JPH09188617A - Medicinal composition of sustained release - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicinal composition of sustained release capable of voluntarily controlling release of a medicine in intragastric or enteral pH region and suitable as a granular formulation of sustained release. SOLUTION: This medical composition of sustained release is obtained by coating an enteric-soluble polymer composed of a methacrylic acid-methyl methacrylate copolymer and an acid-soluble polymer composed of a methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate terpolymer or polyvinyl acetal diethyl acetate on a nucleus granule containing a medicine in turn and a content of the enteric-soluble polymer is 5-15.3wt.% in the medicinal composition, and a content of the acid-soluble polymer is 0.8-5wt.% in the medicinal composition.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a sustained-release pharmaceutical composition, and particularly to a sustained-release pharmaceutical composition suitable as a sustained-release granule formulation in which the drug release is arbitrarily controlled in the gastric pH region and intestinal pH region. Regarding things.

[0002]

2. Description of the Related Art Sustained-release preparations have many medical advantages such as a reduction in the number of doses of preparations, an improvement in patient compliance, and an increase in therapeutic effect.

In order to enhance the therapeutic effect of a sustained-release preparation, it is necessary to maintain an effective blood concentration for a long period of time. As a sustained-release preparation, the drug's solubility in water, acidity / basicity, etc. Regardless, there is a demand for a so-called zero-order sustained-release preparation that releases a certain amount of drug per unit time under various physiological environments after oral administration. Furthermore,
Sustained-release preparations containing gastric mucosa-stimulating drugs, drugs that are unstable in acidic environments, drugs that have the property of undergoing a first-pass effect, etc. suppress drug release in the stomach and release the drug after the small intestine. It is eagerly awaited.

[0004] Therefore, various attempts have been made to control the release of the drug in order to obtain a sustained-release preparation. As typical examples thereof, the diffusion-type release controlling method and the dissolution-type release controlling method are known. .

The diffusion-type controlled release method includes a membrane-type microdialysis membrane granule in which a drug-containing core is coated with a water-insoluble membrane, a microdialysis membrane capsule or a matrix-type gladumet in which the drug is dispersed in a water-insoluble base. There are shapes and wax matrix shapes.

Elution-type controlled release methods include a film-type spansul type in which a drug-containing core is coated with a water-soluble film, and a matrix-type spastab-type, spantab-type, or rontab-type in which a drug is dispersed in a water-soluble base. is there. As an elution-type release control method, there is also a method in which an enteric base is used as a water-soluble base and the drug release is controlled by the pH of the digestive tract. (Development of pharmaceuticals Vol.13 “Drug delivery method” Hirokawa Shoten)

Further, a sustained-release preparation having a water-insoluble film coated on the core of a drug dispersed in an enteric base (Japanese Patent Publication No. 64-7).
No. 047), a sustained-release preparation obtained by coating a drug-containing core with a water-insoluble film and further coating an enteric film (Japanese Patent Publication No. 6-210).
No. 66), a sustained-release preparation in which a drug-containing core is coated with a film composed of an enteric base and a water-insoluble base (JP-A-4-23).
A release control method combining a diffusion type and an elution type has also been proposed.

[0008] The following are problems when oral administration of these sustained-release preparations by the conventional controlled-release methods is performed.

(1) It is said that zero-order release can be easily obtained by a drug release control method using a water-insoluble film. However, when the solubility of the drug is pH-dependent, fluctuations in the digestive tract pH (about pH)
1 to pH 8) changes the drug release rate, and in the case of a drug whose drug release is desirable after the small intestine, the drug release in the stomach may not be suppressed.

(2) It is difficult to obtain a zero-order release by the drug release control method using a water-soluble film, and there is a possibility that the drug release in the stomach cannot be suppressed for a drug whose drug release is desirable after the small intestine. In the drug release control method using an enteric base, it is possible to suppress the drug release in the stomach and deliver the drug into the small intestine when the drug release is desirable after the small intestine. May not be controlled by zero-order release.

(3) In the matrix-type release control method using a water-insoluble base and a water-soluble base, the drug release rate tends to decrease with the passage of time, and zero-order release is difficult to obtain. Further, it may cause a burst phenomenon in the digestive tract.

(4) Dispersing a drug in an enteric-coated base as a drug release control method capable of suppressing the drug release in the stomach, delivering the drug in the small intestine, and making the drug release zero-order release Controlled drug release method in which the prepared core is coated with a water-insoluble film, drug release control method in which the drug-containing core is coated with a water-insoluble film and further coated with an enteric film, enteric-coated base and water-insoluble base for the drug-containing core A controlled drug release method has been proposed which is coated with a film consisting of. However, even in these drug release controlling methods, the solubility of the enteric base material may be affected by the fluctuation of pH in the small intestine (pH 5 to 8), and the drug release rate may change in the small intestine. The solubility of the drug is p
When H-dependency is exhibited, it is presumed that controlled release of the drug will be more difficult.

These facts indicate that when the preparation is actually administered to a patient, the release rate of the drug varies between individuals depending on the physiological factors of the digestive tract, particularly the liquidity and quantity of digestive juice or the quality and quantity of meal. It shows that the drug concentration in blood varies due to the difference in the body, that is, the bioavailability changes, and the sustained drug effect is achieved in all patients.
It is a cause that cannot be said to have obtained an appropriate therapeutic effect. That is, the drug release depends on the pH region in the stomach and the p
Arbitrarily controlled sustained-release pharmaceutical compositions in the H region have not yet been obtained.

[0014]

Therefore, an object of the present invention is to provide a pharmaceutical composition capable of controlling drug release arbitrarily.

[0015]

Under these circumstances, the inventors of the present invention have conducted earnest studies on a more practical drug release control method using various pharmaceutical bases, and as a result, In the case of a sustained-release preparation, in order to stabilize the transition of drug concentration in blood, sustain the drug effect, and improve the therapeutic effect, the drug release under various pH environments can be freely adjusted and arbitrarily controlled release. Focusing on what is effective,
It was found that an excellent drug release controlling effect can be obtained by coating the drug-containing core with an enteric film and further with an acid-soluble film, and completed the present invention.

That is, the present invention provides a sustained-release pharmaceutical composition containing an enteric polymer, an acid-soluble polymer and a drug.

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The pH of the digestive tract is 1 to 1 in the stomach.
Around 3.5, pH 5-6 in the duodenum, p in the jejunum
It is known that H6 is around 7 and pH is around 8 after the ileocecum. In terms of drug absorbability, the stomach pH is pH 1.2, and the intestinal pH is pH 6.5 and pH 7.2.
Is generally known to be particularly involved in drug release from the formulation. The sustained-release pharmaceutical composition of the present invention has a gastric pH
Area (pH 1.2) and intestinal pH area, especially pH 6.5
And drug release at both pH close to pH 7.2 can be controlled arbitrarily.

As the enteric base used in the present invention, hydroxypropylmethyl cellulose-phthalate (trade name:
HP-55, HP-50, manufactured by Shin-Etsu Chemical Co., Ltd., methacrylic acid-methyl methacrylate copolymer (trade name: Eudragit L100, Eudragit L100-55, Eudragit S100, manufactured by Laem Pharma), methacrylic acid-acrylic acid. Ethyl copolymer (trade name: Eudragit L30D-55, manufactured by Laem Pharma Co.), hydroxypropylmethylcellulose acetate acetate succine
(Trade name: AQOAT, manufactured by Shin-Etsu Chemical Co., Ltd.), carboxymethylethyl cellulose (trade name: CMEC, manufactured by Freund Sangyo Co., Ltd.) and the like. These may be used alone or in combination of two or more. Among these, preferred are methacrylic acid-methyl methacrylate copolymer (trade name: Eudragit L100 (alias: methacrylic acid copolymer L), Eudragit L100-55 (alias: methacrylic acid copolymer L), Eudragit S100 (alias: methacrylic acid). Copolymer S), manufactured by Laem Pharma) or a mixture thereof.

The preferable content of the enteric polymer in the composition of the present invention varies depending on the purpose of application such as drug, sustained release type, release rate, etc., but is preferably 1 to 30% by weight and 3 to 2
0% by weight is particularly preferable, and 5 to 15.3% by weight is further preferable.

The acid-soluble polymer used in the present invention includes
The polymer is not particularly limited as long as it is a polymer used for coating a pharmaceutical composition and is soluble in an acid. Examples of such a polymer include aminoalkyl methacrylate copolymer E (trade name: Eudragit E100, manufactured by Laem Pharma Co.), polyvinyl acetal diethyl acetate (trade name: AEA, manufactured by Sankyo Co., Ltd.), and the like. These may be used alone or in combination of two or more.

The content of the acid-soluble polymer in the composition of the present invention is preferably 0.1 to 10% by weight, and is preferably 0.5 to 8 although it varies depending on the drug design, sustained release type, formulation design such as release rate.
Weight% is particularly preferred, and 0.8-5 weight% is even more preferred.

The drug used in the present invention is not particularly limited as long as the drug effect is expected by oral administration. That is, agents for central and peripheral nerves such as benzdiazepine, agents for circulatory organs such as nifedipine and nicardipine, agents for respiratory organs, agents for digestive organs, hormones, vitamins, allergic agents, antipyretic agents, ketoprofen, ketotifen, etc. Selected from the fields of analgesics for steroids, tumor agents such as cisplatin, adreamycin and 5-fluorouracil, antibiotic agents such as fosfomycin and methicillin, and chemotherapeutic agents such as bifonazole and miconazole. Dissolution of the drug in water Regardless of sex, acidity, basicity, etc., commonly used drugs can be added. Also, physiologically acceptable salts of these drugs can be used. Examples of the drug preferably used in the present invention include basic drugs exhibiting pH-dependent solubility. Among basic drugs, such as nicardipine hydrochloride, the solubility of the drug is
Despite being significantly lower in the small intestinal pH region than in the region, it has the property of undergoing the first-pass effect in the liver, so it suppresses drug release in the stomach and delivers a high content of drug to the small intestine. It is particularly preferable because it is desired to release the drug at a constant rate throughout the small intestine.

The content of the drug in the composition of the present invention is
Depending on the type of drug and the purpose of formulation design,
1 to 40% by weight is preferable, 0.5 to 30% by weight is more preferable, and 1 to 200% by weight is further preferable.

The enteric polymer, the acid-soluble polymer and the drug in the pharmaceutical composition of the present invention may be compounded by any method commonly used in the manufacture of pharmaceutical compositions, and is not particularly limited. For example, these components may be mixed with an optional component, granulated, or a core containing a drug may be prepared, and an enteric polymer and an acid-soluble polymer may be coated on the core.
The most preferred method among these is to prepare a core granule containing a drug, coat it with a solution containing an enteric polymer, and then coat it with a solution containing an acid-soluble polymer.

The sustained-release pharmaceutical composition of the present invention is preferably a granule preparation, and the granules and granules which are an intermediate product of the pharmaceutical composition are the usual preparation techniques described in the Japanese Pharmacopoeia or the like or modifications thereof. Method or modified method. As such a method, for example, a drug-containing core granule is a dry granulation method,
It is prepared by stirring granulation method, fluidized bed granulation method, melt granulation method, extrusion granulation method, coating granulation method and the like. Pharmaceutical materials used in the preparation of drug-containing core granules are excipients, binders, lubricants, anti-agglomeration agents, inert core particles, organic acids, surfactants, etc., which are commonly used in pharmaceutical compositions. Any of them can be used.

The drug-containing core granules as an intermediate product preferably have an average particle size of 100 to 1200 μm, preferably 100 to 1200 μm.
It is particularly preferably 500 μm. In the present invention, drug-containing core granules exhibiting immediate release of drug are preferably used. The drug content in the prepared drug-containing core granules is preferably 1 to 50% by weight, but is not necessarily limited to this amount and can be changed depending on the physicochemical properties, dose, etc. of the drug.

The method for coating the drug-containing core granules with the enteric polymer is a pan coating method, a fluidized bed coating method,
A rolling fluidized bed coating method or the like can be adopted. The outer layer of the drug-containing core granules is obtained by spraying a coating solution prepared by dissolving or suspending an enteric polymer in a solvent on a layer in which the drug-containing core granules are rolled and / or fluidized, and drying the solvent by warm air. It forms an enteric film on the.

Further, an acid-soluble coating layer is formed on the outer layer of the enteric coating layer by the same operation as when coating the enteric coating with the acid-soluble polymer.

When the enteric polymer or the acid-soluble polymer is coated, a plasticizer, a lubricant, a dye, a flavoring / flavoring agent, etc. are added, and these may be those usually used. Both can be used. As a solvent, methanol
Examples thereof include ethanol, ethanol, isopropanol, chloroform, acetone, methylene chloride and water. These may be used alone or in an appropriate mixture.

The sustained-release granule preparation thus prepared preferably has an average particle size of 100 to 2000 μm,
100 to 500 μm is particularly preferable.

Since the granules thus obtained have a certain release characteristic, the granules alone can be used as an excellent sustained-release drug. These granules can be used in combination with ordinary fast-acting granules not coated with a polymer and conventional sustained-release granules. Of these, the combination with fast-acting granules is effective for the sparingly soluble circulatory organ drugs such as nifedipine and nicardipine, which require a certain amount of release in the 0th order.

Further, examples of the combination with the immediate-acting drug composition include those obtained by layering an immediate-release drug layer on the sustained-release granules of the present invention. This can be easily obtained by coating the pharmaceutical composition of the present invention with a fast-acting pharmaceutical composition, that is, a composition comprising a drug and optional components in the formulation other than the polymer for coating.

In the above-mentioned combination of the pharmaceutical composition of the present invention and the fast-acting drug, the pharmaceutical composition of the present invention and the conventional sustained-release drug composition can be used as a sustained-release part, a drug without a polymer coating, and a high-performance drug for coating. If a rapid-acting composition consisting of optional ingredients other than molecules is used as the immediate-release part, the ratio of the sustained-release part and the immediate-release part should be appropriately adjusted to obtain an appropriate initial blood concentration and its sustained effect. Good. Generally, the amount of the drug in the sustained release granules and the amount of the drug in the immediate release granules or the immediate release layer are 1: 2 by weight.
˜50: 1 is preferable, 2: 3 to 30: 1 is particularly preferable, and 1: 1 to 20: 1 is further preferable.

In the best mode for carrying out the present invention, nicardipine and / or a physiologically acceptable salt thereof is used as a drug, which is coated with granular sucrose to give drug-containing core granules, A methacrylic acid copolymer film is formed, and then an aminoalkyl methacrylate film is formed on this film.

[0035]

EXAMPLES The present invention will be described in more detail below with reference to Examples, but these are not intended to limit the present invention. Unless otherwise specified,% means% by weight.

Comparative Example 1 Purified white sugar spherical granules (trade name: Nonpareil 103 24-
32 mesh, manufactured by Freund Industrial Co., Ltd.) 200 g, nicardipine hydrochloride 70 g, hydroxypropyl methylose (trade name: TC-5, manufactured by Shin-Etsu Chemical Co., Ltd.) 70 g, polysorbate 80 (trade name: TO-10 M, Nikko Chemicals) 32 g, talc 40 g (trade name: Victory Light SK-C, manufactured by Shokoyama Mining Co., Ltd.), water 178 g dissolved and dispersed in ethanol 1610 g, and a rolling fluid bed coating method is used. After being coated with, the product was dried to obtain drug-containing granules.

Comparative Example 2 50 g of ethyl cellulose was added to 100 g of the granules obtained in Comparative Example 1.
(Trade name: Etocel N-10-G, manufactured by Shin-Etsu Chemical Co., Ltd.), triethyl citrate (trade name: Citroflex, manufactured by Chugai Trading Co., Ltd.) 5 g, talc 15 g dissolved in and dispersed in 930 g of ethanol coating liquid 100 g rolling fluidized bed
Coating was performed by a coating method and then dried to obtain sustained release granules.

Comparative Example 3 Nicardipine hydrochloride 70 was added to 200 g of purified sucrose spherical granules.
g, ethyl cellulose 70 g, polysorbate 80 3
A coating liquid prepared by dissolving and dispersing 2 g and 40 g of talc in 1788 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Comparative Example 4 100 g of the granules obtained in Comparative Example 1 were added to methacrylic acid copolymer.
L (trade name: Eudragit L100, manufactured by Laem Pharma) 70 g, triethyl citrate 7 g, talc 7 g,
A solution prepared by dissolving and dispersing 100 g of water in 916 g of ethanol.
120 g of the coating solution was coated by the tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Comparative Example 5 200 g of purified sucrose spherical granules, 70 g of nicardipine hydrochloride,
Methacrylic acid copolymer L 70 g, polysorbate 80
A coating liquid prepared by dissolving and dispersing 32 g and 40 g of talc in 1788 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Comparative Example 6 100 g of the granules obtained in Comparative Example 5 were mixed with 50 ml of ethyl cellulose.
g, triethyl citrate 5 g, talc 15 g with ethanol
60 g of a coating solution dissolved / dispersed in 930 g of coating solution was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Comparative Example 7 100 g of the granules obtained in Comparative Example 1 were mixed with 50 ml of ethyl cellulose.
g, triethyl citrate 5 g, talc 15 g with ethanol
60 g of a coating solution dissolved / dispersed in 930 g of diol was coated by a tumbling fluidized bed coating method and then dried, and further 70 g of methacrylic acid copolymer L, 7 g of triethyl citrate, 7 g of talc and 100 g of water were added to ethanol. 110 g of the coating solution dissolved / dispersed in 916 g of the solvent was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Comparative Example 8 Methacrylic acid copolymer was added to 100 g of the granules obtained in Comparative Example 1.
L30g, ethylcellulose 30g, triethyl citrate 6g, talc 10g, water 50g ethanol 874g
120 g of the coating solution dissolved / dispersed in was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Comparative Example 9 The granules obtained in Comparative Example 6 and the granules obtained in Comparative Example 1 were mixed at a nicardipine hydrochloride amount of 3: 1 to obtain sustained release granules.

Example 1 (1) Nicardipine hydrochloride 7 was added to 200 g of purified sucrose spherical granules.
0 g, hydroxypropylmethyl cellulose 70 g, polysorbate 80 32 g, talc 40 g, water 178 g
The coating liquid prepared by dissolving and dispersing in 1610 g of ethanol was coated by the tumbling fluidized bed coating method and then dried to obtain drug-containing granules. (2) To 100 g of the granules obtained above, 70 g of methacrylic acid copolymer-S (trade name: Eudragit S100, manufactured by Laem Pharma Co.), 7 g of triethyl citrate, and talc 7
g, 100 g of water was dissolved / dispersed in 916 g of ethanol, 78 g of a coating solution was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 g of water.
25 g of a coating solution prepared by dissolving and dispersing in 364 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 2 100 g of the granules obtained in Example 1 (1) were added with 70 g of methacrylic acid copolymer-S, 7 g of triethyl citrate and 7 g of talc.
g, 100 g of water was dissolved / dispersed in 916 g of ethanol, 78 g of a coating solution was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 g of water.
165 g of a coating solution prepared by dissolving and dispersing in 364 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 3 100 g of the granules obtained in Example 1 (1) were added with 70 g of methacrylic acid copolymer-S, 7 g of triethyl citrate and 7 g of talc.
g, 100 g of water dissolved and dispersed in 916 g of ethanol, 240 g of a coating solution was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 g of water.
25 g of a coating solution prepared by dissolving and dispersing g in 364 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 4 100 g of the granules obtained in Example 1 (1) were added with 70 g of methacrylic acid copolymer-S, 7 g of triethyl citrate, and 7 g of talc.
g, 100 g of water dissolved and dispersed in 916 g of ethanol, 240 g of a coating solution was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 g of water.
165 g of a coating solution prepared by dissolving and dispersing g in 364 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 5 To 100 g of the granules obtained in Example 1 (1), 70 g of methacrylic acid copolymer-S, 7 g of triethyl citrate and 7 g of talc were added.
g, 100 g of water was dissolved and dispersed in 916 g of ethanol, and 240 g of a coating solution was coated by a tumbling fluidized bed coating method and then dried, and polyvinyl acetal diethyl acetate (trade name: AEA, manufactured by Sankyo Co., Ltd.). ) 1
40 g of a coating solution prepared by dissolving and dispersing 2 g, 6 g of talc and 18 g of water in 364 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules. When coating the polyvinyl acetal diethyl acetate, a small amount of Macrogol 6000 can be added to the coating solution if necessary.

Example 6 100 g of the granules obtained in Example 1 (1) were added with 70 g of methacrylic acid copolymer-S, 7 g of triethyl citrate and 7 g of talc.
g, 100 g of water dissolved and dispersed in 916 g of ethanol, 30 g of a coating liquid was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 g of water.
10 g of a coating solution prepared by dissolving and dispersing in 364 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 7 100 g of the granules obtained in Example 1 (1) were added with 70 g of methacrylic acid copolymer-S, 7 g of triethyl citrate and 7 g of talc.
g, 100 g of water dissolved and dispersed in 916 g of ethanol, 30 g of a coating liquid was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 g of water.
A coating solution (330 g) prepared by dissolving / dispersing (1) in ethanol (364 g) was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 8 100 g of the granules obtained in Example 1 (1) were added to 70 g of methacrylic acid copolymer-S, 7 g of triethyl citrate, and 7 g of talc.
g, 100 g of water was dissolved / dispersed in 916 g of ethanol, 400 g of a coating liquid was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc, and 18 of water.
10 g of a coating solution prepared by dissolving and dispersing g in 364 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 9 To 100 g of the granules obtained in Example 1 (1), 70 g of methacrylic acid copolymer-S, 7 g of triethyl citrate and 7 g of talc were added.
g, 100 g of water was dissolved / dispersed in 916 g of ethanol, 400 g of a coating liquid was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc, and 18 of water.
A coating solution (330 g) prepared by dissolving and dispersing g in ethanol (364 g) was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 10 100 g of the granules obtained in Example 1 (1) were added with 23.3 g of methacrylic acid copolymer-S and methacrylic acid copolymer L4.
6.7 g, triethyl citrate 7 g, talc 7 g, water 1
78 g of a coating solution prepared by dissolving and dispersing 00 g in 916 g of ethanol was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 g of water were added to ethanol. 25 g of the coating liquid dissolved and dispersed in 364 g was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 11 100 g of the granules obtained in Example 1 (1) were added to 23.3 g of methacrylic acid copolymer-S and methacrylic acid copolymer L4.
6.7 g, triethyl citrate 7 g, talc 7 g, water 1
78 g of a coating solution prepared by dissolving and dispersing 00 g in 916 g of ethanol was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 g of water were added to ethanol. 165 g of coating liquid dissolved and dispersed in 364 g
Was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 12 100 g of the granules obtained in Example 1 (1) were added to 23.3 g of methacrylic acid copolymer-S and methacrylic acid copolymer L4.
6.7 g, triethyl citrate 7 g, talc 7 g, and water 100 g were dissolved / dispersed in ethanol 916 g, and 240 g of a coating solution was coated by a tumbling fluidized bed coating method and then dried. Coating solution 25 in which 12 g of alkyl methacrylate copolymer E, 6 g of talc and 18 g of water are dissolved and dispersed in 364 g of ethanol.
g was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 13 100 g of the granules obtained in Example 1 (1) were added to 23.3 g of methacrylic acid copolymer-S and methacrylic acid copolymer L4.
6.7 g, triethyl citrate 7 g, talc 7 g, and water 100 g were dissolved / dispersed in ethanol 916 g, and 240 g of a coating solution was coated by a tumbling fluidized bed coating method and then dried. Coating solution 16 in which 12 g of alkyl methacrylate copolymer E, 6 g of talc and 18 g of water are dissolved and dispersed in 364 g of ethanol.
5 g was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 14 To 100 g of the granules obtained in Example 1 (1), 23.3 g of methacrylic acid copolymer-S, methacrylic acid copolymer L46.
7 g, triethyl citrate 7 g, talc 7 g, water 10
160 g of a coating solution prepared by dissolving and dispersing 0 g of ethanol in 916 g of ethanol was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 g of water were added in ethanol. 65 g of a coating solution dissolved / dispersed in 364 g was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 15 100 g of the granules obtained in Example 1 (1) were added to 23.3 g of methacrylic acid copolymer-S and methacrylic acid copolymer L46.
7 g, triethyl citrate 7 g, talc 7 g, water 100
160 g of a coating solution prepared by dissolving and dispersing g in 916 g of ethanol was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of polyvinyl acetal diethyl acetate (trade name: AEA, manufactured by Sankyosha). , Talc 6 g, and water 18 g were dissolved and dispersed in ethanol 364 g, and 100 g of the coating liquid was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.
When coating polyvinyl acetal diethyl acetate, macrogol 6 may be added to the coating solution if necessary.
000 can be added in a slight amount.

Example 16 To 100 g of the granules obtained in Example 1 (1), 70 g of methacrylic acid copolymer L, 7 g of triethyl citrate and 7 g of talc were added.
g, 100 g of water was dissolved / dispersed in 916 g of ethanol, 78 g of a coating solution was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 g of water.
25 g of a coating solution prepared by dissolving and dispersing in 364 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 17 To 100 g of the granules obtained in Example 1 (1), 70 g of methacrylic acid copolymer L, 7 g of triethyl citrate and 7 g of talc were added.
g, 100 g of water was dissolved / dispersed in 916 g of ethanol, 78 g of a coating solution was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 g of water.
165 g of a coating solution prepared by dissolving and dispersing in 364 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 18 To 100 g of the granules obtained in Example 1 (1), 70 g of methacrylic acid copolymer L, 7 g of triethyl citrate and 7 g of talc were added.
g, 100 g of water dissolved and dispersed in 916 g of ethanol, 240 g of a coating solution was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 g of water.
25 g of a coating solution prepared by dissolving and dispersing g in 364 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 19 100 g of the granules obtained in Example 1 (1) were added with 70 g of methacrylic acid copolymer L, 7 g of triethyl citrate, and 7 g of talc.
g, 100 g of water dissolved and dispersed in 916 g of ethanol, 240 g of a coating solution was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 g of water.
165 g of a coating solution prepared by dissolving and dispersing g in 364 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 20 To 100 g of the granules obtained in Example 1 (1), 70 g of methacrylic acid copolymer L, 7 g of triethyl citrate and 7 g of talc were added.
g, 100 g of water was dissolved and dispersed in 916 g of ethanol, 125 g of a coating solution was coated by a tumbling fluidized bed coating method and then dried, and further 12 g of aminoalkyl methacrylate copolymer E, 6 g of talc and 18 of water were added.
65 g of a coating solution prepared by dissolving and dispersing g in 364 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules.

Example 21 100 g of the granules obtained in Example 1 (1) were added with 70 g of methacrylic acid copolymer L, 7 g of triethyl citrate and 7 g of talc.
g, 100 g of water was dissolved and dispersed in 916 g of ethanol, and 125 g of a coating solution was coated by a tumbling fluidized bed coating method and then dried, and further polyvinyl acetal diethyl acetate (trade name: AEA, Sankyosha). Made)
100 g of a coating solution prepared by dissolving and dispersing 12 g, 6 g of talc and 18 g of water in 364 g of ethanol was coated by a tumbling fluidized bed coating method and then dried to obtain sustained release granules. When coating the polyvinyl acetal diethyl acetate, a small amount of Macrogol 6000 can be added to the coating solution if necessary.

Example 22 The granules obtained in Example 1 (1) and the granules obtained in Example 14 were mixed at a nicardipine hydrochloride amount of 3: 1 to obtain sustained release granules.

Example 23 Nicardipine hydrochloride 70 was added to 100 g of the granules obtained in Example 14.
g, hydroxypropylmethylcellulose 70 g, polysorbate 80 32 g, talc 40 g, and water 178 g were dissolved and dispersed in ethanol 1610 g to coat 156 g of a coating liquid by a rolling fluidized bed coating method. It was then dried to obtain sustained release granules.

Example 24 The granules obtained in Example 1 (1) and the granules obtained in Example 15 were mixed at a nicardipine hydrochloride amount of 3: 1 to obtain sustained release granules.

Example 25 Nicardipine hydrochloride 70 was added to 100 g of the granules obtained in Example 15.
g, hydroxypropylmethylcellulose 70 g, polysorbate 80 32 g, talc 40 g, and water 178 g were dissolved / dispersed in ethanol 1610 g, and 155 g of a coating liquid was coated by a tumbling fluidized bed coating method. It was then dried to obtain sustained release granules.

Test Example Regarding the sustained release granules of the present invention obtained in Examples and the sustained release granules obtained in Comparative Examples, the drug (nicardipine hydrochloride) release property and the drug blood when orally administered to dogs The midkinetics were compared as follows.

Test Example 1 (Dissolution Test) Using the sustained release granules obtained in Examples and Comparative Examples in an amount equivalent to 40 mg of nicardipine hydrochloride, the Japanese Pharmacopoeia General Test Method
Dissolution test method The drug release rates were compared by the second method (paddle method). The test liquid is the first pharmacopoeia liquid (pH 1.2), pH
6.5 phosphate buffer (containing 0.1% of polysorbate 80) and pH 7.2 phosphate buffer (polysorbate 80)
(Containing 0.1%), and the liquid volume was 900 ml. The set temperature was 37 ° C., the paddle rotation speed was 100 rpm, and the amount of nicardipine hydrochloride eluted in the test solution was measured by an absorbance method (wavelength 355 nm).

(Test Results) The test results for the sustained release granules of Comparative Examples 1-9 are shown in FIGS. 1-9, and the test results for the sustained release granules of Examples 1-25 are shown in FIGS. 10-34. From these results, the sustained-release granules of the present invention show that the type of enteric polymer used for the enteric coating (methacrylic acid copolymer-L, methacrylic acid copolymer-S or a mixture thereof), amount (based on the drug-containing core granules). About 5 to 15% by weight) and the type (aminoalkyl methacrylate copolymer E, polyvinyl acetal diethyl acetate) and amount (about 0.8 to the drug-containing core granules) of the acid-soluble polymer used for the acid-soluble film.
5% by weight), the pH region in the stomach (p
H1.2) and intestinal pH range (pH 6.5, pH 7.
It is clear that in 2), drug release can be arbitrarily controlled over a long period of time. That is, the sustained-release preparation of the present invention can be arbitrarily controlled over a long period of time.

In the sustained release granules of Examples showing various drug release patterns, drug release was suppressed in the gastric pH region (pH 1.2) desired for nicardipine hydrochloride, and intestinal pH region (pH 6.5, Sustained release granules exhibiting the same drug release rate at pH 7.2) were obtained in Example 14, Example 15, and Example 22, Example 23, Example 24, and Example 25 in which these were combined with the immediate release part. belongs to.

Test Example 2 (Drug pharmacokinetics test in dogs) Six male beagle dogs (about 10 kg) fasted for 12 hours
40 mg of the sustained-release granules obtained in Example 22 and the sustained-release granules obtained in Comparative Example 9 were orally administered to each of them, and blood was collected over time after administration to determine the blood nicardipine hydrochloride concentration. It was determined by a high performance liquid chromatography method.

(Test Results) The test results are shown in FIG. From these results, the sustained-release granules of the present invention show a stable drug blood concentration transition over a long period of time, further exhibit little variation in drug blood concentration between individuals, and have excellent sustained release properties. It was clear.

As shown in the examples, test examples, etc., the sustained-release granules of the present invention have a solubility of the drug in water (water, pH).
Regardless, it is possible to arbitrarily control the drug release over a long period of time in both the gastric pH region (pH 1.2) and the intestinal pH region, particularly both in the vicinity of pH 6.5 and pH 7.2. Yes, stabilization of drug blood concentration transition,
It is clear that variation in blood concentration between (intra) individual drugs can be reduced. From the above, in the sustained release granules of the present invention, it is expected that the therapeutic effect is improved due to the stable and sustained drug effect and the QOL of patients is improved.

[0077]

INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a pharmaceutical composition capable of arbitrarily controlling drug release.

[Brief description of the drawings]

FIG. 1 is a diagram showing results of a dissolution test of Comparative Example 1.

FIG. 2 is a diagram showing a result of a dissolution test of Comparative Example 2.

FIG. 3 is a diagram showing the results of a dissolution test of Comparative Example 3.

FIG. 4 is a diagram showing the results of a dissolution test of Comparative Example 4.

5 is a diagram showing the results of a dissolution test of Comparative Example 5. FIG.

FIG. 6 is a diagram showing the results of a dissolution test of Comparative Example 6.

FIG. 7 is a diagram showing the results of a dissolution test of Comparative Example 7.

8 is a diagram showing the results of a dissolution test of Comparative Example 8. FIG.

9 is a diagram showing the results of a dissolution test of Comparative Example 9. FIG.

FIG. 10 is a diagram showing the results of a dissolution test of Example 1.

FIG. 11 is a diagram showing the results of a dissolution test of Example 2.

FIG. 12 is a diagram showing the results of elution tests in Example 3.

FIG. 13 is a diagram showing the results of dissolution tests in Example 4.

FIG. 14 is a diagram showing the results of dissolution tests in Example 5.

FIG. 15 is a diagram showing the results of elution tests in Example 6.

16 is a diagram showing the results of elution tests in Example 7. FIG.

FIG. 17 is a diagram showing the results of dissolution tests in Example 8.

FIG. 18 is a diagram showing the results of a dissolution test in Example 9.

FIG. 19 is a diagram showing results of dissolution tests in Example 10.

20 is a diagram showing the results of dissolution tests in Example 11. FIG.

FIG. 21 is a diagram showing the results of dissolution tests in Example 12.

22 is a diagram showing the results of elution tests in Example 13. FIG.

FIG. 23 is a diagram showing the result of a dissolution test of Example 14.

FIG. 24 is a diagram showing the results of a dissolution test of Example 15.

FIG. 25 is a diagram showing the results of dissolution tests in Example 16.

FIG. 26 is a diagram showing the result of a dissolution test of Example 17.

FIG. 27 is a diagram showing the result of a dissolution test of Example 18.

28 is a diagram showing the results of elution tests in Example 19. FIG.

FIG. 29 is a diagram showing the results of elution tests of Example 20.

FIG. 30 is a diagram showing the results of dissolution tests in Example 21.

FIG. 31 is a diagram showing the result of a dissolution test of Example 22.

FIG. 32 is a diagram showing the results of elution tests of Example 23.

FIG. 33 is a diagram showing the result of elution test of Example 24.

FIG. 34 is a diagram showing the result of a dissolution test of Example 25.

FIG. 35 is a diagram showing the results of blood kinetic test of sustained-release granules (corresponding to 40 mg of nicardipine hydrochloride) obtained in Comparative Example 9 and Example 22.

Claims (10)

[Claims] 1. A sustained-release pharmaceutical composition comprising an enteric polymer, an acid-soluble polymer and a drug. 2. The enteric polymer is methacrylic acid-methyl methacrylate copolymer, and the acid-soluble polymer is methyl methacrylate-butyl methacrylate-dimethylaminoethyl methacrylate copolymer or polyvinyl acetal diethyl acetate. The sustained-release pharmaceutical composition described. 3. The content of the enteric polymer in the pharmaceutical composition is 5
The sustained-release pharmaceutical composition according to claim 1 or 2, wherein the content of the acid-soluble polymer is 0.8 to 5% by weight in the pharmaceutical composition. 4. The drug-containing core granules are sequentially coated with an enteric polymer and an acid-soluble polymer.
4. The sustained-release pharmaceutical composition according to any one of 3 to 3. 5. The sustained-release pharmaceutical composition according to claim 4, which is a sustained-release granular preparation. 6. A sustained-release pharmaceutical composition comprising the sustained-release granule according to claim 5 and a fast-acting granule. 7. The sustained-release pharmaceutical composition according to claim 6, wherein the drug weight ratio between the sustained-release granules according to claim 5 and the fast-acting granules is 1: 1 to 20: 1. 8. A sustained-release granule preparation in which an immediate-release drug layer is layered on the sustained-release granule according to claim 5 at a drug weight ratio of 1: 1 to 20: 1. 9. The sustained-release pharmaceutical composition according to claim 5, wherein the drug is one or more selected from basic drugs and / or physiologically acceptable salts thereof. 10. The sustained-release granular preparation according to claim 9, wherein the basic drug is nicardipine and / or a physiologically acceptable salt thereof.