A new pharmaceutical composition

 

(57) Abstract:

In the invention described pharmaceutical compositions and methods of treatment and prevention of obesity, containing a lipase inhibitor, preferably orlistat, and prescribe a bile acid. The invention allows the ingestion suppress unpleasant gastrointestinal effects. 6 N. and 28 C.p. f-crystals, 1 table.

The present invention relates to pharmaceutical combinations, compositions and methods for the treatment of obesity. More specifically the invention relates to combinations or compositions that contain a lipase inhibitor, preferably a compound of formula I (orlistat),

pharmaceutically acceptable prescribe (a substance that enhances the excretion of bile acids and optionally one or more pharmaceutically acceptable excipients, such as a diluent or carrier.

Bile acids are synthesized in the liver and part of the bile as conjugates with glycine and taurine. They are in the form of salts are excreted in the bile in the digestive process and act as detergents intended for solubilization and subsequent breakdown of dietary fats.

After completion of the process fixewareout complexes with proteins and returned to the liver through the portal vein of the liver. A small amount of bile salts, which have not been reabsorption through active transport, highlighted through the distal region of the ileum and the colon in the form of an integral piece of excrement. Reducing reabsorption of bile acids within the intestinal tract can reduce levels of bile acids circulating in the enterohepatic system, which could reduce the emulsification of dietary fat in the upper region of the intestinal tract and lower absorption in the intestine-soluble drugs. One way of reducing the number of exposed reabsorption of bile acids is oral administration of compounds that are biliary acids in the intestinal tract and are unable to be absorbed.

Orlistat (Xenical®, tetrahydrolipstatin) is an effective inhibitor present in the gastrointestinal lipases, i.e., lipase, responsible for the breakdown of dietary fat (gastric lipase, carboxylate-lipase, pancreatic lipase). Because of this unabsorbed fat is excreted. Pancreatic lipase is an enzyme that is crucial for having cnice. In pharmacological studies in humans demonstrated that the application of an effective inhibitor absorption of fats acceptable from a medical point of view, the body weight loss. However, in some patients were found to have unpleasant side effects in relation to the gastrointestinal tract, such as anal after oil (oily spots), fatty/oily stools, the urge for defecation, not too rapid defecation and incontinence of stool.

The present invention relates to pharmaceutical combinations and compositions that provide for minimizing or suppressing the above side effects caused by inhibitors present in the gastrointestinal lipases. These compositions or combinations contain a lipase inhibitor, preferably orlistat, pharmaceutically acceptable prescribe a bile acid, optionally in combination with pharmaceutically acceptable excipients, for example, diluent or carrier. The invention relates also to a method of treating obesity and related comorbid pathological processes and other diseases that can be treated with inhibitors of lipases, introducing a therapeutically EF the and of sequestrants bile acids.

With the invention it has been unexpectedly found that pharmaceutically acceptable biliary acids when administered in combination with a lipase inhibitor can suppress unpleasant gastrointestinal effects. Reduction of unpleasant gastrointestinal side effects improves the quality of life for sensitive patients during treatment with the lipase inhibitor, such as orlistat, and also increases the likelihood of compliance by the patient mode and a treatment regimen using drugs and, thus, increases its therapeutic value.

More specifically the present invention relates to a pharmaceutical combination or composition comprising a lipase inhibitor, preferably a compound of formula I (orlistat), and pharmaceutically acceptable prescribe a bile acid, optionally in combination with pharmaceutically acceptable excipients, such as a diluent or carrier. Pharmaceutically acceptable prescribe a bile acid can be selected from the group including cholestyramine, colestipol, diethylaminoethylcellulose (DEAE-pulp) and derivatives of starch type-cyclodextrin and cyclodextrin, more preferably of cholester is Eremin and colestipol, and the most preferred sequestrants bile acids is cholestyramine. The invention relates also to the use of the above-described combination of the compounds for the preparation of medicines intended for the treatment and prevention of obesity. In addition, the invention relates to the combination, intended for the treatment and prevention of obesity.

If not specified, the following concepts are used to illustrate and define the nature and scope of the various terms used for the description.

The term “pharmaceutically acceptable” in the context of the present description denotes that the respective connections are acceptable from the standpoint of toxicity.

The term “pharmaceutically acceptable salt” in the context of the present description refers to salts of inhibitors of lipase or bile acid sequestrants with inorganic or organic acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonate acid, para-toluensulfonate acid, etc., motortechnik ammonium, pharmaceutically acceptable salts are the corresponding chlorides, bromides, sulfates, phosphates, citrate, formate, maleate, acetates, succinate, tartratami, methansulfonate and para-toluensulfonate etc.

The term “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, referred to as policyname. Anglicani are analogues of orlistat (Mutoh and others, 1994). The term “lipase inhibitor” 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 one or more groups, any abscopal lipase. The term “lipase inhibitor” also includes pharmaceutically acceptable salts of these compounds. The term “lipase inhibitor” refers to 2-oxy-4H-3,1-benzoxazin-methyl-4H-3,1-benzoxazin-4-ONU, 6-methyl-2-tetradecenoic-4H-3,1-benzoxazin-4-ONU and 2 hexadecylamine-6-methyl-4H-3,1-benzoxazin-4-ONU. More preferably the term “lipase inhibitor” refers to orlistat.

Orlistat is a known compound, which is used for the treatment or prevention of obesity and hyperlipidemia (see patent US 4598089, issued July 1, 1986, which describes methods of obtaining orlistat, and the US patent 6004996, which describes the corresponding pharmaceutical compositions). Other acceptable pharmaceutical compositions are described, for example, in international 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 is injected 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. CAA 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.

Orlistat can be entered in the conventional oral compositions, such as tablets, filmtablette, hard or soft gelatin capsules, emulsions or suspensions. Examples of media that can be used for tablets, filmtabletten, coated tablets and hard gelatin capsules include lactose, other sugars and sugar alcohols type of sorbitol, mannitol, maltodextrin or other fillers; surfactants of the type of sodium lauryl, Brij 96 or Tween 80; openers type nitroglycol starch, corn starch or its derivatives; polymers of type povidone, crosspovidone; talc; stearic acid or its salts, etc. are Acceptable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. in Addition, the pharmaceutical compositions can contain preservatives, soljubilizatory, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, corrigentov, salts to change omoti the t in a standard dosage form and you can get them by any means, known in the pharmaceutical field. Preferably orlistat is administered using the compositions described in the examples in the patent US 6004996 respectively.

The concept of “prescribe a bile acid” refers to classes of compounds, that possess the ability to bind with bile acids or salts of bile acids in various ways, for example, by anion-exchange polymers containing amino groups, Quaternary ammonium group, and so on (aminobenzamide polymers). More specifically refers to oligomers or polymers of different structure (the grafted copolymers, block, multiblock, homosuperior), dendrimers or hyperbranched structures, which contain a group or Quaternary ammonium, substituted or not substituted pyridinium groups, substituted or unsubstituted primary, secondary or tertiary alkyl or killingray, or any statistical or nonstatistical combination, which have the ability to form complexes with physiologically active bile acids and/or salts of bile acids via non-covalent bonds, van der Waals, hydrophobic and/or ionic interactions. For example, these structures may include, poly(aminoxy, the Oli(N-alkylvinyl), poly(N,N-dialkylamino), poly(N-alkalarian), poly(ethylenimine) and other mono - or disubstituted poly(amines). Other polymers include poly(vinylpyridine), poly(amidoamine), FRAMES-dendrimers, polymers containing athropy, poly(dialkylzincs), poly(phosphazene), poly(acrylates), poly(methacrylates), poly(styrene), poly(amides), poly(esters), a complex of poly(esters). Acceptable side chains may include cationic or neutral group, a substituted or unsubstituted alkyl or aryl group, saturated or unsaturated alkyl groups, amino acids or functional groups such as amine or ammonium fragments, for example, described by Uhrich, etc., Chem. Rev.99, 3181-3198, 1999. In addition, a significant interest are naturally occurring and then modified using the methods of synthesis of polymers, such as poly(aminosaccharides) (chitosan) or cellulose derivatives (for example, diethylaminoethylcellulose, guanidinoacetate). Another important class bile acid sequestrants are represented by the compounds, which have the ability to form inclusion complexes of type “host-guest”, - and-cyclodextrins.

Airing GLCN the aceuticals, Inc.; about polyamine salts of hydrophobic sequestrants), WO 94/27620 (name of firm Geltex Pharmaceuticals, Inc.; regarding obtaining a polymeric bile acid sequestrants) and in WO 94/04596 (in the name of the DuPont company; regarding mesh polymeric ammonium salts).

For example, listeriosis polymers in the context of the present description may be a compound described in international patent application WO 94/27620. The polymers have a repeating element of the formula

or its copolymer, where n denotes an integer; R1denotes H or alkyl group (which may be a straight or branched chain, may be substituted or unsubstituted, for example, WITH1-C8alkyl, such as methyl); M represents-C(O)-R2or-Z-R2; Z represents O, NR3, S, or (CH2)m; m is 0-10; R3denotes H or alkyl group (which may be a straight or branched chain, may be substituted or unsubstituted, for example, C1-C8alkyl, such as methyl); and R2means

where p denotes 0-10 and R4, R5and R6each independently of the other represents H, alkyl group (which may have a direct ITIL) or aryl group (for example, which has one or more rings and which may be substituted or unsubstituted, for example phenyl, naphthyl, imidazolyl or pyridyl). According to preferred variants of implementation, the polymer is a net polymer, crosslinked with multifunctional forming cross-links co monomer, with comonomer is present in amount of about 0.5 to 25 wt.% (more preferably about 2.5-20 wt.% (or about 1-10 wt.%)) in terms of the total weight of monomer. The compositions are non-toxic and stable when administered in therapeutically effective amounts. These compounds are described in international patent application WO 94/27620 (name of firm Geltex Pharmaceuticals Inc.).

The term “biliary acids” refers to compounds obtained using molecular imprints (prints). Obtaining molecular imprints based on the use of polymerization on the template with which the polymers are creating in the presence of molecules of the template, the imprint of which you want to receive. Matrix of the resulting polymers possess the shape and chemical properties of the template and the specific characteristics of the binding molecule template. Maybye can be interpreted at the molecular level: it can be used to design complementary sites of the target molecules, expected to represent specific binding sites, with the aim of molecular self-Assembly and without the use of complicated synthesis. The previously described polymers obtained by molecular imprints, and demonstrated the efficiency obtained using molecular imprinted polymers (Ansell and others, Curr. Opin. Biotechnol., 7(1), 89-94 (1996)). Obtained through imprinted polymers used for chromatographic separation of amino acids, sugars and nucleotides. Obtained through imprinted polymers can be used instead of antibodies for the evaluation of medicinal products based on radio link (Sheaet and others,. Trends Polym. Sci., 2(5), 166-73 (1994); Takeuchi and others, Chromatography, 18(2), 102-103 (1997); Nicholls, J. Molecular Recognition, 11 (1-6), 79-82 (1988)). Under the concept of “biliary acids are also pharmaceutically acceptable salts of these compounds.

More preferably the invention relates to compositions or combinations for which prescribe a bile acid selected from the group including cholestyramine, colestipol, colesevelam, colestimide, sevelamer, proizvode cellulose and dextran, starch and starch derivatives and their pharmaceutically acceptable salts.

Cholestyramine (Quantalan®, Bristol-Myers Squibb) is lcah. This compound is a strong cationic resin containing a functional group Quaternary ammonium associated with polymeric styrene-divinylbenzene structure:

Cholestyramine has been used in therapy since 1959, and it is mainly used to control hypercholesterinemia. therapeutic activity of cholestyramine correlates with the ability of the resin to increase the excretion of bile acids in the intestine, which leads to a 7-8-fold increased allocation with excrement. Application cholestyramine resin as adjunctive therapy to therapy based on the use of diet to treat patients with elevated cholesterol levels mentioned in Remington''s Pharmaceutical Sciences, 15th ed., Mack Publishing Co. (1975), pp. 733-734. Methods of obtaining cholestyramine and related compositions known in the art (see, for example, DE-A-3808191, EP-A-347014, patent US 5695749, patent US 4172120 and EP-A-492235).

Colestipol ( company Pharmacia & decision Upjohn) is a known compound and is described, for example, in patents US 3692895, 3803237 and 5807582 and cited in the references. It represents a basic anion-exchange resin, described as a high molecular weight copolymer of dieselengine proton, ie is a copolymer of Diethylenetriamine and epichlorohydrin, in which approximately one out of five of the amine nitrogen atoms attached proton:

This compound is a yellow resin, which is hygroscopic and swell when placed in water or aqueous medium (see Merck Index (10th ed.) No. 2440, page 2438). Colestipol hydrochloride is supplied in pellet form under the name Colestid granules® (see Physicians Desk Reference (PDR) 42-oe ed., page 2119 (1988). Colestid granules® are sold as gipolipidemicheskoe agent intended for oral administration. Colestipol binds bile acids in the intestine, forming a complex that is excreted in the faeces. This random action leads to partial removal of bile acids from the enterohepatic circulation, preventing their reabsorption.

Colesevelam and hydrochloride colesevelam ( or ) are agents that reduce cholesterol (Polym. Prepr., 41, 735-736 (2000)). Colesevelam is polyamines copolymer of the following three amines, transversely crosslinked with epichlorohydrin. His other names are: 1 hexanamine, N,N,N-trimethyl-6-(2-propylamino)-, chloride, polymer (the emer (chloromethyl)oxirane, 2-propen-1-amine and chloride N,N,N-trimethyl-6-(2-propylamino)-1-hexanamine, hydrochloride (9CI); 2-propen-1-amine, polymer (chloromethyl)oxirane, N-2-propenyl-1-decanamide and chloride N,N,N-trimethyl-6-(2-propylamino)-1-hexanamine, hydrochloride (9CI); oxirane, (chloromethyl)-, polymer with 2-propen-1-amine, N-2-propenyl-1-decanamide and chloride N,N,N-trimethyl-6-(2-propylamino)-1-hexanamine, hydrochloride (9CI);

cholestagel; hydrochloride colesevelam; GT 31-104; or GT-31-104HB (see also Holmes-Farley, S. and others, Polym. Prepr. (Am. Chem. Soc., Div. Polym. Chem.), 41(1), 735-736 (2000)). Three suitable amines have the formula

The epichlorohydrin has the following formula

Colesevelam and hydrochloride colesevelam have been described in patents US 5607669, 5624963, 5679717, 5693675, 5917007 and 5919832:

Sevelamer and its hydrochloride ( firm GelTex) is a polymeric phosphate binder that is designed for oral administration. Hydrochloride sevelamer is a poly(hydrochloride allylamine), crosslinked with epichlorohydrin, in which 40% of amines attached proton:

Its known chemical name hydrochloride poly(allylamine-co-N,N’-diallyl-1,3-diamino-2-hydroxypropane). Hydrochloride sevelamer is the Hydra and in the international patent application WO 95/05184.

Colestimide (Cholebine®; Mitsubishi-Tokoyo Pharmaceuticals) is a polymer of 2-methylimidazole and 1-chloro-2,3-epoxypropane:

The binding of bile acids is described, for example, Mitsuka and others, Japanese Pharmacology & Therapeutics, 24 (Appendix 4), 103 (1996), Mitsuka and others, Japanese Pharmacology & Therapeutics, 24 (Appendix 4), 111 (1996) and Mitsuka and others, Japanese Pharmacology & Therapeutics, 24 (Appendix 4), 127 (1996).

Various anion-exchange derivative of cellulose and dextran bind bile acids in the pH and ionic strength, which correspond to the conditions in the cavity of the small intestine (Thomas M., J. Lipid Res., 8(1), 24-9 (1967); Nichifor, etc., Pharma Sci., 4(6), 447-52 (1994)). From other substances, DEAE-cellulose, guanidinoacetate, DEAE-Sephadex reduce cholesterol when added to a cholesterol-enriched feed for cockerels. In addition, DEAE-Sephadex reduces the level of sterols in the plasma of both males and dogs with normal cholesterol levels, reduces the amount of phospholipids and triglycerides in fed cholesterol-enriched food suffering from hypercholesterolemia cockerels and dogs with a normal level of cholesterol and increases the excretion of faeces bile acids in patients with hypercholesterolemia cockerels. These insoluble cationic poly is the treatment of bile acids. DEAE-cellulose are compounds in which diethylaminoethyl group covalently linked to the hydroxyl groups of cellulose. DEAE-cellulose are known, marketed substances (for example, from the company Sigma-Aldrich).

Guanidinoacetate are compounds in which guanidinoacetate group covalently linked to the hydroxyl groups of cellulose. Guanidinoacetate are known compounds and are sold. DEAE-Sephadex is a crosslinked derivative of dextran, which diethylaminoethyl group covalently linked to dextran. Composition of DEAE-Sephadex go on sale (for example, produced by the firm Pharmacia Fince Chemicals). DEAE-cellulose, guanidinoacetate, DEAE-Sephadex are preferred biliary acids, the most preferred is DEAE-cellulose.

The term “starch and its derivatives” refers to compounds that have the ability to form inclusion complexes with the free and conjugated bile salts and bile acids. Their examples are - and-cyclodextrin, which contain, respectively, 7 and 8 of anhydrous glucose the any state is. Polar hydroxyl group is oriented outwards rings, creating a hydrophilic outer surface. In contrast, the inner cavity is hydrophobic (lipophilic) nature. As a result of this unique structure of cyclodextrins as molecules“owners” have the ability to keep the inside cavity of the molecule-the“guests” that have the appropriate size (typically with a molecular weight of 80-250), shape, and hydrophobicity. (see “Production and Potential Food Applications of Cyclodextrins” Food Technology, January 1988, pp. 96-100). - and-cyclodextrin go on sale (for example, are made by the company Sigma-Aldrich). Other examples of starch and its derivatives are retrogradely and/or split the starch, for example, maltodextrin, hydrophobic starch, amylose and starch derivatives, for example a simple diethylaminoethyl ether of starch, a simple 2-hydroxyethyloxy ether starch, etc. (“Lexikon der Hilfsstoffe Pharmazie, Kosmetik und angrenzende Gebiete”, H. P. Fiedler, Editio Cantor Aulendorf, volume 2, 3rd ed., 1989, pp. 1147-1154). Preferred derivatives of starch is chosen from the group comprising - or-cyclodextrin, retrogradely and/or split starches such as maltodextrin, hydrophobic starch, simple diethylaminoethyl ether of starch and just the ACLs preferred variant implementation prescribe a bile acid is a derivative of cellulose or dextran, for example, DEAE-pulp, guanidinoacetate, DEAE-Sephadex, preferably DEAE-cellulose.

According to another preferred variant implementation of the present invention the starch or the derivative of the starch is chosen from the group comprising - or-cyclodextrin, retrogradely and/or split starch, hydrophobic starch, amylose, simple diethylaminoethyl ether of starch and simple 2-hydroxyethyloxy ether of starch, preferably - or-cyclodextrin.

According to another variant implementation of the present invention prescribe a bile acid selected from the group including cholestyramine, colestipol, colesevelam, colestimide, sevelamer, cellulose, DEAE-pulp, guanidinoacetate, DEAE-Sephadex, starch or cyclodextrin, preferably cholestyramine, colestipol, colesevelam, colestimide, sevelamer, DEAE-pulp and - or-cyclodextrin, more preferably cholestyramine, colestipol, sevelamer, DEAE-pulp and - or-cyclodextrin, most preferably cholestyramine, colestipol and sevelamer.

According to a preferred variant implementation of the present invention as sequestrants bile acids used choset a colestipol. According to another variant implementation prescribe a bile acid is sevelamer.

Pharmaceutical compositions containing as the connection representing a lipase inhibitor, and prescribe bile acids are important variants of implementation of the present invention. Such pharmaceutical compositions contain a therapeutically effective amount of each of these compounds. Each standard dose can contain daily doses of both compounds or may contain a portion of the daily dose, for example one third of the doses. In another embodiment, each daily dose can contain a full dose of one connection and part of the doses of other compounds. In this case, the patient needs each day to take one of the combinations of standard doses and one or more doses, containing only a second connection.

In particular, the above-described compositions include compositions which contain a) from about 5 to about 1000 mg of a lipase inhibitor and (b) from about 0, 1 to about 20 g of sequestrants bile acids. The compositions may contain pharmaceutically acceptable excipient, such as a diluent or carrier. Pharmaceutically acceptable excipient can vnit, maltodextrin, etc.; surfactants such as sodium lauryl sulfate, Brij 96 or Tween 80; leavening agents, such as nitroglycol starch, corn starch or its derivatives; binding agents, such as povidone, crosspovidone, polyvinyl alcohol, hypromellose; oiling agents, such as stearic acid or its salts; amplifiers fluidity, for example silicon dioxide; sweeteners, such as aspartame; and/or dyes, for example-carotene.

The preferred composition may include from about 5 to about 1000 mg of a lipase inhibitor; b) from about 0.1 to about 20 g of sequestrants bile acids; and optionally pharmaceutically acceptable excipients selected from the group comprising from about 0.1 to about 10 g of fillers, from about 0.05 to about 3.0 g of surfactant, from about 0.05 to about 2.0 g of powder, from about 0.02 to about 2.0 g of the binder, from about 0.001 to about 1.0 g of sizing, from about 0.1 to about 5.0 g of the amplifier fluidity, from about 0.01 to about 4.0 g sweeteners and from about 0.001 to about 0.5 g of the dye. A preferred lipase inhibitor is orlistat.

The pharmaceutical compositions can contain from about 0.1 to about 20 g of sequestrants bile acids, preferably about 0.5 to about 10 g, and most preferably from about 1 to about 5,

The invention relates also to a method for producing the above-described composition, providing a mixture of ihibitor lipase or its pharmaceutically acceptable salt sequestrants bile acid or its pharmaceutically acceptable salt and one or neskollkimi compositions for use according to the invention are oral dosage forms, and they are the known pharmaceutical forms intended for such routes of administration, for example tablets, capsules, discs, sachets, granules, syrups and aqueous or oil suspensions. Pharmaceutically acceptable excipients (diluents and carriers are known in the pharmaceutical field. Tablets can be prepared from a mixture of active substances with extenders, such as calcium phosphate; disintegrating agents such as corn starch; oiling agents, such as magnesium stearate; binders, such as microcrystalline cellulose or polyvinylpyrrolidone, and other optional ingredients that are known in this area through tableting mixture of known methods. Similarly, capsules, for example hard or soft gelatin capsules, containing the active ingredient with the addition of excipients or without them, you can get well-known methods. The contents of the capsules can be prepared using known techniques to provide a continuous release of the active substance. For example, it is convenient to each tablet and capsule contained above the number of the lipase inhibitor and sequestrants bile acids.

Composition of active substances according to the present invention can optionally be combined with other compatible pharmacologically active ingredients. Together with the compounds of the present invention is optional, you can take vitamin supplements.

Both compounds, i.e., a lipase inhibitor and prescribe a bile acid, can be administered simultaneously, separately or sequentially. Preferably the compound or composition is administered during the meal and the but to depend on numerous factors, including the patient's age, the severity of the condition and medical history of the patient and his or her determination is the responsibility of the attending physician. For example, - and-cyclodextrin (derivative of starch), cholestyramine, colestipol (listeriosis polymer) and a simple diethylaminoethylamine broadcast cellulose (a derivative of cellulose or dextran), you can enter a rate of 0.1-20 g per day, preferably 1-10 g / day, starch, amylose and others described above, the biliary acids can be entered from the calculation of 1-20 g per day.

The invention relates also to the use of the above combination of the compounds for the preparation of medicines intended for the treatment and prevention of obesity. In addition, it refers to the combination described above compositions intended for use for the treatment and prevention of obesity.

The invention relates also to a kit for the treatment of obesity, which contains a first component representing a lipase inhibitor, and b) the second component, representing prescribe a bile acid, for example, in the form of oral dosage forms, preferably the kit contains (a) from 1 to 100 standard doses of orlistat and b) from 1 to 100 standard doses of Use composition for the preparation of drugs, intended for the treatment and prevention of obesity, for example, to the use of lipase inhibitor for the preparation of medicines intended for the treatment and prevention of obesity in a patient, which are treated with the help of sequestrants bile acid or its pharmaceutically acceptable salt.

In addition, the present invention relates to a method of treating obesity of a person who needs such treatment, introducing a human a therapeutically effective amount of a lipase inhibitor and a therapeutically effective amount of sequestrant bile acids. Both compounds, i.e., a lipase inhibitor and prescribe a bile acid, can be administered simultaneously, separately or sequentially.

Thus, the present invention relates also to the lipase inhibitor and sequestrant bile acids intended for simultaneous, separate or sequential injection for treatment and prevention of obesity, and to the United drug intended for simultaneous, separate or sequential injection for treatment and prevention of obesity.

The invention relates also to the use of ECENA and prevent adverse impacts in respect of the gastrointestinal tract, selected from the group comprising anal after oil (oily spots), fatty/oily stools, the urge for defecation, fast defecation and incontinence of stool. In addition, the invention relates also to a method of treating or preventing side effects in relation to the gastrointestinal tract selected from the group comprising anal after oil (oily spots), fatty/oily stools, the urge for defecation, fast defecation and incontinence of stool, a person in need of such treatment, introducing a human a therapeutically effective amount described above sequestrants bile acids.

Below the invention is illustrated in the examples, not limiting its scope.

Examples

Example 1: Experiment And

Xenical (Xenical) was administered three times per day (t.i.d.) two healthy volunteers of middle age, who were on standard average mixed diet. Both men often experienced one or more of the above unpleasant side effects in relation to the gastrointestinal tract. After taking xenical within 4 weeks they started to give in addition to xenical twice a day (b.i.d.) cholestyramine, nahma meal. The frequency of side effects decreased immediately and then they completely disappeared. After 2-4 weeks of receiving cholestyramine with xenicalcom stopped. With continued introduction of xenical harmful gastrointestinal side effects showed up again.

Example 2: Experiment B

The potential activity of bile acid sequestrants as inhibitors side effects in relation to gastro-intestinal action (LCD) additionally confirmed using short experiments on volunteers. To strengthen the trend towards the manifestation of side effects using this model during three meals (lunch, dinner, Breakfast) was additionally applied xenical, which consisted of 120 mg of orlistat, each time with 10 g of oil. The model is based on the assumption that induced by orlistat side effects regarding LCD tract accelerated due to the formation of free oil. Free oil is an oil that can coalesce into emulsion of dietary fat when passing through the LCD tract and to separate from the stool mass. When using this model, estimate the amount of oil separated from the mass of stool after a bowel movement.

Was ustane free oil was sharply decreased (cholestyramine: 44% relative to a control experiment without addition of cholestyramine) or almost completely suppressed (colestipol: 6% relative to the control experiment without addition of colestipol). The total number of secreted fat remained unchanged (see table 1).

Example 3: Pharmaceutical compositions of orlistat)

Process

1. Mix orlistat, microcrystalline cellulose and nitroglycol starch in a suitable mixer.

2. Granularit with a solution of polyvinylpyrrolidone and lauryl sulfate in purified water.

3. Miss GRANULAT through the extruder and passed the extrudate through spheroidization providing granules.

4. Dried pellets at 30°C.

5. Add talc and mix.

6. Fill hard gelatin capsules.

B)

Process

1. Mix orlistat, microcrystalline cellulose and nitroglycol starch in a suitable mixer.

2. Granularit with a solution of polyvinylpyrrolidone and lauryl sulfate in purified water.

3. Miss GRANULAT through the extruder and passed the extrudate through spheroidization providing granules.

4. Dried pellets at 30°C.

5. Add talc and mix.

6. Fill hard gelatin capsules is a mini pulp and nitroglycol starch in a suitable mixer.

2. Granularit with a solution of polyvinylpyrrolidone and lauryl sulfate in purified water.

3. Miss GRANULAT through the extruder and passed the extrudate through spheroidization providing granules.

4. Dried pellets at 30°C.

5. Add talc and mix.

6. Fill hard gelatin capsules.

Example 4: the Pharmaceutical composition of bile acid sequestrants

Process

1. Mix cholestyramine and silicon dioxide in a suitable mixer.

2. Granularit with a solution/colloidal suspension of aspartame and-carotene in purified water.

3. Pass the granules through a sieve.

4. Dry the granules at 60°C.

5. Pass the dry granules through a sieve.

6. Fill the sachet.

Example 5: Pharmaceutical compositions bile acid sequestrants

Process

1. Mix cholestyramine, silicon dioxide and sucrose in a suitable mixer.

2. Granularit with a solution/colloidal suspension of aspartame and-carotene in purified water.

3. Pass the granules through a sieve.

4. Dry the granules at 60&#cautions composition bile acid sequestrants

Process

1. Make cholestyramine in a suitable mixer.

2. Granularit with a solution/colloidal suspension of aspartame and-carotene in purified water.

3. Pass the granules through a sieve.

4. Dry the granules at 60°C.

5. Pass the dry granules through a sieve.

6. Fill the sachet.

Example 7: Composition of orlistat/sequestrants bile acids

Process

1. Melt orlistat in blender and add maltodextrin.

2. Mix to cure at room temperature (the first part).

3. Add cholestyramine and stirred.

4. Granularit with a solution/colloidal suspension of aspartame in purified water.

5. Pass the granules through a sieve.

6. Dry the granules at 60°C.

7. Pass the dry granules through a sieve (the second part).

8. Mix the two parts in the mixer.

9. Fill the sachet.

Example 8: Composition of orlistat/sequestrants bile acids

Process

1. Mix cholestyramine, orlistat, microcrystalline cellulose (Avicel), nitroglycol starch and crosspovidone in Prigov purified water.

3. Pass the granules through a sieve.

4. Dried pellets at 30°C.

5. Pass the dry granules through a sieve.

6. Fill the sachet.

Example 9: Composition of orlistat/sequestrants bile acids

Process

1. Melt orlistat in blender and add maltodextrin.

2. Mix to cure at room temperature (the first part).

3. Add colestipol and stirred.

4. Granularit with a solution/colloidal suspension of aspartame in purified water.

5. Pass the granules through a sieve.

6. Dry the granules at 60°C.

7. Pass the dry granules through a sieve (the second part).

8. Mix the two parts in the mixer.

9. Fill the sachet.

Example 10: the Songs orlistat/sequestrants bile acids

Process

7. Mix colestipol, orlistat, microcrystalline cellulose (Avicel), nitroglycol starch and crosspovidone in a suitable mixer.

8. Granularit with a solution/colloidal suspension lauryl sodium and aspartame in purified water.

9. Pass the granules through a sieve.

10. Sushi is 2">1. Composition for the treatment and prevention of obesity, containing a lipase inhibitor and a pharmaceutically acceptable prescribe a bile acid.

2. The composition according to p. 1, containing one or more pharmaceutically acceptable excipients.

3. Composition under item 1 or 2, where the lipase inhibitor is a orlistat.

4. Composition according to any one of paragraphs.1-3, where the pharmaceutically acceptable prescribe a bile acid selected from the group including cholestyramine, colestipol, colesevelam, colestimide, sevelamer, derivatives of cellulose and dextran, starch and starch derivatives and their pharmaceutically acceptable salts.

5. Composition according to any one of paragraphs.1-4, where the pharmaceutically acceptable prescribe a bile acid is a derivative of cellulose or dextran.

6. Composition according to any one of paragraphs.1-5, where the derivative of cellulose or dextran selected from the group consisting of DEAE-pulp, guanidinoacetate, DEAE-Sephadex.

7. Composition according to any one of paragraphs.1-6, where the starch or the derivative of the starch is chosen from the group comprising - or-cyclodextrin, retrogradely and/or split starch, hydrophobic starch, amylose, simple diethylaminoethyl chmela choose from or-cyclodextrin.

9. Composition according to any one of paragraphs.1-4, where prescribe a bile acid selected from the group including cholestyramine, colestipol, colesevelam, colestimide, sevelamer, cellulose, DEAE-pulp, guanidinoacetate, DEAE-Sephadex, starch or cyclodextrin.

10. The composition according to p. 9, where prescribe a bile acid selected from the group including cholestyramine, colestipol, colesevelam, colestimide, sevelamer, DEAE-pulp and - or-cyclodextrin.

11. The composition according to PP.9 and 10, where prescribe a bile acid selected from the group including cholestyramine, colestipol, sevelamer, DEAE-pulp and - or-cyclodextrin.

12. Composition according to any one of paragraphs.9-11, where prescribe a bile acid selected from the group including cholestyramine, colestipol and sevelamer.

13. Composition according to any one of paragraphs.9-11, where prescribe a bile acid is a cholestyramine.

14. Composition according to any one of paragraphs.9-11, where prescribe bile acids represents colestipol.

15. Composition according to any one of paragraphs.9-11, where prescribe a bile acid is sevelamer.

16. Composition according to any one of paragraphs.1-15, containing (a) from about 5 to about the Oia according to any one of paragraphs.1-16, where pharmaceutically acceptable excipient chosen from the group comprising fillers, surface-active agents, disintegrating agents, binders, sizing, amplifiers fluidity, sweeteners and dyes.

18. Composition according to any one of paragraphs.1-17, containing (a) from about 5 to about 1000 mg of a lipase inhibitor; b) from about 0.1 to about 20 g of sequestrants bile acids; and optionally pharmaceutically acceptable excipients selected from the group comprising from about 0.1 to about 10 g of fillers, from about 0.05 to about 3.0 g of surfactants, from about 0.05 to about 2.0 g of baking powder, from about 0.02 to about 2.0 g of the binder, from about 0.001 to about 1.0 g of oil, from about 0.1 to about 5.0 g amplifiers fluidity, from about 0.01 to about 4.0 g sweeteners and from about 0.001 to about 0.5 g dye.

19. The composition according to p. 18, where the lipase inhibitor is a orlistat.

20. Composition according to any one of paragraphs.1-19 containing from about 10 to about 500 mg of a lipase inhibitor.

21. Composition according to any one of paragraphs.1-20 containing from about 20 to about 100 mg of lipase inhibitor.

22. Comp the WMD of PP.1-22, containing from about 30 to about 120 mg of orlistat.

24. Composition according to any one of paragraphs.1-23 containing from about 40 to about 80 mg of orlistat.

25. Composition according to any one of paragraphs.1-24 containing from about 0.5 to about 10 g of sequestrants bile acids.

26. Composition according to any one of paragraphs.1-25 containing from about 1 to about 5 g of sequestrants bile acids.

27. The method of preparation of a composition for the treatment and prevention of obesity on PP.1-26, providing a mixture of lipase inhibitor with sequestrants bile acids and optionally one or more pharmaceutically acceptable excipients.

28. Set for the treatment and prevention of obesity, which contains a first component representing a lipase inhibitor, and b) the second component, representing prescribe a bile acid, in the form of a standard oral dosage forms.

29. Composition according to one of paragraphs.1-26, intended for the preparation of drugs intended for the treatment and prevention of obesity.

30. Method for the treatment and prevention of obesity in humans, which need such treatment, introducing a person terapevtychnyj acid according to any one of paragraphs.1-26.

31. The method according to p. 30, providing for simultaneous, separate or sequential administration.

32. Set on p. 28, which is intended for simultaneous, separate or sequential injection for treatment and prevention of obesity.

33. Set on p. 28 in the form of a combined preparation, intended for simultaneous, separate or sequential injection for treatment and prevention of obesity.

34. A method of treating or preventing side effects in relation to the gastrointestinal tract selected from the group including oily spots, fatty/oily stools, the urge for defecation, fast defecation and incontinence of stool, a person who needs such treatment, introducing a human a therapeutically effective amount of sequestrant bile acids according to any one of paragraphs.1-26.



 

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