JPS6399009A - Production of sustained release formulation - Google Patents

Abstract

PURPOSE:To simply and readily obtain a sustained release formulation, by spraying a solution of a binder in water or an alcohol on the surface of solid particles containing a drug while tumbling the particles and sprinkling a hydrophobic solid substance without dissolving in the stomach and intestines. CONSTITUTION:A binder, particularly a solution of a pharmaceutically acceptable high polymer, particularly methyl cellulose, etc., soluble in water or an alcohol in the water or alcohol, particularly ethyl alcohol, is sprayed on the surface of solid particles containing a drug while tumbling the particles and fine particles of a hydrophobic solid substance, which is solid at ordinary temperature, particularly a higher alcohol, etc., such as stearyl alcohol, etc., without readily dissolving in the stomach and intestines are sprinkled at the same time to coat the above-mentioned solid particles with the above-mentioned binder and hydrophobic solid substance. Furthermore, the resultant formulation is preferably heat-treated at a temperature of the melting temperature of the above-mentioned hydrophobic solid substance - the melting temperature + 30 deg.C to economically afford the aimed sustained release formulation by a simple and ready method without using any special equipment.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing a specific drug, and more specifically,
The present invention relates to a simple and efficient method for producing sustained-release preparations by coating solid particles containing a drug with a hydrophobic solid substance.

BACKGROUND ART Sustained-release preparations in which the release of a drug is delayed by coating the surface of drug-containing solid particles with a hydrophobic substance have been known. The manufacturing method for such sustained-release preparations involves dissolving a hydrophobic solid substance in an organic solvent, spraying the resulting solution onto the surface of drug-containing solid particles, and drying the drug-containing solid particles to form a hydrophobic solid. Coating the surface of the drug-containing solid particles with the hydrophobic solid substance by directly spraying a heated melt of the hydrophobic solid substance onto the surface of the drug-containing solid particles without using a coating method or an organic solvent. Examples include a method of forming a .

However, in the former method, usually as an organic solvent,
Halogenated hydrocarbons such as carbon tetrachloride and chloroform, which are harmful to the human body; hydrogen ash such as hexane and benzene; lower alcohols such as methanol and propatool; and ketones such as acetone are used, so they have a long-lasting effect. In manufacturing sex preparations, a large amount of equipment is required to ensure safety for workers and to prevent air pollution. In addition, since a relatively large amount of such organic solvents can be used, it takes a long time, for example, 8 to 10 hours, to remove these solvents from the coated preparation, resulting in extremely poor preparation efficiency. There are other problems.

On the other hand, the latter method, which was developed to avoid these problems, uses a melting pot for melting the hydrophobic substance; requires equipment to maintain the nozzle and nozzle at high temperatures. In addition, in order to uniformly coat the surface of drug-containing solid particles with a hydrophobic substance, it is necessary to spray the melted substance of the hydrophobic substance in extremely fine particles, and to do this, droplets must be sprayed from a nozzle under high pressure. There are problems such as the need for high-pressure equipment. Furthermore, in this method, cleaning after the coating operation is complicated and takes a considerable amount of time, reducing the efficiency of the operation.

An object of the present invention is to provide a method for producing a specific drug that eliminates the above-mentioned problems of conventional methods.

Thus, a principal object of the present invention is to eliminate the need for the use of harmful organic solvents as described above for dissolving hydrophobic solid substances, and to provide a melt kettle for melting hydrophobic substances;
It is an object of the present invention to provide a simple and easy method for producing a specific drug that exhibits excellent sustained drug release properties without requiring equipment for keeping piping or nozzles warm, high-pressure nozzles, etc.

According to the present invention, a water or alcoholic solution of a binder is sprayed onto the surface of solid particles containing a drug while allowing them to tumble, and the solid particles are easily absorbed in the stomach and intestines. A method for producing a specific drug is provided, characterized in that a fine powder of an undissolved hydrophobic solid substance is dispersed, thereby coating the solid particles with the binder and the hydrophobic solid substance.

The drug-containing solid particles to which a specific coating is applied according to the method of the present invention can be prepared by transporting one or more drugs (pharmacologically active substances) to carriers customary for the production of solid preparations, such as Excipients such as corn starch, potato starch, lactose mannitol, etc., lubricants such as magnesium aluminate metasilicate, light anhydrous silicic acid, talc, carboxymethyl cellulose calcium, hydroxypropyl cellulose, microcrystalline cellulose, etc. It is produced by forming solid particles together with a disintegrant and a binder such as hydroxypropylcellulose, hydroxypropylmethylcellulose, or polyvinylpyrrolidone. In this case, the solid particles can be formed into any form such as granules, mini-vellets, or pill-like cotton, and their size, expressed as an average particle size, is generally in the range of 250 to 3000 microns, preferably 500 to 1500 microns. It is appropriate that the value be within the range of . Further, the solid particles may be crystals of the drug itself as long as they have a similar morphology.

Further, as the drug that can be contained in such solid particles, there is no equivalent restriction and any drug can be used as long as sustained release in the body of a mammal is desired.Specifically, for example, indomethacin, Analgesic and anti-inflammatory agents such as ibuprofen and acetaminophen; antihistamines such as chlorpheniramine maleate; cardiovascular agents such as nifedipine, insorbitol nitrate, and propranolol; iron preparations such as ferrous fumarate; antibiotics such as cephalexin; theophylline, etc. anti-asthmatic agents; potassium agents such as potassium chloride; tranquilizers such as thioridazine hydrochloride; muscle relaxants such as chlorphenesin carbamate; and anti-inflammatory agents such as lithium carbonate.

The drug-containing solid particles can be prepared using a rolling granulation method known per se. For example, drug-containing solid particles can be produced by charging 40 to 50 meshes of sugar crystals into a floating granulator and simultaneously spraying the binder solution and dispersing the drug and carrier. It is convenient to carry out the treatment in a suitable rolling device on the drug-containing solid particles once prepared as described above.

The method of the present invention involves rolling the drug-containing solid particles prepared as described above in a particle rolling device such as a rolling granulator, while adding a water or alcohol solution of a binder to the solid particles. It can be carried out by spraying and dispersing a fine powder of a hydrophobic solid substance that does not easily dissolve in the stomach and intestines. In one preferred method, a solution of the binder is sprayed onto the solid particles while rolling the solid particles, and almost simultaneously with the spraying, the fine powder of the hydrophobic solid substance is gradually dispersed; Alternatively, immediately after spraying a predetermined amount of the binder solution, the fine powder of the hydrophobic solid substance is sprinkled, and this operation is repeated. As a result, the fine powder of the hydrophobic solid substance adheres to the surface of the solid particles wetted with the binder solution, and the fine powder of the hydrophobic solid substance coats the surface of the solid particle.

The solid particles coated with the fine powder of the hydrophobic solid substance in this manner are dried to remove the solvent used in the binder solution. The drying temperature is generally in the range of about 40 to about 70'C, preferably 60 to 70'C, depending on the type of solvent, and the drying time is usually 0.5 to 1 hour.

Binders that can be used in the method of the present invention include pharmaceutically acceptable polymeric substances that are soluble in water or alcohol, such as methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylcellulose, etc. Examples include cellulose derivatives such as methylcellulose; water-soluble synthetic polymer substances such as polyvinylpyrrolidone and polyvinyl alcohol. Each of these can be used alone, or two or more kinds can be used in combination. Among these, methylcellulose and ethylcellulose are particularly preferred.

On the other hand, as a solvent for dissolving the binder, in addition to water, non-toxic alcohol such as ethanol can also be used.

The content of the binder in these solvents is not strictly limited, and can be changed depending on the type and form of the drug-containing solid particles, the type of hydrophobic solid substance, the type of binder, etc.

The binder solution can be sprayed onto the drug-containing solid particles using, for example, a spray nozzle.

Furthermore, although the hydrophobic solid substance used in the method of the present invention does not easily dissolve in the stomach and intestines, it is possible to gradually release the drug from the drug-containing solid particles through the coating formed from the substance and the binder. Substances that are solid at possible normal temperatures can be included, and hydrophobic solid substances having a melting point within the range of 50 to 90°C are particularly suitable. Such hydrophobic solid substances can be selected from higher alcohols, higher fatty acids, glycerin esters of higher fatty acids, oils and fats, waxes, higher hydrocarbons, etc. that are solid at room temperature.

Examples of the higher alcohol include cetyl alcohol 1, stearyl alcohol, 16-methyloctadecanol-1, eicosanol-1, 18-methylnonadecanol-1, 18-methyleicosanol 22-methyltetracosanol- 1,24-methylpentacosanol-1,24-methylhexafsanol-1, octacosanol-1, nonacosanol-1, myricylalfu J
Among these higher alcohols, those having 16 to 26 carbon atoms, particularly stearyl alcohol, are preferred.

Examples of the higher fatty acids include myristic acid, balmitic acid, stearic acid, behenic acid, 12-hydroxystearic acid, etc. Among these higher fatty acids, those having 14 to 22 carbon atoms, especially stearic acid. is preferred.

Examples of the higher fatty acid glycerin ester include monoglycerides, diglycerides, and triglycerides of the higher fatty acids and glycerin.

Examples of the fats and oils include hydrogenated soybean oil, hydrogenated castor oil, Japanese wax, hardened lard, and hardened lard, and among these fats and oils, hydrogenated castor oil is particularly preferred.

Examples of the waxes include carnauba wax, hard lanolin, candelilla wax, and beeswax, and among these waxes, carnauba wax is particularly preferred.

Examples of the higher hydrocarbons include hydrocarbons preferably having 16 to 70 carbon atoms, such as paraffin, ceresin, and microcrystalline wax, with paraffin being particularly preferred.

The hydrophobic solid substances mentioned above are used in fine powder form. The particle size must be sufficiently smaller than the particle size of the core drug-containing solid particles. The particle size υ is generally less than 100 microns, preferably 10 to 30 microns.
Preferably, it is in the micron range. By appropriately selecting the particle size and adhesion of the hydrophobic solid material, the release of the drug from the coated drug-containing solid particles can be controlled.

The amount of the binder and the hydrophobic solid substance fine powder described above is not strictly limited, but may be affected by the type of drug, the shape and size of the solid particles containing the drug, the type of binder, the hydrophobic solid substance fine powder, etc. Although it can be varied depending on the type and particle size of the powder, generally the amount of the binder is within the range of 1 to 30 parts by weight, preferably 5 to 15 parts by weight, per 100 parts by weight of the hydrophobic solid material. use. The hydrophobic solid substance is used in an amount of 5 to 60 parts by weight, preferably 10 to 40 parts by weight, based on 100 parts by weight of the drug-containing solid particles, so that the surface of the drug-containing solid particles is hydrophobic. It is desirable to have a uniform coating with a fine powder of solid material.

By drying the drug-containing solid particles coated with the binder and fine particles of the hydrophobic solid substance under the conditions described above, the desired sustained-release preparation can be obtained.

Furthermore, according to the invention, the specific-effect formulation thus produced is prepared at a temperature above the melting temperature of the hydrophobic solid substance and preferably at a temperature within the range of the melting temperature plus 30°C. Heat treatment can make the long-acting coating of binder and hydrophobic solid material more dense. The conditions for the heat treatment include the above-mentioned temperature range, preferably a temperature in the range of 70 to 90°C, and a temperature of about 0.
．． The time can be 5 to 10 hours, preferably 1 to 3 hours.

The above heat treatment can be performed using, for example, a fluidized bed dryer.

Therefore, by appropriately selecting the amount and particle size of the hydrophobic solid substance used and the heat treatment conditions, the thickness and density of the long-lasting coating on the drug-containing solid particles can be adjusted, thereby allowing the solid particles to be separated from the solid particles. drug release can be freely controlled.

According to the method of the present invention described above, it is possible to economically, simply and easily produce a preparation that can continuously release a drug without using any special equipment.

Next, the present invention will be explained in more detail by showing examples and test examples of the present invention.

Example 1 Sand IM crystals 2 of 40 to 50 meshes were produced by rolling granulation method.
00g, gradually sprayed 290g of a 5% aqueous solution of hydroxybupil cellulose as a binder, and at the same time added 300g of anhydrous caffeine and 500g of corn starch.
After the spraying was completed, the granules were dried at 60° C. for 1 hour, and using a sieve, spherical granules containing caffeine with a particle size of 16 to 32 mesh were prepared.

A rolling granulator with a diameter of 36 cm was used and rotated at 150 revolutions per minute to form 50 spherical granules containing the above-mentioned caffeine.
A solution of 8 g of ethyl cellulose dissolved in 192 g of ethyl alcohol as a binder was sprayed on the surface of the granules at a rate of 20 ml/min, while at the same time hydrogenated castor oil 10
0g was gradually spread and the coating was completed.

The granules were dried at 70''C for 1 hour to obtain a sustained-release preparation (Formulation 1).

Example 2 Ethylcellulose 15g1 Ethyl alfur 360g1
Spherical granules (caffeine content H 300 ng/g - same as used in Example 1) Long-acting as in Example 1 above using 200 g of hydrogenated castor oil with 500 g% and average particle size of 30 microns A formulation (Formulation 2) was obtained.

Example 3 22 g of ethyl cellulose 528 g of ethyl alcohol,
A sustained effect was obtained in the same manner as in Example 1 using 500 g of spherical granules (caffeine content; 300+yg/g - the same as used in Example 1) and 300 g of hydrogenated castor oil with an average particle size of 30 microns. A sex preparation (Formulation 3) was obtained.

Example 4 100 g of carnauba wax with an average particle size of 15 microns instead of 100 g of hydrogenated castor oil with an average particle size of 30 microns
A specific drug (
Formulation 4) was obtained.

Example 5 200 g of carnauba wax with an average particle size of 15 microns instead of 200 g of hydrogenated castor oil with an average particle size of 30 microns
A specific-effect formulation (Formulation 5) was obtained in the same manner as in Example 2 except that .

Example 6 300 g of carnauba wax with an average particle size of 15 microns instead of 300 g of hydrogenated castor oil with an average particle size of 30 microns
A sustained-release preparation (Formulation 6) was obtained in the same manner as in Example 3 except that .

Example 7 A specific-effect preparation (
Formulation 7) was obtained.

Example 8 A sustained-release preparation (
Formulation 8) was obtained.

Example 9 A specific-effect formulation (Formulation 9) was obtained in the same manner as in Example 3 except that 9300 g of stearin with an average particle size of 20 microns was used instead of 300 g of hydrogenated castor oil with an average particle size of 30 microns.

Example 10 1 stearyl alcohol with an average particle size of 25 microns instead of 100 g of hydrogenated castor oil with an average particle size of 30 microns
A sustained-release preparation (Formulation 10) was obtained in the same manner as in Example 1 except that 00g was used.

Example 11 Stearyl alcohol 2 with an average particle size of 25 microns instead of 200 g of hydrogenated castor oil with an average particle size of 30 microns
A specific-effect formulation (Formulation 11) was obtained in the same manner as in Example 2 except that 00g was used.

Example 12 Stearyl alcohol 3 with an average particle size of 25 microns instead of 300 g of hydrogenated castor oil with an average particle size of 30 microns
A specific-effect formulation (Formulation 12) was obtained in the same manner as in Example 3 except that 00g was used.

Example 13 A specific-effect formulation (Formulation 13) was obtained in the same manner as in Example 1 except that 100 g of hydrogenated castor oil with an average particle size of 30 microns was replaced with 100 g of paraffin with an average particle size of 30 microns.

Example 14 A specific-effect formulation (Formulation 14) was obtained in the same manner as in Example 2 except that 200 g of paraffin with an average particle diameter of 30 microns was used instead of 200 g of hydrogenated castor oil with an average particle diameter of 30 microns.

Example 15 A sustained-release preparation (Formulation 15) was obtained in the same manner as in Example 3 except that 300 g of paraffin with an average particle size of 30 microns was used instead of 300 g of hydrogenated castor oil with an average particle size of 30 microns.

Test Example 1 The spherical granules used in Example 1 were used as Control Agent 1, and preparations 1 to 3 prepared in Examples 1 to 3 and Control Agent 1 were tested according to the Japanese Pharmacopoeia, 10th Edition, Dissolution Test Method No. The elution property of caffeine was investigated by method 2 (purified water was used as the test liquid, samples were taken at appropriate times and the amount of elution of caffeine was measured).

The results are shown in FIG.

Test Example 2 For formulations 4 to 6 and control agent 1 prepared in Examples 4 to 6, respectively, in the same manner as in Test Example 1,
The dissolution properties of caffeine were investigated.

The results are shown in FIG.

Test Example 3 For formulations 7 to 9 and control agent 1 prepared in Examples 7 to 9, respectively, in the same manner as in Test Example 1,
The dissolution properties of caffeine were investigated.

The results are shown in FIG.

Test Example 4 Preparations 10 to 1 prepared in Examples 10 to 12, respectively
1 and Comparative Agent 1, the elution properties of caffeine were investigated in the same manner as in Test Example 1 above.

The results are shown in FIG.

Test Example 5 Preparations 13 to 1 prepared in Examples 13 to 15 respectively
5 and Comparative Agent 1, the elution properties of caffeine were investigated in the same manner as in Test Example 1 above.

The results are shown in FIG.

Example 16 (1) Ethyl cellulose 8g Ethyl alcohol 192g
200 g of binder solution was prepared by dissolving in

While spraying the binder solution onto the surface of 500 g of 16-32 mesh spherical granules (caffeine content: 300 μ/g - same as used in Example 1) rolling in a coating device. , 100 g of hydrogenated castor oil having an average particle size of 30 microns was gradually sprinkled on the mixture, and this was dried at 60° C. for 1 hour to obtain granules (A).

(2) Roll the granules (A> obtained in <1) above to 8
A sustained-release preparation (Formulation 16) was obtained by heat treatment at 0°C for 1 hour.

Example 17 The granules (A) obtained in Example 16 (1) were converted into Example 16 (2).
A sustained-release formulation (Formulation 17) was obtained by heat treatment at 80°C for 3 hours according to the same procedure.

Example 18 The granules (A) obtained in Example 16 (1) were converted into Example 16 (2).
A specific-effect formulation (Formulation 18) was obtained by heat treatment at 90°C for 1 hour.

Example 19 The granules (A) obtained in Example 16 (1) were converted into Example 16 (2).
A sustained-release preparation (Formulation 19) was obtained by heat treatment at 90° C. for 3 hours according to the same procedure.

Example 20 (1) 100 g of hydrogenated castor oil with an average particle size of 30 microns
Carnauba wax 10 with an average particle size of 15 microns instead of
Granules (B) were obtained in the same manner as in Example 16 (1) except that 0 g was used.

<2) The granules (B) obtained in the previous section (1) were added to Example 16 (2)
A sustained-release preparation (Formulation 20) was obtained by heat treatment at 80° C. for 1 hour according to .

Example 21 The granules (B) obtained in Example 20(1) were converted into Example 20(2).
A sustained-release preparation (Formulation 21) was obtained by heat treatment at 80° C. for 3 hours.

Example 22 The granules (B) obtained in Example 20(1) were converted into Example 20(2).
A sustained-release formulation (Formulation 22) was obtained by heat treatment at 90°C for 1 hour according to .

Example 23 The granules (B) obtained in Example 20(1) were converted into Example 20(2).
A sustained-release preparation (Formulation 23) was obtained by heat treatment at 90° C. for 3 hours according to .

Test Example 6 The spherical granules used in Example 16 (1) were used as control agent 1, the granules (A) prepared in Example 16 (1) were used as formulation 24, and formulations 16 to 19 were prepared in Examples 16 to 19, respectively. For Comparative Agent 1 and Formulation 24, the elution properties of caffeine were examined in the same manner as in Test Example 1 above.

The results are shown in FIG.

Test Example 7 Granules (B) prepared in Example 20 (1) were used as Formulation 25, and Formulation 20 to 23 prepared in Examples 20 to 23, respectively.
For Comparative Agent 1 and Formulation 25, the elution properties of caffeine were examined in the same manner as in Test Example 1 above.

The results are shown in FIG.

[Brief explanation of the drawing]

FIG. 1 to FIG. 7 are dissolution rate one-hour characteristic diagrams showing the dissolution test results for the preparations prepared in the examples and the control agent.

Claims (9)

[Claims] (1) While rolling the solid particles containing the drug, spray a water or alcohol solution of the binder onto the surface of the solid particles, and scatter fine particles of a hydrophobic solid substance that does not easily dissolve in the stomach and intestines. and thereby coating the solid particles with the binder and the hydrophobic solid substance. (2) The method according to claim 1, wherein the binder is a pharmaceutically acceptable polymeric substance soluble in water or alcohol. (3) The method according to claim 2, wherein the polymeric substance is methylcellulose or ethylcellulose. (4) The method according to claim 1, wherein the alcohol is ethyl alcohol. (5) The method according to claim 1, wherein the hydrophobic biosolid substance is selected from higher alcohols, higher fatty acids, higher fatty acid glycerin esters, oils and fats, waxes, and higher hydrocarbons that are solid at room temperature. 6. The method of claim 5, wherein the hydrophobic solid material is selected from stearyl alcohol, stearic acid, hydrogenated castor oil, carnauba wax, and paraffin. (7) The method according to claim 1, wherein the coated solid particles are further heat-treated. (8) The method according to claim 7, wherein the heat treatment is performed at a temperature from the melting temperature of the hydrophobic solid substance to the melting temperature plus 30°C. (9) The method according to claim 1, wherein the solid particles are in the form of granules, mini-pellets, or pills.