KR19980038359A - Preparation of Biphenyl Dimethyl Dicarboxylate (DDB) Formulation with Improved Dissolution Rate - Google Patents

Abstract

The present invention relates to a solubilization method of biphenyl dimethyl dicarboxylate, and more particularly, to dissolution rate of the biphenyl dimethyl dicarboxylate to the carrier to produce a solid dispersion by increasing the dissolution rate and bioavailability A method for the preparation of improved biphenyldimethyldicarboxylate formulations.

Description

Preparation of Biphenyl Dimethyl Dicarboxylate (DDB) Formulation with Improved Dissolution Rate

1 is a graph showing the solubility in water of the DDB formulations of Examples 1-4 and Comparative Examples 1-3.

FIG. 2 is a graph showing the dissolution rate of water in the DDB formulations of Examples 1 and 4 and Comparative Examples 2 and 3. FIG.

3 is a graph showing the dissolution rate of water in the formulations of DDB of Examples 1-4 and Comparative Examples 1 and 2;

The present invention relates to a solubilization method of biphenyldimethyldicarboxylate, and more specifically, to dissolution rate of preparing a granular solid dispersion by spray assembly coating of biphenyldimethyldicarboxylate on a carrier, The present invention relates to a method for preparing a biphenyldimethyldicarboxylate formulation having improved utilization.

Biphenyl dimethyl dicarboxylate (DDB) is a synthetic derivative of Schizandra C. Schizandra C. It has a function of lowering serum transaminase, particularly serum glutaminepyruvate transaminase (SGPT). Accordingly, DDB is known to be a very useful liver disease treatment for treating these diseases by lowering the elevated SGPT of patients suffering from acute and chronic hepatitis, chronic liver disease and hepatotoxicity due to drug toxicity.

However, DDB is a poorly soluble drug having a very low solubility in water, and has a very low elution so that the bioavailability is about 20-30%.

Thus, a method of preparing powdered capsules by mixing polysorbate as an absorption accelerator and polyethylene glycol 6000 as a soluble carrier by melting and solvent method in order to improve the solubility in aqueous solution of DDB is mixed with DDB. In the case of -16098, hydroxypropylmethylcellulose, methylcellulose, aminomethacrylate, and the like have been disclosed in Japanese Patent Application Laid-Open No. 02149518, in which tablets or capsules are powdered in DDB and a crusher to increase solubility.

However, the method disclosed in Korean Patent Publication No. 93-16098 has a small increase in solubility, and the method disclosed in Japanese Patent Publication No. 02149518 uses 5 times more amount of hydroxypropylmethylcellulose than DDB, and the dissolution rate of DDB is It depends on this grinder and there is a fear that heavy metal may be mixed due to the wear of the grinder during use of the grinder.

Polyvinylpyrrolidone, N-vinylpyrrolidone and vinyl acetate copolymers were used for the continuous release of the poorly soluble drug nifedipine, and the mixed solution of nifedipine and these copolymers was sucrose, mannose, lactose or 2 A method of coating on a water soluble carrier which is a mixture of paper has been disclosed in International Patent Application No. 94-702420.

This method has the limitation that the water soluble carrier must be insoluble in the solvent and must use a mixture of polyvinylpyrrolidone, N-vinylpyrrolidone and vinyl acetate copolymers for the sustained formulation.

In this regard, the present inventors studied a method for preparing a DDB formulation that solves the problems of the conventional DDB formulation.

It is an object of the present invention to provide a method for preparing a DDB formulation having increased dissolution rate and improved bioavailability.

The present invention provides a method for preparing a granular solid dispersion by dissolving a water-soluble polymer and DDB in a solvent and then spray-coating and coating the carrier.

Water-soluble polymers used in the present invention include pharmaceutically acceptable polyvinylpyrrolidone (molecular weight 20,000 to 1,200,000), cross polyvinylpyrrolidone, lactose, sorbitol, mannitol, sucrose, polyethylene glycol (molecular weight 4,000-6,000), The hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methyl cellulose, phthalic acid hydroxypropyl methyl cellulose, methyl cellulose, polymethacrylate may be selected one or two or more. In this case, the water-soluble polymer may be used in an amount of 1 times or more with respect to DDB, preferably 2 to 10 times by weight.

In the present invention, in addition to the water-soluble polymer and DDB, the surfactant may be further suspended in a solvent, and then spray-coated and coated.

The surfactant used herein may be selected from pharmaceutically acceptable egg yolk lecithin, soybean lecithin, polysorbate, polyethylene glycol 2,000 to 20,000, floxamer, or one or two or more. In this case, the surfactant may be used in an amount of 0.5 times or more relative to DDB.

The carrier used in the present invention is a water-soluble or insoluble substance, microcrystalline cellulose, crystalline cellulose, starch, granular white sugar, lactose, dextrin, sucrose, sorbitol, mannitol, polyethylene glycol (molecular weight 4,000 to 6,000), low-substituted hydroxy It may be selected from propyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, phthalic acid hydroxypropyl methyl cellulose, methyl cellulose, poly methacrylate, one or two or more, preferably microcrystalline of 200 ㎛ particle size or less Cellulose. At this time, the carrier may be used in more than 1 times by weight relative to DDB. In addition, the carrier is used in 50 to 99% by weight relative to the total amount of the DDB composition.

To the solid dispersion of the present invention, disintegrating agents such as sodium starch glyconate and sodium croscarmellose, and lubricants such as talc, potassium stearate and magnesium stearate can be added to the solid dispersion of the present invention.

In the solvent used in the present invention, an organic solvent such as alcohol, methylene chloride, chloroform, acetone, or water may be used alone or in combination of two or more thereof.

In the spray assembly coating method of the present invention, a fluidized bed assembly coater may be used, and the spray method may be sprayed from the upper, lower or side surfaces of the fluidized bed. It is well known that a fluidized bed precoated coating machine is used for the granulation or coating of powders, but it has not been used as a method of preparing a solid dispersion. It is used.

The solid dispersion of the present invention may be formulated into tablets, capsules, granules, powders by mixing with conventionally used excipients and then pulverizing, filling or tableting.

The solid dispersion of the present invention has excellent dissolution rate and high bioavailability.

In addition, the DDB manufacturing method of the present invention is a simple manufacturing process, takes less time and has excellent reproducibility, and the solid dispersion and granulation are simultaneously performed in one process. Capsules, granules or powders can be formulated in various ways.

The present invention will be described in more detail by the following examples and experimental examples, but the present invention is not limited thereto.

Example 1 Preparation of Powder

26.25 g of DDB was dissolved in a mixture of 245 ml of methylene chloride and 105 ml of ethanol and polyvinylpyrrolidone was added to dissolve by 2 times (52.5 g) relative to DDB. Meanwhile, 502.25 g of microcrystalline cellulose is added to a fluidized bed assembly coater, and heated by hot air, followed by spraying at a rate of 10 g per minute with the above liquid while maintaining the process temperature at 45 ° C. to prepare particles and at the same time prepare a solid dispersion.

Example 2 Preparation of Tablets

26.25 g of DDB was dissolved in a mixture of 245 ml of methylene chloride and 105 ml of ethanol and polyvinylpyrrolidone was added to dissolve by 2 times (52.5 g) relative to DDB. Meanwhile, 502.25 g of microcrystalline cellulose is added to a fluidized bed assembly coater, and heated by applying hot air, followed by spraying at a rate of 10 g / min with the solution while maintaining the process temperature at 45 ° C. to form particles and simultaneously coating a solid dispersion. To the granules prepared as described above, 40 g of sodium starch glycolate as a disintegrating agent and 8 g of stearinine magnesium as a lubricant are added and tableted with a tableting machine to form a tablet.

Example 3: Manufacturing Method of Capsule

26.25 g of DDB was dissolved in a mixture of 245 ml of methylene chloride and 105 ml of ethanol and polyvinylpyrrolidone was added to dissolve by 2 times (52.5 g) relative to DDB. Meanwhile, 502.25 g of microcrystalline cellulose, 40 g of sodium starch glycolate, and 8 g of magnesium stearate as a lubricant are mixed in a fluidized bed granulation coating machine, and heated by applying hot air, followed by spraying at a rate of 10 g per minute while maintaining the process temperature at 45 ° C. To form particles and to coat the solid dispersion. The granules prepared as described above are filled into capsules as powders.

Example 4 Preparation of Tablets

26.25 g of DDB was dissolved in a mixed solution of 245 ml of methylene chloride and 105 ml of ethanol, and polyvinylpyrrolidone was 1 weight (26.3 g) relative to DDB, and 1 wt. g) to dissolve. Meanwhile, 502.25 g of microcrystalline cellulose is added to a fluidized bed assembly coater, and heated by hot air, followed by spraying at a rate of 10 g per minute with the liquid while maintaining the process temperature at 45 ° C. to form particles and simultaneously coating a solid dispersion. 40 g of sodium starch glycolate as a disintegrating agent and 8 g of magnesium stearate as a lubricant are mixed and compressed into the granules prepared as described above.

Comparative Example 1-3

Comparative Example 1 is a commercially available capsule (dibicapel, Daewoong Pharm) which is a pill made by mixing DDB, Tween 80 and polyethylene glycol according to Japanese Patent Publication No. 02149518, and Comparative Example 2 is commercially available. It is a refined tablet (Omitan tablet, Ajou Chemical), and Comparative Example 3 is a solid dispersion in which 2 wt times of polyvinylpyrrolidone with respect to DDB is dissolved in chloroform and the organic solvent is completely removed by a conventional solvent evaporation method. to be.

Experimental Example 1: Solubility Test

The formulations of Example 1 and Comparative Examples 1-3 were weighed in an equivalent amount of 25 mg as DDB, and then dissolved in 500 ml of distilled water, artificial gastric juice, or artificial intestinal fluid, shaken at 37 ± 1 ° C., and dissolved in the eluate after 30 minutes and 1 hour. Solubility was measured by quantifying the amount of DDB prepared. At this time, the artificial gastric juice is a solution prepared by adding 1 g of water to 2 g of sodium chloride and 7 ml of hydrochloric acid (fold 1.2), and the artificial intestinal fluid is mixed with 250 ml of 0.2 M potassium dihydrogen phosphate solution and 118 ml of 0.2N sodium hydroxide solution. Solution (ph 6.8).

The results are as shown in Tables 1, 2, 3 and FIG. 1 below.

Cold solubility in water Formulation Solubility (µg / mL) Comparative Example 1 3.64 ± 0.21 Comparative Example 2 0.89 ± 0.37 Comparative Example 3 8.97 ± 0.28 Example 1 13.98 ± 0.54

Solubility in artificial gastric juice Formulation Solubility (µg / mL) Comparative Example 1 2.98 ± 0.11 Comparative Example 2 0.82 ± 0.37 Comparative Example 3 7.27 ± 0.19 Example 1 12.21 ± 0.21

Solubility in Artificial Serous Formulation Solubility (µg / mL) Comparative Example 1 3.82 ± 0.36 Comparative Example 2 0.92 ± 0.36 Comparative Example 3 9.52 ± 0.27 Example 1 14.33 ± 0.42

According to Tables 1-3, the DDB formulation of Example 1 was found to significantly increase the solubility of DDB in water, artificial gastric juice and artificial intestinal fluid as compared to the DDB formulation of Comparative Examples 1-3. In addition, according to Figure 1, the DDB formulations of Examples 1-4 were found to significantly increase the solubility in water than the DDB formulations of Comparative Examples 1-3.

Experimental Example 2: Dissolution Rate Inspection

15 mg of the equivalent of Example 1-4 and Comparative Example 1-3 as a DDB was weighed into 900 ml of distilled water or a physiological buffer solution, and the dissolution test method of the 6th Amendment of Korean Pharmacopoeia Experimental method was applied to the paddle method. 5 ml of the eluate was taken with time, and 2 ml of the eluate was mixed in the same amount of methanol, and the dissolution rate was measured by measuring the concentration of DDB in the eluate using ultraviolet absorption spectrophotometry.

The results are as shown in FIGS. 2 and 3.

According to FIG. 2, the highest dissolution rate of the formulation of Example 1 was 6-7 times higher than that of Comparative Example 2, and 1.5-1.8 times higher than that of Comparative Example 3.

According to FIG. 3, the dissolution rate of the formulations of Examples 1-4 was significantly higher than those of Comparative Examples 1 and 2, and the time to reach the highest dissolution ratio was also eluted very rapidly within 30 minutes.

Claims (11)

A method for producing a granular solid dispersion obtained by dissolving biphenyldimethyldicarboxylate and a water-soluble polymer in a solvent, and then spray-coating and coating the solution on a carrier. The method of claim 1, wherein the water-soluble polymer is a pharmaceutically acceptable polyvinylpyrrolidone, cross-polyvinylpyrrolidone, lactose, sorbitol, mannitol, sucrose, polyethylene glycol, hydroxypropyl cellulose, low-substituted hydroxypropyl A method for producing granular solid dispersion, characterized in that one or two or more selected from cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, and polymethacrylate. The method for producing granular solid dispersion according to claim 1 or 2, wherein the water-soluble polymer is used at a weight ratio of 1 times or more relative to biphenyldimethyldicarboxylate. The method for producing a granular solid dispersion according to claim 1, wherein the surfactant is further suspended in a solvent. The granular solid dispersion according to claim 4, wherein the surfactant is one or more selected from pharmaceutically acceptable egg yolk lecithin, soy lecithin, polysorbate, polyethylene glycol 2,000-20,000, and floxamer. Manufacturing method. The method for producing granular solid dispersion according to claim 4 or 5, wherein the surfactant is used at a weight ratio of 0.5 times or more relative to biphenyldimethyldicarboxylate. The method for producing granular solid dispersion according to claim 1, wherein the solvent is used alone or in combination with an organic solvent or water. The method for preparing granular solid dispersion according to claim 1, wherein the carrier is selected from one or two or more among microcrystalline cellulose, crystalline cellulose, starch, granular white sugar, lactose, dextrin, sucrose and polymethacrylate. . The method for producing granular solid dispersion according to claim 1 or 8, wherein the carrier is used in a weight ratio of 1 times or more relative to biphenyldimethyldicarboxylate. The method according to claim 1, wherein the spray assembly coating method is sprayed on the upper, lower, and side surfaces of the fluidized bed in the fluidized bed assembly coating machine. A preparation for oral administration of tablets, capsules, granules, powders and the like containing a granular solid dispersion obtained by dissolving biphenyldimethyldicarboxylate and a water-soluble polymer in a solvent and then spray-coating this solution on a carrier.