KR20080040540A - Anti-obesity composition containing dietary fiber and lipase inhibitor, and method for preparing the same - Google Patents

Abstract

A composition for inhibiting obesity is provided to decrease side effects of a lipase inhibitor such as leakage of an oily fat through anus and steatorrhea excretion and maximize the obesity inhibitory effect. A composition for inhibiting obesity comprises a preparation which is prepared by coating a swelling fiber with a lipase inhibitor, wherein the fiber is Plantago asiatica and Psyllium seed husk and the lipase inhibitor is orlistat. A method for preparing the composition comprises the steps of: (a) subjecting a fiber to high pressure injection to obtain a swelling fiber having a swelling degree of 7 or more; and (b) coating the swelling fiber with a lipase inhibitor.

Description

Anti-obesity composition comprising swelling dietary fiber and lipase inhibitor and method for preparing the same {ANTI-OBESITY COMPOSITION CONTAINING DIETARY FIBER AND LIPASE INHIBITOR, AND METHOD FOR PREPARING THE SAME}

Figure 1 is a graph showing the weight change according to the drug administration by test group of Effect Test Example 1.

Figure 2 is a graph showing the daily feed intake change by test group of Effect Test Example 1.

Figure 3 is an HPLC analysis graph of the sides of the test group of Effect Test Example 1.

Figure 4 is a photograph showing the state of the excreted side by test group of Effect Test Example 1.

5 is a graph showing hepatic enzyme levels (ALT, AST) in blood after drug administration for 5 weeks for each test group of Effect Test Example 1. FIG.

Figure 6a is a graph showing the change in weight according to the drug administration by test group of Effect Test Example 2, Figure 6b is a graph showing the weight on the 24th day.

Figure 7 is a graph showing the daily feed intake change by the test group of Effect Test Example 2.

Figure 8 is a photograph showing the state of the excreted side by test group of Effect Test Example 2.

9 is a graph showing hepatic enzyme levels in blood (ALT, AST) after drug administration for 24 days for each test group of Effect Test Example 2. FIG.

The present invention relates to an anti-obesity composition comprising a dietary fiber and a lipase inhibitor, and a method for preparing the same, and specifically, to an agent in which the dietary fiber is processed into a swellable dietary fiber by a special pharmaceutical method, and used as an anti-obesity and therapeutic agent. To a formulation coated with a lipase inhibitor present and a method of making the same.

Dietary fiber is a term that was first submitted in 1972, meaning that it has a physiological meaning. It is a component known as fiber or cellulose, which is found in vegetables, fruits, and algae, and is not digested by human digestive enzymes. It refers to the polymer carbohydrates that are released out of the body.

Plantago asiatica L., which contains a large amount of dietary fiber, is a seed of plantain, contains aquabin and many mucus, and contains plantenolic acid, succinic acid, choline, adenine, vitamin A, and B1. In motion therapy, it is used to remove moist fever and brighten the eyes, so that eye diseases, cystitis, intestinal tract, blood urine, diarrhea and redness are used as medicines, urinary medicine, diarrhea, and respiratory diseases such as cough and bronchitis. It is also used.

Peeler's blood is dried by peeling the seed of the car and becomes mucus when absorbing moisture, and it is processed and applied at a high pressure by applying a special technique to increase its expandability. do.

The chemical formulation of the cha-cha and cha-cha blood mixture increases the swelling degree than the mixed form, which promotes the movement of the large intestine. The insoluble fiber of the drug regulates the movement of the intestine, and the soluble fiber regulates the metabolism of cholesterol, sugar, and bile acids. There is a regulating action, not only can be used for diseases such as irritable bowel syndrome, but also has a function of removing stool from chronic constipation, etc. If it is specially processed into a swelling agent, it can be widely used as an excellent constipation treatment.

On the other hand, orlistat has been developed as an anti-obesity agent among lipase inhibitors. The use of lipase inhibitors to control or prevent obesity and hyperlipidemia is described, for example, in US Pat. No. 4,598,089. Orlistat is currently administered at a dosage of 120 mg per meal and the dosage is independent of the weight of the human subject. Orlistat acts locally in the gastrointestinal (GI) tract, interfering with lipase digestion of triglycerides, thereby inhibiting the formation of absorbent lipolytic products. The lipase inhibitor composition inhibits about 30% of fat absorption after ingestion of a mixed meal, and increasing the lipase inhibitor concentration in the pharmaceutical composition does not increase clinical efficacy while increasing the degree of local side effects. Side effects include anal spotting of oily fat that is not metabolized, and excretion of fatty stools.

U.S. Patent No. 5,477,953 describes that the above-mentioned dietary fiber in combination with orlistat results in greater inhibition of fat absorption in the body. In addition, US Pat. No. 6,358,522 discloses a pharmaceutical composition comprising an additive selected from the group consisting of a lipase inhibitor, a substantially non-digestible and non-fermentable hydrophilic and / or hydrocolloid dietary grade thickener and emulsifier. As disclosed, methyl cellulose, xanthan gum, psyllium seed, plantago ovata seeds, ispaghula husk, karaya gum and the like are exemplified as additives.

Orlistat, on the other hand, has a low melting point of 42-43 ° C., which is currently commercially available orlistat formulations are prepared only in capsule form as a single formulation. When preparing a combination with the swellable dietary fiber to reduce the side effects of orlistat and increase the effect, there is a problem that it is difficult to formulate due to the low melting point of orlistat.

Furthermore, in the case of the simple mixing formulation of orlistat and insoluble dietary fiber mentioned in US Pat. No. 6,358,522, there is a problem that stability effects due to alteration of orlistat occur, and the effect is reduced.

An object of the present invention is to reduce the anal leakage of lipase inhibitors used in obesity and related diseases, and to reduce the excretion of fatty oils, and to increase the stability of the preparations compared to the simple combination of dietary fiber and lipase inhibitors and to suppress obesity. It is to provide a composition and a method of manufacturing the same to maximize the effect.

In order to achieve the above object, the present invention provides a composition for inhibiting obesity, comprising a formulation coated with a lipase inhibitor swellable dietary fiber formulation.

Here, it is preferable that swellable dietary fiber is a chapel and a chapel blood, and a lipase inhibitor is orlistat, and it is preferable that the mixing ratio of a swellable dietary fiber and a lipase inhibitor is 1: 0.005-0.03 by weight ratio.

Method for producing a composition for inhibiting obesity of the present invention for achieving the above another object, the high-pressure injection of dietary fiber is formulated into a swelling dietary fiber with a swelling degree of 7 or more, and coating it with a coating liquid containing a lipase inhibitor.

The present invention is to solve the problem of preparing a formulation of a dietary fiber and lipase inhibitor, that is, difficult to formulate due to the low melting point of orlistat, and the problem that the effect is reduced due to the stability decrease due to the alteration of orlistat In one embodiment, low-temperature coating of the swellable dietary fiber with a lipase inhibitor prevents drug deterioration and increases stability, thereby increasing pharmacological effects and metabolic rate while reducing side effects.

Hereinafter, the composition for inhibiting and treating obesity according to the present invention will be described in detail.

As used herein, the term “swellable charcoal dietary fiber preparation” refers to the preparation of the chaff and the chaff blood according to Example 1 below as a technically swellable preparation.

In the present specification, the chemical name of orlistat is (S) -2-formylamino-4-methyl-pentanoic acid (S) -1-[[(2S, 3S) -3-hexyl-4-oxo-2-oxetanyl ] methyl] dodecyl ester with the chemical formula C ₂₉ H ₅₃ NO ₅ and molecular weight 495.7.

As a swellable dietary fiber preparation and a lipase inhibitor combination according to the present invention, a pharmaceutical composition for inhibiting and treating obesity may be clinically orally administered, and the dosage may vary depending on the age, symptoms, dosage form or type of drug of the patient. It can be adjusted so that the amount of 6 to 24 g can be usually divided into once to several times.

In addition, the composition according to the present invention can be prepared using conventional pharmaceutically acceptable excipients, etc., and the target product can be obtained by using various technical methods (high pressure injection and mini-purification, etc.) in order to obtain high swelling degree. .

Furthermore, the composition according to the present invention may be formulated separately after formulating orlistat as a dietary fiber and orlistat as a lipase inhibitor, respectively, in such a case, which is also included within the scope of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. However, these Examples are only illustrative of the present invention, and the scope of the present invention is not limited to these.

Example  One: With car Car blood  Used Swelling  Preparation of Dietary Fiber Formulations

The electrons and the electrons were pulverized to have a particle size of 50 to 300 mesh, preferably 100 to 200 mesh, respectively.

200g of the chaff powder was mixed with 30g per bag and then uniformly mixed and dried in a double cone mixer with 1,770g of the chaff powder for 5 to 10 minutes to prepare 1000g in powder form and 1,000g in the form of swellable granules through special high-pressure injection. It was.

Example  2: Swelling Difference , Car , Orlistat Powder  Manufacture-1

The electrons and the electrons were pulverized to have a particle size of 50 to 300 mesh, preferably 100 to 200 mesh, respectively.

According to the blending ratio shown in Table 1 below, 120 g of the chaff powder was mixed with 18 g per bag, and then uniformly mixed in a double cone mixer with 1,062 g of the chaff powder for 5 to 10 minutes.

According to the blending ratio shown in Table 1, 240 g of lactose and 300 g of xylitol were mixed in a double cone mixer for 10 minutes, and 18 g of orlistat was distributed by 5 to 10 or more times using a 50 to 100 mesh sieve and mixed.

The two mixtures were mixed in a cone mixer for 10 to 20 minutes, and then 42 g of magnesium stearate was added and further mixed in a double cone mixer for 5 to 10 minutes.

Example  3: Swelling Difference , Car , Orlistat Powder  Manufacture-2

The electrons and the electrons were pulverized to have a particle size of 50 to 300 mesh, preferably 100 to 200 mesh, respectively.

According to the blending ratio shown in Table 1 below, 120 g of the chaff powder was mixed with 18 g per bag, and then uniformly mixed in a double cone mixer with 1,062 g of the chaff powder for 5 to 10 minutes.

According to the blending ratio shown in Table 1, 150 g of lactose, 90 g of mannitol, and 300 g of xylitol were mixed in a double cone mixer for 10 minutes, and 18 g of orlistat was distributed by 5 to 10 or more times using a 50 to 100 mesh sieve.

The two mixtures were mixed in a cone mixer for 10 to 20 minutes, and then 42 g of magnesium stearate was added and further mixed in a double cone mixer for 5 to 10 minutes.

Example  4: Swelling Difference , Car , Orlistat Powder  Manufacture-3

The electrons and the electrons were pulverized to have a particle size of 50 to 300 mesh, preferably 100 to 200 mesh, respectively.

According to the blending ratio shown in Table 1, 120g of the chaff powder was mixed with 18g per bag, and then uniformly mixed in a double cone mixer with 1,062g of the chaff powder for 5 to 10 minutes.

According to the blending ratio shown in Table 1, 120 g of lactose, 120 g of mannitol, and 300 g of xylitol were mixed in a double cone mixer for 10 minutes, and 18 g of orlistat was distributed by 5 to 10 or more times using a 50 to 100 mesh sieve.

The two mixtures were mixed in a cone mixer for 10 to 20 minutes, and then 42 g of magnesium stearate was added and further mixed in a double cone mixer for 5 to 10 minutes.

Ingredients (based on 6,000 mg) Example 2 (mg) Example 3 (mg) Example 4 mg Medicine Tea powder 3,540.0 3,540.0 3,540.0 Medicine Chaff powder 400 400 400 Medicine Orlistat 60.0 60.0 60.0 Excipient White sugar 60.0 60.0 60.0 Excipient Lactose 800.0 500.0 400.0 Excipient Mannitol - 300.0 400.0 Excipient Xylitol 1,000.0 1,000.0 1,000.0 Lubricant Magnesium stearate 140.0 140.0 140.0 Sum 6,000.0 6,000.0 6,000.0

Example  5: Swelling Difference , Car , Orlistat  Preparation of Coating Granules-1

The electrons and the electrons were pulverized to have a particle size of 50 to 300 mesh, preferably 100 to 200 mesh, respectively.

According to the blending ratio shown in Table 2 below, 120 g of the chaff powder was mixed in 18 g per bag and 5-10 minutes in a double cone mixer, and then 1,062 g of the chaser powder was added and further mixed in a double cone mixer for 20 to 30 minutes.

The mixture was kneaded by adding a constant of about 30 to 60% of the total weight of the mixture, and then extruded to granulate a size of about 1 to 5 mm. The drying loss was 10% or less, preferably 5% or less.

According to the mixing ratio shown in Table 2 below, 18 g of orlistat, 10.8 g of hydroxypropylmethyl cellulose and 1.2 g of polyethylene glycol 400 were dissolved in 150 ml of 95% ethanol with a primary coating solution containing orlistat. It was. This solution was first coated at room temperature with 1,200 g of the char and extruded granulated granules using Fluid bed flo-coater systems (Vector Corporation, Japan).

According to the blending ratio shown in Table 2, 310.83 g of xylitol, 219.96 g of talc, 12.72 g of yellow iron oxide, 24.63 g of gum arabic and 1.86 g of titanium oxide were stirred and dissolved in 198 ml of purified water to prepare a secondary coating solution. This solution was secondarily coated at room temperature using Fluid bed flo-coater systems on the first coated charcoal, the chaff extruded granules. It was dried at 35 ° C. so that the final drying loss was 10% or less, preferably 5% or less.

Example  6: Swelling Difference , Car , Orlistat  Preparation of Coated Granules-2

The electrons and the electrons were pulverized to have a particle size of 50 to 300 mesh, preferably 100 to 200 mesh, respectively.

According to the blending ratio shown in Table 2 below, 120 g of the chaff powder was mixed in 18 g per bag and 5-10 minutes in a double cone mixer, and then 1,062 g of the chaser powder was added and further mixed in a double cone mixer for 20 to 30 minutes.

The mixture was kneaded by adding a constant of about 30 to 60% of the total weight of the mixture, and then extruded to granulate a size of about 1 to 5 mm. The drying loss was 10% or less, preferably 5% or less.

According to the mixing ratio shown in Table 2 below, 18 g of orlistat, 8.4 g of hydroxypropylmethyl cellulose and 3.6 g of polyethylene glycol 400 were dissolved in 150 ml of 95% ethanol, and the first coating solution containing orlistat was dissolved. It was. This solution was first coated with 1,200 g of chasing and chaff extruded granules using Fluid bed flo-coater systems at room temperature.

According to the blending ratio shown in Table 2, 310.83 g of xylitol, 219.96 g of talc, 12.72 g of yellow iron oxide, 24.63 g of gum arabic and 1.86 g of titanium oxide were stirred and dissolved in 198 ml of purified water to prepare a secondary coating solution. This solution was secondarily coated at room temperature using Fluid bed flo-coater systems on the first coated charcoal, the chaff extruded granules. It was dried at 35 ° C. so that the final drying loss was 10% or less, preferably 5% or less.

Example  7: Swelling Difference , Car , Orlistat  Preparation of Coated Granules-3

The electrons and the electrons were pulverized to have a particle size of 50 to 300 mesh, preferably 100 to 200 mesh, respectively.

According to the blending ratio shown in Table 2 below, 120 g of the chaff powder was mixed in 18 g per bag and 5-10 minutes in a double cone mixer, and then 1,062 g of the chaser powder was added and further mixed in a double cone mixer for 20 to 30 minutes.

The mixture was kneaded by adding a constant of about 30 to 60% of the total weight of the mixture, and then extruded to granulate a size of about 1 to 5 mm. The drying loss was 10% or less, preferably 5% or less.

According to the mixing ratio shown in Table 2 below, 18 g of orlistat, 6 g of hydroxypropylmethyl cellulose and 6 g of polyethylene glycol 400 were dissolved in 150 ml of 95% ethanol to prepare a primary coating solution containing orlistat. This solution was first coated with 1,200 g of chasing and chaff extruded granules using Fluid bed flo-coater systems at room temperature.

According to the blending ratio shown in Table 2, 310.83 g of xylitol, 219.96 g of talc, 12.72 g of yellow iron oxide, 24.63 g of gum arabic and 1.86 g of titanium oxide were stirred and dissolved in 198 ml of purified water to prepare a secondary coating solution. This solution was secondarily coated at room temperature using Fluid bed flo-coater systems on the first coated charcoal, the chaff extruded granules. It was dried at 35 ° C. so that the final drying loss was 10% or less, preferably 5% or less.

Ingredients (based on 6,000 mg) Example 5 (mg) Example 6 (mg) Example 7 (mg) Medicine Chasers, Chassis Compressed Granules 4,000.0 4,000.0 4,000.0 Medicine Orlistat    60.0    60.0    60.0 Primary coating agent Hydroxypropylmethylcellulose    36.0    28.0    20.0 Primary coating agent Polyethylene Glycol 400     4.0    12.0    20.0 2nd coating agent Xylitol 1,036.1 1,036.1 1,036.1 2nd coating agent Talc   733.2   733.2   733.2 2nd coating agent Yellow iron oxide    42.4    42.4    42.4 2nd coating agent Gum arabic    82.1    82.1    82.1 2nd coating agent Titanium oxide     6.2     6.2     6.2 Sum 6,000.0 6,000.0 6,000.0

Example  8: Swelling Difference , Car , Orlistat  Preparation of Coated Granules-4

The electrons and the electrons were pulverized to have a particle size of 50 to 300 mesh, preferably 100 to 200 mesh, respectively.

According to the blending ratio shown in Table 3 below, 120 g of the chaff powder was mixed with 18 g per bag and 5 to 10 minutes in a double cone mixer, and then 1,062 g of the chaser powder was added and further mixed in the double cone mixer for 20 to 30 minutes.

The mixture was kneaded by adding a constant of about 30 to 60% of the total weight of the mixture, and then extruded to granulate a size of about 1 to 5 mm. The drying loss was 10% or less, preferably 5% or less.

According to the mixing ratio shown in Table 3 below, 36 g of orlistat, 10.8 g of hydroxypropylmethyl cellulose and 1.2 g of polyethylene glycol 400 were dissolved in 150 ml of 95% ethanol, and then the primary coating solution containing orlistat. It was. This solution was first coated at room temperature with 1,200 g of the char and extruded granulated granules using Fluid bed flo-coater systems (Vector Corporation, Japan).

According to the mixing ratio shown in Table 3 below, 310.83 g of xylitol, 219.96 g of talc, 12.72 g of yellow iron oxide, 24.63 g of arabic rubber, and 1.86 g of titanium oxide were stirred and dissolved in 198 ml of purified water to obtain a secondary coating solution. This solution was secondarily coated at room temperature using Fluid bed flo-coater systems on the first coated charcoal, the chaff extruded granules. It was dried at 35 ° C. so that the final drying loss was 10% or less, preferably 5% or less.

Example  9: Swelling Difference , Car , Orlistat  Preparation of Coating Granules-5

The electrons and the electrons were pulverized to have a particle size of 50 to 300 mesh, preferably 100 to 200 mesh, respectively.

According to the blending ratio shown in Table 3 below, 120 g of the chaff powder was mixed with 18 g per bag and 5 to 10 minutes in a double cone mixer, and then 1,062 g of the chaser powder was added and further mixed in the double cone mixer for 20 to 30 minutes.

The mixture was kneaded by adding a constant of about 30 to 60% of the total weight of the mixture, and then extruded to granulate a size of about 1 to 5 mm. The drying loss was 10% or less, preferably 5% or less.

According to the mixing ratio shown in Table 3 below, 36 g of orlistat, 8.4 g of hydroxypropylmethyl cellulose and 3.6 g of polyethylene glycol 400 were dissolved in 150 ml of 95% ethanol, and the first coating solution containing orlistat was dissolved. It was. This solution was first coated with 1,200 g of chasing and chaff extruded granules using Fluid bed flo-coater systems at room temperature.

According to the mixing ratio shown in Table 3 below, 310.83 g of xylitol, 219.96 g of talc, 12.72 g of yellow iron oxide, 24.63 g of arabic rubber, and 1.86 g of titanium oxide were stirred and dissolved in 198 ml of purified water to obtain a secondary coating solution. This solution was secondarily coated at room temperature using Fluid bed flo-coater systems on the first coated charcoal, the chaff extruded granules. It was dried at 35 ° C. so that the final drying loss was 10% or less, preferably 5% or less.

Example  10: Swelling Difference , Car , Orlistat  Preparation of Coated Granules-6

The electrons and the electrons were pulverized to have a particle size of 50 to 300 mesh, preferably 100 to 200 mesh, respectively.

According to the blending ratio shown in Table 3 below, 120 g of the chaff powder was mixed with 18 g per bag and 5 to 10 minutes in a double cone mixer, and then 1,062 g of the chaser powder was added and further mixed in the double cone mixer for 20 to 30 minutes.

The mixture was kneaded by adding a constant of about 30 to 60% of the total weight of the mixture, and then extruded to granulate a size of about 1 to 5 mm. The drying loss was 10% or less, preferably 5% or less.

According to the mixing ratio shown in Table 3 below, 36 g of orlistat, 6 g of hydroxypropylmethyl cellulose and 6 g of polyethylene glycol 400 were dissolved in 150 ml of 95% ethanol to prepare a primary coating solution containing orlistat. This solution was first coated with 1,200 g of chasing and chaff extruded granules using Fluid bed flo-coater systems at room temperature.

According to the mixing ratio shown in Table 3 below, 310.83 g of xylitol, 219.96 g of talc, 12.72 g of yellow iron oxide, 24.63 g of arabic rubber, and 1.86 g of titanium oxide were stirred and dissolved in 198 ml of purified water to obtain a secondary coating solution. This solution was secondarily coated at room temperature using Fluid bed flo-coater systems on the first coated charcoal, the chaff extruded granules. It was dried at 35 ° C. so that the final drying loss was 10% or less, preferably 5% or less.

Ingredients (based on 6,000 mg) Example 8 (mg) Example 9 (mg) Example 10 (mg) Medicine Chasers, Chassis Compressed Granules 4,000.0 4,000.0 4,000.0 Medicine Orlistat   120.0   120.0    60.0 Primary coating agent Hydroxypropylmethylcellulose    36.0    28.0    20.0 Primary coating agent Polyethylene Glycol 400     4.0    12.0    20.0 2nd coating agent Xylitol 1,003.4 1,003.4 1,003.4 2nd coating agent Talc   710.0   710.0   710.0 2nd coating agent Yellow iron oxide    41.1    41.1    41.1 2nd coating agent Gum arabic    79.5    79.5    79.5 2nd coating agent Titanium oxide     6.0     6.0     6.0 Sum 6,000.0 6,000.0 6,000.0

Example  11: Swelling Difference , Car , Orlistat  Preparation of Coated Granules-7

The electrons and the electrons were pulverized to have a particle size of 50 to 300 mesh, preferably 100 to 200 mesh, respectively. 120 g of the chaff powder was mixed with 18 g per bag and 5 to 10 minutes in a double cone mixer.

18 g of orlistat was added to 1,062 g of the char- acter powder and uniformly distributed 5-10 times or more using a 50-100 mesh body.

The mixture and the product were mixed for 5-15 minutes in a double cone mixer.

The mixture was kneaded by adding a constant of about 30 to 60% of the total weight of the mixture, and then extruded to granulate a size of about 1 to 5 mm. The drying loss was 10% or less, preferably 5% or less.

317.94 g of xylitol, 225 g of talc, 7.5 g of yellow iron oxide, 13.56 g of gum arabic, and 6 g of titanium oxide were stirred and dissolved in an appropriate amount of purified water to obtain a coating solution. This solution was coated on gastric granules at room temperature using Fluid bed flo-coater systems. It was dried at 35 ° C. so that the final drying loss was 10% or less, preferably 5% or less.

The swellable chaperone dietary fiber preparations and orlistat preparations prepared in Examples 2 to 11 were pilot batch manufacturing units of 1,800 g each.

The ingredient content of the formulations prepared in Examples 2 to 7 and 11 was based on the provisional standard of 6,000 mg, which is a single adult dose of the swellable charcoal dietary fiber formulation, in which case Orlistat contained 60 mg. Done. On the other hand, orlistat contains 120 mg in the component content of the formulations prepared in Examples 8 to 10.

In the effect test, this prescription was used as a reference.

Test Example

1. Orlistat Quantitative

(1) Preparation of the test liquid

4 g of each of the formulations according to Examples 2 to 11 were precisely taken into a 100 ml volumetric flask, and 80 ml of methanol was added thereto, followed by ultrasonic shaking for 30 minutes. After cooling to room temperature, methanol was added to align the marks, followed by filtration to obtain a sample solution.

(2) Preparation of Standard Solution

About 60 mg and 120 mg of Orlistat standard was precisely weighed and dissolved in methanol to make 100 ml, respectively.

(3) HPLC analysis conditions

Column: Capcell Pak C18 MG 4.6 × 250 mm, 5 μm

Mobile phase: Methanol / acetonitrile / trifluoroacetic acid = 800/200 / 0.05

Flow rate: 0.7 ml / min

Detector: UV detector (210 nm)

2. Swelling test

About 1 g of this solution was put in a stoppered 25 ml measuring cylinder, wetted with 1 ml of 96% ethanol, and 25 ml of water was added thereto. During the first hour, the volume of the swollen drug was determined after being vigorously shaken at 10 minute intervals and left for another 3 hours. Swelling should be at least 7-10 ml, preferably at least 8 ml per gram of sample.

The results of the Orlistat quantification and swelling test of the formulations prepared in Examples 2 to 11 are shown in Table 4 below.

Test Items Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Orlistat content (%) 98.5 97.8 100.2 100.1 98.6 100.0 100.1 98.2 99.6 99.1 Swelling degree (ml / g) 8.9 8.2 8.3 8.4 8.7 8.6 8.5 8.3 8.6 8.5

Effect Test Example  1. Obesity Inhibitory Effect Test

(1) Obesity Inhibitory Effects in Rats

The rats used in this study were SD (Sprague Dawley) based males of 3 weeks of age (70 ± 10 g) and were fed a normal diet (LabDiet, US PicoLab® Rodent Diet 20 # 5053) and unlimited water. During the supply period, they were allowed to have a 7-day acclimation period in the kennel. Body weight was measured before group separation, and divided into five groups of 7 animals per group (5 normal feed groups) so that the average weight was constant. This test was carried out in an animal breeding room automatically set at a temperature of 23 ± 2 ° C., a relative humidity of 55 ± 5%, a number of ventilation times of 10 to 12 times / h, an illumination time of 12 hours, and an illuminance of 150 to 300 Lux.

The test group was divided into a total of five groups as shown in Table 5 to freely consume the prepared feed and water, respectively, and increased the amount of feed according to the increase in feed intake.

County 1  Normal feed County 2  High Fat Feed County 3  Mix 0.2 parts by weight of the formulation of Example 1 to 1 part by weight of high fat feed County 4  Mix 0.002 parts of Orlistat with 1 part of High Fat Feed County 5  Mix 0.2 parts by weight of the formulation of Example 5 to 1 part by weight of high fat feed

Orlistat used in this test was purchased with a purity of 97.8% or more. Solvents, such as methanol and acetonitrile, used for liquid chromatography analysis, were used as solvents for HPLC of Fisher Scientific, and other reagents were used as first-class reagents.

The formulations of Example 1 and Example 5 provided to the test group were used by grinding to a particle size between 20 and 60 mesh using a grinder. The components of the normal diet (LabDiet, PicoLab® Rodent Diet 20 # 5053) used in the test are shown in Table 6, and the components of the high fat diet (Dyets Inc, US # 101556) are shown in Table 7 below. Shown in

Normal feed ingredients content (%) protein 20 Fat (ether extraction) 4.5 Fat (acid hydrolysis) 5.4 Fiber 4.7 Nitrogen-free extract 54.8 mineral 6 vitamin 4.6

High Fat Feed Ingredients ㎉ / g g / kg ㎉ / ㎏ Casein, high nitrogen 3.6 200 720.000 DL-Methionine 4 3 12 Sucrose 4 150 600 Corn starch 3.6 150 540 Cow oil 9 400 3,600 Cellulose 0 50 0 Mineral mix 0.88 35 30.8 Vitamin mix 3.9 10 39 Lee Joo Seok Choline 0 2 0

The weight of rats in the rearing was measured twice a week at about 5:30 pm by the method described above. .

1 is a graph showing the change in weight according to drug administration by test group, the following Table 8 shows the numerical value.

Hours County 1 County 2 County 3 County 4 County 5 0 81.5 ± 4.26 83.29 ± 2.75 79.93 ± 6.42 83.47 ± 4.70 83.64 ± 2.87 3 104.66 ± 1.69 112.39 ± 7.03 99.01 ± 6.29 107.54 ± 7.03 98.10 ± 2.42 7 137.3 ± 4 149.84 ± 11.12 131.86 ± 7.76 134.36 ± 8.54 118.29 ± 4.18 10 162.72 ± 5.08 172.16 ± 13.73 157.29 ± 7.83 157.12 ± 10.88 139.39 ± 6.03 14 193 ± 5.87 210.67 ± 15.74 193.01 ± 8.15 178.83 ± 12.95 151.47 ± 14.27 17 216.68 ± 8.79 237.11 ± 17.99 218.24 ± 8.53 203.73 ± 12.59 161.64 ± 15.14 21 247.28 ± 10.85 271.61 ± 22.13 252.77 ± 10.2 229.13 ± 13.35 151.93 ± 16.02 24 272.04 ± 12.1 301.46 ± 21.49 278.11 ± 11.52 247.86 ± 14.41 143.24 ± 14.27 28 301.32 ± 14.86 337.06 ± 23.62 309.01 ± 13.92 269.24 ± 14.94 161.81 ± 17.33 31 322.58 ± 16.63 362.32 ± 25.3 331.3 ± 15.12 * 281.07 ± 14.87 * 175.29 ± 10 *

◆: mean ± mean error

*: P <0.01

1 and Table 8, there was about 12.3% weight gain in the high fat feed group (group 2) compared to the normal feed group (group 1). The high fat diet / swellable charcoal dietary fiber intake group (group 3) showed a weight loss effect of about 8.6% compared to the high fat diet group (group 2). The high-fat diet / orlistat intake group (Group 4) had an effect of inhibiting weight gain of about 22.4% compared to the high-fat diet group (Group 2), but the high-fat diet / swellable charcoal dietary fiber preparation / orlistat intake group In (Group 5), there was an inhibitory effect of weight gain of about 51.6%. On the other hand, in the comparison of the high fat feed / orlistat intake group (group 4) and the high fat feed / swellable charcoal dietary fiber formulation / orlistat ingestion group (group 5), the high fat feed / swellable charcoal dietary fiber formulation / orlistat ingestion group (Group 5) showed a weight gain inhibitory effect of about 34.8% compared to the high fat diet / orlistat intake group (Group 4).

Figure 2 is a graph showing the daily feed intake change by test group, the following Table 9 shows the feed intake per horse (g) by test group.

Test group Feed Intake per Horse (g) County 1 673.91 County 2 501.66 County 3 495.99 County 4 976.69 County 5 919.64

Referring to Figure 2 and Table 9 look at the feed intake and efficiency of each test group as follows. First, in the high fat feed group (group 2), despite having consumed about 25.6% less feed than the normal feed group (group 1), there was 12.3% weight gain compared to the normal feed group (group 1). The high fat diet / swellable charcoal dietary fiber intake group (group 3) showed a weight loss effect of about 8.6% despite the intake of similar amounts to the high fat diet group (group 2). Meanwhile, the high fat feed / orlistat group (Group 4) and the high fat feed / swellable charcoal fiber preparation / orlistat group (Group 5) were about 94.7% and 83.3% higher than the high fat diet group (Group 2), respectively. Despite the higher intake of diet, the effect of weight gain was significant.

(2) Orlistat analysis on the side

According to the literature on orlistat, it is known that 85-99% of orlistat ingested is excreted in feces, and it was confirmed whether orlistat was excreted in the orlistat ingesting group. Three grams of excreted feces for 24 hours were collected, 10 ml of acetonitrile was added, the stools were well ground using a tissue mill, centrifuged, and the supernatant was again extracted with 5 ml of hexane. Hexane was evaporated using nitrogen gas, and 50 µl of the HPLC mobile phase was dissolved as a solvent, and 20 µl of the sample solution was subjected to HPLC at a flow rate of 0.7 ml / min and UV 210 nm using a C18 250 mm 0.5 µm column. The mobile phase was used in a mixture of (methanol: acetonitrile: trifluoroacetic acid = 800: 200: 0.05): water = 95: 5.

FIG. 3 is a graph of HPLC analysis of sides of test groups. FIG. 3A shows a case of group 4 and FIG. 3B shows a case of group 5. FIG. Referring to Figure 3, it can be seen that high fat feed / orlistat (group 4), high fat feed / swellable charcoal dietary fiber preparation / orlistat intake group (group 5) to discharge orlistat into the stool. As can be seen from these results, it can be confirmed that the formulation in which orlistat is mixed with the swellable charcoal dietary fiber preparation exhibits the same pharmacological action as in the case of orlistat alone administration.

(3) Visual confirmation of excreted stools

In order to confirm the degree and improvement of oily spotting of fatty stools and oils, which are well known as side effects of orlistat, the excreted stools were collected for 24 hours and visually examined for the viscosity and condition of the stools.

Figure 4 is a photograph showing the state of the excreted side by test group. As shown in Figure 4, in the case of normal feed group (group 1), high fat feed group (group 2), high fat feed and swellable charcoal dietary fiber composite administration group (group 3), the color difference of the stool according to the composition of the feed ingested However, there was no difference in the viscosity of the sides and the state of the sides. In contrast, fatty stools were observed in the high-fat diet / orlistat intake group (group 4) and oil leakage was observed in the anus of rats. However, in the high fat feed / swellable charcoal dietary fiber preparation / orlistat ingestion group (group 5) it was confirmed visually that the degree is significantly reduced.

(4) ALT and AST measurement

After 5 weeks of testing, to determine the hepatotoxicity after long-term administration of each drug, Kit (Asan Pharmaceuticals) was used to measure the amount of Aminotransferase (AST, ALT) activity and the effects of each drug on liver damage. Confirmed. Blood was collected from the heart under ether anesthesia, the blood was left at room temperature for 30 minutes and centrifuged to separate serum.

5 is a graph showing hepatic enzyme levels in blood (ALT, AST) after 5 weeks of drug administration by test group. 5, no significant changes in liver enzyme levels were observed between the normal feed group (group 1), the high fat feed group (group 2), and the respective drug intake groups (groups 3 to 5), and all tests It was confirmed that the group shows a value within the normal range. Therefore, it was confirmed that there is no hepatotoxicity by each drug at the time of long-term administration.

Effect Test Example  2. Obesity Treatment Effectiveness Test

(1) Examination of the effect of obesity treatment on mice

The rats used in this study were SD (Sprague Dawley) based males 6 weeks old (weight 130 ± 10g) and purchased a high fat diet (Dyets Inc, US # 101556) and a normal diet (Normal diet; LabDiet, US PicoLab® Rodent Diet 20 # 5053) and an unlimited supply of water were used to induce obesity in the nursery for eight weeks. Body weight was measured before group separation, and divided into five groups of 7 animals per group (5 normal feed groups) so that the average weight was constant. This test was carried out in an animal breeding room automatically set at a temperature of 23 ± 2 ° C., a relative humidity of 55 ± 5%, a number of ventilation times of 10 to 12 times / h, an illumination time of 12 hours, and an illuminance of 150 to 300 Lux.

The test group was divided into a total of five groups as shown in Table 10 to freely consume the prepared feed and water, respectively, and increased the amount of feed according to the increase in feed intake.

County 1  Normal feed County 2  High Fat Feed County 3  1 part of high fat feed is mixed with 0.004 parts of chaff, 0.13 parts of chacha and 0.004 parts by weight of orlistat County 4  Mix 0.2 parts by weight of the formulation of Example 8 to 1 part by weight of high fat feed. County 5  0.004 parts of Orlistat mixed with 1 part of High Fat Feed

Orlistat used in this test was purchased with a purity of 97.8% or more.

The components of the normal diet (LabDiet, US PicoLab® Rodent Diet 20 # 5053) used for the test are shown in Table 6, and the components of the high fat diet (Dyets Inc, US # 101556) are described in Table 7 above. Shown in

The weight of rats in the rearing was measured twice a week at about 5:30 pm by the method described above. .

Figure 6a is a graph showing the change in body weight according to drug administration by test group, Figure 6b is a graph showing the weight on day 24. Table 11 shows the change in weight according to drug administration by test group.

Hours County 1 County 2 County 3 County 4 County 5 0 460.58 ± 24.96 534.90 ± 25.58 535.98 ± 30.96 534.06 ± 18.26 534.50 ± 40.48 3 470.76 ± 29.83 542.50 ± 23.59 536.30 ± 30.04 535.98 ± 18.05 532.60 ± 36.29 7 482.48 ± 33.51 548.43 ± 25.00 528.36 ± 29.54 526.28 ± 16.86 529.10 ± 32.01 10 488.80 ± 37.91 553.93 ± 24.55 523.16 ± 27.09 520.32 ± 15.41 527.72 ± 32.54 14 497.56 ± 40.96 562.03 ± 22.51 520.58 ± 26.59 512.20 ± 15.18 525.76 ± 29.98 17 499.62 ± 44.41 568.63 ± 24.65 519.28 ± 28.55 507.64 ± 14.56 525.60 ± 27.28 21 506.60 ± 45.85 577.50 ± 23.80 514.94 ± 26.41 504.58 ± 13.99 518.02 ± 25.88 24 512.94 ± 47.78 583.00 ± 23.70 513.36 ± 26.13 * 496.64 ± 15.10 * 519.54 ± 24.38 *

◆: mean ± mean error

*: P <0.05

6A and 0 of Table 11 represent 8 weeks after the induction of obesity (test material treatment start date), and the obesity induction group (groups 2 to 5) is about 16% higher in weight than the normal feed group (group 1). The test was divided into groups.

6A and 6B, the weight change after 24 days of drug treatment in each test group, there was a weight gain of about 13.6% in the high fat feed group (Group 2) compared to the normal feed group (Group 1). Compared to the high fat feed group (group 2), the high fat feed / chaser, chaff blood / orlistat simple mixed group (group 3) was about 12%, and the high fat feed / swellable charcoal dietary fiber / orlistat mixed agent group (group 4) was about 14.9% and the high fat / orlistat group (Group 5) had about 10.9% weight loss.

Figure 7 is a graph showing the daily feed intake change by test group, the following Table 12 shows the feed intake (g) per bird by test group.

Test group Feed Intake per Horse (g) County 1 502.86 County 2 367.72 County 3 603.95 County 4 658.49 County 5 652.83

Looking at the feed intake and efficiency of each test group with reference to Figure 7 and Table 12 as follows. The high fat diet / swellable charcoal dietary fiber / orlistat blend preparation group (Group 4) had about 9% more weight than the high fat diet / charcoal, chaff blood / orlistat simple mixed diet group (Group 3). The reduction effect was increased by about 20%, and compared with the high fat diet / orlistat group (group 5), the weight loss effect was increased by about 26.4%.

(2) Visual check of excreted stools

In order to confirm the degree and improvement of oily spotting of fatty stools and oils, which are well known as side effects of orlistat, the excreted stools were collected for 24 hours and visually examined for the viscosity and condition of the stools.

8 is a photograph showing the state of the excreted side by test group. As shown in Figure 8, in the high fat feed / orlistat administration group (group 5), the main side effect of orlistat fatty stool was observed and oil leakage in the anus of rats was also observed. On the other hand, in the case of the high fat feed / charger, chaff blood / orlistat simple mixed administration group (Group 3) and the high fat feed / swellable charcoal dietary fiber / orlistat administration formulation group (Group 4), the stool was changed according to the composition of the ingested feed. Although there was a difference in color, the side effects were significantly reduced in the viscosity and the state of the stool compared to the high fat diet / orlistat group (group 5).

(3) ALT and AST measurement

After 24 days of testing, the kit (Asan Pharmaceuticals) was used to determine the amount of Aminotransferase (AST, ALT) activity and to determine the effects of each drug on liver damage. Confirmed. Blood was collected from the heart under ether anesthesia, the blood was left at room temperature for 30 minutes and centrifuged to separate serum.

9 is a graph showing hepatic enzyme levels (ALT, AST) in blood after 24 days of drug administration by test group. In Figure 9, it was confirmed that all the test group exhibits a value within the normal range. Therefore, it was confirmed that there is no hepatotoxicity by each drug at the time of long-term administration.

(Statistical processing)

In each test, the measured value and mean value were expressed as ± standard error (mean ± SEM), and statistical analysis between each experimental group was performed by one way ANOVA test using Sigma stat.

As above, in vivo using rat As a result, the composite preparation of the swellable dietary fiber and orlistat, which is specially processed according to the present invention, is an oily spotting of fatty stools and oils, which are considered to be side effects of orlistat due to the dietary fiber (charcoal and chaff). It can be seen that the decrease significantly). Moreover, also in the inhibitory effect of weight gain and the weight loss effect, it can be seen that the composition according to the present invention is superior to the orlistat alone formulation or a simple mixed formulation with the swellable dietary fiber. That is, according to the composition of the present invention, not only significantly improve the discomfort due to the side effects of the drug in many obese patients who are prescribed lipase inhibitors as an anti-obesity agent, but also to the main purpose of the weight-inhibiting effect and weight loss effect of the drug. It is also superior to orlistat alone, so it can be used as an effective obesity treatment.

As described above, the complex preparations coated with the lipase inhibitor in the swellable dietary fiber according to the present invention have significantly reduced side effects compared with the lipase inhibitor alone alone, and have a synergistic effect on weight gain inhibition and obesity treatment as well as long-term administration. There was no liver toxicity caused by. Furthermore, the formulation according to the present invention can increase the stability of the formulation without causing a problem of deterioration in stability due to deterioration of orlistat resulting from a simple mixed formulation of orlistat and insoluble dietary fiber, and thus a decrease in effect.

Claims (4)

A composition for inhibiting obesity comprising a formulation in which the swellable dietary fiber is coated with a lipase inhibitor. 2. The composition of claim 1, wherein the swellable dietary fiber is the chacha and chagap and the lipase inhibitor is orlistat. The composition according to claim 1 or 2, wherein the mixing ratio of the swellable dietary fiber and the lipase inhibitor is 1: 0.005 to 0.03 by weight. Method for preparing a composition for inhibiting obesity, comprising the step of high-pressure injection of dietary fiber into a swellable dietary fiber with a swelling degree of 7 or more, and coating it with a coating solution containing a lipase inhibitor.

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