JP2006306766A - Theophylline sustained-release particulate formulation and its manufacturing method - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a theophylline sustained-release particulate formulation. <P>SOLUTION: The method comprises forming nucleus particles by spraying a binder on theophylline by a gas suspension method to coat and granulate and spraying a solution containing a water-insoluble polymer, e.g. ethylcellulose, and a lubricant by the same suspension method to coat and granulate in order to manufacture efficiently and conveniently a theophylline-containing particulate formulation having sustained-release properties. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

The present invention relates to a theophylline sustained-release fine particle preparation and a method for producing the same. The present invention also relates to a dry syrup preparation comprising a theophylline sustained-release fine particle preparation of once-twice daily administration and a method for producing the same.

Theophylline is a drug that is frequently used as a treatment for bronchial asthma, but its half-life is as short as 6 hours, so it can be released once or twice a day for tablets, granules, syrups, and dry syrups Sex preparations are mainly used. As a technique relating to theophylline sustained-release fine particle preparation, Japanese Patent Application Laid-Open No. 61-109711 (Patent Document 1) discloses a method for producing a theophylline controlled-release powder by a submerged drying method. However, the production by the submerged drying method requires special production equipment and explosion-proof equipment, and requires a large amount of cost for recovering and treating the organic solvent and the like. Japanese Patent Application Laid-Open No. 2001-106627 (Patent Document 2) discloses a method for producing a sustained-release fine particle preparation in which a pulverized product of a theophylline and ethylcellulose mixture is coated with ethylcellulose. Here, adhesion and aggregation of the theophylline powder are solved by obtaining theophylline fine powder by crushing the kneaded material, but the theophylline fine powder has a particle size as small as about 20μm, and a large amount of base to control release Therefore, it is not a preferable method because a long time is required and a large amount of cost is required.

JP 61-109711 A JP 2001-106627 A

An object of the present invention is to provide a theophylline sustained-release fine particle preparation which does not have the above-mentioned drawbacks. In particular, it is to manufacture by an inexpensive and simple method using general manufacturing equipment.

As a result of intensive studies to solve the above problems, the present inventors have coated and granulated the core particles containing theophylline, preferably by pulverizing theophylline by spraying a binder by an air suspension method. It has been found that theophylline-containing fine particles having sustained release properties can be produced efficiently and simply by spraying the obtained core particles with a liquid mainly containing a water-insoluble polymer by the air turbidity method and coating granulation.

That is, the present invention
(1) A theophylline sustained-release fine particle formulation, wherein core particles containing theophylline are coated and granulated with a base containing a water-insoluble polymer and a lubricant.
(2) The sustained-release fine particle preparation according to (1), wherein the core particles containing theophylline are those obtained by coating and granulating theophylline with a binder.
(3) A theophylline sustained-release fine particle preparation, wherein core particles containing theophylline are coated and granulated with a base containing a water-insoluble polymer, a lubricant and a water-soluble polymer.
(4) Theophylline sustained-release fine particle preparation according to (3), wherein the core particles containing theophylline are those obtained by coating and granulating theophylline with a binder.
(5) Theophylline sustained-release fine particle formulation according to any one of (1) to (4), wherein the water-insoluble polymer has a property of not dissolving in a physiological pH range, and the lubricant is a fatty acid metal salt.
(6) Theophylline sustained-release fine particle formulation according to (5), wherein the water-insoluble polymer is a cellulose ether.
(7) Theophylline sustained-release fine particle formulation according to (3) or (4), wherein the water-soluble polymer is a water-soluble cellulose derivative.
(8) Theophylline sustained-release fine particle preparation according to (2) or (4), wherein the binder has a property of dissolving in a physiological pH range.
(9) Theophylline sustained-release fine particle preparation according to (8), wherein the binder is a (meth) acrylic acid polymer.
(10) The preparation according to (1) to (9), wherein the core particles containing theophylline have an average particle diameter of 150 μm or less, and the theophylline sustained-release fine particle preparation has an average particle diameter of 200 μm or less.
(11) The preparation according to (10), wherein the theophylline sustained-release fine particle preparation has an average particle size of 150 to 50 μm or less.
(12) A dry syrup containing the theophylline sustained-release fine particle preparation according to (11).
It is.

The present invention is preferable because a theophylline sustained-release fine particle preparation can be efficiently provided by a simple operation compared with the conventional method.

The theophylline sustained-release fine particle preparation of the present invention is obtained by coating and granulating core particles containing theophylline with a base containing a water-insoluble polymer and a lubricant.
In the present invention, theophylline-containing core particles can be used as they are, theophylline crystals, or a pulverized product thereof. Usually, theophylline crystals or the pulverized product thereof are subjected to treatment such as granulating with a binder. used. Preferably, theophylline-containing core particles are obtained by pulverizing theophylline crystals with a small amount of a surfactant and a lubricant, optionally further with a fluidizing agent, and coating and granulating the resulting pulverized product with a binder. The

Specific examples of the lubricant used when pulverizing the theophylline crystals include fatty acid metal salts such as calcium stearate and magnesium stearate and talc. Surfactants include glycerin such as glyceryl monostearate. Examples include fatty acid esters and sodium lauryl sulfate. Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, calcium silicate and the like, and salts thereof.

The binder used in the present invention is not particularly limited as long as it has the property of being dissolved in a solvent and granulating theophylline and capable of being dissolved in a physiological pH range (pH 1 to pH 8). . Specifically, water-soluble cellulose derivatives such as hydroxypropylcellulose and hydroxypropylmethylcellulose, pH-dependent cellulose derivatives such as hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate, and methacrylic acid copolymer L and aminoalkyl methacrylate copolymer And (meth) acrylic acid polymers such as E. Among these, methacrylic acid copolymer L is preferable.
The usage-amount of a binder is 5-50 weight% normally with respect to theophylline, Preferably, it is 8-30 weight%.

The core particles containing theophylline used in the present invention have an average particle size of usually about 150 μm or less, preferably 100 μm or less, particularly preferably 80 to 40 μm.

In the present invention, theophylline-containing core particles are coated and granulated with a base containing a water-insoluble polymer and a lubricant.
A water-insoluble polymer is a substance that does not dissolve within a physiological pH range. Specific examples include cellulose ethers such as ethyl cellulose and ethyl methyl cellulose, and (meth) acrylic acid polymers such as aminoalkyl methacrylate copolymer RS. Of these, ethyl cellulose is preferred.
The amount of the water-insoluble polymer used is usually 20 to 60% by weight, preferably 30 to 50% by weight, based on the core particles containing theophylline.

In the case of coating granulation with a water-insoluble polymer, in order to obtain fine particles in a good yield, usually a lubricant or a fluidizing agent, preferably a lubricant alone or a lubricant and a fluidizing agent are added to the spray liquid. It is preferable to add to prevent aggregation.
Specific examples of the lubricant include fatty acid metal salts such as calcium stearate and magnesium stearate, and talc. Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, silicic acid such as calcium silicate, and salts thereof.
The lubricant may be used in an amount capable of preventing aggregation when spraying the water-insoluble polymer and coating granulation, and is usually 2 to 30% by weight, preferably 5 to 20% by weight based on the water-insoluble polymer. %used.

In the present invention, the theophylline elution rate can be adjusted by the amount of water-insoluble polymer added, but the elution rate can also be increased by adding a water-soluble polymer to the water-insoluble polymer. Examples of the water-soluble polymer include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose and the like, and preferably hydroxypropylcellulose.

The theophylline sustained-release fine particle preparation obtained in the present invention has an average particle size of generally about 200 μm or less, preferably 150 μm or less, more preferably 150 to 50 μm, and most preferably 120 to 70 μm.

The coated granulation in the present invention is performed by an apparatus capable of spraying a water-insoluble polymer or the like dissolved in a solvent such as ethanol onto the core particles containing theophylline by an air suspension method and coating granulation. As these apparatuses, a coated granulator having a stirrer such as a rotor and rotary blades at the bottom of the granulation section is preferable. Specifically, a flow coater with a rotor container (Freund industry), Spiraflow (Freund industry), CF Examples thereof include a centrifugal fluidized bed apparatus or a rolling fluidized bed apparatus such as a granulator (Freund Sangyo), a granurex (Freund Sangyo), a multiplex (Paurek), an agromaster (Hosokawa Micron), and a numeralizer (Dalton).
In the present invention, the same apparatus as described above is also used when core particles containing theophylline are produced by treating a pulverized product of theophylline crystals with a binder to coat granulate.

The theophylline sustained-release fine particle preparation obtained in the present invention can be used in various dosage forms, and is particularly suitable for use as a dry syrup. In that case, it can combine with various additives. For example, excipients (crystalline cellulose, starch, lactose, sucrose, mannitol, xylitol, erythritol, etc.), binders (hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, etc.), suspending agents (crystalline cellulose / carmellose sodium, Carmellose sodium, carmellose, etc.), sweeteners (sodium saccharin, aspartame, acesulfame K, glucose, sucrose, sorbitol, mannitol, maltitol, erythritol, etc.), disintegrants (carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, low substitution Hydroxypropyl cellulose, etc.), lubricants (calcium stearate, magnesium stearate, etc.), fluidizing agents (light anhydrous silicic acid, hydrous carbon dioxide) Arsenide, calcium silicate, silicic acid and its salts such as magnesium metasilicate aluminate), wetting modifiers (polyethylene glycol, glycerine, propylene glycol, etc.) and include perfumes.

Hereinafter, the present invention will be described in detail with reference to examples and test examples, but the scope of the present invention is not limited to these examples.

Example 1
100 parts of theophylline, 0.5 parts of calcium stearate and 1 part of sodium lauryl sulfate were mixed and pulverized with an impact pulverizer sample mill (manufactured by Nara Machinery) to obtain a pulverized theophylline having an average particle size of 18 μm. After 1015g of theophylline pulverized product is put into Agromaster 2PJ (made by Hosokawa Micron), it is fluidized at an air supply temperature of 80 ° C, and a solution of 120g of methacrylic acid copolymer L (Eudragit L-100, Degussa) dissolved in 1080kg of ethanol is sprayed and granulated The product was passed through an 80M sieve to obtain core particles having an average particle size of 60 μm. After 800 g of core particles were put into Agromaster 2PJ, it was fluidized at an air supply temperature of 80 ° C., and a liquid in which 225 g of ethylcellulose (Ethocel # 10, Dow Chemical) and 45 g of calcium stearate were dissolved and dispersed in 2730 g of ethanol was sprayed. The granulated material was sieved with an 80M sieve to obtain theophylline sustained-release fine particles having an average particle diameter of 90 μm.

Example 2
A solution obtained by adding 800 g of theophylline pulverized product described in Example 1 to Agromaster 2PJ (manufactured by Hosokawa Micron), fluidizing at a supply temperature of 80 ° C., and dissolving 400 g of methacrylic acid copolymer L (Eudragit L-100, Degussa) in 3.6 kg of ethanol. Was sprayed, and the granulated material was sieved with an 80M sieve to obtain core particles having an average particle diameter of 70 μm. After adding 750g of core particles to Agromaster 2PJ, fluidize at an air supply temperature of 80 ℃, 360g of ethylcellulose (Etocel # 10, Dow Chemical), 36g of calcium stearate (Nitto Kasei) and 72g of hydroxypropylcellulose L (Nippon Soda) 4332g of ethanol The solution dissolved and dispersed in was sprayed. The granulated material was sieved with an 80M sieve to obtain a sustained-release fine particle preparation having an average particle diameter of 102 μm.

Example 3
1015 g of theophylline pulverized product described in Example 1 was charged into Agromaster 2PJ (manufactured by Hosokawa Micron) and then fluidized at a supply temperature of 80 ° C., and a solution of 120 g of methacrylic acid copolymer L (Eudragit L-100, Degussa) dissolved in 1080 kg of ethanol Spraying was performed, and the granulated product was sieved with an 80M sieve to obtain core particles having an average particle size of 55 μm. After putting 750g of core particles into Agromaster 2PJ, fluidize at an air supply temperature of 80 ℃, 240g of ethyl cellulose (Ethocel # 10, Dow Chemical), 24g of calcium stearate, 12g of hydrous silicon dioxide (Carplex # 80, DSL Japan) 2924g of ethanol The solution dissolved and dispersed in was sprayed. The granulated product was sieved with an 80M sieve to obtain a theophylline sustained-release fine particle preparation having an average particle size of 98 μm.

Example 4
After charging 5 kg of theophylline pulverized product described in Example 1 into Spiraflow type 5 (manufactured by Freund Sangyo), it was fluidized at an air supply temperature of 80 ° C., and 0.6 kg of methacrylic acid copolymer L (Eudragit L-100, Degussa) was 5.4 kg of ethanol. The solution dissolved in was sprayed, and the granulated material was sieved with an 80M sieve to obtain core particles having an average particle diameter of 62 μm. After 3.8 kg of core particles are put into Spiraflow type 5, fluidized at an air supply temperature of 80 ° C, 1.8 kg of ethylcellulose (Etocel # 10, Dow Chemical), 0.09 kg of hydrous silicon dioxide (Carplex # 80, DSL Japan), steer A solution obtained by dissolving and dispersing 0.18 kg of calcium phosphate (Nitto Kasei) and 0.09 kg of hydroxypropylcellulose L (Nippon Soda) in 21.84 kg of ethanol was sprayed. The granulated product was sieved with an 80M sieve to obtain a theophylline sustained-release fine particle preparation having an average particle size of 104 μm.

Example 5
2 kg of sustained-release fine particles obtained in Example 4, 0.31 kg of crystalline cellulose / carmellose sodium (Avicel RCA-591NF, Asahi Kasei) and 3.59 kg of D-mannitol were added to Spiraflow type 5, and the air supply temperature was 80 ° C. Fluidized and sprayed with a solution prepared by dissolving 200 g of hydroxypropylcellulose L (Nippon Soda), 40 g of sodium saccharin and 80 g of polyethylene glycol 6000 in water to obtain a granulated product. The obtained granulated product was mixed with hydrous silicon dioxide and a fragrance to obtain a theophylline dry syrup.

Test example 1
Table 1 shows the theophylline elution rate from the sustained-release fine particles obtained in Examples 1 to 4. The dissolution test was conducted by using a solution of 900 mL of JP 2 disintegration test method 2 solution heated to 37 ° C and adding polysorbate 80 to a final concentration of 0.1%. Method, 50 rpm). As a result, it was confirmed that theophylline was eluted from the sustained-release fine particles of the present invention.

(Table 1)

Test example 2
The elution behavior of the dry syrup obtained in Example 5 is shown in FIG. The dissolution test was carried out using the JP Dissolution Test Method 1st liquid (JP1) or 2nd liquid (JP2) 900mL heated to 37 ° C, and the JP Dissolution Test Method 2 (paddle method, 50rpm). Carried out. As a result, it was confirmed that elution of theophylline from the dry syrup of the present invention was sustained release, and the release was not dependent on pH.

Test example 3
The dry syrup obtained in Example 5 was compared with the commercially available twice-daily theophylline sustained-release dry syrup and the plasma drug concentration at the time of single administration. The test was conducted by the crossover method with 20 healthy adult males. The administration was performed after a high fat meal, and an amount corresponding to 200 mg as theophylline was administered. As a result, the dry syrup preparation of Example 5 showed the same change in plasma drug concentration as the commercially available preparation.

The elution behavior of theophylline of the dry syrup obtained in Example 5 is shown.

Claims (12)

A theophylline sustained-release fine particle formulation, wherein core particles containing theophylline are coated and granulated with a base containing a water-insoluble polymer and a lubricant. 2. The sustained-release fine particle preparation according to claim 1, wherein the core particles containing theophylline are those obtained by coating and granulating theophylline with a binder. A theophylline sustained-release fine particle preparation, wherein core particles containing theophylline are coated and granulated with a base containing a water-insoluble polymer, a lubricant and a water-soluble polymer. 4. The theophylline sustained-release fine particle formulation according to claim 3, wherein the core particles containing theophylline are those obtained by coating and granulating theophylline with a binder. The theophylline sustained-release fine particle preparation according to claims 1 to 4, wherein the water-insoluble polymer has a property of not dissolving in a physiological pH range, and the lubricant is a fatty acid metal salt. The theophylline sustained-release fine particle preparation according to claim 5, wherein the water-insoluble polymer is a cellulose ether. The theophylline sustained-release fine particle preparation according to claim 3 or 4, wherein the water-soluble polymer is a water-soluble cellulose derivative. The theophylline sustained-release fine particle preparation according to claim 2 or 4, wherein the binder has a property of dissolving in a physiological pH range. The theophylline sustained-release fine particle preparation according to claim 8, wherein the binder is a (meth) acrylic acid polymer. The preparation according to any one of claims 1 to 9, wherein the core particles containing theophylline have an average particle diameter of 150 µm or less, and the theophylline sustained-release fine particle preparation has an average particle diameter of 200 µm or less. The preparation according to claim 10, wherein the theophylline sustained-release fine particle preparation has an average particle size of 150 to 50 µm or less. A dry syrup comprising the theophylline sustained-release fine particle preparation according to claim 11.

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