsions and, therefore, to take esters of sucrose with high potential to control side effects. The results of studies on the stability of emulsions, depending on the concentrations shown in tables 1-3.

Table 1

The stability of the studied emulsions Surfhope SE Pharma D-1815 at various concentrations with and centrifugation time t
C (% wt./wt.)The stability of the emulsion Surfhope SE Pharma D-1815 t/min
1070100160220300
0,01low*lowlowlowlowlow
0,1highaverageaverageaverageaverageaverage
0,5highaverageaverageaverageaverageaverage
1,0highaverageaverageaverageaverageaverage
1,5highaverageaverageaverageaverageaverage
2,0highaverageaverageaverageaverageaverage
* low: oil and water form two clearly separated different phases;

medium: emulsion partially destroyed;

high: no signs of coalescence, optically opaque stable emulsion.

Table 2

The stability of the studied emulsions Surfhope SE Pharma D-1811 at various concentrations with and centrifugation time t
C (% wt./wt.)The stability of the emulsion Surfhope SE Pharma D-1811 t/min
1070100160220300
0,01low*lowlowlowlowlow
0,1highhighaverageaverageaverageaverage
0,5highhighaverageaverageaverageaverage
1,0highhighhighaverageaverageaverage
1,5highhighhighaverageaverageaverage
2,0highhighhighhighhighhigh
* low: oil and water form two clearly separated different phases;

medium: emulsion partially destroyed;

high: no signs of coalescence, optically opaque stable emulsion.

Table 3

The stability of the studied emulsions Surfhope SE Pharma D-1811 at various concentrations with and centrifugation time t
C (% wt./wt.)The stability of the emulsion Surfhope SE Pharma D-1805 t/min
1070100160220300
0,01low*lowlowlowlowlow
0,1lowlowlowlowlowlow
0,5averageaverageaverageaverageaverageaverage
1,0averageaverageaverageaverageaverageaverage
1,5highaverageaverageaverageaverageaverage
2,0highhighhighaverageaverageaverage
* the izkuyu: oil and water form two clearly separated different phase; < / br>
medium: emulsion partially destroyed;

high: no signs of coalescence, optically opaque stable emulsion.

It is proved that the esters of sucrose, such as Surfhope SE Pharma D-1811 (table 2), having an average HLB value equal to 11, slightly superior in its ability to stabilize the emulsion is relatively Surfhope SE Pharma D-1815 (table 1) and Surfhope SE Pharma D-1805 (table 3), respectively. At a concentration of 2% (wt./wt.) Surfhope SE Pharma D-1811 appear stable emulsion without any visible signs of coalescence during centrifugation time t up to 300 min (figure 1). As Surfhope SE Pharma D-1815, and Surfhope SE Pharma D-1805 are only slightly less stable the emulsion stability. In addition, measurement of the emulsions prepared in this way, stored at room temperature for 1 week without the use of any centrifugal force found that the state generated in the experiment centrifugation, corresponds to a period of normal storage for about 2-3 days, which is well comparable with the average time of passage through the GI tract in humans.

Figure 3 shows the studied emulsions Surfhope SE Pharma D-1811 after centrifugation at 3100g for t=1 min (a) and t=300 min (b), respectively. Emulsion containing a 2.0% (wt./wt.) complex ester of sucrose remained ostoich the howl even after centrifugation at time t=300 min ((b), right capillary). Left to right: standard (a mixture of soybean oil/buffer); C=0,01%; C=0,1%; C=0,5%; C=1,0%; C=1,5%; C=2,0% (wt./wt.).

Similar studies of the stability of the emulsions was performed using combinations of esters of sucrose and hydrocolloids (suprise, xanthan resin, Gellan resin, carraginanous resin), sphingomyelin derived Aerosil, carboxymethylcellulose sodium form, chitosan, bentonite, concentrates, whey protein, pectin and polyvinyl alcohol. Interestingly, these studies showed that the combination of 1:1 (wt./wt.) Surfhope SE Pharma D-1815 and Aerosil 200, carraginanous resin and whey protein concentrates form emulsions with clearly better stability than single compounds separately, due to yet unknown mechanism of synergism.

To study the stability of emulsions at different pH values were prepared analyzed emulsion with a concentration of surface-active substances s=1.0% wt./wt., covering the range of pH 4-9 (table 4-7). At pH>7 all the investigated fatty acid esters of sucrose showed good emulsifier properties. After centrifugation for 300 min, only a small upper free oil phase was separated from the optically opaque phase of the emulsion. Esters of sucrose with an HLB value below 11 showed only NESN is significant emulsifying properties at pH values< 7 (table 5-7). Surprisingly, Surfhope SE Pharma D-1815, having an HLB value equal to 15, formed a highly stable emulsion. This clearly indicates that esters of sucrose with a relatively high HLB value (usually around 15) upon receipt of the emulsions provide almost does not depend on excellent pH stability.

Table 4

The stability of the studied emulsions Surfhope SE Pharma D-1815 (C=1.0 wt./wt.) at different pH values and centrifugation time t
pHThe stability of emulsions Surfhope SE Pharma D-1815 t/min
13060120300
4high*highhighhighhigh
5highhighhighhighhigh
6highhighhighhighhigh
7highhighhighhighaverage
8highhighaverageaverage
9highhighaverageaverageaverage
* low: oil and water form two clearly separated different phases;

medium: emulsion partially destroyed;

high: no signs of coalescence, optically opaque stable emulsion.

Table 5

The stability of the studied emulsions Surfhope SE Pharma D-1811 (C=1.0 wt./wt.) at different pH values and centrifugation time t
pHThe stability of emulsions Surfhope SE Pharma D-1811 t/min
13060120300
4high*averageaverageaveragelow
5highaverageaverageaveragelow
6highhighaverageaverageaverage
7highhighaverage averageaverage
pHThe stability of emulsions Surfhope SE Pharma D-1811 t/min
8highhighhighhighaverage
9highhighhighhighaverage
* low: oil and water form two clearly separated different phases;

medium: emulsion partially destroyed;

high: no signs of coalescence, optically opaque stable emulsion.

Table 6

The stability of the studied emulsions Surfhope SE Pharma D-1807 (C=1.0 wt./wt.) at different pH values and centrifugation time t
pHThe stability of emulsions Surfhope SE Pharma D-1807 t/min
13060120300
4high*averageaverageaveragelow
5highaverageaverageaveragelow
6 highhighaverageaveragelow
7highhighhighaverageaverage
8highhighhighhighaverage
9highhighhighhighaverage
* low: oil and water form two clearly separated different phases;

medium: emulsion partially destroyed;

high: no signs of coalescence, optically opaque stable emulsion.

Table 7

The stability of the studied emulsions Surfhope SE Pharma D-1805 (C=1.0 wt./wt.) at different pH values and centrifugation time t
pHThe stability of emulsions Surfhope SE Pharma D-1805 t/min
13060120300
4low*lowlowlowlow
5averageaveragelowlowlow
6averageaverageaverageaverageaverage
7highhighaverageaverageaverage
8highhighhighhighhigh
pHThe stability of emulsions Surfhope SE Pharma D-1805 t/min
9highhighhighhighhigh
* low: oil and water form two clearly separated different phases;

medium: emulsion partially destroyed;

high: no signs of coalescence, optically opaque stable emulsion.

Figure 4 shows the studied emulsions Surfhope SE Pharma D-1811 after centrifugation at 3100 g for 1 min (a) and 300 min (b), respectively. Emulsions stabilized with 1% (wt./wt.) of ester sakh the roses at different pH values. While the emulsion at pH≤7 clearly demonstrate the separation of the phases after centrifugation for 300 min, the emulsion at pH>7 emit significantly less free oil. Left to right: standard (a mixture of soybean oil/buffer) at pH 7; pH 4; m; pH 6, pH 7, pH 8, pH 9.

In contrast, fatty acid ester of sucrose S-370F showed very poor emulsifying properties. Due to the high hydrophobicity of the solubility of compounds in a continuous aqueous phase was very low. However, the compound is very readily soluble in soybean oil, which leads to a substantial increase in the viscosity of the oil.

Example 15. Side effect of in vivo studies

Murine model in vivo was established to study the ability of esters of sucrose to reduce the formation of free oil after treatment with orlistat. Orlistat was mixed with oil and was added to the feed. The concentration of orlistat injected mice was 150 Ámol/kg body weight. The experiment is based on the observation that mouse when consuming food with high fat content, treated with orlistat or other inhibitors of lipase, in the care of the body surface is distributed free-apoptotic genes oil on top of their skins (US patent 5431949). A number of esters of sucrose, mentioned above, were investigated for their ability to reduce or stop the formation of free the oil. The results of these studies are summarized in figure 5.

In this view excretion of free oil control group that received orlistat, but did not receive any agent, regulating gastrointestinal side effects, was adopted as the background level, which is arbitrarily set to zero. Any improvement in the formation of free oil are presented as negative values relative to the background. These experiments found that esters of sucrose, such as Surfhope D-1811 and Surfhope D-1805, having an average HLB value, show the highest relative reduction in the excretion of free oil. In contrast, esters of sucrose, which is located at the other end of the scale HLB that are, or very hydrophilic (Surfhope D-1815), or very lipophilic (Surfhope D-1803), show weaker activity.

Example 16. The composition of the granules compressed into chewable tablet

Composition 8
Orlistat240 g
Sucrose palmitate R60 g
Avicel PH-105210 g
Starch-modified glycolate sodium60 g
Povidone30 g
Stearin is acid 6 g

The ingredients were subjected to dry mixing in a high speed mixer Aeromatic Fielder GP 1. Added portions 240 g of water and continued procedure mixing for about 5 minutes this material fills the extruder (NICA; mesh hole size 0.8 mm, 1.0 mm thick). The material was extrudible in the form of small tubes of appropriate length. The temperature of the extrudate does not exceed 35°C. the Extrudate was transferred into spheronization (NICA) and processed to give a spherical shape for 0.5-5 minutes Wet granules were dried in the apparatus for drying in pseudouridine layer (Aeromatic MP-1) at temperatures below 35°C. the Dried granules were sifted through a sieve with inserts with hole sizes of sieves of 0.5 and 1.25 mm, and fractions less than and greater than the specified size are discarded. Added stearic acid and distributed to a homogeneous state by dry mixing pellets. The resulting mixture was extruded with the formation of chewable tablets containing 120 mg of orlistat, 30 mg of sucrose palmitate, 105 mg avicula, 30 mg of starch, modified by glycolate sodium, 15 mg of povidone and 3 mg of stearic acid.

Example 17. Two-layer chewable tablet

Composition 9
a) Orlistat240 g
b) Sucrose palmitate R60 g
in)Avicell-105210 g
g) Starch, modified glycolate sodium60 g
d) Povidone K30 g
(e) Stearic acid6 g
W) Lactose monohydrate (powder)1460 g
C)Avicell 102200 g
and) Corn starch 1500100 g
K) Starch, modified glycolate sodium100 g
l) 90F Povidone60 g
m) Glycerinated60 g
n) magnesium Stearate20 g

Layer 1: the ingredients a-d were subjected to dry mixing in a high speed mixer Aeromatic Fielder GP 1 for 5 minutes was Added in portions 240 g of water and continued procedure mixing for about 5 minutes this material fills the extruder (NICA; mesh hole size 0.8 mm, 1.0 mm thick). The material was extrudible in the form of small tubes of appropriate length. The temperature of the extrudate does not exceed 35°C. the Extrudate was transferred into spheronization (NICA) and processed to give a spherical shape for 0.5-5 minutes Wet granules were dried in the apparatus for drying in the fluidized bed (Aeromatic MP-1) when the temperature below 35° C. the Dried granules were sifted through a sieve with inserts with hole sizes of sieves of 0.5 and 1.25 mm, and fractions less than and greater than the specified size are discarded. Added stearic acid and distributed to a homogeneous state by dry mixed with the granules.

Layer 2: fillers W-n was mixed in a high speed mixer Aeromatic Fielder GP 1 for 5 minutes was Added 400 ml of water for granulation. The wet granulate was sieved and dried in the apparatus for drying in the fluidized bed (Aeromatic MP-1). The dried granulate was sieved and mixed with magnesium stearate to a homogeneous state.

The resulting mixture layer 1 and 2 extruded with the formation of two-layer tablets (apparatus for pressing from Kilian)containing 120 mg of orlistat, 30 mg of sucrose palmitate, 105 mg avicula, 30 mg of starch, modified by glycolate sodium, 15 mg of povidone and 3 mg of stearic acid in the layer 1 and containing 730 mg lactose 100 mg avicula, 50 mg of corn starch, 50 mg of starch, modified by glycolate sodium, 30 mg of povidone, 30 mg of glycerinate and 10 mg of magnesium stearate in the second layer.

Example 18. Rapidly disintegrating chewable tablet

Composition 10
Orlistat48 g
Sucrose palmitate R12 g
Starch-modified glycolate sodium48 g
PEG 600072 g
Xylitol122,4 g
Mannitol powder122,4 g
Myrj 52 (stearate PEG 40)12 g
Plasdone S63024 g
Magnesium stearate4.8 g
Talc24 g

Ingredients (except magnesium stearate and talc) was mixed in a high speed mixer (Aeromatic Fielder GP 1) for 5 minutes was Added 32 g of water for granulation. The wet granulate was sieved (filter centrifuge with perforated (5.0 mm) drum, Bergmeier) and dried in apparatus for drying in the fluidized bed (Aeromatic Strea) at temperatures below 37°C. the Dry granulate was sieved (Fitzpatrick, 1,62 mm), mixed with magnesium stearate and talc and extruded in a chewable tablet (teletrauma machine Korsch PH 250).

Example 19. Rapidly disintegrating chewable tablet

Composition 11
Orlistat48 g
Sucrose palmitate R12 g
Starch-modified glycolate sodium48 g
PEG 600072 g
Xylitolto 98.4 g
Mannitol powderto 98.4 g
Myrj 52 (stearate PEG 40)12 g
Alginic acid32,64 g
Plasdone S63024 g
Magnesium stearate4.8 g
Talc14,4 g
Calcium carbonate15,36 g

Ingredients (except magnesium stearate, talc and calcium carbonate) was mixed in a high speed mixer (Aeromatic Fielder GP 1) for 5 minutes was Added 30 g of water for granulation. The wet granulate was sieved (filter centrifuge with perforated (5.0 mm) drum, Bergmeier) and dried in apparatus for drying in the fluidized bed (Aeromatic Strea) at temperatures below 37°C. the Dry granulate was sieved (Fitzpatrick, 1,62 mm), mixed to a homogeneous state with magnesium stearate, talc and calcium carbonate and extruded in a chewable tablet (teletrauma machine Korsch PH 250).

1. Pharmaceutical composition including orlistat, fatty acid ester of sucrose, where the fatty acid ester of sucrose means mono-, di-, tri - or tetraethyl, and optionally one or more pharmaceutically acceptable excipients, and fatty acid part in fatty acid complex di-, tri - or therefore means cm is camping residues of two or more fatty acids.

2. The composition according to claim 1 where the ester means a mono-, di - or triavir.

3. The composition according to claim 1 where the ester means a mono - or fluids.

4. The composition according to claim 1 where the ester means monoether.

5. The composition according to claim 1 where the fatty acid part of the ester are identical.

6. The composition according to claim 1, where 0.05 to 20 mg of fatty acid complex ester of sucrose used 1 mg of orlistat.

7. The composition according to claim 6, comprising 0.1 to 10 mg of fatty acid complex ester of sucrose, 1 mg of orlistat.

8. The composition according to claim 7, comprising about 0.1-2 mg fatty acid complex ester of sucrose, 1 mg of orlistat.

9. The composition according to claim 8, comprising 0.15 to 1 mg of fatty acid complex ester of sucrose, 1 mg of orlistat.

10. The composition according to claim 1 where the fatty acid portion of the fatty acid complex ester of sucrose means the remainder of (C8-C24fatty acids, saturated or partially unsaturated.

11. The composition of claim 10, where the fatty acid portion of the fatty acid complex ester of sucrose means the residue saturated (C12-C18) fatty acids.

12. The composition according to claim 11, where an ester of a fatty acid selected from the group consisting of laurate sucrose, myristate sucrose, sucrose palmitate, sucrose stearate, arachidonate sucrose and behenate sucrose.

13. The composition according to item 12, where an ester of a fatty acid selected from the group status is the present from laurate sucrose, myristate sucrose, sucrose palmitate, sucrose stearate.

14. The composition according to item 13, where a complex fatty acid ester is a sucrose palmitate.

15. The composition according to item 13, where a complex fatty acid ester is sucrose stearate.

16. The composition of claim 10, where the fatty acid portion of the fatty acid complex ester of sucrose means the residue of mono - or polyunsaturated (C12-C18) fatty acids.

17. The composition according to item 16, where the fatty acid is chosen from the group consisting of palmitoleic acid, oleic acid, elaidic acid, erucic acid, linoleic acid, γ-linolenic acid, α-linolenic acid and arachidonic acid.

18. The composition according to 17, where fatty acid complex ester of sucrose is sucrose oleate.

19. The composition according to 17, where fatty acid complex ester of sucrose is palmitostearate sucrose.

20. The composition according to claim 1, comprising 10-240 mg of orlistat.

21. The composition according to claim 20, comprising 30-120 mg of orlistat.

22. The composition according to item 21, including, 30, 40, 60, 80, 100 or 120 mg of orlistat.

23. The composition according to claim 1, comprising 60 to 120 mg of orlistat and 20-100 mg of fatty acid complex ester of sucrose.

24. The composition according to claim 1, comprising 120 mg of orlistat, and 30 mg of ester of sucrose.

25. The composition according to claim 1, comprising 80-120 mg of orlistat and 10-40 mg fatty acid complex is Fira sucrose.

26. The composition according to claim 1, comprising 20 to 60 mg of orlistat and 5-15 mg fatty acid complex ester of sucrose.

27. The composition according to claim 1, comprising one or more pharmaceutically acceptable excipients selected from the group consisting of mannitol, lactose, receiver array, talc, sorbitol, polyvinylpyrrolidone, lecithin, polyethylene glycol, Polysorbate, polyoxyethylenated and dimeticone.

28. The composition according to item 27, including lactose as a pharmaceutically acceptable excipient.

29. The composition according to claim 1, comprising 10-240 mg orlistat and 0.5-1000 mg of fatty acid complex ester of sucrose.

30. The composition according to clause 29, which includes one or more fillers selected from the group consisting of maltodextrin, lactose and cellulose.

31. Composition according to one of claims 1 to 30 for use in the treatment and prevention of obesity.

32. The method of obtaining the composition according to one of claims 1 to 30, comprising a mixture of orlistat with fatty acid complex ester of sucrose and optionally one or more pharmaceutically acceptable excipients.

33. Set for the treatment of obesity, comprising the first component, which is the orlistat, and the second component, which is a fatty acid complex ester of sucrose in standard dosage form.

34. The use of a composition according to one of claims 1 to 30 in the manufacture of drug substances is, applicable for the treatment and prevention of obesity.

35. A method of treating obesity in a human in need of such treatment, which comprises administration to a human a therapeutically effective amount of orlistat and fatty acid complex ester of sucrose, as defined in claims 1 to 30.

36. The lipase inhibitor orlistat and fatty acid ester of sucrose, as defined in claims 1 to 30, for the treatment and prevention of obesity.



 

Same patents:

FIELD: medicine, infectology.

SUBSTANCE: in acute period of bacterial dysentery one should perorally introduce azitromycin once daily at the dosage of 5 mg/kg for 5 d at simultaneous introduction of 1.5%-rheamberin solution by drops at its daily dosage being 10 ml/kg, course of 1.5-2 d. The present innovation enables to overcome antibioticoresistance of dysenteric microbes at the background of keeping and restoring intestinal microflora.

EFFECT: higher efficiency of therapy.

2 ex, 2 tbl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to lyophilized composition comprising epotilone in the effective amount and mannitol or cyclodextrin. The second variant of the lyophilized composition involves epotilone and hydroxypropyl-beta-cyclodextrin. The preferable content of epotilone in the lyophilized composition is from 0.1% to 1.5%, and cyclodextrin - from 90% to 99% as measured for the total mass of solid components. Epotilone-containing lyophilized compositions can be used fro preparing an anti-tumor medicinal agent useful for parenteral administration and the lyophilized composition can be reduced preferably before administration directly. Epotilone-containing lyophilized compositions show improved indices of epotilone solubility and can retain stability for 24-36 months at temperature from 2°C to 30°C being without change of the solubility index.

EFFECT: improved and valuable properties of composition.

10 cl, 4 tbl, 14 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to compositions used for treatment and/or prophylaxis of chlamydium infections caused by C. pheumoniae. Pharmaceutical composition used for treatment and/or prophylaxis of chlamydium infection caused by C. pneumoniae comprises the taken phenolic compound, or extract, or fraction, or incomplete fraction comprising the taken phenolic compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction obtained from plants and comprising indicated compound or corresponding synthetic compound on C. pneumoniae represents the definite percent of inhibition for formation of inclusions. The composition useful for health eliciting an anti-chlamydium effect with respect to C. pneumoniae comprises the taken phenolic compound or extract, or fraction, or incomplete fraction containing indicated compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent for inhibition in formation of inclusions. Also, invention relates to applying the composition useful for health in preparing foodstuffs or as supplements for nutrition for every day. Also, invention relates to applying phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound or mixture of indicated compounds obtained from plants in manufacturing a medicinal agent used for treatment and/or prophylaxis of chlamydium infections caused by C. pneumoniae. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent in inhibition in formation of inclusions. Compositions promote to effective prophylaxis and treatment of chlamydium infections caused by C. pneumoniae.

EFFECT: valuable medicinal properties of compounds.

21 cl, 1 dwg, 1 tbl, 6 ex

FIELD: medicine, cosmetology.

SUBSTANCE: one should apply acid composition onto patient's skin scar, moreover, this composition consists of the following ratio of components, weight%: alpha-hydroacid 0.1-70; gamma-lactone of 2,3-dehydro-L-gulonic acid 0.1-10; 1,2,3-propanetriol 1-10; strontium nitrate 0.5-10, water - the rest. Moreover, for steady penetration of this composition for desired depth against scars and surrounding skin one should treat them with alcoholic solution of beta-hydroxyacid for 3-7 d, and for improved regeneration one should lubricate it with an ointment supplemented with hydroxyacid for 7 d.

EFFECT: higher efficiency of therapy.

2 cl, 2 ex

The invention relates to the field of medicine and for the application of cyclic ether (R)-3-hydroxybutyrate of formula (1) for the treatment of disease conditions mediated by free radicals, toxic agents, such as peptides and proteins, and genetic defects, harmful to the cell metabolism, insulin resistance or other defects in glucose metabolism or conditions that cause the defect, ischemia, head injury, and/or improve the efficiency of cells

A therapeutic agent // 2234917
The invention relates to medicine, to a method of treating obesity in a human in need of such treatment, by appointing such a person a therapeutically effective amount of the compounds of formula I, including enantiomers and pharmaceutically acceptable salts, where R1and R2independently mean hydrogen or methyl, and therapeutically effective amounts of compounds of formula II, in which the compound of formula I and the compound of formula II appointed simultaneously, separately or sequentially, and farbkomposition, including the compounds of formula I and II

The invention relates to medicine and can be used for prevention, diagnosis and treatment of TORCH infections with the purpose of recovery of the various contingents that characterize the family - mother and child

The invention relates to medicine, in particular to endocrinology and therapy, and for the treatment of pathological conditions associated with obesity

The invention relates to the field of medicine

FIELD: medicine, cosmetology.

SUBSTANCE: one should apply acid composition onto patient's skin scar, moreover, this composition consists of the following ratio of components, weight%: alpha-hydroacid 0.1-70; gamma-lactone of 2,3-dehydro-L-gulonic acid 0.1-10; 1,2,3-propanetriol 1-10; strontium nitrate 0.5-10, water - the rest. Moreover, for steady penetration of this composition for desired depth against scars and surrounding skin one should treat them with alcoholic solution of beta-hydroxyacid for 3-7 d, and for improved regeneration one should lubricate it with an ointment supplemented with hydroxyacid for 7 d.

EFFECT: higher efficiency of therapy.

2 cl, 2 ex

FIELD: medicine, pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to compositions used for treatment and/or prophylaxis of chlamydium infections caused by C. pheumoniae. Pharmaceutical composition used for treatment and/or prophylaxis of chlamydium infection caused by C. pneumoniae comprises the taken phenolic compound, or extract, or fraction, or incomplete fraction comprising the taken phenolic compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction obtained from plants and comprising indicated compound or corresponding synthetic compound on C. pneumoniae represents the definite percent of inhibition for formation of inclusions. The composition useful for health eliciting an anti-chlamydium effect with respect to C. pneumoniae comprises the taken phenolic compound or extract, or fraction, or incomplete fraction containing indicated compound or corresponding synthetic compound, or mixture of indicated compounds obtained from plants. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent for inhibition in formation of inclusions. Also, invention relates to applying the composition useful for health in preparing foodstuffs or as supplements for nutrition for every day. Also, invention relates to applying phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound or mixture of indicated compounds obtained from plants in manufacturing a medicinal agent used for treatment and/or prophylaxis of chlamydium infections caused by C. pneumoniae. An anti-chlamydium effect of phenolic compound or extract, or fraction, or incomplete fraction comprising indicated compound or corresponding synthetic compound obtained from plants on C. pneumoniae represents the definite percent in inhibition in formation of inclusions. Compositions promote to effective prophylaxis and treatment of chlamydium infections caused by C. pneumoniae.

EFFECT: valuable medicinal properties of compounds.

21 cl, 1 dwg, 1 tbl, 6 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to lyophilized composition comprising epotilone in the effective amount and mannitol or cyclodextrin. The second variant of the lyophilized composition involves epotilone and hydroxypropyl-beta-cyclodextrin. The preferable content of epotilone in the lyophilized composition is from 0.1% to 1.5%, and cyclodextrin - from 90% to 99% as measured for the total mass of solid components. Epotilone-containing lyophilized compositions can be used fro preparing an anti-tumor medicinal agent useful for parenteral administration and the lyophilized composition can be reduced preferably before administration directly. Epotilone-containing lyophilized compositions show improved indices of epotilone solubility and can retain stability for 24-36 months at temperature from 2°C to 30°C being without change of the solubility index.

EFFECT: improved and valuable properties of composition.

10 cl, 4 tbl, 14 ex

FIELD: medicine, pharmacology, biochemistry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition that comprises a medicine orlistat and sucrose fatty acid ester wherein fatty acid moiety in fatty acid di-, tri- or tetra-ester means a mixture of two or some fatty acids. Also, invention relates to a method for treatment of obesity by using the claimed composition. Invention provides enhancing effectiveness of treatment.

EFFECT: enhanced and valuable properties of composition.

36 cl, 5 dwg, 7 tbl, 19 ex

FIELD: pharmacy, chemical technology.

SUBSTANCE: invention relates to methods for preparing simvastatin of high purity degree from lovastatin by the following stages: (a) opening lactone ring in addition of lovastatin in reaction with amine for formation of amide; (b) protection of 1,3-diol moiety by a protecting group; (c) removal of 2-methylbutyryl group joined by ester bond through oxygen atom at position 8 in hexahydronaphthalene ring; (d) joining of 2,2-dimethylbutyrate group by formation of ester bond to hydroxyl at position 8; (e) removal of protecting group; (f) conversion of amide to acid salt, and lactone ring closure resulting to formation of simvastatin. Semi-synthetic statin is prepared from statin by carrying out the following steps: (a) opening lactone ring by reaction of statin with amine resulting to formation of amide; (b) protection of 1,3-diol moiety by using the protecting group; (c) removal of group R1 joined by ester bond through oxygen atom at position 8 in hexahydronaphthalene ring; (d) joining group R2 by formation of ester bond to hydroxyl at position 8; (e) removal of protecting group; (f) conversion of amide to acid salt, and (g) lactone ring closure with formation of semi-synthetic statin. Invention provides enhancing purity degree of the product.

EFFECT: improved preparing methods of statins.

17 cl, 19 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of discodermolid and its analogs of the formula (V): At the first step method involves the coupling reaction of ketone compound of the formula (I): with aldehyde compound of the formula (II): in the presence of dialkylboron halide or triphlate, amine base and polar organic solvent to yield β-hydroxyketone of the formula (III): at the second step method involves reduction of ketone compound synthesized at the first step by its treatment with boron hydride reagent in polar organic solvent medium and proton solvent to yield 1,3-diol of the formula (IV): at the third step method involves lactonization and removal of free acid-labile hydroxyl protective group of 1,3-diol synthesized at the second step by its treatment with hydrogen halide dissolved in polar solvent or mixture of solvents to yield the end compound of the formula (V) wherein R1 means (C1-C6)-alkyl; R2 means (C1-C6)-alkyl; R3 means hydrogen atom or acid-labile hydroxyl protective group; R3'' means acid-labile hydroxyl protective group; R4 means hydrogen atom or methyl group; X means oxygen atom (O) under condition that when X means O and R3 means acid-labile hydroxyl protective group of compound of the formula (I) then residue -X-R3 in compound of the formula (V) represents hydroxyl group (-OH). Also, invention relates to novel intermediate compounds of formulae (I), (III) and (IV) and to a method for synthesis of compound of the formula (I). Invention provides a new method for synthesis of the valuable compound discodermolid and its analogs with the satisfied yields.

EFFECT: improved method of synthesis.

16 cl, 4 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: pharmacology, in particular composition and methods for obesity treatment.

SUBSTANCE: claimed composition contains lipase inhibitor, namely orlistat and koniac or glucomannan and pharmaceutically acceptable excipients.

EFFECT: composition preventing gastrointestinal disturbances associated with administration of lipase inhibitor orlistat.

35 cl, 10 ex, 3 dwg

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the general formula (I) wherein R1 and R2 mean independently of on another hydrogen atom (H) or fluorine atom (F); R3 means -CH3 or -CF3 ; Ar means structural formulae (a) or (b) Invention relates also to a pharmaceutical composition possessing the modulating activity with respect to progesterone receptor and containing compound of the formula (I), adjuvants, carriers and excipents. Compounds of the formula (I) are used in preparing a medicinal agent designated for selective modulation of processes in organ-targets mediated by progesterone receptor, such as uterus/breast and for selective activation of transcription of progesterone receptor isoform A as compared with transcription of progesterone receptor isoform B, selective enhancing processes mediated by progesterone receptor isoform A as compared with processes mediated by progesterone receptor isoform B and as a contraceptive. Invention provides a compound using as a medicinal agent in hormone-substitution therapy and for control of reproductive function.

EFFECT: valuable medicinal and biological properties of compound and pharmaceutical composition.

45 cl, 4 dwg, 5 tbl, 6 ex

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