JPH0753355A - Pharmaceutical preparation having controlled releasability and long-acting preparation containing the pharmaceutical preparation - Google Patents

Abstract

PURPOSE:To provide a pharmaceutical preparation capable of controlling the release of drug in high accuracy and enabling the zeroth order release by using a water-dispersed coating agent of a water-insoluble polymer (aqueous polymer latex) without using an organic solvent and attaining sustained release function by an economical, easy and safe production process. CONSTITUTION:This sustained-release pharmaceutical preparation is produced by laminating (a) a layer containing a drug having high affinity to water to (b) a core substance, further laminating (c) a powder coating layer consisting of corn starch and/or talc to the product to obtain a quickly releasing preparation, coating the preparation with a high-molecular substance membrane layer formed from an aqueous latex, essentially insoluble in water and having a drug-releasing characteristic independent of hydrogen ion concentration and compounding the obtained preparation having multi-layer structure and controlled drug-releasability in an amount of 25-400% with a quickly releasing pharmaceutical preparation. A stable release control can be achieved by the use of a small amount of the coating agent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention provides a preparation in which the release of a drug having a high affinity for water is precisely controlled and a sustained-release preparation containing the same.

[0002]

2. Description of the Related Art Conventionally, a sustained-release technique has been known in which the surface of a solid substance containing a drug is coated to control the release of the drug. The coating and coating method include a method of laminating different types of pH-dependent film coatings in multiple layers, or a multi-layer in which a sustained-release layer is formed by a film layer containing hydrogenated oil and an immediate-release layer is surrounded on the outer side. Granules (JP-A 1-1
97433) or as a method not using an organic solvent, a non-melting elution control in which a fusible substance melted by heating is formed around a drug-containing layer formed as a binder, and a fusible substance melted by heating is formed as a binder. Examples include a method of achieving sustained release by a coating layer containing an agent (JP-A-4-31524).

[0003]

However, laminating a plurality of sustained-release film layers or pH-dependent film coating film layers complicates the manufacturing process control. Further, in order to achieve appropriate sustained release, a large amount of coating base is used, and as a result, there is a problem that the drug is trapped in the coating layer film and the drug utilization rate becomes insufficient. In addition, a multi-layered granule in which the drug in the granule is divided and integrated into a sustained release part and an immediate release part is efficiently produced,
A long-acting preparation that releases the drug stably over a long period of time has been obtained. However, since an organic solvent is used in the method for producing this preparation, it is necessary to thoroughly ensure safety for workers at the production site in the work environment, and there are problems such as recovery of the organic solvent and correspondence to explosion-proof equipment. Further, since such an organic solvent is used in a relatively large amount, it is not an economical manufacturing method, resulting in problems such as an increase in product cost. On the other hand, the use of a fusible substance by heating and melting without using a solvent, in order to achieve stable quality control such as drug release control,
Process control such as heating and cooling in the granulation and coating process is extremely strictly required. Alternatively, the cleaning after the work is complicated and takes time, and the work effect is reduced. Further, a product using a fusible substance having a relatively low melting point has a problem that the quality is deteriorated under high temperature storage.

[0004]

SUMMARY OF THE INVENTION In view of the above points, the present invention is directed to the infiltration and sustained release of a drug having a high affinity for water from the drug layer into the sustained release membrane layer during the aqueous sustained release coating operation. It is an object of the present invention to eliminate the early release of the drug from the formulation due to the formation of water channels in the membrane layer and to obtain a formulation with controlled release with high accuracy and a sustained release formulation containing the same. More specifically, the present invention relates to one of cornstarch or talc, which is formed by coating a core substance with a powder spraying agent consisting of a drug and an additive and a binding liquid, and subsequently using the same binding liquid. Alternatively, both are laminated to form a powder coating layer, and then dried to obtain an immediate release preparation of elementary granules, which does not substantially dissolve in water in an aqueous system and the drug release characteristics are hydrogen ion concentration. By coating with a polymer substance that does not depend on the drug layer, the drug layer and the polymer substance membrane layer are blocked, and the drug is rapidly released from the formulation due to the infiltration of the drug having a high affinity for water into the sustained-release membrane layer. Disclosed is a formulation with controlled release capable of eliminating release and enabling zero-order release, and a sustained-release formulation containing the same.

Thus, the controlled release formulation of the present invention comprises:
a. The core material, b. Laminating a layer containing a drug having a high affinity for water, and further c. An immediate release preparation having a powder coating layer made of cornstarch or talc or both, d. It is characterized by having a multi-layer structure formed by coating a membrane layer of a polymeric substance which is substantially insoluble in water and whose drug release characteristics do not depend on hydrogen ion concentration.

Further, the sustained-release preparation of the present invention comprises (A) the above-mentioned controlled release preparation and (B) a. The core material, b.
Laminating a layer containing a drug having a high affinity for water, and further c.
An immediate-release preparation having a powder coating layer comprising one or both of cornstarch and talc, and (B) an immediate-release preparation for a drug having a high affinity for water contained in a preparation with controlled release (A). It is characterized in that the content of the drug having a high affinity for water contained in the preparation is in the range of 25 to 400% by weight.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION a. Examples of the core substance include sucrose granules, sucrose / corn starch mixed granules, crystalline cellulose granules, and lactose / crystalline cellulose mixed granules, which are generally supplied for producing spherical granules. However, the present invention is not limited by the kind of the core substance or the production method, and any pharmaceutically acceptable component can be used as the core substance, and there is no problem even if it is used after being appropriately granulated.

An essential component b. As a drug having a high affinity for water, dl-chlorpheniramine maleate, d-
Chlorpheniramine maleate, phenylpropanolamine hydrochloride, caffeine and anhydrous caffeine, mequitazine, belladonna total alkaloids, glycyrrhizic acid,
Glycyrrhizic acid potassium or ammonium salt,
Phenylephrine hydrochloride, dl-methylephedrine hydrochloride,
d-methylephedrine hydrochloride, methoxyphenamine hydrochloride, datura extract, isopropamide iodide, funnel extract, lysozyme chloride, bromelain, licorice extract,
Sodium benzoate caffeine, acetaminophen,
Aspirin, isothipendyl hydrochloride, diphenylpyraline hydrochloride, diphenhydramine hydrochloride, difeterol hydrochloride,
Triprrolidine hydrochloride, triperenamine hydrochloride, tonzylamine hydrochloride, phenetadine hydrochloride, metzirazine hydrochloride, aloclamide hydrochloride, cloperastine hydrochloride, hydrobromic acid, dextromethorphan, codeine phosphate, dihydrocodeine phosphate, noscapine hydrochloride, dl-methylephedrine, guaiacol sulfone Potassium acid, guaifenesin, vitamin B1 and derivatives thereof and salts thereof, vitamin B2 and derivatives thereof and salts thereof,
Examples of components include vitamin C and its derivatives and salts thereof, vitamin B12 and its derivatives and salts thereof, sodium salicylate, aminoacetic acid, etc., but the drugs used in the present invention are limited to the above drug group However, any pharmaceutically acceptable active ingredient can be used in combination.

Laminated to the outside of the drug layer c. As the powder coating layer consisting of cornstarch or talc, or both, it is preferable to use both cornstarch and talc. The blending amount and the ratio thereof differ depending on the affinity of the drug with water, but the higher the affinity, the higher the talc. It is preferable that the ratio and amount of are large. Generally, the ratio of corn starch and talc is preferably 1: 4 to 24: 1, more preferably 1: 1 to 9: 1. The blending amount of corn starch and talc is preferably 1 to 30% by weight, more preferably 2 to 10% by weight based on the whole elementary granule immediate release preparation including the layer.

It is substantially insoluble in water and the release characteristics of the drug do not depend on the hydrogen ion concentration. D. As the polymer substance, a sustained-release coating agent such as ethyl cellulose, ethyl methacrylate / trimethylammonium methacrylic acid trimethylammonium copolymer (Eudragit RS: trade name) is particularly preferable. Although the coating agent can be used alone, it can be used in the form of an aqueous latex by mixing an appropriate additive and dispersing it in water. Further, a plasticizer, a lubricant, a water-soluble polymer, an enteric base and the like may be appropriately used in combination. Further, if desired, it can be used by dissolving it in a suitable solvent.

Specifically, as the plasticizer, fatty acid monoglycerin ester (acetylated monoglyceride), triethyl citrate, triacetin, dibutyl sebacate,
Diethyl phthalate etc. can be mentioned. Further, examples of the lubricant include stearic acid and salts thereof. As the water-soluble polymer to be added, hydroxypropylmethyl cellulose, hydroxypropyl cellulose,
Examples thereof include gelatin, starch, sodium alginate, methyl cellulose, polyvinylpyrrolidone and the like. Examples of the enteric base include hydroxypropyl methylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylic acid / methyl methacrylate copolymer, and cellulose acetate phthalate. d. The coating amount of the sustained-release coating material as a polymer substance is preferably 5 to 20%, more preferably 8 to 14% by weight ratio with respect to the total weight of the whole elementary granule immediate release preparation. If it exceeds 20% by weight, the drug utilization rate in the digestive tract may be significantly reduced.
If it is less than wt%, it may be difficult to constantly maintain the sustained release mechanism.

A general method for producing the controlled release preparation and sustained release preparation of the present invention is shown below. While spraying a binding solution prepared by dissolving a water-soluble polymer in water onto the core substance, a powder-dispersing agent containing a drug having a high affinity for water as an essential component and an additive is laminated to form spherical granules. Let it form. Subsequently, the powder mixture of cornstarch and talc is surrounded and laminated around the spherical granules under spraying of the binding solution to form a powder coating layer, which is then dried to obtain an immediate release preparation for elementary granules. The series of powder lamination methods is not particularly limited, but rolling CF granulation is preferable as long as the formation of spherical granules is achieved, but granulation by a pan coater or fluidization may be used.

Next, a polymer substance, which is a sustained-release coating agent, is sprayed onto the elementary granule immediate release preparation in the form of an aqueous latex,
A sustained release membrane layer is formed to obtain a controlled release preparation having a multi-layered structure. The method of spraying the polymer substance is not particularly limited as in the case of the above powder lamination method, but a rolling CF device or a fluidizing device is preferable. Further, the spherical granules or elementary granules immediate release preparation before forming the sustained release membrane layer obtained in the middle of the above production method is provided as an immediate release preparation without drug release control.

Thus, the (A) controlled release preparation and the (B) immediate release preparation of the present invention obtained by the above-mentioned production method are contained in the (A) controlled release preparation. 25 to 400 parts of the drug having a high affinity for water contained in the immediate release preparation (B) per 100 parts by weight of the drug having a high affinity for water
The sustained-release preparation of the present invention can be obtained by blending so as to be contained in an amount of 50 parts by weight, preferably 50 to 200 parts by weight. The (A) controlled-release preparation of the present invention should be mixed with an immediate-release preparation other than the (B) immediate-release preparation of the present invention at an appropriate mixing ratio to prepare a sustained-release preparation. You can also

[0015]

EFFECT OF THE INVENTION Using the controlled release formulation of the present invention,
Various elution patterns can be freely controlled by combining granules having different elution rates or combining with granules having a fast elution. According to the present invention, an accurate dispersion of a drug can be controlled by a water-dispersible coating agent (water-based polymer latex) of a water-insoluble polymer without using an organic solvent, and economical, simple and safe production is possible. The method provides a sustained release function. Furthermore, stable release control is possible with a small amount of coating agent.

Further, the controlled-release preparation of the present invention and the sustained-release preparation containing the same are used as granules as they are, or by filling them into capsules, sachets, and tablets to obtain tablets. It can also be used as a base material. Specific applications include drugs for rhinitis, cold remedies, antipyretic analgesics and the like.

[0017]

The present invention will be described in more detail with reference to Examples and Experimental Examples below, but these do not limit the present invention.

Example 1 As a core substance, 840 g of nonpareil 103 (purified sucrose manufactured by Freund, particle size 500 to 710 μm) was put into a CF granulator (CF-360 type machine manufactured by Freund), and the rotation speed of the rotor was 160 r. ． p. m. Hydroxypropyl cellulose (Nippon Soda, HPC-L)
While spraying 230 g of a 4% (W / W) aqueous solution of 4% on the core substance, the powder-dispersing agent and the powder-coating agent, which are preliminarily and homogeneously mixed as shown in the composition of Table 1 below, are gradually surrounded and laminated in a non-pareil. After air-dried at 60 ° C. for 8 hours, a spherical elementary granule having a particle diameter of 710 to 1180 μm was obtained using a sieve. 500 g of the elementary granules were put into the same CF granulation apparatus as described above, and the rotation speed of the rotor was 180 rpm. p. m. While controlling the temperature of the product to 38 ° C, the water-based latex shown in the composition of Table 1 below (Aquacoat, manufactured by Asahi Kasei Kogyo)
Aqueous dispersion 350 containing a sustained-release coating material containing
g was sprayed to form a sustained-release film layer by performing an aqueous sustained-release coating, and curing was performed at 70 ° C. for 1 hour to obtain a controlled-release granule formulation for rhinitis (controlled-release formulation). Aquacoat (trade name) is an aqueous latex having a solid content of 30% by weight, and the solid content is 87% by weight of ethyl cellulose, 4% by weight of sodium lauryl sulfate, and 9% by weight of cetanol.

[0019]

[Table 1] Component weight (g) Powder spraying agent d-Chlorpheniramine maleate 19 Phenylpropanolamine hydrochloride 378 Belladonna total alkaloid 3 Glycyrrhizic acid 210 Anhydrous caffeine 504 Lactose 473 Powder coating Corn starch 84 Talc 14 Sustained release water Dispersion Aquacoat 167 Acetylated monoglyceride 17 Fine particle talc 17 Water 132

Example 2 As a core substance, 840 g of Nonpareil 103 (manufactured by Freund, particle size: 500 to 710 μm) was put into a CF granulator (manufactured by Freund, CF-360 type machine), and the rotation speed of the rotor was 160 rpm. 5% of hydroxypropylmethylcellulose (TC-5-E manufactured by Shin-Etsu Chemical Co., Ltd.)
While spraying 245 g of the (W / W) aqueous solution toward the core substance, the powder-dispersing agent and the powder-coating agent, which are preliminarily and homogeneously mixed shown in the composition of Table 2 below, are gradually surrounded and laminated in a non-pareil at 60 ° C. After air-dried for 8 hours, spherical elementary granules having a particle diameter of 710 to 1180 μm were obtained using a sieve. 500 g of these elementary granules were put into the same CF granulating apparatus as above, tumbled at a rotor speed of 180 rpm to control the product temperature at 38 ° C., while controlling the product temperature at 38 ° C., the water-based latex (Aqua Coat) shown in Table 2 below. , Manufactured by Asahi Kasei Co., Ltd.) is sprayed with 450 g of an aqueous dispersion containing a sustained-release coating agent to form a sustained-release film layer by water-based sustained-release coating, followed by curing at 70 ° C. for 1 hour. Thus, a granular controlled release formulation for rhinitis was obtained.

[0021]

[Table 2] Component weight (g) Powder spraying agent d-Chlorpheniramine maleate 19 Phenylpropanolamine hydrochloride 378 Belladonna total alkaloid 3 Dipotassium glycyrrhizinate 210 Caffeine 504 Lactose 470 Powder coating Corn starch 126 Talc 98 Sustained release water Dispersion Aquacoat 167 Triethyl citrate 24 Fine particle talc 60 Water 176

Example 3 By the same production method as in Example 1, a granular controlled release formulation for rhinitis having the composition shown in Table 3 below was obtained.

[0023]

[Table 3] Component weight (g) Powder spraying agent Phenylpropanolamine hydrochloride 378 Belladonna total alkaloid 3 Glycyrrhizic acid 210 Caffeine anhydrous 504 Lactose 473 Powder coating agent Corn starch 84 Talc 14 Sustained release water dispersion Aquacoat 167 Acetylated monoglyceride 17 Fine particle talc 17 Water 133

Example 4 By the same production method as in Example 1, a granular controlled release preparation for rhinitis having the composition shown in Table 4 below was obtained.

[0025]

[Table 4] Component weight (g) Powder spraying agent Phenylpropanolamine hydrochloride 378 Belladonna total alkaloid 3 Dipotassium glycyrrhizinate 210 Anhydrous caffeine 504 Lactose 410 Powder coating Corn starch 38 Talc 70 Sustained release water dispersion Aquacoat 167 Citric acid Triethyl 17 Fine particle talc 34 Water 132

Comparative Example 1 840 g of Nonpareil 103 (manufactured by Freund, particle size: 500 to 710 μm) as a core substance was put into a CF granulator (manufactured by Freund, CF-360 type machine), and the rotation speed of the rotor was 160 rpm. p. m. 4% of hydroxypropyl cellulose (Nippon Soda, HPC-L)
While spraying 230 g of the (W / W) aqueous solution toward the core substance, the pre-homogeneously mixed powder-dispersing agent shown in the composition of Table 5 below was gradually wrapped around the non-pareil and laminated.
After air-drying at ℃ for 8 hours, use a sieve to obtain grain diameters of 710-1
180 μm spherical elementary granules were obtained. 500g of this elementary granule
Was charged into the same CF granulation apparatus as described above, and the rotation speed of the rotor was 180 r. p. m. While controlling the temperature of the product to 38 ° C., 350 g of an aqueous dispersion containing a sustained-release coating agent containing water-based latex (Aquacoat, manufactured by Asahi Kasei Co., Ltd.) shown in Table 5 below as a main component is sprayed. Then, a water-based sustained-release coating was performed to form a sustained-release membrane layer, and curing was performed at 70 ° C. for 1 hour to obtain a granular controlled-release preparation for rhinitis.

[0027]

[Table 5] Component weight (g) Powder dusting agent Chlorpheniramine maleate 19 Phenylpropanolamine hydrochloride 378 Belladonna total alkaloid 3 Glycyrrhizic acid 210 Anhydrous caffeine 504 Lactose 571 Sustained release water dispersion Aquacoat 167 Acetylation Monoglyceride 17 Fine particle talc 17 Water 132

Comparative Example 2 840 g of Nonpareil 103 (manufactured by Freund, particle size: 500 to 710 μm) as a core substance was put into a CF granulator (manufactured by Freund, CF-360 type machine), and the rotation speed of the rotor was 160 rpm. p. m. Hydroxypropylmethylcellulose (TC-5-E manufactured by Shin-Etsu Chemical Co., Ltd.)
While spraying 245 g of a 5% (W / W) aqueous solution of No. 5 onto the core substance, the powder spraying agents shown in the composition of Table 6 below and preliminarily and homogeneously mixed were gradually wrapped around the non-pareil, and then laminated.
Dry with ventilation at 60 ° C for 8 hours, and use a sieve to granulate 710
Spherical elementary granules of ˜1180 μm were obtained. This elementary granule 50
0 g was put into the same CF granulation device as above, and the rotation speed of the rotor was 180 rpm. p. m. And roll the product to a temperature of 38
While controlling the temperature to ℃, 450 g of an aqueous dispersion containing a sustained-release coating agent containing a water-based latex (Aquacoat, manufactured by Asahi Kasei Co., Ltd.) shown in Table 6 below as a main component is sprayed to perform an aqueous sustained-release coating. Forming a sustained release membrane layer,
Curing was carried out at 0 ° C. for 1 hour to obtain a granular controlled release formulation for rhinitis.

[0029]

[Table 6] Component weight (g) Powder spraying agent d-Chlorpheniramine maleate 19 Phenylpropanolamine hydrochloride 378 Belladonna total alkaloid 3 Dipotassium glycyrrhizinate 210 Caffeine 504 Lactose 694 Sustained release water dispersion Aquacoat 167 Citric acid Triethyl 24 Fine particle talc 60 Water 176

Comparative Example 3 840 g of Nonpareil 103 (manufactured by Freund, particle size: 500 to 710 μm) as a core substance was put into a CF granulator (manufactured by Freund, CF-360 type machine), and the rotation speed of the rotor was 160 r.p.m. p. m. 4% of hydroxypropyl cellulose (Nippon Soda, HPC-L)
While spraying 210 g of the (W / W) aqueous solution onto the core substance, the pre-homogeneously mixed powder-dispersing agent shown in the composition of Table 7 below was gradually wrapped around the non-pareil and laminated.
After air-drying at ℃ for 8 hours, use a sieve to obtain grain diameters of 710-1
180 μm spherical elementary granules were obtained. 500g of this elementary granule
Was charged into the same CF granulation apparatus as described above, and the rotation speed of the rotor was 180 r. p. m. While controlling the temperature of the product to 38 ° C., 350 g of an aqueous dispersion containing a sustained-release coating material containing a water-based latex (Aquacoat, manufactured by Asahi Kasei Co., Ltd.) shown in Table 7 below as a main component is sprayed. Then, a water-based sustained-release coating was performed to form a sustained-release membrane layer, and curing was performed at 70 ° C. for 1 hour to obtain a granular controlled-release preparation for rhinitis.

[0031]

TABLE 7 Ingredient Weight (g) powdered dusting powder phenylpropanolamine hydrochloride 378 belladonna total alkaloids 3 glycyrrhizinate 210 caffeine anhydrous 504 Lactose 473 sustained Kamizu dispersion Aquacoat 167 acetylated monoglycerides 17 fine talc 17 Water 133

Comparative Example 4 By the same production method as in Comparative Example 3, a granular controlled release formulation for rhinitis having the composition shown in Table 8 below was obtained.

[0033]

[Table 8] Component weight (g) Powder spraying agent Phenylpropanolamine hydrochloride 378 Belladonna total alkaloid 3 Dipotassium glycyrrhizinate 210 Anhydrous caffeine 504 Lactose 410 Sustained release water dispersion Aquacoat 167 Triethyl citrate 17 Fine particle talc 34 Water 132

Experimental Example 1 With respect to the controlled release preparations obtained in Examples 1 to 4 and Comparative Examples 1 to 4, according to the Japanese Pharmacopoeia 12th Edition dissolution test method, paddle method, 100 revolutions, the test solution was Japanese Pharmacopoeia No. 1 A dissolution test was performed with the liquid. The eluate was collected over time, and the elution rate (%) of phenylpropanolamine hydrochloride as an index of a drug having a high affinity for water was determined by high performance liquid chromatography. The results of elution rate (%) are shown in Table 9.

[0035]

[Table 9] Table 9: Results of dissolution test of controlled release formulation Leaching rate (%) 1 hour 4 hours 8 hours 12 hours Example 1 8.0 31.9 61.3 94.4 Example 2 8.4 32 0.0 65.2 97.9 Example 3 5.4 34.3 63.3 94.7 Example 4 9.0 30.2 66.2 96.6 Comparative Example 1 21.1 63.5 83.9 96.1 Comparative example 2 20.8 60.0 88.4 98.7 Comparative example 3 25.6 54.7 87.5 94.4 Comparative example 4 25.3 73.8 88.8 94.2

Experimental Example 2 The controlled release preparations obtained in Examples 1 to 4 and Comparative Examples 1 to 4 and the immediate release preparations obtained in Reference Examples 1 to 4 below were used at a high water-soluble drug weight ratio. It was mixed in the combinations shown in Table 14 below so as to have a ratio of 4: 6 to obtain a sustained-release preparation. The dissolution rate (%) of this sustained-release preparation was determined in the same manner as in Experimental Example 1, and the results are shown in Table 14.

Reference Example 1 As a core substance, 800 g of Nonpareil 103 (manufactured by Freund, particle size: 500 to 710 μm) was charged into a CF granulator (manufactured by Freund, CF-360 type machine), and the rotation speed of the rotor was 160 rpm. p. m. Hydroxypropylmethylcellulose (TC-5-E manufactured by Shin-Etsu Chemical Co., Ltd.)
While spraying 240 g of a 5% (W / W) aqueous solution of 5% of the above on the core substance, the powder-dispersing agent and the powder-coating agent shown in the composition of Table 10 below were sequentially surrounded and laminated in a non-pareil, After air-dried at 60 ° C. for 8 hours, a spherical elementary granule having a particle diameter of 710 to 1180 μm was obtained using a sieve. This elementary granule was used as a granular immediate release preparation.

[0038]

[Table 10] Component weight (g) Powder spraying agent d-Chlorpheniramine maleate 20 Phenylpropanolamine hydrochloride 360 Belladonna total alkaloid 3 Glycyrrhizic acid 200 Anhydrous caffeine 480 Lactose 440 Powder coating Corn starch 220 Talc 15

Reference Example 2 By the same production method as in Reference Example 1, a granular immediate release preparation having the following Table 11 was obtained.

[0040]

Table 11 Component weight (g) Powder dusting agent Chlorpheniramine maleate 20 Phenylpropanolamine hydrochloride 360 Belladonna total alkaloid 3 Dipotassium glycyrrhizinate 200 Caffeine 480 Lactose 480 Powder coating Cornstarch 120 Talc 100

Reference Example 3 As a core substance, 800 g of Nonpareil 103 (manufactured by Freund, particle size: 500 to 710 μm) was put into a CF granulator (manufactured by Freund, CF-360 type machine), and the rotation speed of the rotor was 160 rpm. p. m. 4% of hydroxypropyl cellulose (Nippon Soda, HPC-L)
While spraying 230 g of the (W / W) aqueous solution toward the core substance, the powder-dispersing agent and the powder-coating agent, which are preliminarily and homogeneously mixed as shown in Table 12 below, are gradually gradually wrapped around the non-pareil and laminated at 60 ° C. After air-dried for 8 hours, spherical elementary granules having a particle diameter of 710 to 1180 μm were obtained using a sieve. This elementary granule was used as a granular immediate release preparation.

[0042]

[Table 12] Component weight (g) Powder dusting agent Mequitazine 40 Phenylpropanolamine hydrochloride 360 Belladonna total alkaloid 3 Glycyrrhizic acid 200 Anhydrous caffeine 480 Lactose 442 Powder coating Corn starch 140 Talc 20

Reference Example 4 800 g of Nonpareil 103 (manufactured by Freund, particle size: 500 to 710 μm) was charged as a core substance into a CF granulator (manufactured by Freund, CF-360 type machine), and the rotation speed of the rotor was 160 rpm. p. m. 4% of hydroxypropyl cellulose (Nippon Soda, HPC-L)
While spraying 205 g of the (W / W) aqueous solution onto the core substance, the powder-dispersing agent and the powder-coating agent, which are preliminarily and homogeneously mixed as shown in Table 13 below, were gradually wrapped around the non-pareil and laminated, and then at 60 ° C. for 8 hours. After air-drying for an hour, spherical elementary granules having a particle diameter of 710 to 1180 μm were obtained using a sieve.
This elementary granule was used as a granular immediate release preparation.

[0044]

[Table 13] Component weight (g) Powder dusting agent Mequitazine 40 Phenylpropanolamine hydrochloride 360 Belladonna total alkaloid 3 Dipotassium glycyrrhizinate 200 Anhydrous caffeine 480 Lactose 410 Powder coating Cornstarch 80 Talc 110

[0045]

[Table 14]Table 14: Results of dissolution test of sustained-release preparations Release control Rapid releaseLeach rate (%) Preparation Preparation 30 minutes 2 hours 6 hours 10 hours Example 5 Example 1 Reference Example 1 37.3 49.1 68.2 89.0 Example 6 Example 2 Reference Example 2 35.4 47.8 67.9 88.7 Example 7 Example 3 Reference Example 3 38.6 48.8 69.1 90.3 Example 8 Example 4 Reference Example 4 37.0 49.5 69.4 91.2 Comparative Example 5 Comparative Example 1 Reference Example 1 35.1 49.5 89.6 97.8 Comparative Example 6 Comparative Example 2 Reference Example 2 40.1 54.8 94.3 98.3 Comparative Example 7 Comparative Example 3 Reference Example 3 38.2 53.9 92.8 97.4 Comparative Example 8 Comparative Example 4 Reference Example 4 37.4 49.2 93.2 96.5

In Examples 5 to 8 composed of the controlled release preparations obtained in Examples 1 to 4, the almost zero-order release pattern was shown, but the controlled release obtained in Comparative Examples 1 to 4 was controlled. In Comparative Examples 5 to 8 composed of the above preparations, the pattern of the primary release was taken and almost the entire amount was eluted within 6 hours, and the function as a sustained preparation was not sufficient. From the above results, the sustained-release preparation comprising the controlled-release preparation of the present invention as a constituent element was capable of achieving stable zero-order release and sufficiently satisfied the function as a sustained-release preparation.

Claims (5)

[Claims] 1. A. The core material, b. Laminating a layer containing a drug having a high affinity for water, and further c. An immediate release preparation having a powder coating layer made of cornstarch or talc or both, d. A controlled-release preparation characterized by having a multi-layer structure comprising a membrane layer of a polymeric substance which is substantially insoluble in water and whose drug release characteristics do not depend on hydrogen ion concentration. 2. The controlled release formulation of claim 1, wherein the polymeric material is formed from an aqueous latex. 3. A controlled release formulation according to claim 1; (B) a. The core material, b. Laminating a layer containing a drug having a high affinity for water, and further c. An immediate-release preparation having a powder coating layer comprising one or both of cornstarch and talc, and (B) an immediate-release preparation for a drug having a high affinity for water contained in a preparation with controlled release (A). The amount of the drug having a high affinity for water contained in the preparation is 25 to 4
A sustained-release preparation characterized by being blended so as to be in a range of 00% by weight. 4. The sustained-release preparation according to claim 3, wherein the polymer substance is formed of an aqueous latex. 5. The drug having a high affinity for water in the immediate release preparation is one or two selected from mequitazine, phenylpropanolamine hydrochloride, anhydrous caffeine, caffeine, glycyrrhizic acid or salts thereof, and total belladonna alkaloids. The sustained-release preparation according to claim 3 or 4, which is one or more kinds.