KR20080015550A - Oral formulation - Google Patents

Abstract

An orally administering formulation is provided to be able to inhibit wetting, solidification and coloration change and be stable without the combination change even through ibuprofen and an antacid are contained in one granule, and be convenient for preparation with decreased manufacturing cost. An orally administering formulation is obtained by wet-granulating a composition comprising ibuprofen, an antacid, a swelling agent, wherein the antacid is magnesium oxide or sodium hydrogen carbonate, and the swelling agent is at least one selected from the group consisting of lowly substituted hydroxypropylcellulose, carmellose or a salt thereof, croscarmellose sodium, carboxymethyl starch sodium, crospovidone and crystalline cellulose.carmellose sodium.

Description

Oral Formulations {ORAL FORMULATION}

The present invention relates to a preparation for oral administration.

Many general-purpose pharmaceuticals contain a plurality of active ingredients, and on the other hand, when two or more active ingredients are blended, a compounding change often occurs. Acidic substances and basic substances are typical of these. For example, ibuprofen, an acidic drug, reacts with an antacid, which is a basic drug, to cause wetting, solidification, and color change. Granules combined with ibuprofen and sodium bicarbonate were changed to pale brown after 14 days under conditions of 20 ° C and 75% RH, and the granules became wet due to a change in appearance. (Nonpatent Literature 1). Therefore, the method of formulating it as two granules which divided granules into granules containing ibuprofen and granules containing an antacid, and the method of coating to granules again are taken. However, stabilization is achieved by using the granule formulation, but the production cost increases, and problems such as mixing uniformity of the active ingredient occur.

In addition, it is known that the swelling agent used in the present invention can mask the unpleasant taste of the drug (Patent Documents 1 and 2), but it is not known to prevent the change of the formulation of the formulation containing ibuprofen and an antacid.

[Patent Document 1] Japanese Patent Application Laid-Open No. 9-208458

[Patent Document 2] Japanese Patent Application Laid-Open No. 2004-189756

[Non-Patent Document 1] Japanese Pharmacy Room Vol. 27, N0. 12, 73-78 (1976)

SUMMARY OF THE INVENTION An object of the present invention is to provide an oral dosage form in which granules of ibuprofen and an antacid are not divided into individual granules, and in one granule, without causing a change in formulation, the active ingredients are uniformly blended and manufactured by a simple manufacturing method. have.

The present invention provides a preparation for oral administration obtained by wet granulation of a composition containing ibuprofen, an antacid and a swelling agent.

Moreover, this invention provides the manufacturing method of the formulation for oral administration which knead | mixes the composition containing ibuprofen, an antacid, and a swelling agent with water or alcohol content of 30 mass% or less, and then wet granulate.

Ibuprofen [2- (4-isobutylphenyl) propionic acid] used in the present invention is in powder form, with an average particle diameter of 1 to 500 µm, more preferably 10 to 355 µm, particularly 20 L to 150 µm. The average particle diameter uses the value measured by the laser diffraction method.

It is preferable to contain 1-95 mass% of ibuprofen in 5 to 90 mass% further in the formulation for oral administration.

Examples of the antacid used in the present invention include magnesium oxide, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, synthetic hydrotalcite, magnesium aluminum silicate, magnesium metasilicate, magnesium silicate, synthetic aluminum silicate and anhydrous calcium hydrogen phosphate, Calcium Hydrogen Phosphate, Dry Aluminum Hydroxide Gel, Magnesium Hydroxide, Magnesium Hydroxide, Aluminum Hydroxide Gel, Aluminum Hydroxide, Sodium Hydrogen Carbonate Coprecipitation Product, Aluminum Hydroxide, Magnesium Carbonate Mixture Dry Gel, Aluminum Hydroxide, Magnesium Carbonate, Calcium Carbonate Coprecipitation Product, Squid bone, crystallization, grain, amino acetic acid, dihydroxyaluminum aminoacetate, raw extract, etc. are mentioned, magnesium oxide and sodium hydrogencarbonate are preferable, and magnesium oxide is especially preferable. The average particle diameter of the antacid is preferably 0.1 to 500 µm, more preferably 1 to 255 µm, particularly 1 to 150 µm.

It is preferable to contain 1 to 95 mass%, and also 5 to 90 mass% in an antacid formulation.

The mass ratio of ibuprofen and antacid in the formulation for oral administration of the present invention is preferably 0.2 to 10, more preferably 0.5 to 5.0, particularly 0.9 to 2.0, by mass ratio of ibuprofen / antacid.

The swelling agent used in the present invention is a substance that absorbs water and swells. In the process of adding water or hydrous alcohol to the swelling agent, kneading the ibuprofen and the antacid, and drying and removing the water or the hydrous alcohol, the swelling agent shrinks to isolate the ibuprofen and the antacid from the swelling agent. The antacid stabilizes without solidification.

As the swelling agent, for example, low-substituted hydroxypropyl cellulose, caramelose (carboxymethyl cellulose) or salts thereof, croscarmellose sodium (pharmaceutical additive standard description: cross-linked carboxymethyl cellulose sodium) , Carboxymethyl starch sodium, crospovidone (crosslinked polyvinylpyrrolidone), crystalline cellulose-carotene sodium, and the like. Examples of the salts of caramelose include sodium salts and calcium salts. As the swelling agent, low-substituted hydroxypropyl cellulose, salts of caramelose and croscarmellose sodium are preferable, and low-substituted hydroxypropyl cellulose is particularly preferable. Swelling agent may use together 1 type (s) or 2 or more types.

When using low substituted hydroxypropyl cellulose as a swelling agent, it is preferable that content of the hydroxypropyl group is 5.0-16.0 mass%, Furthermore, it is 10.0-13.0 mass%.

It is preferable to contain 15-85 mass% of swelling agents in the formulation for oral administration of this invention. The swelling agent is preferably 0.1 to 7.5 and further 0.2 to 5.0 in the mass ratio of the swelling agent / (ibuprofen + antacid) to the total mass of the ibuprofen and the antacid.

In the oral dosage form of the present invention, in addition to ibuprofen, an antacid and a swelling agent, drugs other than ibuprofen, an antacid, and components commonly used in granules may be appropriately mixed according to the purpose. For example, an excipient (diluent), a binder, a disintegrant, a sweetener, a flavoring agent, a pigment | dye, etc. are mentioned. Here, as an excipient, For example, sugars, such as lactose, refined white sugar, glucose; And sugar alcohols such as D-mannitol, sorbitol, xylitol, and erythritol. Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyvinyl pyrrolidone, dextrin, alpha starch, and the like. Examples of disintegrating agents include starch such as corn starch. Examples of sweeteners include saccharin sodium, aspartame, and the like. Examples of the flavors include citrus flavors such as oranges and lemons, menthol and peppermint oil. As a pigment | dye, a natural pigment, a synthetic pigment | dye, etc. are mentioned.

The formulation for oral administration of the present invention is prepared by kneading a composition containing ibuprofen, an antacid, and a swelling agent in a water-containing alcohol having a water or alcohol content of 30% by mass or less, followed by wet granulation. Here, as alcohol used, lower alcohols, such as ethanol and isopropanol, are preferable, and ethanol is especially preferable. Examples of the water include purified water and ion exchanged water. Of water or hydrous alcohols, water is preferred.

The wet granulation is not particularly limited as long as it is a wet granulation method used in conventional medicines such as stirring granulation, fluidized bed granulation, extrusion granulation, and the like, but is preferably extrusion granulation.

The formulation for oral administration of this invention can be manufactured as follows, for example.

A swelling agent and, if necessary, an ingredient to be added are added to ibuprofen and an antacid, and mixed with a stirring mixer, followed by kneading in water of 2 to 5% by mass of the swelling agent or an aqueous solution of 30% by mass or less of alcohol to obtain a swelling state. . The dough is then granulated in an extrusion granulator and then water or hydrous alcohol is dried in a box-type drier or a fluid bed granulation drier to produce granules. In addition, after extrusion granulation as necessary, granules having a desired particle size can be formed by using a whisk, and may be spherical granules by spherical treatment with a marmizer.

In addition, the dough is dried in a box-type drier or a fluidized bed granulation drier, and pulverized again as necessary, and granules of a desired particle size can be obtained using a shaker. The particle size control of the granules may be performed by adjusting the amount of water or hydrous alcohol or by changing the screen diameter during extrusion granulation in the range of 0.3 to 1.2 mm. The obtained granules may be coated with sugars, polymers, or the like in consideration of the feeling of taking them, the stability of the drug, and the like.

The average particle diameter of the granules obtained by wet granulation is preferably from 100 to 1000 µm, more preferably from 150 to 900 µm, particularly from 200 to 800 µm, in view of the improvement of wetness and solidification and the improvement of fluidity. In addition, the particle size of particle | grains uses the value measured by the sampling method.

The granules prepared in this way can be used as powders, fine granules and the like as they are because they have improved wetting and solidification, do not change color, and have good fluidity. Soluble tablet-type pharmaceutical formulations can be produced easily. Therefore, granules, powders, tablets, capsules, etc. are mentioned as a preparation for oral administration of this invention. In preparing these oral preparations, ingredients commonly used in solid preparations, for example, starch, calcium carbonate, calcium sulfate, crystalline cellulose, plant powders and other excipients, colorants, tinting agents, odorants, and light blocking agents You may mix | blend a flavor, a sweetener, etc.

EXAMPLE

Example 1

Ibuprofen 150 g, magnesium oxide 100 g, low-substituted hydroxypropyl cellulose (L-HPC LH31: Shin-Etsukagaku Co., Ltd.) 466 g, caramelose calcium (manufactured by Kodokuyaku Hinggo Kogyo Co., Ltd.) 144 g, anhydrous caffeine 80 g, and allyl isopropylacetyl urea 60 g were mixed with a vertical granulator VG-25 (manufactured by Faurek Co., Ltd.), followed by kneading with addition of 2465 g of purified water, followed by Twindom Gran TDG-80. (Fuji Powder Co., Ltd. product) The extrusion granulation was carried out with the 0.6 mm screen, and it dried with the fluidized-bed drier WSG-5 (made by Okawara Seisakusho Co., Ltd.), and obtained the granule of the average particle diameter of 500 micrometers. 1 g 1 g of granules were distributed in an aluminum sheet heel (thickness: 0.012 m).

Example 2

Vertical granules 300 g of ibuprofen, 200 g of magnesium oxide, 620 g of low-substituted hydroxypropyl cellulose (L-HPC LH31: Shin-Etsukagaku Co., Ltd.), 160 g of anhydrous caffeine, 120 g of allylisopropylacetyl urea After mixing with Rator VG-25 (manufactured by Faurek Co., Ltd.), kneading with addition of 2380 g of purified water, extruded into a twin dome gran DG-80 (manufactured by Fuji Powder Co., Ltd.) 0.6 mm screen, It spherically processed with Marumeizer Q-400 (manufactured by Fuji Powder Co., Ltd.), and dried in a fluidized bed dryer WSG-5 (manufactured by Okawara Seisakusho Co., Ltd.) to obtain a granule having an average particle diameter of 600 µm. A capsule was prepared by charging 350 mg of granules into a No. 1 capsule.

Example 3

Vertical granules 750 g of ibuprofen, 500 g of magnesium oxide, 1290 g of low-substituted hydroxypropyl cellulose (L-HPC LH31: Shin-Etsukagaku Co., Ltd.), 400 g of anhydrous caffeine, 300 g of allylisopropylacetyl urea After mixing in Rator VG-25 (manufactured by Faurek Co., Ltd.), adding 5234 g of purified water, kneading, and extruding with 0.6 mm screen of Twin Dome Gran TDG-80 (manufactured by Fuji Powder Co., Ltd.) It dried with the fluidized-bed drier WSG-5 (made by Okawara Seisakusho Co., Ltd.), it was made up to quadrocomil (the diameter of the screen made by Faurek Co., Ltd .: 1270 micrometers), and the granule of the average particle diameter of 600 micrometers was obtained.

To this granule, it is crystal cellulose (Avisel PH 101: Asahi Kasei Co., Ltd.), croscarmellose sodium (aczisol: Asahi Kasei Co., Ltd.), hard silicic acid (adso) by the prescription of Table 1 Rida 101: Freud Industries Co., Ltd.), talc (manufactured by Kihara Kasei Co., Ltd.), magnesium stearate (Taihei Kagaku Kogyo Co., Ltd.) was added, and a rotary tableting machine (RS-T15-S35: Kikusu Iseisakusho Co., Ltd., tablets of 9 mm in diameter and 1 tablet of 250 mg were prepared.

TABLE 1

ingredient Content (in 3 tablets) mg Granule Ibuprofen Magnesium Oxide Low Substitution Hydroxypropyl Cellulose Anhydrous Caffeine Allylisopropylacetyl Urea 150.0 100.0 258.0 80.0 60.0 (Total 648.0) Crystalline cellulose  39.0 Croscarmellose Sodium  50.0 Hard silicic anhydride   3.7 Talc   5.7 Magnesium stearate   3.7 Sum 750.0

Example 4

Vertical granules 450 g of ibuprofen, 300 g of magnesium oxide, 219 g of low-substituted hydroxypropyl cellulose (L-HPC LH31: Shin-Etsukagaku Co., Ltd.), 240 g of anhydrous caffeine, 180 g of allylisopropyl acetyl urea After mixing in Rator VG-25 (manufactured by Faurek Co., Ltd.), adding 100 g of purified water, kneading, and extruding with 0.6 mm screen of Twin Dome Gran TDG-80 (manufactured by Fuji Powder Co., Ltd.) It dried with the fluidized-bed drier WSG-5 (made by Okawara Seisakusho Co., Ltd.), and it was grain-formed by quadrocomil (The diameter of the powder made by Paulek Co., Ltd .: 1270 micrometer).

Using the prepared granules, tablets having a diameter of 9 mm and one tablet of 260 mg having the compositions shown in Table 2 were prepared in the same manner as in Example 3.

TABLE 2

ingredient Content (in 3 tablets) mg Granule Ibuprofen Magnesium Oxide Low Substitution Hydroxypropyl Cellulose Anhydrous Caffeine Allylisopropylacetyl Urea 150.0 100.0 73.0 80.0 60.0 (Total 463.0) Crystalline cellulose  27.7 Croscarmellose Sodium  20.0 Hard silicic anhydride   2.7 Talc   4.0 Magnesium stearate   27 Sum 520.0

Comparative Example 1

150 g of ibuprofen, 100 g of magnesium oxide, 258 g of crystalline cellulose (Avisel PH 101: manufactured by Asahi Kasei Co., Ltd.), 80 g of anhydrous caffeine, and 60 g of allylisopropylacetyl urea are vertical granulator VG-10 (Paulek ( Note) After mixing in), kneaded by adding 120 g of purified water, dried in a fluidized bed dryer WSG-5 (manufactured by Okawara Seisakusho Co., Ltd.), Quadrocomil Co., Ltd. (Micrometer).

Using the granules thus prepared, tablets having a diameter of 9 mm and one tablet of 250 mg having the compositions shown in Table 3 were prepared in the same manner as in Example 3.

TABLE 3

ingredient Content (in 3 tablets) mg Granule Ibuprofen Magnesium Oxide Low Substitution Hydroxypropyl Cellulose Anhydrous Caffeine Allyl Isopropylacetyl Urea 150.0 100.0 258.0 80.0 60.0 (Total 648.0) Crystalline cellulose  39.0 Croscarmellose Sodium  50.0 Hard silicic anhydride   3.7 Talc   5.7 Magnesium stearate   3.7 Sum 750.0

Comparative Example 2

Ibuprofen 300 g, crystalline cellulose (Avisel PH 101: Asahi Kasei Co., Ltd.) 258 g, anhydrous caffeine 160 g, allyl isopropylacetyl urea 120 g of Vertical Granulator VG-10 (manufactured by Faurek Co., Ltd.) 80 g of purified water was added thereto, followed by kneading, followed by drying in a fluidized bed dryer WSG-5 (manufactured by Okawara Seisakusho Co., Ltd.), and quadrocomyl (Paurec Co., Ltd. screen diameter: 1270 µm). Formulated to Prepare Granule A

300 g of magnesium oxide and 387 g of crystalline cellulose (Avisel PH 101: manufactured by Asahi Kasei Co., Ltd.) were mixed with a vertical granulator VG-10 (made by Faurek Co., Ltd.), and then 120 g of purified water was added thereto to knead the dough. Thereafter, the resultant was dried in a fluidized bed dryer WSG-5 (manufactured by Okawara Seisakusho Co., Ltd.), and the granules B were prepared by quantifying quadrocomil (Faurex Co., Ltd. screen diameter: 1270 µm).

Subsequently, tablets having a diameter of 9 mm and one tablet 250 mg having the composition shown in Table 4 were prepared using the granules A and B in the same manner as in Example 3.

TABLE 4

ingredient Content (in 3 tablets) mg Granule Ibuprofen Crystalline Cellulose Anhydrous Caffeine Allylisopropylacetyl Urea 150.0 129.0 80.0 60.0 (Total 419.0) Granule Magnesium Oxide Crystal Cellulose 100.0 129.0 (total 229.0) Crystalline cellulose  39.0 Croscarmellose Sodium  50.0 Hard silicic anhydride   3.7 Talc   5.7 Magnesium stearate   3.7 Sum 750.0

Comparative Example 3

300 g of ibuprofen, crystalline cellulose (Avisel PH 101: product made by Asahi Kasei Co., Ltd.), 160 g of anhydrous caffeine, 120 g of allyl isopropylacetyl urea are vertical granulator VG-25 (made by Faurek Co., Ltd.) After mixing, the mixture was kneaded by adding 120 g of purified water, dried in a fluidized bed dryer WSG-5 (manufactured by Okawara Seisakusho Co., Ltd.), and made into quadrocomil (Paurek Co., Ltd. screen diameter: 1 270 μm). It was sized and granules were obtained. Subsequently, the granules of croscarmellose sodium (Cujizol solution: made by Asahi Kasei Co., Ltd.), hard silicic anhydride (Adsorida 101: made by Freud's Co., Ltd.), and talc (Kihara Kasei Co., Ltd.) of Table 5 were added to this granule. ) And magnesium stearate (Taihei Kagaku Kogyo Co., Ltd.) were added to manufacture an outer layer granule.

Meanwhile, 300 g of magnesium oxide and 415.5 g of crystalline cellulose (Avisel PH 101: manufactured by Asahi Kasei Co., Ltd.) were mixed with a vertical granulator VG-10 (manufactured by Faurek Co., Ltd.), and then 100 g of purified water was added thereto. After kneading and kneading, the resultant was dried in a fluidized bed dryer WSG-5 (manufactured by Okawara Seisakusho Co., Ltd.), and the quadrocomil (Purarex Co., Ltd. screen diameter: 1270 µm) was grained to obtain granules. Subsequently, the granules of croscarmellose sodium shown in Table 5 (aczisol: manufactured by Asahi Kasei Co., Ltd.), hard silicic anhydride (Adsorida 101: manufactured by Freud Co., Ltd.), and talc (Kihara Kasei) Ltd.) and magnesium stearate (Taihei Chemical Co., Ltd.) were added, and the inner granules were manufactured.

Again, using this outer granule and inner granules, a rotary tableting machine (RT-3L-14: manufactured by Kikusui Seisakusho Co., Ltd.), three layers (diameter 80 mg ㅧ 2: inner layer 90 mg) of diameter 9 mm, 1 tablet 250 mg Tablets were prepared.

 TABLE 5

Comparative Example 4

Ibuprofen 150 g, magnesium oxide 100 g, low-substituted hydroxypropyl cellulose (L-HPC LH31: Shin-Etsukagaku Co., Ltd.) 490.6 g, talc 5.7 g, magnesium stearate 3.7 g is mixed, and a rotary tableting machine ( RS-T15-S35: Kikusui Seisakusho) 250 mg of tablets of 9 mm in diameter and one tablet were manufactured.

Test Example 1

The granulation formulations for oral administration of Examples 1 to 4 and Comparative Examples 1 to 4 were placed in a glass container (No. 6 standard glass bottle: 61.5 ml in volume, 24.7 mm in diameter) and wet and solidified under the accelerated conditions described in Table 6 and Table 7. And color change were evaluated by visual evaluation using the following evaluation criteria.

* Wetting and solidification test:-no change

+ Wetting

++ Slightly solidified

+++ Visible

* Coloring test:-no change

+ Slightly yellowish coloring

++ yellow coloration

+++ brown tint visible

Table 6 shows the results of the wet / solidification test and Table 7 shows the results of the coloring test.

TABLE 6

 TABLE 7

The preparations for oral administration of the present invention containing ibuprofen, an antacid and a swelling agent in one granule were all excellent in stability without wet, solidification, or color change.

Example 5

200 g of ibuprofen, 200 g of sodium bicarbonate, low-substituted hydroxypropyl cellulose (L-HPC LH31: Shin-Etsu Kagaku Co., Ltd.) 1600 g of vertical granulator VG-25 (made by Faurek Co., Ltd.) After mixing at 5200 g of purified water, kneading, and then extrusion granulated with a Twin Dome Gran TDG-80 (manufactured by Fuji Powder Co., Ltd.) 0.6 mm screen, fluidized bed dryer WSG-5 (Okawara Seisakusho) The granules of the particle size of 355-500 micrometers were manufactured using the No. 16 and 42 housing | casing dried by the note).

Comparative Example 5

After mixing 200 g of ibuprofen, 200 g of sodium bicarbonate, and 1600 g of lactose (200M: manufactured by DMV) in a vertical granulator VG-25 (manufactured by Faurek Co., Ltd.), and then kneading with 500 g of purified water, Twin-Dome Gran TDG-80 (manufactured by Fuji Powder Co., Ltd.) Extruded into a 0.6 mm screen, dried in a fluid bed dryer WSG-5 (manufactured by Okawara Seisakusho Co., Ltd.), No. 16 and No. 42 Using to prepare a granule having a particle size of 355 ~ 500㎛.

Test Example 2

1.0 g of the granules prepared in Example 5 and Comparative Example 5 were distributed in an aluminum heat seal (12 μm). Visual changes were evaluated by visual observation when stored at 50 ° C and 75% RH.

The results are shown in Table 8.

TABLE 8

7 days later 14 days later 30 days later Example 5 No change No change No change Comparative Example 5 Wetting Wetting, solidifying See solidification

The granules of the present invention were stable without causing changes in the appearance of wetting and solidification.

Example 6

Instead of the low-substituted hydroxypropyl cellulose of Example 5, caramelose sodium (ECG-505: manufactured by Godoku Yakuching Co., Ltd.), croscarmellose sodium (Ac-Di-sol: Asahi Kasei Kogyo Co., Ltd.) Ltd.)), carboxymethyl starch sodium (primogel: Matsuya Kagaku Kogyo Co., Ltd.), crospovidone (Corizon CL: BASF Takeda Co., Ltd.) or crystalline cellulose carmelorose sodium (avicel) RC-A591NF: The granule was manufactured by the same method using Asahi Kasei Kogyo Co., Ltd. product. Even if these granules were allowed to stand at 50 degreeC and 75% RH for 30 days, they were stable without causing the change of the appearance of wet and solidified.

Although the ibuprofen and the antacid agent are contained in one granule, the preparation for oral administration of the present invention is suppressed from change in wetting, solidification and coloring, is stable without causing a change in formulation, and an effective ingredient is uniformly blended. Moreover, manufacturing is easy and manufacturing cost can be reduced.

Claims (6)

A formulation for oral administration obtained by wet granulation of a composition containing ibuprofen, an antacid, and a swelling agent. The preparation for oral administration according to claim 1, wherein the antacid is magnesium oxide or sodium hydrogen carbonate. The swelling agent according to claim 1 or 2, wherein the swelling agent is a low-substituted hydroxypropyl cellulose, caramelose or a salt thereof, croscarmellose sodium, carboxymethyl starch sodium, crospovidone and crystalline cellulose-carotene. One or two or more preparations selected from the group consisting of mellow sodium. The preparation for oral administration according to any one of claims 1 to 3, wherein the content of the swelling agent is 15 to 85% by mass. A method for producing an oral preparation, wherein the composition containing ibuprofen, an antacid and a swelling agent is kneaded with a water or an alcohol having a content of 30% by mass or less, followed by wet granulation. The method for producing an oral preparation according to claim 5, wherein the amount of water or hydrous alcohol is 2 to 5 mass times of the swelling agent.