Dispersion compositions containing lipase inhibitors

 

(57) Abstract:

Pharmaceutical composition for treating or preventing obesity includes at least one lipase inhibitor, preferably an inhibitor of gastrointestinal and pancreatic lipases, such as orlistat, at least one surfactant and at least one dispersant. Surfactant is a nonionic surfactant or zwitterionic surface-active substance or mixtures thereof. The described method of preparation of pharmaceutical compositions and method of treating or preventing obesity. The present invention allows to significantly reduce the amount of active substance in the composition, while maintaining the same level of inhibition of lipases and thereby minimizing undesirable side effects. 3 N. and 22 C.p. f-crystals, 1 table.

The present invention relates to pharmaceutical compositions containing the inhibitors of lipases.

Examples of such inhibitors of lipases are lipstatin and orlistat. The latter is also known as tetrahydrolipstatin or THL, and it is a derivative of a natural product secreted by Streptomyces toxytricini. It is established that this is 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; the increase in the concentration of lipase inhibitors in the pharmaceutical composition does not increase clinical efficiency, 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 piticescu 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, and/or minimized, or that are completely devoid of the above disadvantages.

This task is solved by a pharmaceutical composition comprising at least one lipase inhibitor, at least one surfactant and at least one dispersant.

The term “dispersant” or “dispersing agent” refers to products that facilitate the initial dispersion of the compounds and further enhance uniform distribution in the environment.

The concept of surfactants (surfactant) refers to a substance such as detergent, which when added to the liquid reduces the surface tension between the lipophilic and hydrophilic phase. Surface-active molecule must be partially hydrophilic (water-soluble) and partially lipophilic (soluble in lipids or oils). It focuses on the interfaces between water and oil or lipids, acting as an emulsifying agent or PI zwitterionic surfactants.

In the context of the present description the term “lipase inhibitor” and “lipase inhibitor” refers to compounds that have the ability to inhibit the action of lipases, such as gastric and pancreatic lipases. For example, orlistat and lipstatin described in patent US 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, lent out the respective pharmaceutical compositions). Other acceptable pharmaceutical compositions are described, for example, in international patent applications 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.

With the invention it has been unexpectedly found that the introduction of a lipase inhibitor in the composition, which includes at least one surfactant of ihibitor lipases. Furthermore, the 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 the efficiency and/or activity higher than that of already existing songs. In addition, the composition of the invention when evaluated using the same test Breakfast reduce unpleasant side effects compared to existing compositions (see example 1), 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 more amount of fat.

According to the present invention, a lipase inhibitor, preferably an inhibitor glucocerebrosidase from 5 to 30% based on the total weight of the composition.

The presence of at least one surfactant is important for optimal distribution of particles in the stomach. According to a preferred variant of the invention, the surfactant is chosen from the group comprising anionic surfactants, nonionic surfactants, zwitterionic surfactants and mixtures thereof. Most preferred are surfactants selected from the group comprising polyethylene glycol(1000)succinate vitamin E (TPGS), esters of fatty acids and poly(oksietilenom)sorbitan, poly(oksietilenom)stearates, simple poly(oksietilenom)alkalemia esters, poliglecaprone glycerides, poly(acetyltyrosine) castor oil, esters of fatty acids and sorbitan, poloxamer, salts of fatty acids, salts of bile acids, alkyl sulphates, lecithins, mixed micelles of bile salts and lecithins, sugar esters, and their mixtures.

“Esters of fatty acids and poly(oksietilenom)sorbitane” are potage and denote a mono-, di-or truefire sorbitan and fatty acids (C8-C18), such as PoE(20)sorbitanoleat (Polysorbate 20), PoE(20)sorbic 65), PoE(6)sorbitanoleat(PEG(6)servicestart), PoE(20)servicemanual (Polysorbate 80), PoE(20)sarbatorile (Polysorbate 85), PoE(6)servicethread (PEG(6)sorbifolia) and PoE(20)servicemonitor (PEG(20)serbianization).

The term “poly(oksietilenom)stearates” refers to esters of polyoxyethyleneglycol and stearic acid, for example, PEG(22)stearate, PEG(32)stearate and PEG(40)stearate. These compounds are known in this field and are sold, for example, as a class of compounds having the trademark Myrj.

The concept is simple poly(oksietilenom)alkalemia esters denotes esters consisting of polyoxyethylene and alkyl groups, for example, PoE(7)-C12-C14alkilany ether, PoE(9)-C12-C14alkilany ether, PoE(3)-C12-C14alkilany ether, PoE(9)-C12-C14alkilany ether, for example belonging to the class of compounds having the trademark Brij.

The concept of “poliglecaprone glycerides” refers to surface-active substances obtained (a) by saponification of oils and b) transesterification of fatty acids with polyethylene glycol (PEG), for example, belonging to the class of compounds having the trademark Gelucire; or a mixture of glycerides with esters of poly(oxyethyl the oil, subjected to interaction with polyethylene glycol, for example, polyoxyl(35)castor oil (Cremophor EL), PEG(30)castor oil, PEG(40)castor oil, PEG - (25)-hydrogenated castor oil and PEG(40)-hydrogenated castor oil (Cremophor RH).

The term “salts of fatty acids” refers to pharmaceutically acceptable salts of fatty12-C18acids, preferably naturally occurring fatty acids, for example, Na-oleate.

The concept of “alkylsulfate” means12-C18the alkyl sulphates, for example sodium dodecyl sulphate.

The term “esters of fatty acids and sorbitan” refers to esters WITH fatty12-C18Acids, preferably naturally occurring fatty acids, a type of arbitraria, sorbifolia, orbitastarmedia, servicestart, corbettreport, sorbitrate and so on

The term “lecithin” refers to natural or synthetic lecithin. Lecithin has the following structure:

where R1-COOH and R2-COOH indicate fatty acids R1-COOH and R2-COOH as defined above (see definition for salts of fatty acids).

Lecithins can be SEL is the definition depolymerisation, partially or fully hydrogenated lecithin, and mixtures thereof.

The term “bile salts” refers to pharmaceutically acceptable salts, e.g. sodium salts of bile acids, for example Holt, and conjugated bile acids, such as Na-glycocholate.

The term “sugar esters” refers to esters of sugars and of fatty acids, for example fatty12-C18acids, for example fatty acid and of sucrose, type stearate sucrose or sucrose palmitate.

The notion of “poloxamer” refers to block copolymers of poly(oxicological) and poly(oxypropylene), for example, which has a General formula

where and denotes 2-130, b denotes 15-67.

The above compounds are known in this field and are commercially available.

The term “pharmaceutically acceptable” in the context of the present description indicates that the excipients is acceptable from the point of view of their toxicity.

Preferred surface-active substances are selected from the group comprising polyethylene glycol(1000)succinate vitamin E, such as TPGS, the company Eastman Chemicals; poly(ethoxylated) castor oil such as Cremophor EL, BASF, and Paul who are in the amount of at least 0.1%, calculated on the total weight of the composition, preferably in an amount of 0.1-90%, more preferably in an amount of 1-20%.

The presence of at least one dispersant is important to accelerate the initial dispersion products in physiological environments in which the lipase inhibitor should act. The dispersant can be selected from the group comprising water - and fat-soluble substances. They usually present in amounts of at least 5% based on the total weight of the composition, preferably in an amount of 5 to 70% based on the total weight of the composition.

In one of the embodiments of the invention apply a water-soluble dispersant. Acceptable water-soluble dispersant is chosen from the group comprising sugars, sugar alcohols, alcohols, effervescent mixtures, baking powder, and mixtures thereof. Preferred dispersing agents can be selected from the group comprising glucose, sorbitol, mannitol, maltodextrin, lactose, sucrose, polyethylene glycol, glycerin, triacetin, glycoluril, effervescent mixtures, for example mixtures Panso3/acid, for example Panso3/citric acid, and mixtures thereof. The most preferred water-soluble dispersing agents include sorbitol, mannitol, maltodextrin, lactose, sucrose, per polyethylene glycol 400, glycerin, triacetin, glycoluril and mixtures thereof. Using hammastunturi found that effervescent mixture (Panso3/citric acid) have a marked effect on the dispersion content hydroxypropylmethylcellulose (HPMC) capsules in the stomach.

Some compositions according to the invention, including fat-soluble compounds as dispersing agents, known as self emulsifiable system for administering drugs (Self-Emulsifying Drug Delivery Systems (SEDDS)). SEDDS possess specific characteristics of emulsification of the oil components under conditions of careful mixing and lead to the formation of micro - or submicroscale. Description of SEDDS formulations can be detected, for example, C. W. Pouton, Advanced Drug Delivery Reviews, 25, 47-58 (1997). It was found that after dispersion in aqueous medium SEDDS can be divided into a transparent micellar phase and consisting of droplets of lipid emulsion, and a lipase inhibitor, if present, is in both phases.

Thus, another object of the invention is the above pharmaceutical composition, comprising at least one dispersant, which is a fat-soluble compound and LM is the nutrient used in an amount of from 20 to 90%, calculated on the total weight of the compositions, and it must be liquid at body temperature (i.e., >37°C).

The dispersant can be selected from the group comprising triglycerides, diglycerides, monoglycerides, mixtures of di/mono/triglycerides, vitamin E, tocopherol acetate, terpenes, squalene, and mixtures thereof, more preferably a fat-soluble substance selected from the group comprising triglycerides, diglycerides, monoglycerides, mixtures of di/mono/triglycerides, vitamin E, tocopherol acetate, and mixtures thereof. Preferred examples are medium chain triglycerides (medium chain) or a mixture of triglycerides of medium chain length, such as fractionated coconut oil (triglycerides medium chain length, MCT, Miglyol 812, the firm AG, Neobee M-5, the company Stepan, Captex 355, firm Abitec). Preferably the composition according to the invention may also include additional surfactant secondary surfactant).

The concept of “glycerides” refers to the ester of glycerol and fatty acids having 2-7 (short circuit; triglycerides with short chain), 8-12 (medium chain; triglycerides medium chain length) and >12 (long chain; triglycerides with long-chain) carbon atoms. Their examples include glyceryltrinitrate, glycerylmonostearate etc. Note ilonolulu and glycerylmonostearate. According to the invention it is also possible to apply an appropriate mixture of mono-, di - and triglycerides.

The composition of the invention can be entered using the conventional dosage forms, such as hydroxypropylmethylcellulose (HPMC) capsules, soft gelatin capsules, hard gelatin capsules, starch capsules, tablets, chewable tablets and capsules, syrups and so on

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 the orlistat.

The preferred composition of the present invention includes:

a) from 1 to 50% of the lipase inhibitor, calculated on the total weight of the composition;

b) from 5 to 70% of at least one dispersant, calculated on the total weight of the composition;

C) from 0.1 to 90% of at least one surface-active substance, calculated on the total weight of the composition, and optional

g) one or more pharmaceutically acceptable excipients.

More preferably, the lipase inhibitor, such as orlistat, is present in an amount of 3-30%, and the surfactant in the amount of 1-2 songs which includes a mixture of at least one inhibitor of lipases at least one surface-active substance and at least one dispersant.

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 is illustrated in more detail by using examples.

Performance data regarding the excretion of fat compositions on the basis of orlistat from examples 1-7 and Xenical® as a reference in the table.

EXAMPLES

Example 1

150 mg MCT (triglycerides of medium chain length. Medium Chain Triglycerides, fractionated coconut oil (triglycerides medium chain length, MCT, Miglyol 812, the firm AG, Neobee M-5, the company Stepan, Captex 355, firm Abitec) and 120 mg of polyethylene glycol(1000)succinate vitamin E (TPGS, the company Eastman Chemicals) were introduced into a glass vessel and mixed by heating/stirring at 45°C. Then, the obtained transparent idcok vitamin C was added under stirring, was cooled to room temperature (25°C), this was accompanied by solidification of the mixture. Thus obtained composition was filled hydroxypropylmethylcellulose capsules.

Capsules containing the above composition, comprising 60 mg of orlistat, gave 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), the total fat content 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 Dyer, W. J., 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

Using the process described in example 1 was obtained a composition including 180 shipuchin tablets of vitamin C.

Hydroxypropylmethylcellulose capsules containing the above composition, comprising 60 mg of orlistat, was tested on human volunteers according to the method described in example 1.

Example 3

Using the process described in example 1 was obtained a composition which includes 450 mg Gelucire 44/14 (glycerides of lauromacrogol-32, firm France), 90 mg MCT, 60 mg of orlistat and 200 mg of finely effervescent tablets vitamin C.

Hydroxypropylmethylcellulose capsules containing the above composition, comprising 60 mg of orlistat, was tested on human volunteers according to the method described in example 1.

Example 4

Received the composition described in example 1, in which instead of the fizzy mixture as an additional excipient used 200 mg of finely glucose.

Hydroxypropylmethylcellulose capsules containing composition obtained above, including 30 mg of orlistat, was tested on human volunteers according to the method described in example 1.

Example 5

Composition containing 1700 mg TPGS and 300 mg of orlistat made in a planetary mixer, in which the metal chemical beaker was heated to 60°C. After melting the mixture lane is for 30 min, during this time, the composition was cooled to room temperature. Then the solid mixture was sifted through a sieve with openings of 2 mm

Hydroxypropylmethylcellulose capsules containing composition obtained above, including 30 mg of orlistat, was tested on human volunteers according to the method described in example 1.

Example 6

210 mg of polyethylene glycol 400 (PEG 400, the company Clariant) was mixed with 300 mg of glycerin. Added 30 mg of polyethylene glycol(40)stearate (Myrj 52, firm Serva, Germany; Crodet S40, the company Croda, UK). The mixture was heated to 60°C and then with stirring, cooled to room temperature. Then the resulting suspension was added 60 mg of orlistat and mixed to a homogeneous state. The obtained composition was filled hydroxypropylmethylcellulose capsules. Capsules containing the above composition, comprising 60 mg of orlistat, was tested on human volunteers according to the method described in example 1.

Example 7

340 mg of glycerol was mixed with 30 mg of polyethylene glycol(40)stearate. The mixture was heated to 60°C, and then cooled with stirring to room temperature. Then, the resulting solution was added 30 mg of orlistat, 100 mg of polyethylene glycol all capsules. Capsules containing the above composition, comprising 30 mg of orlistat, was tested on human volunteers according to the method described in example 1.

As can be seen from the table, 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 a significantly 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, thereby minimizing undesirable side effects.

In the table 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 undesired hair is azizia for treating or preventing obesity, comprising at least one lipase inhibitor, at least one surfactant selected from the group comprising non-ionic surfactants, zwitterionic surfactants and mixtures thereof and at least one dispersant in the following ratio, wt.%: 1-50 lipase inhibitor, 0.1 to 90 surfactants, 5-70 dispersant.

2. The pharmaceutical composition under item 1, where the surfactant is chosen from the group comprising polyethylene glycol (1000) succinate vitamin E (TPGS), esters of fatty acids and poly(oksietilenom)sorbitan, poly(oksietilenom)stearates, simple poly(oksietilenom)alkalemia ethers, poly(acetyltyrosine) castor oil, poliglecaprone glycerides, esters of fatty acids and sorbitan, poloxamer, salts of fatty acids, salts of bile acids, alkyl sulphates, lecithins, mixed micelles of bile salts and lecithins, sugar esters, and their mixtures.

3. The pharmaceutical composition according to p. 2, where the surface-active substance selected from the group including polyethylene glycol (1000) succinate vitamin E (TPGS), poly(ethoxylated) castor oil and polyethylene glycol (40) stearate.

4. FPO least 0.1%, calculated on the total weight of the composition.

5. The pharmaceutical composition according to p. 4, where the surfactant is present in an amount of 0.1 - 90%, calculated on the total weight of the composition.

6. The pharmaceutical composition according to any one of paragraphs.1-5, includes a water-soluble dispersant.

7. The pharmaceutical composition according to p. 6, where the dispersant is chosen from the group comprising sugars, sugar alcohols, alcohols, effervescent mixtures, baking powder, and mixtures thereof.

8. The pharmaceutical composition according to p. 7, where the dispersant is chosen from the group comprising glucose, sorbitol, mannitol, maltodextrin, lactose, sucrose, polyethylene glycol, glycerin, triacetin, glycoluril, effervescent mixtures, and mixtures thereof.

9. The pharmaceutical composition under item 7 or 8, wherein the dispersant is chosen from the group comprising sorbitol, mannitol, maltodextrin, lactose, sucrose, polyethylene glycol, glycerin, triacetin, glycoluril and mixtures thereof.

10. The pharmaceutical composition according to any one of paragraphs.1-9, which additionally contains at least one dispersant, representing a fat-soluble compound that is liquid at body temperature.

11. The pharmaceutical composition according to p. 10, where fat-soluble compound selected from the group, including the ENES, squalene, and mixtures thereof.

12. The pharmaceutical composition according to p. 11, where fat-soluble compound selected from the group comprising triglycerides, diglycerides, monoglycerides, mixtures of di/mono/triglycerides, vitamin E, tocopherol acetate, and mixtures thereof.

13. The pharmaceutical composition according to p. 12, where fat-soluble compound is a triglyceride with a medium chain length WITH8-C12or a mixture of triglycerides of medium chain length.

14. The pharmaceutical composition according to any one of paragraphs.1-13, where the dispersant is present in amount of at least 5% based on the total weight of the composition.

15. The pharmaceutical composition according to p. 14, where the dispersant is present in an amount of 5 to 70% based on the total weight of the composition.

16. The pharmaceutical composition according to any one of paragraphs.1-15, where fat-soluble dispersant is present in an amount of 20 to 90%, calculated on the total weight of the composition.

17. The pharmaceutical composition according to any one of paragraphs.1-16, further comprising a secondary surfactant.

18. The pharmaceutical composition according to any one of paragraphs.1-17, where the lipase inhibitor is an inhibitor of gastrointestinal and pancreatic lipases.

20. The pharmaceutical composition according to any one of paragraphs.1-19, where the lipase inhibitor is present in quantities of 1 to 50% based on the total weight of the composition.

21. The pharmaceutical composition according to p. 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 paragraphs.1-20 containing pharmaceutically acceptable excipients selected from the group comprising carbohydrates, antioxidants, co-solvents and thickeners, preservatives and oil.

23. The pharmaceutical composition according to any one of paragraphs.1-22, including, wt.%: 1-50 inhibitor of lipases; 5-70 at least one dispersant; about 0.1-90 at least one surfactant, and one or more pharmaceutically acceptable excipients.

24. The method of preparation of the pharmaceutical composition according to any one of paragraphs.1-21, providing a mixture of at least one inhibitor of lipases at least one surface-active substance selected from the group comprising non-ionic surfactants, zwitterionic surfactants and mixtures thereof and at least one dispersant.

25. The way Le is according to any one of paragraphs.1-23.



 

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