KR20080002313A - Pharmaceutical compositions of an oral medication for improved dissolution rate of poorly water soluble sibutramine - Google Patents

Abstract

Oral pharmaceutical compositions comprising sibutramine are provided to improve biocompatibility of sibutramine having no addition salts by improving solubility and dissolution rate of sibutramine having no addition salts which is poorly water-soluble and simply synthesized, so that they are useful for prevention and treatment obesity. An oral pharmaceutical composition for prevention and treatment obesity comprises 1 part by weight of sibutramine, 0.1-20 parts by weight of inorganic acid, 0.1-20 parts by weight of high molecular compound polymer of 1-40cp and 0.1-20 parts by weight of dispersing agent, wherein the inorganic acid is sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid or carbonic acid; the high molecular compound polymer is saccharide, cellulose derivative, gum, protein, polyvinyl derivative, polymethacrylate copolymer or polyethylene derivative; and the dispersing agent is sodium starch glycolate, calcium carboxymethylcellulose, low substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, microcrystalline cellulose, hard anhydrous silicic acid, lactose or starch.

Description

Pharmaceutical compositions of an oral medication for improved dissolution rate of poorly water soluble sibutramine}

1 is a view showing the solubility of sibutramine in Experimental Example 1 according to the present invention.

2 is a view comparing elution degree of sibutramine in Experimental Example 2 according to the present invention.

3 is a view comparing elution degree of sibutramine in Experimental Example 3 according to the present invention.

The present invention relates to a pharmaceutical composition for oral administration containing sibutramine with improved dissolution rate, and more particularly, without using sibutramine hydrochloride monohydrate that undergoes a complex synthetic process for use in the prevention and treatment of comorbidities and pathological conditions associated with obesity. Improving solubility of sibutramine, which does not have addition salts, which have not been used as a poor solubility problem, by preparing a solid dispersion by spray-drying an inorganic acid, a low-viscosity polymer and a dispersant, as an effective drug. And it relates to a sibutramine-containing oral pharmaceutical composition improved dissolution rate than the existing drug.

Sibutramine has the structural formula of N, N-dimethyl-1- [1- (4-chlorophenyl) -cyclobutyl] -3-methylbutylamine, and reabsorption of 5-hydroxytryptamine and noradrenaline in vivo Inhibitors [Buckett, WR, Thomas, PC & Luscombe, G.P. (1988). Prog. Neuro-Psychopharmacol. Biol. Psychiat. 12, 575-584 and Luscombe, G.P., Hopcroft, R.H., Thomas, P.C. & Buckett, W. R. (1989). Neuropharmacology, 28, 129-134. Sibutramine has been reported to reduce weight by the dual action of increasing satiety, reducing food intake, stimulating heat generation and increasing energy consumption [Fantino, M. & Souquet, A.-M. (1995). lnt. J. Obesity, 19, 145; Haliford, J. C. G., Heal, D. J. & Blundell, J. E. (1995). Brit. J. Pharmacol. 114, 387P; and Stricker-Krongrad, A., Souquet, A-M. & Burlet, C. (1995). lnt. J. Obesity, 19, 145; Connoley, l. P., Heal, D. J. & Stock, M J. (1995). Brit. J. Pharmacol. 114, 388P; and Connoley, l P., Frost, l., Heal, D.J. & stock, M.J. (1996). Brit. J. Pharmacol. 117,179P].

Sibutramine is known to be used for the prevention or treatment of obesity (see Korean Patent Publication No. 99-164435). In addition, examples of the use of sibutramine in the treatment of depression are described in British Patent No. 2098602, and examples of the use in the treatment of Parkinson's disease are described in International Patent Publication No. WO 88/06444 to reduce insulin resistance or to reduce glucose tolerance. It is known that it can be used to prevent and treat diseases such as gout, hyperacidemia, hyperlipidemia, osteoarthritis, anxiety disorder, sleep disorder, sexual dysfunction, chronic fatigue syndrome and cholelithiasis [US Patent No. 6174925]. , 55459164, 6187820, 6162831, 6232347, 6355685, 6365631, 6376554, 6376554, 6376552].

However, since sibutramine without such an addition salt is poorly soluble in water, the ratio of sibutramine absorbed into the blood during oral administration is insufficient, and the bioavailability is low during oral administration, making it difficult to handle the pharmaceutical.

British Patent No. 2,098,602 and Korean Patent Publication No. 90-00274 disclose a method for preparing hydrochloride anhydride, which is sibutramine and its pharmaceutically acceptable acid-addition salts, but such sibutramine hydrochloride anhydride is very hygroscopic, It is difficult to keep the content of, and the absorbed moisture may cause hydrolysis and chemical decomposition of the active ingredient and eventually affect the quality of the product, making it difficult to use as an active ingredient of the pharmaceutical composition.

In order to solve this problem, non-hygroscopic sibutramine hydrochloride monohydrate has been developed (British Patent No. 2,184,122 and Korean Patent Publication No. 94-08913). It became. Sibutramine hydrochloride monohydrate is used as an active ingredient in medicines such as Meridia or Reductil, which are known as therapeutic agents for obesity.

As described above, although sibutramine is an excellent active ingredient having a wide range of pharmacological use, pharmaceutical use has been limited due to the low bioavailability due to low solubility.

Conventional methods for increasing the solubility of poorly soluble drugs include chemical and physical modification. Common methods of chemical modification include salt attachment and water soluble prodrugs, and general methods of physical modification include particle size, crystalline modification, crystal polymorph formation, complex formation using surfactants or cyclodextrins, and drug dispersion through dispersants. There is this.

Currently, technology has been developed to transform sibutramine into sibutramine hydrochloride monohydrate, which is an acid-added salt form through chemical modification, but this is caused by the generation of impurities during the chemical modification of raw materials, the hassle of having to go through various synthetic processes, and each synthesis. It is disadvantageous for commercial use because more effort and costs are incurred than necessary, such as securing yield at the stage.

Accordingly, the present inventors have made efforts to solve the above problems, and do not use sibutramine hydrochloride monohydrate that undergoes a complex synthetic process for use in the prevention and treatment of the accompanying disease-related morbidity associated with obesity. To improve the solubility of sibutramine, which does not have additional salts that have not been used as a poor solubility problem by preparing a solid dispersion by spray-drying an inorganic acid, a low viscosity polymer and a dispersant, as an effective drug. It relates to a sibutramine-containing oral pharmaceutical composition with improved dissolution rate.

Accordingly, an object of the present invention is to provide a pharmaceutical composition for oral administration containing sibutramine with improved dissolution rate.

The present invention is characterized by a sibutramine-containing oral pharmaceutical composition with improved dissolution rate containing 0.1 to 20 parts by weight of inorganic acid, 0.1 to 20 parts by weight of low viscosity polymer polymer and 0.1 to 20 parts by weight of dispersant based on 1 part by weight of sibutramine. .

The present invention will be described in more detail as follows.

The present invention does not require a complex synthesis process of the sibutramine hydrochloride monohydrate used for the prevention and treatment of the accompanying disease-related diseases associated with obesity, and contains sibutramine as an effective drug, but by spray-drying inorganic acids, low-viscosity polymers and dispersants The present invention relates to a pharmaceutical composition for oral administration containing sibutramine in which the dissolution rate is improved by preparing a solid dispersion.

First, in the present invention, the inorganic acid serves as a solubilizer in the sibutramine solid dispersion, preferably at least one selected from sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid and carbonic acid, more preferably phosphoric acid is used. . The preferred content of the inorganic acid is suitably 0.1 to 20 parts by weight, more preferably 0.1 to 5 parts by weight based on 1 part by weight of the active ingredient sibutramine. If the content thereof is less than 0.1 parts by weight, there is a problem in that the solubility of sibutramine cannot be improved, and if it exceeds 20 parts by weight, the properties are unsuitable for pharmaceutical use.

In the present invention, the low-viscosity polymer polymer for physically attaching sibutramine and an inorganic acid to be pharmaceutically usable includes sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers and polyethylene derivatives. At least one selected from among them is preferable.

The saccharide is one selected from dextrin, polydextrin, dextran, pectin, pectin derivative, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose and amylopectin Above;

The cellulose derivative is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose sodium, cellulose acetate, cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate At least one selected from nate and hydroxyethylmethylcellulose;

The gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum and arabic gum;

The protein is at least one selected from gelatin, casein and zein,

The polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyrrolidone and polyvinyl acetal diethylamino acetate;

The polymethacrylate copolymer is a poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) copolymer [Eudragit E], poly (methacrylic acid, methyl methacrylate) ) Copolymer [Eudragit L], Poly (Methacrylic Acid, Ethylacrylate) Copolymer [Eudragit L100-55] and Poly (Methacrylic Acid, Methyl Methacrylate) Copolymer [Euradragit S] At least one selected from

The polyethylene derivative may be used at least one selected from polyethylene glycol and polyethylene oxide,

More preferably, hydroxypropylmethylcellulose having a viscosity of 1 to 40 cp, measured at 20 ° C. and 2 w / w% aqueous solution, is used at 0.1 to 20 parts by weight based on 1 part by weight of sibutramine, based on the USP viscosity measurement method. More preferably, hydroxypropylmethylcellulose having a viscosity of 3 to 15 cps measured at 20 ° C. in a 2 w / w% aqueous solution based on the USP viscosity measurement method is used at 0.1 to 5 parts by weight based on 1 part by weight of sibutramine. If the content is less than 0.1 parts by weight, the solid dispersion is not formed, which is not suitable for pharmaceutical use. If the content is more than 20 parts by weight, the release of sibutramine is delayed due to an increase in the viscosity of the polymer. have.

In the present invention, a dispersant should be used to control the release of sibutramine, and preferred dispersants include sodium starch glycolate, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, and microcrystalline cellulose. One or more selected from os, hard silicic anhydride, lactose and starch may be used. Preferably crospovidone is used in an amount of 0.1 to 20 parts by weight based on 1 part by weight of sibutramine, and more preferably 0.1 parts by weight of sibutramine. It is used at 5 parts by weight. If the content thereof is less than 0.1 parts by weight, there is a problem that the release of sibutramine is slow, and if it exceeds 20 parts by weight, there is a problem that does not significantly affect the increase in the release rate of sibutramine.

Sibutramine solid dispersion can be prepared by spray-drying and solid-dispersing the above-described pharmaceutical composition using a solution in which methylene chloride and ethanol are dispersed in a solvent mixed in a 1: 1 to 5 weight ratio range, but are not limited thereto. Does not.

Sibutramine solid dispersion of the present invention prepared by the above method and a pharmaceutically acceptable carrier, the treatment of the accompanying disease pathology associated with obesity in the form of tablets, soft capsules, hard capsules, pills, granules or powders And prophylactic pharmaceutical formulations can be prepared.

At this time, the pharmaceutically acceptable carrier may be used starch, microcrystalline cellulose, lactose, glucose, mannitol, alginate, light silicic anhydride, alkaline earth metal salt, clay, polyethylene glycol and dicalcium phosphate. As binders, starch, microcrystalline cellulose, highly dispersible silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, natural gums, synthetic gums, copovidone and gelatin can be used. Can be. Starch or modified starch such as sodium starch glycolate, corn starch, potato starch or pregelatinized starch as a disintegrating agent, clays such as bentonite, montmorillonite, veegum, microcrystalline cellulose, hydroxypropyl cellulose or carboxy Celluloses such as methyl cellulose, algins such as sodium alginate or alginic acid, cross-linked celluloses such as croscarmellose sodium, gums such as guar gum and xanthan gum, and crosslinks such as crospovidone A polymer and boiling agents, such as sodium bicarbonate and a citric acid, can be mixed and used. Examples of lubricants include talc, hard silicic anhydride, magnesium stearate and alkaline earth metal stearate-type calcium, zinc, lauryl sulfate, hydrogenated vegetable oils, sodium benzoate, sodium stearyl fumarate, glyceryl monostearate and polyethylene glycol 4000. In addition to the above, pharmaceutically acceptable additives may be selected and used as various additives selected from colorants and fragrances. Such a pharmaceutically acceptable carrier is preferably used in an amount of 10 to 50 parts by weight based on 1 part by weight of sibutramine.

The above-mentioned oral sibutramine preparations use inorganic acids in the preparation of sibutramine solid dispersions, and act as carriers of sibutramine in solid dispersions in which sibutramine is evenly distributed to increase solubility and increase drug release rate to increase bioavailability. I can let you.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .

Example 1 Preparation of Sibutramine Solid Dispersion

After dissolving sibutramine and hydroxypropylmethylcellulose (Pharmacoat 603, ShinEtsu, Japan) and phosphoric acid in 2000 mg of a mixed solvent of methylene chloride: ethanol (1: 1, w / w) as shown in the following Table 1 Crospovidone was dispersed in the mixed solvent in this solution. The sibutramine solution was spray dried using a spray dryer (Eyela, SD1000, Japan) to prepare a sibutramine solid dispersion, and the prepared solid dispersion was a white powder.

Example 2 Preparation of Capsules Containing Sibutramine 8.37 mg

After dissolving sibutramine and hydroxypropylmethylcellulose (Pharmacoat 603, ShinEtsu, Japan) and phosphoric acid in 335 mg of a mixed solvent of methylene chloride: ethanol (1: 1, w / w) as shown in the following Table 1 Crospovidone was dispersed in the mixed solvent in this solution. The sibutramine solution was spray dried using a spray dryer (Eyela, SD1000, Japan) to prepare a sibutramine solid dispersion, and the prepared solid dispersion was a white powder.

The obtained sibutramine solid dispersion, microcrystalline cellulose, lactose, and sodium starch glycolate were sieved through a No. 35 sieve and mixed using a mixer. Then, the hard silicic anhydride and magnesium stearate were sieved through a No. 35 sieve and mixed using a mixer. It was. The resulting mixture was filled into gelatin capsules containing 8.37 mg of sibutramine per capsule.

Example 3: Preparation of Capsules Containing 8.37 mg Sibutramine

Dissolve sibutramine and hydroxypropylmethylcellulose (E15 premium LA EP, Colorcon, USA) and phosphoric acid in 335 mg of a mixed solvent of methylene chloride: ethanol (1: 1, w / w) as shown in the following Table 1. After this, crospovidone was dispersed in the mixed solvent in this solution. The sibutramine solution was spray dried using a spray dryer (Eyela, SD1000, Japan) to prepare a sibutramine solid dispersion, and the prepared solid dispersion was a white powder.

The obtained sibutramine solid dispersion, microcrystalline cellulose, lactose, and sodium starch glycolate were sieved through a No. 35 sieve and mixed using a mixer. Then, the hard silicic anhydride and magnesium stearate were sieved through a No. 35 sieve and mixed using a mixer. It was. The resulting mixture was filled into gelatin capsules containing 8.37 mg of sibutramine per capsule.

Example 4 Preparation of Capsules Containing 8.37 mg Sibutramine

Dissolve sibutramine, hydroxypropylmethylcellulose (E15 premium LA EP, Colorcon, USA) and sulfuric acid in 335 mg of a mixed solvent of methylene chloride: ethanol (1: 1, w / w) as shown in the following Table 1. After this, crospovidone was dispersed in the mixed solvent in this solution. The sibutramine solution was spray dried using a spray dryer (Eyela, SD1000, Japan) to prepare a sibutramine solid dispersion, and the prepared solid dispersion was a white powder.

The obtained sibutramine solid dispersion, microcrystalline cellulose, lactose, and sodium starch glycolate were sieved through a No. 35 sieve and mixed using a mixer. Then, the hard silicic anhydride and magnesium stearate were sieved through a No. 35 sieve and mixed using a mixer. It was. The resulting mixture was filled into gelatin capsules containing 8.37 mg of sibutramine per capsule.

Example 5 Preparation of Capsules Containing Sibutramine 8.37 mg

As shown in Table 1, sibutramine, polyvinylpyrrolidone, and phosphoric acid were dissolved in 335 mg of a mixed solvent of methylene chloride: ethanol (1: 1, w / w), and then croscarmellose sodium was added to this solution. It was dispersed in a mixed solvent. The sibutramine solution was spray dried using a spray dryer (Eyela, SD1000, Japan) to prepare a sibutramine solid dispersion, and the prepared solid dispersion was a white powder.

The obtained sibutramine solid dispersion, microcrystalline cellulose, lactose and sodium starch glycolate were sieved through a No. 35 sieve and mixed using a mixer. Magnesium stearate was sieved through a No. 35 sieve and then mixed using a mixer. The resulting mixture was filled into gelatin capsules containing 8.37 mg of sibutramine per capsule.

Example 6 Preparation of Capsules Containing Sibutramine 8.37 mg

After dissolving sibutramine and hydroxypropylmethylcellulose (Pharmacoat 603, ShinEtsu, Japan) and phosphoric acid in 335 mg of a mixed solvent of methylene chloride: ethanol (1: 1, w / w) as shown in the following Table 1 In this solution, sodium starch glycolate was dispersed in a mixed solvent. The sibutramine solution was spray dried using a spray dryer (Eyela, SD1000, Japan) to prepare a sibutramine solid dispersion, and the prepared solid dispersion was a white powder.

The obtained sibutramine solid dispersion, microcrystalline cellulose, lactose and sodium starch glycolate were sieved through a No. 35 sieve and mixed using a mixer. Magnesium stearate was sieved through a No. 35 sieve and then mixed using a mixer. The resulting mixture was filled into gelatin capsules containing 8.37 mg of sibutramine per capsule.

Comparative example  One

It was prepared in the same manner as in Example 1, except that sibutramine solid dispersion was prepared without adding phosphoric acid, which is an inorganic acid.

Comparative Example 2

A sibutramine solid dispersion and a sibutramine oral preparation were prepared in the same manner as in Example 2, except that the hydroxypropylmethylcellulose (E50 premium LA EP, Colorcon, USA) having a viscosity of 50 cp was used.

Test Example 1: Solubility Test

The solubility patterns of Example 1, Comparative Example 1, and sibutramine raw materials were compared.

In the solubility test, 500 mL of purified water was added to the dissolution tester, and the sample was added at an amount corresponding to 150 mg of sibutramine while maintaining the solution at 37 ° C., and the solubility was measured over time while stirring at a rate of 50 revolutions per minute. At each time point, 5 mL of the solution was taken in a tube coated with silicon, filtered through a filter having a pore size of 0.2 μm, and analyzed by HPLC.

Solubility test results are shown in FIG. The composition of the sibutramine solid dispersion of Example 1 showed a solubility of 0.25 mg / mL or more, but the solubility of the sibutramine solid dispersion and the sibutramine raw material of Comparative Example 1 was 0.002 mg / mL or less and 0.001 mg / mL or less, respectively. .

Test Example 2 Dissolution Test (Influence of Viscosity of Polymer Polymer)

The dissolution patterns of Examples 2 and 3 and Comparative Example 2 were compared.

The dissolution test was carried out according to the Pharmacopoeia Dissolution Test Method 2 (Pattle Method). First, add 900 mL of Disintegration Test No. 1 (pH 1.2) in the Pharmacopoeia Disintegration Test Method, add the sample corresponding to 8.37 mg of sibutramine while maintaining the temperature at 37 ° C, and stir at a rate of 50 revolutions per minute. Dissolution rate was measured. At each time point, 5 mL of the solution was taken in a tube coated with silicon, filtered through a filter having a pore size of 0.2 μm, and analyzed by HPLC.

The results are shown in FIG. The viscosity of each of the polymers used was changed to 3, 15 and 50 cps in the order of Example 2, 3 and Comparative Example 2. Sibutramine oral preparations of Examples 2 and 3 and Comparative Example 2 all showed a relatively high dissolution rate, but in particular, sibutramine prepared using a 3, 15 cp polymer compared to a polymer having a viscosity of 50 cp. Solid dispersions (Examples 2 and 3) showed higher dissolution rates.

Test Example 3: Comparative Dissolution Test

The elution pattern of Example 2 and the commercially available reductyl preparation was compared.

One capsule of the formulation according to Example 2 (8.37 mg of sibutramine) and one capsule of commercially available reductyl capsule (8.37 mg of sibutramine) were tested for comparative dissolution according to the Pharmacologic Dissolution Test Method 2 (paddle method). Other experimental methods were the same as in Experimental Example 1, but the second solution (pH 6.8) of the disintegration test was used in the KEPCO disintegration test.

The results are shown in FIG. The commercial formulation showed a dissolution rate of about 40% after 1 hour, but the dissolution rate after about 1 hour for the capsule of the present invention was about 60%.

As described above, the composition of the present invention increases the solubility of poorly soluble sibutramine, not only can greatly increase the bioavailability, but also is suitable for the preparation of oral preparations, compared to the process for preparing sibutramine hydrochloride monohydrate. It can be expected to make a great contribution both economically and therapeutically since it can be produced in this way.

Claims (12)

A dissolution rate-enhanced sibutramine-containing oral pharmaceutical composition comprising 0.1 to 20 parts by weight of an inorganic acid, 0.1 to 20 parts by weight of a polymer polymer of 1 to 40 cp, and 0.1 to 20 parts by weight of a dispersant, based on 1 part by weight of sibutramine. The composition of claim 1, wherein the inorganic acid is at least one selected from sulfuric acid, hydrochloric acid, nitric acid, phosphoric acid, and carbonic acid. The composition of claim 1, wherein the polymer is at least one selected from sugars, cellulose derivatives, gums, proteins, polyvinyl derivatives, polymethacrylate copolymers, and polyethylene derivatives. 4. The saccharide according to claim 3, wherein the saccharide is dextrin, polydextrin, dextran, pectin, pectin derivative, alginate, polygalacturonic acid, xylan, arabinoxylan, arabinogalactan, starch, hydroxypropyl starch, amylose And at least one selected from amylopectin. According to claim 3, wherein the cellulose derivative is hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose sodium, cellulose acetate, cellulose acetate phthalate, hydride And at least one selected from hydroxypropyl methylcellulose acetate succinate and hydroxyethylmethylcellulose. The composition of claim 3, wherein the gum is at least one selected from guar gum, locust bean gum, tragacanta, carrageenan, acacia gum, and gum arabic. The composition of claim 3, wherein the protein is at least one selected from gelatin, casein and zein. The composition according to claim 3, wherein the polyvinyl derivative is at least one selected from polyvinyl alcohol, polyvinyl pyrrolidone and polyvinyl acetal diethylamino acetate. The method of claim 3, wherein the polymethacrylate copolymer is a poly (butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) copolymer, poly (methacrylic acid, methyl methacrylate) A) a copolymer, a poly (methacrylic acid, ethyl acrylate) copolymer, and a poly (methacrylic acid, methyl methacrylate) copolymer. The composition of claim 3, wherein the polyethylene derivative is at least one selected from polyethylene glycol and polyethylene oxide. The dispersant according to claim 1, wherein the dispersant is one selected from sodium starch glycolate, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, microcrystalline cellulose, hard silicic anhydride, lactose and starch. The composition characterized by the above. The composition of claim 1, wherein the composition further comprises 10 to 50 parts by weight based on 1 part by weight of the pharmaceutically acceptable sibutramine.

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