WO2010001930A1 - Solid preparation for internal application - Google Patents

Abstract

Disclosed is a solid preparation for internal application, which comprises: (A) sucralfate; and (B) a medicinal particle comprising a poorly water-soluble carrier particle and a medicinal agent which is different from sucralfate and is supported on the poorly water-soluble carrier particle.

Description

Solid oral preparation

The present invention relates to a solid oral preparation containing sucralfate and a drug other than sucralfate and improving the dissolution of the drug when dissolved into the body.

Sucrose octasulfate aluminum (sucralfate) is a drug used in gastrointestinal drugs as a protective agent for gastric mucosa, and has the property of gelling when it contains water in the acidic range. Then, the gel-like substance produced by the gastric acid covers the gastric mucosa and protects it. However, when an active ingredient other than sucralfate, particularly a water-soluble drug, is blended in the same preparation, sucralfate gelled with gastric acid tends to take other active ingredients into the gel and exclude release. As a result, there has been a problem that the amount of other drugs absorbed into the body decreases.

As a technique for solving the above-mentioned problems, sucralfate is mixed with other drugs in the same preparation and is composed of an immediate-release part containing other drugs and a delayed-release part containing sucralfate so that the drug is sucralfate. In preparations that quickly elute without being adsorbed and trapped in the preparation (Patent Document 1: JP-A-8-333259), preparations comprising sucralfate and other drugs and antacids, other drugs are adsorbed by sucralfate Alternatively, preparations that prevent trapping (see Patent Document 2: JP-A-9-278657), absorption of one or more types of H2 blockers and one or more types of mucosal protective / strengthening agents are absorbed with a time difference. A pharmaceutical agent that acts on the treatment or prevention of chronic gastritis and acute gastritis characterized by the above (Patent Document 3: JP-A-20062006) No. 76956), including famotidine and sucralfate, which is for the treatment of gastric disorders characterized by having a barrier layer that prevents the interaction between famotidine and sucralfate in the dosage form A solid oral dosage form (Patent Document 4: Japanese Patent Publication No. 10-509180) has been proposed. However, these effects are not yet satisfactory and improvements have been desired.

JP-A-8-333259 Japanese Patent Laid-Open No. 9-278657 JP 2006-76956 A Japanese National Patent Publication No. 10-509180

The present invention has been made in view of the above circumstances, and contains sucralfate and other drugs other than sucralfate (hereinafter referred to as “other drugs”), and the adsorption of other drugs to sucralfate is suppressed and dissolved into the body. An object of the present invention is to provide a solid internal preparation that improves the dissolution of other drugs.

As a result of diligent investigations to achieve the above object, the present inventors have used drug particles in which a drug other than sucralfate is supported on poorly water-soluble carrier particles and sucralfate, thereby allowing other drugs to be added to sucralfate. It has been found that adsorption is suppressed and the elution of other drugs is improved, and the present invention has been made.

Accordingly, the present invention provides the following solid internal preparation.
[1]. A solid internal preparation containing (A) sucralfate and (B) drug particles in which a drug other than sucralfate is supported on poorly water-soluble carrier particles.
[2]. (B) The solid oral preparation according to [1], wherein the drug other than sucralfate is a water-soluble or hydrophilic solvent-soluble drug.
[3]. (B) The solid internal preparation according to [1] or [2], wherein the drug particles other than sucralfate are drug particles obtained by impregnating a poorly water-soluble carrier particle with a drug solution or dispersion and then drying.
[4]. The solid internal preparation according to [1], [2], or [3], wherein the drug particles (B) are drug particles in which ranitidine or a hydrochloride thereof is supported on magnesium and / or calcium-containing poorly water-soluble carrier particles.

According to the present invention, it is possible to provide a solid oral preparation containing sucralfate and other drugs, suppressing the adsorption of other drugs to sucralfate, and improving the dissolution of other drugs when dissolved into the body. it can.

(A) Sucralfate Sucralfate forms a bioadhesive gel by gastric acid in the gastrointestinal tract and adheres to the gastrointestinal mucosa to provide a local protective barrier. In the inflammation or ulcer site, this protective barrier contains excess gastric acid or the like. It is a drug that exerts a healing effect by protecting the gastrointestinal mucosa and promoting the gastric mucosa repair action of the living body itself. The sucralfate used in the present invention can be blended with sucralfate as it is, but granulated particles may be used.

The granulation is not particularly limited as long as it is a known granulation method such as fluidized bed granulation, tumbling granulation or kneading granulation, and for example, a slurry obtained by slurrying with a binder such as polyethylene glycol and the like are used. be able to. Examples of such commercially available products include “Stomacsin: manufactured by Fuji Chemical Industry Co., Ltd. The particle size is not particularly limited, but using a sieve having openings of 1000 μm and 850 μm, 1000 μm on is 0% by mass, and 850 μm on. Is preferably 3% by mass or less.

The content of (A) sucralfate in the solid internal preparation of the present invention can be adjusted as appropriate so that the usual dose of sucralfate is 300 to 1200 mg, preferably 500 to 750 mg. . For example, the content of the component (A) is preferably 10 to 90% by mass and more preferably 25 to 80% by mass in the solid oral preparation.

(B) Drug particles Drug particles other than sucralfate are drug particles carried on poorly water-soluble carrier particles, and can be used alone or in combination of two or more other drug particles. As will be described later, the drug particles are preferably obtained by impregnating and drying a drug solution in poorly water-soluble carrier particles.

(1) Other drugs As drugs other than sucralfate, water-soluble or hydrophilic solvent-soluble drugs are preferable, and water-soluble or ethanol-soluble drugs are more preferable. Water soluble or hydrophilic solvent soluble means that the amount of solvent capable of dissolving 1 g of drug is less than 100 mL. Specific examples include herbal extracts such as funnel extract, ranitidine or its hydrochloride, diphenhydramine hydrochloride, azulene sulfonate sodium, aspirin, ibuprofen, acetaminophen, glycyrrhizinate and the like, one kind alone or two kinds The above can be used in appropriate combination. The amount of each drug can be set within the effective amount range of the target drug.

(2) Poorly water-soluble carrier particles As the carrier, poorly water-soluble carrier particles are used. In addition, poorly water-soluble means that the amount of dissolution in 1000 mL of water is less than 1 g. Specifically, organic carrier particles such as starch (water insoluble), hydroxypropyl starch, crystalline cellulose, microcrystalline cellulose, powdered cellulose, carboxymethylcellulose calcium, light anhydrous silicic acid, talc, silicon oxide, dry aluminum hydroxide gel, Magnesium silicate, magnesium aluminum silicate, calcium silicate, aluminum oxide, aluminum silicate, synthetic hydrotalcite, calcium oxide, titanium oxide, magnesium oxide, dihydroxyaluminum acetate, aluminum magnesium hydroxide, aluminum hydroxide, alumina hydroxide Magnesium, magnesium hydroxide, calcium carbonate, calcium hydroxide, magnesium carbonate, silicon dioxide (synthetic silica), magnesium metasilicate magnesium aluminate, anhydrous phosphoric acid Carrier particles may be mentioned of inorganic compounds such as iodine calcium, it can be used alone or in admixture of two or more as appropriate. Among them, porous particles such as crystalline cellulose, anhydrous calcium hydrogen phosphate, synthetic hydrotalcite, silicon dioxide (synthetic silica), calcium carbonate are preferable because they can be impregnated with a large amount of drug, and anhydrous phosphorus Inorganic porous particles such as calcium oxyhydrogen, synthetic hydrotalcite, silicon dioxide (synthetic silica), magnesium aluminate metasilicate, and calcium carbonate are preferred.

(3) Ranitidine Particles In particular, when the other drug is ranitidine or a hydrochloride thereof, discoloration of the ranitidine-containing particles can be suppressed by using the poorly water-soluble carrier particles as the poorly water-soluble particles containing magnesium and / or calcium. Hereinafter, drug particles in which ranitidine or a hydrochloride thereof is supported on magnesium and / or calcium-containing poorly water-soluble carrier particles are abbreviated as ranitidine particles.

Magnesium and / or calcium-containing poorly water-soluble particles can be obtained as particles of magnesium and / or calcium-containing compounds. As the magnesium and / or calcium-containing compound, the antacid power required by the antacid test method of Japanese Pharmacopoeia (No. 15) is 200 mL or more from the viewpoint of further improving the discoloration suppressing effect of ranitidine, and magnesium and The calcium content is preferably 20% by mass or more in the compound. Examples of such magnesium or a calcium-containing compound include magnesium hydroxide, magnesium oxide, magnesium hydroxide alumina, synthetic hydrotalcite, magnesium carbonate, calcium carbonate, calcium hydroxide and the like, one kind alone or two kinds or more. Can be used in appropriate combination.

The antacid power determined by the Japanese Pharmacopoeia (Station 15) antacid test method is indicated by the consumption (mL) of 0.1 mol / L hydrochloric acid per gram. In the present invention, 200 mL or more is preferred, more preferably 260 mL or more, and even more preferably 290 mL, and the upper limit is not particularly limited. The antacid power of the above compound is shown below. Magnesium hydroxide (340 mL), magnesium oxide (480 mL), magnesium alumina hydroxide (300 mL), synthetic hydrotalcite (290 mL), magnesium carbonate (210 mL), calcium carbonate (200 mL), calcium hydroxide (260 mL).

Further, the magnesium and / or calcium content in the compound is preferably 20% by mass or more, more preferably 23% by mass or more, and further preferably 24% by mass or more in the compound. Specifically, magnesium hydroxide (42% by mass), magnesium oxide (60% by mass), magnesium alumina hydroxide (21% by mass), synthetic hydrotalcite (24% by mass), magnesium carbonate (28% by mass), carbonic acid They are calcium (40 mass%) and calcium hydroxide (30 mass%).

Of these, magnesium hydroxide, magnesium oxide, synthetic hydrotalcite, calcium carbonate and calcium hydroxide are preferred, and magnesium hydroxide, magnesium oxide, synthetic hydrotalcite and calcium hydroxide are more preferred.

The content of the magnesium or calcium-containing compound in the solid oral preparation is preferably 20 to 99% by mass, more preferably 25 to 80% by mass. In addition, the molar ratio represented by (magnesium and / or calcium) / ranitidine in the ranitidine particles is preferably 10 or more, more preferably 20 or more, from the viewpoint of the discoloration inhibiting effect of ranitidine. The upper limit is not particularly limited, and is about 9000, although it is determined by the size of the tablet and the pharmaceutical formulation restrictions of the antacid. However, the content can be used up to 5000 mg (daily dose) as the amount used in normal treatment of inorganic compounds.

The particle size of the poorly water-soluble carrier particles is not particularly limited, and fine particles having an average particle size of 60 μm or less or particles of about 250 to 300 μm can be used. Further, the poorly water-soluble carrier particles are uniformly uniform when the solvent to be impregnated (hydrophilic solvent for dissolving other drugs such as water and ethanol) is dropped little by little while kneading 1 g of carrier particles with a spatula or the like. Porous particles having an amount of solution (amount of liquid absorption) required to become a mass are 1.0 mL or more. Examples of such poorly water-soluble carrier particles include crystalline cellulose, anhydrous calcium hydrogen phosphate, synthetic hydrotalcite, magnesium aluminate metasilicate, and the like.

As the drug particles of the present invention, one or two or more of the above drugs supported on one or more of the poorly water-soluble carrier particles can be used. In this case, the mass ratio represented by poorly water-soluble carrier particles: drug is preferably 1: 0.04 to 1, more preferably 1: 0.05 to 0.8. Within this range, even when coexisting with sucralfate, particularly good drug elution can be obtained. The total content of the other drugs in the drug particles and the poorly water-soluble carrier particles is preferably 80 to 100% by mass, and may be 90 to 98% by mass.

(4) Binder The (B) drug particles are preferably blended with a binder from the viewpoint of easy control of particle size physical properties (strength, tabletability, etc.). Examples of the binder include celluloses such as carmellose sodium, croscarmellose sodium, hydroxypropylcellulose, hydroxypropylmethylcellulose, gum arabic, carboxyvinyl polymer, povidone, crospovidone, polyvinyl alcohol, polyacrylic acid, polyvinylpyrrolidone and the like. Can be used alone or in combination of two or more. Among these, hydroxypropyl cellulose is preferable. The content of the binder is preferably 2 to 10% by mass in the (B) drug particles, more preferably 2 to 9% by mass, and further preferably 2 to 8% by mass.

(5) Surfactant (B) As the drug particles, a surfactant that can be used in an oral preparation, preferably a nonionic surfactant can be used. Nonionic surfactants include polyoxyethylene alkyl ether, polyoxyethylene castor oil, polyoxyethylene glycerin fatty acid ester, polyglycerin fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene sterol, hydrogenated sterol , Polyethylene glycol fatty acid ester, polyoxyethylene lanolin, alkyl glucoside, fatty acid sucrose ester and the like. The content of the surfactant is preferably 0.01 to 20% by mass, more preferably 0.05 to 10% by mass in the drug particles (B).

In the drug particles (B), in addition to the above, arbitrary additives (such as an excipient, a coloring agent, and a fragrance) can be blended within a range that does not impair the effects of the present invention.

The drug particles include, for example, a drug solution containing another drug, or a solution or dispersion liquid (hereinafter referred to as “drug solution or dispersion liquid”) further containing a binder, a surfactant, and other optional components in the drug solution. It can be obtained by impregnating poorly water-soluble carrier particles and then drying. As the solvent of the drug solution or dispersion, a hydrophilic solvent is used, and water, ethanol, and a water-ethanol mixed solvent are preferable, and the concentration of other drugs in the drug solution or dispersion is preferably 1 to 60% by mass. 1 to 50% by mass is more preferable. In addition, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, pregelatinized starch, gelatin and the like may be added to the drug solution or dispersion, and the concentration in the drug solution or dispersion is 1 to 10 mass. % Is preferred. Specific examples of the impregnation method include a method in which the drug solution or dispersion is sprayed on poorly water-soluble carrier particles. Further, fluidized bed granulation, rolling granulation or kneading granulation may be performed, and if necessary, a binder or any additive may be added and granulation may be performed simultaneously with impregnation. Drying includes fluidized bed drying, dry oven, freeze drying, and the like. From the viewpoint of efficiency, fluidized bed granulation can be performed consistently until drying. The drying temperature (supply air temperature) time is not particularly limited, and is carried out at 40 to 90 ° C. for about 15 to 90 minutes.

The particle size of the drug particles is not particularly limited, but 1000 μm on is preferably 0% by mass and 850 μm on is preferably 3% by mass or less. In the present invention, the particle size is a robot shifter (RPS-95 manufactured by Seishin Enterprise Co., Ltd.), a vibration level of 5 minutes using a sieve having openings of 850 μm, 500 μm, 355 μm, 250 μm, 150 μm, and 75 μm, The measurement is performed at a pulse interval of 5 seconds, and is obtained as a mass percentage of the remaining mass on each sieve with respect to the total sample mass. The average particle size (% by weight) is determined using the above.

(B) The content of the drug particles is preferably 10 to 70% by mass, more preferably 10 to 65% by mass, and further preferably 15 to 60% by mass in the solid internal preparation.

The solid internal preparation of the present invention contains (A) sucralfate and (B) drug particles, and can be a granule that is a mixture of (A) and (B). And (B) can be mixed and compressed into tablets.

In the solid internal preparation of the present invention, in addition to (A) sucralfate and (B) drug particles, depending on the purpose, sugars such as D-mannitol and lactose, sugar alcohols, hydroxypropylcellulose, hydroxypropylmethylcellulose and the like are soluble. Waxes such as cellulose ether, macrogol, liquid paraffin, and excipients such as corn starch, lubricants such as stearic acid, calcium stearate, magnesium stearate, aluminum stearate, sodium stearyl fumarate, surfactants, corrigents Coloring agents, fragrances and the like can be blended singly or in appropriate combination of two or more. The amount can also be appropriately selected.

Hereinafter, although an Example and a comparative example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. Unless otherwise specified, the amounts in the table are pure component amounts.

[Drug solutions A to E]
Drugs or drugs and binders were added to chemical additive standard water or pharmacopoeia ethanol and dissolved by stirring well to obtain drug solutions A to E having the compositions shown in Table 1.

[Examples 1 to 4]
In a fluidized bed granulator multiplex MP-01 (manufactured by POWREC), the poorly water-soluble carrier particles shown in Table 2 are placed, and the drug solution is supplied with an air flow at an air supply temperature of 80 ° C and an exhaust temperature of 30-35 ° C. A to D are set to 10 g / min. Spray granulation at a speed of This was dried at 80 ° C. for 15 minutes to obtain drug particles. The obtained drug particles had a particle size of 850 μm 0% by mass and an average particle size of 40 to 250 μm.
The obtained drug particles were mixed with sucralfate ("Stomacsin" manufactured by Fuji Chemical Industry Co., Ltd.), magnesium stearate, and corn starch, and then tableted with a clean press (manufactured by Kikusui Seisakusho Co., Ltd.). And a round tablet having a mass of 330 mg and 9 mmφ was obtained.

[Example 5]
(Fine granules)
Synthetic hydrotalcite 250 g is put into a fluidized bed granulator multiplex MP-01 (manufactured by POWREC), and the drug solution prepared above with an air volume of 80 ° C. and an exhaust temperature of 30 to 35 ° C. E 480 g was sprayed at a rate of 20 g / min. This was dried at 80 ° C. for 15 minutes to obtain drug particles (particle size 850 μm on 0% by mass, average particle size 270 μm).
Next, multiplex MP-01 (manufactured by POWREC) was charged with 500 g of sucralfate (“Sucralfate”, 550 g manufactured by Fuji Chemical Industry Co., Ltd. (500 g as sucralfate pure)), and 30 g of D-mannitol (Pairitol, produced by Rocket Corporation). Into this, 350 g of an 8.0 mass% hydroxypropylcellulose aqueous solution (HPC-L manufactured by Nippon Soda Co., Ltd.) with an air volume of 80 ° C. and an exhaust temperature of 30 to 35 ° C. was added at a rate of 20 g / min. Spraying was performed at a speed, followed by drying at 80 ° C. for 15 minutes to obtain a sucralfate granulated product (particle size 850 μm on 0% by mass, average particle size 280 μm).
355 g of the drug particles and 608 g of sucralfate granulated product were introduced into Boule Container Mixer LM10 manufactured by Kotobuki Industries Co., Ltd. and stirred to obtain a fine granule (particle size 850 μm on 0 mass%, average particle size 270 μm).

<Test Example 1>
The preparations of Examples 1 to 5 were subjected to a dissolution test using the Dissolution Tester manufactured by Toyama Sangyo Co., Ltd. according to the Japanese Pharmacopoeia Preparation Test Dissolution Test Method, and the dissolution rate (%) after 30 minutes of other drugs was determined. It was measured. In the test, the first solution of dissolution test (pH 1.2) was used. As Comparative Example 1, a mixture in which ranitidine hydrochloride (powder 21 mg) and sucralfate (powder 167 mg) were mixed was tested at the same time. All tablets used in the test disintegrated completely in about 1.5 minutes.

[Examples 6 to 10]
The drug particles prepared in the same manner as in Example 1 were mixed with sucralfate (“Stomacsin” manufactured by Fuji Chemical Industry Co., Ltd.), magnesium stearate, and corn starch, and then tableted (compressed) with a clean press (manufactured by Kikusui Seisakusho). The tablet pressure was 1.0 t), and a circular tablet having a composition shown in Table 4 and a mass of 400 mg and 9 mmφ was obtained. The obtained round tablet was evaluated in the same manner as in Test Example 1. The results are shown in Table 5.

[Examples 11 to 18]
A drug particle was obtained in the same manner as in Example 1 except that the concentration of the aqueous drug solution was fixed at 50% by mass and that described in Tables 6 and 7 below was used.
The obtained drug particles, sucralfate ("Stomacsin" manufactured by Fuji Chemical Industry Co., Ltd.), magnesium stearate, and corn starch were mixed and then tableted with a clean press (manufactured by Kikusui Seisakusho Co., Ltd.). Thus, a circular tablet having a composition shown in Tables 6 and 7 and having a mass of 330 mg and 9 mmφ was obtained. The obtained round tablet was evaluated in the same manner as in Test Example 1. The results are shown in Tables 8 and 9.

[Examples 19 to 28]
Tablets having the compositions shown in Tables 10 and 11 (adult daily dose) were obtained by the following method.
Carrier particles are placed in a fluidized bed granulator MP-01 (manufactured by POWREC), and each carrier particle is sprayed and impregnated with a 50% by mass ranitidine hydrochloride aqueous solution so that a predetermined amount is obtained. Obtained. As granulation conditions, air supply temperature: 80 ° C., atomizing air amount: 50.0 L / min. [20 ° C., 1 atm], spray liquid speed: 20 g / min. The drying process was performed until the exhaust air temperature reached 50 ° C. The particle size of the drug particles was 0% by mass at 850 μm, and the average particle size was 100 to 300 μm.
Next, the obtained drug particles, sucralfate ("Stomaxin" manufactured by Fuji Chemical Industry Co., Ltd.) and other components excluding magnesium stearate were used using a Bole container mixer (20 model manufactured by 24 rpm Kotobuki Industries Co., Ltd.). And mixed thoroughly. Magnesium stearate is added to the obtained mixed powder and mixed for 5 minutes using a Boule container mixer (model type 20 manufactured by Kotobuki Kogyo Co., Ltd.), then φ8 mm, two-stage R (R = 9.5 mm, 3. Using a rotary tableting machine (Libra tableting machine: manufactured by Kikusui Seisakusho) equipped with 2 mm) punches and mortars, tableting was performed at a tableting pressure of 1000 kgf to obtain one tablet of 310 mg.

The obtained tablets were packaged with PTP (polypropylene PTP molded product R-1T-2 manufactured by Kanae Corporation) and placed in an aluminum gusset. This was stored in a constant temperature layer of 50 ° C. and 75% RH for 2 weeks. The color difference of the tablet after storage was measured with a color difference meter (manufactured by MINOLTA, spectral colorimeter CM-2022 type), and color change suppression evaluation was performed according to the following evaluation criteria. The results are also shown in the table.
<Evaluation criteria>
Compare the color difference (b *) between the sample stored in the same way as above except that 50 ° C / 75% RH was changed to 5 ° C. Those exceeding 3 or less were evaluated as “◯”, those exceeding 3 or less as “Δ”, and those exceeding 5 as “X”.

Claims (4)

A solid oral preparation containing (A) sucralfate and (B) drug particles in which a drug other than sucralfate is supported on poorly water-soluble carrier particles. (B) The solid internal preparation according to claim 1, wherein the drug other than sucralfate is a water-soluble or hydrophilic solvent-soluble drug. (B) The solid internal preparation according to claim 1 or 2, wherein the drug particles other than sucralfate are drug particles obtained by impregnating a poorly water-soluble carrier particle with a drug solution or dispersion and then drying. The solid oral preparation according to claim 1, 2 or 3, wherein the drug particles (B) are drug particles in which ranitidine or its hydrochloride is supported on magnesium and / or calcium-containing poorly water-soluble carrier particles.