JPH01149719A - Long-acting drug preparation - Google Patents

Abstract

PURPOSE:To obtain a long-acting drug preparation capable of continuously releasing a drug at nearly a constant rate (0-th order release), by coating the surface of a drug-containing solid particle with a sucrose fatty acid ester and coating the surface of the coating layer with a hydrophobic substance. CONSTITUTION:The surface of a drug-containing solid particle is coated with a sucrose fatty acid ester having an HLB of preferably >=6 and the surface of the coated particle is further coated with a hydrophobic substance (e.g., an oil-soluble substance such as higher alcohol, higher fatty acid or waxes or an inorganic substance such as talc or titanium oxide). The coating substance is powder preferably having particle size sufficiently smaller than the diameter of the solid particle used as a core and the particle diameter is usually <=100mum, especially 10-30mum. The amounts of the sucrose fatty acid ester and the hydrophobic substance are 5-50wt.% and 5-60wt.% based on the solid particle, respectively.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to sustained-release preparations, and more particularly, to sustained-release preparations in which a drug continuously dissolves at a substantially constant rate (zero-order release). .

[Prior Art and its Problems] Many sustained-release preparations have been developed in the past in order to increase the effectiveness and reduce side effects when administering drugs.

Long-acting preparations originally maintain the drug concentration in the blood constant for a long period of time, thereby prolonging the onset of drug efficacy and increasing the therapeutic effect, so the elution of the drug from the preparation is almost constant over a sustained period of time. It is desirable to elute (zero-order release) at a rate of .

European Patent Application Publication No. 222411 describes a specific granule that delays the elution of a drug by providing a coating layer of a hydrophobic substance on the surface of solid particles containing the drug.

Further, JP-A-57-163320 describes a sustained-release preparation in which particulate matter is coated with an aqueous solution prepared by adding a small amount of sucrose fatty acid ester to a water-soluble polymeric substance.

However, for all of these sustained-release preparations, even if the initial dissolution is 0-order, the amount of elution decreases over time (first-order release), and the bioavailability also tends to be low. It has its drawbacks.

JP-A-61-112012 describes a special-effect tablet having zero-order release ability that is manufactured by blending a sucrose fatty acid ester and a water-soluble polymeric substance and compression molding the mixture. However, because these tablets are manufactured by compression molding, the dissolution properties change even with slight differences in tableting pressure, and compared to granules and fine granules, it is difficult to set the dosage at the time of administration. There are problems.

Capsules are also known in which a wide variety of granules with different elution behaviors are prepared and appropriate amounts of each are filled into capsules for zero-order release. However, preparing a wide variety of granules is very time-consuming and uneconomical, and there are many problems such as poor blendability due to differences in specific gravity or particle size of each granule.

[Means for Solving the Problems] As a result of various studies to solve these problems, the present inventors discovered that a sucrose fatty acid ester layer and a hydrophobic substance layer were formed on the surface of solid particles containing a drug. The present invention was completed by discovering that by providing two coating layers, the drug can be released in zero order.

The preparation of the present invention is a sustained-release preparation in which the surface of drug-containing solid particles is coated with sucrose fatty acid ester, and the surface of the sucrose fatty acid ester layer is further coated with a hydrophobic substance.

Sucrose fatty acid esters used in the present invention include esters of higher fatty acids such as caprylic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, oleic acid, and linoleic acid; One or more types of powder consisting of esters of mixed fatty acids such as hydrogenated oils may be used.
Among them, those having an HLB of 6 or more have particularly excellent zero-order release properties. The amount of sucrose fatty acid ester used is 5 to 50% by weight based on the weight of the solid particles containing the drug.

If the amount of sucrose fatty acid ester used is less than 5% by weight, 0
It will not be released next time. If it exceeds 50% by weight, the bulk of the coated preparation will increase, which is also undesirable from the viewpoint of manufacturing costs.

Further, the hydrophobic substance may be insoluble or poorly soluble in water, and may be in powder form. For example, the oil-solubility of higher alcohols (e.g. stearyl alcohol, etc.), higher fatty acids (e.g. stearic acid, etc.), higher fatty acid glycerin esters (e.g. hydrogenated castor oil, etc.), waxes (e.g. carnauba wax, etc.), and hydrocarbons (e.g. paraffin, etc.) Materials and inorganic materials such as talc, titanium oxide, magnesium aluminosilicate, etc. can be used.

Note that two or more of these hydrophobic substances may be used in combination.

The amount of hydrophobic substance used is 5-60% by weight based on the weight of the solid particles containing the drug. The amount of hydrophobic substances used is 5
If it is less than 60% by weight, it may not be possible to maintain the sustained effect of the drug, and if it exceeds 60% by weight, it is not preferred for the same reason as the case of sucrose fatty acid ester.

It is preferable that the sucrose fatty acid ester and the hydrophobic substance are in powder form, and the particle size thereof is sufficiently smaller than the particle size of the core drug. The particle size is usually 100 μm or less, preferably 10 to 30 μm.

There are no particular restrictions on the drug as long as it can further increase the therapeutic effect by making it more effective, such as analgesic and anti-inflammatory drugs such as indomethacin, ibuprofen, and acetaminophen; antihistamines such as chlorpheniramine maleate. ; Cardiovascular drugs such as nifedipine, isosorbitate nitrate, and propranol; Hematopoietic drugs such as ferrous fumarate; Antibiotics such as cephalexin; Antiasthmatic drugs such as theophylline; Salt diuretics such as potassium chloride; Examples include tranquilizers such as Dagin; muscle relaxants such as chlorphenesin carbamate; psychotropic drugs such as lithium suboxide.

Moreover, when manufacturing the formulation of the present invention, conventional binders can be used.

The binder can be prepared using a polymer compound that is soluble in water or alcohol, such as methylcellulose, ethylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, and the like.

The amount of this binder used is 1 to 30% by weight, preferably 5 to 15% by weight, based on the sum of the amounts of sucrose fatty acid ester and the hydrophobic substance used. If the amount of the binder used is less than 1% by weight, or if it exceeds 30% by weight, it may not be possible to form a uniform coating layer of sucrose fatty acid ester and hydrophobic substance on the surface of the preparation.

The formulation of the present invention can be manufactured, for example, as follows.

That is, the solid particles containing the drug are transferred and fluidized, and while a binder in which a polymer compound is dissolved in water and/or ethanol is sprayed, a certain amount (5 to 50% based on the weight of the solid particles containing the drug) is sprayed. 50%) of powdered sucrose fatty acid ester is gradually sprinkled, followed by a powdered hydrophobic substance and dried. This drying is preferably carried out by drying the drug using a fluidized bed dryer at a blowing temperature of 60 to 70° C. for about 1 hour.

[Effects of the Invention] The formulation of the present invention allows the drug to elute at a constant rate over a long period of time, and shows an elution rate close to 100%, and the drug elution rate can be adjusted by changing the amount of the hydrophobic substance. can do. Furthermore, since compression molding is not required, elution control is easy, dosage setting is easy, there are no problems with compatibility, and production is easy.

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

Example 1 500 spherical granules of 16-32 meshes (theophylline content: 500 mg/g) rolling in a coating device
While spraying a binder solution (prepared by dissolving 8 g of ethyl cellulose in 192 g of ethanol) onto the surface of the DK ester F- with an average particle size of 30 μm and HL B 9.5.
90 [Product name of sucrose fatty acid ester, Daiichi Kogyo Seiyaku (
After spraying, 100g of powder of Crown Talc DRA [manufactured by Co., Ltd.] with an average particle size of 30 μm was gradually sprinkled.
The coating was completed by gradually scattering 50 g of powder of talc (trade name, manufactured by Matsuzai Sangyo Co., Ltd.). 70°
A sustained-release preparation was obtained by drying at C for 1 hour.

Example 2 Binder solution of 10 g of ethylcellulose dissolved in 240 g of ethanol, spherical granules (indomethacin content;
500mg/g) 500g, average particle size 30μm, H
150 g of DK Ester F-90 powder with LB9.5 and talc SW with an average particle size of 30 μm [talc brand name,
A sustained-release preparation was obtained in the same manner as in Example 1 except that 50 g of powder manufactured by Asada Seifun Co., Ltd. was used.

Example 3 A binder solution in which 12 g of ethyl cellulose was dissolved in 288 g of ethanol, spherical granules (cephalexin content;
500mg/g) 500g, average particle size 30μm,
A sustained-release preparation was obtained in the same manner as in Example 1, except that 200 g of DK ester F-90 powder with HLB 9.5 and 50 g of talc SW powder with an average particle size of 309 m were used.

Example 4 Binder solution in which 10 g of ethyl cellulose was dissolved in 240 g of ethanol, 500 g of spherical granules (chlorphenesin carbamate content; 500 mg/g), average particle size of 30 am, DK ester F-90 with HL B9.5
A sustained-release preparation was obtained in the same manner as in Example 1, except that 100 g of powder and 100 g of crown talc DRA powder with an average particle size of 30 μm were used.

Example 5 Crown talc DRA powder 10 with an average particle size of 30 μm
A sustained-release preparation was obtained in the same manner as in Example 4, except that 100 g of Lovely Wax 101 [trade name of hydrogenated castor oil, manufactured by Yoken Fine Chemical Co., Ltd.] powder with an average particle size of 30 μm was used instead of 0 g. .

Example 6 Crown talc DRA powder 10 with an average particle size of 30 μm
Polishing wax 103 with an average particle size of 15 μm instead of 0 g [trade name of carnauba wax, Freund Sangyo (
A sustained-release preparation was obtained in the same manner as in Example 4, except that 100 g of powder from Co., Ltd. was used.

Example 7 Crown talc DRA powder 10 with an average particle size of 30 μm
Paraffin 100 with an average particle size of 30 μm instead of 0 g
A sustained-release preparation was obtained in the same manner as in Example 4, except that g was used.

Example 8 Crown talc DRA powder 10 with an average particle size of 30 μm
Stearic acid 10 with an average particle size of 20 μm instead of 0 g
A sustained-release preparation was obtained in the same manner as in Example 4, except that 0 g was used.

Example 9 Average particle size 30jm, HL Instead of DK Ester F-90 powder of B9.5, average particle size 25jm, HL
A sustained-release preparation was obtained in the same manner as in Example 1, except that 100 g of powder of B1 mung sugar ester S-170 (trade name of sucrose fatty acid ester, manufactured by Mitsubishi Kasei Foods Co., Ltd.) was used.

Example 10 Average particle size 301m, HL Instead of DK Ester F-90 powder of B9.5, average particle size 25jm, HL
A sustained-release preparation was obtained in the same manner as in Example 1, except that 100 g of powder of B2 DK ester F-20 (trade name of sucrose fatty acid ester, manufactured by Daiichi Kogyo Seiyaku Co., Ltd.) was used.

Example 11 Average particle size 30Jm, instead of DK-r-Stel F-90 powder with HL B9.5, average particle size 30Jm,
100 g of powder of DK ester F-50 of HL B6 [trade name of sucrose fatty acid ester, manufactured by Daiichi Kogyo Seiyaku Co., Ltd.]
A sustained-release preparation was obtained in the same manner as in Example 1 except that .

Example 12 An average particle size of 301 m was used instead of DK Ester F-90 powder with an average particle size of 30 Jm and HL B9.5.
HL B13 DK ester F-140 [trade name of sucrose fatty acid ester, manufactured by Daiichi Kogyo Seiyaku Co., Ltd.] powder 10
A sustained-release preparation was obtained in the same manner as in Example 1, except that 0 g was used.

Example 13 DK-r with average particle diameter of 30 Jm and HL B9.5
-Instead of Stell F-90 powder with an average particle size of 30 Jm
, HL B15 myoto sugar ester S-1
Example 1 except that 100 g of powder of 570 [trade name of sucrose fatty acid ester, produced by Mitsubishi Kasei Foods Co., Ltd.] was used.
A sustained-release preparation was obtained in the same manner as above.

Test Example (Sample Preparation) (1) Spherical granules of 16 to 32 meshes (theophylline content: 500 mg/g) were prepared as follows. Example 4 except that the above theophylline-containing spherical granules were used.
Prepare the formulations in the same manner as in 5.6.7, and prepare each sample 1.
．． 2.3.4.

■6g of ethyl cellulose to 144g of ethanol4. :i
Control Sample 1 was a formulation prepared in the same manner as in Example 1, except that the binder solution was used in the same manner as in Example 1, and the hydrophobic substance was not used.

The same procedure as in Example 1 was carried out except that a binder solution containing 6 g of ethyl cellulose dissolved in 144 g of ethanol was used, sucrose fatty acid ester powder was not used, and 100 g of Lovely Wax 101 powder with an average particle size of 30 μm was used as the hydrophobic substance. A formulation was prepared and used as control sample 2.

(Test) For sample 1.2.3.4 and control sample 1.2, the 10th revised Japanese Pharmacopoeia dissolution test method 2 (purified water is used as the test solution, samples are taken at appropriate times and theophylline The dissolution properties of theophylline were investigated by measuring the elution amount. The results are shown in FIG.

It is clear from FIG. 1 that the elution of theophylline in sample 1.2.3.4 is zero-order elution, and the elution of theophylline in control sample 1.2 is not zero-order elution.

[Brief explanation of the drawing]

FIG. 1 is an elution rate-time characteristic diagram for a sample of the present invention and a control sample.

Claims (3)

[Claims] (1) A sustained-release preparation in which the surface of solid particles containing a drug is coated with a sucrose fatty acid ester, and the surface of the sucrose fatty acid ester layer is further coated with a hydrophobic substance. (2) The sustained-release preparation according to claim 1, wherein the content of the sucrose fatty acid ester is 5 to 50% by weight based on the weight of the solid particles containing the drug. (3) The hydrophobic substance is a higher alcohol, a higher fatty acid, a higher fatty acid glycerin ester, a wax, a hydrocarbon,
The sustained-release preparation according to claim 1, which is one or more powdered substances selected from the group consisting of talc, titanium oxide, and magnesium aluminosilicate.