KR19980015551A - Release controlled ibuprofen granule and method for its manufacture - Google Patents

Abstract

The present invention relates to a controlled release ibuprofen granule and a process for its preparation. More specifically, the present invention relates to a release-controlled ibuprofen granule made by coating a hydrophobic coating and a hydrophilic coating thereon with ibuprofen or a spherical sugar as a crystal nucleus, and a process for producing such a controlled-release ibuprofen granule. The ibuprofen release-controlled granule provided according to the present invention is a granule of ibuprofen which is controlled by a coating liquid containing ibuprofen which is an effective drug is coated in a double layer around a seed nucleus so that the drug is dissolved in the gastric juice and intestinal juice according to the kind and amount of the polymer constituting the coating liquid It is advantageous in that it is discharged stepwise and actively copes with the stomach environment, thereby providing consistent and continuous absorption, exhibiting a high bioavailability and being easy to produce.

Description

Release controlled ibuprofen granule and method for its manufacture

FIG. 1 is a simplified schematic diagram of a fluidized bed granulator (SFC-MINI, Freund Co., Japan) used for the preparation of the controlled release ibuprofen granules of the present invention.

FIG. 2 is a scanning electron microscope (SEM) photograph of the granules prepared in Example 1 according to the present invention. FIG. 2 (A) is a photograph of the granules at 600 magnifications, FIG. It is a picture taken.

FIG. 3 is a graph showing the effect of the granules (-? -) of Example 1 prepared according to the present invention, the granules (-? -) of Example 2 and the granules (- + - (400 mg as ibuprofen) as compared with the elution pattern in the first solution.

FIG. 4 is a graph showing the results obtained by comparing the granules (-? -) of Example 1 prepared according to the present invention, the granules (-? -) of Example 2 and the granules (- + - 2 is a graph showing changes in blood concentration of ibuprofen over time after administration to beagle dogs at a dose of 10 mg / kg as ibuprofen.

DETAILED DESCRIPTION OF THE INVENTION [

[Object of the invention]

The present invention relates to a controlled release ibuprofen granule and a process for its preparation. More specifically, the present invention relates to a release-controlled ibuprofen granule made by coating a hydrophobic coating and a hydrophilic coating thereon with ibuprofen or a spherical sugar as a crystal nucleus, and a process for producing such a controlled-release ibuprofen granule.

[TECHNICAL FIELD OF THE INVENTION AND RELATED ART OF THE SAME]

Ibuprofen, acetylsalicylic acid and indymethacin are non-steroidal anti-inflammatory drugs and have been widely used in the treatment of rheumatoid arthritis and osteoarthritis in recent decades. Particularly, among these nonsteroidal anti-inflammatory analgesics, ibuprofen [= 2- (4-isobutylphenyl) -propionic acid] is an arylalkanoic acid-based anti-inflammatory analgesic agent and exhibits a strong anti-inflammatory analgesic effect, It is medicine.

However, arthritis medications such as ibuprofen should be administered in large doses in most cases. That is, in the case of ibuprofen, the daily dosage for adults is 1.2 to 1.8 g, and for some patients, the dose is increased to 2.4 to 3.2 g. In the case of pediatric patients, the daily dose of ibuprofen is generally 20 mg per kg of body weight, and in the case of pediatric rheumatoid arthritis, the dose may be increased to 40 mg per kg of body weight. Although ibuprofen has a relatively high dosage and ibuprofen should be used continuously over a long period of time in most cases for the treatment of arthritis and the like, the side effects of such a large dose of long-term administration Can not be ignored. Side effects of ibuprofen are mainly gastrointestinal disorders, peptic ulcer, gastrointestinal bleeding, and rarely skin rashes and ocular hyperemia. Therefore, in order to reduce adverse effects caused by long-term overdose of ibuprofen and improve the dosage regimen to improve patient compliance, it is necessary to develop a controlled-release ibuprofen formulation capable of maintaining an effective blood concentration continuously.

The controlled-release formulation of ibuprofen, which has been developed until now, was mainly used to induce the sustained release of ibuprofen by prolonging the retention time of the drug in the gastrointestinal tract by using a method of swelling and sticking in the stomach using a polymer material as a tablet form. These agents were greatly influenced by drug release or absorption depending on the patient's stomach environment and dietary habits, and it was difficult to expect consistent absorption of the drug.

In addition, since these tablets are manufactured using a polymer material, there is a problem that the polymer material is squeezed on punches during tableting in actual production, and a special designed tablet machine is indispensably required for the production thereof.

[Technical Problem]

Therefore, the present inventors have conducted studies to develop ibuprofen preparations which can continuously release ibuprofen and which are easy to manufacture, and in particular, they are capable of being easily coated and microencapsulated in stomach, An intensive study was conducted on the preparation.

As a result, the present inventors have found that a granule produced by spraying a water-soluble polymer and a hydrophobic polymer together with a drug in succession while floating spherical crystal seeds in a chamber of a fluidized bed granulator or the like, Pattern and in vivo bioavailability.

Based on these findings, the inventors of the present invention found that ibuprofen is multilayer-coated with a coating liquid composed of various polymers and biprofen, and the water-soluble coating and the hydrophobic coating sequentially dissolve or swell as time elapses after oral administration, The inventors of the present invention have developed an ibuprofen-coated granule which exhibits sustained release and sustained release of ibuprofen at the same time while extending the gastric retention time of the above-mentioned ibuprofen-coated granules.

[Structure and operation of the invention]

Therefore, the present invention relates to a controlled-release ibuprofen granule wherein a hydrophobic coating layer containing ibuprofen and a hydrophobic polymer substance in a crystal nucleus composed of ibuprofen powder or sugar, and a hydrophilic coating layer containing a hydrophilic polymer substance and ibuprofen are coated.

(A) spraying a hydrophobic coating liquid containing ibuprofen, a hydrophobic polymer material and a solvent while floating a spherical crystal nucleus composed of a raw material ibuprofen powder or sugar, and drying the hydrophobic coating layer to prepare a hydrophobic coating granule; and b) spraying a hydrophilic coating solution containing ibuprofen, a hydrophilic polymer material and a solvent while suspending the hydrophobic coating granules, and drying to form a hydrophilic coating layer. The present invention also provides a method for producing a controlled release ibuprofen coated granule.

The coating granules of ibuprofen prepared according to the method of the present invention as described above are prepared by coating a coating liquid containing ibuprofen, which is an effective drug, in a double layer around a seed nucleus, depending on the kind and amount of the polymer constituting the coating liquid Drugs are gradually released from stomach fluids and intestinal fluids to actively cope with the stomach environment, thereby providing consistent and continuous absorption, as well as high bioavailability and ease of production.

Hereinafter, the composition and production method of the controlled release ibuprofen granule according to the present invention will be described in more detail.

At the center of the granule of the present invention, crystal nuclei exist, which are composed of ibuprofen powder or sugar. When the crystal nucleus is composed of ibuprofen powder, ibuprofen constituting the crystal nucleus is 1-80%, preferably 5-60% of the total amount of ibuprofen contained in the granule. Examples of the sugar that can be used in the case of using the crystal nucleus composed of sugar include saccharide, mannitol, sorbitol and the like, and preferably the same as those commercially available under the trade name of Nonpareil 103 (manufactured by Freund Co., Japan) Crystal nuclei are used.

The weight of the crystal nucleus accounts for 1 to 60%, preferably 10 to 50% of the total weight of the prepared coating granules.

As described above, the crystal nucleus composed of ibuprofen or sugar is first coated with a hydrophobic coating liquid to form a hydrophobic coating layer. The hydrophobic coating liquid includes ibuprofen, a hydrophobic polymer material and a solvent, which are effective ingredients. The hydrophobic polymer material used in the hydrophobic coating liquid is selected from the group consisting of eudragit, shellac, ethyl cellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, and mixtures thereof. The content of the hydrophobic polymer substance is hydrophobic But is present in a proportion of from 5 to 90%, preferably from 10 to 80% of the weight of ibuprofen contained in the coating liquid. Depending on the type of hydrophobic polymeric material used in the hydrophobic coating, they may also act as an enteric coating. When hydroxypropylmethylcellulose phthalate (HPMCP), shellac, cellulose acetate phthalate and the like are used, they can act as an enteric coating because they have properties such as high solubility at pH (6.8-8.0) of the intestine.

On the other hand, the hydrophobic coating liquid contains a part of the total amount of ibuprofen which is an active ingredient contained in the medicament, and generally 5 to 80%, preferably 10 to 60% of the total amount of ibuprofen is included.

The solvent used in the hydrophobic coating liquid may be selected from water, alcohol, acetone, acetonitrile, methylene chloride, ether, hexane, chloroform, 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, ethyl acetate, methyl acetate, The most preferred solvents used are alcohol solvents such as ethanol, methanol and the like. The amount of the solvent to be used may vary depending on the kind of the polymer material used in the hydrophobic coating liquid, but is generally 10 to 300 parts by volume, preferably 50 to 200 parts by volume based on 1 part by weight of the polymer material.

The hydrophobic coating liquid is sprayed on the hydrophobic coating granules on which the hydrophobic coating layer is formed by spraying the hydrophobic coating liquid as described above to the crystal nuclei to form a hydrophilic coating layer. The hydrophilic coating liquid forming the hydrophilic coating layer contains ibuprofen, a hydrophilic polymer material and a solvent. The hydrophilic polymer material used in the hydrophilic coating liquid is preferably selected from the group consisting of carbohydrates, carboxymethylcellulose sodium, hydroxymethylcellulose, methylcellulose, hydroxypropylcellulose, povidone, polyvinyl alcohol, poloxamer, polyethylene glycol Polyoxyethylene sorbitan fatty acid esters, such as polyoxyethylene sorbitan monolaurate, also known as tween, polyvinylcellulose, and mixtures thereof. The content of the hydrophilic polymer substance is present in a proportion of 5 to 90%, preferably 10 to 80% of the weight of the ibuprofen contained in the hydrophilic coating liquid.

The hydrophilic coating liquid also contains a part of the total amount of ibuprofen as an active ingredient, and generally includes 5 to 80%, preferably 10 to 60% of the total amount of ibuprofen.

The solvent used in the hydrophilic coating liquid may be selected from water, alcohol, acetone, acetonitrile, methylene chloride, ether, hexane, chloroform, 1,4-dioxane, tetrahydrofuran, dimethyl sulfoxide, ethyl acetate, methyl acetate, Is selected. Most preferably, the solvent used is an alcohol solvent such as ethanol, methanol or the like. The amount of the solvent to be used may vary depending on the type of the polymer material used in the hydrophilic coating liquid, but is generally 10 to 300 parts by volume, preferably 20 to 200 parts by volume based on 1 part by weight of the polymer material.

According to the present invention, the hydrophobic coating layer and the hydrophilic coating layer as described above may be repeatedly coated, if necessary, to form multi-layer coated coating granules.

As described above, the coating granules of the present invention can be prepared by using an apparatus capable of spray coating a coating liquid while floating crystal nuclei or granules, for example, a fluidized bed granulator, a CF-granulator or the like have. For example, in the case of using the fluidized bed granulator to produce the coating granules of the present invention, the temperature of the inlet air is generally 40 to 90 DEG C, the flow rate of the inlet air is 30 to 10 m < 3 > / min, The number of revolutions of the rotor is 150 to 800 rpm, the number of revolutions of the agitator is 200 to 900 rpm, the number of revolutions of the lump breaker is 1 to 500 rpm or more, the velocity of the spray liquid is 7 to 25 ml / 10 to 50 m < 3 > / min is suitable, and in order to prevent moisture absorption and agglomeration of granules, the temperature of the granules in the stepwise apparatus should always be kept at 40 DEG C or higher (see Fig. 1).

The controlled-release ibuprofen granule produced according to the present invention can be formulated into capsules, preferably filled in a hard capsule. When the granule of the present invention is formulated into a capsule, considering the daily dose of ibuprofen, ibuprofen is preferably 200 mg or more, preferably 200 to 900 mg per capsule.

As described above, the ibuprofen capsules formulated according to the present invention exhibit similar bioavailability to tablets containing 200 mg of ibuprofen, which is commercially available when 100 mg of ibuprofen is contained. Therefore, the ibuprofen capsules prepared according to the present invention When the effective dose of ibuprofen is taken into consideration, it is advantageous in terms of the reduction of the dose of the patient and the reduction of the side effect, thereby improving the dosage regimen. In addition, the preparation technique according to the present invention is intended to maximize the absorption of the absorption site according to the human stomach environment by varying the type and amount of the polymer for each coating layer and varying amounts of the drug. And a consistent blood concentration can be expected.

The present invention will be more specifically explained by the following examples. However, the scope of the present invention is not limited in any way by these embodiments.

[Example 1]

A. Hydrophobic coating

Crystal nucleus: 240 mg of ibuprofen

Coating solution: 120 mg ibuprofen

35.7 mg of ethyl cellulose

0.6 ml of ethanol

The coating solution was sprayed while floating ibuprofen as a crystal nucleus in a fluidized bed granulator to coat it. At this time, the fluidized bed granulator was operated under the conditions shown in Table 1 below, and the temperature of the device of the ibuprofen powder and the coated powder was adjusted so as not to be below 45 ° C.

B. Hydrophilic coating

Crystal nucleus: hydrophobic coating granules of A 395.7 mg

Coating solution: 120 mg ibuprofen

7.9 mg of hydroxypropylcellulose (M)

0.6 ml of ethanol

Hydrophilic coating liquid composed of ibuprofen, hydroxypropylcellulose and ethanol was sprayed on the hydrophobic coating granules obtained in A above while floating in a fluidized bed granulator using the hydrophobic coating granules obtained as the crystal nuclei. The fluidized bed granulator was operated under the conditions shown in Table 1 below, and the granules of the fluidized bed granulator were maintained at not below 45 ° C.

The operating conditions of the fluidized bed granulator used in Example 1 are shown in Table 1 below.

STEP condition Hydrophobic coating Hydrophilic coating Inlet air temperature (℃) 80 80 In-apparatus granulation temperature (캜) 50 50 Inflow air volume (㎥ / min) 9 9 Exhaust air volume (㎥ / min) 10 10 Slit air flow rate (㎥ / min) 7 7 Fluid air flow rate (㎥ / min) 7 7 Coating solution spraying rate (ml / min) 10 12 Air flow rate (㎥ / min) 35 35 Rotor speed (rpm) 300 300 Agitator speed (rpm) 500 500 Lump breaker rpm (rpm) 2500 1700 On-off < / RTI > Every 20 seconds Every 20 seconds

[Example 2]

A hydrophobic coating and a hydrophilic coating were prepared in the same manner as described in Example 1 using the following ingredients to prepare ibuprofen granules.

A. Hydrophobic coating

Crystal nucleus: Nonpareil (sugar nucleus) 257.1 mg

Coating solution: ibuprofen 257.1 mg

200.0 mg of hydroxypropylmethylcellulose phthalate

Ethanol 0.7 ml

Water 0.7 ml

B. Hydrophilic coating

Crystal nucleus: 508.5 mg of hydrophobic coating granules of A

Coating solution: ibuprofen 342.8 mg

Carbopol 934P 11.0 mg

Ethanol 0.7 ml

Example 3

A hydrophobic coating and a hydrophilic coating were prepared in the same manner as described in Example 1 using the following ingredients to prepare ibuprofen granules.

A. Hydrophobic coating (enteric coating)

Crystalline nucleus: ibuprofen 250 mg

Coating solution: 110 mg of ibuprofen

Shellac 30 mg

0.6 ml of ethanol

B. Hydrophilic coating

Crystal nucleus: 390 mg of hydrophobic coating granules of A

Coating solution: 120 mg ibuprofen

7.9 mg of hydroxypropylcellulose (M)

0.6 ml of ethanol

The ibuprofen granules prepared according to Examples 1 to 3 can be formulated into capsules by filling in hard gelatine capsules.

[Effects of the Invention]

Experimental Example 1: Injection micrograph of granules according to the present invention

The granules prepared in Example 1 were taken with a scanning electron microscope (SEM) (Jeol 35CF, Jeol Co., USA) according to the present invention. The photograph shows the whole spherical particle of the granule, and the photograph (B) shows the granule coated with the 3000 μm magnification and the dense polymer layer coated on the granule surface.

Experimental Example 2: Drug Release Test

The granules prepared according to Examples 1 and 2 corresponding to 40 mg of ibuprofen and commercially available ibuprofen tablets (400 mg buplofen tablets, manufactured by Samil Pharmaceuticals) were placed in 900 mL of the first solution (artificial gastric juice prescribed in the Korean Pharmacopoeia) The release of ibuprofen was measured by HPLC. The measured results are shown graphically in Fig.

From the results shown in FIG. 3, it can be seen that the granules prepared in Examples 1, 2 and 3 of the present invention release drugs slowly and continuously over commercially available tablets, You can expect.

Experimental Example 3: Drug concentration test

Five granules of the present invention were each administered with the granules of the present invention prepared in accordance with the above Example 2. Five tablets of the same species as the control group were administered ibuprofen tablets (400 mg of buplofen, manufactured by Samil Pharmaceutical) Blood concentrations of ibuprofen were measured and averaged over time. Here, each drug was an amount equivalent to 10 mg / kg of ibuprofen. The measured results are as shown in Fig.

From the results shown in FIG. 4, it can be seen that the granules prepared according to the present invention exhibit a relatively large AUC as compared with the commercial tablets and rapidly reach the efficacy of the efficacy, thereby maintaining a consistent effective blood concentration for a long time.

Claims (14)

A controlled-release ibuprofen granule wherein a hydrophobic coating layer containing ibuprofen and a hydrophobic polymer substance and a hydrophilic coating layer containing a hydrophilic polymer substance and ibuprofen are sequentially coated on crystal nucleus composed of ibuprofen powder or sugar. The controlled release ibuprofen granule according to claim 1, wherein the crystal nucleus is composed of ibuprofen powder. The controlled release ibuprofen granule according to claim 2, wherein the ibuprofen powder constituting the crystal nucleus is 5 to 60% of the total weight of ibuprofen in the granule. The controlled release ibuprofen granule according to claim 1, wherein the polymeric material used in the hydrophobic coating layer is selected from the group consisting of edulid, shellac, ethyl cellulose, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate and mixtures thereof. The controlled release ibuprofen granule according to claim 1, wherein the hydrophobic polymer material used in the hydrophobic coating layer is 10 to 80% by weight of the ibuprofen contained in the hydrophobic coating layer. The controlled release ibuprofen granule according to claim 1, wherein the ibuprofen contained in the hydrophobic coating layer is 10 to 60% of the total weight of the ibuprofen contained in the granule. The method according to claim 1, wherein the polymer used in the hydrophilic coating layer is selected from the group consisting of a carbolol, carboxymethylcellulose sodium, hydroxymethylcellulose, methylcellulose, hydroxypropylcellulose, povidone, polyvinylalcohol, poloxamer, polyethylene glycol Release controlled-type ibuprofen granules selected from the group consisting of polyoxyethylene sorbitan fatty acid esters, polyvinyl celluloses and mixtures thereof. The release-controlled ibuprofen granule according to claim 1, wherein the hydrophilic polymer material used in the hydrophilic coating layer is 10 to 80% by weight of the ibuprofen contained in the hydrophilic coating layer. The controlled release ibuprofen granule according to claim 1, wherein the ibuprofen contained in the hydrophilic coating layer is 10 to 60% of the total weight of ibuprofen contained in the granule. The controlled-release ibuprofen granule according to claim 1, which is filled in a hard gelatin capsule and is formulated into a capsule. (a) spraying a hydrophobic coating solution containing ibuprofen, a hydrophobic polymer material and a solvent while floating a spherical crystal nucleus composed of a raw material ibuprofen powder or sugar to form a hydrophobic coating layer to form a hydrophobic coating granule, (b) Characterized in that a hydrophilic coating layer is formed by spraying a hydrophilic coating liquid containing ibuprofen, a hydrophilic polymer substance and a solvent while drying the hydrophobic coating granules, and drying the resultant to form a hydrophilic coating layer. The method of claim 11, wherein the solvent used in the hydrophobic coating solution is at least one selected from the group consisting of water, alcohols, acetone, acetonitrile, methylene chloride, ether, hexane, chloroform, 1,4-dioxane, tetrahydrofuran, dimethylsulfoxide, ≪ / RTI > acetate, and mixtures thereof. 12. The method of claim 11, wherein the solvent used in the hydrophilic coating is selected from the group consisting of water, alcohols, acetone, acetonitrile, methylene chloride, ether, hexane, chloroform, 1,4-dioxane, tetrahydrofuran, dimethylsulfoxide, ≪ / RTI > acetate, and mixtures thereof. 12. The process according to claim 11, which is carried out using a fluid bed granulator or a CF-granulator.