KR100222306B1 - A fast effective nilbadipine preparation and the preparation process thereof - Google Patents

Abstract

The present invention comprises dissolving 1 part by weight of a Nilfadin pin in an appropriate amount of an organic solvent capable of dissolving a poorly soluble drug at a temperature of not higher than the boiling point, The present invention relates to a method for producing a solid formulation of Neil-Bodipin fast-acting solid, which comprises dispersing the above-mentioned solid dispersion in a solubilized polymer composed of 10 parts by weight of methyl cellulose, polyvinyl pyrrolidone or a mixture thereof to prepare a solid dispersion and drying it.

Description

Neil-Bodipine fast-acting solid preparation and its preparation method

The present invention relates to a composition of a solubilizer for a non-water-soluble Neil-Bodipine fast-acting solid preparation and a process for preparing the same.

Nealbodipine is low in solubility in water when administered orally and has low blood transfusability and thus low bioavailability. Therefore, the solubilization of neublastin is indispensable in terms of improvement of bioavailability. It is necessary to reduce the dosage for a large dose of drug and to reduce the adverse effects due to the drug while having equivalent effect, or for a drug having a low bioavailability The use of various manufacturing methods and solubilizing agents has been studied for the purpose of designing agents exhibiting sufficient pharmaceutical efficacy.

BACKGROUND ART Inclusion compounds, surfactants, polymeric substances having solubilization effect, and the like are generally used as solubilizing methods used for preparation of granules, capsules and tablets while increasing the solubility of poorly soluble drugs. Among them, formation of a complex using an inclusion compound and a surfactant is troublesome in the production process, and there is a great difference in the solubility of the product depending on the production method. Examples of the use of a polymer material having a solubilizing effect include a method in which a polymer material is dissolved and dissolved in a suitable organic solvent such as a pellet to prepare a pellet type, a method in which an organic solvent solution of a polymer material and a pellet is dried under reduced pressure to evaporate the organic solvent, A method of producing a common mixture by eutecticizing a polymer substance and a sugar solution at a temperature below the melting point, and then cooling the resultant mixture to produce a common mixture.

Korean Patent Publication No. 91-3559 describes a process in which HPMC is dissolved in a suitable organic solvent such as neil-bodipine and then dried under reduced pressure to remove the organic solvent. However, this process requires a separate vacuum drying apparatus and consumes an excessive amount of organic solvent. Korean Patent Publication No. 93-16091 describes a process for obtaining a water-insoluble drug and a water-insoluble polymer at a temperature below the melting point of the drug to obtain a solid dispersion liquid. This process, however, Or more, a warming reaction is required for 1 hour or more and there is room for improvement. In addition, the method of producing pellet type has a disadvantage in that the processing time is prolonged because the nuclei must be coated with a certain amount or more.

An object of the present invention is to dissolve 1 part by weight of the poorly soluble drug Nilbodipine in an appropriate amount of an organic solvent capable of dissolving at a temperature below the boiling point, Soluble polymer composed of 10 parts by weight of methylcellulose, polyvinylpyrrolidone or a mixture thereof to prepare a solid dispersion, and drying the solid dispersion. The present invention also provides a method for producing a rapid acting solid preparation of neublastin.

More specifically, the present invention solves the problem of poor solubility by using methyl cellulose and polyvinyl pyrrolidone having a low viscosity in an aqueous solution, either alone or in combination. The insoluble drug prepared from a solid preparation is dissolved in a usual granulating method As a granule and a tablet according to the present invention. In addition, in order to increase the solubility of the poorly soluble drug, a polymer material having a solubilizing effect is used, and a granule is manufactured by a usual manufacturing method without a manufacturing process and a separate solid dispersion, Characterized by producing a fast acting solid preparation of the drug.

Hereinafter, the present invention will be described in detail.

The solid preparation of the present invention is prepared by dissolving an insoluble drug in an organic solvent heated to a suitable temperature below the boiling point and adding this solution to a mixture of solubilized polymers containing methyl cellulose and polyvinyl pyrrolidone alone or in a mixture. By heating the organic solvent to be used at this time, the amount of the organic solvent to be used can be significantly reduced compared to when the organic solvent is dissolved at room temperature. For example, the nil-bodipine is dissolved in an organic solvent which has been heated to a low temperature, and the obtained solution is added to a uniform dispersion of solubilized polymers such as methyl cellulose and polyvinyl pyrrolidone alone or a mixture thereof and other diluents. The granules are prepared by a conventional wet granulation method, and the organic solvent is evaporated in a warm drier. The obtained granules are activated with magnesium stearate to form fine granules or capsules filled with the granules, or tablets which are tableted with a certain weight.

Suitable examples of the aforementioned solvents include alcohols (e.g., methanol, ethanol, etc.), acetone, chloroform, methylene chloride, acetic acid ethyl acetate and the like. There is no limitation to the organic solvent used in the present process, and any organic solvent which volatilizes in a drier in which the poorly soluble drug used can be dissolved can be used.

Methylcellulose, which is swollen in water and slowly dispersed in water, has been used as an emulsifying agent or a donating agent for oral liquids, and methyl cellulose having a low viscosity has been used as an emulsifying agent or a donating agent for orally administered liquids. The methylcellulose having a high viscosity is a cream or gel thickener . Methylcellulose is almost insoluble in hot water and swells in cold water to dissolve slowly to form a clear viscous solution and has been generally used as a base for sustained-release preparations. However, the low-viscosity grade methylcellulose used in the present invention 37 ± 0.5 It was swollen and dissolved rapidly in the acidic artificial gastric juice of the present invention and was found to have an excellent solubilization effect, thus completing the present invention.

Polyvinylpyrrolidone has been widely used as a binder in a wet granulation method or as a film coating agent since it has been widely used in the formulation of solid preparations. It is known that polyvinylpyrrolidone, which is very soluble in water and alcohols and has low viscosity of low molecular weight, has a solubilizing effect on insoluble drugs.

The amount of methylcellulose and polyvinylpyrrolidone to be used is not limited, but it is preferable to use 1-10 times of the poorly soluble drug. If the amount of methyl cellulose and polyvinylpyrrolidone used is less than 1 time (weight ratio), the solubilization effect may not be sufficient. If the amount of methyl cellulose and polyvinylpyrrolidone is 10 times or more that of the poorly soluble drug, have.

When methylcellulose and polyvinylpyrrolidone were used singly or in combination, the higher the ratio of methylcellulose was, the faster the disintegration and the initial dissolution rate were, and the higher the percentage of polyvinylpyrrolidone was, the slower the initial dissolution rate was. In the case of the mixture, the ratio of methylcellulose to polyvinylpyrrolidone is preferably used in a ratio of 1: 1 to 5: 1.

If necessary, the composition of the solid preparation of the present invention produced by the above process may contain a coloring agent, a diluent (e.g., mannitol, sugar, lactose, starch, microcrystalline cellulose, low-substituted hydroxypropylcellulose, (E.g., magnesium stearate, silicon dioxide, talc, etc.). It is also possible to film-coat the solid preparation prepared above so as to enhance the appearance or increase the user's preference and stability.

Hereinafter, in order to demonstrate the effectiveness of the fast-acting solid preparation of the present invention, examples will be described in more detail.

[Example 1]

[Preparation of tablets]

8.0 g of Neil body pin was dissolved in 60 70 , Dissolved in 140 ml of anhydrous ethanol, sufficiently dispersed in an upright type granulator containing a mixture of 24.0 g of methylcellulose (Methocel A15LV), 187.0 g of lactose and 120.0 g of low substituted hydroxypropylcellulose, Lt; / RTI > in a circulating drier adjusted to < RTI ID =

The dried product is prepared by a conventional method and the fine granules activated with magnesium stearate are kneaded in a unit of 170 mg to obtain a preparation (yield: 95 98 ).

[Example 2]

[Preparation of tablets]

The formulation is prepared in the same manner as in Example 1 by the following prescription.

[Example 3]

[Preparation of tablets]

The formulation is prepared in the same manner as in Example 1 by the following prescription.

[Example 4]

[Preparation of tablets]

8.0 g of Neil body pin was dissolved in 60 70 , And the resulting mixture was added to a vertical granulator containing a mixture of 6.0 g of methyl cellulose, 18.0 g of polyvinylpyrrolidone, 187.0 g of lactose and 120.0 g of low-substituted hydroxypropylcellulose, Dispersed, Lt; / RTI > in a circulating drier adjusted to < RTI ID = The dried product is prepared by a conventional method and the fine granules activated with magnesium stearate are kneaded in a unit of 170 mg to obtain a preparation (yield: 95 98 )

[Example 5]

[Preparation of tablets]

The formulation is prepared in the same manner as in Example 4 by the following prescription.

[Example 6]

[Preparation of tablets]

The formulation is prepared in the same manner as in Example 4 by the following prescription.

[Example 7]

[Preparation of tablets]

The formulation is prepared in the same manner as in Example 4 by the following prescription.

[Example 8]

[Preparation of tablets]

The formulation is prepared in the same manner as in Example 4 by the following prescription.

[Example 9]

[Preparation of tablets]

The formulation is prepared in the same manner as in Example 4 by the following prescription.

[Example 10]

[Preparation of Coated Tablets]

For each tablets obtained in Examples 2, 7 and 9, coating was carried out by a conventional film coating method such that 5.0 mg of hydroxypropylmethylcellulose, 1.2 mg of titanium oxide, 1.0 mg of polyethylene glycol, 0.8 mg of talc and 0.02 mg of yellow No. 4 dye To prepare a film-coated tablet.

[Experimental Example 1]

[Experiments on Deburring]

The test solution of the disintegration test is carried out by the disintegration test method 2 (paddle method) of the Korean Pharmacopoeia (sixth edition), which measures the disintegration rate after 15 minutes from the start of each disintegration test using water.

[Experimental Example 2]

[Dissolution Experiment]

Example 1 (Containing 4.0 mg of purified nalbuphine), 4.0 mg of neil bodypin, 105.5 mg of lactose, 60.0 mg of low-substituted hydroxypropylcellulose, and 0.5 mg of magnesium stearate, excluding methylcellulose and polyvinylpyrrolidone And the tablets prepared in the same manner as in Example 1 are subjected to the test with the test specimen being adjusted.

500 ml of the first solution (artificial gastric juice, pH 1.2) was used as one test solution per each of the six tablets, and the test was conducted by the second method (paddle method, 100 rpm) of Korean Pharmacopoeia (6th Edition) After 30 minutes samples are taken and analyzed.

[Experimental Example 3]

[Dissolution test]

The film-coated tablets of Example 10 (prescription of Example 2), Example 10-2 (prescription of Example 7) and Example 10-3 (prescription of Example 9) and Comparative Example 2 The film-coated tablets were prepared by the same coating formulation and coating method as in Example 10 and used as reference tablets. The dissolution experiment was carried out in the same manner as in Experimental Example 2.

[Comparative Experimental Example 1]

[Dissolution test]

Comparative Example 10-1, Example 10-2, Example 10-3 and a comparative dissolution test were conducted using a commercial product of Korean Patent Publication No. 91-3559 as a control. Test method The same procedure as in Experimental Example 2 was carried out except that sampling time was 5 minutes, 10 minutes, 30 minutes and 60 minutes.

The solid formulation compositions of the present invention and the solid formulations prepared by the methods described above have significantly improved solubility compared to the insoluble drug alone materials.

Claims (2)

1 part by weight of nil-body pin was dissolved in an appropriate amount of an organic solvent capable of dissolving the poorly soluble drug at a temperature of not higher than the boiling point, and 1 10 parts by weight of methylcellulose and polyvinylpyrrolidone at a mixing ratio of 0.2 5: 1 to prepare a solid dispersion, and drying the solid dispersion. The solid formulation according to claim 1, wherein the organic solvent is at least one solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol and the like, acetone, chloroform, methylene chloride and ethyl acetate. Gt;