WO2012070702A1 - Composition containing orlistat and chitosan and preparation method thereof - Google Patents

Abstract

Disclosed are a composition containing orlistat and chitosan as active ingredients and a preparation method thereof. The composition has an effect of reducing side effects occurring in the administration of orlistat, particularly oily spotting. As a result, the composition can be used in various fields such as medicine or diet compositions and the like.

Description

Olistat and chitosan-containing compositions and methods for preparing same

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.

Unlike conventional obesity treatments that act on the central nervous system and suppress appetite, olistat is a potent and specific inhibitor that irreversibly inhibits lipases in the stomach and pancreas without any nerve stimulation or hormonal changes. However, 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 β-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. For example, 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.

It is an object of one embodiment of the present invention to provide a composition that can reduce the side effects of the administration of Olistat.

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.

The 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.

As described above, 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.

1 is a graph showing the amount of oil discharged according to the amount of chitosan administered after the administration of the olistat / chitosan composition according to Experimental Example 1;

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.

The 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. However, Olistat is accompanied by a number of side effects, among which the incidence of oily spotting is high, which reduces dose compliance.

In the present invention, chitosan, a cationic polymer, was used to minimize side effects after the administration of Olistat. In other words, when chitosan is administered together with the olistate, the oily spot stool is remarkably improved by fixing the oil into the stool without reducing the amount of excretion of the oil.

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.

In one embodiment, 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. In addition, since the anionic bile acid discharged by the digestive action, the oil and chitosan is wrapped in a large aggregate (aggregate), it is possible to effectively remove the oil spot spots. On the other hand, when the average molecular weight of chitosan is less than the said molecular weight, the effect of reducing the oil phase spot variation by olistate administration cannot be obtained. Chitosan, which has a low molecular weight and low viscosity, does not enclose the oil well so that the oil phase is separated, and oil which is not enclosed by chitosan is micelleized by bile acid and excreted. Moreover, when the molecular weight of chitosan of this invention exceeds the said range, there exists a problem that the solubility degree of chitosan in the body is inhibited.

In one embodiment of the invention, 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. Therefore, in the case of the ionic complex formed by the chitosan and the weak acid, even if the molecular weight of the chitosan is large, it can be dissolved in the weakly basic aqueous solution. On the other hand, it is preferable that 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. Thus, for solubilization of chitosan, it may include chitosan to which the anion of the weak acid is bound. In one embodiment, the kind of the weak acid is not particularly limited, and may be, for example, acetic acid, ascorbic acid, or lactic acid.

In one embodiment of the present invention, 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.

In another embodiment, 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. In one embodiment, the manufacturing method,

(a) dissolving chitosan in a weak acid solution and drying to prepare chitosan to which anions of the weak acid are bound; And

(b) mixing chitosan, to which the anion of the weak acid is bound, with olistat.

In another embodiment, the chitosan used in the preparation method is as described above. For example, 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,

(a-1) dialysis after dissolving chitosan in a weak acid solution; And

(a-2) drying the solution passed through dialysis to produce chitosan to which anions of weak acids are bound. That is, excess anion can also be removed by dialysis after dissolving chitosan in a weak acid solution.

In another embodiment, the mixing in the step (b) may be a mixture of the dried chitosan powder and olistat powder with a mixer or the like. Alternatively, 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. or higher, it is possible to dissolve in the form of a dispersion, but when the temperature decreases, it is solidified and extracted. Therefore, in the step (b), in order to form a complex with chitosan, the olistate 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.

The 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. In one embodiment, 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).

The composition according to the present invention is not particularly limited, but may be, for example, a composition for diet. In addition, the composition according to the invention may be a pharmaceutical composition, specifically, may be a composition for inhibiting lipase (lipase). By adding the polymer chitosan together with the olistat, the effect of suppressing side effects caused by the administration of the olistat, in particular oily spotting, is recognized.

The diet composition may be formulated in various forms such as, for example, powders, tablets, granules, tablets, capsules and drinks. In the diet composition, one or two or more of the following additives may be added and blended as necessary. As an additive, For example, various fruits (concentrated juice, powder juice, etc.), such as grapefruit, an apple, an orange, a lemon, a pineapple, a banana, a pear, may be used; Vitamins (remithol palmitate, riboflavin, pyridoxine, cyanocobalamine, sodium ascorbate, nicotinic acid amide, calcium pantothenate, folic acid, biotin, cholecalciferol, cholinergic acid choline, tocopherol, β 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 glutamate, glycine, alanine, aspartic acid, sodium aspartate, inosinic acid, etc.); Plant fibers (polydextrose, pectin, xanthan gum, glucomannan, alginic acid, etc.); Or minerals (sodium chloride, sodium acetate, magnesium sulfate, potassium chloride, magnesium chloride, magnesium carbonate, calcium chloride, dipotassium phosphate, monosodium phosphate, glycerophosphate, ferrous citrate, ammonium ferric citrate, iron citrate, Manganese sulfate, copper sulfate, sodium iodide, potassium sorbate, zinc, manganese, copper, iodine, cobalt, and the like.

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.

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. Examples: 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. In addition, 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.

Determination of the dosage of the active ingredient is within the level of those skilled in the art, and 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.

Hereinafter, the present invention will be described in more detail with reference to examples. However, the following Examples and the like are only for illustrating the present invention, but the scope of the present invention is not limited to these.

Example 1 Preparation of Olistat / Chitosan Complex Composition

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. After dialysis, 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 Preparation of Olistat / Chitosan Complex Composition

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.

Example 3 Preparation of Olistat / Chitosan Complex Composition

The 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 4 Preparation of Olistat / Chitosan Complex Composition

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.

Comparative Example 1 Preparation of Olistat / Chitosan Composite Composition Using Low Molecular Weight Chitosan

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.

Comparative Example 2 Preparation of Olistat / Chitosan Composite Composition Using Low Molecular Weight Chitosan

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.

Experimental Example 1 Oil Excretion Test Using Olistat / Chitosan Composition

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.

To prevent the mice from licking their bodies, a protective collar for rodents was worn to eliminate errors. 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.

Referring to FIG. 1, 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.

[Experimental Example 2] Oil excretion test using the olistat / chitosan composition using chitosan having different molecular weight

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.

Referring to FIG. 2, the oil-only control (negative 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%. In the group to which 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 In the group to which the olistat / chitosan complex (Experimental Group 3) was administered, only about 0.2% of the hair was buried.

Claims (13)

1. Olistat and chitosan containing, the molecular weight of the chitosan is 1x10 ⁵ to 1x10 ¹⁰ Da (Dalton), characterized in that olistat and chitosan containing composition.
2. The method of claim 1,

   The molecular weight of the chitosan is 2x10 ⁵ to 1x10 ⁸ Da (Dalton) olistat and chitosan containing composition, characterized in that.
3. The method of claim 1,

   The molecular weight of the chitosan is 5x10 ⁵ to 1x10 ⁶ Da (Dalton), characterized in that the olistat and chitosan-containing composition.
4. The method of claim 1,

   The chitosan is olistat and chitosan-containing composition, characterized in that the chitosan to which the anion of the weak acid is bound.
5. The method of claim 4, wherein

   The weak acid is acetic acid, ascorbic acid or lactic acid, characterized in that the olistate and chitosan-containing composition.
6. The method of claim 1,

   The content of the olistat, olistat and chitosan-containing composition, characterized in that 0.1 to 50% by weight based on the weight of the composition.
7. The method of claim 1,

   The olistat and chitosan-containing composition, characterized in that the weight ratio of the olistat and chitosan is 1: 1 to 1: 100.
8. The method of claim 7, wherein

   Olistat and chitosan-containing composition, characterized in that the weight ratio of the olistat and chitosan is 1: 2.5 ~ 1:25.
9. (a) dissolving chitosan in a weak acid solution and drying to prepare chitosan to which anions of the weak acid are bound; And

   (b) a method for producing an olistat and chitosan-containing composition comprising the step of mixing chitosan, to which the anion of the weak acid is bound, with olistat.
10. The method of claim 9,

    Said weak acid is acetic acid, ascorbic acid, or lactic acid, The manufacturing method of the olistat and chitosan containing composition characterized by the above-mentioned.
11. The method according to claim 9 or 10,

    The manufacturing method, after the step (b),

    (c) A method for preparing an olistat and chitosan-containing composition further comprising the step of formulating the prepared mixture in powder, tablet, granule or capsule form.
12. A composition for inhibiting lipase, comprising the olistat and chitosan-containing composition according to any one of claims 1 to 8.
13. A composition for diet comprising the olistat and chitosan-containing composition according to any one of claims 1 to 8.

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