KR101912191B1 - Pharmaceutical composition comprising Mosapride or salt thereof and preparation method for the same - Google Patents

Abstract

The present invention relates to a pharmaceutical preparation comprising moscafide or a salt thereof which simultaneously exhibits rapid and sustained release properties and a method for preparing the same, and a sustained release or controlled release formulation containing the mothafide or a salt thereof according to the present invention is a conventional It is possible to reach the effective therapeutic blood concentration quickly as compared with the pharmaceutical preparations, thereby having an immediate effect of improving the gastrointestinal motility disorder, and at the same time, it is possible to maintain sustained drug elution. Therefore, it is possible to increase the drug adaptability to the patients, thereby increasing the compliance and decreasing the frequency of administration.
In addition, the method can be manufactured by a simple method as compared with the conventional method, thereby saving manufacturing time and improving productivity.

Description

[0001] The present invention relates to pharmaceutical preparations comprising mosaic fibrids or salts thereof and to a process for the preparation thereof,

The present invention relates to a pharmaceutical preparation comprising moscafide or a salt thereof which simultaneously exhibits rapid and sustained release properties, and a method for producing the same.

Gastrointestinal diseases are classified as inflammatory gastrointestinal diseases and functional gastrointestinal diseases. Functional gastrointestinal diseases are chronic intractable diseases, which are increasingly important due to stress and aging of society in the present, and are major diseases showing a market size of 100 billion won.

Functional gastrointestinal disease is a functional symptom that is not a histopathologic or biochemical functional lesion. It refers to symptoms such as persistent discomfort or pain in the upper abdomen. Serotonin (5-HT, 5-hydroxytryptamine), dopamine Which is a complex disease involving the nervous system. Functional gastrointestinal diseases are caused by ulcerative dyspepsia, dysmotility-like dyspepsia, relux-like dyspepsia, nonspecific or unspecified functional dyspepsia, As shown in Fig. Especially in Korea and Japan, the frequency of stomach gastrointestinal diseases is the highest.

Gastrointestinal motility modulating drugs for treating playground gastrointestinal diseases can be classified into drugs that promote gastrointestinal motility and drugs that inhibit gastrointestinal motility. In addition to these two groups, there are other drugs that decrease gastric relaxation and lower esophageal sphincter relaxation. The most important part of this is the gastrointestinal motility promoter. Gastrointestinal motility promoters include all compounds that have a pharmacological action to stimulate gastrointestinal motility. These drugs stimulate the smooth muscle of the intestine and promote gastrointestinal motility. Therefore, these medicines are mainly used for symptoms and diseases caused by lowering of gastrointestinal motility. A variety of gastrointestinal motility promoters have been developed and used. Gastrointestinal motility stimulants commonly used include 5-HT4 receptor agonists, dopamine receptor antagonists, motilin receptor agonists, and cholestystin receptor antagonists.

An example of a gastrointestinal motility enhancer is Mosapride. Mosapride is a selective serotonin 5-hydroxytryptamine 4 (hereinafter referred to as '5-HT4') receptor agonist that selectively stimulates serotonin 5-HT4 receptors present in the carotid plexus, This acetylcholine increases the secretion of acetylcholine at the terminal and promotes gastrointestinal motility by contracting the smooth muscle of the digestive tract to exert excellent efficacy in the treatment of diabetic hyperglycemia, dyspepsia, gastritis and reflux esophagitis . There was no fear of arrhythmia and cardiogenic sudden death due to prolonged QT interval in Sisaafrid, a nonselective 5-HT4 receptor agonist, and there was no dopamine-2 receptor antagonistic action, resulting in central nervous system side effects (extrapyramidal symptoms), hyperprolactinemia (Milk secretion, feminized breast), etc. are safe drugs without side effects.

However, since the half-life is short as 1.3 to 2 hours, the drug is quickly lost after being absorbed into the body and has a short duration of pharmacological effect. Therefore, it is necessary to take several times a day. A reduction in the patient 's compliance with the medication, and even a single dose of 24 hours to maintain the drug efficacy of the sustained sustained maintenance is needed.

In the case of general slow-release, sustained efficacy can be maintained for 24 hours, but it takes a long time to reach effective blood levels at the beginning. It is also difficult to maintain effective pharmacological activity for 24 hours if it exhibits rapid pharmacological activity.

The present study investigated the effect of the drug of the present invention on the preparation of the drug of the present invention and the drug of the present invention. There are capsule formulations containing mini tablets and atypical granules. Other than that, there is only Western formulation that does not have quick effect. However, the conventional techniques having the above-mentioned inevitability and sustained-release characteristics necessarily require special facilities or complicated processes.

Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made keeping in mind the above problems occurring in the prior art, and it is an object of the present invention to provide a pharmaceutical preparation comprising mothafide or a salt thereof having both rapid and sustained release properties.

More particularly, the present invention relates to a process for the preparation of a simple, single capsule or granule which comprises a conventional complex multi-layered tablet and multi-unit (mini tablet, fluidized-bed assembly pellets, etc.) And which can maintain a long-term drug efficacy.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising a mixture comprising an effective ingredient containing a mosaic friide or a salt thereof and a release-

Wherein the release control agent is selected from the group consisting of C ₈ -C ₂₆ fatty acids, C ₈ -C ₅₀ fatty acid esters, C ₆ -C ₃₀ higher alcohols, hydrogenated vegetable oils, hardened castor oil, and waxes,

 Wherein the sustained release or controlled release formulation is characterized by satisfying the following dissolution profile at 37 占 폚 water according to the Korean Pharmacopoeia dissolution assay method 2 (paddle method).

1) Within 30 minutes 10% to 50% of the total weight of the mothafide or salt thereof is released,

2) The release of 50% to 95% of the total weight of the simulated fried or its salt is achieved between 6 hours and 20 hours.

The active ingredient may be contained in an amount of 1 to 50% by weight based on the total weight of the composition.

The release control agent may be contained in an amount of 5 to 90% by weight based on the total weight of the composition.

Wherein said disintegrant is selected from the group consisting of low substituted hydroxypropylcellulose, microcrystalline cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, carboxymethylcellulose sodium, lactose, mannitol, polyethylene glycol 6000, pregelatinized starch, corn starch, And the like.

The mixture may further comprise an excipient, a solubilizer, a binder or a binding solvent.

The excipient may be any one or more selected from the group consisting of microcrystalline cellulose, lactose, mannitol, corn starch, potassium hydrogen phosphate, silicon dioxide and pregelatinized starch.

The solubilizing agent is selected from the group consisting of citric acid, tartaric acid, glutamic acid, malic acid, lactic acid, fumaric acid, phosphoric acid, succinic acid, stearic acid, acetic acid, maleic acid, adipic acid, cholic acid, orotic acid, hydrochloric acid, , Sodium lauryl sulfate, and polysorbate.

The binder may be any one or more selected from the group consisting of polyvinylpyrrolidone, copovidone, polyvinyl alcohol, hydroxypropylcellulose, pregelatinized starch and sodium alginate.

The coupling solvent may be any one or more selected from the group consisting of ethanol, water, isopropyl alcohol and methylene chloride.

The sustained-release or controlled-release formulation may further comprise at least one lubricant selected from the group consisting of salts of stearic acid, glyceryl behenate, talc and silicon dioxide.

The sustained-release or controlled-release formulation containing the mosaic fibrin or salt thereof according to the present invention can reach the effective therapeutic blood concentration quickly compared to the conventional pharmaceutical preparation, and has immediate gastrointestinal motility disorder improvement effect. At the same time, It is possible to keep. Therefore, it is possible to increase the drug adaptability to the patients, thereby increasing the compliance and decreasing the frequency of administration.

In addition, the method can be manufactured by a simple method as compared with the conventional method, thereby saving manufacturing time and improving productivity.

FIG. 1 is a graph showing the results of Experimental Example 1 for confirming the dissolution rate of a single-layered solution using a swellable polymer not containing a disintegrant.
FIG. 2 is a graph showing the results of Experimental Example 2 for confirming the dissolution rate of each of the western granule release control systems.
3 is a graph showing the results of Experimental Example 3 for confirming the dissolution rate of each of the granules of the present invention.
FIG. 4 is a graph showing the results of Experimental Example 4 for confirming the dissolution rate of the western granular binder.
FIG. 5 is a graph showing the results of Experimental Example 5 for confirming the dissolution rate upon addition of the solubilized granule.
FIG. 6 is a graph showing the results of Experimental Example 6 for confirming the dissolution rate depending on the kind of the solvent for the granule bound to the granules and the presence or absence of the solvent.
FIG. 7 is a graph showing the result of Experimental Example 7 for confirming the type of post-mix disintegrant and the dissolution rate depending on the use.
8 is a graph showing the results of Experimental Example 8 for confirming the dissolution rate of the post-mixed lubricant.
FIG. 9 is a graph showing the results of Experimental Example 9 for comparing the dissolution rates at the time of mixing after the simulated frying.

Hereinafter, the present invention will be described in detail. Prior to this, terms and words used in the present specification and claims should not be construed as limited to ordinary or dictionary terms, and the inventor should appropriately interpret the concepts of the terms appropriately It should be interpreted in accordance with the meaning and concept consistent with the technical idea of the present invention based on the principle that it can be defined. Therefore, the constitutions described in the embodiments described herein are merely the most preferred embodiments of the present invention, and are not intended to represent all of the technical ideas of the present invention. Therefore, various equivalents which can be substituted at the time of application It should be understood that variations can be made.

The present invention comprises a mixture comprising an active ingredient containing a mosaic pride or salt thereof and a release-controlling agent,

Wherein the release control agent is selected from the group consisting of C ₈ -C ₂₆ fatty acids, C ₈ -C ₅₀ fatty acid esters, C ₆ -C ₃₀ higher alcohols, hydrogenated vegetable oils, hardened castor oil, and waxes,

 Wherein the sustained release or controlled release formulation is characterized by satisfying the following dissolution profile at 37 占 폚 water according to the Korean Pharmacopoeia dissolution assay method 2 (paddle method).

1) Within 30 minutes 10% to 50% of the total weight of the mothafide or salt thereof is released,

2) The release of 50% to 95% of the total weight of the simulated fried or its salt is achieved between 6 hours and 20 hours.

The sustained-release or controlled-release formulation is characterized in that it contains moscafide or a salt thereof as an active ingredient and exhibits persistence and a fast dissolution rate including a release-controlling agent.

The release control agent means a substance which is hydrophobic and is used to release the drug over a long period of time. The term 'hydrophobicity' refers to a property of being immiscible with water molecules, .

The release control agent may be selected from the group consisting of C ₈ to C ₂₆ fatty acids, C ₈ to C ₅₀ fatty acid esters, C ₆ to C ₃₀ higher alcohols, hydrogenated vegetable oils, hardened castor oil, and waxes have.

Examples of the C ₈ to C ₂₆ fatty acids include, but are not limited to, stearic acid, magnesium stearate, lauric acid, myristic acid or palmitic acid.

Examples of the C ₈ to C ₅₀ fatty acid esters include glycerin fatty acid esters, acetyl glycerin fatty acid esters, propylene glycol fatty acid esters, glyceryl monostearate, glyceryl behenate, sorbitan monostearate, tributyl citrate, acetyl But are not limited to, tributyl citrate, glyceryl monooleate, glyceryl monolinolate, glyceryl palmitostearate, polyoxyglyceride, diethyl sebacate, isopropyl palmitate, polymethacrylate, But are not limited thereto.

Examples of the C ₆ -C ₃₀ higher alcohol include, but are not limited to, cetyl alcohol, stearyl alcohol, cetostearyl alcohol, lauryl alcohol or myristyl alcohol.

Examples of the wax include, but are not limited to, white lead, yellow lead, carnauba wax, or acetyl ester wax.

Shellac, zein, etc. may be used as the emission control agent.

The release-controlling agent, due to its hydrophobic nature, inhibits the penetration of water into the granulate, thereby significantly reducing the rate of dissolution of the drug, resulting in the gradual release of the drug.

Said sustained or controlled release formulations may be prepared by methods commonly known to those skilled in the art.

The sustained-release or controlled-release formulation can be prepared using a wet granulation method or a dry granulation method, which is a general method of producing solid granules.

At this time, fine particles are generated in pulverizing and granulating the granules into a predetermined size, and 10% to 50% of the pulverized particles are released within 30 minutes.

Since the granule exhibits sustained release and rapid efficacy at the same time, the granule can be used as a granule without being tableted, or it can be prepared into a single capsule form by filling into capsules.

In addition, it can be manufactured in a single defined form by tableting with an excipient so that it can be disintegrated in the form of a sustained release granule within 1 hour.

Furthermore, the granules may be prepared by combining the active ingredient and the disintegrant containing the mashafide or a salt thereof and then adding the granules to the granules in a single defined form. The active ingredient containing the mashafide or a salt thereof and the disintegrant Can be mixed and granulated to form a single defined form.

Specifically, it is preferable to mix the mashafide or a salt thereof with a release-controlling agent, then add the solvent, and dry the mixture at 30 to 60 DEG C for sizing, and then adding the disintegrant and the lubricant to the sizing product, To prepare a sustained or controlled release formulation.

In addition, it is also possible to mix the mashafide or a salt thereof with a release-controlling agent, granulate the mixture through roller compacting or extrusion, and then formulate the mixture. The disintegrant is mixed with a disintegrant and a lubricant, A controlled-release preparation can be prepared.

 As another example, it is possible to prepare a sustained-release or controlled-release formulation by mixing the mashafide or its salt and the release-controlling agent, then adding the solvent and combining and drying at 30 to 60 ° C, can do.

When the release-controlled or release-controlled preparation is subjected to a dissolution test at 37 ± 0.5 ° C and 50 rpm in 900 ml of water using Method 2 (paddle method) of the Korean Pharmacopoeia dissolution assay, the dissolution rate of the drug within 1 hour is 20 to 60% , The dissolution rate of the drug within 20 hours may be 80% or more, preferably 85% or more. Accordingly, when administered into the body, the drug can exhibit a desirable drug effect even under a reduced number of times of once daily dosing, thereby improving the convenience of taking the patient.

The sustained-release or controlled-release formulation is capable of sustaining the drug efficacy only once a day by allowing rapid drug efficacy and simultaneously releasing the drug to maintain the drug concentration over a certain period of time, It can be used mainly for chronic diseases.

The active ingredient may be contained in an amount of 1 to 50% by weight, preferably 1 to 30% by weight, and more preferably 1 to 10% by weight based on the total weight.

If the active ingredient is contained in an amount of less than 1% by weight based on the total weight, the active ingredient may not be exhibited, and if the active ingredient is contained in an amount of more than 50% by weight based on the total weight, .

The release control agent may be contained in an amount of 5 to 90% by weight, preferably 10 to 80% by weight, and more preferably 20 to 75% by weight based on the total weight.

If the release control agent is contained in an amount of less than 5% by weight based on the total weight, there is a problem that the effect of releasing the active ingredient by 80% or more over 20 hours can not be exhibited. If it is contained in an amount of more than 90% by weight, it may be uneconomical and the total weight of the unit dosage form may become large, which may lead to inconvenience to take.

The disintegrant may be used for absorbing moisture to promote disintegration of the preparation to improve the rapid release of the simulated fried or its salt, preferably from 0.1 to 80% by weight.

Wherein said disintegrant is selected from the group consisting of low substituted hydroxypropylcellulose, microcrystalline cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, carboxymethylcellulose sodium, lactose, mannitol, polyethylene glycol 6000, pregelatinized starch, corn starch, , And preferably low-substituted hydroxypropylcellulose, crospovidone, sodium starch glycolate, or a mixture thereof.

The disintegrant may be added in addition to the solid oral preparation in a pharmaceutically acceptable manner, and a secondary disintegrant may be further used for the purpose of more rapid release of the preparation.

The mixture may further comprise an excipient, a solubilizer, a binder or a binding solvent.

The excipient may be used to increase the volume so as to make granules and tablets of the desired size, preferably 5 to 90% by weight based on the total weight.

The excipient may be any one or more selected from the group consisting of microcrystalline cellulose, lactose, mannitol, corn starch, potassium hydrogen phosphate, silicon dioxide and pregelatinized starch, preferably lactose hydrate, microcrystalline cellulose, mannitol, have.

The solubilizing agent may be used to increase the solubility of the granular components, preferably 0.5 to 50% by weight based on the total weight.

As the solubilizing agent, an acidifying agent such as an inorganic acid or an organic acid or a surfactant may be used.

The solubilizing agent is selected from the group consisting of citric acid, tartaric acid, glutamic acid, malic acid, lactic acid, fumaric acid, phosphoric acid, succinic acid, stearic acid, acetic acid, maleic acid, adipic acid, cholic acid, orotic acid, hydrochloric acid, , Sodium lauryl sulfate, and polysorbate.

The binder may be used to increase the binding force of the preparation, preferably 0.5 to 30% by weight, preferably 1 to 10% by weight, more preferably 1 to 5% by weight, % By weight.

The binder may be any one or more selected from the group consisting of polyvinylpyrrolidone, copovidone, polyvinyl alcohol, hydroxypropylcellulose, pregelatinized starch and sodium alginate.

The coupling solvent may be any one or more selected from the group consisting of ethanol, water, isopropyl alcohol and methylene chloride.

The sustained-release or controlled-release formulation may further comprise at least one lubricant selected from the group consisting of salts of stearic acid, glyceryl behenate, talc and silicon dioxide.

The lubricant improves the fluidity of the powder, increases the filling of the die, which is the lower part of the tablet machine, and reduces the friction between the powder and the punch-die, which is the upper part of the powder and the tablet. To facilitate compression and release of the tablet.

The lubricant may be included in an amount of 0.1 to 20% by weight, and preferably 0.5 to 10% by weight based on the total weight of the lubricant.

The sustained release or controlled release formulation may further comprise a coating agent.

Examples of the coating agent include hydroxypropylmethylcellulose, polyvinyl alcohol, polypropylene glycol, acrylic acid polymer, polymethacrylate copolymer, polyethylene glycol, polyvinyl acetate, titanium oxide, iron oxide, tar pigment, talc, and mixtures thereof But the present invention is not limited thereto.

In addition, the sustained-release or controlled-release formulation may further comprise a pharmaceutically acceptable additive.

The additive may be a general additive capable of improving the manufacture, appearance, compression, and the like of the drug within a range that does not impair the biological activity and properties of the drug, and the specific content is not limited only to the solubility and chemical properties of the active ingredient, But can be determined by standard pharmaceutical practice.

Examples of the additives include, but are not limited to, excipients, diluents, binders, lubricants, preservatives, stabilizers, antiadherents, fluidizers or colorants.

Examples of the diluent include starch, microcrystalline cellulose, lactose, glucose, mannitol, or dicalcium phosphate.

Examples of the binder include, but are not limited to, polyvinylpyrrolidine derivatives such as hydroxypropylcellulose, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, and copovidone, natural gums, synthetic gums, and gelatin.

Examples of the lubricant include, but are not limited to, silicon dioxide, talc, magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate and the like.

In addition, various additives such as an antioxidant, a coloring agent, a flavoring agent, a preservative, a taste-masking agent and the like can be used within the usual range by the person skilled in the art.

The foregoing description is merely illustrative of the technical idea of the present invention, and various changes and modifications may be made by those skilled in the art without departing from the essential characteristics of the present invention. Therefore, the embodiments disclosed in the present invention are intended to illustrate rather than limit the scope of the present invention, and the scope of the technical idea of the present invention is not limited by these embodiments. The scope of protection of the present invention should be construed according to the following claims, and all technical ideas within the scope of equivalents should be construed as falling within the scope of the present invention.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

EXAMPLES 1 to 11: Preparation of Hydrophobic Release Control Agent Formulation

Mossafide or its salt, release control agent and excipient were mixed and then mixed with a solvent. It was dried and dried at 30 ~ 60 ℃. The disintegrant was mixed with a disintegrant and a lubricant, and the tablets or capsules were filled.

division Purpose of blending Ingredients (mg) Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Union, Drying, Formation (West) chief ingredient Simulated fly 15 15 15 15 15 15 15 15 15 15 15 Emission control mechanism Hardened castor oil 110 - - - - - - - - - - Vegetable hydrogenated oil - 110 - - - - - - - - - Stearic acid - - 110 - - - - - - - - Glyceryl behenate - - - 110 - - - - - - - Magnesium stearate - - - - 110 - - - - - - Stearyl alcohol - - - - - 80 - - - - - Glycerin fatty acid ester - - - - - - 80 - - - - Propylene glycol fatty acid ester - - - - - - - 80 - - - Sorbitan monostearate - - - - - - - - 80 - - Glyceryl monostearate - - - - - - - - - 80 - Carnavar - - - - - - - - - - 110 Excipient Microcrystalline cellulose 15 15 15 15 15 45 45 45 45 45 45 menstruum ethanol 50 50 50 50 50 50 50 50 50 50 50 Disintegration Low-substituted hydroxypropylcellulose 10 10 10 10 10 10 10 10 10 10 10 Microcrystalline cellulose 150 150 150 150 150 150 150 150 150 150 150 Lubricant Magnesium stearate 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8

Examples 12 to 17: Preparation of formulation by excipient

Mossafide or its salt, release control agent and excipient were mixed and then mixed with a solvent. It was dried and dried at 30 ~ 60 ℃. The disintegrant was mixed with a disintegrant and a lubricant, and the tablets or capsules were filled.

division Purpose of blending Ingredients (mg) Example
One Example 12 Example 13 Example 14 Example 15 Example 16 Example 17 Union, Drying, Formation (West) chief ingredient Simulated fly 15 15 15 15 15 15 15 Emission control mechanism Hardened castor oil 110 110 110 110 110 110 110 Excipient Microcrystalline cellulose 15 - - - - - - Lactose - 15 - - - - - Mannitol - - 15 - - - - Corn starch - - - 15 - - - Potassium hydrogen phosphate - - - - 15 - - Silicon dioxide - - - - - 15 - Pregelatinized starch - - - - - - 15 menstruum ethanol 50 50 50 50 50 50 50 After mixing (internal preservation) Disintegration Low-substituted hydroxypropylcellulose 10 10 10 10 10 10 10 Microcrystalline cellulose 150 150 150 150 150 150 150 Lubricant Magnesium stearate 3.8 3.8 3.8 3.8 3.8 3.8 3.8

EXAMPLES 18-23: Preparation of Formulation for Western Granule Binder

Or a salt thereof, a release control agent, an excipient, and a binder are mixed and then mixed with a solution containing a binder dissolved in a solvent. It was dried and dried at 30 ~ 60 ℃. The disintegrant was mixed with a disintegrant and a lubricant, and the tablets or capsules were filled.

division Purpose of blending Ingredients (mg) Example 18 Example 19 Example 20 Example 21 Example 22 Example 23 Union, Drying, Formation (West) chief ingredient Simulated fly 15 15 15 15 15 15 Emission control mechanism Hardened castor oil 110 110 110 110 110 110 Excipient Microcrystalline cellulose 15 15 15 15 15 15 Binder Polyvinylpyrrolidone 7 - - - - - Co-povidone - 7 - - - - Polyvinyl alcohol - - 7 - - - Hydroxypropylcellulose - - - 7 - - Pregelatinized starch - - - - 7 - Sodium alginate - - - - - 7 menstruum ethanol 50 50 50 50 50 50 After mixing (internal preservation) Disintegration Low-substituted hydroxypropylcellulose 10 10 10 10 10 10 Microcrystalline cellulose 150 150 150 150 150 150 Lubricant Magnesium stearate 3.8 3.8 3.8 3.8 3.8 3.8

Examples 24-29: Preparation of formulation with solubilizing agent

And the release control agent, the excipient, and the solubilizing agent were mixed, and the solvent was added thereto. It was dried and dried at 30 ~ 60 ℃. The disintegrant was mixed with a disintegrant and a lubricant, and the tablets or capsules were filled.

division Purpose of blending Ingredients (mg) Example 24 Example 25 Example 26 Example 27 Example 28 Example 29 Union, Drying, Formation (West) chief ingredient Simulated fly 15 15 15 15 15 15 Emission control mechanism Hardened castor oil 110 110 110 110 110 110 Excipient Microcrystalline cellulose 15 15 15 15 15 15 Solubilizing agent Citric acid 15 - - - - - Tartaric acid - 15 - - - - Fumaric acid - - 15 - - - Polyethylene glycol 8000 - - - 15 - - Polysorbate 80 - - - - 5 - Sodium lauryl sulfate - - - - - 5 menstruum ethanol 50 50 50 50 50 50 After mixing (internal preservation) Disintegration Low-substituted hydroxypropylcellulose 10 10 10 10 10 10 Microcrystalline cellulose 150 150 150 150 150 150 Lubricant Magnesium stearate 3.8 3.8 3.8 3.8 3.8 3.8

Examples 30 to 35: Preparation of formulation for sustained-wet granule solvent

Mossafide or its salt, release control agent and excipient were mixed and then mixed with a solvent. It was dried and dried at 30 ~ 60 ℃. The disintegrant was mixed with a disintegrant and a lubricant, and the tablets or capsules were filled.

Example 36: Preparation of sustained release granule formulation

After mixing the simulated free or salt thereof with the release control agent and the excipient, the mixture was granulated through roller compacting or extrusion and then granulated. The disintegrant was mixed with a disintegrant and a lubricant, and the tablets or capsules were filled.

division Purpose of blending Ingredients (mg) Example 1 Example 30 Example 31 Example 32 Example 33 Example 34 Example 35 Example 36 Union, Drying, Formation (West) chief ingredient Simulated fly 15 15 15 15 15 15 15 15 Emission control mechanism Hardened castor oil 110 110 110 110 110 110 110 110 Excipient Microcrystalline cellulose 15 15 15 15 15 15 15 15 menstruum ethanol 50 - 40 - - - 30 - water - 80 40 - 40 - - - Isopropyl alcohol - - - 50 40 - - - Methylene chloride - - - - - 60 30 - After mixing (internal preservation) Disintegration Low-substituted hydroxypropylcellulose 10 10 10 10 10 10 10 10 Microcrystalline cellulose 150 150 150 150 150 150 150 150 Lubricant Magnesium stearate 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8

Examples 37 to 45: Preparation of disintegrating star formulations

Mossafide or its salt, release control agent and excipient were mixed and then mixed with a solvent. It was dried and dried at 30 ~ 60 ℃. The disintegrant was mixed with a disintegrant and a lubricant, and the tablets or capsules were filled.

division Purpose of blending Ingredients (mg) Example
One Example
37 Example
38 Example
39 Example
40 Example
41 Example
42 Example
43 Example
44 Example
45 Union, Drying, Formation (West) chief ingredient Simulated fly 15 15 15 15 15 15 15 15 15 15 Emission control mechanism Hardened castor oil 110 110 110 110 110 110 110 110 110 110 Excipient Microcrystalline cellulose 15 15 15 15 15 15 15 15 15 15 menstruum ethanol 50 50 50 50 50 50 50 50 50 50 After mixing (internal preservation) Disintegration Low-substituted hydroxypropylcellulose 10 - - - - - - - - - Microcrystalline cellulose 150 150 150 150 150 150 - 130 - 130 Crospovidone - 10 - - - - - - - - Croscarmellose sodium - - 10 - - - - - - - Starch glycolate sodium - - - 10 - - - - - - Carboxymethylcellulose sodium - - - - 10 - - - - - Lactose - - - - - 150 - - 60 - Mannitol - - - - - - 150 - - - Polyethylene glycol 6000 - - - - - - - 30 - - Pregelatinized starch - - - - - - - - 100 - Corn starch - - - - - - - - - 30 Silicon dioxide - - - - - 10 - - - - Lubricant Magnesium stearate 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8 3.8

Examples 46 to 53: Preparation of lubricant-type preparations

Mossafide or its salt, release control agent and excipient were mixed and then mixed with a solvent. It was dried and dried at 30 ~ 60 ℃. The disintegrant was mixed with a disintegrant and a lubricant, and the tablets or capsules were filled.

division Purpose of blending Ingredients (mg) Example 1 Example 46 Example 47 Example 48 Example 49 Example 50 Example 51 Example 52 Example 53 Union, Drying, Formation (West) chief ingredient Simulated fly 15 15 15 15 15 15 15 15 15 Emission control mechanism Hardened castor oil 110 110 110 110 110 110 110 110 110 Excipient Microcrystalline cellulose 15 15 15 15 15 15 15 15 15 menstruum ethanol 50 50 50 50 50 50 50 50 50 After mixing (internal preservation) Disintegration Low-substituted hydroxypropylcellulose 10 10 10 10 10 10 10 10 10 Microcrystalline cellulose 150 150 150 150 150 150 150 150 150 Lubricant Magnesium stearate 3.8 - - - - 2 2 - - Magnesium fumarate - 3.8 - - - - - - - Glyceryl behenate - - 5 - - - - 3 3 Talc - - - 5 - - 2 - 2 Silicon dioxide - - - - 5 4 - 3 -

Examples 54 to 55: Mixed post-granulate post-granulation

Mossafide or its salt, release control agent and excipient were mixed and then mixed with a solvent. It was dried and dried at 30 ~ 60 ℃.

Separately, the coarse powder or the salt thereof, the excipient, the disintegrant, and the binder were mixed, and the solvent was added, dried, and sized, and then the granules and the lubricant were mixed and filled into the tablets or capsules.

Example 56: Mixed post-mortem mixture

Mossafide or its salt, release control agent and excipient were mixed and then mixed with a solvent. It was dried and dried at 30 ~ 60 ℃.

Separately, the simulated freed or salt thereof, the excipient, and the disintegrant were mixed, and the granules and the lubricant were mixed and filled into the tablets or capsules.

division Purpose of blending Ingredients (mg) Example 54 Example 55 Example 56 Union, Drying, Formation (West) chief ingredient Simulated fly 12 12 12 Emission control mechanism Hardened castor oil 110 110 110 Excipient Microcrystalline cellulose 15 15 15 menstruum ethanol 50 50 50 After mixing (internal preservation) chief ingredient Simulated fly 3 3 3 Excipient Microcrystalline cellulose 150 150 140 Disintegration Low-substituted hydroxypropylcellulose 10 10 20 Binder Polyvinylpyrrolidone 2 2 - menstruum ethanol 30 - - water - 30 - Lubricant Magnesium stearate 3.8 3.8 3.8

Examples 57 to 60: Preparation of formulation by weight of hydrophobic release-controlling agent

Mossafide or its salt, release control agent and excipient were mixed and then mixed with a solvent. It was dried and dried at 30 ~ 60 ℃. The disintegrant was mixed with a disintegrant and a lubricant, and the tablets or capsules were filled.

division Purpose of blending Ingredients (mg) Example
One Example 57 Example 58 Example 59 Example 60 Union, Drying, Formation (West) chief ingredient Simulated fly 15 15 15 15 15 Emission control mechanism Hardened castor oil 110 30 150 300 400 Excipient Microcrystalline cellulose 15 5 15 15 15 menstruum ethanol 50 20 70 100 130 After mixing (internal preservation) Disintegration Low-substituted hydroxypropylcellulose 10 100 10 50 - Crospovidone - - - - 30 Microcrystalline cellulose 150 200 150 50 - Silicon dioxide - - - - 10 Lubricant Magnesium stearate 3.8 3.8 3.8 5 5

COMPARATIVE EXAMPLES 1 TO 4 Preparation of Preparations with Swelling Release Control Units Excluding Disintegrants

After spraying with the solvent, the mixture was dried at 30 to 60 ° C and dried. The sizing product was mixed with a lubricant and filled into tablets or capsules.

COMPARATIVE EXAMPLE 5 Preparation of Hydrophobic Release Control Agent without Disintegrant

After spraying with the solvent, the mixture was dried at 30 to 60 ° C and dried. The sizing product was mixed with a lubricant and filled into tablets or capsules.

COMPARATIVE EXAMPLES 7 SIMILAR 9: Preparation of a formulation according to a swelling release control agent using a disintegrant

After spraying with the solvent, the mixture was dried at 30 to 60 ° C and dried. The disintegrant was mixed with a disintegrant and a lubricant, and the tablets or capsules were filled.

division Purpose of blending Ingredients (mg) Comparative Example
One Comparative Example
2 Comparative Example
3 Comparative Example
4 Comparative Example
5 Comparative Example
6 Comparative Example
7 Comparative Example
8 Comparative Example
9 Union, Drying, Formation (West) chief ingredient Simulated fly 15 15 15 15 15 15 15 15 15 Emission control mechanism Hydroxypropyl methylcellulose (100,000 cPs) 110 - - - - 110 - - - Polyethylene oxide 2,000,000 - 110 - - - - 110 - - Carbomer - - 110 - - - - 110 - Xanthan gum - - - 110 - - - - 110 Hardened castor oil - - - - 110 - - - - Excipient Microcrystalline cellulose 15 15 15 15 15 15 15 15 15 menstruum ethanol 50 50 50 50 50 50 50 50 50 Disintegration Low-substituted hydroxypropylcellulose - - - - - 10 10 10 10 Microcrystalline cellulose - - - - - 150 150 150 150 Lubricant Magnesium stearate 2 2 2 2 2 3.8 3.8 3.8 3.8

Experimental Examples 1 to 10: Comparative dissolution test

Exam conditions

Elution test solution: water, 900 mL, 37 ± 0.5 ℃

Elution method: Korean Pharmacopoeia dissolution test Method 2 (paddle method), 50 rotations per minute

Experimental Example 1: Dissolution test using a swollen monolayer using a swellable polymer not containing a disintegrant

The dissolution test was carried out using the sustained-release monolayer prepared in Comparative Examples 1 to 4, and the results are shown in Table 11 and FIG.

Dissolution rate (%) 0.5 One 3 6 8 10 14 20 Comparative Example 1 6.1 12.7 25.7 40.8 50.6 56.8 63.1 66.6 Comparative Example 2 5.3 10.9 21.1 33.9 41.7 49.6 58.1 61.8 Comparative Example 3 3.9 9.4 19.8 31.8 38.5 43.7 53.1 58.9 Comparative Example 4 2.0 7.6 22.6 36.4 44.8 53.1 60.6 64.8

As shown in Table 11 and FIG. 1, the dissolution rate of the drug in Comparative Examples 1 to 4 was less than 10% within 30 minutes and less than 20% within 1 hour.

Thus, it can be confirmed that when the tablets are prepared in a single-layer tablet using a conventional swelling polymer, sustained release of the drug occurs but no rapid release that can manifest rapid efficacy.

Experimental Example 2: Comparison of dissolution rate of each granule release control system

The elution tests were carried out using the controlled release tablets prepared in Comparative Examples 6 to 9 and Examples 1 to 11, and the results are shown in Table 12 and FIG.

Dissolution rate (%) 0.5 One 3 6 8 10 14 20 Comparative Example 6 6.1 12.7 25.7 40.8 50.6 56.8 63.1 66.6 Comparative Example 7 5.3 10.9 21.1 33.9 41.7 49.6 58.1 61.8 Comparative Example 8 3.9 9.4 19.8 31.8 38.5 43.7 53.1 58.9 Comparative Example 9 2.0 7.6 22.6 36.4 44.8 53.1 60.6 64.8 Example 1 22.6 30.3 44.9 65.9 75.1 83.6 93.3 98.9 Example 2 12.1 22.9 38.6 54.7 66.2 74.2 85.6 92.3 Example 3 33.5 42.0 58.3 71.0 74.5 77.8 82.7 87.7 Example 4 21.7 34.0 54.5 70.2 76.9 80.9 90.8 95.0 Example 5 26.5 33.8 54.2 62.1 67.5 71.2 77.6 84.4 Example 6 25.2 31.9 45.5 65.2 74.7 80.4 87.9 94.9 Example 7 24.0 32.7 48.4 69.3 79.4 84.4 88.3 92.3 Example 8 31.0 37.9 48.4 59.4 67.3 75.4 88.5 99.5 Example 9 28.6 40.6 49.3 59.6 64.7 69.6 80.6 97.4 Example 10 32.8 40.1 51.5 65.5 70.1 73.4 79.8 86.9 Example 11 31.0 39.3 55.7 68.9 73.1 77.8 83.6 89.0

As shown in Table 12 and FIG. 2, the controlled release formulations prepared in Comparative Examples 6 to 9 showed a dissolution rate of less than 10% within 30 minutes and less than 20% within 1 hour, The controlled release formulations prepared in ~ 11 showed that the dissolution rate of the drug was 10-40% in 30 minutes, 20-50% in 1 hour, and 80% or more within 20 hours.

As a result, as in Examples 1 to 11, a disintegrant was added to the post-mixing to cause water to penetrate between the western granules. As a result, the surface of the western blend of the swellable polymer was melted, And it becomes a single matrix again, and it can be confirmed that the rapid release which can express the quick effect does not occur.

However, the western granule using the hydrophobic release control agent disintegrates within 1 hour in the form of granules in the initial stage state, and the rapid release occurs, and the disintegrated western granule maintains its shape, Is satisfied at the same time.

EXPERIMENTAL EXAMPLE 3: Comparison of dissolution rate of each granule according to the present invention

The dissolution test was carried out using the controlled release tablets prepared in Examples 1, 12 to 17, and the results are shown in Table 13 and FIG.

Dissolution rate (%) 0.5 One 3 6 8 10 14 20 Example 1 22.6 30.3 44.9 65.9 75.1 83.6 93.3 98.9 Example 12 25.2 31.9 45.5 65.2 74.7 80.4 85.8 89.9 Example 13 24.0 32.7 48.4 69.3 79.4 84.4 88.4 90.3 Example 14 30.2 34.8 47.0 66.3 78.5 78.0 86.4 96.2 Example 15 28.3 33.4 45.6 64.0 70.5 76.9 87.0 101.0 Example 16 28.1 39.6 51.8 69.4 73.6 78.4 83.5 89.6 Example 17 27.4 40.0 55.2 73.5 79.7 85.1 88.4 90.2

As shown in Table 13 and FIG. 3, the controlled release formulations prepared in Examples 1, 12 to 17 showed a dissolution rate of 10-40% in 30 minutes, 20-50% in 1 hour, 80% Respectively.

As a result, it can be confirmed that the excipients used in Examples 1, 12 to 17 maintain sustained drug release while maintaining the shape of the western granules as in the case of the hydrophobic release-controlling agent. Therefore, it can be confirmed that both the quickness and the sustainability are satisfied at the same time.

Experimental Example 4: Comparison of dissolution rate when adding a western granular binder

The dissolution tests were carried out using the controlled release tablets prepared in Examples 18 to 23, and the results are shown in Table 14 and FIG.

Dissolution rate (%) 0.5 One 3 6 8 10 14 20 Example 1 22.6 30.3 44.9 65.9 75.1 83.6 93.3 98.9 Example 18 14.9 27.4 46.0 62.3 72.2 79.6 91.5 96.7 Example 19 17.3 24.8 38.4 57.6 70.3 79.6 85.2 90.9 Example 20 15.7 29.7 42.8 55.0 66.8 78.4 86.9 91.8 Example 21 20.3 30.0 43.6 55.4 64.7 72.4 81.5 92.9 Example 22 24.1 34.2 45.2 60.1 73.2 76.7 85.5 92.8 Example 23 17.8 22.7 37.9 58.6 66.7 72.1 79.1 90.3

As shown in Table 14 and FIG. 4, the controlled release formulations prepared in Examples 1, 18-23 had a drug dissolution rate of 10-40% in 30 minutes, 20-50% in 1 hour, 80% Respectively.

As a result, the binders added in Examples 18 to 23 increase the strength of the western granules as in the case of the hydrophobic release control agent, while one tablet disintegrates in the form of granules within one hour, and the disintegrated granules are again matrix- It can be confirmed that there is no effect. Therefore, it can be confirmed that both the quickness and the sustainability are satisfied at the same time.

Experimental Example 5: Comparison of dissolution rate of solubilized western granules

The dissolution test was carried out using the release-controlled tablets prepared in Examples 1, 24 to 29, and the results are shown in Table 15 and FIG.

Dissolution rate (%) 0.5 One 3 6 8 10 14 20 Example 1 22.6 30.3 44.9 65.9 75.1 83.6 93.3 98.9 Example 24 26.3 32.8 47.7 68.5 76.3 82.3 97.7 98.3 Example 25 27.0 32.6 47.0 71.7 80.5 86.6 99.4 99.6 Example 26 28.6 32.9 46.9 70.7 78.7 84.0 96.7 99.0 Example 27 26.6 35.7 50.2 71.4 84.3 93.4 102.4 102.5 Example 28 24.9 34.2 53.1 68.7 73.4 82.0 95.3 98.6 Example 29 30.7 37.1 53.9 75.0 85.5 91.3 95.7 99.7

As shown in Table 14 and FIG. 5, the controlled release formulation prepared in Examples 1, 24-29 showed that the dissolution rate of the drug was 10-40% in 30 minutes, 20-50% in 1 hour, 85% Respectively.

Thus, it was confirmed that the solubilizing agents added in Examples 24 to 29 exhibited a rapid release of the same dissolution rate as in Example 1, and the permeability of water to the western granules by hydrophobic release control was increased to be 95% or more at 14 hours . Therefore, it can be confirmed that both the quickness and the sustainability are satisfied at the same time.

Experimental Example 6: Comparison of dissolution rate depending on the kind of the solvent and the use

The dissolution test was carried out using the controlled release tablets prepared in Examples 1, 30 to 36, and the results are shown in Table 16 and FIG.

Dissolution rate (%) 0.5 One 3 6 8 10 14 20 Example 1 22.6 30.3 44.9 65.9 75.1 83.6 93.3 98.9 Example 30 36.2 41.3 52.8 67.2 77.5 84.1 95.9 99.8 Example 31 27.4 39.1 49.0 68.2 78.1 85.1 92.0 100.6 Example 32 25.9 35.4 45.4 63.7 75.7 82.4 89.0 91.3 Example 33 31.8 41.5 52.5 69.0 80.2 91.3 98.3 100.6 Example 34 25.5 33.8 47.9 65.4 77.5 81.4 90.9 93.8 Example 35 21.8 34.6 45.1 64.2 74.3 85 92.3 95.9 Example 36 27.7 36.8 50.1 71.8 78.6 83.5 95.6 99.1

As shown in Table 16 and FIG. 6, the controlled release formulations prepared in Examples 1, 30-36 had a drug dissolution rate of 10-40% in 30 minutes, 20-50% in 1 hour, 80% Respectively.

Thus, it can be confirmed that the binding solvent used in Examples 1, 30-36 does not significantly affect the rapidity and persistence of the western granules.

Experimental Example 7: Comparison of dissolution rate depending on the kind of post-mix disintegrant and use or not

The dissolution test was carried out using the controlled release tablets prepared in Comparative Example 5 and Examples 1 and 37 to 45, and the results are shown in Table 17 and FIG.

Dissolution rate (%) 0.5 One 3 6 8 10 14 20 Comparative Example 5 3.9 6.1 13.2 16.3 18.5 20.2 23.5 26.0 Example 1 22.6 30.3 44.9 65.9 75.1 83.6 93.3 98.9 Example 37 25.8 33.8 44.5 64.8 77.4 85.2 90.1 97.1 Example 38 26.9 32.6 43.3 64.0 74.5 80.4 86.5 93.0 Example 39 27.5 31.2 46.1 65.6 74.8 80.5 86.4 95.4 Example 40 23.8 34.1 44.8 60.7 74.1 78.9 84.9 91.9 Example 41 26.1 36.5 42.1 59.7 71.4 82.0 97.9 98.3 Example 42 28.1 36.2 41.8 58.1 69.1 77.9 88.5 96.7 Example 43 30.6 35.6 45.3 60.1 70.2 77.4 90.4 94.5 Example 44 23.2 30.5 42.6 63.2 77.1 86.7 93.6 100.7 Example 45 27.9 37.1 48.7 59.1 73.9 85.0 96.7 100.5

As shown in Table 17 and FIG. 7, the controlled release formulations prepared in Comparative Examples 6 to 9 showed less than 10% dissolution rate of drug within 30 minutes, less than 20% within 1 hour, less than 60% over 20 hours However, the controlled release formulations prepared in Examples 1, 37 to 45 showed a drug dissolution rate of 10-40% in 30 minutes, 20-50% in 1 hour, and 80% or more within 20 hours.

As a result, as in Example 1, 37 to 45, the disintegrant was added to the post-mix to cause water to penetrate through the hydrophobic fine granules and disintegrate in the form of granules within 1 hour to induce rapid release. It can be confirmed that sustained release occurs while maintaining the shape, and at the same time, it satisfies both the quickness and the sustainability.

However, in Comparative Example 5, when there is no disintegration between the hydrophobic fine granules and the pressure is applied to form a single matrix, it can be confirmed that the disintegration into water is not disintegrated in the form of granules so that the rapid release does not appear.

Experimental Example 8: Comparison of dissolution rate by post-mixing lubricant

The dissolution test was carried out using the release-controlled tablets prepared in Examples 1, 46 to 53, and the results are shown in Table 18 and FIG.

Dissolution rate (%) 0.5 One 3 6 8 10 14 20 Example 1 22.6 30.3 44.9 65.9 75.1 83.6 93.3 98.9 Example 46 27.4 32.7 45.4 63.4 76.3 86.1 93.7 96.9 Example 47 29.3 33.5 51.0 68.3 77.9 86.5 92.9 96.7 Example 48 22.5 29.5 44.7 65.0 74.6 84.6 93.7 93.7 Example 49 21.5 29.8 42.6 63.5 77.7 84.6 93.8 103.5 Example 50 26.3 32.7 41.4 62.1 79.8 88.4 95.7 100.7 Example 51 22.8 29.7 41.5 58.9 70.3 81.4 91.6 97.6 Example 52 20.6 27.5 42.8 65.9 76.0 88.8 93.9 98.6 Example 53 24.9 29.7 43.3 63.8 78.3 89.2 92.1 99.1

As shown in Table 18 and FIG. 8, the controlled release pharmaceutical preparations prepared in Examples 1, 46 to 53 had a drug dissolution rate of 10-40% in 30 minutes, 20-50% in 1 hour, 80% Respectively.

Thus, it can be confirmed that the lubricant used in Examples 1, 46 to 53 did not have a significant effect on the quickness and persistence of the release-controlled formulation.

Experimental Example 9: Comparison of dissolution rate when adding the mixture after the simulation fly

The dissolution test was carried out using the controlled release tablets prepared in Examples 1, 54 to 56, and the results are shown in Table 19 and FIG.

Dissolution rate (%) 0.5 One 3 6 8 10 14 20 Example 1 22.6 30.3 44.9 65.9 75.1 83.6 93.3 98.9 Example 54 36.8 42.9 57.0 73.5 81.6 87.5 90.9 100.3 Example 55 37.4 46.8 61.3 70.7 81.1 85.6 95.2 98.6 Example 56 38.3 43.1 54.5 64.6 74.2 86.5 96.3 99.7

As shown in Table 19 and FIG. 9, the controlled release formulations prepared in Examples 54 to 56 had a drug dissolution rate of 10-40% in 30 minutes, 20-50% in 1 hour, and 80% or more within 20 hours Respectively.

As a result, as in Examples 54 to 56, when an immediate mixture or an inner granule containing about 20% or less of the active ingredient was further added to the post-mix, the granules disintegrated in the form of granules within 1 hour, The drug release rate is 10-40% in 30 minutes, 20-50% in 1 hour, and contains about 80% or more active ingredient. In a western granule, sustained release occurs and elution of more than 80% is observed in 6 ~ 20 hours, so that the rapidity of the drug can be maintained naturally and persistence can be maintained.

Experimental Example 10: Comparison of dissolution rate by weight of release controller

The dissolution tests were carried out using the controlled release tablets prepared in Examples 1, 57 to 60, and the results are shown in Table 20 below.

Dissolution rate (%) One 6 20 Example 1 30.3 65.9 98.9 Example 57 39.4 72.9 99.5 Example 58 29.5 60.7 88.8 Example 59 25.1 57.6 86.9 Example 60 21.3 53.4 82.7

As shown in Table 20, the controlled release formulations prepared in Examples 1, 57 to 60 showed a drug elution rate of 20 to 50% per hour and 80% or more within 20 hours.

As a result, it can be confirmed that, even when the release controller is contained in an amount of 5 to 90% by weight based on the total weight, as in Examples 1, 57 to 60, it simultaneously satisfies both the quick-action and the sustainability.

Claims (10)

And a disintegrant comprising an effective ingredient containing a mosaic pride or salt thereof and a release-controlling agent,
The release control agent may be selected from the group consisting of stearic acid, magnesium stearate, glycerin fatty acid esters, propylene glycol fatty acid esters, glyceryl monostearate, glyceryl behenate, sorbitan monostearate, stearyl alcohol, At least one selected from the group consisting of
Wherein said disintegrant is selected from the group consisting of low substituted hydroxypropylcellulose, microcrystalline cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, carboxymethylcellulose sodium, lactose, mannitol, polyethylene glycol 6000, pregelatinized starch, corn starch, At least one kind selected from the group consisting of
The active ingredient comprises 1 to 50% by weight, based on the total weight of the preparation,
Wherein the release control agent comprises from 5 to 90% by weight, based on the total weight of the formulation,
Characterized by satisfying the following dissolution profile in water at 37 占 폚 according to Method 2 of the Korean Pharmacopoeia Assay (paddle method):
1) Within 30 minutes 10% to 50% of the total weight of the mothafide or salt thereof is released,
2) The release of 50% to 95% of the total weight of the simulated fried or its salt is achieved between 6 hours and 20 hours.
delete delete delete The method according to claim 1,
Wherein said mixture further comprises an excipient, a solubilizing agent, a binder or a binding solvent.
6. The method of claim 5,
Wherein the excipient is at least one selected from the group consisting of microcrystalline cellulose, lactose, mannitol, corn starch, potassium hydrogen phosphate, silicon dioxide and pregelatinized starch.
6. The method of claim 5,
The solubilizing agent is selected from the group consisting of citric acid, tartaric acid, glutamic acid, malic acid, lactic acid, fumaric acid, phosphoric acid, succinic acid, stearic acid, acetic acid, maleic acid, adipic acid, cholic acid, orotic acid, hydrochloric acid, , Sodium lauryl sulfate, and polysorbate. ≪ RTI ID = 0.0 > 21. < / RTI >
6. The method of claim 5,
Wherein the binder is at least one selected from the group consisting of polyvinylpyrrolidone, copovidone, polyvinyl alcohol, hydroxypropylcellulose, pregelatinized starch and sodium alginate.
6. The method of claim 5,
Wherein the binding solvent is at least one selected from the group consisting of ethanol, water, isopropyl alcohol and methylene chloride.
The method according to claim 1,
Wherein the sustained release or controlled release formulation further comprises at least one lubricant selected from the group consisting of salts of stearic acid, glyceryl behenate, talc and silicon dioxide.

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