FI107432B - Use of microcrystalline chitosan - Google Patents

Description

107432 The parent chitosan and / or chitosan and fatty acid compound, which can also be added to the diet, binds lipids and inhibits their absorption. The effective dosage unit of this invention for the treatment of obesity and gallbladder and gastrointestinal disorders is up to 12 g of chitosan. The medicinal product should be administered orally, preferably in a single dose unit and preferably before meals, however always following a special diet. The starting chitosan and / or the fatty acid complex of U.S. Pat. No. 4,223,023 may be added to any medically neutral carrier to form a drug preparation. The finished medicinal product binds up to 10-15 g of fatty acids per g of chitosan.

However, the known lipid-binding preparation has several disadvantages: One must follow a particularly low-calorie diet, up to 15,200 kcal per day. In addition, when used particularly in conjunction with foodstuffs, it has no direct tableting ability. The substance is not effective enough to bind lipids or reduce weight. The chitosan particles used are too large because they cannot be reduced in size in this form of natural polymer.

It is an object of the present invention to reduce the absorption of lipids in mammals, especially humans, by using microcrystalline chitosan in the form of a microcrystalline powder and / or gel dispersion by oral administration to a mammal in an amount effective to reduce lipid absorption.

According to the present invention, a microcrystalline chitosan is used in the preparation of an oral pharmaceutical preparation or nutrient for reducing lipid absorption in mammals. Microcrystalline chitosan is in the form of a powder having an average particle size of less than 100 µm and / or as a gel-like dispersion having an average particle size of less than 100 µm and having ··. characterized in that the average molecular weight is greater than 10,000 daltons, preferably 50,000-700,000 daltons, and the degree of deacetylation-35 is greater than 60%, most preferably 70-95%.

According to a preferred embodiment of the invention, the microcrystalline chitosan powder prepared by air spray drying has a known 107432

Use of microcrystalline chitosan

The invention relates to the use of microcrystalline chitosan.

5

Lipids play an important role in many biological processes, and very often components such as triglycerides, fatty acids and bile acids, and cholesterol and other sterols have a negative effect on certain mammals, especially humans. The negative effects of lipids in several biological processes have been described, e.g. in Laboratory Investigation, vol. 39, pp. 574-583, 1978; Biochimica Biophysica Acta, vol. 515, pp. 163-205, 1978 or International Journal of Pharmacy, vol. 74, pp. 137-146, 1991. Dietary intake and absorption of lipids adversely affect weight control and cause health problems.

Some results have been described on the behavior of chitosan - poly (2-deoxy-2-amino-glucose) in the presence of lipids, which have shown the hypolipid effect of this natural polymer, particularly on cholesterol and triglycerides. This phenomenon is described in "Overtake", Pergamon Press, 1977; Nutrition Report International, vol. 18, pp. 531-537, 1978; butter. 19, pp. 327-334, 1979; butter. 20, pp. 677-684, 1979; American Journal of Clinical Nutrition, vol. 33, pp. 787-793, 1980; Lipids, Vol. 23, pp. 187-191, 1988; Journal of Processing Society, Experimental 25 Biology and Medicine, vol. 189, pp. 13-20, 1988. The interaction between fatty acids and chitosan is described in Carbohydrate Polymers, vol. 22, pp. 117-126, 1993; Macromolecular Reports, vol. A31, pp. 849-856, 1994; Carbohydrate Polymers, vol. 24, pp. 177-184, 1994 and Planta, vol. 178, pp. 385-392, 1989.

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In all the tests described in the aforementioned publications and books. is used in the form of flake starting chitosan, which is mechanically ground or dissolved in aqueous acids.

U.S. Patent 4,223,023 describes a known, nonabsorbable, lipid-binding parent chitosan, which is a mechanically powdered powder of more than 80 mesh units and a fatty acid complex.

4, 107432

The advantage of using microcrystalline chitosan as a lipid binder is related to its ability to exist in the form of a powder and / or gel dispersion characterized by an average particle size of less than 100 µm, usually 10-50 µm, which is impossible to achieve. mechanical grinding of the starting chitosan. The above particle size has a direct effect on lipid binding capacity.

At the same time, lipid binding capacity is affected by the average molecular weight range of microcrystalline chitosan when used in accordance with the invention to reduce lipid absorption in mammals as it passes through the gastrointestinal tract. The average molecular weight of the microcrystalline chitosan used for lipid reduction is at least 10,000 daltons, preferably 50,000-700,000 daltons, and the degree of deacetylation is at least 60%, in particular 70-95%. These structural properties of microcrystalline chitosan-15 have a direct effect on lipid binding capacity.

Microcrystalline chitosan as an air-spray dried powder having an average molecular weight Mv of 84,000 and a deacetylation degree of 82%, contains 20,6% sodium basecandec binds 82.6% of sodium dundecylene, giving it a 1.3 fold binding capacity. Under the same conditions, the known 25 initial chitosan sold under the product name "L112 fat binder", having a polymer content of 88% by weight, a water retention value of WRV 232%, Mv 129,000 and a deacetylation degree of 71%, is characterized by 62% sodium dundecylene. Microcrystalline chitosan in gel-like dispersion exhibited a higher binding capacity of sodium dundecylene in experiment 30. The dispersion form microcrystalline chitosan having a MW of 165,000 and a deacetylation degree of 82% is characterized by a 78% binding capacity after 15 minutes of treatment, while this same form, having a MW of 608,000 and a deacetylation degree of 78%, is characterized by 4% binding capacity after 15 minutes of treatment. Air-dried powdered microcrystalline chitosan with an Mv of 123,000 and a deacetylation degree of 81.8% and a fat binding capacity of 15% after 15 minutes was administered to a group of overweight subjects in clinical trials, 3,107,432 with a water retention value of at least 150%, preferably 200-300%, and good direct tableting.

According to a preferred embodiment of the invention, the microcrystalline chitosan * 5 powder prepared by freeze-drying is characterized by a water retention value of at least 200%, preferably 250-400%.

According to a preferred embodiment of the invention, the gel-like dispersion of microcrystalline chitosan, containing at least 0.1% by weight and preferably 1-4% by weight of microcrystalline polymer, is characterized by a water retention value of at least 500%, preferably 800-5000%.

According to a preferred embodiment of the invention, the microcrystalline chitosan is used in the preparation of an oral preparation in the form of a powder, gel dispersion, tablets and / or capsules for oral administration to a mammal or added to food.

The use of microcrystalline chitosan according to the invention for binding lipids in mammals is associated with its high flocculation capacity and interaction with lipid components such as fatty acids, bile acids, cholesterol or triglycerides. This property is much more potent with microcrystalline chitosan than the previously known starting chitosan. Microcrystalline chitosan has exceptional properties that are superior to the known starting chitosan. These include an advanced specific surface, a strong tendency to form strong hydrogen bonds, a controlled biodegradation, biological adaptability, a strong ability to form ionic bonds, and a strong tendency to flocculate lipids.

At the same time, microcrystalline chitosan, especially in the form of air-dried powder, is the only form of chitosan that is directly applicable to tablets.

The microcrystalline chitosan of the invention is used in air spray-35 as a dried powder, freeze-dried powder or gel dispersion, in the form of pellets, tablets, capsules, gel, dispersion or syrup, alone or in combination with food.

107432 - Fatty Acid Binding Ability of Chitosan and Microcrystalline Chitosan: by the Applied Method described in Carbohydrate Polymers, v. 22, p. 117, 1993.

Percent binding is calculated as the ratio of the amount of salt of fatty acid in the form of chitosan bound 5 sodium dundecylene to the total amount of salt used in this experiment.

- average particle size of microcrystalline chitosan: 10 by microscopic method using computer estimation

The invention will be explained in more detail in the following examples, which do not limit the scope of the claims.

Example 1

Microcrystalline chitosan as a gel dispersion having a polymer content of 4.22% by weight, an average molecular weight of Mv 165,000 and a deacetylation degree of 82% and a water retention value of WRV 768%, spray-dried in air using an aqueous dispersion containing 1.8% by weight of polymer, with an inlet air temperature of 185 ° C, an outlet air temperature of 80 ° C and a drying rate of 0.04 L of dispersion per minute.

The microcrystalline chitosan powder thus obtained had a polymer content of 25 91.6% by weight, a water retention value of WRV of 215%, a Mv of 123,000 Daltons and an average particle size of 48 µm. This microcrystalline chitosan, after 15 minutes of treatment, obtained a 66% binding capacity of sodium dundecylene. Capsules containing 0.383 g of microcrystalline chitosan powder obtained were used in clinical trials in vivo. Overweight souls weighing 80-120 kg were given 8 capsules daily, resulting in a total dose of 3.064 g of microcrystalline chitosan. Subjects did not follow any particular diet. After a two-week trial period, individuals lost an average of about 2 kg.

5 107432 weighing 80 to 120 kg. This microcrystalline chitosan powder with an average particle size of 48 µm was administered daily in 8 capsules each containing 0.383 g of microcrystalline chitosan, giving a total dose of 3.064 g per day. Subjects did not follow any of the 5 special diets. During the two test weeks, individuals lost an average of 2 kg. When using the known starting chitosan produced under U.S. Patent 4,223,023, sold under the tradename "L 112 fat binder", there is a daily dose of up to 12 g of chitosan and in addition a low calorie diet must be followed.

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The daily dose of microcrystalline chitosan is significantly lower than the daily dose of the known starting chitosan, and in addition, the effect of dieting is greater. The use of microcrystalline chitosan as a freeze-dried powder or gel dispersion increases the specific surface area and thus the effect of the effect.

The benefits of using microcrystalline chitosan to reduce lipid absorption in mammals, particularly the human body, are associated with its efficacy at low doses, dietary intolerance, variability in useful forms, non-toxicity, ease of use, and its tabletability.

The following methods have been used to determine the properties of microcrystalline chitosan: - average molecular weight of microcrystalline chitosan: by the method described in "Chitin", Pergamon Press, New York, 1977 30 - deacetylation degree of microcrystalline chitosan: by the method described in International: Journal of Biological Macromolecules, v. 2, p. 115, 1980 - Water retention of microcrystalline chitosan: by the method described in Cellulose Chemistry and Technology, v. 11, p. 633,1977 8 107432 The air content of the air-dried powder thus obtained was 94.5% by weight. , WRV 273%, average molecular weight 101 Dalton and average particle size 35 µm. The binding capacity of this microcrystalline chitosan was 64.6% after 15 minutes of treatment. movement.

Example 6

The microcrystalline chitosome as a gel dispersion having the properties 10 described in Example 5 was used for binding fatty acids.

After 15 minutes of treatment, the sodiumundecylene binding capacity was 86.6%.

15 Example 7

Microcrystalline chitosan as a gel dispersion having a polymer content of 4.68% by weight, WRV 794%, deacetylation degree 87% and Mv 520,000 Daltons was spray dried in air as in Example 1.

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The resulting air-dried powder had a polymer content of 94.7% by weight, WRV of 300%, Mv of 180,000 daltons and a degree of deacetylation of 87.4% and a binding capacity of 153.4% after treatment.

Example 8

Microcrystalline chitosan in the form of a gel-like dispersion whose properties are described in Example 7 was used for binding fatty acids. The binding capacity of sodiumundecylene after 15 minutes of treatment was 86.2%. 30

Example 9 «« «

Microcrystalline chitosan as a gel dispersion having a polymer content of 4.94%, a WRV of 776%, a deacetylation value of 86.8% and a Mv of 35,503,000 Daltons was spray dried in air as in Example 3.

7 107432

Example 2

Microcrystalline chitosan as a gel dispersion having the properties described in Example 1 was used for binding fatty acids. The binding capacity of this 5 dispersion after 15 minutes treatment was 78%.

Example 3

Microcrystalline chitosan as a gel dispersion having a polymer content of 3.08 wt%, an average molecular weight Mv of 277,000 Daltons and a deacetylation degree of 83% and a gel water retention value of WRV 1096% was spray dried in air with an incoming air temperature of 210 ° C. temperature 70 ° C and drying rate 72 ml dispersion per minute. The air-dried powder thus obtained had a poly-15 polymer content of 92.6% by weight, a deacetylation degree of 83%, a water retention value of WRV of 288%, and an average molecular weight of 185,000 daltons and an average particle size of 40 µm.

This microcrystalline chitosan powder, after 15 minutes of treatment, bound: 71.8% sodium dundecylene.

Example 4

Microcrystalline chitosan as a gel dispersion having the properties described in Example 3 was used for binding fatty acids.

After 15 minutes of treatment, the sodiumundecylene binding capacity was 76.6%.

Example 5

The microcrystalline chitosan as a gel dispersion having a polymer content of 4.72% by weight, an average molecular weight Mv of 387,000 daltons, a deacetylation degree of 81% and a WRV of 809% was spray dried in air 35 with an incoming air temperature of 180 ° C and an outlet air temperature of 70 ° C and drying rate 60 ml dispersion per minute.

10 107432 Permanent Modified Cream Cheese With Special Dairy Dairy Product Behavior That Reduces Fat Absorption In The Human Body.

As stated above, the lipid absorption reducing agent may be provided in a suitable form that can be administered separately, for example, an effective amount of microcrystalline chitosan may be combined with pharmaceutically acceptable inert carriers. The agent may also be added to a diet, particularly lipid-containing food, whereby micro-crystalline chitosan is administered with food.

Further, in addition to the human body, the agent may also be administered to the body of other mammals, such as domestic animals and pets, if there is a need to reduce lipid absorption in these animals. Also in this alternative-15, chitosan can be administered in all of the above oral formulations.

The microcrystalline chitosan powder thus obtained had a polymer content of 83.1%, a WRV of 310%, a deacetylation degree of 84% and a Mv of 422,000 daltons and a binding capacity of 82.6% after 15 minutes of treatment.

5. Example 10

Microcrystalline chitosan, in the form of a gel-like dispersion whose properties are described in Example 9, was used to bind fatty acids. After 15 minutes of treatment, the sodiumundecylene had a binding capacity of 86.8%.

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Example 11

Freeze-dried microcrystalline chitosan with a polymer content of 89.1% by weight, WRV 132%, deacetylation degree 71% and a molecular weight of 15,330,000 Daltons was used for binding of fatty acids. Its sodium undecylene binding capacity after 15 minutes of treatment was 81%.

Example 12: 1.0 parts by weight of microcrystalline chitosan in the form of a gel dispersion having the characteristics described in Example 3 were homogenized for 5 minutes at 50 rpm in 10 parts by weight of yoghurt to give a stable dispersion having the specific behavior of a non-fat dairy product. .

• Example 13 1.5 parts by weight of microcrystalline chitosan in the form of a gel-like dispersion whose properties are described in Example 3 were homogenized for 30 minutes at 30 to 30 rpm with 10 parts by weight of low-calorie butter. This resulted in a permanent butter with a special behavior of low fat butter which reduces the absorption of fats into the human body.

Example 14 0.7 parts by weight of microcrystalline chitosan in the form of a gel dispersion having the characteristics described in Example 10 were homogenized for 20 minutes at 150 rpm in 15 parts by weight of cheese. That's how it was

Claims (6)

Use of microcrystalline chitosan in the preparation of an oral pharmaceutical preparation or nutrient for reducing lipid absorption, wherein the microcrystalline chitosan is in the form of a powder having an average particle size of less than 100 μηι and / or a gel dispersion having an average particle size of less than 100 μηι characterized by an average molecular weight of more than 10,000 daltons, preferably 50,000-700,000 daltons, and a deacety-10 degree of flux greater than 60%, preferably 70-95%. Use according to claim 1, wherein the microcrystalline chitosan powder formed by spray drying in air has a water retention value of WRV of at least 150%, in particular 200-300%, and good direct tabletability. The use according to claim 1, wherein the microcrystalline chitosan powder formed by freeze-drying has a water retention value WRV of at least 200%, in particular 250-400%. 20 The use according to claim 1, wherein the gel-like dispersion of microcrystalline chitosan containing more than 0.1% by weight and preferably 1-4% by weight of the microcrystalline polymer has a water retention value WRV of at least 500%, in particular 800-5000%. 25 The use according to claim 1 for the preparation of a separate preparation in the form of a powder, gel dispersion, tablets and / or capsules, optionally by combining microcrystalline chitosan with pharmaceutically acceptable inert carriers. Use according to claim 1 by adding microcrystalline. chitosan in a nutrient such as yogurt, butter or cheese.