KR20080076627A - A composition for solubilizing sibutramine and a method for preparing the same - Google Patents

Abstract

A composition comprising solubilized sibutramine is provided to enhance bioavailability of sibutramine by improving solubility and solubility rate of sibutramine through the conventional solid composition preparation process, and reduce the preparation time and costs by removing additional solid dispersion-forming process. A composition for improving solubility of sibutramine comprises 1 part by weight of sibutramine free base and 0.1-20 parts by weight of alginic acid, and optionally comprises 1-20 parts by weight of hydrophilic polymer, which is selected from polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, low substituted hydroxypropylcellulose and a mixture thereof, or 0.1-20 parts by weight of sugar alcohol, which is selected from maltitol, maltitol syrup, sorbitol, isomalt, erythritol, lactitol, inositol, mannitol, ribitol, galactitol, xylitol, maltotriitol and a mixture thereof, or water-soluble sugar, which is selected from sucrose, glucose, fructose and a mixture thereof, and is formulated as tablet, granule or powder. Further, the composition for improving solubility of sibutramine additionally comprises a solubilizer.

Description

Solubilizing composition of sibutramine and a method for preparing the same {A composition for solubilizing sibutramine and a method for preparing the same}

BRIEF DESCRIPTION OF THE DRAWINGS It is a graph which compared the elution rate (%) of Examples 1-4, Comparative Examples 1-2, and the sibutramine hydrochloride monohydrate commercially available formulation (Reductilcapel ^TM , the following commercially available formulation).

2 is a graph comparing the dissolution rates (%) of Examples 5 to 8 and the commercially available formulations.

3 is a graph comparing the dissolution rates (%) of Examples 9 to 14 and the commercially available formulations.

The present invention relates to a sibutramine solubilizing composition having improved bioavailability by improving the solubility and dissolution rate of sibutramine, a poorly soluble drug, a preparation method thereof, and a pharmaceutical formulation containing the composition as a main component.

Sibutramine has the chemical name "1- (4-chlorophenyl) -N, N-dimethyl-α- (2-methylpropyl) -cyclobutanemethaneamine (1- (4-chloro phenyl) -N, N-dimethyl-α- (2-methylpropyl) -cyclo butanemethanamine) ", the molecular weight is 279.85 g / mol, the structure is represented by the following formula (1).

Sibutramine is a reuptake inhibitor of serotonin and noradrenaline disclosed in US Pat. Nos. 4746680 and 4806570 (Neuropharmacology, 28, 129-134p). Sibutramine reduces weight intake by increasing satiety, reducing food intake, and stimulating heat generation to increase energy expenditure (Int. J. Ob-esity, 19, 145p; Brit.J. Pharmacol. 114, 388 p)

Research on sibutramine has been widely conducted, and it is known that it is being used as a therapeutic agent for depression, Parkinson's disease and obesity in particular (UK Patent No. 2098602, Republic of Korea Patent Publication No. 90-00274, International Publication No. WO 88/06444, Korean Patent Publication No. 99-164435).

Sibutramine can also be used to reduce insulin resistance or to enhance glucose tolerance, and to treat various diseases such as gout, hyperacidemia, hyperlipidemia, osteoarthritis, anxiety disorders, sleep disorders, sexual dysfunction, chronic fatigue syndrome and cholelithiasis and It is reported that it can be used for prevention.

Such free base of sibutramine is a poorly water-soluble drug that rapidly changes in solubility according to pH, and as shown in Table 1, it can be seen that the solubility decreases rapidly in water or pH 6.8 buffer. This rapid change in pH dependent solubility leads to a decrease in bioavailability, making it difficult to prepare pharmaceutical preparations containing sibutramine free base as a main component.

pH 1.2 pH 4.0 water pH 6.8 Solubility 2.1 mg / mL 1.9 mg / mL 0.01 mg / mL 0.03 mg / mL ※ Solubility evaluation condition (water, pH 1.2, pH 4.0, pH 6.8, 4 hours, 100rpm)

In addition, sibutramine free base is sometimes obtained in an oil phase, and due to low melting point, handling is not easy and problems of stability in long-term storage have been reported.

In order to overcome these problems and to prepare a pharmaceutical formulation, a pharmaceutically acceptable salt has been introduced to secure a poorly soluble and stable drug, ease of handling and the like.

British Patent No. 2098602 and Korean Patent Publication No. 90-00274 propose a method for preparing sibutramine hydrochloride anhydride, a pharmaceutically acceptable acid addition salt of sibutramine. However, in the case of hydrochloric anhydride, the hygroscopicity is very high, making it difficult to keep the content of the active ingredient constant, and the absorbed moisture causes hydrolysis and chemical degradation of the active ingredient, which may cause problems in product stability. There are many problems to be used as an active ingredient.

British Patent No. 2184122 and Korean Patent Publication No. 94-08913 have proposed a non-hygroscopic sibutramine hydrochloride monohydrate that improves the hygroscopic problem of sibutramine hydrochloride anhydride. Meridia ^™ , Reductil ^™ ].

Korean Patent Laid-Open Publication No. 2004-0031574 suggests that the active ingredient used in the pharmaceutical composition should have a high solubility in water or an aqueous solution in a wide pH range in order to exhibit high bioavailability, and the sibutramine hydrochloride monohydrate is water and a wide range. It was pointed out that the solubility in the pH aqueous solution was not suitable for use as an active ingredient of the pharmaceutical composition, and to improve this problem, the excellent solubility of sibutramine methanesulfonate hemihydrate was presented.

Korean Patent Publication No. 2006-0093564 does not improve the hygroscopicity of sibutramine acid addition salt anhydride in any of the above known patents, and was developed in the form of monohydrate or hemihydrate in order to improve it, but the solubility of sibutramine hydrochloride monohydrate ( 2.9mg / mL) also pointed out the lack of high bioavailability. In addition, in order to improve the stability and non-hygroscopicity to heat and moisture, as well as high solubility in water or aqueous solution in a wide pH range to provide a sibutramine malate.

In Korean Patent Laid-Open Publication No. 2006-0080899, the manufacturing process of sibutramine hydrochloride monohydrate, which is disclosed in Korean Patent Publication No. 94-8913, is prepared by preparing anhydride, adding a solvent containing water thereto, and suspending and stirring for a long time. As a result, it is very cumbersome, and the current commercially available hydrochloride monohydrate points out a problem of low solubility in water and aqueous solutions over a wide pH range. For this purpose, phosphate hydrate is highly hygroscopic, having excellent solubility in water, but having a high solubility in water but much higher solubility than conventional butyrate monohydrate. In addition, Korean Laid-Open Patent Publication No. 2006-0080818 discloses sibutramine benzenesulfonate (beta), camphorsulfonate (camsylate), para-toluenesulfonate (tosylate) and ethanedi to improve the low solubility of sibutramine hydrochloride monohydrate. Sibutramine sulfonates, such as sulfonates (edylates), are shown.

Korean Patent Publication No. 10-0617856 pointed out that the oral dosage form, which was mainly proposed in the prior art, requires water when taking a drug, and is inconvenient for taking patients or the elderly who have difficulty in swallowing oral preparations and improving it. To provide a gum-type novel sibutramine formulation. However, such gum-type formulations contain sibutramine hydrochloride monohydrate in the gum base used in foods to prepare the formulations, and the stability of the formulations according to the storage conditions (usually more than two years of shelf life of the pharmaceutical formulation). There is a problem that cannot be secured.

In Korean Patent Publication No. 10-0627687, the above-described prior art and the like have an acidic salt prepared by additional reaction with a sibutramine free base, which usually has a problem of increasing the manufacturing cost, and salts are minimized to minimize potential side effects. It is pointed out that it is desirable to minimize the amount of additional components, including acids to form (eg methanesulfonic acid). In addition, sibutramine free base is used to provide a sibutramine free base-containing composition having a good dissolution rate, low dissolution deviation according to pH, easy mass production, and stability.

However, in order to secure drug stability and improve dissolution rate, the sibutramine free base-containing composition requires a difficult manufacturing process in which sibutramine free base is combined with an organic acid and a hydrophilic polymer to form a separate solid dispersion. Cost- and time-consuming process for preparing the formulation is not economical.

In addition, the solid dispersion of the sibutramine free base is dissolved in a solvent in which an organic acid (citric acid) is dissolved, and then the hydrophilic polymer is dissolved therein to form a solid dispersion through a process such as spray drying. Problems such as precipitation of (citric acid) may occur, and there is a problem such as poor recovery of the obtained product.

Despite various technical attempts as described above, Korean Patent Publication No. 10-0627687 provides a pharmaceutical composition by improving the poor solubility of sibutramine free base, and in most cases, the addition of sibutramine acid addition salt hydrate. Most of the research is on manufacturing.

In the present invention, to improve the poor solubility of sibutramine free base to improve the dissolution rate in aqueous solution and water in a wide pH range, to develop a pharmaceutical formulation composition having a high bioavailability, which can be mass-produced in a simple and easy way, Sibutramine glass Using base and alginic acid, sugar alcohols and sugars, hydrophilic polymers, and the like through the conventional process for preparing solid solvents, the inventors have found that they have improved the dissolution rate and have high bioavailability and completed the present invention. It became.

The present invention provides an oral pharmaceutical preparation of a poorly soluble obesity therapeutic agent, which is improved significantly in dissolution rate and bioavailability of the drug only by the conventional solid-state preparation process, without going through a separate difficult solid dispersion manufacturing process Can provide.

It is an object of the present invention to provide a sibutramine free base formulation composition having improved dissolution rate and bioavailability of a drug comprising 1 part by weight of sibutramine free base and 0.1 to 20 parts by weight of alginic acid.

Another object of the present invention is to provide a pharmaceutical formulation of sibutramine comprising the sibutramine free base formulation composition of the present invention and an excipient or adjuvant.

In accordance with the above object, in one embodiment, Sibutramine free base and 0.1 to 20 parts by weight of alginic acid are included as one embodiment, wherein the sibutramine free base and alginic acid are mixed homogeneously while maintaining a state of mutual physical bonding. Sibutramine free base formulation composition is provided.

Sibutramine free base to be used in the present invention can be prepared using a method known in the prior art, for example, the method disclosed in Korean Patent Publication No. 90-00274.

Alginic acid used in the present invention is a seaweed-derived polysaccharide, which is linked to hundreds of mannuronic acid and L-glulonic acid by β-1, 4 bonds, and is also called seaweed. Alginic acid is a polymer of two kinds of uronic acid, and has a degree of polymerization of 80 and a molecular weight of about 1,500. Mammals are polymers that are not metabolized and are excreted because there are no enzymes that degrade alginic acid. Alginic acid is found in algae as a broad component of cell walls in the form of some mixed forms of its alkali salts, in particular sodium salts. These salts are usually extracted in the form of an aqueous solution using sodium carbonate solution, which can be precipitated directly from the extract, for example, with an inorganic acid such as hydrochloric acid to obtain alginic acid. In addition, according to the indirect manufacturing method, first, a soluble calcium salt such as chloride is added to form an insoluble calcium salt, and the salt is washed and then treated with an acid to obtain alginic acid.

Therefore, the alginic acid used by this invention can use the alginic acid manufactured or marketed by the well-known method as mentioned above. Preferably the composition of the present invention comprises 0.1 to 20 parts by weight of alginic acid relative to 1 part by weight of sibutramine.

Although Korean Patent Publication No. 10-0627687 mentions that alginic acid has high viscosity, it is difficult to use it in a composition for solubilizing sibutramine free base, but the composition of the present invention has a solubilized composition with sibutramine free base despite the high viscosity of alginic acid. Formation can significantly improve bioavailability and solubility. In addition, compared to the prior art using an organic acid for the solubilization of the drug, alginic acid does not have calories because it does not undergo body metabolism and additionally removes impurities and stool in the intestine to form a solubilizing composition with sibutramine free base. It is the most optimal polymer.

Alginic acid used in the present invention is swelled in the body by mixing with sibutramine free base to form an acidic condition in which the sibutramine free base can be easily dissolved at the periphery, so as not to be affected by the particle size or the manufacturer of the sibutramine free base. It is thought to play a role of dissolving sibutramine free base quickly.

The composition of the present invention is characterized in that the sibutramine free base and alginic acid are homogeneously mixed while maintaining a physically bonded state with each other. This is because the sibutramine solubilization mechanism of the composition of the present invention physically binds alginic acid with sibutramine at the level of micronized or dispersed particles, so that sibutramine is liable to dissolve around the alginic acid bound with the sibutramine particles when the alginic acid swells in the eluate. This is because it is possible to form a diffusion layer, through which sibutramine can be more easily dissolved into the eluate. Thus, this state means that alginic acid and sibutramine are substantially physically contacted, combined, and homogeneously mixed in the composition, in contrast to simply existing alginic acid and sibutramine in a mixed state. Compositions, such as, but not limited to, mixed grinding, dispersion, melting, etc., which are carried out in a solid preparation composition manufacturing process such as mixed grinding, wet granulation, low temperature melting and the like as are well known to those skilled in the art. It can be made by a pharmaceutical method capable of inducing physical binding of the mixed components within.

In a preferred embodiment, the composition of the present invention may further comprise 1 to 20 parts by weight of the hydrophilic polymer relative to 1 part by weight of sibutramine.

As a specific embodiment, the composition used in the present invention is not limited to, for example, polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate One or more hydrophilic polymers selected from the group consisting of nates, low-substituted hydroxypropyl celluloses, and mixtures thereof. As a specific embodiment, in order to prepare the composition of the present invention, the hydrophilic polymer may be dissolved in purified water or 80% ethanol. Preferably, the hydrophilic polymer may be dissolved in purified water or 80% ethanol at a concentration of 50 to 70% by weight.

In another preferred embodiment, the composition of the present invention may further comprise 0.1 to 20 parts by weight of sugar alcohol or water-soluble sugars relative to 1 part by weight of sibutramine.

Sugar alcohols are also called polyols, and those having two or more OH groups in sugar alcohols are called polyols. It is chemically partly a sugar-like structure and another part is alcohol, which has both the properties of sugar and the properties of alcohol, generally called sugar alcohol. Polyols include both sugar alcohols of the monosaccharide family and sugar alcohols of the disaccharide family, and their chemical structure is different from that of sugar. In general, hydrogen is added to have an OH group, which is more chemically and thermodynamically stable than the sugar used in the past, and is recently used as a substitute for sugar.

As a specific embodiment, the composition of the present invention is not limited thereto, for example, maltitol, maltitol syrup, sorbitol, isomalt (palatnit), erythritol, lactitol, inositol, mannitol, ribitol, galactitol, xylitol At least one sugar alcohol selected from the group consisting of maltotritol and mixtures thereof; Or one or more water-soluble sugars selected from the group consisting of white sugar, glucose, fructose and mixtures thereof. Preferably, the sugar alcohol or water-soluble sugars may be used to make a syrup having a concentration of 70% by weight or more. It is preferable to use purified water as a solvent.

In another preferred embodiment, the composition of the present invention may additionally include a solubilizer.

The term "solubilizer" refers to a substance that enhances the solubility of the active ingredient, and the solubilizer used in the present invention is not limited thereto, for example, in diethyleneglycolmonoethyl ester, fatty acid glyceride. At least one selected from the group consisting of oxylated and mixtures thereof. Preferably the solubilizer of the present invention may be included in the composition of the present invention from 0.1 to 10 parts by weight relative to 1 part by weight of sibutramine.

In addition, the composition of the present invention may be prepared by a mixed grinding method, wet granulation method and low temperature melting method and one or a combination thereof.

As a specific embodiment, the formulation composition according to the "mixed grinding method" according to the present invention can be prepared by the following method.

① mixing and grinding 1 part by weight of sibutramine free base and 0.1-20 parts by weight of alginic acid; And

② Mix and mix the pharmaceutically acceptable excipient with the ground material of “①”.

In addition, as another specific embodiment, the formulation composition according to the "wet granulation method" according to the present invention may be prepared by the following method.

① first mixing (grinding) 1 part by weight of sibutramine free base and 0.1-20 parts by weight of alginic acid;

② put the mixture (grinding) of "①" into a high-speed mixer, put crospovidone, and then put the purified water warmed to 50 ~ 90 ℃ in advance to disperse homogeneously;

③ uniformly sizing the mixture of "②" (particle diameter: 0.1mm ~ 100mm); And

④ The step of drying the formulation of "③" at a temperature of 40 ~ 80 ℃.

In addition, as another specific embodiment, the formulation composition according to the "low temperature application method" according to the present invention may be prepared by the following method.

① First, add 0.1 ~ 10 parts by weight of hydrophilic polymer (hydroxypropylmethylcellulose, vinyl acetate vinylpyrrolidone copolymer, maltitol syrup, and white sugar syrup) to 80% ethanol solution or purified water. Dissolving by warming to ~ 80 ℃ (or 0.1 to 10 parts by weight of diethylene glycol monoethyl ester (relative to 1 part by weight of sibutramine free base), if necessary) The concentration of the solution is preferably 50 ~ Prepared at a concentration of 70%;

② melt-mixing 1 part by weight of sibutramine free base into the solution of "①";

③ 0.1 ~ 20 parts by weight of alginic acid in a high speed mixer to put a mixed melt of "②" to disperse homogeneously;

④ mixed homogeneously by adding 0.1-20 parts by weight of crospovidone to the mixture of “③”;

⑤ homogenizing the mixture of "④" (particle diameter: 0.1mm ~ 100mm); And

⑥ Drying the substance of “⑤” at the temperature of 40 ~ 80 ℃.

In addition, as another specific embodiment, another formulation composition according to the “cold dissolution method” may be prepared by the following method.

① add purified water to sugar alcohol (maltitol, sorbitol) to dissolve at a concentration of 50-70% and then warm to 50-90 ℃;

② melt-mixing 1 part by weight of sibutramine free base in the solution of "①";

③ 0.1 ~ 20 parts by weight of alginic acid in a high speed mixer to put a mixed melt of "②" to disperse homogeneously;

④ homogeneously mixing 0.1-20 parts by weight of crospovidone in the mixture of “③”;

⑤ homogenizing the mixture of "④" (particle diameter: 0.1mm ~ 100mm); And

⑥ Drying the substance of “⑤” at the temperature of 40 ~ 80 ℃.

Therefore, the composition of the present invention can prepare a sibutramine formulation showing improved dissolution rate in a variety of simple and reproducible methods that do not go through a separate solid dispersion forming process such as time-consuming and expensive spray drying.

Furthermore, as another aspect of the present invention, the present invention provides a sibutramine pharmaceutical formulation comprising the conventional excipient or adjuvant pharmaceutically acceptable in the sibutramine composition of the present invention, the ratio and nature of which is determined by the selected route of administration. And pharmaceutical practice of the standard.

In treating a patient, the sibutramine pharmaceutical formulation of the present invention may be administered in any form or manner in formulating a bioavailable effective amount. For example, they may be administered orally, ie in the form of pills, tablets, lacquer tablets, coated tablets, granules, hard and soft gelatin capsules and the like. Those skilled in the art of preparing the formulations can readily select the appropriate form and mode of administration depending on the condition of the disease being treated, the stage of the disease and other related situations. Preferably it is a tablet, a capsule, a granule, a fine granule, a powder, a pellet preparation, These can be manufactured by a conventional manufacturing method.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. These examples are intended to illustrate the present invention in detail, and the scope of the present invention is not limited to these examples.

Example

[ Example  1-4 and Comparative example  1 ~ 2]

By mixed grinding method Formulation Composition  Produce

To prepare a composition and the comparative example according to the present invention in the composition shown in Table 2 below.

Drug substance Example 1 (g) Example 2 (g) Example 3 (g) Example 4 (g) Comparative Example 1 (g) Comparative Example 2 (g) Sibutramine freebase One One One One One One Al Long Mountains One 2 3 4 3 4 Crospovidone 3 3 3 3 3 3 Lactose 95 94 93 92 93 92

1) First, mix the sibutramine free base and alginic acid homogeneously and well.

2) The mixture is ground with a mill under the following conditions to obtain a mixed grinding composition.

Machine used: Hammer Mill (Alpine Mill) / RPM: 1000 ~ 3000rpm / Separator: 1.5mm

3) Crospovidone and lactose were added to the pulverized product and mixed homogeneously to obtain a formulation composition.

4) The comparative example is sieved simply by mixing the components of the above table.

[ Example  5 ~ 8]

Wet In granulation  by Formulation Composition  Produce

To prepare a formulation composition according to the invention in the composition shown in Table 3.

Drug substance Example 5 (g) Example 6 (g) Example 7 (g) Example 8 (g) Sibutramine freebase One One One One Al Long Mountains 2 3 2 3 Crospovidone 3 3 - - Sodium starch glycolate - - 3 3 Lactose 94 93 94 93

1) First, sibutramine free base and alginic acid are added to a high speed mixer and mixed under the following conditions.

Machine used: High speed mixer (SPG-5) / Rotating speed: Main wing 200rpm / Mixing time: 30 seconds

2) 15 g of purified water warmed to about 50 ~ 90 ℃ to the mixture of "1) divided into three to five times and dispersed under the following conditions.

Machine used: High speed mixer (SPG-5) / Rotational speed: Main rotor 300rpm, Chopper: 3000rpm / Mixing time: 3 ~ 5 minutes

3) Add crospovidone (or sodium starch glycolate) to it and disperse it under the following conditions.

4) The granules produced in 3) were sieved (1-3 mm) and dried (60 ° C., 4 hours).

5) The dried product was pulverized again under the following conditions using a solid pulverizer to obtain a powdered formulation having a particle size of 200 μm or less.

Machine: Hammer Mill (Alpine Mill) / RPM: 500 ~ 3000rpm / Separator: 1.5mm

6) The dried product was again pulverized under the following conditions using a solid pulverizer, and the particles were made into powder having a particle size of 200 μm or less, and then lactose was added and mixed homogeneously to obtain a formulation composition.

[ Example  9 ~ 14]

By low temperature melting method Formulation Composition  Produce

To prepare a formulation composition according to the invention in the composition shown in Table 4.

Drug substance Example 9 (g) Example 10 (g) Example 11 (g) Example 12 (g) Example 13 (g) Example 14 (g) Sibutramine freebase One One One One One One Al Long Mountains 2 2 2 2 2 2 Vinyl acetate vinyl pyrrolidone copolymer 2 2 - - - - Hydroxypropyl Methyl Cellulose - - 2 2 - - Maltitol - - - - 4 - Sorbitol - - - - - 4 Crospovidone 3 3 3 3 3 3 Diethylene glycol monoethyl ester - One - One - - Lactose 92 92 92 92 90 90

1) First, put alginic acid and crospovidone into a high speed mixer and mix under the following conditions.

Machine used: High speed mixer (SPG-5) / Rotating speed: Main wing 200rpm / Mixing time: 30 seconds

2) Separately, add purified water (or 80% ethanol) to hydroxypropyl methyl cellulose (or vinyl acetate vinylpyrrolidone copolymer), warm to 50-90 ° C. Disperse. Alternatively, maltitol (sorbitol) 70% syrup is heated to 50-90 ° C., and then sibutramine free base is melted and stirred to disperse homogeneously.

3) Disperse the above dispersion liquid under the following conditions while dividing the above-mentioned dispersion liquid into the high-speed mixer two to five times.

Machine used: High speed mixer (SPG-5) / Rotational speed: Main rotor 300rpm, Chopper: 3000rpm / Mixing time: 3 ~ 5 minutes

4) The granules produced in 3) were sieved (1-3 mm) and dried (60 ° C., 4 hours).

5) The dried product was ground again using a solid grinder under the following conditions to make a powder, and then lactose was added and mixed homogeneously to obtain a formulation composition.

Experimental Examples 1-4

By mixed grinding method Formulation Composition Dissolution rate  Comparative test

The dissolution rate of was compared with Examples 1-4, Comparative Examples 1-2, and the commercially available formulation (Reductilcapcel ^TM) containing 10 mg of sibutramine hydrochloride monohydrate. The dissolution test was conducted in accordance with the dissolution test method No. 2 (paddle method) of the general test method of the Korean Pharmacopoeia, the eluent was used for water and pH 1.2 artificial gastric fluid, 60 minutes at the eluent temperature 37 ℃, paddle rotation speed 50rpm 5 mL of the sample was taken at 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes, filtered using a 0.45 μm filter, and the filtrate was analyzed by high-performance liquid chromatography. Examples 1 to 4 and Comparative Examples 1 and 2 were filled in capsules so that the amount of sibutramine free base was 8.37 mg, and the dissolution test was carried out under the same conditions as those of the commercially available 10 mg sibutramine hydrochloride monohydrate. The results analyzed under the above conditions are shown in Table 5 below.

division Eluate 5 minutes (%) 10 minutes (%) 15 minutes (%) 30 minutes (%) 45 minutes (%) 60 minutes (%) Example 1 water 45 57 64 69 70 74 pH 1.2 76 90 92 98 101 101 Example 2 water 49 61 69 71 75 79 pH 1.2 73 89 95 99 102 103 Example 3 water 49 60 72 75 81 81 pH 1.2 76 89 95 101 98 99 Example 4 water 50 68 76 79 85 84 pH 1.2 81 93 96 103 102 103 Commercially available ^{* 1)} water 42 58 68 74 76 77 pH 1.2 71 91 101 101 105 103 Comparative Example 1 water 6 8 14 17 16 18 pH 1.2 25 42 58 62 69 70 Comparative Example 2 water 7 9 15 18 16 17 pH 1.2 28 51 55 67 72 73

* 1) Commercially available formulation: Sibutramine hydrochloride monohydrate 10mg Commercially available formulation (Reductilcapsule ^TM )

As can be seen from the above results, the solubility of the sibutramine free base itself in the pH 1.2 artificial gastric juice showed a similar dissolution rate in both the commercial preparation and the examples of the present invention. It was disintegrated and the dissolution rate was not less than 45 minutes and 85% dissolution rate in water as well as the same or considerably higher dissolution rate than the commercially available formulations.

Experimental Examples 5-8

In wet granulation  by Formulation Composition Dissolution rate  Comparative test

The dissolution test was carried out in the same manner as in the dissolution test method of Experimental Example 1 with Examples 4 to 7 and the commercially available sibutramine hydrochloride monohydrate commercially available. The eluate was carried out only in water since the sibutramine free base was dissolved in artificial gastric juice of pH 1.2. The results analyzed under the above conditions are shown in Table 6 below.

division Eluate 5 minutes (%) 10 minutes (%) 15 minutes (%) 30 minutes (%) 45 minutes (%) 60 minutes (%) Commercially available ^{* 1)} water 42 58 68 74 76 77 Example 9 water 61 80 85 90 95 94 Example 10 water 63 79 86 93 95 96 Example 11 water 69 83 90 96 97 99 Example 12 water 70 86 91 95 94 95 Example 13 water 57 67 75 81 83 84 Example 14 water 53 61 73 79 79 81

* 1) Commercially available formulation: Sibutramine hydrochloride monohydrate 10mg Commercially available formulation (Reductilcapsule ^TM )

Experimental results of Experimental Examples 9 to 14 showed that the dissolution rate or the dissolution rate of the equivalent or more than the commercially available formulations were significantly improved.

As described above, the present invention can significantly improve the dissolution rate and bioavailability of sibutramine free base by forming a formulation composition containing sibutramine free base and alginic acid which are poorly soluble obesity treatment agents. In addition, the present invention can be easily and easily prepared through the conventional solid-liquid solid granules manufacturing process without going through the solid dispersion manufacturing process provided in the prior art, the formulation composition obtained through this is significantly improved Dissolution rate and bioavailability are shown. The solubilization mechanism of the present invention is completed by physically combining alginic acid and sibutramine to form a diffusion layer in which sibutramine is easy to dissolve around alginic acid when the alginic acid swells in the eluate, thereby easily dissolving sibutramine physically bound with alginic acid.

Generally, alginic acid has a high viscosity when it meets water, and thus has a disadvantage of being very difficult to use as a process for forming a conventional solid dispersion. In the present invention, it is possible to provide a pharmaceutical preparation containing the same and to provide a manufacturing process and formulation that can be easily prepared to overcome these disadvantages.

Claims (10)

Sibutramine free base containing 1 part by weight and 0.1 to 20 parts by weight of alginic acid, characterized in that the sibutramine free base and alginic acid are mixed homogeneously while maintaining a physically bonded state, sibutramine free base having improved solubility and bioavailability Formulation composition. The method according to claim 1, 1 to 20 parts by weight of the hydrophilic polymer (relative to 1 part by weight of sibutramine); Or 0.1 to 20 parts by weight of sugar alcohol or water-soluble sugars (relative to 1 part by weight of sibutramine). The method of claim 2, wherein the hydrophilic polymer is polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose acetate succinate, low-substituted hydroxypropyl cellulose, and At least one composition selected from the group consisting of mixtures thereof. According to claim 2, wherein the sugar alcohol is maltitol, maltitol syrup, sorbitol, isomalt (palatnit), erythritol, lactitol, inositol, mannitol, ribitol, galactitol, xylitol, maltotritol and mixtures thereof At least one composition selected from the group consisting of. The composition of claim 2, wherein the water soluble sugar is at least one selected from the group consisting of white sugar, glucose, fructose and mixtures thereof. The composition of claim 1 further comprising a solubilizer. The composition of claim 6, wherein the solubilizer is at least one selected from the group consisting of diethylene glycol monoethyl ester, fatty acid glyceride ethoxylate, and mixtures thereof. The composition according to any one of claims 1 to 6, further comprising a pharmaceutically acceptable excipient or adjuvant. The method for producing the composition of any one of claims 1 to 8, characterized in that one or selected from a mixed grinding method, a wet granulation method and a low temperature melting method is prepared through a complex method. The pharmaceutical formulation of claim 9, wherein the pharmaceutical formulation is a tablet, granule, granule, or powder.

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