KR20170034707A - An oral solid formulation containing roflumilast and a process for the preparation thereof - Google Patents

Abstract

The present invention is to provide an oral solid formulation comprising roflumilast or a pharmaceutically allowable salt thereof as an active ingredient, polyvinyl alcohol as a bonding agent, and a pharmaceutically allowable additive, and a preparation method thereof. According to the present invention, the oral solid formulation comprising roflumilast uses polyvinyl alcohol as a bonding agent so solubility of roflumilast is increased, and an elution rate and bioavailability are increased.

Description

[0001] The present invention relates to an oral solid formulation containing roflumilast and an oral solid formulation containing roflumilast and a process for preparing the same,

The present invention relates to an oral solid preparation containing roflumilast as an active ingredient and more particularly to a solid preparation for oral use containing roflumilast in which the solubility and dissolution rate of roflumilast is improved and thereby the bioavailability is increased, And a manufacturing method thereof.

The roflumilast is a compound in which the chemical name is N- (3,5-dichloropyrid-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide, . Roflumilast is currently marketed worldwide under the trade name Daxas.

 [Chemical Formula 1]

The roflumilast of formula 1 is a phosphodiesterase (PDE) 4 inhibitor, which can be used in the treatment of acute or chronic airway obstruction, and is typically characterized by severe chronic obstructive pulmonary disease with chronic bronchitis or with allergic bronchitis ≪ / RTI > are known. The use of the compound and the compound as a phosphodiesterase (PDE) 4 inhibitor is disclosed in Patent Document 1.

The above-mentioned roflumilast is known to be a very poorly soluble drug at a water solubility of about 0.53 mg / L at 21 캜, and thus, in the case of a drug having low water solubility, the bioavailability is limited by solubility and dissolution rate. Therefore, in order to increase the bioavailability of such poorly soluble drugs, it is necessary to increase the solubility and dissolution rate in water.

Patent Document 1: WO 1995/001338

It is an object of the present invention to provide an oral solid preparation of roflumilast in which the solubility and dissolution rate of roflumilast is increased and, consequently, the bioavailability is improved.

It is another object of the present invention to provide a process for the preparation of the oral solid preparation of roflumilast.

One aspect of the present invention is

There is provided an oral solid preparation comprising roflumilast or a pharmaceutically acceptable salt thereof as an active ingredient, polyvinyl alcohol as a binder, and a pharmaceutically acceptable additive.

In another aspect of the present invention,

Preparing a mixture with a pharmaceutical additive comprising a diluent and a disintegrant;

And granulating the mixture with an aqueous solution containing polyvinyl alcohol.

The present invention also provides a method for producing the oral solid preparation according to the present invention.

The oral solid preparations containing roflumilast according to the present invention show that the solubility of roflumilast is increased by using polyvinyl alcohol as a binder and consequently the dissolution rate and bioavailability are increased.

FIG. 1 is a graph showing the results of measurement of solubility in a supersaturated state in a pH 1.2 test solution for tablets of Examples 1 to 3 and Comparative Examples 1 to 6. FIG.
FIG. 2 is a graph showing the results of measurement of the solubility of supernatant in the pH 4.0 test solution for the tablets of Examples 1 to 3 and Comparative Examples 1 to 6. FIG.
FIG. 3 is a graph showing the results of measurement of solubility in a supersaturated state in a test solution of pH 6.8 for the tablets of Examples 1 to 3 and Comparative Examples 1 to 6. FIG.
4 is a graph showing the results of measurement of the solubility of supernatant in the purified water for the tablets of Examples 1 to 3 and Comparative Examples 1 to 6. Fig.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

One aspect of the present invention is

There is provided an oral solid preparation comprising roflumilast or a pharmaceutically acceptable salt thereof as an active ingredient, polyvinyl alcohol as a binder, and a pharmaceutically acceptable additive.

The pharmaceutically acceptable salt of roflumilast may be an acid addition salt or a base addition salt. The acid addition salt includes a salt with an inorganic acid or an organic acid. Examples of the inorganic acid salt include salts with hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid. Examples of the organic acid salt include acetic acid, trifluoroacetic acid, propionic acid, maleic acid, fumaric acid, malic acid, citric acid, , Benzoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, or naphthalenedisulfonic acid, but is not limited thereto. The base addition salts include, for example, alkali metal salts such as sodium or potassium salts, alkaline earth metal salts such as calcium or magnesium salts, or ammonia salts or organic amine salts such as diethylamine, triethylamine, ethyl And salts with diisopropylamine, procaine, dibenzylamine, N-methylmorpholine, or dihydroabiethylamine.

It is understood herein that roflumilast or a pharmaceutically acceptable salt thereof may exist in any form selected from the group consisting of any of its crystalline and amorphous forms, and hydrates, solvates, and co-crystals thereof.

The inventors of the present invention have conducted intensive studies for the development of a solid preparation of roflumilast having improved solubility and dissolution rate of the active ingredient. As a result, it has been found that when a solid preparation is prepared using polyvinyl alcohol as a binder, It is possible to increase solubility, dissolution rate, and bioavailability of the solid preparation compared to the case of preparing solid preparations. Specifically, as a result of the supersaturation solubility test for a solid preparation of roflumilast prepared by different kinds of binders, it was found that the solid formulations prepared by using polyvinyl alcohol as a binder as compared with other binders (pH 1.2, pH 4.0, pH 6.8, purified water) showed the highest solubility. In addition, it exhibited improved solubility and dissolution rate compared to the conventional Dacosus tablet using polyvinylpyrrolidone as a binder (see Experimental Example 1). Thus, the solid preparation according to the present invention has improved solubility and dissolution rate due to the inclusion of polyvinyl alcohol as a binder. In addition, the solubility improvement of the poorly soluble drug has a relatively large effect on the bioavailability when administered in vivo even though the degree of improvement is not large. Therefore, the solid formulation of roflumilast according to the present invention is remarkably improved Lt; RTI ID = 0.0 > bioavailability. ≪ / RTI >

The polyvinyl alcohol may be present in an amount of about 0.2 to 5 wt% based on the total weight of the solid formulation. If the content is less than about 0.2% by weight, the solubility improvement effect can not be sufficiently obtained. If the content is more than about 5% by weight, not only the process setting becomes difficult due to the high viscosity, but also the granulation becomes hard during manufacture of the granules, Thereby lowering the bioavailability.

In one embodiment of the present invention, the polyvinyl alcohol may have a molecular weight of about 26,300 to 30,000, but is not limited thereto.

The solid preparation may be any solid preparation including roflumilast or a pharmaceutically acceptable salt thereof, polyvinyl alcohol, and a mixture of pharmaceutically acceptable additives. The solid preparation can be formulated into, for example, pellets, capsules, tablets, powders, granules, or dry syrups, but is not limited thereto. More specifically, the oral solid preparation may be in the form of a capsule or tablet. When the complex preparation of the present invention is a capsule, the capsule may be in the form of powders, granules, tablets, dry syrups, pellets and the like.

In one embodiment, the solid preparation is a tablet, which may be a tablet by direct compression method, which is directly tabletting the raw material mixture, or may be a tablet by granule compression method, prepared after granulation of the raw material mixture.

In the granule compression method, granules can be produced by a wet granulation method or a dry granulation method. The wet granulation process may be carried out by any method known in the art and may be carried out by any method known in the art including, for example, a high speed mixer, a fluid-bed granulator, a spray dryer, (ConSigma), followed by drying, but is not limited thereto. In one embodiment, the wet granules are wet granules produced by a fluid bed granulator. When the wet granules are prepared by a fluidized bed granulator, the amount of water used in the preparation of the binding liquid can be less than that of other wet granule production methods, and the hardness of the granules obtained at the time of production is low, .

The pharmaceutically acceptable excipients included in the oral solid preparations according to the present invention may be any excipients conventionally included in oral solid preparations, for example, diluents, additional binders, disintegrants, lubricants, and And any combination thereof.

The diluent may be selected from the group consisting of lactose or its hydrate, microcrystalline cellulose, mannitol, starch, sucrose, lactose, sorbitol, xylitol, glucose, calcium dihydrogenphosphate, and any combination thereof, The diluent is lactose hydrate. The diluent may be contained in an amount of 60 to 80% by weight, specifically 70 to 80% by weight, based on the total weight of the solid preparation.

The above-mentioned binder means a binder which can be optionally further added in addition to polyvinyl alcohol. Such additional binders include hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, copovidone, macrogol, light silicic anhydride , Calcium carbonate (e.g. calcium carbonate), and any combination thereof, but it is not limited thereto, and may be selected from the group consisting of calcium carbonate, calcium carbonate, magnesium carbonate, It is not.

Wherein said disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glyconate, low substituted hydroxypropylcellulose, starch, alginic acid or its sodium salt, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, crospovidone, Gelatinized starch, and any combination thereof, but is not limited thereto. In one embodiment, the disintegrant is corn starch. The disintegrant may be contained in an amount of 10 to 30% by weight, specifically 15 to 20% by weight, based on the total weight of the solid preparation.

The lubricant may be selected from the group consisting of stearic acid, metal salts of stearic acid (e.g. calcium stearate, magnesium stearate), talc, colloidal silica, sucrose fatty acid esters, hydrogenated vegetable oils, high melting point waxes, glyceryl fatty acid esters, But are not limited to, sodium lauryl sulfate, sodium stearyl fumarate, polyethylene glycol, sodium benzoate, talc, and any combination thereof. In one embodiment, the lubricant is magnesium stearate. The lubricant may be contained in an amount of 0.5 to 5% by weight, specifically 0.7 to 3% by weight, based on the total weight of the solid preparation.

The solid preparation can lower the content of the active ingredient contained per unit dosage form due to the increase in the solubility and dissolution rate of roflumilast, and hence the increase in bioavailability. When the content of the active ingredient is low, it is pharmaceutically preferable because it is easy to formulate.

The oral solid preparation may further include a coating layer formed by coating with a conventional coating agent to prevent the pharmacologically active ingredient from being contacted with human hands or skin during handling.

The coater may be selected from the group consisting of hypromellose, hydroxypropylcellulose, methylcellulose, ethylcellulose, polyvinylalcohol, hydroxyethylcellulose, and any combination thereof, for example, Hydroxypropylcellulose and the like may be used, but the present invention is not limited thereto. In one embodiment, the coating agent is a commercially available Opadry.

The coater is preferably maintained in a minimal amount for providing an optimal solid formulation size and for the production of an effective solid formulation and is present in an amount of from about 0.5 to 20% by weight, more specifically from about 1 to 10% by weight, , ≪ / RTI >

In one embodiment, the solid formulation may contain from about 0.01 to 5 mg, more specifically from 0.1 mg to 1 mg, of the ropililast free base per unit dosage form, one embodiment of the present invention is a unit About 0.5 mg per formulation.

The solid preparation can be administered to a mammal, including a human having any indication of roflumilast or a pharmaceutically acceptable salt thereof. Thus, the oral solid preparation can be used for the treatment of acute or chronic airway obstruction diseases and can be used for treating chronic obstructive pulmonary disease, bronchitis, or allergic bronchitis.

In another aspect of the present invention,

Preparing a mixture with a pharmaceutical additive comprising a diluent and a disintegrant; or a pharmaceutically acceptable salt thereof;

And granulating the mixture into a polyvinyl alcohol-containing binding liquid.

The present invention also provides a method for producing the oral solid preparation according to the present invention.

The details of the method for producing the oral solid preparation can be applied to the oral preparation according to one aspect of the present invention.

The steps of each step involved in the method for producing the oral solid preparation can be carried out based on the conventional granules, pellets, dry syrup, capsules, and tablets manufacturing processes performed in the art.

The polyvinyl alcohol-containing binding liquid may be a solution in which polyvinyl alcohol is added to water, ethanol, isopropanol, acetone, or any combination thereof as a solvent. The binding liquid may further comprise an additional binder in addition to polyvinyl alcohol and may be prepared by adding additives other than the binder commonly used in the pharmaceutical field, for example, a surfactant, a buffer, or any combination thereof . For example, the solvent of the binding solution is water, specifically, purified water.

The granulating step may be prepared by any wet granulation method known in the art and may be prepared by, for example, drying the wet granules by a high-speed mixer, fluidized bed granulator, spray dryer, or con Sigma However, the present invention is not limited thereto. In one embodiment, the wet granules are wet granules produced by a fluid bed granulator.

The wet granules thus obtained may be formulated into oral solid formulations according to any method known in the art for the preparation of solid form preparations, for example, granules, dry syrups, pellets, tablets, or capsules Can be carried out according to any known method. In one embodiment, the step of formulating is a step of preparing the tablet.

[Example]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1 and Comparative Examples 1 to 6: Preparation of tablets

Tablets containing the active ingredient were prepared using the components and contents shown in Table 1 below. First, roflumliast, lactose hydrate (# 100) and corn starch were mixed to prepare a granular part mixture. The binder was dissolved in purified water to prepare a binding solution, which was then granulated through the fluidized bed granulator together with the granular part mixture.

Magnesium stearate was added to the granules and finally mixed. The final mixture was tableted using a circular punch having a diameter of 8 mm to prepare tablets containing 0.5 mg of the active ingredient.

The purified tablets thus prepared were coated with the above-prepared solution of opaque yellow in purified water to complete the tablets of Example 1. The tablets thus obtained had an average hardness of 6 to 8 kp and a degree of warpage of 0.1%.

The tablets of Comparative Examples 2 to 6 were prepared in the same manner as the preparation method of Example 1 except that the kind and content of the binder as shown in Table 1 below. In Comparative Example 2, no binder was used, and in Comparative Example 3, polyvinyl alcohol was used in an amount of 0.1% by weight based on the total weight of the tablet. In Comparative Examples 4 to 6, 2% by weight of a binder other than polyvinyl alcohol was used as a binder.

Also, Daxas tab. (Takeda Pharmaceutical, Korea), which is currently on the market, is used as Comparative Example 1.

(Unit: mg) Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Granule portion Rofluililast 0.5 0.5 0.5 0.5 0.5 0.5 Lactose Luggage (# 100) 197.6 203.0 202.73 197.6 197.6 197.6 Corn starch 54.0 54.0 54.0 54.0 54.0 54.0 Engaging portion Polyvinyl alcohol 5.4 - 0.27 - - - Corn starch - - - 5.4 - - Hydroxypropylcellulose - - - - 5.4 - Co-povidone - - - - - 5.4 Final mixing Magnesium stearate 2.5 2.5 2.5 2.5 2.5 2.5 coating Opa Dry Yellow 7.0 7.0 7.0 7.0 7.0 7.0 Gross weight 267.0 267.0 267.0 267.0 267.0 267.0

Examples 2 to 3: Preparation of polyvinyl alcohol-containing tablets in various ratios

The tablets of Examples 2 and 3 were prepared in the same manner as in Example 1 except that the ratio of polyvinyl alcohol was changed only as shown in Table 2 below.

(Unit: mg) Example 1 Example 2 Example 3 Granule portion Rofluililast 0.5 0.5 0.5 Lactose Luggage (# 100) 197.6 201.65 192.2 Corn starch 54.0 54.0 54.0 Engaging portion Polyvinyl alcohol 5.4 1.35 10.8 Final mixing Magnesium stearate 2.5 2.5 2.5 coating Opa Dry Yellow 7.0 7.0 7.0 Gross weight 267.0 267.0 267.0

Test Example 1: Supersaturation solubility test

The tablets of Examples 1 to 3 and Comparative Examples 1 to 6 were subjected to a supersaturation solubility test under the following liquid chromatography conditions.

≪ Roflumilast supersaturation solubility test conditions >

Test Solution: pH 1.2, pH 4.0, pH 6.8, and purified water pH 1.2 solution First Amendment of Korea Pharmacopoeia 11

pH 4.0 solution 0.05 Mol / L acetic acid: 0.05 Mol / L sodium acetate mixed solution (82: 18) was prepared and adjusted to pH 4.0.

pH 6.8 solution Korean Pharmacopoeia 11th Revision Disintegration Test Method 2nd solution

Condition: Three tablets were added to 300 mL of each test solution, and the test was conducted at 50 rpm for 120 minutes

Sampling: 15, 30, 60, 90, 120 minutes

≪ Conditions for analysis of roflumilast solubility >

Used equipment: HPLC (Hitachi 2000 series, Japan)

Detector: ultraviolet absorption spectrophotometer (measuring wavelength: 250 nm)

Column: A stainless steel tube having an internal diameter of 4.6 mm and a length of 150 mm was charged with a column packed with octadecylsilylated silica gel for a liquid chromatograph having a particle diameter of 5 μm

The mobile phase: KH ₂ PO ₄ (6.8 g / L) buffer (pH 6.0): ACN = 35: 65 (v / v)

Flow rate: 1.0 mL / min

Column temperature: 30 ° C

The above supersaturation solubility test results are shown in Tables 3 to 6 and Figs.

sample Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Example 2 Example 3 0 minutes 0 % 0 % 0 % 0 % 0 % 0 % 0 % 0 % 0 % 15 minutes 24.1% 22.5% 19.2% 20.9% 19.3% 21.1% 23.0% 24.6% 24.8% 30 minutes 25.6% 24.2% 20.4% 21.9% 20.6% 22.1% 23.7% 25.0% 25.1% 60 minutes 26.8% 25.2% 21.1% 22.7% 20.8% 23.0% 24.0% 26.4% 26.0% 90 minutes 27.0% 25.0% 20.7% 22.5% 21.1% 22.8% 24.5% 26.2% 26.8% 120 minutes 27.0% 25.4% 21.1% 22.9% 21.0% 22.8% 24.9% 26.2% 27.2%

sample Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Example 2 Example 3 0 minutes 0 % 0 % 0 % 0 % 0 % 0 % 0 % 0 % 0 % 15 minutes 23.0% 22.4% 17.6% 19.8% 16.9% 20.3% 21.8% 23.0% 22.4% 30 minutes 24.1% 23.7% 18.6% 20.3% 18.0% 20.7% 22.5% 23.9% 24.0% 60 minutes 25.5% 24.0% 19.4% 21.5% 19.9% 22.0% 23.1% 25.0% 25.2% 90 minutes 25.2% 24.6% 18.9% 22.0% 19.6% 22.5% 22.8% 24.4% 25.2% 120 minutes 25.8% 24.6% 19.6% 22.0% 19.5% 22.6% 22.7% 24.4% 25.2%

sample Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Example 2 Example 3 0 minutes 0 % 0 % 0 % 0 % 0 % 0 % 0 % 0 % 0 % 15 minutes 19.6% 20.6% 16.6% 17.6% 17.0% 18.5% 20.0% 21.6% 20.6% 30 minutes 22.1% 21.9% 17.0% 20.4% 16.8% 20.8% 21.1% 22.5% 21.9% 60 minutes 24.0% 23.1% 17.4% 20.9% 17.2% 21.3% 21.6% 23.0% 23.6% 90 minutes 23.4% 23.3% 17.3% 21.2% 17.4% 21.6% 21.8% 23.1% 24.0% 120 minutes 23.0% 23.5% 17.6% 21.3% 17.7% 21.6% 21.7% 22.8% 24.0%

sample Example 1 Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Example 2 Example 3 0 minutes 0 % 0 % 0 % 0 % 0 % 0 % 0 % 0 % 0 % 15 minutes 20.0% 21.0% 18.5% 20.2% 18.0% 19.7% 20.1% 23.6% 22.6% 30 minutes 22.9% 23.2% 19.0% 21.7% 18.6% 20.8% 22.7% 26.0% 25.0% 60 minutes 26.0% 25.4% 19.8% 22.9% 20.0% 21.9% 23.0% 26.8% 26.2% 90 minutes 26.2% 25.4% 19.9% 23.1% 21.0% 22.1% 23.1% 26.6% 26.3% 120 minutes 27.2% 26.2% 19.9% 22.8% 22.1% 22.6% 23.5% 26.4% 26.4%

According to Tables 3 to 6 and Figs. 1 to 4, the tablets of Examples 1 to 3 containing polyvinyl alcohol as a binder were prepared in the same manner as in Comparative Examples 4 to 6 (Comparative Examples 4 to 6) containing other binders (corn starch, hydroxypropylcellulose, (PH 1.2, 4.0, 6.8, purified water), the solubility was improved compared with that of Comparative Example 1 (Dacax), which is a commercially available product.

It was also confirmed that Examples 1 to 3 are superior in solubility improvement to Comparative Example 3 containing less than 0.2% of polyvinyl alcohol as a binder.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the above-described embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (16)

An oral solid preparation comprising roflumilast or a pharmaceutically acceptable salt thereof as an active ingredient, polyvinyl alcohol as a binder, and a pharmaceutically acceptable additive. 2. The oral solid preparation according to claim 1, wherein the polyvinyl alcohol is present in an amount of 0.2 to 5% by weight based on the total weight of the solid preparation. The oral solid preparation according to claim 1, wherein the polyvinyl alcohol has a molecular weight of 26,300 to 30,000. The oral solid preparation according to claim 1, wherein the solid formulations are selected from the group consisting of powders, granules, dry syrups, tablets, and capsules. The oral solid preparation according to claim 4, wherein the tablet is a tablet prepared by a direct compression method or a granular compression method. 6. The oral solid preparation according to claim 5, wherein the granule is produced by a wet granulation method. 7. The oral solid preparation according to claim 6, wherein the wet granulation method is a drying method after the production of wet granules by a fluidized bed granulator. 2. The oral solid preparation of claim 1, wherein the pharmaceutically acceptable additive is selected from the group consisting of a diluent, a binder, a disintegrant, a lubricant, and any combination thereof. 9. The method of claim 8,
Wherein the diluent is selected from the group consisting of lactose or a hydrate thereof, microcrystalline cellulose, mannitol, starch, sucrose, lactose, sorbitol, xylitol, glucose, calcium dihydrogenphosphate,
Wherein the binder is selected from the group consisting of hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, copovidone, macrogol, light anhydrous silicic acid, silicates, phosphates, carbonates, and any combination thereof,
Wherein said disintegrant is selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glyconate, low substituted hydroxypropylcellulose, starch, alginic acid or its sodium salt, carboxymethylcellulose sodium, microcrystalline cellulose, powdered cellulose, crospovidone, ≪ / RTI > gelatinized starch, and any combination thereof,
The lubricant may be selected from the group consisting of stearic acid, metal stearate, talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, high melting wax, glyceryl fatty acid ester, glycerol dibehenate, sodium lauryl sulfate, sodium stearyl fumarate, Polyethylene glycol, sodium benzoate, talc, and any combination thereof. 2. The oral solid preparation according to claim 1, wherein the roflumilast is contained in an amount of 0.01 mg to 5 mg per unit dosage form as a free base. The oral solid preparation according to claim 10, wherein the loplumilast is contained in an amount of 0.1 mg to 1 mg per unit dosage form as a free base. The oral solid preparation according to claim 1, which is for the treatment of acute or chronic airway obstruction diseases. 13. The oral solid preparation according to claim 12, wherein the disease is chronic obstructive pulmonary disease, bronchitis, or allergic bronchitis. Preparing a mixture with a pharmaceutical additive comprising a diluent and a disintegrant; or a pharmaceutically acceptable salt thereof;
And granulating the mixture with an aqueous solution containing polyvinyl alcohol.
14. A method for producing a solid preparation for oral use according to any one of claims 1 to 13. 15. The method according to claim 14, wherein the granulation is carried out in a fluidized bed granulator. 15. The method of claim 14, further comprising the step of mixing the granulate with a pharmaceutical additive including a lubricant and then tableting.

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