TWI336252B - Pharmaceutical composition for the treatment and prevention of obesity - Google Patents

Description

1336252 V. INSTRUCTION DESCRIPTION (!) 4g of the Invention The present invention relates to a pharmaceutical composition comprising a lipolytic enzyme inhibitor, preferably ollistat, which has a melting point & hunger, A saccharide fatty acid ester wherein sucrose fatty acid ester is mono-, di-, tri-, or tetraester, and optionally, or a plurality of pharmaceutically acceptable excipients. Background of the main technology The examples of such lipolytic enzyme inhibitors are liposmin and ollistat. The latter, also known as tetrahydrolipstatin or THL, is derived from a natural product secreted by strept〇myces t〇XytriCini (species of streptococci). It has been found that such compounds are present in test tubes and in m against many lipolytic enzymes such as "reactive" such as lingual (four) lyase, (four) lysing enzymes, gastric fat decomposing enzymes, and occupational (iv) lysing enzymes. The material (4) or the prevention of obesity and the case of lipemia are described, for example, in U.S. Patent 4,598,. Orlistat is usually taken at a dose of 12 mg per meal, regardless of the weight of the human subject. Orlistat (〇rHstat) is applied topically to the gastrointestinal (gi, gastro〇intestina丨) tract and avoids the lipoprotection enzyme to digest the triglyceride (4) and thus inhibits the formation of absorbable lipolysis products. Therefore, the lipid anti-degrading enzyme inhibitor does not need to achieve a systemic effect, but is preferably present locally in the gastrointestinal tract. A lipolytic enzyme inhibitor composition can generally inhibit about 30% of fat absorption after ingesting a mixed meal; increasing the concentration of a lipolytic enzyme inhibitor in a pharmaceutical composition does not increase its clinical efficacy and/or efficacy, but local side effects The intensity will increase. 78622-950ll3.doc

Anal oil leakage (oil fouling) is a side effect, which is occasionally observed by patients treated with lipolytic enzyme inhibitors. This phenomenon is reflected in the lower part of the large intestine - the physical separation of some liquid unabsorbed dietary oils and solid fibrous substances. It is shown in U.S. Patent No. 5,447,953 that the inhibitory effect of oil absorption can be increased by combining a lipolytic enzyme inhibitor with a large amount of water-insoluble crude fiber. It has been demonstrated in the patent application 〇〇〇/〇 9123 that an anus can be obtained by combining a lipid anti-degrading enzyme inhibitor such as orlistat with a small amount of chitin or a derivative or salt thereof. The phenomenon of oil leakage is reduced. The World Patent Application No. 01/19378 discloses a solid fat formula for use in lipolytic enzyme inhibitors to reduce or prevent oil excretion or annoying formation of free oil. It has been found that higher efficacy (high oil excretion) can be combined with the reduction of unpleasant side effects such as free oil. It has recently been confirmed that the efficacy of a lipid anti-decomposing enzyme inhibitor may strongly depend on the type of food to be ingested. It has been found to be highly effective in meals consisting of French fries, sausages and burgers, while observing low work on cheese and other dairy products. The strong food relevance of the formulation efficacy is an annoying phenomenon because the formulation is ineffective for overdose (with free oil formation) or less susceptible food. Therefore, the reduction in food-related properties was preceded by a low-dose inhibitor, high efficacy, and fewer side effects. Surprisingly, it has been found that some of the recommended glycolipids can increase the activity of lipid-deficient enzyme inhibitors, reduce food-related properties, and reduce the shape of free oils. Figure 1 shows a comparison of Roche woven 78822-950II3.doc -6 - 1336252 A7 B7 in a double-dish test on human volunteers. V. Illustrative (3) (XENICAL) 39.7 (±8.1%, n=5), sucrose ester The base formulation showed approximately I.7 times higher efficacy 240 mg sucrose ester P1670 ··67.4 (±5.3%, n=5), 30 mg sucrose ester P1670: 66.6 (± 13%, n=4). Figure 2 shows that the efficacy of XENIC AL is only 48.4% of the susceptible population in the less susceptible meal, while the sucrose ester-based formula 30 mg sucrose ester P1670 reaches 73.9% (double in human volunteers) Meal test). Figure 3 shows the test emulsion after Surfhope SE Pharma D-18 11 was centrifuged at 3 100g for t = 1 minute (a) and t = 300 minutes (b). The emulsion containing 2,0% (w/w) sucrose ester remained stable even after t = 3 离心 centrifugation time (photo (b), right capillary). From left to right: reference (mixture large oil/buffer solution); c = 0.01%, c = 0.1%; c = 0.5%; c = .1.0%; c = 2_0% (w/w). Figure 4 shows the test emulsion after Surfhope SE Pharma D-1811 was centrifuged at 3i〇〇g for t = 1 minute (a) and t = 300 minutes (b). The emulsion was stabilized with 1.0% (w/w) sucrose ester at various pH values. While the emulsion at pH $7 clearly showed phase separation after centrifugation t = 300 minutes, the emulsion at ρη > 7 significantly showed less free oil. SUMMARY OF THE INVENTION The present invention relates to a pharmaceutical composition comprising a lipolytic enzyme inhibitor, preferably orlistat (0 r丨丨stat), which has a bright point of 3 7 , a saccharide An acid ester wherein the sucrose fatty acid ester is mono-, di-, r, or tetraester, and optionally one or more pharmaceutically acceptable excipients. Detailed Description of the Invention Sweet Sugar Fatty Acid @ is a nonionic surfactant n sugar as hydrophilic

1336252

The fraction and the one or more fatty acid moieties are composed as a lipophilic moiety. It is made from alcoholized sugars and vegetable oils. Since the recommended sugar has a total of 8 groups, a compound ranging from a sucrose mono- to octa fatty acid ester can be produced. The following formula shows the chemical structure of sucrose monostearic acid as an example:

The use of "sweet sugar fat 1 brewing" contains a single heptose fat acid-proof vinegar and a mixture of two or more sucrose fatty acids, as defined below. In a preferred embodiment of the invention, the degree of substitution of the sucrose fatty acid ester varies between 1 and 4, such as mono-, di-, tri-, and tetra-derivatives of fatty acids and saccharides. This term includes pure canola esters and mixtures of sucrose esters, wherein the sucrose esters can be esterified with different fatty acids and can have several degrees of substitution, such as mono-, di-, tri- or tetra-substituted. Sucrose fatty acid esters and mixtures thereof are known in the art and are commercially available (Mitsubishi-Kagaku Fpods Corp., Montello Inc., Multi-Kem Corp., et al; also found in Garti, Ν·; Clement , V.; Leser, M.; Aserin, A.; Fanun, M. Sucrose ester microemulsions. J. Mol. Liq. (1999), 80(2,3), 253-296); Carbonhy drate-alkyl ester Derivatives as biosurfactants. Allen, DK; Tao, BY, J. Surfactants Deterg. (1999), 2(3), 383-390) » -8- 78622-9501I3.doc This paper and scale apply to Chinese national standards (CNS) ) A4 size (210X 297 mm) 1336252

The term "lipase inhibitor" means a compound capable of inhibiting the action of lipolytic enzymes such as lipolytic enzymes in the stomach and pancreas. For example, orlistat and lipstatin, described in U.S. Patent No. 4,598,89, are potent inhibitors of lipolytic enzymes. Lipsutin is a natural product of microbial origin, while 〇rUstat is the hydrogenation product of 11P s t at i η. Other lipolytic enzyme inhibitors include a class of compounds commonly known as panelicins. Panclicins are analogs of orlistat (Mutoh et al., J. Antibiot., 47(12): 1369-1375 (1994)). The term "lipase inhibitor" also means a synthetic lipolytic enzyme inhibitor such as described in World Patent Application WO 99/34786 (Geltex Pharmaceuticals Inc.). These polymers are characterized by their substitution by one or more groups that inhibit lipolytic enzymes. The term "lipase inhibitor" also encompasses pharmaceutically acceptable salts of such compounds. In addition, the term "lipolytic enzyme inhibitor" also means 2-oxo-4hydro-3,1-benzoindole-4-one, which is described in World Patent Application WO 00/40569 (Alizyme Therapeutics Ltd) .), such as 2-mercapto-6-methyl-4H-3, 1-benzo- morphine-4-, 6-methyl 2 -tetradecyloxy-4H-3, 1-benzene And 4 11 well -4- 鲷, and 2-hexadecyloxy-6-methyl. 4H-3,1 - stupid 啰 啰 -4- ketone and other descriptions in, for example, the world brick application W0 01 / 32616 'W0 01/32669 and Ethylpropionate in W0 01/32670" More preferably, the word "lipase inhibitor" means orlistat 0 in German patent DE 1 965 13 3 (Merck), indicating that some poly(phenylene)-derived polymers exhibit direct lipolytic enzyme inhibition and bile acid 78622-950113.doc This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297) PCT) 1336252 A7 B7 V. Description of invention (6) and triglyceride binding properties. Orlistat (〇 r 1 i s t at) is a known compound (Formula I), which is used to control # to avoid obesity and hyperlipemia.

ρ (. See U.S. Patent No. 4,598,089, issued July 1, 1986, which also discloses the disclosure of the entire entire entire entire entire entire entire entire content The pharmaceutical compositions are disclosed in, for example, World Patent Applications WO 00/09 122, WO 00/09123, WO 01/19340, and WO 01/19378. Another method of preparing orlistat reveals European patent applications. In the preferred embodiments of the present invention, the sucrose ester molecule is mono-, di- or tri- vinegar. More preferably, the sucrose ester molecule is mono- or di- The ester, preferably, the vegetable vinegar molecule is mono-vinegar. The fatty acid moieties in the di-, tri- or tetraester may be the same or different (eg, sucrose stearic acid g), preferably the same.

A preferred ratio (weight ratio) between the lipolytic enzyme inhibitor and the sucrose fatty acid ester is as follows: per mg of the lipolytic enzyme inhibitor, the composition may comprise 0.05 mg to 2 mg of sucrose fatty acid ester, preferably Yes, every 1 gram of lipolytic enzyme inhibitor is 〇. 丨 mg to 1 〇 蔗糖 sucrose fat I 78622-950113.doc _ This paper size applies to China's 豕 &; 准 (CNS) A4 specifications (210X297 public ) " ' -- 1336252 A7 B7 Five inventions description (detailed, better is! per milligram of lipolytic enzyme inhibitor 妓 (1) mg agarose fat ❹ 'best is every 1 milligram of lipid ❹ lyase inhibitor CM5 to 1 mg of sucrose ester acid ester. Preferably, the lipolytic enzyme inhibitor is a lipophilic compound. Most preferably, the lipolytic enzyme inhibitor is orlistat (〇riista). In a preferred embodiment, the fatty y acid portion of the yoghurt is a CS to C24 saturated or partially unsaturated fatty acid. Preferably, the fatty acid portion of the sucrose fatty acid ester is a Ci8 saturated fatty acid. , such as Tibetan sugar, laurel money, meat Vegetable acid m standard palmitic acid brewing, sucrose stearate, sucrose arachidate and sucrose sulphate, preferably sucrose laurate, sucrose succulent acid, sucrose palmitic acid,糖 糖 硬 , , , , , , , , , 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐 荐Preferably, (:^ to 匕8, single or polyunsaturated fatty acids are selected, such as palmitoleic acid, oleic acid, oleic acid, erucic acid, linoleic acid, tau-linolenic acid, beta-linolenic acid And selected from the group consisting of arachidonic acid, the most preferred is oleic acid, that is, the sucrose fatty acid ester can be sucrose oleate. The fatty acid moiety in the di-, tri- or tetra-sucrose fatty acid ester can be two or a mixture of a plurality of fatty acids, such as a sugar palmitate stearate. For a lipolytic enzyme inhibitor such as orlistat, the preferred composition comprises from 1 to 240 mg, more Preferably, it is 30 to 1203⁄4 grams, such as 30, 40, 60, 80, 100, or 120 mg. A particularly preferred composition comprises 6〇 to 12〇 mg orlistat (〇rHstat) and 78622-950113.doc _ ^

This paper scale is suitable for S s material (CNS) A4 specification (21GX 297 mm) 1336252 A7 B7 V. Description of invention (8) 20 mg to 100 mg of sucrose fatty acid ester. For example, the composition as described above may comprise 120 mg of orlistat and 60 mg of sucrose fatty acid ester or 120 mg of orlistat and 30 mg of sucrose fatty acid ester. Another composition may comprise 80 to 120 mg of orlistat and 10 to 40 mg of sucrose fatty acid ester or 20 to 60 mg of orlistat and 5 to 15 mg of sucrose fatty acid ester. Each dosage unit of the above pharmaceutical compositions may provide a weekly dose of the pharmaceutically active compound or may contain a portion of the daily dose, such as one third of the dose. Alternatively, each dosage unit may contain a complete dose of one compound, and a sub-dose of another compound. In this case, the patient should take one combination dose unit per day, and one or more greens containing another compound. Orlistat is preferably administered orally 3 to 8 mg per day in two to three doses per day (see above). Other preferred daily dosages range from 12 to 360 mg, more preferably from 18 to 27 mg per day, most preferably 180 mg. It is preferably divided into two or more, in particular, three times a day. In general, it is preferred to take a lipolytic enzyme for about one or two hours after eating a fat-containing meal. In general, for the administration of a lipolytic enzyme inhibitor as described above, (4) the treatment is administered to a family with a strong family history of obesity or having a body mass index of 25 or more. The composition of the oral composition, such as a soft gelatin capsule, a money, a suspension, a sachet, a stick or a tablet, and a hard composition can be applied to the human body. Can be used for tablets, coatings;: ί invented pills, hard gelatin capsules and sachets of the carrier as examples; 2::: -12- 78622-950113.doc This paper is a New Zealand currency (a) to the standard (CNS) μ specifications (4) 297 297 public) 1336252 A7 B7 V. Description of the invention (forms such as lactose, other sugars and sugar alcohols such as sorbitol, mannitol, maltodextrin, or other fillers; surfactants such as sodium lauryl sulfate, B 96, Tween 80; decomposition of substances such as sodium starch glycolate, corn starch or its derivatives 'polymers such as povidone (p〇vid〇ne), cross-linked polyglycol (cr〇Spovidone); lubricants such as talc; Stearic acid or a salt thereof and the like. Further, the pharmaceutical preparation may contain a preservative, a solubilizer, a stabilizer, a wetting agent, a binder, an emulsifier, a sweetener, a dye, a flavoring agent, and the like. Osmotic salts, buffer solutions, coatings and antioxidants. They may also contain other therapeutically valuable substances. This formulation may conveniently be presented in unit dosage form and may be known in any pharmaceutical skill, in particular The object may contain one or more medicines that can be connected to ^ Forming agent, from mannitol, lactose, HPMC, talc, sorbitol, poly-hoofosporin, phosphorus, glycerin, glycerol, sorbate, polyoxyethylene A narrow group consisting of a fatty acid ester and a dimethyl eucalyptus oil is preferably selected from the group consisting of lactose. + = The agent (4) is a composition which is preferably used in the invention, and the like: "known medicine" Forms such as tablets, capsules or sachets. The formula = thinner and carrier are known in the art of pharmaceuticals. The tablets are filled with active compound such as corn powder... ", for example, "calcium; , for example, % ^ = u彳 'such as magnesium stearate; binder, such as microcrystalline ·. 'years old, 隹 或 or 永乙归 P formed with a mixture of P and ketones and !^ P 4 The ingredients selected in the technique can be made into tablets by examining the mixture. A similar or gray-powered cylinder such as a hard or soft gelatin capsule (containing active compound and "σ" shape Prepared by known methods. Known methods can be used 78624-950113.doc I________ * ΙΟ * 5 scales applicable to China 13 1336252 A7 B7 V. INSTRUCTIONS (10) The contents of the capsules are formulated to produce a sustained release of the active compound. For example, the tablets and capsules may conveniently contain the amounts of the pharmaceutically active compound and the sucrose ester as described above. "Pharmaceutically acceptable" means that the buffer or salt is acceptable from a toxicity standpoint. The oral dosage form can be a chewable tablet containing 10-24 mg of orlistat, 0.5-1000 mg of sucrose fatty acid ester. And additional excipients such as maltodextrin, lactose or cellulose, such as i 2 mg mg of orlistat (〇r 11 stat), 30 grams of sucrose palmitate, such as sucrose palmitate P1670, 9603⁄4 Maltodextrin, 36 mg of Cellulose, and 15 mg of talc. In the compositions of the present invention, the active compound may be combined with other compatible pharmaceutically active ingredients, if desired. The vitamin supplement can be administered with the compound of the present invention as the case may be. The invention also relates to a process for the preparation of a composition as described above which comprises mixing a pharmaceutically active compound and a sucrose fatty acid ester together with one or more pharmaceutically acceptable diluents and/or carriers. "The present invention also provides an agent for treating and preventing obesity by using the above compounds in combination. Furthermore, it provides the above composition for the treatment and prevention of obesity. Further, the present invention relates to a method of treating obesity in a human in need of treatment comprising a pharmaceutically active compound as defined above and a sugar cane fatty acid ester, and optionally a pharmaceutically acceptable excipient. ^ The present invention also relates to the use of the defined composition for the treatment and prevention of the fatty side 3*, 14. ^ paper scale application in the self-sleeping standard (CNS> M specification (expanding g_----- 1336252

fat. Another embodiment of the present invention relates to the preparation of a composition as defined above, which comprises mixing a pharmaceutically active compound as defined in the scope of the patent, and a saccharide, and optionally, < A multi-pharmaceutically acceptable diluent and/or carrier. Further, the present invention relates to a kit for treating obesity, the kit comprising a first component which is a lipid anti-degrading enzyme inhibitor, & a second component which is a saccharide fatty acid ester in a unit dosage form . Further - specific embodiments relate to the use of a composition as defined above for the manufacture of M for the treatment and prevention of obesity and for the treatment of obesity in a human body in need of such treatment, which comprises administering to the body a therapeutically effective amount of lipolysis An enzyme inhibitor and a sugar fatty acid as defined above. The present invention also relates to a lipolytic enzyme inhibitor as defined above and a silk gum vinegar for use in the treatment and prevention of obesity. The invention will be better understood by reference to the following examples, which are illustrated but not limited to the invention herein. EXAMPLES General Note: All compounds used in the examples are commercially available. 78622-950113.doc -15- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)

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Formulation--- Transfer to cream (%) Transfer to roll-'---1 Soy oil in 10' after 60', after 10' after 60, after XENICAL 5 10 35 70 L-1695 55 65 55 80 P- 1670 25 45 50 80 S-1670 10 25 60 90 0-1570 55 65 45 80 Transfer the suspension of orlistar (4 mg) from sucrose fatty acid ester (2 mg) to 5 ml 10% Oil in water emulsion (pΗ value 4.5;

Oil composition: olive oil and cream). The dispersion was mixed at a small axis angle for a desired period of time. The oil phase was separated by cold centrifugation and the 〇r丨i s t a t content in the oil phase was determined by HPlc. For comparison, appropriate experiments were performed simultaneously with xeNIC AL® suspension. ]^ 1695,? - 1670, 8-1.670, 0-1570 are commercially available sugar fatty acid esters available from Mitsubishi-Kagaku Foods, Japan (sucrose laurate, sucrose palmitate, sucrose stearate, sucrose oleic acid, respectively) g)). The results show that sucrose fatty acid esters have a higher transfer than .XENIC AL®. Efficacy Transfers orlistat (〇 r 1 i s t a t) into the oil phase. In addition to the generally higher transfer efficiency, oristatat can be transferred to different types of oils at a higher rate than XENICAL® (creams, emulsified and casein-coated oil droplets; olives) Oil: Unprotected oil) ^ Orlistat - 16 - Order

Line 78622-950113.doc This paper and scale apply to China National Standard (CNS) A4 specification (21〇X297 公藿) 1336252

The high food relevance of (orlistat) can be transferred to olive oil after 1 minute and is 7 times more efficient than transferring human cream. Liquid fatty acids show less food relevance. Therefore, dose reduction and side effects can be expected. F-Example 2 Pills and preparations The chewable tablets of the following compositions were prepared:

-17- Maltodextrin------- Lactose Cellulose Complex Talc ~~ ____-- — Mix orlistat, sucrose palmitate and maltodextrin Continue stirring to add 35 grams of water step by step. With the help of the river ejector, the uniform dispersion was spread over the track, '罔 (mesh size 0.5 mm). Place the screen in the adjustment to 2 5 . In a vacuum oven (Heraeus VT 5050 EK). Reduce the pressure in the tank to 3 〇 phase (Leybold Heraeus TRIVAC D8B; COMAT AG DPI 700). : After a minute, the development of the foam structure is completed. The foam was dried in vacuo for 1 hour. Carefully control the foam temperature to no more than 35t. The formed foam is decomposed and screened to achieve a uniform flowable powder. The lactose fiber clearing compound and talc are added and uniformly dispersed by dry mixing, and the resulting composition is compressed to contain 120 mg of orlis tat, 30 mg of sucrose palmitate, 960 mg of maltodextrin, Lactose Cellulose Complex 36〇mg, and Talc78622-950113.doc This paper scale applies to China National Standard (CNS) A4 Specification (210X 297 mm) Binding

1336252 A7 B7 V. INSTRUCTIONS (14) 15 mg tablets. Example 3: Chewable Tablet Formulations Chewable tablets of the following compositions were prepared: Composition 2 Orlistat 120 grams of sucrose palmitate P1670 240 grams of maltodextrin 750 grams of lactose cellulose complex 375 grams of talc 15 The tablets were prepared by the same procedure as described in Example 2. Example 4: Chewable Tablet Formulations Chewable tablets of the following compositions were prepared: Composition 3 Orlistat 60 grams of sucrose palmitate P1670 60 grams of maltodextrin 750 grams of lactose cellulose complex 375 grams of talc 15 The tablets were prepared by the same procedure as described in Example 2. 78622-950113.doc - 18 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm)

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Line 1364252 A7 B7 V. INSTRUCTIONS (15) Example 5: Chewable Tablet Formulations Chewable tablets of the following compositions were prepared: Composition 4 orlistat 60 grams of sucrose stearate S1811 60 grams of maltose paste Fine 750 g of lactose cellulose complex 375 g of talc 15 g of the tablet was prepared by the same procedure as described in Example 2. Example 6: Chewable Tablet Formulations Chewable tablets of the following compositions were prepared: Composition 5 Orlistat 60 grams of sucrose myristate M1695 60 grams of maltodextrin 750 grams of lactose cellulose complex 375 grams of talc 15 g of the tablets were prepared by the same procedure as described in Example 2. 78622-950113.doc - 19 - This paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1336252 A7 B7 V. Description of invention (16) Example 7: Chewable tablet formula The following composition can be chewed Tablet Preparation: Composition 6 Orlistat 60 g sucrose stearate S1816 60 g maltodextrin 750 g lactose cellulose complex 375 g talc 15 g Pill preparation by the same procedure as described in Example 2 . Example 8: Pill Formulation Composition 7 Orlistat 240 g of sucrose palmitate P1670 60 g Avicel PH-105 35 g sodium starch glycolate 60 g povidone K30 30 g in a high speed mixer (Diosna P50) ingredients are mixed together. 240 grams of water was added stepwise and the mixing procedure was continued for about 5 minutes. This material was used to feed the extruder (NICA lab E-140; sieve 0.8 mm mesh size, thickness 1.0 mm, screened by a cooling device). Extrude the material into a tube of the appropriate length. The temperature of the extrudate does not exceed 35 °C. The extrudate was transferred to a spheronizer (NICA lab S320) and spheronized at 700 rpm for 0.5 to 3 minutes. Will be 78622-950H3.doc - 20 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1336252 A7 --------- B7 V. Invention! ~ —— Wet pills are below 35. (The temperature is dried in a fluid bed dryer (Aer〇matic, P 0. The dried pellets are screened through a sieve inserted into a 5 and 125 mm sieve hole, and the following and excess are discarded. The pill is taken as i06 The t-gram dose (equivalent to 60 mg orlistat) was filled in a sachet. Example _9" Capsule Formulation The above pills were filled in with a dose of 106 mg (equivalent to 60 mg of orlistat). In gelatin capsules of Example I. Example 10: Tablets Magnesium stearate was added in an amount of 1% (w / w) to the pellets described in Example 8 and uniformly distributed by appropriate mixing. Pressed into a 107-gram weighted tablet' which is equivalent to 60 mg of oristatat. Example 11: In-vitro exhortation. In the in vitro nicheolytic inhibition assay with susceptible and resistant oils' Reduced food-related efficacy of the sucrose-based orlistat (〇rHstat) formulation. Study xenicai pills and tablets of Examples 2 and 3. Add water to disperse the tablets to produce orlistat (〇rlistat) ) The concentration is 6.64 mg / ml. The sample will be The mixture was mixed for 5 minutes and diluted in equal steps. The aliquot from each dilution step was mixed with the substrate and subjected to lipolytic enzyme inhibition analysis. The final emulsion contained 2.5% (w/v) fat and oil. 10 mg/ml USP pancreatic. • 21 - 78622-950ll3.doc This paper size applies to China National Standard (CNS) A4 size (210X297 mm) I336252

Intravenous lipid anti-degrading enzyme ^ related to the inhibition of lipid decomposition. In this test, the lipid (4) dezymase is qualitative (creamy and granulated hamburger/fries, representing resistant and susceptible oils, respectively) under simulated gastric conditions (ie in the presence of 20% human gastric juice) Called 4.5 hours) to cultivate in the THL formula. Pre-cultured (4), the formula can be given a small droplet of THL. The decomposition of fat is then initiated by the addition of an artificial intestinal fluid containing bile salts, phospholipids, and hydrolyzing enzymes (pancreatin). After one hour, an organic solvent was added to stop the reaction, and the free fatty acid was quantified. The dose-response curve is dependent on the formulation and the type of substrate used. The β IC^ curve is a concentration that inhibits triglyceride g by 5%. For high food correlation observed in Xenical, IC5Q increased by a factor of two. The sucrose ester-based orlistat (〇 r 11 s t a t) formulation has a 6-fold smaller comparison of the in-vitro food correlation compared to Xenical. 22- 78622-950113.doc This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1336252 A7 B7 V. Description of invention (19 Example 12: In vivo efficacy by double meal test, Composed of susceptible oils (lunch: hamburger, french fries) and less susceptible oils (dinner: cheese meal), illustrated in Example 2 (30 mg sucrose palmate) and Example 3 (240 150 mg of sucrose sucrose ester) of 120 mg of orlistal (〇r 1 istat) tablet formulation, and Roxel (Xenical) in human volunteer test. According to Bligh & Dyer (; Bligh, EG; Dyer, WJ Can. J. Biochem. Physiol 37 (1959) 91 1) Determination of non-absorbed fats. The results show that compared with Roche's fiber (乂^(^1) 39.7 (±8.1%, 11=5), (Fig. 1 The sucrose ester-based formulation showed approximately 1.7 times higher efficacy with a formulation of 24 mg of sweet and sour P1670: 67'4 (±5.3%, n = 5) with 3 mg of sucrose ester P1670: 66·6 (± Formulation of 13%, n=4) f Example 13: Analysis of fatty acids in the body and in the stool, allowing for selective determination of lunch and dinner meals Lipid uptake. The results show that (Figure 2) Rox's fiber (XENiC al) is only 48 4% of the more susceptible foods in the less susceptible meal, while the sugar § base formula 3 0 Ai Kejian sugar @旨p 16 7 0 reaches 7 3 · 9 %. From this data it can be inferred that the food relevance of orlistat (〇rHstat) can be substantially minimized by the sucrose ester-based formulation. f Example 14: In vitro Studying the side effects of sputum in many other strategies to control anal leakage, it is highly important to produce a stable diet oil emulsion in the colon. Therefore, the centrifugation method is used to study the hydrophilicity and lipophilic balance (HLB, which covers the broad κ target circumference. Emulsifying properties of sucrose esters of hydr〇phile_lip〇phile-balance). Intratube method 78622-950113.doc _ 23 This paper scale is suitable for the standard of M standard (21QX297 public ^ -- 1336252 A7 B7 V. Invention Note (20) allows the emulsion stability of both concentration and pH to be examined, thus selecting the sucrose ester with the highest possible control side effects. The results of the concentration-related emulsion stability studies are listed in Table 1-3. Table 1. Different concentrations c and centrifugation time t Surfhope SE Pharma D-18 15 Test emulsion stability c (% w/w) Surfhope SE Pharma D-1815 Emulsion stability t / min 10 70 100 160 220 300 0.01 Low * Low Low Low Low 0.1 High Medium Medium Medium Medium Medium 0.5 High Medium Medium Medium Medium Medium 1.0 High Medium Medium Medium Medium Medium 1.5 High Medium, Medium Medium Medium Medium 2.0 High Medium Medium Medium Medium Medium* Low: Oil and water form two distinct distinct phases; Medium: Partially broken emulsion High: no signs of bonding, optically opaque, stable emulsion 0 Table 2. Stability of the tested emulsion at different concentrations c and centrifugation time t Surfhope SE Pharma D-1811. 78622-950113.doc - 24 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1336252 A7 B7 V. Invention description (21 ) c(% w/w) Surfhope SE Pharma D-1811 Emulsion stability t/min 10 70 100 160 220 300 0.01 Low* Low Low Low Low 0.1 Low High Direction Medium Medium Medium Medium 0.5 High Medium Medium Medium Medium 1.0 High Direction High Medium Medium Medium 1.5 High South Medium Medium Medium 2.0 High High to high * low: oil and water form two distinct distinct phases; medium: partially broken emulsion; high: no signs of bonding, optically opaque, stable emulsion. Table 3. Stability of Surfhope SE Pharma D-1805 test emulsion at various concentrations c and centrifugation time t. c(% w/w) Surfhope SE Pharma D-1805 Emulsion stability t/min 10 70 100 160 220 300 0.01 Low* Low Low Low Low 0.1 Low Low Low Low Low Low 0.5 Medium Medium Medium Medium Medium Medium 1.0 Medium Medium Medium Moderate Medium Medium 1.5 High Medium Medium Medium Medium Medium 2.0 South Medium Medium Medium 78622-950U3.doc - 25 - This paper size applies to Chinese National Standard (CNS) A4 Specification (210 X 297 mm) 1336252 A7 B7 Five Inventions Description (22 * low: oil and water form two distinct distinct phases; medium I: partially broken emulsion; high: no signs of bonding, optically opaque, stable emulsion. sucrose esters such as Surfhope SE Pharma D-I8ll ( Table 2) has a medium HLb value of 11 to confirm that the ability to stabilize the emulsion is slightly better than Surfh〇pe %

Pharma D-1815 (Table 1) and Surfhope SE Pharma D- 1805 (Table 3). At a concentration of 2.0% (w/w) Surfhope SE Pharma D l8u showed a stable emulsion without any visible joints at the same centrifugation time of t = 300 minutes.

Like (Figure 1). Surfhope SE Pharma D-1815 and Surfhope SE

Both Phama D-1805 showed only slightly less stable emulsion stability. In addition, measurements prepared in a similarly prepared emulsion at room temperature for one week without any centrifugal force showed that the conditions resulting from the centrifugation experiment were related to the normal resting period of about 2 to 3 days' which was consistent with the average human gastrointestinal transit time. Figure 3 shows the test emulsion after Surfhope SE Pharma D-18.ll was centrifuged at 3 100g for t = 1 minute (a) and t = 300 minutes (b). The emulsion containing 2.0% (w/w) sucrose ester remained stable even after t = 3 离心 centrifugation time (photo (b) 'right capillary) ^ from left to right: reference (mixture big five oil plant buffer Liquid), c = 0 · 〇 1 %, c = 0 · 1 % ; c = 〇 · 5 % ; c = 1. 〇% ; c = 1.5%; c = 2.0% (w/w). Similar emulsion stability tests utilize sucrose esters and hydrocolloids (eg, xanthan gum, gellan gum (Gellan Gum), carrageenan (carrageenan), sphingomyelin, silica gel derivatives, carbonyl thiocellulose, chitin, A combination of colloidal clay, serum protein concentrate, pectin, and poly(vinyl alcohol). Interestingly, 'These studies show a 1:1 combination (w/w) of Surfhope SE Pharma 78622-950113.doc - 26 - This paper size applies to Chinese National Standard (CNS) A4 specification (210x 297 public) 1336252 A7 B7

V. INSTRUCTIONS (23 EM815 and Aer〇sii 200, carrageenan, and serum protein concentrates produce emulsions with significantly better stability than single compounds alone, due to the unclear increase in utility of the machine) pH Study Emulsion stability, test emulsions with a surfactant concentration c == 1.0% w/w covering pH 4 to 9 were prepared (Table 7). At pH &gt; 7, all observed sucrose fatty acid esters appeared Good emulsifying properties. After 300 minutes of centrifugation time, only a small free oil phase separates from the optically opaque emulsion phase. At pH <7, sucrose vinegar with an HLB value below 11 produces only poor emulsification (Table 5-7). Surprisingly, Surfhope SE Pharma D-1815 with an HLB value of 15 produced a highly stable emulsion. This clearly shows that sucrose esters with a higher HLB value (usually about 15) provide superior pH-independent emulsification stability. 4. The stability of the Surfhope SE Pharma D-1815 test emulsion (c=i.〇% w/w) at different pΗ values and centrifugation time. PH Surfhope SE Pharma D-1815 Emulsion stability t / min 1 30 60 120 300 4 high* high, high 5 High High High 6 High High High 7 High High Medium Medium High High Medium Medium Medium High Medium Medium Medium -27- 78622-950113.doc This paper scale applies to China National Standard (CNS) A4 Specification ( 210X297 mm) 1336252 A7 B7 V. INSTRUCTIONS (24) *Low: oil and water form two distinct distinct phases; medium: partially broken emulsion; high: no signs of bonding, optically opaque, stable emulsion Table 5. Stability of Surfhope SE Pharma D-1 8 11 test emulsion (c = 1.0 % w / w) at different pH values and centrifugation time. PH Surfhope SE Pharma D-1811 Emulsion stability t / min 1 30 60 120 300 4 High* Medium Medium Medium Low 5 High Medium Medium Medium Low 6 South Medium Medium Medium 7 Medium Medium Medium Medium 8 High South Medium 9 South South South Medium* Low: Oil and water form two distinct Separation phase; medium: partial rupture of emulsion; high: no signs of bonding, optically opaque, stable emulsion. Table 6. Surfhope SE Pharma D-1 807 test at different pH and centrifugation time Solution stability (c = 1 · 0% \ v / w) of. 78622-950113.doc - 28 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1336252 A7 B7 V. Description of invention ( 25 ) pH Surfhope SE Pharma D-l807 Emulsion stability t/min 1 30 60 120 300 4 High* Medium Medium Medium Low 5 Medium Medium Medium Low 6 High South Medium Medium Low 7 High High Medium Medium 8 High High South South Medium Medium 9 High High Two Medium* Low: Oil and Water Form Two Different Clear Separations Medium; medium part of the emulsion is high: no signs of bonding, optically opaque, stable emulsion. Table 7. Stability of Surfhope SE Pharma D-1805 test emulsion (c = 1.0% w / w) at different pH values and centrifugation time. pH Surfhope SE Pharma D-1805 Emulsion Stability t/min 1 30 60 120 300 4 Low* Low Low Low Low 5 Medium Medium Low Low Low. 6 Medium Medium Medium Medium Medium 7 High South Medium Medium Medium Medium High Side High 9 Southward direction 78622-950113.doc -29- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1336252 A7 _B7 V. Invention description (26 ) *Low · oil and water form two Different distinct separation phases; medium: partially broken emulsion, no signs of jointing, optically opaque, stable emulsion. Figure 4 shows the test emulsion after Surfhope SE Pharma D.1811 was centrifuged at 31 〇〇g for t = 1 minute (a) and t = 300 minutes (b). The emulsion was stabilized with 1.0% (w/w) sucrose ester at different pH values. The pH of the guest 7 emulsion clearly showed phase separation after centrifugation t = 300 minutes. The emulsion of 11 &gt; 7 significantly showed less free oil. From left to right: reference (mixture soy oil/buffer solution) at pH=7; pH=4, pH=5; pH=6; PH=7; pH=8; pH=9. In contrast, the sucrose fatty acid ester S_370F showed very poor emulsifying properties. Due to the high hydrophobicity of the compounds, the solubility in the continuous aqueous phase is very low. However, this compound is very soluble in soy oil, causing a significant increase in oil viscosity. Exemption - 1 5: In vivo study of Φ Μ Μ 作 q Develop an in vivo mouse model to study the ability of sucrose esters to reduce free oil formation after treatment with oristat (orUstat). Orlistat (oHistat) was mixed with cream and added to the feed, and the concentration of orlistat administered to the mice was 150 micrograms of olvista (〇rUstat) per kg body weight. This experiment was based on the observation that mice in a high-fat diet were treated with orlistat or other lipolytic enzyme inhibitors to disperse the free oil excreted to the fur during grooming (US Patent No. 5.431.949) . A number of sucrose esters as described above are examined for their ability to reduce or eliminate free oil formation. The results of these studies are summarized in Figure 5. In this picture, Orlistat will be accepted without side effects 78622-9501l3.doc

1336252 A7B7 V OBJECT DESCRIPTION OF THE INVENTION (27) The free oil discharge of the control group of the control agent is regarded as the background value and is set to zero. Any improvement in free oil production is considered a negative percentage value relative to the background. These experiments show that a sugar with a medium HLB value such as Surfhope D-1 8 1 1 or Surfhope D-1 805 shows the highest relative reduction in free oil excretion. Conversely, the recommended sugar on both ends of the HLB scale is very hydrophilic (Surfhope D-1815) or very lipophilic (Surfhope D-1803.), showing less activity. Example 16: Pill formulation pressed into chewable tablet composition 8 orlistat 240 g sucrose palmitate P1670 60 g Avicel PH-105 210 g sodium starch glycolate. 60 g povidone K30 30 6 g of gram stearic acid was dry blended together in a high speed mixer (Aeromatic Fielder GP1). 240 grams of water was added stepwise and the mixing procedure was continued for about 5 minutes. This material was fed to the extruder (NICA extruder; sieve 0.8 mm screen size, thickness 1.0 mm). Extrude the material into tubes of appropriate length. The temperature of the extrudate does not exceed 35 °C. The extrudate was transferred to a spheronizer (NICA spheronizer) and spheroidized for 0.5 to 5 minutes. The wet pellets were dried in a fluid bed dryer (Aeromatic, MP-1) at a temperature below 35 °C. The dried pellets are screened by inserting a sieve of 0.5 and 1.25 mm mesh size, and the following and above 78622-950113.doc -31 - the paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm)

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Line 1336252 A7 B7 V. Partial Disclosure of Invention Note (28). Stearic acid was added and evenly distributed by dry mixing. The resulting mixture was compressed into tablets containing 120 mg of orlistat, 30 mg of sucrose palmitate, 105 mg of Avicel, 30 mg of sodium starch glycolate, 15 mg of povidone, and 3 mg of stearic acid. Example 1 7: Two-layer chewable tablet composition 9 a) Orlistat 240 g b) Sucrose palmitate P1670 60 g c) Avicel PH-105 210 g d) Sodium starch glycolate 60 g e) Povidone K30 30 g f) Stearic acid 6 g g) Lactose monohydrate (powder) 1460 g h) Avicel PH-102 200 g i) Corn starch 1500 100 g k) Temple powder by sodium acetate 100 g 1) povidone 90F 60 g m) glycerin citrate 60 g η) magnesium stearate 20 g first layer: component a in a high speed mixer (Aero mat ic Fielder GP 1) ) - e ) Dry mix together. 240 grams of water was gradually added and the mixing procedure was continued for about 5 minutes. This material was fed to the extruder (NIC A extruder; sieve 0.8 mm mesh size, thickness 1.0 mm). Extrude the material to the appropriate length 7S622-950113.doc - 32 - This paper wave scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1336252

-33- of the e son. The temperature of the extrudate does not exceed 35. Hey. The extrudate was transferred to a spheroidized state (NIC spheroidizer) and spheroidized for 5 to 5 minutes. The wet pellets were dried in a fluid bed dryer (Aer〇matic, MIM) at a temperature below 35C. The dried pellets were screened through a sieve of 0 5 and 125 mm mesh size, and the following and excess were discarded. Stearic acid was added and evenly distributed by dry mixing. First layer • The components g) - m ) were mixed together for 5 minutes in an Aer〇 inatic Fielder (GP1), and 4 g of water was added for granulation. The wet granules were sieved and dried in a fluid bed dryer (Aer〇matic, MU). The dried granules are sieved and uniformly mixed with magnesium stearate. The mixture formed by the first layer and the second layer is compressed to contain 120 mg of orlistat, 3 gram of sucrose palmitate, Avicel 1 〇 5 mg, 30 mg of sodium acetate, and povidone oxime 5 mg and 3 mg of stearic acid in the first layer and 73 mg of lactose, 1 mg of Avicei, 50* g of corn starch, 5 mg of sodium starch glycolate, 3 mg of povidone, glycerin citrate 30 mg, 1 mg of magnesium stearate in two layers of the second layer (Ki丨丨 &amp; 11 pressing equipment). 78622-9501l3.doc This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)

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Line 1364252 A7 B7 V. INSTRUCTIONS (30) Example 1 8: Rapid decomposition of chewable tablet composition 10 Orlistat 48 g of sucrose palmitate P1670 12 g of sodium starch glycolate 48 g PEG 6000 72 g Xylit 122.4 grams of Mannit pulvis 122.4 grams of Myrj 52 12 grams of Plasdone S630 24 grams of magnesium stearate 4.8 grams of talc 24 grams in a high speed mixer. (Aeromatic Fielder GP1.) ingredients (except magnesium stearate and talc) mixed together 5 minute. 32 grams of water was added for granulation. The wet granules were sieved (Siebschleuder Bergmeier 5.0 mm) and dried in a fluid bed dryer (Aeromatic Strea) below 37 °C. The dried granules were sieved (Fitzpatrick 1.62 mm) and mixed with magnesium stearate and talc and compressed into chewable tablets (Korsch PH 250 Pharmaceutical Tablet). 78622-950113.doc - 34 - This paper wave scale applies China National Standard (CNS) A4 specification (210 X 297 mm) 1336252 A7 B7 V. Invention description (31) Example 19: Rapid decomposition of chewable tablet composition 11 Orlistat 48 g sucrose palmitate P1670 12 g sodium starch glycolate 48 g PEG 6000 72 g Xylit 98.4 g Mannit pulvis 98.4 g Myrj52 12 g alginic acid 32.64 g Plasdone S630 24 g magnesium stearate 4.8 g talc 14.4 grams of calcium carbonate 15.36 grams The ingredients (except magnesium stearate, talc and calcium carbonate) were mixed together for 5 minutes in a high speed mixer (Aeromatic Fielder GP1). 30 g of water was added for granulation. The wet granules were sieved (Siebschleuder Bergmeier 5.0 mm) and dried in a fluid bed dryer (Aeromatic Strea) below 37 °C. The dried granules were sieved (Fitzpatrick 1.62 mm) and uniformly mixed with magnesium stearate, talc and calcium carbonate and compressed into chewable tablets (Korseh PH 250 pharmaceutical tablet machine). 78622-950113.doc - 35 - This paper wave scale applies Chinese National Standard (CNS) A4 specification (210X 297 mm)

Claims (1)

1336252 ABCD No. 091111848 Patent Application Renewal of Patent Application (May 98) VI. Application for Patent Fanyuan. ' w 2...- 1. A pharmaceutical composition for treating and preventing obesity, comprising a melting point 2 a lipolytic enzyme inhibitor at 37 ° C (in which the lipolytic enzyme inhibitor is orlistat), a sucrose fatty acid ester (wherein the fatty acid ester is mono-ester), and optionally one or more Pharmaceutically acceptable excipients. 2. The pharmaceutical composition according to claim 1 of the patent application, wherein each milligram of the lipolytic enzyme inhibitor is used in an amount of from 5 mg to 20 mg of sucrose fatty acid. 3. The pharmaceutical composition according to claim 2, wherein the 1 mg of the fat decomposing enzyme inhibitor comprises 0.1 mg to 1 mg of the sucrose fatty acid mono-ester. 4. The pharmaceutical composition according to item 3 of the patent application, wherein each 1 mg of the fat-decomposing enzyme inhibitor comprises 11 to 2 mg of a sucrose fatty acid mono-ester. 5. The pharmaceutical composition according to claim 4, wherein the 1 mg of the fat decomposing enzyme inhibitor comprises 0.15 to 1 mg of a sucrose fatty acid mono-ester. 6. The pharmaceutical composition according to claim 1, wherein the fatty acid portion of the sucrose fatty acid mono-acetic acid is (^ to 24 saturated or partially unsaturated fatty acid. 7. The pharmaceutical composition according to claim 6 of the patent application scope, The sucrose fatty acid single-branched fatty acid portion is a ci2 to c18 saturated fatty acid. The pharmaceutical composition according to claim 7 wherein the fatty acid mono-ester is composed of sucrose laurate, sucrose myristate, sucrose palm Selected from the group consisting of acid esters, sucrose stearate, sucrose arachidate and sucrose ester. 9. Pharmaceutical composition according to item 8 of the patent application, wherein fatty acid single · 78622-990513.doc ^ The scale applies to China National Materials (CNS) A4^~q; &lt;297 public love) 1336252 A8 B8 C8 _________ D8 VI. Application 'A = sucrose laurate, sucrose myristate, sucrose palmitate, Selected from the group consisting of sucrose stearate. Ίο. The pharmaceutical composition according to claim 9, wherein the fatty acid is sucrose palmitic acid vinegar. The pharmaceutical composition according to claim 9 wherein the fatty acid mono-ester is stearyl stearate. 12. The pharmaceutical composition according to claim 6 wherein the fatty acid moiety of the sucrose fatty acid mono-ester is Cu to (: 18 mono- or polyunsaturated fatty acid). 13. Pharmaceutical composition according to claim 12 The fatty acid is selected from the group consisting of palmitic acid, oleic acid, oleic acid, erucic acid, linoleic acid, quinone oleic acid, alpha-linolenic acid and arachidonic acid. The pharmaceutical composition of claim 13, wherein the sucrose fatty acid mono-ester is sucrose oleate. The pharmaceutical composition according to claim 1, wherein the sucrose fatty acid mono-ester is sucrose palmitate stearate. 16. The pharmaceutical composition according to claim 1 of the patent application, comprising from 1 to 24 mg of orlistat. 17. The pharmaceutical composition according to claim 16 of the patent application, comprising 3 to 120 mg of orlistat (0rHstat) 18. The pharmaceutical composition according to claim 17 of the patent application, comprising 3, 40, 60, 80, 1 〇〇, or 120 mg of orlistat. 19· According to the scope of patent application The pharmaceutical composition comprises 60 to 120 mg of orlistat and 20 to 100 mg of sucrose fatty acid ester. -2- 78622-990513.doc This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) 1336252 A8 B8 C8 D8 VI. Application for Patent Park 20. The pharmaceutical composition according to the scope of claim 1 contains 120 mg of orlistat and 30 mg of saccharide ester. _ According to the pharmaceutical composition of claim 1, the pharmaceutical composition comprises 80 to 120 mg of orlistat and 10 to 40 mg of vegetable fatty acid ester. 22. Pharmaceutical composition according to claim 1 Containing 2 to 60 mg of orlistat and 5 to 15 mg of sucrose fatty acid ester. 23. The pharmaceutical composition according to claim 1 of the patent application, comprising one or more pharmaceutically acceptable excipients It is selected from the group consisting of mannitol, lactose, HPM C, talc, sorbitol, polyvinylpyrrolidone, lecithin, glyceryl trimyristate, polyethylene glycol, sucrose ester, polysorbate Ester, polyoxyethylene stearate, and dimethyl The pharmaceutical composition according to claim 23, comprising lactose as a pharmaceutically acceptable excipient. 25. The pharmaceutical composition according to claim 1 of the patent application, comprising 1〇24〇 Mg of orlistat and 0.5-1000 mg of sucrose-fat _ vinegar. 26. The pharmaceutical composition according to claim 25, comprising a group consisting of maltodextrin, lactose and cellulose. One or more excipients. 27. A method of preparing a pharmaceutical composition according to any one of claims 1 to 26, comprising a mixed lipolytic enzyme inhibitor and a sucrose fatty acid mono-ester, and optionally, one or more pharmaceuticals Excipients. 28. A kit for the treatment of obesity, the kit containing the first component, which is -3- 78622-990513.doc This paper scale applies to the Chinese National Standard (CMS) A4 specification (210X 297 public Chu:) 1336252 A8 B8 C8 D8 6. Apply for a patented fat degrading enzyme inhibitor, and a second component, which is a sucrose fatty acid mono-ester in a unit dosage form. 29. Use of a pharmaceutical composition according to any one of claims 1 to 26 for the manufacture of a medicament for the treatment and prevention of obesity. 30. A lipolytic enzyme inhibitor as defined in claims 1 to 26 and a sucrose fatty acid mono-ester for use in the treatment and prevention of obesity. 78622-9905I3.doc - 4 - This paper wave scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm)