WO2012070702A1 - Composition contenant de l'orlistat et du chitosane et son procédé de préparation - Google Patents

Composition contenant de l'orlistat et du chitosane et son procédé de préparation Download PDF

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Publication number
WO2012070702A1
WO2012070702A1 PCT/KR2010/008382 KR2010008382W WO2012070702A1 WO 2012070702 A1 WO2012070702 A1 WO 2012070702A1 KR 2010008382 W KR2010008382 W KR 2010008382W WO 2012070702 A1 WO2012070702 A1 WO 2012070702A1
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WO
WIPO (PCT)
Prior art keywords
chitosan
olistat
composition
containing composition
acid
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Application number
PCT/KR2010/008382
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English (en)
Korean (ko)
Inventor
김경희
장유라
정혜선
배철민
Original Assignee
주식회사 삼양사
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Priority to PCT/KR2010/008382 priority Critical patent/WO2012070702A1/fr
Publication of WO2012070702A1 publication Critical patent/WO2012070702A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/722—Chitin, chitosan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • a composition containing olistat and chitosan and a method for producing the same is a composition containing olistat and chitosan and a method for producing the same.
  • Orlistat is chemically synthesized from the hydrolysis products of lipstatin obtained from microorganisms of the genus Streptomyces (eg Streptomyces toxytricini ), and has the effect of inhibiting lipase, an intestinal lipolytic enzyme. There is this.
  • Olistat inactivates the lipase by covalently binding to the serine of the active site of lipase secreted by the stomach and pancreas in the lumen of the intestine. When lipase is inactivated, triglycerides are not broken down into monoglycerides and free fatty acids, and undegraded triglycerides are not absorbed into the body and are released. Therefore, Olistat may be used for the purpose of treating obesity.
  • olistat is a potent and specific inhibitor that irreversibly inhibits lipases in the stomach and pancreas without any nerve stimulation or hormonal changes.
  • Olistat has a problem that is accompanied by a number of side effects, the most frequent of which is the oily spotting (oily spotting), the discharge of the oil from time to time caused a lot of inconvenience in daily life.
  • Chitin a precursor of chitosan, is a polymer in which N-acetyl-D-glucosamine composed of amino sugars is polymerized by ⁇ -1,4 bonds.
  • Chitin is a polysaccharide containing nitrogen that forms not only the hard epidermis and shell of arthropods, but also is an important component of fungal cell walls.Natural polymers are also present in cyclic, mollusk, protozoan and tonic animals. to be.
  • Chitosan is obtained by removing the acetyl group of chitin.
  • chitosan can be obtained by dipping a shell of shellfish in hydrochloric acid, eluting calcium carbonate, heating with alkali, and removing protein.
  • Chitosan is widely used as it is known to be excellent in cell adsorption, biocompatibility, biodegradability and moldability.
  • Chitosan which consists of glucosamine bonds, has a molecular structure very similar to that of human tissues. Therefore, chitosan is excellent in human friendliness and does not generate an immune response, and is widely used as a biomaterial.
  • Another object of one embodiment of the present invention is to provide a method for preparing a composition that can reduce the side effects of the administration of Olistat.
  • composition according to an embodiment of the present invention is characterized by containing olistat and chitosan as an active ingredient. Also disclosed is a method of making the composition.
  • the composition according to the present invention has an effect of reducing side effects, especially oily soptting, which occurs when the olistate is administered. Through this, it can be variously used in the field of medicine or diet composition.
  • Figure 2 is a graph showing the amount of oil discharged according to the molecular weight of chitosan administered after administration of the olistat / chitosan complex according to Experimental Example 2.
  • composition according to an embodiment of the present invention is characterized by containing olistat and chitosan as an active ingredient.
  • Orlistat inhibits lipase, an intestinal lipolytic enzyme, and is also used for the purpose of treating obesity.
  • Olistat is accompanied by a number of side effects, among which the incidence of oily spotting is high, which reduces dose compliance.
  • chitosan a cationic polymer
  • Olistat a cationic polymer
  • Chitosan used in the present invention is a concept including both conventional chitosan and glycol chitosan.
  • the deacetylation degree of the chitosan is preferably 50 to 90%. If the deacetylation degree of chitosan is 50% or more, it is dissolved in water depending on the pH. That is, chitosan is insoluble in water in the form of a gel when the pH is higher than 6.5, but is solubilized at a lower pH. Therefore, when the deacetylation degree of chitosan is 50% or more, particle formation is possible in aqueous solution. However, if the degree of deacetylation of chitosan exceeds 90%, its physicochemical and biochemical properties may vary.
  • the chitosan has an average molecular weight of at least 1 ⁇ 10 5 Da (Dalton). In another embodiment, the molecular weight of the chitosan is 1x10 5 to 1x10 10 Da, specifically 2x10 5 to 1x10 8 Da, more specifically 5x10 5 to 1x10 6 Da, even more specifically 7x10 5 to 1x10 6 It can be Da. For example, the chitosan has an average molecular weight of 750,000 Da. Chitosan having a molecular weight in the above range has an appropriate viscosity and small droplets of oil are stabilized by the electrostatic interaction of cationic chitosan and anionic oil.
  • chitosan may be in the form of anions bonded. Chitosan is positively charged in a weakly acidic aqueous solution by an amine group. However, when the acidity becomes high and not positively charged, it becomes soluble and loses solubility, and may exist in a gel form. That is, when the counter ion of chitosan is an anion of a weak acid such as acetate, chitosan may be dissolved in the form of an ionic complex even in a neutral or weakly basic aqueous solution. On the other hand, if the counterion is a chloride anion, for example, it gels immediately in a neutral or weakly basic solution.
  • the chitosan is solubilized in the intestine for the effect of chitosan oil discharge and the inhibition of oily spot stools. This is because the gel phase is viscous and difficult to mix with the oil, whereas the dissolved chitosan can physically contact the oil more physically, which is advantageous for oil droplet formation.
  • the kind of the weak acid is not particularly limited, and may be, for example, acetic acid, ascorbic acid, or lactic acid.
  • the content of the olistate based on the weight of the composition may be 0.1 to 50% by weight, specifically 1 to 30% by weight, more specifically 5 to 10% by weight. If the content of olistat is less than the above range, the lipase inhibitory effect is insignificant, and if the content of the olistat is exceeded, the side effect of the administration of the olistat may be increased.
  • the content ratio of olistat and chitosan contained in the composition is based on the weight ratio of olistat: chitosan 1: 1 to 1: 100, specifically 1: 2 to 1:50 More specifically, 1: 5 to 1:25, and more specifically, 1:15 to 1:20. If the content of chitosan is less than the ratio, the effect of alleviating the side effects of the administration of olistat is not sufficient.On the contrary, if the content of chitosan exceeds the ratio, an effective amount of olistat is included in the formulation due to the increase of the content of chitosan. It is difficult.
  • the present invention also provides a method of preparing a composition comprising olistat and chitosan.
  • the manufacturing method the manufacturing method
  • the chitosan used in the preparation method is as described above.
  • the molecular weight of the chitosan may be 1x10 5 to 1x10 10 Da, specifically 2x10 5 to 1x10 8 Da, more specifically 5x10 5 to 1x10 6 Da, even more specifically 7x10 5 to 1x10 6 Da have.
  • the step (a) is a step of dissolving chitosan in a weak acid solution and drying to form an ion conjugate of an anion of weak acid and chitosan. Drying can be carried out by a method such as lyophilization, fluid bed drying. In one embodiment, the step (a) is preferably,
  • the mixing in the step (b) may be a mixture of the dried chitosan powder and olistat powder with a mixer or the like.
  • the olistate may be mixed with chitosan while dispersed in water of 60 ° C. or higher. Olistate is almost insoluble in water ( ⁇ 1mg / 100mL) and very soluble in organic solvents such as chloroform, methanol and ethanol. In addition, olistate has a low solubility in bile salts and is a fat soluble substance having a partition coefficient between octanol and buffer of 1,000 or more at pH 7.45. However, in water of 60 ° C.
  • the olistate in order to form a complex with chitosan, may be dispersed and dissolved in water of 60 ° C or higher. Olystat and chitosan dispersed in the water can be utilized in a solid form by liquid or dry.
  • composition comprising olistat and chitosan according to the present invention is not particularly limited and may be, for example, a powder, tablet, granule, or capsule formulation.
  • the method of preparing the composition may further comprise the step of formulating the powder, tablets, granules or capsules of the prepared mixed powder (c) after the step (a) and (b).
  • composition according to the present invention is not particularly limited, but may be, for example, a composition for diet.
  • composition according to the invention may be a pharmaceutical composition, specifically, may be a composition for inhibiting lipase (lipase).
  • lipase lipase
  • the diet composition may be formulated in various forms such as, for example, powders, tablets, granules, tablets, capsules and drinks.
  • one or two or more of the following additives may be added and blended as necessary.
  • various fruits such as grapefruit, an apple, an orange, a lemon, a pineapple, a banana, a pear
  • Vitamins remithol palmitate, riboflavin, pyridoxine, cyanocobalamine, sodium ascorbate, nicotinic acid amide, calcium pantothenate, folic acid, biotin, cholecalciferol, cholinergic acid choline, tocopherol, ⁇ Water-soluble and fat-soluble vitamins such as carotene);
  • Flavorings (lemon flavor, orange flavor, strawberry flavor, grapefruit flavor, vanilla essence, etc.); Amino acids, nucleic acids and salts thereof (glutamic acid, sodium gluta
  • the pharmaceutical composition may further contain pharmaceutical adjuvants such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for controlling osmotic pressure, and other therapeutically useful substances, and various oral in accordance with conventional methods. Or in parenteral dosage forms.
  • pharmaceutical adjuvants such as preservatives, stabilizers, hydrating or emulsifying accelerators, salts and / or buffers for controlling osmotic pressure, and other therapeutically useful substances, and various oral in accordance with conventional methods. Or in parenteral dosage forms.
  • Formulations for oral administration include, for example, powders, tablets, granules, capsules, tablets, pills, hard and soft capsules, solutions, suspensions, emulsifiers, syrups, granules, and the like.
  • lactose dextrose, sucrose, mannitol, sorbitol, cellulose and glycine
  • glidants such as silica, talc, stearic acid and its magnesium or calcium salts and polyethylene glycols.
  • Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and polyvinylpyrrolidine, optionally starch, agar, alginic acid or its sodium salt Pharmaceutical additives such as disintegrants, absorbents, colorants, flavors, and sweeteners. Tablets may be prepared by conventional mixing, granulating or coating methods.
  • formulations for parenteral administration include external skin preparations, injections, and the like, and particularly, may be isotonic aqueous solutions or suspensions in the injection formulation.
  • the daily dose of the drug according to the present invention depends on various factors such as the progression of obesity, the onset of disease, age, health condition, complications, etc. Although based on an adult, generally 1 to 500 mg / kg, preferably 30 to 200 mg / kg, of the composition combined in the above-mentioned weight ratios may be administered once or twice a day. Dosage does not limit the scope of the invention in any way.
  • Chitosan (Wako Chemical, Wako 100) having a molecular weight of 750,000 Da was dissolved in an aqueous 3% acetic acid solution to prepare an aqueous 3% (w / v) chitosan solution.
  • the aqueous chitosan solution was dialyzed with excess water to remove excess acetic anion that did not bind chitosan.
  • the chitosan aqueous solution was lyophilized and ground to prepare a chitosan powder in which acetic anion was bound.
  • Olistat powder and chitosan powder were mixed at a weight ratio of 2: 5, 2:10, 2:30, and 2:50, respectively, to prepare a composition. It was observed that the prepared composition was added to water at 60 ° C. to form a viscous dispersion.
  • Example 2 Except for removing the acetic acid after dialysis, a composition was prepared in the same manner as in Example 1. The prepared composition was dissolved in water at 60 ° C. to form a viscous dispersion.
  • composition was prepared in the same manner as in Example 1, except that ascorbic acid was used instead of acetic acid.
  • the prepared composition was dissolved in water at 60 ° C. to form a viscous dispersion.
  • Example 3 Except for removing the ascorbic acid by dialysis, a composition was prepared in the same manner as in Example 3. The prepared composition was dissolved in water at 60 ° C. to form a viscous dispersion.
  • a composition was prepared in the same manner as in Example 1, except that a low molecular weight water soluble chitosan (Wako Chemical) having a molecular weight of 5,000 Da was used.
  • the prepared mixed composition was dissolved in water at 60 ° C. to form a viscous dispersion.
  • a composition was prepared in the same manner as in Example 1, except that low molecular weight chitosan (Primax, cg10) having a molecular weight of 24,000 Da was used.
  • the prepared composition was dissolved in water at 60 ° C. to form a viscous dispersion.
  • mice Experimental rats weighing 20 g (7-week old Female Balb / c mice) were administered with oil after dispersing the Olistat / chitosan complex prepared in Example 1 in water. After 24 hours, the amount of oil recovered from the feces, the hair on the hair and the total amount of excreted oil were measured.
  • Oil was administered at a dose of 2.5 ml / kg (2.3 g / kg) of cooking oil per mouse, Olistat at a dose of 20 mg / kg, and chitosan at doses of 50, 100, 300 and 500 mg / kg, respectively. Administered. The measurement results are shown in FIG. 1.
  • the olistat / chitosan composition when the olistat / chitosan composition was administered, the amount of oil on the hair was significantly reduced compared to when only olistat was administered, and the higher the amount of chitosan, the amount of oil on the hair. This was less. Even when the olestat / chitosan composition was administered, the total amount of oil discharged was not reduced.
  • the olistat / chitosan composition was prepared using chitosan having a different molecular weight and administered to mice in the same manner as in Experimental Example 1 to determine the amount of excreted oil.
  • Oil was administered at a dose of 2.5 ml / kg (2.3 g / kg) of cooking oil per mouse, olistat at a dose of 20 mg / kg, and chitosan at a dose of 300 mg / kg.
  • the measurement results are shown in FIG. 2.
  • the oil-only control did not have any oil on the hair at all, and in the Olestat and oil-only group (positive control), the amount of oil on the hair was about the amount of total emissions. It reached 20%.
  • the olistat / chitosan complex prepared using chitosan having molecular weights of 5,000 and 24,000 Da, respectively (experimental groups 1 and 2)
  • the amount of oil on the hair amounted to about 20% of the total emissions, but the present invention
  • the olistat / chitosan complex Example 3

Abstract

L'invention porte sur une composition contenant de l'orlistat et du chitosane en tant que principes actifs et sur son procédé de préparation. La composition a un effet de réduction d'effets secondaires se produisant dans l'administration d'orlistat, en particulier la microrragie grasse. En résultat, la composition peut être utilisée dans divers domaines tels que la médecine ou les compositions de régime et analogues.
PCT/KR2010/008382 2010-11-25 2010-11-25 Composition contenant de l'orlistat et du chitosane et son procédé de préparation WO2012070702A1 (fr)

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PCT/KR2010/008382 WO2012070702A1 (fr) 2010-11-25 2010-11-25 Composition contenant de l'orlistat et du chitosane et son procédé de préparation

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Application Number Priority Date Filing Date Title
PCT/KR2010/008382 WO2012070702A1 (fr) 2010-11-25 2010-11-25 Composition contenant de l'orlistat et du chitosane et son procédé de préparation

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114159480A (zh) * 2022-01-19 2022-03-11 广州臻卓生物技术有限公司 一种具有减肥作用的组合物及其制备方法和用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5447953A (en) * 1992-06-24 1995-09-05 Hoffmann-La Roche Inc. Biomasses to treat non-human animals
KR20010079636A (ko) * 1998-08-14 2001-08-22 프리돌린 클라우스너, 롤란드 비. 보레르 라이페이즈 저해제 및 키토산을 포함하는 약학 조성물
US20060135471A1 (en) * 2002-04-26 2006-06-22 Jacques Bailly Anti-obesity compositions

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5447953A (en) * 1992-06-24 1995-09-05 Hoffmann-La Roche Inc. Biomasses to treat non-human animals
KR20010079636A (ko) * 1998-08-14 2001-08-22 프리돌린 클라우스너, 롤란드 비. 보레르 라이페이즈 저해제 및 키토산을 포함하는 약학 조성물
US20060135471A1 (en) * 2002-04-26 2006-06-22 Jacques Bailly Anti-obesity compositions

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114159480A (zh) * 2022-01-19 2022-03-11 广州臻卓生物技术有限公司 一种具有减肥作用的组合物及其制备方法和用途
CN114159480B (zh) * 2022-01-19 2022-08-30 夏文华 一种具有减肥作用的组合物及其制备方法和用途

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