JP2015193611A - stable solid pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a stable solid pharmaceutical composition which contains 4-({[(3S,4S)-3-({[(1R)-1-(1-naphthyl) ethyl] amino} methyl)-4-phenylpyrrolidine-1-yl] carbonyl} oxy) benzoic acid (compound A) or a pharmaceutically acceptable salt thereof, and in which production of analogues during storage is inhibited.SOLUTION: The granular pharmaceutical composition contains a compound A or a pharmaceutically acceptable salt thereof, and is coated with a film coating layer.

Description

  The present invention relates to 4-({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl] amino} methyl) -4-phenylpyrrolidin-1-yl] carbonyl} oxy ) It relates to a stable solid pharmaceutical composition comprising benzoic acid or a pharmaceutically acceptable salt thereof and film-coated with a film coating layer.

で表される４−（｛［（３Ｓ，４Ｓ）−３−（｛［（１Ｒ）−１−（１−ナフチル）エチル］アミノ｝メチル）−４−フェニルピロリジン−１−イル］カルボニル｝オキシ）安息香酸（以下、化合物Ａと略すことがある）又はその製薬学的に許容される塩は、カルシウム感知受容体（Ｃａｌｃｉｕｍ ｓｅｎｓｉｎｇ ｒｅｃｅｐｔｏｒ；ＣａＳＲ）調節作用を有し、副甲状腺機能亢進症、二次性副甲状腺機能亢進症、腎性骨異栄養症、高カルシウム血症の治療剤の有効成分として有用であることが知られている（特許文献１）。 The following structural formula:

4-({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl] amino} methyl) -4-phenylpyrrolidin-1-yl] carbonyl} oxy represented by ) Benzoic acid (hereinafter sometimes abbreviated as Compound A) or a pharmaceutically acceptable salt thereof has a calcium sensing receptor (CaSR) modulatory action, and has hyperparathyroidism. It is known to be useful as an active ingredient of a therapeutic agent for secondary hyperparathyroidism, renal osteodystrophy and hypercalcemia (Patent Document 1).

  The active ingredient is usually used in the medical field as various pharmaceutical preparations. For example, pharmaceutical preparations such as tablets are made into plain tablets in consideration of stabilization, taste-masking, flavoring, etc. of the active ingredients. The film coating layer is often film coated.

On the other hand, from the viewpoint of patient safety, it is desirable to suppress the generation of related substances during storage.
For example, on June 24, 2003, the Ministry of Health, Labor and Welfare has published a standard on formulation, that is, a concept regarding related substances (impurities) in the formulation that are recognized in the stability test (Pharmaceutical Appeal No. 0624001 “ Revision of guidelines on drug impurities among drugs containing new active ingredients "). According to the revised guidelines, in the case of a drug substance with a daily dose of less than 10 mg, the threshold value of the related substance in the drug product that requires safety confirmation is the related substance contained in the drug substance. Percentage of 1.0% or the total daily intake of related substances is defined as 50 μg, whichever is lower.
Therefore, it is useful to provide a stable pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof that suppresses the formation of related substances during storage.

International Publication WO2006 / 123725 Pamphlet

  The subject of this invention is providing the stable solid pharmaceutical composition containing the compound A or its pharmaceutically acceptable salt which suppressed the production | generation of the related substance during a preservation | save.

Compound A hydrochloride itself is stable to heat and light, and no significant increase in related substances was observed even under certain storage conditions such as harsh testing of pharmaceuticals.
Based on the information regarding the stability of the compound hydrochloride, in providing a pharmaceutical composition containing the compound A hydrochloride, the present inventors have applied a film to the pharmaceutical composition (uncoated tablet) containing the compound A hydrochloride. When a film coating layer containing hypromellose as a coating base and polyethylene glycol as a plasticizer was film-coated, the related substances (for example, diastereomer of Compound A) increased after storage (Comparative Example 1 and Comparative Example described later) Example 2) was found.

Therefore, as a result of intensive studies to suppress the generation of related substances during storage, the present inventors can suppress the generation of diastereomers of compound A during storage by not incorporating polyethylene glycol into the film coating layer. Furthermore, it was found that not only the diastereomer of Compound A but also the production of other related substances can be suppressed.
Furthermore, the present invention was completed by discovering that a pharmaceutical composition in which discoloration of the film coating layer can be suppressed can be provided by blending triacetin as a plasticizer in the film coating layer.

  In addition, as a technique which improved the stability by film-coating a film coating layer substantially free of polyethylene glycol on a solid pharmaceutical composition, JP 2011-236188 A and JP 2011-162531 A As a technique for suppressing discoloration of the film coating layer, Japanese Patent Application Laid-Open No. 2004-51506 is known, but all relate to a specific active ingredient.

The present invention
[1] 4-({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl] amino} methyl) -4-phenylpyrrolidin-1-yl] carbonyl} oxy) A stable solid pharmaceutical composition comprising benzoic acid or a pharmaceutically acceptable salt thereof and film-coated with a film coating layer;
[2] The pharmaceutically acceptable salt is 4-({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl] amino} methyl) -4- A solid pharmaceutical composition of [1], which is phenylpyrrolidin-1-yl] carbonyl} oxy) benzoic acid hydrochloride,
[3] The solid pharmaceutical composition according to [1] or [2], wherein the film coating layer contains substantially no polyethylene glycol,
[4] The solid pharmaceutical composition according to any one of [1] to [3], comprising triacetin in the film coating layer,
[5] The solid pharmaceutical composition of [4], wherein the blending ratio of triacetin is about 0.01 wt% to about 10 wt% with respect to the weight of the solid pharmaceutical composition,
[6] The solid pharmaceutical composition according to any one of [1] to [5], wherein the solid pharmaceutical composition is a tablet,
[7] 4-({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl] amino} methyl) -4-phenylpyrrolidin-1-yl] carbonyl} oxy) A method for producing a stable solid pharmaceutical composition, comprising film-coating a composition containing benzoic acid or a pharmaceutically acceptable salt thereof with a film coating layer;
[8] 4-({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl] amino} methyl)-, characterized in that the film coating layer is film-coated. 4-phenylpyrrolidin-1-yl] carbonyl} oxy) benzoic acid or a pharmaceutically acceptable salt thereof, a method for stabilizing a solid pharmaceutical composition,
About.

ADVANTAGE OF THE INVENTION According to this invention, the stable solid pharmaceutical composition containing the compound A or its pharmaceutically acceptable salt which suppressed the production | generation of the related substance during a preservation | save can be provided.
Moreover, according to this invention, the stable solid pharmaceutical composition containing the compound A or its pharmaceutically acceptable salt which suppressed discoloration of the film coating layer can be provided.

  In the present specification, “stable” means stable to heat, light, temperature, and / or humidity, for example. For example, after storing a solid pharmaceutical composition under the following conditions, the related substance of Compound A contained in the solid pharmaceutical composition is defined as an embodiment having a specific percentage or less. For example, the pharmaceutical composition is 70 ° C. for 9 days, in one embodiment at 40 ° C. and relative humidity 75% (hereinafter sometimes abbreviated as% RH) for 6 months, and in another embodiment at 40 ° C. and 75% RH 3 1 month at 40 ° C./75% RH, 12 months at 25 ° C./60% RH, 6 months at 25 ° C./60% RH, yet another embodiment As 25 ° C./60% RH for 3 months, and as another embodiment, measured at 25 ° C./60% RH for 1 month after storage, by high performance liquid chromatography (hereinafter sometimes abbreviated as HPLC method), The percentage of diastereomers of Compound A in the solid pharmaceutical composition is, for example, 1.0% or less, 0.8% or less in some embodiments, 0.6% or less in other embodiments, and 0.4% in another embodiment. % In a solid pharmaceutical composition The percentage of the other largest related substance of A is, for example, 1.0% or less, 0.8% or less as one embodiment, 0.6% or less as another embodiment, and 0.4% or less as another embodiment. It prescribes.

  More specifically, for example, after storage at 70 ° C. for 9 days, the percentage of the diastereomer of Compound A in the solid pharmaceutical composition measured by HPLC is, for example, 1.0% or less, and 0 as an embodiment. 0.8% or less, 0.6% or less in another embodiment, 0.4% or less in another embodiment, and the percentage of the other largest analog of Compound A in the solid pharmaceutical composition is, for example, 1.0 %, 0.8% or less as one embodiment, 0.6% or less as another embodiment, and 0.4% or less as another embodiment.

  As a certain aspect, the percentage of the diastereomer of the compound A in the solid pharmaceutical composition measured by HPLC method after storage at 40 ° C. and 75% RH for one month is, for example, 1.0% or less. 0.8% or less as another embodiment, 0.6% or less as another embodiment, 0.4% or less as another embodiment, and the percentage of the other largest analog of Compound A in the solid pharmaceutical composition is, for example, 1 0.0% or less, 0.8% or less as one embodiment, 0.6% or less as another embodiment, and 0.4% or less as another embodiment.

  In another embodiment, the percentage of the diastereomer of Compound A in the solid pharmaceutical composition measured by HPLC after storage at 25 ° C. and 60% RH for one month is, for example, 1.0% or less. 0.8% or less as an aspect, 0.6% or less as another aspect, 0.4% or less as another aspect, and the percentage of the largest other related substance of Compound A in the solid pharmaceutical composition is, for example, It is defined as 1.0% or less, 0.8% or less as one embodiment, 0.6% or less as another embodiment, and 0.4% or less as another embodiment.

  In the present specification, the “diastereomer of Compound A” means a stereoisomer of Compound A that is not an enantiomer. More specifically, for example, when a related substance is measured by the HPLC method described later, it is defined that the relative retention time with respect to the peak of Compound A is about 0.91.

  In the present specification, the “other largest related substance” refers to a related substance of Compound A (relative to the peak of Compound A) when the related substance is measured by, for example, the HPLC method described later. Means a substance having the largest peak area among those having a retention time of about 0.91).

  In the present specification, the “percentage of diastereomers of compound A” or “percentage of other largest related substances” is specifically determined by measuring the related substances contained in the solid pharmaceutical composition by the HPLC method. And the percentage of each peak area relative to the total peak area of the related substance.

As used herein, “discoloration” means that when a solid pharmaceutical composition is exposed to light, the color of the film coating layer has changed compared to before exposure. Specifically, for example, when measuring using a color difference meter (CR-5, Konica Minolta Co., Ltd.), the color difference (ΔE ^* ) of the sample after irradiation with a D65 lamp for 50 days (total illuminance: 1.2 million lux · hr) ab) is defined to be, for example, greater than 7.0, greater than 5.0 in some embodiments, and greater than 3.0 in other embodiments as compared to before storage.

As used herein, “inhibition of discoloration” means that when a solid pharmaceutical composition is exposed to light, the color of the film coating layer is not changed by visual observation compared to before exposure. . Further, “inhibition of discoloration” can be expressed as a measured value using a color difference meter as a certain numerical value or less. Specifically, for example, when measuring using a color difference meter (CR-5, Konica Minolta Co., Ltd.), the color difference (ΔE ^* ) of the sample after irradiation with a D65 lamp for 50 days (total illuminance: 1.2 million lux · hr) For example, it is specified that ab) is 7.0 or less, that is, 5.0 or less as one embodiment, and 3.0 or less as another embodiment.

  The solid pharmaceutical composition of the present invention will be described in detail below.

The compound A or a pharmaceutically acceptable salt thereof used in the present invention can be easily obtained by, for example, the method described in Patent Document 1, the method obvious to those skilled in the art, or a modified method thereof.
Compound A may form an acid addition salt or a salt with a base. Such salts are pharmaceutically acceptable salts such as acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, formic acid, acetic acid, propionic acid, Acid addition salts with organic acids such as oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, ethanesulfonic acid, aspartic acid, glutamic acid, salts with inorganic bases such as sodium, magnesium, calcium, aluminum, methylamine, A salt with an organic base such as ethylamine, ethanolamine, lysine, ornithine, an ammonium salt, and the like can be given. As an embodiment, a hydrochloride can be given.

  Furthermore, the compound A or a pharmaceutically acceptable salt thereof includes various hydrates, solvates, or crystalline polymorphs of the compound A described above or a pharmaceutically acceptable salt thereof. . Compound A or a pharmaceutically acceptable salt thereof can be used alone or in combination.

  Compound A or a pharmaceutically acceptable salt thereof has a CaSR regulating action and is a therapeutic agent for hyperparathyroidism, secondary hyperparathyroidism, renal osteodystrophy, hypercalcemia Can be used as

The dose (dose) of Compound A or a pharmaceutically acceptable salt thereof is appropriately determined according to individual cases in consideration of the administration route, disease symptoms, age, race, sex, etc. of the administration subject. be able to.
In the case of oral administration, it is about 0.001 mg / kg to 100 mg / kg per day for an adult, and this can be administered once or divided into 2 to 4 times. In addition, in the case of intravenous administration, it can usually be administered once to a plurality of times per day in the range of 0.0001 mg / kg to 10 mg / kg per adult. In the case of nasal administration, it can be administered once to a plurality of times a day in the range of 0.0001 mg / kg to 10 mg / kg per adult. Moreover, in the case of inhalation, it can be usually administered once to several times a day in the range of 0.0001 mg / kg to 1 mg / kg per adult.

The compounding amount of Compound A or a pharmaceutically acceptable salt thereof is, for example, from about 0.001 mg to about 1000 mg, in some embodiments from about 0.01 mg to about 100 mg, in other embodiments, per solid pharmaceutical composition of the present invention. About 0.1 mg to about 10 mg.
The compounding ratio of Compound A or a pharmaceutically acceptable salt thereof is, for example, from about 0.001% by weight to about 90% by weight with respect to the weight of the solid pharmaceutical composition of the present invention. 01 wt% to about 50 wt%, in another embodiment about 0.01 wt% to about 20 wt%, in another embodiment about 0.01 wt% to about 10 wt%, and in yet another embodiment about 0.01 % By weight to about 5% by weight.

  As a film coating layer to be film-coated on a pharmaceutical composition containing Compound A or a pharmaceutically acceptable salt thereof, the solid pharmaceutical composition of the present invention is film-coated, and Compound A or a pharmaceutically acceptable salt thereof. There is no particular limitation as long as it does not affect the stabilization of the salt produced.

Here, the base (film coating base) for forming the film coating layer includes those that do not affect the stabilization of Compound A or a pharmaceutically acceptable salt thereof. Specifically, for example, those that suppress the production of a compound A or a pharmaceutically acceptable salt analog (for example, a diastereomer of compound A and / or the largest analog). .
Specific examples of the film coating base include hypromellose, polyvinyl alcohol, polyvinyl alcohol copolymer, polyvinyl pyrrolidone, and the like, and hypromellose can be given as an embodiment.

The blending ratio of the film coating base includes the amount by which the film coating layer is formed with respect to the solid pharmaceutical composition of the present invention.
Specifically, the blending ratio of the film coating base is, for example, about 0.1 wt% to about 10 wt%, and in one embodiment about 0.5 wt% with respect to the weight of the solid pharmaceutical composition of the present invention. To about 5% by weight, and in another embodiment from about 1% to about 3% by weight. The blending ratio of the film coating base is, for example, from about 30% to about 80% by weight, and in some embodiments, from about 50% to about 70% by weight with respect to the weight of the film coating layer.

A plasticizer (however, excluding polyethylene glycol) can be further blended in the film coating layer. As the plasticizer, triacetin can be blended as an embodiment. Triacetin is also known as triacetylglycerol, 1,2,3-propanetriol triacetate, glyceryl triacetate, triacetylglycerin and the like.
Triacetin includes those that conform to Japanese Pharmaceutical Additives Standards, US Pharmacopoeia, European Pharmacopoeia and the like. Specific examples include triacetin (organic synthetic chemical industry).

The blending amount of triacetin includes an amount capable of suppressing discoloration of the film coating layer in the film coating layer. For example, per solid pharmaceutical composition of the present invention, for example, from about 0.001 mg to about 10 mg, in some embodiments from about 0.01 mg to about 5 mg, and in another embodiment from about 0.1 mg to about 1 mg.
The blending ratio of triacetin includes a ratio capable of suppressing discoloration of the film coating layer in the film coating layer. Specifically, for example, for example, about 0.01 wt% to about 10 wt%, and in some embodiments, about 0.01 wt% to about 5 wt%, etc., relative to the weight of the solid pharmaceutical composition of the present invention In another embodiment, it is about 0.01 wt% to about 1 wt%, and in another embodiment about 0.1 wt% to about 1 wt%. Further, specifically, for example, from about 1% by weight to about 50% by weight, in some embodiments from about 1% by weight to about 30% by weight, and in other embodiments from about 1% by weight to the weight of the film coating layer. About 20% by weight, in another embodiment from about 5% to about 15% by weight.

A colorant etc. can be further mix | blended with a film coating layer.
Examples of the colorant include those capable of imparting distinctiveness to the solid pharmaceutical composition of the present invention. Specifically, for example, yellow iron sesquioxide, iron sesquioxide, black iron oxide, titanium oxide, talc, edible yellow No. 4, No. 5, edible red No. 3, No. 102, edible blue No. 3, etc. it can. As a certain aspect, they are yellow ferric oxide, ferric oxide, titanium oxide, and talc. One or more colorants can be used in appropriate combination.
The blending ratio of the colorant includes a ratio capable of imparting discrimination to the solid pharmaceutical composition of the present invention. Specifically, for example, from about 1 wt% to about 50 wt%, in some embodiments from about 5 wt% to about 50 wt%, and in other embodiments from about 10 wt% to about 50 wt%, based on the weight of the film coating layer. % By weight, in another embodiment from about 20% to about 50% by weight.

  The solid pharmaceutical composition of the present invention includes, for example, tablets, capsules, granules, powders, fine granules and the like, and includes tablets as a certain embodiment. In the solid pharmaceutical composition of the present invention, various pharmaceutical additives can be appropriately used and formulated as desired. Such pharmaceutical additives are not particularly limited as long as they are pharmaceutically acceptable and pharmacologically acceptable, and examples thereof include excipients, disintegrants, taste-masking agents, foaming agents, sweeteners, and flavors. , Lubricants, buffers, antioxidants, surfactants, fluidizing agents, binders and the like.

  Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silica Examples thereof include acid, synthetic aluminum silicate, magnesium aluminate metasilicate, and the like.

  Examples of the disintegrant include corn starch, potato starch, carmellose calcium, carmellose sodium, and low-substituted hydroxypropylcellulose.

  Examples of the corrigent include citric acid, tartaric acid, malic acid and the like.

  Examples of the foaming agent include baking soda.

  Examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, thaumatin and the like.

  As a fragrance | flavor, lemon, lemon lime, orange, menthol etc. can be mentioned, for example.

  Examples of the lubricant include magnesium stearate and calcium stearate.

  Examples of the buffer include citric acid, succinic acid, fumaric acid, tartaric acid, ascorbic acid or salts thereof, glutamic acid, glutamine, glycine, aspartic acid, alanine, arginine or salts thereof, magnesium oxide, zinc oxide, magnesium hydroxide, Examples thereof include phosphoric acid, boric acid or salts thereof.

  Examples of the antioxidant include ascorbic acid, dibutylhydroxytoluene, propyl gallate and the like.

  Examples of the surfactant include polysorbate 80, sodium lauryl sulfate, polyoxyethylene hydrogenated castor oil, and the like.

  Examples of the fluidizing agent include light anhydrous silicic acid.

  Examples of the binder include gum arabic, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose and the like.

  These pharmaceutical additives can be appropriately added in an appropriate amount by one or a combination of two or more if desired.

  About the solid pharmaceutical composition of this invention, the aspect which shields light from a pharmaceutical composition by use of a packaging material is also employable. Specifically, for example, a pharmaceutical composition in which a film coating layer not containing triacetin is film-coated is provided as a pharmaceutical composition in which production of related substances is suppressed by adopting the packaging mode. Can do.

Next, the manufacturing method of the solid pharmaceutical composition of this invention is demonstrated below.
The solid pharmaceutical composition of the present invention can be produced by a known method including steps such as pulverization, mixing, granulation, drying, molding (tableting), and film coating.

As a method of pulverizing in the pulverizing step, a method that can pulverize each component pharmaceutically can be used. As the device, for example, a hammer mill, a ball mill, a jet mill, a pin mill, or the like can be used.

As a method of mixing in the mixing step, a method in which each component can be uniformly mixed usually pharmaceutically can be used. As the apparatus, for example, a V-type mixer, a ribbon-type mixer, a container mixer, a high-speed stirring mixer, or the like can be used.

As a granulation method, a pharmaceutically granulating method can be used. Examples of the apparatus include a fluidized bed granulator, a melt stirring granulator, a high speed stirring granulator, a crushing (pulverizing) granulator, an extrusion granulator, a rolling fluidized bed granulator, and a spray granulator. , A dry granulator, a twin screw extruder, etc. can be used, a fluidized bed granulator, a high-speed agitation granulator can be used as one embodiment, and a fluidized bed granulator can be used as another embodiment. be able to.

  The binder liquid can be prepared by dissolving or dispersing a desired binder in a solvent such as purified water, ethanol, or methanol. The binder may be put into a granulator in a powder state and granulated while adding purified water, ethanol, methanol or the like.

As a method for drying in the drying step, a method that can be usually pharmaceutically dried can be used. As the apparatus, for example, an air dryer, a vacuum dryer, a vacuum dryer, a fluidized bed dryer or the like can be used.
After drying, sieving and sizing may be performed with a sieve, a comil or the like.

As a method for forming the forming step, a method that can be usually formed pharmaceutically can be used. As the apparatus, for example, a rotary tableting machine, a single tableting machine, an oil press or the like can be used. In the molding process, a granulated product or a method of compressing a granulated product or a mixture of various pharmaceutical additives such as a lubricant into the granulated product to form a tablet can be used. Alternatively, a direct compression method may be used in which a tablet is obtained by compression molding after mixing a drug and an appropriate pharmaceutical additive.

Film Coating Process As a film coating method, a pharmaceutically film coating method can be usually used. As an apparatus, a pan coating machine, a fluidized bed coating machine, etc. can be used, for example.

  In the film coating step, film coating can be performed on the tablet obtained through the molding step or the granulated product (powder) obtained through the granulation step. Film-coated tablets can be provided as film-coated tablets of pharmaceutical formulations, and film-coated granules (powder) can be provided as film-coated granules, film-coated powders, or film-coated fine granules. . Alternatively, a film-coated tablet, a film-coated granule, a film-coated powder, or a film-coated fine granule can be provided as a pharmaceutical preparation as a capsule after being filled in a capsule. Examples of the material of the capsule include gelatin and hypromellose.

  You may dry after film coating. As a method, a pharmaceutically dry method can be used. As an apparatus, a pan coating machine, a fluidized bed coating machine, etc. can be used, for example. The drying conditions are not particularly limited as long as they are appropriately set in consideration of, for example, the stability of the preparation.

<Reference example>

  4-({[(3R, 4S) -3-({(tert-butoxycarbonyl) [(1R) -1- (1-naphthyl) ethyl] amino} methyl) -4-phenylpyrrolidin-1-yl] carbonyl } Oxy) 1.05 g of benzoic acid was dissolved in 10 mL of 4 mol / L hydrogen chloride / 1,4-dioxane solution and stirred at room temperature for 1 hour, and then the reaction solution was concentrated under reduced pressure. In order to remove excess hydrogen chloride, the residue was dissolved in chloroform and concentrated again under reduced pressure. The obtained residue was dissolved in 50 mL of tetrahydrofuran (THF), further diluted with 100 mL of toluene, and concentrated under reduced pressure. Toluene was added to the precipitated solid to form a suspension, and the solid was collected by filtration. The operation of obtaining a solid from the THF-toluene solution was further repeated twice on the obtained solid as a crude product 4-({[(3S, 4S) -3-({[(1R) -1- (1- Naphthyl) ethyl] amino} methyl) -4-phenylpyrrolidin-1-yl] carbonyl} oxy) benzoic acid hydrochloride 784 mg was obtained. The target product attached to the container or the like was recovered by washing with THF and chloroform, and 4-({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl]] was obtained as a crude product. 90 mg of amino} methyl) -4-phenylpyrrolidin-1-yl] carbonyl} oxy) benzoic acid hydrochloride was obtained.

First, 4-({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl] amino} methyl) -4-phenylpyrrolidin-1-yl] carbonyl} oxy) benzoic acid Crystallization conditions were examined using 5 mg each of the crude hydrochloride product.
<Condition A> Acetonitrile (1.0 mL) was added.
<Condition B> 1% water-acetonitrile (1.0 mL) was added.
<Condition C> After adding THF (1.0 mL), the mixture was heated to an oil bath temperature of 120 ° C. and dried.

  After suspending the residue of <Condition C> by adding 5 mL of THF, this suspension was recovered from <Condition A> and <Condition B> 4-({[(3S, 4S) -3-({[ (1R) -1- (1-Naphtyl) ethyl] amino} methyl) -4-phenylpyrrolidin-1-yl] carbonyl} oxy) benzoic acid hydrochloride crude product and 4-step obtained in the previous step ({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl] amino} methyl) -4-phenylpyrrolidin-1-yl] carbonyl} oxy) benzoic acid hydrochloride The crude product mixture was added to 595 mg. The mixture was stirred for 10 minutes with heating under reflux, and then 45 mL of toluene was gradually added. The mixture was stirred with heating under reflux for 20 minutes and then cooled to room temperature. The mixture was stirred for 30 minutes under ice cooling, and the precipitated crystals were collected by filtration and washed with a cooled THF-toluene mixed solvent (1: 9). It was dried at 60 ° C. under reduced pressure, and 4-({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl] amino} methyl) -4-phenylpyrrolidine as white crystals. -1-yl] carbonyl} oxy) benzoic acid hydrochloride (Compound A hydrochloride) was obtained in an amount of 484 mg.

Table 1 shows the physicochemical data of Compound A hydrochloride (MS: mass spectrometry, FAB +: m / z value in mass spectrometry (ionization method FAB, (M + H) ⁺ ) and NMR ( ¹ H− in DMSO-d ₆ ). NMR peak δ (ppm) is shown.

Next, powder X-ray diffraction measurement of Compound A hydrochloride was performed. Measurement Powder X-ray diffraction was measured using MXP18TAHF22 manufactured by MAC Science (currently Bruker). Radiation source: Cu, wavelength: 1.54056 mm, measurement diffraction angle range (2θ): 3 to 40 °, sampling interval: 0.02 °, scanning speed: 3 ° / min, tube voltage: 40 kV, tube current: 200 mA, The measurement was performed under the conditions of divergence slit: 1.00 deg, scattering slit: 1.00 deg, light receiving slit: 0.15 mm, and handling of the apparatus including data processing was in accordance with the method and procedure instructed by the apparatus. Note that the diffraction angle may vary somewhat depending on the crystal growth direction, particle size, measurement conditions, and the like. Therefore, those numbers should not be interpreted exactly.
As a result, 2θ (°) is 8.5, 10.2, 12.7, 15.1, 16.7, 18.0, 19.3, 19.7, 21.2, and 27.7. It had a characteristic peak.

  EXAMPLES Hereinafter, although an Example, a comparative example, and a test example are given and this invention is demonstrated further in detail, this invention is not limitedly interpreted by these. In addition, the compound A hydrochloride manufactured according to the above-mentioned method was used.

<Example 1>
According to the formulation described in Table 2, 5.773 g of Compound A hydrochloride and 4.986 kg of D-mannitol (Pearlitol 50C, manufactured by Roquette) were mixed using a fluid bed granulator (GPCG-5 / 15, manufactured by Glatt). did. After mixing, an aqueous solution of hydroxypropylcellulose (HPC-L, manufactured by Nippon Soda) (solid content: 7% by weight) was sprayed as a binding liquid to perform granulation, and then dried to obtain a granulated product.
After sieving 4.500 kg of the resulting granulated product, low substituted hydroxypropyl cellulose (L-HPC LH11, manufactured by Shin-Etsu Chemical Co., Ltd.) 505.6 g, magnesium stearate (Parteck (registered trademark) LUB MST, manufactured by MERCK) ) 50.56 g was added and mixed using a mixer (LМ-20, manufactured by Kotobuki Kogyo) to obtain a mixed product (tablet granules).
The obtained mixed product was tableted using a rotary tableting machine (EX-10, manufactured by Hata Plant) to obtain tablets (plain tablets).

  Using the film coating machine (Flow coater mini, manufactured by Freund Industries), the total concentration of hypromellose, titanium oxide, and yellow ferric oxide is 10% by weight (solid component concentration). Thus, the film was coated with a solution dissolved and dispersed in purified water to obtain a tablet (film-coated tablet) of the present invention.

<Example 2>
In accordance with the formulation described in Table 2, using the film coating machine (Flow coater mini, manufactured by Freund Corporation), the uncoated tablets 540 obtained in Example 1 were hypromellose, talc, titanium oxide, yellow ferric oxide, and triacetin. Film-coating was performed with a solution dissolved and dispersed in purified water so that the total concentration of 10% by weight (concentration of solid component) was obtained, thereby obtaining a tablet (film-coated tablet) of the present invention.

<Example 3>
In accordance with the formulation shown in Table 2, using the film coating machine (Flowcoater Mini, manufactured by Freund Sangyo Co., Ltd.), the uncoated tablets 540 obtained in Example 1 were hypromellose, talc, titanium oxide, yellow ferric oxide, and three Film coating was performed with a solution dissolved and dispersed in purified water so that the total concentration of iron dioxide was 10% by weight (concentration of solid component) to obtain a tablet (film-coated tablet) of the present invention.

<Example 4>
According to the formulation described in Table 2, 43000 tablets obtained by the same production method as in Example 1 were film coated with the same formulation as Example 2 using a film coating machine (DRC-500, manufactured by POWREC). The film was coated with the liquid to obtain the tablet of the present invention (film-coated tablet).

<Comparative Example 1>
In accordance with the formulation described in Table 2, using the film coating machine (Flow coater mini, manufactured by Freund Sangyo), the uncoated tablets 540 obtained in Example 1 were hypromellose, polyethylene glycol 6000, talc, yellow ferric oxide, and Film coating was performed with a solution dissolved and dispersed in purified water so that the total concentration of iron sesquioxide was 10% by weight (concentration of solid component), and a comparative tablet (film-coated tablet) was obtained.

<Comparative Example 2>
In accordance with the formulation described in Table 2, 43000 tablets obtained by the same production method as in Example 1 were subjected to hypromellose, polyethylene glycol 6000, talc, titanium oxide using a film coating machine (DRC-500, manufactured by POWREC). , Yellow iron sesquioxide and iron sesquioxide were film-coated with a solution dissolved and dispersed in purified water so that the total concentration would be 10% by weight (solid component concentration). )

<Test Example 1>
The tablets (film-coated tablets) of Examples 1 to 3 and Comparative Examples 1 to 2 were packaged in polypropylene bottles (DUMA bottles) and stored at 70 ° C. for 9 days. The related substances after storage were measured by HPLC method.
The related substances were measured under the following conditions:
-As a HPLC column, YMC Pack Pro C18, particle diameter 5 micrometers, 4.6 mm (inside diameter) x 25 cm (made by YMC) or its equivalent was used, and it maintained at 45 degreeC.
As mobile phase A, 10 mmol / L perchlorate buffer (pH 2.5) / acetonitrile mixed solution (16: 9), as mobile phase B, 10 mmol / L perchlorate buffer (pH 2.5) / A mixture of acetonitrile (3: 7) was used.
The sample solution used was diluted with mobile phase A so that the concentration of compound A was 62.5 μg / mL.
-With the gradient program shown in Table 3 below, the flow rate was adjusted so that the retention time of Compound A was about 18 minutes, and the related substances were measured with an ultraviolet absorptiometer (wavelength: 225 nm). As a percentage of the total peak area of the related substance, the percentage of the peak area of each related substance was calculated.

Table 4 shows the measurement results.
As a result of the measurement, the percentages of the diastereomer of Compound A after storage and the largest related substance in the tablets of Comparative Examples 1 and 2 were both 1% or more. On the other hand, in the tablets of Examples 1 to 3, the percentages of the diastereomer of Compound A after storage and other largest related substances were both 1% or less, and were stable against heat.

<Test Example 2>
The tablets of Example 4 (film-coated tablets) were packaged in aluminum / aluminum blisters and stored at 25 ° C. 60% RH and 40 ° C. 75% RH for 1 month. Similar substances after storage were measured by HPLC as in Test Example 1. Table 5 shows the measurement results. In the tablet of Example 4, the percentage of the diastereomer of Compound A after storage and other largest related substances was 1% or less, and was stable to heat.

<Test Example 3>
The tablets (film-coated tablets) of Examples 1 to 3 were placed in a plastic petri dish, covered with a wrap, and then irradiated for 50 days with a D65 lamp illumination of 1000 lux. The appearance change of the sample after irradiation with that at the start of the test was visually observed. Further, the color difference (ΔE ^* ab) was measured using a color difference meter (CR-5, Konica Minolta, Inc.). The measurement results are shown in Table 6.
As shown in Table 6, in the film-coated tablet of Example 2 containing triacetin in the film coating layer, the color difference between the start of the test and after storage was 3.0 or less, and discoloration could be suppressed.

ADVANTAGE OF THE INVENTION According to this invention, the stable solid pharmaceutical composition containing the compound A or its pharmaceutically acceptable salt which suppressed the production | generation of the related substance during a preservation | save can be provided.
Moreover, according to this invention, the stable solid pharmaceutical composition containing the compound A or its pharmaceutically acceptable salt which suppressed discoloration of the film coating layer can be provided.
As mentioned above, although this invention was demonstrated along the specific aspect, the modification and improvement obvious to those skilled in the art are contained in the scope of the present invention.

Claims (8)

  4-({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl] amino} methyl) -4-phenylpyrrolidin-1-yl] carbonyl} oxy) benzoic acid or A stable solid pharmaceutical composition comprising the pharmaceutically acceptable salt and film-coated with a film coating layer.   The pharmaceutically acceptable salt is 4-({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl] amino} methyl) -4-phenylpyrrolidine- The solid pharmaceutical composition according to claim 1, which is 1-yl] carbonyl} oxy) benzoic acid hydrochloride.   The solid pharmaceutical composition according to claim 1 or 2, wherein the film coating layer contains substantially no polyethylene glycol.   The solid pharmaceutical composition according to any one of claims 1 to 3, wherein the film coating layer contains triacetin.   The solid pharmaceutical composition according to claim 4, wherein the proportion of triacetin is about 0.01 wt% to about 10 wt% based on the weight of the solid pharmaceutical composition.   The solid pharmaceutical composition according to any one of claims 1 to 5, wherein the solid pharmaceutical composition is a tablet.   4-({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl] amino} methyl) -4-phenylpyrrolidin-1-yl] carbonyl} oxy) benzoic acid or A method for producing a stable solid pharmaceutical composition, comprising coating a composition containing a pharmaceutically acceptable salt thereof with a film coating layer.   4-({[(3S, 4S) -3-({[(1R) -1- (1-naphthyl) ethyl] amino} methyl) -4-phenyl, characterized by film-coating the film coating layer Pyrrolidin-1-yl] carbonyl} oxy) A method for stabilizing a solid pharmaceutical composition comprising benzoic acid or a pharmaceutically acceptable salt thereof.