JPWO2020066392A1 - Oral solid preparation and its manufacturing method - Google Patents

Abstract

The subject of the present invention is N- (2,5-bis (trifluoromethyl) phenyl) -3-oxo-4-aza-5α-androsta-1-ene-17β-carboxamide (hereinafter, "Compound A"). By overcoming the drawbacks of soft gelatin capsules and the like containing (referred to as), providing an oral solid preparation containing compound A having a small total mass per unit preparation and having sufficient bioavailability as a pharmaceutical. is there. An oral solid preparation containing compound A and hydroxypropyl cellulose and / or low degree of substitution hydroxypropyl cellulose is useful as a compound A-containing oral solid preparation that solves the above problems. Further, a compound A-containing oral solid preparation that solves the above-mentioned problems by dissolving compound A in an organic solvent and producing by a method including a step of mixing or granulating with hydroxypropyl cellulose and / or low degree of substitution hydroxypropyl cellulose Can be provided. [Selection diagram] None

Description

The present invention relates to an oral solid preparation containing N- (2,5-bis (trifluoromethyl) phenyl) -3-oxo-4-aza-5α-androsta-1-ene-17β-carboxamide. ..

N- (2,5-bis (trifluoromethyl) phenyl) -3-oxo-4-aza-5α-androsta-1-ene-17β-carboxamide (hereinafter referred to as "Compound A") is dihydro. It is a type 1 and type 2 5α-reductase inhibitor that suppresses the conversion of testosterone to testosterone. Compound A is used for the treatment of benign prostatic hyperplasia and androgenetic alopecia (Patent Document 1).

Compound A is a poorly water-soluble drug that is slightly soluble in ethanol, slightly soluble in medium-chain monodiglycerides, and practically insoluble in water.
The water solubility of a drug affects the rate of absorption of the drug and the rate of release from the formulation into the gastrointestinal lumen. Methods for improving the solubility of poorly water-soluble drugs include dissolution in oily additives, miniaturization and solid dispersion.

As a pharmaceutical product, a solution in which 0.5 mg of compound A is dissolved in a medium-chain monodiglyceride which is a solubilizer is filled in an oblong soft gelatin capsule and is commercially available in Japan as a therapeutic agent for benign prostatic hyperplasia (non-patented). Document 1). In addition, a solution prepared by dissolving 0.1 mg or 0.5 mg of compound A in medium-chain mono-diglyceride, which is a solubilizer, filled in an oblong soft gelatin capsule is commercially available in Japan as a therapeutic agent for androgenetic alopecia. (Non-Patent Document 2).
However, the compound A-containing soft gelatin capsule has the following drawbacks.
The size of the compound A-containing soft gelatin capsule has a total length of 19.3 mm, a thickness of 6.6 mm, and a weight of 599 mg. Soft gelatin capsules are bulkier than tablets because the contents are not compressed, and are not easy to take, especially in patients who have difficulty swallowing. In addition, if the capsule is taken in an insufficient amount of water, the capsule may stick to the larynx or the like, and the high concentration of compound A may irritate the oropharyngeal mucosa. For the same reason, care should be taken not to inadvertently bite when taking. In addition, rupture of the capsule capsule may cause the drug to leak, and Compound A may cause problems for pharmacist and patient safety due to its transdermal absorbability. In addition, since the contents of the soft gelatin capsule are present in a liquid state, the drug may migrate to the membrane of the soft gelatin capsule over time. In fact, there is a report that compound A was detected on the surface of a soft gelatin capsule containing compound A and on the inside of a PTP sheet (Non-Patent Document 3). Furthermore, soft gelatin capsules cannot be packaged because they soften under high temperature and high humidity.

In Patent Document 2, compound A is dissolved in propylene glycol monocaprylate as a solubilizer, adsorbed on lactose hydrate, microcrystalline cellulose and colloidal silicon dioxide, and then wet granulated using a binding solution. The tablets produced in the above are listed. However, Patent Document 2 does not disclose any evaluation results such as the dissolution property and bioavailability of the tablet. Further, since propylene glycol monocaprylate used as a solubilizer for compound A is an oily additive, when a solid preparation is produced, if the amount of the solubilizer used is reduced, the content of compound A in the preparation becomes uniform. It is difficult to secure sex. On the other hand, if the amount of the solubilizer used is large, the preparation cannot be molded or has low hardness and is difficult to handle. To overcome this, a large amount of excipient is required, which makes it difficult to take a large tablet.

Patent Document 3 describes 150 mg of tablets per tablet produced using the pulverized compound A. Although no specific data are presented, it is stated that more than 80% of the drug was released within 10 minutes in the dissolution test using the tablet, but no bioavailability was stated. .. Further, unlike commercially available soft gelatin capsules, the tablets contain compound A, which is a poorly water-soluble drug, in a powder state, so that it is difficult to obtain sufficient bioavailability as a pharmaceutical product. is expected.

Patent Document 4 describes an amorphous solid dispersion of Compound A using the polymers hydroxypropylmethylcellulose, polyvinylpyrrolidone, copolyvidone or aminoalkylmethacrylate copolymer E, and tablets produced using the same. There is. Patent Document 4 describes that the tablets of Examples showed an excellent dissolution rate in the dissolution test (paddle rotation speed 50 rpm, pH 1.2 test solution), but the bioavailability was not considered at all. Not listed.

International Publication No. 1995/007927 International Publication No. 2012/0766516 European Patent Application Publication No. 2050436 Special Table 2018-20982

Avolve® Capsule Package Insert Zagaro® Capsule Package Insert Medical Pharmacy 42 (7) 536-542 (2016)

An object to be solved by the present invention is to provide a compound A-containing oral solid preparation having sufficient bioavailability as a pharmaceutical product by overcoming the above-mentioned drawbacks of soft gelatin capsules and tablets.

Under these circumstances, the present inventors have conducted intensive studies and found that the total mass of the oral solid preparation containing compound A and hydroxypropyl cellulose and / or low degree of substitution hydroxypropyl cellulose per unit preparation is The present invention has been completed by finding that it is small and exhibits bioequivalence to a commercially available compound A-containing soft gelatin capsule.
In addition, the present inventors have dissolved compound A in an organic solvent and mixed or granulated with hydroxypropyl cellulose and / or low-degree-of-substitution hydroxypropyl cellulose to reduce the total mass per unit preparation and to market it. The present invention has been completed by finding that it is possible to provide an oral solid preparation containing compound A that exhibits bioequivalence to the soft gelatin capsule containing compound A of the above.

According to the present invention, it is possible to provide a compound A-containing oral solid preparation having a small total mass per unit preparation and having sufficient bioavailability as a pharmaceutical product. In addition, it is possible to provide a method for producing an oral solid preparation containing compound A, which has a small total mass per unit preparation and has sufficient bioavailability as a pharmaceutical product.

FIG. 1 is a graph showing the results of changes in the concentration of compound A in plasma in the bioequivalence test of Test Example 1.

The present invention will be described in detail below.
In the present specification,% is mass% unless otherwise specified.
In the present specification, the numerical range indicated by using "~" means a range including the numerical values before and after "~" as the minimum value and the maximum value, respectively.

The oral solid preparation of the present invention is an oral solid preparation containing compound A and hydroxypropyl cellulose and / or low degree of substitution hydroxypropyl cellulose, having a total mass of less than 200 mg per unit preparation and containing commercially available compound A. Shows bioequivalence to soft gelatin capsules.
The oral solid preparation of the present invention can be produced by dissolving compound A in an organic solvent and mixing or granulating with hydroxypropyl cellulose and / or low degree of substitution hydroxypropyl cellulose. It is considered that the amorphous compound A is formed by dissolving the compound A in an organic solvent and mixing or granulating with hydroxypropyl cellulose and / or low degree of substitution hydroxypropyl cellulose.

As used herein, "sufficient bioavailability" refers to compound A-containing soft gelatin capsules (Avolve® capsules) or male alopecia treatments that are commercially available in Japan as therapeutic agents for prostatic hypertrophy. It means that it exhibits bioavailability equal to or higher than that of compound A-containing soft gelatin capsules (Zagaro (registered trademark) capsules) marketed in Japan as a drug. "Equivalent or better bioavailability" includes bioequivalence.
"Shows bioequivalence to commercially available compound A-containing soft gelatin capsules" of the present invention means that when the preparation is orally administered to a fasting human with water once, the test preparation and the commercially available compound A-containing soft It means that the 90% confidence interval of the difference in pharmacokinetic parameters (AUCt, Cmax) of gelatin capsules is within the range of log (0.8) to log (1.25) (“Bioequivalence test guidelines for generic drugs, etc.” Partial amendment of "(February 29, 2012, Pharmaceutical and Food Safety Review No. 0229, No. 10) Attachment 1 Guidelines for bioequivalence testing of generic drugs).

The "oral solid preparation" of the present invention means a solid preparation that can be taken orally, and examples thereof include tablets, granules, fine granules, powders and pills. "Tablets" include uncoated tablets and coated tablets.

As used herein, the term "coating" refers to coating the surface of an oral solid preparation with a sugar or a polymer to form a film, and the coated portion is referred to as a "coating layer".
In the present specification, the “main part of the oral solid preparation” refers to a portion other than the coating layer of the oral solid preparation.
When the oral solid preparation of the present invention is not coated, the oral solid preparation is composed of only the main body of the oral solid preparation. When the oral solid preparation of the present invention is coated, the oral solid preparation of the present invention is composed of an oral solid preparation main body and a coating layer. When the oral solid preparation of the present invention is a tablet, the "oral solid preparation main body" is also referred to as an "uncoated tablet". When the oral solid preparation of the present invention is an uncoated tablet, the oral solid preparation of the present invention is an "uncoated tablet" composed of only the uncoated tablet portion. When the oral solid preparation of the present invention is a coated tablet, the oral solid preparation of the present invention is a "coated tablet" composed of an uncoated tablet portion and a coating layer. In general, coating with sugar is called sugar coating, and coating with polymer is called film coating.

It is preferable that the main body of the oral solid preparation of the present invention is present in a state in which Compound A and hydroxypropyl cellulose and / or low-degree-of-substitution hydroxypropyl cellulose are in direct contact with each other.
The oral solid preparation of the present invention preferably contains sugar or sugar alcohol in the main body of the oral solid preparation. The oral solid preparation of the present invention preferably contains a binder in the main body of the oral solid preparation. The oral solid preparation of the present invention preferably contains one or more additives selected from the group consisting of excipients, lubricants, and disintegrants in the main body of the oral solid preparation. The oral solid preparation of the present invention preferably does not contain an oil additive in the main body of the oral solid preparation.

Compound A used in the present invention can be produced, for example, according to the method described in Patent Document 1. Compound A used in the present invention includes, for example, free forms, pharmacologically acceptable salts and hydrates thereof, and various crystalline or amorphous forms thereof can be used.
The amount of Compound A contained in the oral solid preparation of the present invention is not particularly limited. In one embodiment, the compound A is preferably contained in an amount of 0.1 to 0.5 mg, more preferably 0.1 mg or 0.5 mg, and most preferably 0.5 mg per unit preparation.

In general, hydroxypropyl cellulose and low-substituted hydroxypropyl cellulose are both hydroxypropyl ethers of cellulose, and when quantifying the dried product, hydroxypropyl cellulose contains 53.4 to 77.5% of hydroxypropoxyl groups (1 glucose residue). The number of substitution moles per group is 2.0 to 4.2), and low-substituted hydroxypropyl cellulose contains 5.0 to 16.0% of hydroxypropoxyl groups (0.11 to 0.39 in terms of the number of substitution moles per glucose residue). However, in the present invention, hydroxypropyl ether of cellulose containing 16.0 to 53.4% of hydroxypropoxyl group also corresponds to hydroxypropyl cellulose.
The content of hydroxypropyl cellulose and / or low-substituted hydroxypropyl cellulose is preferably 1 to 15%, more preferably 5 to 10%, based on the main body of the oral solid preparation. The mass ratio of hydroxypropyl cellulose and / or low degree of substitution hydroxypropyl cellulose to compound A is preferably hydroxypropyl cellulose and / or low degree of substitution hydroxypropyl cellulose: compound A = 2: 1 to 150: 1, preferably 15: 1 to 15. 110: 1 is more preferred.

The oral solid preparation of the present invention preferably contains sugar or sugar alcohol.
The sugar or sugar alcohol used in the present invention is not particularly limited, but is preferably one that is sparingly soluble in an organic solvent and easily soluble in water, for example, lactose (anhydrous lactose, lactose hydrate), maltose, mannitol, isomalt. , Maltose, glucose, trehalose, xylitol and the like, and lactose is more preferable, and lactose hydrate is more preferable. Examples of lactose hydrate include Lactochem (registered trademark) Fine Powder, Lactochem (registered trademark) Extra Fine Powder, Lactochem (registered trademark) Super Fine Powder, Pharmatose (registered trademark) 200M, Pharmatose (registered trademark) 350M, and Pharmatose. (Registered trademark) 400M (both manufactured by DFE Pharma) and the like can be used.
The content of sugar or sugar alcohol is preferably 50 to 80%, more preferably 60 to 80%, based on the main body of the oral solid preparation.

The present invention may contain a binder. Examples of the binder used in the present invention include one or more selected from hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, sodium carmellose, methyl cellulose and the like, and hydroxypropyl cellulose is preferable.
The content of the binder is preferably 0.5 to 5%, more preferably 0.5 to 2%, based on the mass of the main body of the oral solid preparation.

The present invention may contain excipients. Excipients used in the present invention include, for example, crystalline cellulose and / or microcrystalline cellulose; starches such as corn starch, potato starch and partially pregelatinized starch; calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate and the like. Phosphates: One or more selected from carbonates such as precipitated calcium carbonate, etc., preferably celluloses, more preferably crystalline celluloses. As the crystalline cellulose, for example, Theoras (registered trademark) PH grade (manufactured by Asahi Kasei Chemicals Co., Ltd.) can be used.
The content of the excipient is preferably 5% to 30%, more preferably 10 to 20% with respect to the main body of the oral solid preparation.

The oral solid preparation of the present invention may contain a lubricant. Examples of the lubricant used in the present invention include one or more selected from stearic acid, magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, light anhydrous silicic acid, sucrose fatty acid ester and the like. Therefore, magnesium stearate is preferable.
The content of the lubricant is preferably 0.1 to 3%, more preferably 0.5 to 1.5%, based on the main body of the oral solid preparation.

The oral solid preparation of the present invention may contain a disintegrant. Examples of the disintegrant used in the present invention include one or more selected from carboxymethyl cellulose, croscarmellose sodium, carmellose calcium, carboxymethyl starch sodium and the like.
The content of the disintegrant is preferably 1% to 20%, more preferably 1 to 10% with respect to the main body of the oral solid preparation.

The oral solid preparation of the present invention may contain additives usually used in oral solid preparations, preferably tablets, as long as the effects of the present invention are not impaired.
The blending amount of these additives is not particularly limited, and a necessary amount may be appropriately blended according to each purpose.

The main body of the oral solid preparation of the present invention preferably does not contain an oil additive. Oily additives include, for example, propylene glycol monocaprylate, diethylene glycol monoethyl ether and medium chain glycerides. Medium chain glycerides are esters of glycerin and saturated aliphatic carboxylic acids having 6 to 10 carbon atoms and are monoglycerides, diglycerides, triglycerides or mixtures thereof. Examples of the saturated aliphatic carboxylic acid having 6 to 10 carbon atoms include caproic acid, caprylic acid and capric acid.

Examples of the coating agent used in the present invention include one or more selected from sugars, polymer compounds, plasticizers, colorants, lubricants, brighteners and the like.
Examples of the sugar used in the coating agent include white sugar.
As the polymer compound used for the coating agent, for example, one or more selected from hypromellose, polyvinyl alcohol, polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer, polyvinyl alcohol / polyethylene glycol / graft copolymer and the like can be used. Hypromerose is preferred. As the hypromellose, for example, METOLOSE (registered trademark) SR, TC-5 (registered trademark) (both manufactured by Shin-Etsu Chemical Co., Ltd.) and the like can be used.
Examples of the plasticizer used for the coating agent include one or more selected from triacetin citrate, dibutyl phthalate, polyethylene glycol, triacetin, glycerol monocaprilka plate, lecithin, propylene glycol and the like, and polyethylene glycol is used. preferable.
Examples of the colorant used for the coating agent include one or more selected from titanium oxide, iron sesquioxide, yellow sesquioxide, edible yellow No. 4 and edible yellow No. 5.
Examples of the lubricant used as the coating agent include talc and the like.
Examples of the brightener used for coating include one or more selected from carnauba wax, beeswax, beeswax and the like.
The amount of the polymer compound, plasticizer, colorant, lubricant and brightener used in the coating agent is not particularly limited, and a necessary amount may be appropriately blended according to the purpose.

The oral solid preparation of the present invention may further contain one or more additional active ingredients. Active ingredients include, for example, α ₁ adrenergic receptor blockers such as tamsulosin, naphthopidyl, silodosin, terrazosin, alfzosin, doxazosin, urapidil and prazosin, pharmaceutically acceptable salts thereof, or mixtures thereof; vardenafil. , PDE5 (phosphodiesterase 5) inhibitors such as sildenafil and tadalafil, pharmaceutically acceptable salts thereof, or solvates thereof; pharmaceutically acceptable these such as anti-androgen agents such as chlormaginone and allylestrenol. Salts, or their solvates; muscarinic receptor antagonists such as solifenacin, imidafenacin, oxybutinin, fesoterosin, tortellodin, propiverine, these pharmaceutically acceptable salts, or solvates thereof; Silodosin derivatives such as caproic acid esters, pharmaceutically acceptable salts thereof, or solvates thereof; glutamate, alanine, aminoacetic acid and the like.

The mass of the oral solid preparation of the present invention is preferably less than 300 mg, more preferably less than 200 mg, still more preferably 100 to 180 mg, and most preferably 120 to 120 mg when the content of compound A per unit preparation is 0.1 to 0.5 mg. It is 150 mg.
When the oral solid preparation of the present invention is a round tablet containing 0.1 to 0.5 mg of compound A, the size of one tablet (unit preparation) is preferably 5.0 to 10.0 mm in diameter and 2.0 to 6.0 mm in thickness, more preferably. Is 5.0 to 7.9 mm in diameter and 2.0 to 5.0 mm in thickness, most preferably 6.0 to 7.5 mm in diameter and 2.5 to 3.5 mm in thickness. Examples of round tablets include disc-shaped tablets having upper and lower surfaces on flat plates, and go-stone-shaped tablets having rounded upper and lower surfaces and protruding.
When the oral solid preparation of the present invention is an oval tablet containing 0.1 to 0.5 mg of compound A, it is preferable that the sum of the major axis and the minor axis is less than 20 mm and the thickness is 6 mm or less. More preferably, the sum of the major axis and the minor axis is less than 16 mm and the thickness is 5 mm or less, and most preferably the sum of the major axis and the minor axis is 15 mm or less and the thickness is 3.5 mm or less. ..

The method for producing an oral solid preparation of the present invention includes the following steps 1 to 3.
(1) Step 1 of preparing a solution, suspension or powder containing hydroxypropyl cellulose and / or low degree of substitution hydroxypropyl cellulose.
(2) Step 2 of preparing a compound A solution by dissolving compound A in an organic solvent.
(3) Step 3 of mixing or granulating the solution, suspension or powder prepared in step 1 with the compound A solution prepared in step 2 to obtain a mixture or granules.

The method for producing an oral solid preparation of the present invention may include one or more of the following steps 4 to 6 in addition to the above steps 1 to 3, if necessary.
(4) Step 4 of adding a solution of a binder to the mixture or granulated product obtained in step 3 and granulating to obtain a granulated product.
(5) Step 5 of removing the organic solvent from the mixture or granulated product obtained in step 3 or the granulated product obtained in step 4.
(6) One or two selected from the group consisting of excipients, lubricants, and disintegrants in the mixture or granules obtained in step 3 or step 5 or the granules obtained in step 4. Step 6 of adding the above additives and tableting. In addition, one kind or two or more kinds of additional active ingredients may be added together with the said additive.

Further, the method for producing an oral solid preparation of the present invention may include (7) a step 7 of coating the tableted product obtained in step 6 with a coating agent, if necessary.
In the production method of the present invention, it is preferable that the solution, suspension or powder containing hydroxypropyl cellulose and / or low degree of substitution hydroxypropyl cellulose contains sugar or sugar alcohol in step 1.

As used herein, "mixing" means mixing raw materials such as solutions, suspensions, powders or lumps, and includes dissolution, dispersion, mixing, kneading, kneading and the like.
As used herein, "granulation" means producing grains having a substantially uniform shape and size from raw materials such as solutions, suspensions, powders or lumps.

Examples of the granulation method include agitation granulation method, rolling granulation method, extrusion granulation method, kneading granulation method, spray granulation method, fluidized bed granulation method and rolling fluidized bed granulation method. The stirring granulation method is preferable.

Examples of the method for removing the organic solvent include vacuum drying, freeze drying, ventilation drying, spray drying and the like, and ventilation drying is preferable. The drying temperature can be, for example, 60 ° C.
It is preferable that the oral solid preparation of the present invention contains substantially no organic solvent.

Examples of the organic solvent used in the present invention include one or more selected from alcohols having 1 to 4 carbon atoms, alkyl ketones, esters, ethers and the like, and alcohols having 1 to 4 carbon atoms are preferable. Ethanol is more preferred.
Examples of alcohols having 1 to 4 carbon atoms include ethanol, propanol, 2-propanol, butanol, 2-butanol and the like.
Examples of the alkyl ketone include acetone, methyl ethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone and the like.
Examples of the ester include ethyl formate, ethyl acetate and butyl acetate.
Examples of the ether include t-butyl methyl ether and the like.
The organic solvent may be used alone or as a mixed solvent with water. When a mixed solvent of an organic solvent and water is used, the content of water with respect to the mixed solvent is not particularly limited as long as it can completely dissolve the compound A and does not hinder the removal of the solvent. For example, it is preferably 50% or less, more preferably 30% or less, and even more preferably 20% or less.
The amount of the organic solvent used in the present invention is not particularly limited, but the mass ratio of compound A to the organic solvent is 1: 1 to 100, preferably 1: 5 to 50, and more preferably 1: 15 to 40. Is.

The oral solid preparation produced by the above-mentioned production method has a small total mass per unit preparation, and has sufficient bioavailability as a pharmaceutical product.

The oral solid preparation of the present invention is preferably contained in an airtight container or a sealed container.
An airtight container is a container that can prevent solid or liquid foreign matter from entering and prevent loss, efflorescence, deliquescent or evaporation of the contents of the drug under normal handling, transportation or storage conditions. As the airtight container, a material and a shape having high moisture resistance are preferable under normal handling, transportation or storage state. It is more preferable to enclose a desiccant or the like in the airtight container. A sealed container is a container that does not allow gas to enter under normal handling, transportation, or storage conditions.
When the oral solid preparation is a tablet, it is preferably contained in a PTP package or a polyethylene bottle package which is an airtight container. The PTP packaging may be further sealed with a moisture-proof material such as an aluminum laminated film and an aluminum vapor-deposited film for secondary packaging.

The usefulness of the oral solid preparation of the present invention will be described in the following Test Examples and Examples, but the present invention is not limited thereto.

Example 1
9.72 kg of lactose hydrate and 1 kg of low-degree-of-substitution hydroxypropyl cellulose were mixed, and a solution of Compound A in which 50 g of Compound A was dissolved in absolute ethanol was added and mixed to obtain a mixture. A solution prepared by dissolving 100 g of hydroxypropyl cellulose in 1900 g of purified water was added to the mixture and granulated to obtain a granulated product. After drying this granulated product, 2 kg of crystalline cellulose and 130 g of magnesium stearate were mixed, and then a tablet (130 mg per tablet) having a diameter of 7 mm was obtained. The obtained uncoated tablets showed a hardness of 61.7 N.
Next, the obtained uncoated tablets were coated with a coating agent (hypromellose 480 g, titanium oxide 48 g, talc 24 g, macrogol 6000 48 g and a small amount of yellow sesquioxide), and polished with a small amount of carnauba wax, 135 mg per tablet. A film-coated tablet (containing 0.5 mg of compound A) having a diameter of 7 mm and a thickness of 3 mm was obtained.
The obtained film-coated tablet was a preparation having a smaller mass and size than a soft gelatin capsule containing 0.5 mg of compound A (1 capsule 599 mg, total length 19.3 mm, thickness 6.6 mm).

Test Example 1
The film-coated lock of Example 1 was used as the test preparation. As a standard preparation, a soft gelatin capsule containing 0.5 mg of compound A (manufacturer and distributor of GlaxoSmithKline Co., Ltd.), which is commercially available as a therapeutic agent for benign prostatic hyperplasia, was used.
The bioequivalence test was conducted on 75 healthy Japanese adult males, "Regarding partial revision of the bioequivalence test guidelines for generic drugs" (February 29, 2012, Pharmaceutical and Food Safety Examination) 0229 No. 10) Attachment 4 Bioequivalence test guidelines for the addition of preparations with different dosage forms ”was carried out by the crossover method. One tablet of the test formulation or one capsule of the standard formulation was orally administered to a fasting subject together with water, the concentration of compound A in plasma was measured, the pharmacokinetic parameters (AUCt and Cmax) were determined, and the 90% confidence interval method was used. Statistical analysis was performed. The transition of the concentration of compound A in plasma is shown in FIG. The results of the statistical analysis are shown in Table 1.

The obtained pharmacokinetic parameters (AUC, Cmax) were statistically analyzed by the 90% confidence interval method and found to be in the range of log (0.8) to log (1.25), and the test preparations were standard preparations and biological ones. Was shown to be equivalent to.
From these results, it was confirmed that the film-coated tablet of Example 1 has sufficient bioavailability of Compound A.

Claims (14)

N- (2,5-bis (trifluoromethyl) phenyl) -3-oxo-4-aza-5α-androsta-1-ene-17β-carboxamide, and hydroxypropyl cellulose and / or low degree of substitution hydroxypropyl An oral solid preparation containing cellulose, which contains commercially available N- (2,5-bis (trifluoromethyl) phenyl) -3-oxo-4-aza-5α-androsta-1-ene-17β-carboxamide. An oral solid preparation that is bioequivalent to soft gelatin capsules. The oral solid preparation according to claim 1, wherein the mass of the oral solid preparation is less than 200 mg per unit preparation. The oral solid preparation according to claim 1 or 2, which does not contain one or more oily additives selected from propylene glycol monocaprylate, diethylene glycol monoethyl ether and medium chain glyceride. N- (2,5-bis (trifluoromethyl) phenyl) -3-oxo-4-aza-5α-androsta-1-ene-17β-carboxamide was dissolved in an organic solvent and hydroxypropyl cellulose and / or low The oral solid preparation according to any one of claims 1 to 3, which is obtained by mixing or granulating with degree of substitution hydroxypropyl cellulose. The oral solid preparation according to any one of claims 1 to 4, wherein the oral solid preparation contains sugar or sugar alcohol. The oral solid preparation according to any one of claims 1 to 5, wherein the oral solid preparation is a tablet. A method for producing an oral solid preparation,
(1) Step 1 of preparing a solution, suspension or powder containing hydroxypropyl cellulose and / or low degree of substitution hydroxypropyl cellulose 1.
(2) N- (2,5-bis (trifluoromethyl) phenyl) -3-oxo-4-aza-5α-androsta-1-ene-17β-carboxamide was dissolved in an organic solvent to dissolve N- (2). , 5-Bis (trifluoromethyl) phenyl) -3-oxo-4-aza-5α-androsta-1-ene-17β-carboxamide solution 2.
(3) N- (2,5-bis (trifluoromethyl) phenyl) -3-oxo-4-aza-5α-androsta prepared in step 2 of the solution, suspension or powder prepared in step 1. Step 3, to obtain a mixture or granules by mixing or granulating with a -1-ene-17β-carboxamide solution.
Manufacturing method including. The method for manufacturing oral solid preparations is
(4) Including step 4 of adding a solution of a binder to the mixture or granulated product obtained in step 3 and granulating to obtain a granulated product.
The manufacturing method according to claim 7. The method for manufacturing oral solid preparations is
(5) Step 5 of removing the organic solvent from the mixture or granulated product obtained in step 3 or the granulated product obtained in step 4.
7. The manufacturing method according to claim 7 or 8. The method for manufacturing oral solid preparations is
(6) One or two selected from the group consisting of excipients, lubricants, and disintegrants in the mixture or granules obtained in step 3 or step 5 or the granules obtained in step 4. Including step 6 of adding the above additives and tableting.
The manufacturing method according to any one of claims 7 to 9. The production method according to any one of claims 7 to 10, wherein the solution, suspension or powder containing hydroxypropyl cellulose and / or low degree of substitution hydroxypropyl cellulose contains sugar or sugar alcohol. The production method according to any one of claims 7 to 11, wherein the organic solvent is ethanol. An oral solid preparation produced by the production method according to any one of claims 7 to 12. The oral solid preparation according to claim 13, wherein the oral solid preparation is a tablet.

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