KR100712146B1 - A sustained composition comprising isradipin and the method thereof - Google Patents

Abstract

The present invention relates to a sustained-release preparation containing isradypine and a method for preparing the same, and more specifically, to 1 part by weight of an isradipine agent, 0.1 to 10 parts by weight of a water-soluble polymer or surfactant, and a residual amount of an organic solvent. After that, spray-drying or coprecipitation using a speed mixer to prepare an amorphous solid dispersion, the sustained release comprising 2 to 90 parts by weight of excipient and 1 to 30 parts by weight of sustained-release base based on 1 part by weight of the solid dispersion. It provides a formulation and a method for preparing the same.

Sustained release formulation according to the present invention can sustain the dissolution rate of isradipine for a long time, is easy to manufacture and excellent in economic efficiency.

Isradipine, water-soluble polymers, surfactants, solid dispersions, sustained release preparations.

Description

Sustained release formulations comprising isradin and methods for preparing the same. {A SUSTAINED COMPOSITION COMPRISING ISRADIPIN AND THE METHOD THEREOF}

Figure 1 shows the amorphous form of the composition through X-ray diffraction analysis on isradipine and mixtures thereof.

Figure 2 is a dissolution test according to the eluent speed for Example 1.

Figure 3 is a dissolution test of the original isradin formulations, Example 1, Example 5, and commercially available formulations (manufacturer: Daewoong Pharmaceutical, brand name: Dynacirc sustained-release capsule).

[Industrial use]

The present invention relates to a sustained-release preparation containing isradipine and a method for preparing the same, and more particularly, to an isradipine-containing sustained-release preparation in which a dissolution rate of isradin can be sustained for a long time and a manufacturing method is convenient. .

[Private Technology]

Osmotic release agents disclosed in US Patent No. 4816263 Using the pressure generated by osmotic pressure in the tablet, the zero-order release pattern in the digestive tract through the precisely sized micropores enables uniform release over a long period of time. However, the osmotic release modulator should be prepared constantly because the release modulator releases the drug by a very sophisticated mechanism of action, if it is not constant, dose dumping or irregular release due to breakage in vivo, etc. It can also represent a pattern. Therefore, the osmotic release control agent has a disadvantage in that the production process is complicated and expensive. In addition, the release controlling agent is inefficient in terms of bioavailability of the active ingredient because about 10% of the drug contained in the formulation itself is left in the formulation and discharged to the body as it is. In addition, the release control agent has a disadvantage in that the expression of the drug is delayed because it has a release delay time of about 2 hours to hydrate in vivo to express osmotic pressure.

In addition, according to Patent Publication No. 1987-0003777, a sustained composition comprising hydroxypropylmethylcellulose and fatty acid esters in a fixed ratio with isradypine, after melting and melting the fatty acid esters and isradypine at 56 ° C., cooling and grinding them. Capsules are prepared after mixing with phosphorus excipients. However, since the drug and the carrier must be melted during manufacture, it may affect the stability of the drug and the performance of the preparation may be affected by the cooling conditions of the melt. This has the disadvantage of lengthening.

The present invention is to solve the above problems, an object of the present invention is to maintain the increased dissolution rate of isradipine for a long time, and to facilitate the production by applying a conventional wet granulation process as israradi It is to provide a sustained release formulation comprising a solid dispersion containing a pin.

In order to achieve the above object, the present invention mixes 1 part by weight of an isradipine agent, 0.1 to 10 parts by weight of a water-soluble polymer or surfactant and a residual amount of an organic solvent, and then spray-drys the mixture or coprecipitates using a speed mixer. It provides a sustained release formulation comprising 2 to 90 parts by weight of excipient and 1 to 30 parts by weight of sustained-release base based on 1 part by weight of the solid dispersion prepared in the amorphous form.

Hereinafter, the present invention will be described in more detail.

The present invention is to formulate a composition containing isradipine, a poorly water-soluble agent as a main component, 1 part by weight of the isradipine agent and 0.1 to 10 parts by weight of a water-soluble polymer or 0.1 to 10 parts by weight of surfactant in an organic solvent together The amorphous solid dispersion prepared by heating, dissolving and spray drying is prepared by mixing a sustained-release base, or by heating and dissolving an isradicin agent and a water-soluble polymer or surfactant in an organic solvent and then using a speed mixer. The present invention relates to a sustained-release preparation capable of sustaining an increased dissolution rate of poorly soluble isradipine by preparing a solid dispersion by coprecipitation and then mixing with a sustained-release base.

Coprecipitation in a wet granulation process using the speed mixer is a step of granulating isradin in an organic solvent with a water-soluble polymer or a surfactant and then dissolving it with an excipient.

Isradin is a dihydropyridine calcium channel blocker and is a cardiovascular drug. Since isradipine is a poorly soluble drug, a water-soluble polymer or surfactant may be heated and dissolved in an organic solvent.

Examples of the water-soluble polymer include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, hydroxypentyl cellulose, hydroxypropyl butyl cellulose, hydroxypropyl alkyl cellulose, At least one selected from the group consisting of polyvinylpyrrolidone and polyvinyl alcohol, and may be a water-soluble polymer having a viscosity of 1 c solution (w / v) of 100 cps or less, preferably a viscosity of 1% solution (w / v) May be a water-soluble polymer having a value of 30 cps or less. The water-soluble polymer may contain 0.1 to 10 parts by weight based on the solid dispersion. In the case of containing less than 0.1 parts by weight of water-soluble polymers, the dissolution rate is fast, so that it is difficult to formulate sustained release.

Examples of the surfactant include tocoxate chloride, sodium lauryl sulfate, benzalkonium chloride, benzetonium chloride, cetride, polyethylene-polypropylene polymer, polyoxyethylene-polyoxypropylene polymer (hereinafter referred to as 'poloxamer'), It may be one or more selected from the group consisting of polyoxyethylene hardened castor oil, propylene glycol mono, polyoxyethylene alkyl ether, polyoxyethylene lauryl ether, polyoxyethylene propylene glycol mono fatty acid ester and di fatty acid ester. The surfactant may contain 0.1 to 10 parts by weight based on the solid dispersion. Surfactant If it is out of the above range does not help the solubility of isradinine or if it exceeds the weight part may cause side effects due to a sharp increase in dissolution.

When the raw agent of isradinine is heated and dissolved with a water-soluble polymer or a surfactant, examples of the organic solvent may include ethanol, dichloromethane, methanol, or a mixture thereof.

Sustained release formulations for oral administration according to the present invention may affect the stability of the drug by melting the drug and the carrier during preparation by the spray drying step, and may affect the performance of the preparation depending on the conditions for cooling the melt. Concerns that can be avoided.

In the method of spray drying, the isadipine agent, the surfactant, and the water-soluble polymer were heated and dissolved in ethanol. This solution was sprayed using a spray dryer (model, B-191 Mini Spray Dryer, Buchi Co., Swiss) to prepare a solid dispersion in which isradin was amorphously dispersed in a water-soluble polymer or a surfactant. And mixed with additives.

In addition, the coprecipitation method is to heat and dissolve the isradipine raw agent and the surfactant or water-soluble polymer in ethanol, and then add the additive to the speed mixer (model, YC-SMG-10, Yenchen Machinery Co., LTD. Taiwan) A solid dispersion was prepared by adding and co-precipitating a solution in which the radicals were dissolved, followed by mixing with a sustained release base and an additive.

Examples of the excipient include lactose, white sugar, glucose, fructose, mannitol, corn starch, potato starch, wheat starch, pregelatinized starch, microcrystalline cellulose or cellulose derivatives, dextrin, calcium dihydrogen phosphate, calcium dihydrogen phosphate, and carbonic acid. Group consisting of calcium, potassium polyacrylic acid, acetic acid, ammonium carbonate, ammonium phosphate, boric acid, lactic acid, citric acid, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate, sodium lactate, ascorbic acid, ascorbyl parmitate It may be one or more selected from. The excipient may contain 2 to 90 parts by weight based on the total sustained release formulation. If the excipient is less than 2 parts by weight, there is a fear that the tablets are not formed. If the excipient is more than 90 parts by weight, the size of the tablet becomes large, which makes it difficult to take the tablet.

Examples of the sustained-release base include hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethyl cellulose, collidone SR, Eudragit RL, Eudragit RS, Eudragit S, Eudragit E30D, Eudra One or more selected from the group consisting of L30D, sodium alginate, propylene glycol ester of alginic acid, xanthan gum and locust bean gum, the viscosity of 1% solution (w / v) of 100 cps or more, preferably 1% solution (w / v) may be a cellulose polymer having a viscosity of 5,000 cps or more. The sustained release base serves as a sustained release base rather than a binder when the viscosity is 100 cps or more. The sustained release base may contain 0.1 to 30 parts by weight based on the total sustained release formulation. If it is less than 0.1 part by weight, the dissolution rate is fast, so that the sustained release formulation is difficult. If it exceeds 30 parts by weight, the dissolution rate may be too slow.

Sustained release formulations of the present invention may further comprise additives such as binders, lubricants and the like.

Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxy cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, polyvinylpyrrolidone, polyvinyl alcohol, gelatin, dextrin, microcrystalline cellulose. It may be one or more selected from the group, the binder of the viscosity of 1% solution (w / v) is 100 cps or less, preferably the binder of the viscosity of 1% solution (w / v) of 30 cps or less. The binder may serve as a binder when the viscosity is 100 cps or less. The binder may be contained in an amount of 0.1 to 40 parts by weight based on the total pharmaceutical composition.

Examples of the lubricant may be one or more selected from the group consisting of magnesium stearate, stearic acid, zinc stearate, calcium stearate, talc, sodium stearyl fumarate, talc, silicon dioxide, colloidal silicon dioxide. The glidant may contain 0.1 to 20 parts by weight based on the total sustained release formulation. When it contains less than 0.1 part by weight of lubricant, problems may occur in tableting or the like, and when it exceeds 20 parts by weight, dissolution rate may be slow.

In addition, the sustained-release preparation of the present invention may further include a coating layer including the coating agent. Examples of the coating agent include ethyl cellulose, shellac, ammonio methacrylate copolymer, polyvinylacetate, polyvinylpyrrolidone, polyvinyl alcohol, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxy It may be one or more components selected from the group consisting of butyl cellulose, hydroxypentyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl butyl cellulose, hydroxypropyl pentyl cellulose and Opadry (manufacturer: Colorcon Co.). As examples of the ammonio methacrylate copolymer, Eudragit RS or Eudragit RL may be used. Coating with the coating agent can give color, stability, dissolution control is possible and has the effect of masking the taste of the drug.

The coating layer may further include a plasticizer, and may further include pigments, antioxidants, talc, titanium dioxide, and flavoring agents. Examples of the plasticizer may be at least one component selected from the group consisting of castor oil, fatty acids, substituted triglycerides and glycerides, polyethylene glycol having a molecular weight of 300 to 50,000, and derivatives thereof.

Water or an organic solvent may be used as a solvent of the coating solution for preparing the coating layer, and examples of the organic solvent may be methanol, ethanol, isopropanol, acetone, chloroform, dichloromethane or a mixture thereof.

The sustained-release preparation may be co-precipitated by a wet granulation process to prepare a sustained preparation containing a solubilized solid dispersion isradipine to sustain an increased dissolution rate of isradipine for a long time. The coprecipitation step is performed by dissolving isradinine in a solvent by heating a water-soluble polymer or surfactant in an organic solvent and then granulating the remaining excipient.

Hereinafter, preferred embodiments of the present invention are described. However, the following examples are only preferred embodiments of the present invention, and the present invention is not limited by the following examples.

EXAMPLE

Example 1-4 Preparation of Solid Dispersion by Mixing Isradipine and a Water-Soluble Polymer

After dissolving 5 mg of isradinine in 5.0 g of ethanol, the solution prepared by evenly dissolving the water-soluble polymer as shown in Table 1 was spray dried at 90 ° C. for 45 hours (B-191 Mini Spray Dryer, Buchi Co., Swiss) was used to produce a solid dispersion in which isradipine was dispersed in an aqueous polymer, thereby preparing an amorphous powder.

Example 1 Example 2 Example 3 Example 4 Isradipine 5mg 5mg 5mg 5mg Hydroxypropyl cellulose 5mg - - - Hydroxypropyl Methyl Cellulose - 5mg - - Povidone K-30 - - 5mg - Polyvinyl alcohol - - - 5mg

Example 5-7 Preparation of Tablets Containing Isradipine

Isradipine, a pharmacologically active ingredient, was dissolved by heating in ethanol at 60 ° C. as shown in Table 2 below, followed by mixing and dissolving hydroxypropyl cellulose as a water-soluble polymer. Lactose as an excipient, microcrystalline cellulose, and hydroxypropyl cellulose as a binder were mixed together, granulated, granulated, dried, and then screened with 35 mesh sieve. Hydroxypromethylcellulose, collidone SR, and sodium alginate were mixed with each other as a sustained-release base, and magnesium stearate as a lubricant was added through a 35 mesh body, followed by mixing for 5 minutes. The resulting mixture was compressed on a suitable machine to a hardness of 10 to 14 Kg to produce isradypine tablets.

Ingredient (mg) Example 5 Example 6 Example 7 Isradipine 5 5 5 Hydroxypropyl cellulose 5 5 5 Microcrystalline cellulose 57 57 57 Lactose 67 67 67 Hydroxypropylmethylcellulose (15,000 cps) SR 6 - - Hydroxypropylmethylcellulose (100,000 cps) SR 17 - - Kolidon SR - 23 - Sodium alginate - - 23 Colloidal silicon dioxide One One One Magnesium stearate 2 2 2 moisture Quantity Quantity Quantity Total amount 160 160 160

The moisture in Table 2 was removed during the manufacturing process.

Comparative Example

Comparative Example 1

Isradipine tablets were prepared in the same manner as in Examples 5-7, except that no sustained-release base was added. In this case, hydroxypropyl cellulose having a viscosity of 30 cps or less was used.

ingredient Content (mg) Isradipine 5 Hydroxypropyl cellulose 5 Microcrystalline cellulose 67 Lactose 80 Colloidal silicon dioxide One Magnesium stearate 2 moisture Quantity Total amount 160

Experimental Example 1: X-ray Diffraction Analysis

About the solid dispersion (I) of an isradicin raw material (A), a mixture of an isradicine raw material and the hydroxypropyl cellulose which is a water-soluble polymer, and a hydroxypropyl cellulose which is an isradipine raw material and a water-soluble polymer (C) X The result of the -ray diffraction analysis experiment is shown in FIG.

Experimental Example 2: Dissolution Test

The dissolution test was carried out according to the dissolution test method 2 (paddle method) of the general pharmacopoeia of the isradipine raw material itself and the release trend of the formulations prepared in Examples 1 to 4. The eluate was pH6.8 and 1% polysorbate 80 (Polysorbate 80, PSB), and the dissolution rate of the drug over time was measured under rotational speed of 100 rpm / 500 ml. The results are shown in Table 4 below.

Hours (hr) Isradipine Raw Material Example 1 Example 2 Example 3 Example 4 0 0.0 0.0 0.0 0.0 0.0 One 1.4 17.8 15.9 20.3 18.6 2 3.2 40.3 41.7 39.7 35.7 4 5.7 74.3 80.9 76.5 69.5 6 8.7 99.7 100.1 98.9 89.3

As shown in Table 4, it can be seen that only the isradine raw material itself is not eluted, and in the case of a solid dispersion formed by mixing with a water-soluble polymer, the dissolution rate is increased.

Experimental Example 3: Dissolution Test

For the sustained-release preparations prepared in Examples 5 to 7 and commercially available 5 mg of dynac sustained-release capsules, and tablets prepared according to Comparative Example 1, according to the dissolution test No. 2 method (paddle method) The dissolution test was performed and shown in Table 5 below.

Hours (hr) Example 5 Example 6 Example 7 Comparative Example 1 Commercially available 0 0.0 0.0 0.0 0.0 0.0 One 1.7 29.8 3.0 30.6 1.5 2 4.9 41.7 45.7 65.6 4.6 4 10.8 49.3 55.3 89.3 9.4 6 17.9 61.5 64.7 98.7 16.3 8 23.8 73.4 75.6 - 22.2 10 29.7 81.9 84.3 - 28.2 12 35.8 90.4 92.3 - 33.7 16 44.5 99.5 98.7 - 43.1 20 57.1 100.1 99.3 - 54.9 24 68.4 101.9 99.8 - 65.4 36 97.8 100.3 100.3 - 95.7

In the dissolution test, Labfine, DST-600 apparatus was used, and the eluate was measured at three revolutions of 50 rpm, 100 rpm, and 150 rpm at about 37.5 ° C. using pH6.8 and 1% polysorbate 80. This was shown in FIG. 3 by measuring 85% methanol as a mobile phase using Xterra RP18 column by liquid chromatography and measuring the cumulative emission at 326 nm at a flow rate of 1.2 ml / min. As shown in FIG. 3, the dissolution test results showed that the dissolution difference according to the stirring speed was small, and the preparation according to the present invention had a small difference in dissolution rate according to the gastrointestinal motility, resulting in a consistently reproducible release pattern during administration. It can be seen that.

According to Table 5 and Figure 3 it was confirmed that only the raw material itself is not eluted, it can be seen that the elution rate is significantly improved when the solid dispersion with the water-soluble polymer as in Examples 5 to 7. In addition, when comparing the dissolution results of the formulation prepared in Example 5 and the commercial formulation it can be confirmed that the preparation of the same to high dissolution rate can be prepared and that the zero-order emission pattern is seen over 36 hours.

In addition, when comparing the results of Examples 1 to 4 of Experimental Example 2 and Examples 5 to 7 of Experimental Example 3, it was found that a mixture of isradinine and a water-soluble polymer made in the form of a solid dispersion can be melted for a long time. .

In the present invention, the poorly soluble isradipine is dissolved in an organic solvent such as ethanol with a water-soluble polymer or surfactant, and then spray-dried to form a solid dispersion, and an excipient and a sustained release base are added to the solid dispersion and wet granulated. By coprecipitation, a sustained-release preparation containing isradinine may be prepared to sustain the dissolution rate of isradinine for a long time. In addition, by applying the conventional wet granulation process as it is possible to provide a pharmaceutical composition that is easy to manufacture and excellent in economic efficiency.

Claims (7)

1 part by weight of isadipine agent, and hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, hydroxypentyl cellulose, hydroxypropyl butyl cellulose, hydroxy 0.1-10 parts by weight of a water-soluble polymer selected from the group consisting of propylalkylcellulose, polyvinylpyrrolidone and polyvinyl alcohol and having a viscosity of 1 c solution (w / v) of 30 cps or less with ethanol, dichloromethane and methanol A solid dispersion prepared in an amorphous form by dissolving in at least one organic solvent selected from the group consisting of spray drying and coprecipitation using a speed mixer; Per 1 part by weight of the solid dispersion 2 to 90 parts by weight of excipients; And At least one selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinylacetate-polyvinylpyrrolidone copolymer, amonomethacrylate copolymer, sodium alginate and xanthan gum 1 to 30 parts by weight of a sustained release base having a viscosity of 5,000 cps or more in a 1% solution (w / v) Sustained release formulation comprising a. delete delete delete The method of claim 1, wherein the excipient is lactose, white sugar, glucose, fructose, mannitol, corn starch, potato starch, wheat starch, pregelatinized starch, microcrystalline cellulose or cellulose derivative, dextrin, calcium dihydrogen phosphate, phosphoric acid Calcium dihydrogen, calcium carbonate, potassium polyacrylate, acetic acid, ammonium carbonate, ammonium phosphate, boric acid, lactic acid, citric acid, potassium phosphate, sodium phosphate, sodium acetate, sodium citrate, sodium lactate, ascorbic acid and ascorbyl parmi Sustained release preparation characterized in that at least one member selected from the group consisting of tate. delete Isradinic agents; And hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxybutyl cellulose, hydroxypentyl cellulose, hydroxypropyl butyl cellulose, hydroxypropyl alkyl cellulose, polyvinylpyrrolidone And a water-soluble polymer having at least one selected from the group consisting of polyvinyl alcohol and having a viscosity of 30 cps or less in a 1% solution (w / v) dissolved in at least one organic solvent selected from the group consisting of ethanol, dichloromethane and methanol. Preparing a solid dispersion by coprecipitation using spray drying or a speed mixer, and Excipients in the solid dispersion; And at least one selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, polyvinylacetate-polyvinylpyrrolidone copolymer, amonomethacrylate copolymer, sodium alginate and xanthan gum. Adding and co-precipitating a sustained release base selected and having a viscosity of 1% solution (w / v) of at least 5,000 cps A method for producing a sustained release formulation containing an isradin solid dispersion comprising a powder.

Images