KR102241487B1 - Pharmaceutical composition consisting of sustained-release pellets - Google Patents

Abstract

The present invention comprises a drug layer containing carvedilol and a disintegrant having an average particle size of 100 μm or less on the surface of the inert nucleus, a water-soluble polymer, and a polymer dissolved at pH 5.5 to pH 7.4 on the surface of the drug layer, and a solid fat component. As a pharmaceutical composition comprising a controlled-release oral pellet coated with a sustained-release layer, the composition of the present invention is characterized in that it does not have a latent state for drug release, and is preferable for a once-a-day administration. to be.

Description

Pharmaceutical composition consisting of sustained-release pellets

The present invention relates to a pharmaceutical composition capable of controlled release of carvedilol.

Carvedilol is a competitive non-selective β-adrenergic blocker with _{α 1 -blocking action. It induces vasodilation through α 1} -blocking activity and can prevent reflex tachycardia caused by hypertension through β-adrenergic blocking activity.

Carvedilol is a third-generation β-blocker with indications for hypertension, chronic stable angina and congestive heart failure in Korea. Unlike other antihypertensive drugs, carvedilol has antihypertensive effect by reducing overall peripheral vascular resistance without causing incidental reflex changes in heart rate. Represents. Also, there are no side effects such as edema, reflex tachycardia, and dry cough.

When carvedilol is administered for 6 to 12 months for congestive heart failure, it has been shown to reduce patient mortality by 65% compared to conventional drugs.It is the first treatment for hypertension by the U.S. Food and Drug Administration (FDA) as a treatment for congestive heart failure. Has also been approved.

According to the usage of carvedilol, it is administered twice a day for hypertension, chronic stable angina and congestive heart failure. However, in the case of high blood pressure, clinically used once to twice a day may be mixed, but twice a day is suitable for preventing side effects such as orthostatic hypotension.

The present invention relates to a sustained-release formulation of carvedilol for changing the dosage of carvedilol twice a day to once a day.

International Publication No. WO 2005/051322 is a controlled-release formulation consisting of microparticles having an immediate-release layer containing carvedilol and at least two types of sustained-release layers, and has two peaks in blood concentration in a blood profile when administered orally. Has a characteristic. However, the present invention is different from the formulation of the patent in that it is a controlled-release formulation composed of microparticles having a single type of sustained-release layer, and has a single blood concentration peak when administered orally.

International Patent Publication No. WO 2004/096182 discloses a dual release matrix tablet in which an enteric layer is coated between a core containing carvedilol and an immediate release layer. However, the present invention differs from the formulation of the above patent in that it is a pellet formulation in which a sustained release layer is coated on a core containing carvedilol.

International Patent Publication No. WO 2001/010419 discloses that a pharmaceutical composition contains a porous matrix and at least one drug, sugar, at least one gas-generating component, and optionally a pharmaceutically acceptable auxiliary component while the drug is actually released in the stomach. Disclosed is a pharmaceutical composition constituting a maintenance oral drug delivery system. However, the above patent differs from the present invention in that it is intended to increase the bioavailability by increasing the residence time in the upper gastrointestinal tract including a gas-generating component as a key component in designing the release delay matrix.

International Publication No. WO 2004/103349 discloses a controlled release device comprising a core comprising an active material, a wall surrounding the core, and a pre-formed passage. However, the above device differs from the present invention in that the drug tablet core is coated and then drilled through a hole to provide a passage through which the active substance is released.

International Patent Publication No. WO 2002/092078 is permeable to the surrounding liquid in the core containing carvedilol, a polymerizable swelling agent, one or more water-soluble compounds for inducing osmotic pressure, and other pharmaceutical excipients, but with respect to the contents of the core. Disclosed is a controlled release matrix composition having a semi-permeable film surrounding the impermeable core. However, the composition is substantially different from the present invention in that it is a matrix-type tablet using a semi-permeable coating layer.

International Patent Publication No. WO 2008/062440 discloses a system for programmatically delivering an active agent in a spatiotemporal manner, comprising a core, one or more layers coated on the core, and a pre-formed empty space, wherein the active agent is the system It discloses a system characterized in that it is present in any of the layers or in the core. However, in the case of the system, heat is applied to create an empty space and then expanded and then cooled, which is different from the present invention.

International Publication No. WO 2003/030878 discloses a system in which an active source is released by a mechanism of time dependence and pH dependence as a pharmaceutical form of microparticles for delayed release of an active source. However, the system is different from the pharmaceutical composition of the present invention in which the latent state does not exist in that it has an elution mode in the latent state of 1 to 5 hours for delayed release.

International Publication Nos. WO 2005/046561 and WO 2005/046649 disclose multilayer pharmaceutical dosage forms having a core and a matrix that influences the delivery of modulators. However, the matrix-type multilayer pharmaceutical form for delivery of the modulator is different from the controlled-release formulation of the present invention consisting of a core layer, an inner control layer, an active ingredient layer, and an outer control layer. .

International Patent Publication No. WO 2005/046647 essentially contains a neutral support, contains at least one polymer, and is coated with a polymer layer that allows the active ingredient to be released from an aqueous medium, wherein there is at least one active A formulation to which an active layer containing an ingredient is applied is disclosed. However, the formulation differs from the present invention because it is characterized by directly compressing the particulate formulation containing the active ingredient in order to modify the release profile.

International Publication No. WO 2011/049309 is coated on the surface with a water-insoluble polymer, and a first pharmaceutical active ingredient, a water-insoluble polymer, and at least one controlled-release base selected from the group consisting of water-soluble and viscous polymers and pharmaceutical acceptable Disclosed is a pharmaceutical composition comprising a sustained release part including a carrier and a second pharmaceutically active ingredient, and an immediate release part including a pharmaceutically acceptable carrier. However, the above formulation has an independent granular form of the sustained-release part and the immediate-release part in which the drug is homogeneously dispersed, and the sustained-release part does not contain a pharmaceutical active ingredient in that the pharmaceutical active ingredient and the controlled-release base are mixed to form the sustained-release part. It differs from the present invention in which a layer is coated to produce a pellet.

Korean Patent Publication No. 10-2004-0077244 consists of a single pellet coated with an immediate-release drug layer containing a drug on the surface of a sustained-release drug layer containing an inert nucleus and a drug, and the sustained-release drug layer is a hydrophobic polymer and a hydrophilic polymer. Is composed of a mixture, and the immediate-release drug layer is composed of a hydrophilic polymer to provide a formulation for controlling the release of the drug. However, the pharmaceutical composition of the present invention is different in that it is a pellet formulation in which an inert nucleus is coated with a drug layer and a sustained release layer containing no drug is coated on the surface of the drug layer.

International Publication Patent Publication No. WO 2005/051322 International Publication Patent Publication No. WO 2004/096182 International Publication Patent Publication No. WO 2001/010419 International Patent Publication No. WO 2004/103349 International Publication Patent Publication No. WO 2002/092078 International Publication Patent Publication No. WO 2008/062440 International Publication Patent Publication No. WO 2003/030878 International Publication Patent Publication No. WO 2005/046561 International Publication Patent Publication No. WO 2005/046649 International Publication Patent Publication No. WO 2005/046647 International Publication Patent Publication No. WO 2011/049309 Korean Patent Publication No. 10-2004-0077244

An object of the present invention is to provide a pharmaceutical composition of oral pellets capable of controlled release of carvedilol by using a pellet coated with a drug layer containing carvedilol on the surface of an inactive nucleus and coated with a sustained-release layer on the surface of the drug layer. It is in providing.

In addition, an object of the present invention is to provide a pharmaceutical composition for oral pellets having a uniform particle size and shape while enabling controlled release of carvedilol.

The present invention comprises a drug layer containing carvedilol and a disintegrant and a water-soluble polymer having an average particle size of 100 µm or less on the surface of the inert nucleus, and a polymer and a solid fat component dissolved at pH 5.5 to pH 7.4 on the surface of the drug layer. It provides a pharmaceutical composition capable of controlled release of carvedilol by coating the containing sustained-release layer.

The present invention is characterized by a dissolution aspect that does not have a latent state, and provides a sustained-release formulation of carvedilol, which is preferable for once-a-day administration. The dissolution mode that does not have a latent state induces rapid onset of drug effects similar to when taking an immediate-release formulation, and subsequent controlled release sustains the drug effect.

Carvedilol, the pharmacologically active substance of the present invention, is (±)-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxphenoxy)ethyl] As an amine{(±)-[3-(9H-carbazol-4-yloxy)-2-hydroxypropyl][2-(2-methoxyphenoxy)ethyl]amine}, vasodilating through _{β 1} , β ₂ and α _{1 blocking action} It has an action, and it exhibits excellent effects as a first-line drug for circulatory system diseases such as high blood pressure, angina and heart failure.

In the pharmaceutical composition of the present invention, carvedilol may be in the form of a free base or salt, a solvate, or an anhydride, and may have 5 mg to 150 mg based on the free base as an active ingredient.

The inert nucleus of the present invention may be selected from monosaccharides, disaccharides, polysaccharides, cellulose, microcrystalline cellulose, cellulose derivatives, and mixtures thereof, which are commonly used as pharmaceutical excipients, and preferably, an inert having an average particle size of 300 μm or less. Nuclei can be used.

The disintegrant of the present invention contributes to the promotion of elution through swelling of the drug layer, and may be selected from sodium starch glycolate, pregelatinized starch, sodium crosscarboxymethylcellulose, crospovidone, and mixtures thereof. Preferably, the disintegrant having an average particle size of 100 μm or less may be used. More preferably, the disintegrant having an average particle size of 20 µm or less may be used, and most preferably, the disintegrating agent having an average particle size of 10 µm or less may be used. When a disintegrant having an average particle size in the preferred range is used, pellets having a uniform particle size and shape can be produced, and the controlled release desired in the present invention can be achieved.

The water-soluble polymer of the present invention contributes to the formation of a coating film of the drug layer and dispersion of the drug, and as a cellulose series, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, and their One or more can be selected from the mixture. In addition, the water-soluble polymer of the present invention may be selected from polyvinyl alcohol, polyvinylpyrrolidone, and mixtures thereof.

The polymer dissolved in pH 5.5 to pH 7.4 of the present invention is a release-controlling material for controlled release of pharmacologically active substances contained in the sustained release layer, and as a methacrylic acid copolymer, 2-dimethylaminoethyl methacrylate, methyl methacrylate , Methacrylic acid, ethyl acrylate, butyl methacrylate, or a mixture thereof and a cellulose-based polymer dissolved in pH 5.5 to pH 7.4 as a cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose It may be selected from one or more phthalates, and mixtures thereof.

The solid fat component of the present invention is included in the sustained release layer to induce continuous controlled release of the drug, and sorbitan fatty acid ester, sucrose fatty acid ester, fatty acid, fatty acid glycerol ester, fatty alcohol, fatty fatty alcohol ester, fatty acid propylene glycol, and these One or more may be selected from a mixture of. Preferably, the fatty acids and fatty alcohols of the above components may be selected from saturated fatty acids and saturated fatty alcohols. Specifically, the solid fat component of the present invention is hydrogenated vegetable oil, hydrogenated castor oil, hardened soybean oil, hardened cottonseed oil, hardened palm oil, glyceryl monostearic acid, glyceryl behenate, glyceryl palmitostearic acid, sorbitan monostearic acid, sorbitan One or more may be selected from monopalmitate, stearic acid, stearyl alcohol, sucrose lauric acid, sucrose stearic acid, and mixtures thereof.

Plasticizers, solubilizers, and stabilizers commonly used as pharmaceutical excipients may be additionally added to the composition of the present invention.

Plasticizers that can be additionally used in the present invention are dibutyl sebacate, dibutyl phthalate, diacetylated monoglyceride, diethyl phthalate, stearic acid polyoxyl 40, acetyl tributyl citrate, acetyl triethyl citrate, tributyl citrate, One or more of triacetin, triethyl citrate, polyethylene glycol, propylene glycol, and mixtures thereof may be selected.

Solubilizing agents that can be additionally used in the present invention are light anhydrous silicic acid, glyceryl monooleate, docusate sodium, lauryl dimethylamino acetate betaine, lauryl sulfate sodium, myristyl alcohol, benzalkonium chloride, vitamin E polyethylene glycol succinate. Nate, cetrimide, cetylpyridinium chloride, sorbitan sesquioleate, sorbitan ester, sorbitan trioleate, phospholipid, cocamidopropylbetaine, cocamido DEA, tricapryline, polysorbate, polyoxyl Glyceride, polyethylene glycol monostearic acid, polyoxyethylene nonylphenyl ether, polyoxyethylene alkyl ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene stearate, polyoxyethylene castor oil, polyoxyl 40 hardened castor oil, propylene glycol Dilaurate, propylene glycol monolaurate, thyroxapol, TEA-cocoyl glutamate, and a mixture thereof may be selected from one or more.

Stabilizing agents that can be additionally used in the present invention include sodium gluconate, glutamic acid, glycerin, glycolic acid, dibutylhydroxytoluene, lactic acid, lecithin, D-mannitol, D-sorbitol, maleic acid, malic acid, meglumine, butyl Rated hydroxyanisole, boric acid, sucrose, xanthan gum, magnesium oxide, succinic acid, disodium succinate, β-cyclodextrin, simethicone, citric acid, sodium citrate, ascorbic acid, sodium hydrogen sulfite, hydrochloric acid, lactose, liquid paraffin , Silicon dioxide, phosphoric acid, sodium dihydrogen phosphate, calcium phosphate, L-phenylalanine, tartaric acid, talc, tocopherol, tocopherol acetate, glucose, poloxamer, fumaric acid, sodium pyrosulfite, sulfuric acid, and mixtures thereof. I can.

The pharmaceutical composition capable of controlled-release of the present invention may further include a drug layer-coated pellet together with a controlled-release drug pellet.

The pharmaceutical composition capable of controlled release of the present invention has an elution mode that does not have a latent state, and when tested at 100 rpm for 0 to 18 hours under the condition of pH 1.2, 10% or more and less than 40% of carvedilol is 1 1 day when carvedilol is released according to the dissolution profile released in time, the dissolution profile in which more than 40% and less than 70% of carvedilol is released in 5 hours, and the dissolution profile in which more than 70% carvedilol is released after 18 hours It is a controlled-release pharmaceutical composition of carvedilol suitable for single use.

The pharmaceutical composition capable of controlled release of the present invention may be administered orally, and may be taken with food.

Carvedilol pharmaceutical composition composed of pellets capable of controlled release of the present invention is a pharmaceutical composition suitable for oral administration once a day.

In addition, the pharmaceutical composition of the present invention includes oral pellets having a uniform particle size and shape while allowing controlled release of carvedilol.

1 shows a schematic diagram of particles of an inert nucleus and a disintegrant used in the present invention.
Figure 2 shows the pellet structure of the controlled-release pharmaceutical composition according to the present invention.
3A to 3C show micrographs of drug layer coated pellets prepared according to Examples 3, 7 and Comparative Example 2 of the present invention.
4A to 4C show particle size distribution graphs of drug layer coated pellets prepared according to Examples 3, 7 and Comparative Example 2 of the present invention.
5 shows a comparison of drug release of Example 3, Comparative Example 1, and Comparative Example 2 of the present invention.

Hereinafter, the present invention will be described in detail through examples and experimental examples. However, these Examples and Experimental Examples are only examples of the present invention, and the scope of the present invention is not limited thereto.

[ Example 1 to 8] of the present invention Carvedilol Manufacture of sustained-release formulation

A sustained-release formulation of carvedilol was prepared in the composition shown in Table 1 below.

Examples 1 to 8 are pharmacologically active substances with carvedilol as a disintegrant and crospovidone (Polyplasdone XL-10 ^{® , ISP) having an average particle size of 100 μm or less or crospovidone (Kollidon CL-M ®} ) having an average particle size of 20 μm or less as a disintegrant. , BASF), as a water-soluble polymer, hydroxypropylmethylcellulose and povidone, and other additives were dissolved or dispersed in about 0.4 ml of methylene chloride and about 0.6 ml of ethanol to prepare a drug coating solution. A coating solution was added to microcrystalline cellulose having a particle size of 300 μm or less to prepare a drug layer coated pellet. Eudragit L100-55, Eudragit S100 and hydroxypropylmethylcellulose acetate succinate as a sustained-release layer as a polymer dissolved in pH 5.5 to pH 7.4, hydrogenated castor oil, stearic acid and fatty acid glycerol esters as solid fat components, Other additives were dissolved or dispersed in about 1 ml of ethanol and about 0.5 ml of purified water to prepare a sustained-release coating solution, and a controlled-release drug pellet was prepared by adding the sustained-release coating solution to the drug layer coating pellet using a fluidized bed granulator/coating machine. The prepared carvedilol sustained-release pellets were filled in capsules so that 100 mg per capsule was carvedilol.

[Table 1]

[ Comparative example One] Of carvedilol Immediate release formulation

Comparative Example 1 is an immediate-release formulation containing 25 mg of carvedilol as a pharmacologically active substance (dilatren tablet 25 mg, Chong Kun Dang).

[ Comparative example 2 to 4] average Particle size Exceeding 100 μm Disintegrant Used Kar Bedilol sustained-release formulation manufacturing

A sustained-release formulation of carvedilol was prepared with the composition shown in Table 2 below.

Comparative Examples 2 to 4 include carvedilol as a pharmacologically active substance, crospovidone (Polyplasdone XL ^® , ISP) having an average particle size of more than 100 μm as a disintegrant, hydroxypropylmethylcellulose and povidone as a water-soluble polymer, and other additives. A drug coating solution was prepared by dissolving or dispersing in about 0.4 ml of methylene chloride and about 0.6 ml of ethanol, and a drug layer coated pellet was prepared by adding the coating solution to microcrystalline cellulose having an average particle size of 300 μm or less as an inert nucleus using a fluidized bed granulator/coating machine. . Eudragit L100-55, Eudragit S100 and hydroxypropylmethylcellulose acetate succinate as a sustained-release layer as a polymer dissolved in pH 5.5 to pH 7.4, hydrogenated castor oil, stearic acid and fatty acid glycerol esters as solid fat components, Other additives were dissolved or dispersed in about 1 ml of ethanol and about 0.5 ml of purified water to prepare a sustained-release coating solution, and a controlled-release drug pellet was prepared by adding the sustained-release coating solution to the drug layer coating pellet using a fluidized bed granulator/coating machine. The prepared carvedilol sustained-release pellets were filled in capsules so that 100 mg per capsule was carvedilol.

[Table 2]

[ Experimental example One] Drug layer Checking the process yield of coated pellets

The drug layer coated pellets prepared according to Example 3, Example 7 and Comparative Example 2 were separated using a standard body (US Sieve No.35, No.100) and weighed to confirm the process yield [Table 3] .

[Table 3]

As shown in the results of [Table 3], Comparative Example 2 using Polyplasdone XL as a disintegrant having an average particle size exceeding 100 µm showed a low yield of about 67.0% of drug layer coated pellets having a particle size of 150 to 500 µm. , It was confirmed that a lot of fine powders of 150 μm or less and pellets having a large particle size of 500 μm or more were formed. On the other hand, in the case of Examples 3 and 7 using the disintegrant having an average particle size of 100 μm or less, it was confirmed that the formation of fine powder and pellets having a large particle size was suppressed.

[ Experimental example 2] Drug layer Check the shape of coated pellets

In order to confirm the shape of the drug layer coated pellet according to the average particle size of the disintegrant, the drug layer coated pellets prepared according to Examples 3, 7 and Comparative Example 2 were confirmed at 40x magnification on a microscope (ECLIPSE 80i, Nikon). [Figs. 3a to 3c].

As shown in the result of [Fig. 3c], in the case of Comparative Example 2 in which a disintegrant having an average particle size exceeding 100 µm was used, the shape and particle size of the drug layer coated pellet was not uniform, and the proportion of fine powder and agglomerated particles was It was confirmed that it increased. However, as shown in the results of [Figs. 3a and 3b], in the case of Examples 3 and 7 in which the disintegrants having an average particle size of 100 μm or less were used, it was confirmed that the shape and particle size of the drug layer coated pellets were uniformly prepared.

[ Experimental example 3] Drug layer Confirmation of particle size distribution of coated pellets

In order to check the particle size distribution of the drug layer-coated pellets prepared according to Example 3, Example 7 and Comparative Example 2, a laser diffraction type particle size distribution measuring apparatus was used to measure the particle size under the following conditions [Figs. 4A to 4C].

<Particle size distribution measurement conditions>

Equipment: laser diffraction type particle size distribution measuring device (Mastersizer 3000, Malvern)

Dry unit (Aero S, Malvern)

・Sample measurement time: 2 seconds

Background measurement time: 10 seconds

Pressure: 2.0 bar

・Feed rate: 20%

Dv 10, Dv 50, and Dv 90 in [Table 4] are indices for defining the particle size distribution. In the particle size distribution, Dv 10 is defined as the particle size at 10% in the entire distribution, Dv 50 at 50% in the entire distribution, and Dv 90 is defined as the particle size at 90% in the entire distribution.

[Table 4]

As shown in the results of [Table 4], in Comparative Example 2, a fine powder having a Dv 10 of 37.4 µm was formed, and as shown in Fig. 4c, particle agglomeration having a particle size of 1,000 µm or more was observed. However, in Example 3 of the present invention, as shown in the result of [Table 4], Dv 10 is 236 µm, Dv 50 is 281 µm, and Dv 90 is 338 µm. As shown in the results of [Figs. 4a and 4b], it was confirmed that particle aggregation did not appear.

[ Experimental example 4] Of carvedilol Controlled release check

The controlled release effect of the composition of the present invention was confirmed through the following dissolution test.

With respect to the capsules prepared through Example 3 and Comparative Example 2, 6 capsules were eluted under conditions of 100 rotations per minute and 37 ± 0.5 °C. After the start of the dissolution test in 900 ml of the elution medium of pH 1.2, 5 ml of the eluate was taken for each time. The filtered eluate was filtered through a membrane filter with a pore diameter of 0.45 µm, and the filtrate was analyzed by the following HPLC analysis method to calculate the dissolution rate, and an elution graph was prepared [Fig. 5].

<HPLC analysis method of carvedilol>

Column: Kromasil C18 (4.6 X 150 mm, 5㎛)

Detector: Ultraviolet absorption spectrophotometer (measurement wavelength: 285 nm)

Flow rate: 1.7 ml/min

·Injection amount: 40 µl

Mobile phase: A mixture of pH 2.0 phosphate buffer and methanol (50:50)

As shown in the result of [Fig. 5], in the case of Comparative Example 1, which is an immediate-release formulation of carvedilol, a dissolution rate of 80% or more was shown within 1 hour. In addition, as a result of confirming the dissolution rates of Example 3 using a disintegrant having an average particle size of 20 μm or less as a carvedilol sustained-release formulation and Comparative Example 2 using a disintegrant having an average particle size of more than 100 μm, Comparative Example 2 is a drug Since the initial release rate of was high, only about 30% of the drug was released until 24 hours after 1 hour of the initial release, but in Example 3, about 60% of the drug was slowly released until 24 hours after 1 hour of the initial release. Specifically, Example 3 shows a dissolution rate of 10% or more and less than 40% for 1 hour, a dissolution rate of 40% or more and less than 70% for 5 hours, and a dissolution rate of 70% or more for 18 hours. It was confirmed that it was a pharmaceutical composition.

Therefore, it was confirmed that the average particle size of disintegration affects not only the shape and particle size distribution of the pellets, but also the sustained-release dissolution rate of the sustained-release formulation.

Claims (11)

A drug layer containing carvedilol and a disintegrant and a water-soluble polymer having an average particle size of 100 μm or less on the surface of the inert nucleus, and a sustained-release layer containing a solid fat component and a polymer dissolved at pH 5.5 to pH 7.4 on the surface of the drug layer Containing coated pellets,
The disintegrant is a controlled-release oral pharmaceutical composition selected from the group consisting of crosscarboxymethylcellulose sodium, crospovidone, sodium starch glycolate, pregelatinized starch, and mixtures thereof. The pharmaceutical composition according to claim 1, wherein the average particle size of the inactive nuclei is 300 μm or less. The pharmaceutical composition according to claim 1, wherein the disintegrant has an average particle size of 20 μm or less. The pharmaceutical composition according to claim 1, wherein the disintegrant has an average particle size of 10 μm or less. delete The method according to any one of claims 1 to 4, wherein the water-soluble polymer is a cellulose-based methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, and mixtures thereof. A pharmaceutical composition selected from the group consisting of. The pharmaceutical composition according to any one of claims 1 to 4, wherein the water-soluble polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, and mixtures thereof. The method according to any one of claims 1 to 4, wherein the polymer dissolved at pH 5.5 to pH 7.4 is a methacrylic acid copolymer, which is butyl methacrylate, 2-dimethylaminoethyl methacrylate, methyl methacrylate, and ethyl. A pharmaceutical composition selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and mixtures thereof as acrylate, methacrylic acid, methylmethacrylate and cellulose-based polymers . The method of any one of claims 1 to 4, wherein the solid fat component is fatty acid, fatty alcohol, fatty fatty alcohol ester, fatty acid glycerol ester, fatty acid propylene glycol, sorbitan fatty acid ester and sucrose fatty acid ester, and mixtures thereof. A pharmaceutical composition selected from the group consisting of. The pharmaceutical composition according to any one of claims 1 to 4, further comprising a plasticizer, a solubilizing agent and a stabilizer which are commonly used. The pharmaceutical composition according to any one of claims 1 to 4, further comprising a drug layer coated pellet.

Images