KR100814384B1 - Pharmaceutical composition containing sibutramine salt, and manufacturing method thereof - Google Patents

Abstract

The present invention relates to a novel sibutramine salt and a composition for preventing or treating obesity or obesity-related diseases containing the same as an active ingredient. The novel sibutramine salt of the present invention is excellent in dissolution rate in the pH range of water and stomach, bioavailability is improved, characterized in that it has an excellent effect in the treatment and prevention of obesity-related diseases.

 Sibutramine, obesity, new salt, dissolution rate

Description

PHARMACEUTICAL COMPOSITION CONTAINING SIBUTRAMINE SALT, AND MANUFACTURING METHOD THEREOF

1 is a graph showing the elution tendency in pH = water of sibutramine salt-containing preparations obtained in Examples 1, 6, 8 and Comparative Examples.

▲: Example 1, ◆: Example 6, ■: Example 8, ○: Comparative Example

Fig. 2 is a graph showing the dissolution tendency at pH = 1.2 of sibutramine salt-containing preparations obtained in Examples 1, 6, 8 and Comparative Examples.

▲: Example 1, ◆: Example 6, ■: Example 8, ○: Comparative Example

The present invention relates to a novel sibutramine salt and a composition for preventing or treating obesity or obesity-related diseases containing the same as an active ingredient. The novel sibutramine salt of the present invention is excellent in dissolution rate in the pH range of water and stomach, bioavailability is improved, characterized in that it has an excellent effect in the treatment and prevention of obesity-related diseases.

Sibutramine, ie, N-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl-N, N-dimethylamine, is a compound having the structure of Formula 9 below.

[Formula 9]

Sibutramine is a substance that reduces appetite by inhibiting resorption of serotonin and noradrenaline, the neurohormones that regulate appetite in the brain. Developed as a therapeutic.

Since sibutramine is in an oil state, there is a problem in that it is difficult to handle pharmaceuticals. To improve this handling difficulty, British Patent No. 2,098,602 and Korean Patent Publication No. 90-00274 disclose hydrochloride anhydride, which is a pharmaceutically acceptable acid-addition salt of sibutramine. However, the sibutramine hydrochloride anhydride is very hygroscopic, it is difficult to maintain a constant content of the active ingredient, there is a problem that the absorbed moisture may affect the efficacy by causing hydrolysis and chemical decomposition of the active ingredient.

In order to solve this problem, British Patent No. 2,184,122 and Korean Patent Publication No. 94-08913 disclose sibutramine hydrochloride monohydrate having a structure of Formula 10, which is a non-hygroscopic sibutramine hydrochloride.

[Formula 10]

The hydrochloride monohydrate of sibutramine is commercially available under the trade name of Meridia or Reductil. However, the sibutramine hydrochloride monohydrate has a problem in that the solubility in water required as the active ingredient of the pharmaceutical composition is relatively low, and the solubility in the low pH range is low, so that the dissolution rate is lowered and the bioavailability is low.

 In addition, Korean Patent Laid-Open Publication No. 10-2004-0031574 discloses sibutramine methansufonate hemihydrate, which has good solubility in water compared to known sibutramine hydrochloride monohydrate, and has excellent stability at moisture and high temperature. have. This document describes the solubility in water at pH 5.2 and discloses that crystalline sibutramine methanesulfonate hemihydrate has inherent crystallographic physicochemical properties that cannot be readily prepared by conventional methods. However, this document does not describe the solubility in water in the pH environment (about pH 1 to 2) in the stomach, which has the greatest effect on the bioavailability of oral preparations, so that the effect of improving the actual bioavailability is assured. There is no evidence of this.

Therefore, it has been required to develop a novel sibutramine salt with excellent dissolution rate in water and gastric pH environment excellent in weight loss effect.

In order to meet the above requirements, the present invention provides a novel sibutramine salt having a high dissolution rate in water and gastric pH environment and excellent bioavailability and excellent weight loss effect, a method for preparing the same, and an obesity and obesity-related disease containing the same or It is an object to provide a therapeutic composition.

The present invention relates to a novel sibutramine salt and a composition for preventing or treating obesity or obesity-related diseases containing the same as an active ingredient. The novel sibutramine salt of the present invention is excellent in dissolution rate in the pH range of water and stomach, bioavailability is improved, characterized in that it has an excellent effect in the treatment and prevention of obesity-related diseases.

First, the present invention provides a novel sibutramine salt which has high dissolution rate in water and gastric pH environment, thereby improving bioavailability and excellent weight loss effect, and can be easily manufactured. The novel sibutramine salts of the present invention include sibutramine oxalate having a structure of Formula 1 below; Sibutramine fumalate having a structure of Formula 2; Sibutramine tartarate having a structure of Formula 3; Sibutramine citrate having a structure of Formula 4; Sibutramine succinate having the structure of Formula 5; Sibutramine sulfate having a structure of Formula 6; Sibutramine acetate having a structure of Formula 7; And sibutramine phosphate having the structure of Formula 8:

[Formula 1]

[Formula 2]

[Formula 3]

[Formula 4]

[Formula 5]

[Formula 6]

[Formula 7]

[Formula 8]

In the present invention, sibutramine means sibutramine of racemate unless otherwise stated.

The present invention also provides a simple and easy process for preparing sibutramine salts. The method for preparing the sibutramine salt of the present invention

Sibutramine having the structure of Formula 9, ie, N-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl-N, N-dimethylamine, is dissolved in alcohol,

To the obtained solution, an acid corresponding to a molar equivalent of the sibutramine and an equivalent or more molar equivalent is dissolved in a solid state or an organic solvent and added.

Obtaining a sibutramine salt corresponding to the acid which is the desired compound produced:

[Formula 9]

In the method for preparing sibutramine salt of the present invention, the acid used is selected from the group consisting of oxalic acid, fumaric acid, tartaric acid, citric acid, succinic acid, sulfuric acid, acetic acid and phosphoric acid. The amount of the acid used is preferably 1: 1 to 1: 1.2 (mobut equivalent of sibutramine: molar equivalent to acid) in a molar equivalent ratio with sibutramine. Since the amount of sibutramine that can participate in the reaction is determined, if the amount of acid used is less than the above, the complete reaction of sibutramine does not occur, and the reaction rate is slow, and if more than the above, an effect proportional to the amount of acid used is not obtained. do.

As the organic solvent that can be used by dissolving the acid, lower alcohols of C1 to C5 may be used, and methanol is preferable.

The sibutramine salts produced according to the acid used are sibutramine oxalate, sibutramine fumarate, sibutramine tartrate, sibutramine citrate, sibutramine succinate, sibutramine sulfate, sibutramine acetate, or sibutramine phosphate, respectively.

In the production method of the present invention, the alcohol may be a C1 to C5 lower alcohol, methanol, ethanol and isopropyl alcohol are preferred, and methanol is more preferred. The use amount of the alcohol is sufficient to dissolve sibutramine, it is preferable to use in an amount of 50 to 200 mL with respect to 1 g of sibutramine, more preferably in an amount of 50 to 150 mL.

In the production method of the present invention, after the reaction proceeds, the reaction product can be concentrated under reduced pressure and filtered to obtain the resulting sibutramine salt, or an appropriate precipitation solvent can be added to the reaction product to obtain the sibutramine salt. Diethyl ether, diisopropyl ether, normal-hexane and the like can be used as the precipitation solvent.

In the production method of the present invention, the reaction time is 1 to 10 minutes is sufficient.

The sibutramine salt selected from the group consisting of sibutramine oxalate, sibutramine fumarate, sibutramine tartrate, sibutramine citrate, sibutramine succinate, sibutramine sulfate, sibutramine acetate and sibutramine phosphate prepared in the present invention is pH 1 similar to water and gastric environment 2 to 2, preferably, the dissolution rate and bioavailability at pH 1.2 are excellent, and thus obesity prevention and prevention effects are excellent.

In addition, the present invention is an active ingredient sibutramine oxalate (sibutramine oxalate) having the structure of formula (1); Sibutramine fumalate having a structure of Formula 2; Sibutramine tartarate having a structure of Formula 3; Sibutramine citrate having the structure of formula 4; Sibutramine succinate having a structure of Formula 5; Sibutramine sulfate having a structure of Formula 6; Sibutramine acetate having a structure of Formula 7; And it provides a composition for treating obesity or obesity related to a pharmaceutically effective amount of the sibutramine salt selected from the group consisting of sibutramine phosphate having a structure of formula (8).

The amount of active ingredient contained in the composition of the present invention depends on the condition of the subject to be administered, the desired degree of treatment, and the like. Preferably, the composition of the present invention comprises a sibutramine salt selected from the group consisting of sibutramine oxalate, sibutramine fumarate, sibutramine tartrate, sibutramine citrate, sibutramine succinate, sibutramine sulfate, sibutramine acetate and sibutramine phosphate as active ingredients With respect to 250 parts by weight of 1 to 50 parts by weight (0.4 to 20% by weight based on the total composition weight), preferably 2 to 30 parts by weight (8 to 12% by weight based on the total composition weight). Can be.

The sibutramine salt-containing composition of the present invention may further contain one or more additives selected from the group consisting of pharmaceutically acceptable excipients, binders, disintegrants and suspending agents, in addition to the active ingredient sibutramine salts.

The excipient may be at least one selected from the group consisting of lactose, sugar, starch, mannitol, sorbitol, calcium carbonate, and other inorganic salts and microcrystalline cellulose. The binder is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxy cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, gelatin, dextrin, microcrystalline cellulose, gum arabic and It may be one or more selected from the group consisting of carboxymethyl cellulose. The disintegrant may be at least one selected from the group consisting of sodium croscarmellose, crospovidone, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, corn starch and microcrystalline cellulose. The glidant may be at least one substance selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba lead, stearin and glycerol bihenate, which are fatty acid glycerides.

In one specific embodiment of the present invention, the composition of the present invention may contain 10 mg of sibutramine oxalate of Formula 1, 150 mg of starch, 87 mg of microcrystalline cellulose and 3 mg of magnesium stearate as active ingredients based on a total weight of 250 mg of the composition. have. However, the composition ratio of the composition is only one example and does not limit the scope of the present invention.

The sibutramine salt containing composition of the present invention can be formulated into tablets, pills, capsules, suspensions and the like. The route of administration of the sibutramine salt-containing composition of the present invention is not limited, but oral administration is preferred.

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples.

Example 1 Preparation of Sibutramine Oxalate (Formula 1)

2.79 g of sibutramine (N-1- [1- (4-chlorophenyl) cyclobutyl] -3-methylbutyl-N, N-dimethylamine) was dissolved in 250 mL of methanol, and 1.27 g of oxalic acid dihydrate. Was added at room temperature to give a clear solution. The resulting solution was concentrated under reduced pressure, and the resulting crystals were filtered and dried under vacuum at 30 ° C. to obtain 3.68 g of a white sibutramine oxalate having the structure of Formula 1 below.

[Formula 1]

¹ H NMR (δ, CD ₃ OD): 7.52-7.43 (4H), 3.3 (1H), 1.08-1.03 (6H)

Melting Point: 141 ~ 144 ℃

Example 2: Preparation of Sibutramine Fumarate (Formula 2)

2.79 g of sibutramine was dissolved in 250 mL of methanol, and a solution of 1.17 g of fumaric acid in 50 mL of methanol was added at room temperature to form a clear solution. The resulting solution was concentrated under reduced pressure, and the resulting crystals were filtered and dried under vacuum at 30 ° C. to obtain 3.56 g of a white sibutramine fumarate having the structure of Formula 2 below.

[Formula 2]

¹ H NMR (δ, CD ₃ OD): 7.50-7.42 (4H), 3.3 (1H), 1.08-1.03 (6H)

Melting Point: 168 ~ 171 ℃

Example 3: Preparation of Sibutramine Tartrate (Formula 3)

2.79 g of sibutramine was dissolved in 250 mL of methanol, and a solution of 1.51 g of tartaric acid in 50 mL of methanol was added at room temperature to form a clear solution. The resulting solution was concentrated under reduced pressure, and the resulting crystals were filtered and dried under vacuum at 30 ° C. to obtain 3.98 g of a white sibutramine tartrate having the structure of Formula 3 below.

[Formula 3]

¹ H NMR (δ, CD ₃ OD): 7.51-7.43 (4H), 3.30 (1H), 1.08-1.04 (6H)

Melting Point: 93 ~ 96 ℃

Example 4: Preparation of Sibutramine Citrate (Formula 4)

2.79 g of sibutramine was dissolved in 250 mL of methanol, and a solution of 2.11 g of citric acid in 50 mL of methanol was added at room temperature to form a clear solution. The resulting solution was concentrated under reduced pressure, and the resulting crystals were filtered off and dried at 30 deg. 4.28 g of white sibutramine citrate having the structure of formula (4) was obtained.

[Formula 4]

¹ H NMR (δ, CD ₃ OD): 7.51 ~ 7.43 (4H), 3.3 (1H), 1.08 ~ 1.04 (6H)

Melting Point: 129 ~ 131 ℃

Example 5: Preparation of Sibutramine Succinate (Formula 5)

2.79 g of sibutramine was dissolved in 250 mL of methanol, and a solution of 1.19 g of succinic acid in 50 mL of methanol was added at room temperature to form a clear solution. The resulting solution was concentrated under reduced pressure, and the resulting crystals were dried at 30 ° C. and in vacuo to give 3.37 g of a white sibutramine succinate having the structure of Formula 5 below.

[Formula 5]

Melting Point: 148 ~ 155 ℃

Example 6: Preparation of Sibutramine Sulfate (Formula 6)

2.79 g of sibutramine was dissolved in 250 mL of methanol, and a solution of 1.03 g of concentrated sulfuric acid in 20 mL of methanol was added at room temperature to form a clear solution. The resulting solution was concentrated under reduced pressure, diethyl ether was added, and the resulting crystals were filtered and dried under vacuum at 30 ° C. to obtain 3.62 g of a white sibutramine sulfate having a structure of the following formula (6).

[Formula 6]

¹ H NMR (δ, CD ₃ OD): 7.52 ~ 7.44 (4H), 3.3 (1H), 1.09 ~ 1.05 (6H)

Melting Point: 191 ~ 192.0 ℃

Example 7: Preparation of Sibutramine Acetate (Formula 7)

2.79 g of sibutramine was dissolved in 250 mL of methanol, and a solution of 0.63 g of acetic acid in 20 mL of methanol was added at room temperature to give a clear solution. The resulting solution was concentrated under reduced pressure, diethyl ether was added, and the resulting crystals were filtered and dried under vacuum at 30 ° C. to obtain 2.98 g of a white sibutramine acetate salt having the structure of Formula 7 below.

[Formula 7]

¹ H NMR (δ, CD ₃ OD): 7.28-7.21 (4H), 3.3 (1H), 0.99-0.99 (6H)

Melting Point: 50 ~ 52 ℃

Example 8 Preparation of Sibutramine Phosphate (Formula 8)

2.79 g of sibutramine was dissolved in 250 mL of methanol, and a solution of 1.2 g of 85% phosphoric acid in 20 mL of methanol was added at room temperature to form a clear solution. The resulting solution was concentrated under reduced pressure, diethyl ether was added, and the resulting crystals were filtered and dried under vacuum at 30 ° C. to obtain 3.47 g of a white sibutramine phosphate having the structure of Formula 8 below.

[Formula 8]

¹ H NMR (δ, CD ₃ OD): 7.57-7.43 (4H), 3.3 (1H), 1.08-1.04 (6H)

Melting Point: 145 ~ 147 ℃

Example 9 Preparation of Capsules for Measuring Dissolution Rate

Sibutramine salts obtained in Examples 1, 6 and 8 (Example 1: sibutramine oxalate, Example 6: Sibutramine sulfate, Example 8: Sibutramine phosphate), and as a comparative example, a known structure having the structure of Formula 10 150 mg of starch, 87 mg of microcrystalline cellulose and magnesium stearate 3 to 10 mg equivalent of sibutramine of each salt using sibutramine hydrochloride monohydrate (synthesized according to the method described in Korean Patent Publication No. 10-2004-0031574) A total weight of 250 mg was added to prepare a capsule for measuring dissolution rate. The capsule was made of a hard capsule of a conventional gelatin.

Experimental Example 1: Dissolution Test

Using a capsule containing the sibutramine salt obtained in Examples 1, 6 and 8 and a known sibutramine hydrochloride monohydrate as a comparative example, at a time of water and pH = 1.2 according to the dissolution test method in the 8 general test methods of KP The dissolution rate accordingly was measured. The dissolution rate was measured by liquid chromatograph (HPLC) with respect to the sample collected at each dissolution time. The operating conditions of HPLC were as follows:

HPLC operating conditions

Detector: ultraviolet absorbance photometer (wavelength 225 nm)

Column: Filled with stainless steel pipe with an inner diameter of about 4 mm and a length of about 30 cm, octadecylsilylated silica gel for 5 μm liquid chromatography.

Column temperature: 35 ℃

This phase:

0.05M diammonium hydrogen phosphate (adjusted to pH = 6.8): acetonitrile

= 350 mL: 650 mL

Flow rate: 1.0mL / min

Injection volume: 10 μl

Dissolution patterns measured by the PHLC are shown in FIGS. 1 and 2. As shown in Figs. 1 and 2, the sibutramine salts of Example 1 (-▲-), 6 (-◆-) and 8 (-■-) prepared in the present invention are known sibutramine hydrochloride monohydrate (-○- ), It showed a significantly higher dissolution rate at pH 1.2, similar to the water and gastric environment. These results show that the sibutramine salt of the present invention has a significantly improved bioavailability compared to the existing sibutramine salt, and thus has a better effect on the treatment and prevention of obesity and obesity related diseases.

Experimental Example 2: Weight Loss Test

In order to examine the obesity treatment or prophylactic effect of the sibutramine salts of Examples 1 (cibutramine oxalate), 2 (cibutramine fumarate), 3 (cibutramine tartrate), 6 (cibutramine sulfate) and 8 (cibutramine phosphate), The experiment was performed.

Obesity-induced 70 ICR mice (males) were prepared as high-fat foods, and each of them was divided into 10 drug groups, 5 drug administration groups, a negative control group, and a positive control group. Each subject was weighed before the test. The sibutramine salts prepared in Examples 1, 2, 3, 6, and 8, respectively, were dissolved in water and orally administered daily at 14 mg / kg dose for 14 days, and the positive control group was the known sibutramine hydrochloride number of days. The cargo was dissolved in water and orally administered at a daily dose of 3 mg / Kg for 14 days, and the negative control group received only vehicle (water without sibutramine salt).

All groups were free to eat high fat foods throughout the test period. After 14 days, the weight change of each subject was measured, and the weight gain of the positive and negative controls and the drug administration group was measured as an average value of 10 subjects, and the weight loss effect was calculated and shown in Table 1 below.

TABLE 1

Example 1 Example 2 Example 3 Example 6 Example 8 Positive control group Negative Control Average weight before test (g): A 45.4 45.8 44.9 44.3 44.9 45.2 47.2 Average weight after test (g): B 47.9 51.3 48.4 47.3 48.5 51.4 57.6 Weight gain (g): B-A 2.5 5.5 3.5 3 3.6 6.2 10.4 Weight loss effect (g): positive control group-drug administration group 3.7 0.7 2.7 3.2 2.6 - - Weight loss effect (g): negative control group-drug administration group 7.9 4.9 6.9 7.4 6.8 - -

As can be seen in Table 1, the weight gain in mice administered with the sibutramine salts of Examples 1, 2, 3, 6, and 8 was significantly higher than that of the negative control as well as the positive control administered with the basic sibutramine hydrochloride monohydrate. It can be seen that the degradation. Therefore, it can be seen that the sibutramine salt of the present invention is effective in treating and preventing obesity by effectively inhibiting weight gain.

The novel sibutramine salt having a structure selected from the group consisting of Formulas 1, 2, 3, 4, 5, 6, 7 and 8 prepared in the present invention has high bioavailability due to high dissolution rate at pH = 1.2 similar to water and gastric environment. It is effective in the treatment and prevention of obesity, and has the advantage that the manufacturing method is simple and easy to manufacture.

Claims (9)

It contains the sibutramine salt of sibutramine succinate having the structure of formula 5 as an active ingredient, Improved gastric dissolution rate and bioavailability Compositions for the prevention or treatment of obesity or obesity-related diseases: [Formula 5]

delete The method of claim 1, The content of the sibutramine salt is 0.4 to 20% by weight based on the total composition weight. The composition of claim 1 further comprising one or more additives selected from the group consisting of pharmaceutically acceptable excipients, binders, disintegrants and lubricants. The method of claim 4, wherein The excipient is at least one selected from the group consisting of lactose, sugar, starch, mannitol, sorbitol, inorganic salts of calcium carbonate and microcrystalline cellulose; The binder is hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxy cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, gelatin, dextrin, microcrystalline cellulose, gum arabic and At least one selected from the group consisting of carboxymethyl cellulose; The disintegrant is at least one selected from the group consisting of sodium croscarmellose, crospovidone, sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, corn starch and microcrystalline cellulose; Wherein the lubricant is at least one selected from the group consisting of magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba lead, stearin and fatty acid slylides. 6. A composition according to claim 1, 3, 4 or 5 formulated into tablets, pills, capsules or suspensions. Sibutramine having the structure of Formula 9 is dissolved in alcohol, Citric acid is added to the obtained solution in an amount corresponding to a molar equivalent of sibutramine in a ratio of 1: 1 to 1: 1.2 (mobut equivalent of sibutramine: molar equivalent of acid), Obtaining the resulting sibutramine salt, Characterized by increasing the gastric dissolution rate and bioavailability of the resulting sibutramine salt, Method for preparing a composition for preventing or treating obesity-related diseases according to claim 1: [Formula 9]

The method according to claim 7, wherein the alcohol is a C1 to C5 lower alcohol and is used in an amount of 50 to 200 mL with respect to 1 g of sibutramine. The method of claim 7, wherein the step of obtaining the resulting sibutramine salt is carried out by concentration under reduced pressure and filtration, or by adding a precipitation solvent selected from the group consisting of diethyl ether, diisopropyl ether and normal-hexane. Manufacturing method.

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