KR100783286B1 - Solid pharmaceutical composition containing S-clopidogrel free base - Google Patents

Abstract

The present invention relates to a solid clopidogrel preferential optical isomeric pharmaceutical composition containing the free base of the preferred clopidogrel optical isomer in an oil phase.

The present invention can structurally stably solidify the oily clopidogrel free base, and can be easily formulated by having a powdery phase with high fluidity.

Priority optical isomers of clopidogrel, stabilizer, silica, clopidogrel free base

Description

Solid pharmaceutical composition containing S-clopidogrel free base containing free base of clopidogrel preferential optical isomer

Figure 1 shows a comparison of the pH stability of Examples 1, 3, 6, Comparative Example 4 and Clopidogrel preferential optical isomer sulfonic acid salts,

Figure 2 shows a comparison of the pH-specific stability of the formulations prepared by Examples 13-15.

The present invention relates to a solid pharmaceutical composition that is structurally stable and has excellent flowability, containing free bases of clopidogrel preferential optical isomers.

Clopidogrel is a drug used to prevent thromboembolism, such as stroke or myocardial infarction, because it inhibits platelet aggregation. Clopidogrel's racemates or preferential optical isomers are known to have superior pharmacological activity compared to left-eye optical isomers.

Clopidogrel racemates or optical isomers are not solid, but exhibit sticky semisolid properties with high viscosity fluid properties. This is not only difficult to dissolve in water, it is almost impossible to manufacture a drug as a solid formulation, so the industrial value of the drug is significantly reduced. Therefore, in order to be manufactured as a medicine and administered to humans, clopidogrel is required to be converted into a solid form, and preferably solidified in powder form.

Korean Patent Publication No. 1987-1270 describes an example in which clopidogrel racemate, an oily substance, is prepared in the form of acid salts with hydrochloric acid, sulfuric acid, etc., and Korean Patent No. 1996-3615 gives priority to clopidogrel, an oily substance. Sulfates, taurocholates and bromates are proposed as water-soluble salts in which the optical isomers are easily crystallized in inorganic or organic acid salts, have no hygroscopicity and can be used as active pharmaceuticals.

International Patent Publications WO 04/106344, International Patent Publications WO 05/016931, US Patent Publication Nos. 4,847,265, US Patent Publications US2004 / 0132765 and US Patent Publication US2005 / 0059696 are common monoclonal clopidogrel acidic substances. Salts are disclosed, and Korean Patent Laid-Open Publication No. 2005-8692 discloses a sulfonate salt of clopidogrel.

However, clopidogrel generally has a crystalline or amorphous solid form in the form of an acid salt such as an inorganic or organic acid concentrated in a free base state, but such monomolecular acid is esterified in the clopidogrel molecule during the manufacturing process. It adversely affects the stability of the structure, it is difficult for the structure to remain stable until the drug is delivered in vivo, as well as problems with the efficacy and safety of clopidogrel in the gastrointestinal tract.

In particular, clopidogrel has a strong acidic inorganic acid such as sulfonic acid, rather than weakly acidic organic acid, is advantageous for obtaining a solid salt material, and to prepare it, concentrated strong acid must be used. Therefore, strong acidic protons and clopidogrel react unavoidably during the manufacturing process. According to WO 2004/072085, salts of sulfonic acid containing clopidogrel have desirable properties with respect to their crystallinity when they contain solvent molecules, in which case the solution is toluene, acetone, dioxane The use of methyl-t-butyl ether, ethyl ether, ethyl acetate, or mixtures thereof results in the reverse reaction of clopidogrel salts containing another toxic impurity.

In addition, in order to maximize the efficacy and safety of clopidogrel, its structure must remain stable until the drug is delivered from the gastrointestinal tract to the body by oral administration, and impurities with no safety should be minimized. In particular, clopidogrel does not have good stability, and impurities are continuously generated by heat or time, which in turn causes a significant decrease in the effectiveness of drugs. Therefore, stabilizing clopidogrel free base is very important in the manufacture of pharmaceutical products with solidification.

Examples of the prior art describing the addition of silicon dioxide to the drug are as follows. US 2004/0022848 discloses compositions in which granules contain aluminum silicate or silicon dioxide to inhibit adhesion or caking to the machine during the granulation process in granulating the waxy material. The technique is intended only for the prevention of stickiness using silicon dioxide and is not related to the stabilization of clopidogrel freebase materials of the present invention.

US Patent No. 6,923,988 aims to increase the dissolution of drugs using surfactants for solubilization and hydrophilic surfactants that can cause solidification at room temperature. Although the solidification-inducing surfactant is expanded to include silica, a semi-solid surfactant substantially derived from lipids is applied. The present invention is different in that it does not use a surfactant and does not aim for elution.

US 2004/0022844 describes the preparation of 10-120 μm particle granules using silicon dioxide produced by exotherm. The purpose of the present invention is to improve the dissolution rate and is different from the present invention for stabilizing clopidogrel free base which does not secure stability against heat because the particles are manufactured by spraying at a high temperature of 100 ° C. or higher.

WO 2004/000924 describes a process for combining antibiotics and antithrombogenic drugs with resin polymers without the use of solvents. However, this technique is clearly distinguished not only for the purpose of preventing infection or thrombus formation of medical devices such as catheters, but also for adsorbing and dispersing insoluble carriers using water or solvents.

Therefore, the present inventors have found that the acidic substance of a single molecule, which is an inorganic acid or an organic acid used to crystallize the preferred optical isomer of clopidogrel, adversely affects the stability of the ester structure in the clopidogrel molecule in the manufacturing process, thereby preventing the efficacy and safety of the drug. In order to solve the problem, it is possible to prepare a medicine easily by having a high fluidity powder form by preparing a solid material having good hygroscopicity without compromising the structural stability of the preferential clopidogrel optical isomer using the free base of the oil-like prior clopidogrel optical isomer. The present invention can be completed.

The present invention aims to provide a pharmaceutical composition capable of solidifying an oily clopidogrel free base.

At the same time, an object of the present invention is to provide a pharmaceutical composition of clopidogrel having a powdery form with excellent structural stability and high flowability.

The present invention,

a) a preferred optical isomer of clopidogrel free base as an active ingredient;

b) at least one stabilizer containing from 1: 0.001 to 1: 5 by weight relative to the preferred optical isomer of clopidogrel free base;

c) a porous insoluble carrier;

Solid Clopidogrel preferential optical isomeric pharmaceutical composition comprising a.

The present invention is used in the preparation of tablets, capsules, powders, granules, dry syrups as well as solid pharmaceutical composition powders or granules as well as solid formulations commonly defined in the art, and are used as a preparation that is dissolved or suspended in liquid form. Can be prepared.

The preferred optical isomer of clopidogrel free base of the present invention is 'methyl α-5 (4,5,6,7-tetrahydro (3,2-C) thienopyridyl) (2-chlorophenyl) -acetate' It is a preferential optical isomer and is an oily, non-crystalline, semi-solid material that can be transparent and colorless or light brown or brown at room temperature.

Stabilizer of the present invention inhibits the degradation of clopidogrel including racemization, preferably means a stabilizer capable of maintaining the content of the preferred optical isomer of clopidogrel free base at about two times or more in a neutral or higher pH conditions do. Antioxidants including butylhydroxyanisole, butylhydroxytoluene, carotene, retinol, ascorbic acid, tocopherol, tocopherol polyethylene glycol succinic acid (TPGS), propyl gallate and their derivatives including salts as stabilizers of the invention Cyclic compounds of saccharides including the group, cyclodextrin, carboxyl cyclodextrin, hydroxypropyl cyclodextrin, sulfobutyether cyclodextrin, phosphoric acid, polyphosphate having two or more phosphoric acids, and alkali metal or earth metal salts thereof At least one may be selected from inorganic phosphate compounds including. In addition, since the stabilizing action of the antioxidant group can be further increased in parallel with organic acids such as lactic acid, acetic acid, citric acid, tartaric acid, succinic acid, malic acid, fumaric acid, glycolic acid, propionic acid, gluconic acid, and glucuronic acid, Organic acids may also be included in the scope of stabilizers of the invention.

The porous insoluble carrier of the present invention is a porous powder of silica or silicon, and is processed to have high dispersion by processing silicon dioxide (SiO ₂ ), and may be referred to as porous silica, amorphous silica, and colloidal silica. In the brand name Aerosil  ), Syloid  ), Sillysia  And the like, but the scope of the present invention is not limited thereto, and mixtures or combinations of alkali metal or earth metal oxides containing silicon dioxide such as aluminum silicate, aluminum sodium silicate, sodium silicate and magnesium silicate may also be used as the silica of the present invention. Or insoluble carriers including porous powders of silicon.

The porous powder and the like have a very large surface area and excellent adsorption ability, so that the preferred optical isomer of the oily clopidogrel free base can be solidified.

In addition, the insoluble carrier applicable to the porous powder of the present invention together with the porous silica may be a porous polymer derived from cellulose, starch or pyrrolidone structure insoluble, and specific examples thereof include sodium starch glycolate, crosslinked Carboxymethylcellulose sodium, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, crosslinked polyvinylpyrrolidone polymers and the like.

However, conventionally acceptable pharmaceutically acceptable carriers, especially water-soluble polymers, sugars, lipids, amino acids, etc., which are widely used, are water-soluble and cannot be solidified by supporting the preferred optical isomers of clopidogrel free bases in oil. Since it is impossible to manufacture and maintain the physical and chemical stability of the product can not be insoluble carrier of the present invention.

The present invention may further contain conventional pharmaceutical excipients. Examples include diluents, dissolution aids, pigments, foaming agents, lubricants, and the like. The diluents include microcrystalline cellulose, lactose, dextrose, and starch. The dissolution aids include polysorbate, cremopoa, and sucrose fatty acid ester. The pigments include water-soluble and tar pigments, foaming agents include calcium carbonate, sodium carbonate, potassium bicarbonate and the like, and the lubricants include stearic acid, magnesium stearate, talc and the like, but the present invention is not limited thereto.

The present invention can be produced through the following manufacturing process, but the present invention is not limited thereto.

In the present invention, the stabilizer is first dissolved in water or an organic solvent, preferably alcohol, and then wet-adsorbed to the porous powder and completely dried to remove moisture or the organic solvent. The preferred optical isomers of the oily clopidogrel free base are dissolved in an organic solvent, preferably alcohol, wet adsorbed to the porous powder to which the stabilizer is adsorbed, and completely dried to remove the organic solvent. In addition, the preferred optical isomers of the stabilizer and the clopidogrel free base in oil phase may be dissolved in the same phase, followed by wet adsorption and complete drying to remove the organic solvent.

The dry matter is pulverized or established as a standard mesh to prepare a powder or granule of a certain size. After using the prepared powder or granule form itself or adding a conventional excipient thereto, it is compressed into tablets or filled into capsules to prepare solid preparations such as capsules. The pharmaceutical composition prepared as described above may exhibit an excellent stabilizing effect because the oily clopidogrel and the stabilizer are homogeneously dispersed in an insoluble carrier.

Hereinafter, the present invention will be described through specific examples, which can be reproduced by those skilled in the art, but the present invention is not limited thereto.

<Example 1>

1 g of the preferred optical isomer and 1 g of TPGS of the clopidogrel free base in oil phase were completely dissolved in 2 g of ethanol. The solution was wetted with 1 g of porous silica (siloid), adsorbed, granulated with a standard mesh of 14 mesh, and vacuum dried at room temperature. The resulting dried product was again sized to 20 mesh standard mesh to obtain granules.

<Example 2>

1 g of the preferred optical isomer of oily clopidogrel free base and 0.02 g of butylhydroxyanisole were completely dissolved in 2 g of ethanol. The solution was wetted with 1 g of porous silica (siloid), adsorbed, granulated with a standard mesh of 14 mesh, and vacuum dried at room temperature. The resulting dried product was again sized to 20 mesh standard mesh to obtain granules.

<Example 3>

1 g of hydroxypropyl-β-cyclodextrin was completely dissolved in 5 g of purified water. The solution was wet adsorbed on 1 g of porous silica (siloid) and dried in vacuo at 60 ° C. to prepare a fine powder. Here, 1 g of the preferred optical isomer of oily clopidogrel free base was dissolved in 2 g of ethanol, wetted with the powder, adsorbed, granulated with 14 mesh standard network, and vacuum dried at room temperature. The resulting dried product was again sized to 20 mesh standard mesh to obtain granules.

<Example 4>

0.5 g of polyphosphate sodium salt was completely dissolved in 5 g of purified water. The solution was wet adsorbed onto 1 g of porous silica (siloid) and dried in vacuo at 40 ° C. to prepare a fine powder. 1 g of the preferred optical isomer of oily clopidogrel free base was mixed with 2 g of ethanol, wetted with the powder, adsorbed, granulated with 14 mesh standard network, and vacuum dried at room temperature. The resulting dried product was again sized to 20 mesh standard mesh to obtain granules.

<Example 5>

2 g of 10% phosphoric acid solution was wet adsorbed onto 1 g of porous silica (siloid), and dried in vacuo at 60 ° C. to prepare a fine powder. 1 g of the preferred optical isomer of oily clopidogrel free base was mixed with 2 g of ethanol, wetted with the powder, adsorbed, granulated with 14 mesh standard network, and vacuum dried at room temperature. The resulting dried product was again sized to 20 mesh standard mesh to obtain granules.

<Example 6>

0.5 g of polyphosphate sodium salt was completely dissolved in 5 g of purified water. The solution was wet adsorbed onto 1 g of porous silica (siloid) and dried in vacuo at 40 ° C. to prepare a fine powder. Here, 1 g of primary optical isomer and 1 g of TPGS of oily clopidogrel free base were completely dissolved in 2 g of ethanol, wetted with the powder, adsorbed, granulated with 14 mesh standard network, and vacuum dried at room temperature. The resulting dried product was again sized to 20 mesh standard mesh to obtain granules.

<Example 7>

0.5 g of polyphosphate sodium salt and 1 g of hydroxypropyl-β-cyclodextrin were completely dissolved in 5 g of purified water. The solution was wet adsorbed onto 1 g of porous silica (siloid) and dried in vacuo at 40 ° C. to prepare a fine powder. Here, 1 g of the preferred optical isomer of oily clopidogrel free base was completely dissolved in 2 g of ethanol, wetted with the powder, adsorbed, granulated with 14 mesh standard network, and vacuum dried at room temperature. The resulting dried product was again sized to 20 mesh standard mesh to obtain granules.

<Example 8>

2 g of 10% phosphoric acid solution was wet adsorbed onto 1 g of porous silica (siloid), and dried in vacuo at 60 ° C. to prepare a fine powder. Here, 1 g of primary optical isomer and 1 g of TPGS of oily clopidogrel free base were completely dissolved in 2 g of ethanol, wetted with the powder, adsorbed, granulated with 14 mesh standard network, and vacuum dried at room temperature. The resulting dried product was again sized to 20 mesh standard mesh to obtain granules.

Example 9

1 g of hydroxypropyl-β-cyclodextrin was completely dissolved in 5 g of purified water. The solution was wet adsorbed onto 3 g of crosslinked polyvinylpyrrolidone (copobividone) and dried in vacuo at 60 ° C. to prepare a fine powder. Here, 1 g of the preferred optical isomer of oily clopidogrel free base was dissolved in 2 g of ethanol, wetted with the powder, adsorbed, granulated with 14 mesh standard network, and vacuum dried at room temperature. The resulting dried product was again sized to 20 mesh standard mesh to obtain granules.

<Example 10>

0.5 g of polyphosphate sodium salt was completely dissolved in 5 g of purified water. The solution was wet adsorbed onto 3 g of cross-linked polyvinylpyrrolidone (copovidone) and dried in vacuo at 40 ° C. to prepare a fine powder. 1 g of the preferred optical isomer of oily clopidogrel free base was mixed with 2 g of ethanol, wetted with the powder, adsorbed, granulated with 14 mesh standard network, and vacuum dried at room temperature. The resulting dried product was again sized to 20 mesh standard mesh to obtain granules.

<Example 11>

1 g of the preferred optical isomer and 1 g of TPGS of the clopidogrel free base in oil phase were completely dissolved in 2 g of ethanol. The solution was wetted with 2 g of aluminum silicate, adsorbed, granulated with a 14 mesh standard mesh and vacuum dried at room temperature. The resulting dried product was again sized to 20 mesh standard mesh to obtain granules.

<Example 12>

1 g of the preferred optical isomer of oily clopidogrel free base and 0.02 g of butylhydroxyanisole were completely dissolved in 2 g of ethanol. The solution was wetted with 2 g of aluminum silicate, adsorbed, granulated with a 14 mesh standard mesh and vacuum dried at room temperature. The resulting dried product was again sized to 20 mesh standard mesh to obtain granules.

<Examples 13 to 15>

Homogeneous 0.1 g of sodium starch glycolate as insoluble carrier, 0.1 g of microcrystalline cellulose as diluent, 0.02 g of magnesium stearate as lubricant and 0.05 g of talc to 1 g of each granule obtained in Examples 1, 3 and 6 Mixed well. Each of these was filled into a tablet machine and compressed to form tablets, which were determined as Examples 13 to 15, respectively.

<Examples 16 to 18>

To 1 g of the granule obtained in Example 2, 0.2 g of microcrystalline cellulose as a diluent, 0.02 g of magnesium stearate as a lubricant and 0.05 g of talc were mixed homogeneously. Each of these was filled in a capsule filling machine to form ingots at low pressure, and the capsules were prepared.

1 g of the granules obtained in Example 4 and Example 7 were prepared in the same manner as in Example 16 to obtain Examples 17 and 18, respectively.

<Comparative Example 1 to Comparative Example 3>

1 g of the preferred optical isomer of clopidogrel free base in oil phase was completely dissolved in 2 g of ethanol. The solution was wetted with 5 g of lactose, 3 g of glyceryl behenate, and 3 g of hydroxypropylmethylcellulose, adsorbed, granulated with a standard mesh of 14 mesh, and vacuum dried at room temperature to obtain Comparative Examples 1 to 3.

<Comparative Example 4>

1 g of the preferred optical isomer of clopidogrel free base in oil phase was completely dissolved in 2 g of ethanol. The solution was wetted with 1 g of porous silica (siloid), adsorbed, granulated with a standard mesh of 14 mesh, and vacuum dried at room temperature. The obtained dried product was again sieved to a 20 mesh standard network to obtain granules.

Experimental Example 1

The granules of Examples 1 to 4 and the granules of Comparative Examples 1 to 3 were taken and observed to show the properties of the powder. Powder particles were broken by passing through a 60-mesh standard mesh, and powder particles were split, and the angle of repose was measured from the angle between the inclined plane and the horizontal plane formed by free fall of the solid phase to evaluate the fluidity of the powder. It was.

As a result, as shown in Table 1, the granules of Examples 1 to 4 exhibited good solid phase properties due to easy cleavage of the particles. Unlike the Comparative Examples 1 to 3, it can be seen that the solid pharmaceutical composition containing the clopidogrel free base according to the present invention exhibits the characteristics exhibited by the typical solid powder. On the contrary, the compositions of Comparative Examples 1 to 3, which are not according to the present invention, are in the form of solids in spite of the excessive use of solid carriers, but in reality, oils are not mixed with solids and dispersed so that they cannot be prepared in solid pharmaceutical formulations. It can be seen that

Evaluation of Physical Properties of Examples 1-4 and Comparative Examples 1-3 Overpass (60 mesh standard mesh) Fluidity (repose angle) Example 1 All passed 30 ° Example 2 All passed 24 ° Example 3 All passed 28 ° Example 4 All passed 35 ° Comparative Example 1 Crushed without passing 67 ° Comparative Example 2 Crushed without passing No liquidity Comparative Example 3 Crushed without passing No liquidity

Experimental Example 2

Preferred optical of the clopidogrel free base by adding the granules of Examples 1, 3 and 6, the granules of Comparative Example 4, and the preferred optical isomer sulfonate salt of the commercial drug Clopidogrel free base to pH 3.3, 5.3, 7.3 and 9.3 buffer. Isomers were prepared in homogeneous solution to a concentration of 10 μg / mL and stored in a chamber at 80 ° C. The contents of clopidogrel 4 hours after the start of the test were analyzed by HPLC according to the test method described in the US Pharmacopoeia.

As shown in FIG. 1, the solid granules of Examples 1, 3, and 6 have very excellent stability and are not only the simple solids of Comparative Example 4 containing the preferred optical isomers of clopidogrel free bases, but also the preferred optics of clopidogrel free bases. It was confirmed that it was more stable than isomer sulfonate. In particular, it was confirmed that the pharmaceutical composition of the present invention is very stable or stable to preserve the drug even in the neutral or alkaline region where the stability of the preferred optical isomer of clopidogrel free base is weak.

Experimental Example 3

Powders obtained by grinding the tablets of Examples 13 to 15 were added to buffers of pH 3.3, 5.3, 7.3, and 9.3 to prepare homogeneous solutions in which the preferred optical isomer of clopidogrel free base was 10 μg / mL. Stored in a chamber at &lt; RTI ID = 0.0 &gt; Four hours after the start of the test, the content of the preferred optical isomer of clopidogrel free base was analyzed by HPLC according to the test method described in the US Pharmacopoeia.

As shown in FIG. 2, it was confirmed that the solid preparations of Examples 13 to 15 maintained the same high or similar stability as Experimental Example 2. It can be confirmed that the pharmaceutical composition of the present invention maintains the same stability not only in powders and granules but also in compression-molded solid preparations.

Accordingly, the present invention provides a solid pharmaceutical composition containing an oily clopidogrel free base, thereby overcoming the oil phase properties of the preferred optical isomers of the clopidogrel free base, and processing with a solid preparation as well as stability. It is possible to provide a pharmaceutical composition that is much more stable at pH of neutral phase than clopidogrel sulfonate, which is most stable with respect to the preferred optical isomer of weak clopidogrel free base.

In addition, the present invention can be easily prepared by providing a pharmaceutical composition of a solid clopidogrel having a low hygroscopic and high fluidity powder form.

Claims (16)

a) a preferred optical isomer of clopidogrel free base as an active ingredient; b) 1 selected from butylhydroxyanisole, tocopherol polyethylene glycol succinic acid (TPGS), hydroxypropyl cyclodextrin, and polyphosphate sodium, which contain 1: 0.001 to 1: 5 in weight ratio relative to the preferred optical isomer of clopidogrel free base. Species or more stabilizers; c) at least one selected from porous silica, aluminum silicate, sodium starch glycolic acid, and crosslinked polyvinylpyrrolidone polymer containing 1: 0.2 to 1: 5 by weight relative to the preferred optical isomer of clopidogrel free base. Porous insoluble carriers; Solid clopidogrel preferential optical isomeric pharmaceutical composition comprising a. delete delete delete delete delete delete delete delete delete delete delete The solid clopidogrel preferential optical isomeric pharmaceutical composition according to claim 1, further comprising at least one selected from pharmaceutically acceptable diluents, dissolution aids, pigments, foaming agents, and lubricants. The clopidogrel preferential optical isomeric pharmaceutical composition according to claim 1, wherein the formulation is a tablet, capsule, powder, granule, dry syrup, or a solid formulation which is dissolved or suspended in liquid form when used. Dissolving the stabilizer in water or an organic solvent and then wet adsorbing to a porous insoluble carrier and completely drying to remove moisture or an organic solvent; Dissolving the preferential optical isomer of oily clopidogrel free base in an organic solvent, wet adsorbing to a porous insoluble carrier having a stabilizer adsorbed thereon, and removing the organic solvent; A method for producing a solid clopidogrel preferential optical isomeric pharmaceutical composition, wherein the preferred optical isomer and stabilizer of the oily clopidogrel free base are homogeneously dispersed in an insoluble carrier. The preferred optical isomer of the stabilizer and the clopidogrel free base in oil phase is dissolved in an organic solvent of the same phase, and then wet-adsorbed to a porous insoluble carrier and completely dried to remove moisture or organic solvent. A method for producing a solid clopidogrel preferential optical isomeric pharmaceutical composition, wherein the preferred optical isomer and stabilizer are homogeneously dispersed in an insoluble carrier.

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