JPH0764726B2 - Method for manufacturing sustained-release preparations - Google Patents

Description

TECHNICAL FIELD The present invention relates to a method for producing a sustained-release preparation, and more specifically,
The present invention relates to a simple and efficient method for producing a sustained-release preparation by coating solid particles containing a drug with a hydrophobic solid substance.

2. Description of the Related Art Conventionally, 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. As a method for producing such a sustained-release preparation, a hydrophobic solid substance is dissolved in an organic solvent, and the resulting solution is sprayed onto the surface of the drug-containing solid particles, followed by drying to remove the drug-containing solid particles into a hydrophobic solid. A method of coating with a substance or a method in which a heated melt of a hydrophobic solid substance is directly sprayed onto the surface of a drug-containing solid particle without using an organic solvent, and the surface of the drug-containing solid particle is coated with the hydrophobic solid substance. And the like.

Problems to be Solved by the Invention However, in the former method, usually as an organic solvent,
Halogenated hydrocarbons such as carbon tetrachloride and chloroform that are harmful to the human body; hydrocarbons such as hexane and benzene; lower alcohols such as methanol and propanol; and ketones such as acetone are used. In manufacturing, a large amount of equipment is required to ensure safety for workers and prevent air pollution. In addition, since such an organic solvent is used in a relatively large amount, it takes a great amount of time, for example, 8 to 10 hours to remove these solvents from the coated preparation, resulting in extremely high production efficiency of the preparation. There are problems such as badness.

On the other hand, the latter method developed in order to avoid these problems is a melting pot for melting a hydrophobic substance; and a pipe or a spray nozzle so that the molten hydrophobic substance does not solidify in the pipe. Equipment is required to keep the nozzles and nozzles at a high temperature. Further, in order to uniformly coat the surface of the drug-containing solid particles with the hydrophobic substance, it is necessary to make the melt of the hydrophobic substance extremely fine and spray it. For that purpose, the droplets are sprayed from the nozzle at high pressure. There is a problem that a high-pressure device is required to do so. Further, this method requires complicated cleaning and cleaning after the coating operation, which requires a considerable amount of time, and reduces the working effect.

An object of the present invention is to provide a method for producing a sustained-release preparation, which solves the above-mentioned problems in the conventional method.

Thus, the main object of the present invention is to eliminate the need for the use of harmful organic solvents as mentioned above for dissolving hydrophobic solid substances, and also for the melting pot for melting hydrophobic substances,
It is an object of the present invention to provide a method for easily and easily producing a sustained-release preparation that exhibits excellent sustained drug release properties, without the need for equipment for maintaining heat in pipes and nozzles, high-pressure nozzles, and the like.

Means for Solving the Problems According to the present invention, while rolling solid particles containing a drug, the surface of the solid particles is sprayed with a water or alcohol solution of a binder, and is easy in the stomach and intestines. Provided is a method for producing a sustained release preparation, which comprises spraying a fine powder of a hydrophobic solid substance which does not dissolve in water, thereby coating the solid particles with the binder and the hydrophobic solid substance.

The solid particles containing a drug to which a sustained-release coating is applied according to the method of the present invention include one or more drugs (pharmacologically active substances), a carrier commonly used in the production of solid preparations, For example, corn starch, potato starch, lactose, sugar, excipients such as mannitol, magnesium metasilicate aluminate, light anhydrous silicic acid, lubricants such as talc, carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, microcrystalline Disintegrants such as cellulose, hydroxypropyl cellulose,
It is produced by forming it into solid particles with a binder such as hydroxypropylmethyl cellulose or polyvinylpyrrolidone. At that time, the solid particles can be formed into any shape such as granules, mini-pellets, pills, etc., and the size thereof is generally expressed in the average particle diameter in the range of 250 to 3000 microns, preferably 500 to 1500 microns. It is suitable to be within the range. The solid particles may be crystals of the drug itself, as long as they have a similar morphology.

The drug that can be contained in such solid particles is not particularly limited as long as it is desired to be sustained-released in the body of a mammal, and can be any drug. Specifically, for example, indomethacin, Anti-inflammatory agents such as ibuprofen and acetaminophen; antihistamines such as chlorpheniramine maleate; cardiovascular agents such as nifedipine, isosorbite nitrate and propranolol; iron agents such as ferrous fumarate; antibiotics such as cephalexin; theophylline etc. Anti-asthma agents such as potassium chloride; potassium agents such as potassium chloride; tranquilizers such as thioridazine hydrochloride; muscle relaxants such as chlorphenesin carbamate; anti-manic agents such as lithium carbonate.

Preparation of the drug-containing solid particles can be carried out by using a tumbling granulation method known per se. For example, drug-containing solid particles can be produced by charging 40 to 50 mesh sugar crystals in a tumbling granulator, and spraying the binder solution and simultaneously spraying the drug and carrier. The drug-containing solid particles once prepared as described above are conveniently carried out in a suitable rolling device.

In the method of the present invention, in a particle rolling device such as a rolling granulator, while rolling the drug-containing solid particles prepared as described above, a water or alcohol solution of a binder is added to the solid particles. It is carried out by spraying and dusting with a fine powder of a hydrophobic solid substance which does not dissolve readily in the stomach and intestines. In a preferred method thereof, while the solid particles are being rolled, a solution of a binder is sprayed onto the solid particles, and the hydrophobic solid substance fine powder is sprinkled little by little at the same time as the spraying. Alternatively, the fine powder of the hydrophobic solid substance is sprayed immediately after the spraying of a predetermined amount of the binder solution is finished, and this operation is repeated. As a result, the fine powder of the hydrophobic solid substance adheres to the surface of the solid particle wetted with the binder solution, and the fine powder of the hydrophobic solid substance covers the surface of the solid particle.

In this way, the solid particles coated with the fine powder of the hydrophobic solid substance are dried to remove the solvent used for 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 kind of the solvent,
The drying time can be usually about 0.5 to 1 hour.

The binder that can be used in the method of the present invention includes a pharmaceutically acceptable polymer substance soluble in water or alcohol, such as methyl cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl. Cellulose derivatives such as methyl cellulose; and water-soluble synthetic polymer substances such as polyvinylpyrrolidone and polyvinyl alcohol. These may be used alone or in combination of two or more. Of these, methyl cellulose and ethyl cellulose are particularly preferable.

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

The content of the binder in these solvents is not strictly limited, and can be changed according to the type and morphology of the drug-containing solid particles, the type of hydrophobic solid substance, the type of binder and the like.

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

In addition, the hydrophobic solid substance used in the method of the present invention does not readily dissolve in the stomach and intestine, but gradually releases the drug from the drug-containing solid particles through the coating formed from the substance and the binder. A substance that is solid at room temperature is included, and a hydrophobic solid substance having a melting point in the range of 50 to 90 ° C. is particularly suitable. Such a hydrophobic solid substance is
It can be selected from higher alcohols, higher fatty acids, higher fatty acid glycerin esters, oils and fats, waxes, higher hydrocarbons and the like which are solid at room temperature.

Examples of the higher alcohols include cetyl alcohol, 14-methylhexadecanol-1, stearyl alcohol, 16-methyloctadecanol-1, eicosanol-1,18-methylnonadecanol-1,18-methyleicosa. Nor-1, docosanol-1,20-methylpheneiconanol-1,20-methyldocosanol-
1, tetracosanol-1,22-methyltricosanol-1,22-methyltetracosanol-1,24-methylpentacosanol-1,24-methylhexacosanol-
1, octacosanol-1, nonacosanol-1, mylysyl alcohol, cholesterol and the like are mentioned. Among these higher alcohols, those having 16 to 26 carbon atoms, particularly stearyl alcohol are preferable.

Examples of the higher fatty acid include myristic acid, palmitic acid, stearic acid, behenic acid, 12-hydroxystearic acid, and the like, and among these higher fatty acids, those having 14 to 22 carbon atoms, particularly stearic acid. Is preferred.

As the higher fatty acid glycerin ester, for example, a monoglyceride of the higher fatty acid and glycerin,
Diglyceride, triglyceride and the like can be mentioned.

Examples of the oils and fats include hydrogenated soybean oil, hydrogenated castor oil, sorghum, hydrogenated beef tallow, hydrogenated lard, and the like. Among these oils and fats, hydrogenated castor oil is particularly preferable.

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

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

The above hydrophobic solid substance is used in the form of fine powder. The particle size must be sufficiently smaller than the particle size of the core drug-containing solid particles. The particle size is generally less than 100 microns, preferably in the range of 10-30 microns. The release of the drug from the coated drug-containing solid particles can be controlled by appropriately selecting the particle size and the adhesion amount of the hydrophobic solid substance.

The use amount of the binder and the hydrophobic solid substance fine powder described above is not strictly limited, and the kind of drug, the shape and size of solid particles containing the drug, the kind of binder, the hydrophobic solid substance are used. Although it can be changed according to the kind and particle size of the fine powder, the binder is generally in an amount of 1 to 30 parts by weight, preferably 5 to 15 parts by weight, per 100 parts by weight of the hydrophobic solid substance. Used in. The hydrophobic solid substance is 5 to 60 parts by weight, preferably 10 to 4 parts by weight, based on 100 parts by weight of the drug-containing solid particles.
It is preferably used in an amount within the range of 0 part by weight so that the surface of the drug-containing solid particles is uniformly coated with a fine powder of the hydrophobic solid substance.

The drug-containing solid particles coated with the binder and the fine particles of the hydrophobic solid substance can be dried under the above conditions to obtain the desired sustained-release preparation.

Furthermore, according to the present invention, the sustained-release preparation thus produced is treated at a temperature equal to or higher than the melting temperature of the hydrophobic solid substance, and preferably at a temperature within the range of the melting temperature plus 30 ° C. The heat treatment can make the sustained-release coating made of the binder and the hydrophobic solid substance more dense. The conditions for the heat treatment can be the temperature range described above, preferably a temperature in the range of 70 to 90 ° C., and about 0.5 to 10 hours, preferably 1 to 3 hours. The above heat treatment can be performed, for example, by a fluidized bed dryer or the like.

Therefore, by appropriately selecting the amount and the particle size of the hydrophobic solid substance and the heat treatment condition, the thickness and the denseness of the sustained-release coating on the drug-containing solid particles are adjusted, whereby the solid particles are The release of the drug can be controlled freely.

EFFECTS OF THE INVENTION According to the method of the present invention described above, it is possible to produce a preparation that allows sustained release of a drug economically, easily and easily without using any special device.

EXAMPLES Next, the present invention will be described more specifically by showing Examples and Test Examples of the present invention.

Example 1 By a tumbling granulation method, 200 g of 40-50 mesh sugar crystals were gradually sprayed with 290 g of a 5% aqueous solution of hydroxypropylcellulose as a binder, and at the same time, anhydrous caffeine 30
Gradually sprinkle a mixture of 0 g and 500 g of corn starch, and after finishing the sprinkling, dry the granules at 60 ° C for 1 hour and use a sieve to obtain spherical granules containing caffeine with a particle size of 16 to 32 mesh. Prepared.

Using a rolling granulator with a diameter of 36 cm, rotating at 150 rpm, charging 500 g of the spherical granules containing the above caffeine therein and rolling, 8 g of ethyl cellulose as a binder on the surface of the granules ethyl alcohol While spraying the solution dissolved in 192 g at a rate of 20 ml per minute, at the same time, average particle size
100 g of 30 micron hydrogenated castor oil was slowly sprinkled on to complete the coating.

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

Example 2 Using 15 g of ethyl cellulose, 360 g of ethyl alcohol, 500 g of spherical granules (caffeine content; 300 mg / g-the same as used in Example 1), and 200 g of hydrogenated castor oil with an average particle size of 30 microns. A sustained-release preparation (Preparation 2) was obtained in the same manner as in Example 1.

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

Example 4 A sustained-release preparation (formulation 4) was obtained in the same manner as in Example 1 except that 100 g of carnauba wax having an average particle size of 15 microns was used in place of 100 g of hydrogenated castor oil having an average particle size of 30 microns.

Example 5 A sustained-release preparation (formulation 5) was obtained in the same manner as in Example 2 except that 200 g of carnauba wax having an average particle size of 15 microns was used in place of 200 g of hydrogenated castor oil having an average particle size of 30 microns.

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

Example 7 A sustained-release preparation (Formulation 7) was obtained in the same manner as in Example 1 except that 100 g of hydrogenated castor oil having an average particle size of 30 microns was used instead of 100 g of stearic acid having an average particle size of 20 microns.

Example 8 A sustained-release preparation (Preparation 8) was obtained in the same manner as in Example 2 except that 200 g of stearic acid having an average particle size of 20 μm was used instead of 200 g of hydrogenated castor oil having an average particle size of 30 μm.

Example 9 A sustained-release preparation (Formulation 9) was obtained in the same manner as in Example 3 except that 300 g of hydrogenated castor oil having an average particle diameter of 30 microns was used instead of 300 g of stearic acid having an average particle diameter of 20 microns.

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

Example 11 In the same manner as in Example 2 except that 200 g of hydrogenated castor oil having an average particle diameter of 30 microns and 200 g of stearyl alcohol having an average particle diameter of 25 microns are used, a sustained-release preparation (Formulation 1)
1) got.

Example 12 In the same manner as in Example 3 except that 300 g of hydrogenated castor oil having an average particle size of 30 μm and 300 g of stearyl alcohol having an average particle size of 25 μm were used, a sustained-release preparation (formulation) was prepared.
12) got.

Example 13 A sustained-release preparation (Preparation 13) was obtained in the same manner as in Example 1 except that 100 g of hydrogenated castor oil having an average particle size of 30 microns was used instead of 100 g of paraffin having an average particle size of 30 microns.

Example 14 A sustained-release preparation (Preparation 14) was obtained in the same manner as in Example 2 except that 200 g of paraffin having an average particle size of 30 microns was used instead of 200 g of hydrogenated castor oil having an average particle size of 30 microns.

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

Test Example 1 The spherical granules used in Example 1 were used as the control agent 1, and the preparations 1 to 3 and the control agent 1 prepared in Examples 1 to 3 were respectively analyzed by the 10th revised Japanese Pharmacopoeia, Dissolution Test Method 1. The elution property of caffeine was examined by Method 2 (purified water was used as a test solution, and samples were collected at appropriate times to measure the elution amount of caffeine).

The results are shown in FIG.

Test Example 2 For the preparations 4 to 6 and the control agent 1 prepared in Examples 4 to 6 respectively, in the same manner as in Test Example 1 above,
The elution property of caffeine was examined.

The results are shown in FIG.

Test Example 3 For the preparations 7 to 9 and the control agent 1 prepared in Examples 7 to 9 respectively, in the same manner as in Test Example 1 above,
The elution property of caffeine was examined.

The results are shown in FIG.

Test Example 4 For the formulations 10 to 11 and the control agent 1 prepared in Examples 10 to 12 respectively, in the same manner as in Test Example 1 above,
The elution property of caffeine was examined.

The results are shown in FIG.

Test Example 5 For the preparations 13 to 15 and the control agent 1 prepared in Examples 13 to 15 respectively, in the same manner as in Test Example 1 above,
The elution property of caffeine was examined.

The result is shown in FIG.

Example 16 (1) 8 g of ethyl cellulose was dissolved in 192 g of ethyl alcohol to prepare 200 g of a binder solution.

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

(2) While rolling the granules (A) obtained in (1) above,
It was heat-treated at ℃ for 1 hour to obtain a sustained-release preparation (Preparation 16).

Example 17 In accordance with Example 16 (2), the granules (A) obtained in Example 16 (1) were heat-treated at 80 ° C. for 3 hours to obtain a sustained-release preparation (Formulation 17).

Example 18 The granules (A) obtained in Example 16 (1) were heat-treated at 90 ° C. for 1 hour according to Example 16 (2) to obtain a sustained-release preparation (Preparation 18).

Example 19 The granules (A) obtained in Example 16 (1) were heat-treated at 90 ° C. for 3 hours according to Example 16 (2) to obtain a sustained-release preparation (Preparation 19).

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

(2) According to Example 16 (2), the granules (B) obtained in (1) above are heat-treated at 80 ° C. for 1 hour to produce a sustained release preparation (Preparation 20)
Got

Example 21 In accordance with Example 20 (2), the granules (B) obtained in Example 20 (1) were heat-treated at 80 ° C for 3 hours to obtain a sustained-release preparation (Formulation 21).

Example 22 The granules (B) obtained in Example 20 (1) were heat-treated at 90 ° C. for 1 hour according to Example 20 (2) to obtain a sustained-release preparation (Preparation 22).

Example 23 In accordance with Example 20 (2), the granules (B) obtained in Example 20 (1) were heat-treated at 90 ° C for 3 hours to obtain a sustained-release preparation (Preparation 23).

Test Example 6 The spherical granules used in Example 16 (1) were the control agent 1 and Example 16
The granules (A) prepared in (1) were used as preparation 24, and
Preparations 16 to 19 prepared in 19 respectively, Control Agent 1 and preparation
For No. 24, the dissolution of caffeine was examined in the same manner as in Test Example 1 above.

The result is shown in FIG.

Test Example 7 The granules (B) prepared in Example 20 (1) were used as the preparation 25, and the preparations 20 to 23 prepared in Examples 20 to 23, the control agent 1 and the preparation 25 were the same as those in the above Test Example 1. Similarly, the elution property of caffeine was examined.

The results are shown in FIG.

[Brief description of drawings]

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

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Katsushi Nakamori 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (56) Reference JP-A-51-38413 (JP, A)

Claims (9)

[Claims] 1. Microparticles of a hydrophobic solid substance which are sprayed with a water or alcohol solution of a binder on the surface of solid particles containing a drug while rolling, and which are not easily dissolved in the stomach and intestines. Is sprayed, 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 polymer substance soluble in water or alcohol. 3. The method according to claim 2, wherein the polymer substance is methyl cellulose or ethyl cellulose. 4. The method according to claim 1, wherein the alcohol is ethyl alcohol. 5. The method according to claim 1, wherein the hydrophobic solid substance is selected from higher alcohols, higher fatty acids, higher fatty acid glycerin esters, fats and oils, waxes and higher hydrocarbons, which are solid at room temperature. 6. The method of claim 5 wherein said hydrophobic solid material is selected from stearyl alcohol, stearic acid, hydrogenated castor oil, carnauba wax and paraffin. 7. The method according to claim 1, further comprising heat-treating the coated solid particles. 8. The method according to claim 7, wherein the heat treatment is carried out 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.