JP4684545B2 - Oral preparation of isoxazole derivative with good dissolution - Google Patents

Description

  The present invention relates to an oral preparation useful as a therapeutic agent for autoimmune diseases and inflammatory diseases.

Conventionally, 3-[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole represented by the following formula 1 is It is known that it is useful as a therapeutic agent for excellent autoimmune diseases and inflammatory diseases (see, for example, Patent Documents 1 to 3).
Formula 1:

  However, although these publications describe isoxazole derivatives of formula 1, there is no description of crystalline isoxazole derivatives of formula 1 that are easy to handle and stable in the preparation process and pharmaceutical preparations containing them.

  In addition, “Pharmaceutical Examination Guidelines for Biosolids with Different Content” in Pharmaceutical Examination No. 64 (issued on Feb. 14, 2000) It became necessary to show the same elution behavior in each test solution such as a buffer solution of pH 1.2, 3.0 to 5.0 and 6.8 corresponding to the pH value, and water. It is relatively easy to make a preparation having good dissolution property even if the content is different, but it is relatively easy to make it, but in the case of a poorly water-soluble compound such as the isoxazole derivative of Formula 1, the affinity with water Is generally not easy to manufacture.

JP-A-11-240873 JP 2000-186038 A JP 2000-186077 A

  The problem to be solved by the present invention is to provide an oral preparation having a good dissolution property of the isoxazole derivative of the formula 1, which is useful as a therapeutic agent for autoimmune diseases, inflammatory diseases and the like.

  The present inventors have intensively studied the formulation of an isoxazole derivative of formula 1. The present inventors have found that at least two crystal forms (referred to as α-type crystals and β-type crystals) exist in the isoxazole derivative of formula 1. Since the isoxazole derivative of Formula 1 is poorly water-soluble, it is desirable to finely pulverize the crystals during formulation. Therefore, these crystals were subjected to airflow pulverization and wet pulverization while being suspended in water. The test results performed in Test Examples 1 to 4 are summarized below.

(1) Crushing of α-type crystals In airflow grinding, α-type crystals are extremely fixed inside the grinding device. Therefore, it is difficult to reduce the size to the desired size by one grinding, and repeated grinding is required several times. Met. Since the operation of removing the fixed matter is frequently required, the grinding efficiency and yield are poor. In the wet pulverization method, α-type crystals are very bulky, and it is difficult to disperse them in a dispersion medium in water or the like, so that they cannot be practically used for formulation. In the wet pulverization under the high pressure pulverization condition, it changed to β-type crystals during the treatment in the water suspension state.

(2) Pulverization of β-type crystals When β-type crystals were air-flow pulverized, they were hardly fixed inside the pulverizer, easy to handle in the preparation process, and continuous pulverization was possible. Even with the wet pulverization method, it was possible to produce a fine powder that could be easily pulverized and that could be supplied to a formulation. In addition, there was no change in crystal state due to these pulverizations.

From the above test results, it was found that the crystalline isoxazole derivative of the formula 1 according to the present invention which is a β-type crystal is very easy to handle in the preparation process and is stable.
Furthermore, the inventors have (1) an isoxazole derivative of formula 1, (2) a water-soluble excipient of 2.5 to 100 times by weight with respect to (1), (3) a disintegrant, and (4) It was found that an oral preparation containing a water-soluble binder has a good dissolution property.

  Based on the above findings, the present inventors have completed the present invention. The present invention is as follows.

    [1] (1) In powder X-ray diffraction, crystallinity having main peaks at diffraction angles (2θ): 6.1, 14.1, 16.0, 18.5, 20.0 and 25.4 degrees 3-[(1S) -1- (2-Fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole, (2) against (1) An oral preparation containing 2.5 to 100 times by weight of a water-soluble excipient, (3) a disintegrant, and (4) a water-soluble binder.

    [2] Sieve of crystalline 3-[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole D50% The oral preparation of [1], wherein the particle size is 20 μm or less.

    [3] Sieve of crystalline 3-[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole D50% The oral preparation of [1], wherein the particle size is 10 μm or less.

    [4] Sieve of crystalline 3-[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole D50% The oral preparation of [1], wherein the particle size is 7 μm or less.

[5] The oral preparation according to any one of [1] to [4], wherein each content is the following weight ratio with respect to the total amount of the preparation.
Crystalline 3-[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole: 1-25%
Water-soluble excipient: 35-90%
Disintegrant: 1-40%
Water-soluble binder: 0.5-10%.

[6] The oral preparation according to any one of [1] to [4], wherein each content is the following weight ratio with respect to the total amount of the preparation.
Crystalline 3-[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole: 1-25%
Water-soluble excipient: 50-90%
Disintegrant: 2 to 35%,
Water-soluble binder: 1-5%.

[7] The oral preparation according to any one of [1] to [6], wherein the water-soluble excipient is lactose, mannitol, erythritol, xylitol or a mixture thereof.
[8] The oral medicine according to any one of [1] to [7], wherein the disintegrant is croscarmellose sodium, carboxymethyl starch sodium, crospovidone, carmellose calcium, low-substituted hydroxypropylcellulose, starch or a mixture thereof. Formulation.
[9] The oral preparation according to any one of [1] to [8], wherein the water-soluble binder is hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, or a mixture thereof.

[10] The oral preparation according to any one of [1] to [9], which is a tablet.
[11] The oral preparation of [10], which is film-coated.
[12] The oral preparation according to [11], wherein the film coating has the following composition.
Water-soluble film agent: 1 to 5% by weight based on the total amount of the preparation
Plasticizer: 0 to 1% by weight based on the total amount of the preparation
Light-shielding agent: 0.2 to 2% by weight based on the total amount of the preparation
[13] A therapeutic or prophylactic agent for autoimmune disease or inflammatory disease, comprising the oral preparation according to any one of [1] to [12].

[14] The method for producing an oral preparation according to any one of [1] to [10], comprising the following steps.
(1) Mixing a water-soluble excipient and a disintegrant to prepare a mixture,
(2) 3-[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole in an aqueous solution of a water-soluble binder To prepare a suspension
(3) Prepare a granulated product by spraying the suspension of (2) onto the mixture of (1), and
(4) Compress the granulated product of (3).

[15] The method for producing an oral preparation according to any one of [1] to [10], comprising the following steps.
(1) 3-[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole, water-soluble excipients and Mix the disintegrant to prepare a mixture,
(2) preparing an aqueous solution of a water-soluble binder,
(3) Prepare a granulated product by spraying the aqueous solution of (2) onto the mixture of (1), and
(4) Compress the granulated product of (3).

[16] The method for producing an oral preparation according to any one of [1] to [10], comprising the following steps.
(1) 3-[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole, a water-soluble excipient, Mixing a disintegrant and a water-soluble binder to prepare a mixture;
(2) spraying water on the mixture of (1) to prepare a granulated product, and
(3) Compress the granulated product of (2).
[17] The method for producing an oral preparation according to any one of [14] to [16], further comprising film coating.
[18] The method for producing an oral preparation according to [17], wherein the film coating has the following composition.
Water-soluble film agent: 1 to 5% by weight based on the total amount of the preparation,
Plasticizer: 0 to 1% by weight relative to the total amount of the preparation,
Light-shielding agent: 0.2 to 2% by weight based on the total amount of the preparation.

  According to the present invention, it is possible to provide an oral preparation having a good dissolution property of an isoxazole derivative that is useful as a therapeutic agent for autoimmune diseases and inflammatory diseases.

  The crystalline isoxazole derivative of formula 1 (β-type crystal) of the present invention can be produced, for example, by crystallizing the isoxazole derivative of formula 1 from a mixed solvent of a hydrophilic solvent and water. Here, the isoxazole derivative of Formula 1 can be produced by the methods described in Patent Documents 1 to 3, and the like. Examples of the hydrophilic solvent include alcohol (2-propanol, ethanol, methanol, t-butanol, etc.), ketone (acetone, 2-butanone, etc.), nitrile (acetonitrile, propionitrile, etc.), amide (N, N- Dimethylformamide and the like, and mixed solvents thereof, and the like, preferably alcohols such as 2-propanol, ethanol and methanol, and ketones such as acetone, and particularly preferably 2-propanol. Aromatic hydrocarbons (toluene, chlorobenzene, benzene, etc.), ethers (t-butyl methyl ether, diisopropyl ether, diethyl ether, etc.), aliphatic hydrocarbons (cyclohexane, hexane, heptane, etc.), halogenated solvents (chloroform, chloride) Methylene, 1,2-dichloroethane, etc.) and esters (ethyl acetate, etc.) can be mixed in small amounts.

  The amount of the mixed solvent of the hydrophilic solvent and water varies depending on the type of the hydrophilic solvent to be used, but from the viewpoint of handling, it is usually about 5 to about 100 times by weight with respect to the isoxazole derivative of the formula 1, preferably A range of about 10 to about 50 times by weight is mentioned. The weight ratio of the hydrophilic solvent to water varies depending on the type of the hydrophilic solvent used, and for example, about 100: 0 to about 1:10 can be mentioned, and preferably about 1: 1 to about 1: 5. It is done. In crystallization, it is desirable to add seed crystals of β-type crystals. Examples of the crystallization temperature include a range of about 70 to about 0 ° C. Preferably, it is first dissolved at about 70 to about 40 ° C., gradually cooled stepwise or continuously, and crystallized at about 20 to about 0 ° C. It is also preferable to dissolve the isoxazole derivative of formula 1 in a hydrophilic solvent and add water later to crystallize.

  In order to obtain a highly pure crystalline isoxazole derivative of the formula 1, it is preferable to isolate the crystal once as a phosphate or the like and then to make it free and crystallize. In that case, the salt of the isoxazole derivative of Formula 1 is freed, and when the reaction solvent is a hydrophobic organic solvent, it is converted to a hydrophilic organic solvent. When the reaction solvent is a hydrophilic organic solvent, the same reaction is performed as it is. It can also be crystallized in a bath. Examples of the base used for free formation include alkali hydroxide (sodium hydroxide, potassium hydroxide, etc.), alkali carbonate (sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, etc.) and the like. Can be used.

  The β-type crystals of the present invention can also be obtained by stirring the isoxazole derivative phosphate of formula 1 or α-type crystals in water for a certain period of time under suspension. In the case of phosphate, for example, β-type crystals were obtained by stirring at 50 ° C. for about 5 hours. This also shows that the β-type crystal is thermodynamically stable as compared with the α-type crystal. In addition, as long as β-type seed crystals are used, aromatic hydrocarbons (toluene, benzene, etc.), ethers (t-butyl methyl ether, diisopropyl ether, diethyl ether, etc.), aliphatic hydrocarbons (cyclohexane, hexane, heptane, etc.) Etc.), halogen-type solvents (chloroform, methylene chloride, 1,2-dichloroethane, etc.), and hydrophobic organic solvents such as esters (ethyl acetate, etc.) can be used to produce β-type crystals. For example, the isoxazole derivative of the formula 1 can be dissolved in a mixed solvent of toluene and 2-propanol, and hexane can be added for crystallization.

  On the other hand, α-type crystals can be obtained by dissolving the isoxazole derivative phosphate of Formula 1 in water and quenching.

  The crystalline isoxazole derivatives of formula 1 of the present invention are used orally or parenterally (eg intravenous, subcutaneous or intramuscular injection, topical, rectal, transdermal, Or nasally). Examples of forms for oral administration include tablets, capsules, pills, granules, powders, solutions, syrups, suspensions, etc. Examples of forms for parenteral administration include, for example, injection. Aqueous or oily agents, ointments, creams, lotions, aerosols, suppositories, patches and the like. These preparations can be prepared by using a conventionally known technique, and can contain acceptable ordinary carriers, excipients, binders, stabilizers and the like. In addition, when used in an injection form, an acceptable buffer, solubilizing agent, isotonic agent and the like can be added.

  The dose and number of administrations of the crystalline isoxazole derivative of formula 1 vary depending on symptoms, age, body weight, and administration form, but are usually 1 day as the active ingredient amount of the compound of the present invention for adults (body weight 50 kg). About 5-200 mg per dose, preferably 10-140 mg can be administered in one or several divided doses.

  Crystalline isoxazole derivatives of formula 1 are found in autoimmune diseases [eg, rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma, Sjogren's syndrome, Hashimoto's disease, myasthenia gravis, Basedaud's disease, Addison's disease, young Type diabetes mellitus (type I diabetes), autoimmune hematological disorders (eg, aplastic anemia, hemolytic anemia, idiopathic thrombocytopenia, etc.), ulcerative colitis, chronic active hepatitis, glomerulonephritis, stroma Pulmonary fibrosis, multiple sclerosis, etc.), and inflammatory diseases (for example, osteoarthritis, gout, atopic dermatitis, psoriasis, etc.) and the like, they are useful as therapeutic or preventive agents.

  (1) a crystalline isoxazole derivative of formula 1 of the present invention, (2) a water-soluble excipient of 2.5 to 100 times by weight with respect to (1), (3) a disintegrant, and (4) ) Oral preparations containing a water-soluble binder have good dissolution properties. Preferable oral dosage forms include tablets. This oral preparation exhibited a dissolution property of 75% or more in 15 minutes in a test solution having a pH of 3.5 even if the content was different.

  Examples of water-soluble excipients include lactose, sucrose, fructooligosaccharide, palatinose, glucose, maltose, reduced maltose, flour, fructose, isomerized lactose, reduced lactose, honey sugar and other sugars, mannitol, erythritol, xylitol, multi Examples thereof include sugar alcohols such as Toll, and mixtures thereof. Preferable water-soluble excipients include lactose, mannitol, erythritol, xylitol, or a mixture thereof.

  Disintegrants include croscarmellose sodium, carboxymethyl starch sodium, crospovidone, carmellose calcium, low-substituted hydroxypropylcellulose, starch, crystalline cellulose, carmellose, carmellose sodium, anhydrous calcium hydrogen phosphate, calcium phosphate, metasilicate Examples thereof include magnesium aluminate, synthetic hydrotalcite, synthetic aluminum silicate, and a mixture thereof. Preferred disintegrants include croscarmellose sodium, carboxymethyl starch sodium, crospovidone, carmellose calcium, low-substituted hydroxypropylcellulose, starch (for example, natural starch such as corn starch) and mixtures thereof. It is done.

  Examples of the water-soluble binder include hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, starch, dextrin, gelatin, and mixtures thereof. Preferred water-soluble binders include hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyvinyl alcohol, pullulan, and mixtures thereof.

  In addition to the above components, other non-toxic and inert additives usually used in the pharmaceutical field, such as colorants, flavoring / flavoring agents, preservatives, stabilizers, antistatic agents, surfactants, A foaming agent, a coloring agent, etc. can also be added.

Examples of preferable weight ratios include the following weight ratios with respect to the total amount of the preparation.
Crystalline 3-[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole: 1-25%
Water-soluble excipient: 35-90%
Disintegrant: 1-40%
Water-soluble binder: 0.5-10%.

More preferable examples of these weight ratios include the following weight ratios with respect to the total amount of the preparation.
Crystalline 3-[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole: 1-25%
Water-soluble excipient: 50-90%
Disintegrant: 2 to 35%,
Water-soluble binder: 1-5%.

  This oral preparation can be produced, for example, according to the following production methods 1, 2, or 3. In production, the crystalline isoxazole derivative of Formula 1 is preferably finely pulverized, and the D50% particle size under sieve is preferably about 20 μm or less, more preferably about 10 μm or less, more preferably about 7 μm or less. For example, the range of about 1 to about 7 μm can be mentioned.

Manufacturing method 1
(1) Preparation of aqueous solution of water-soluble binder An aqueous solution can be prepared by dissolving a water-soluble binder in purified water. The amount of purified water used is, for example, about 1 to about 100 times by weight, preferably about 5 to about 40 times by weight with respect to the water-soluble binder.
(2) Preparation of aqueous suspension of crystalline isoxazole derivative of formula 1 The suspension can be prepared by dispersing the crystalline isoxazole derivative of formula 1 in the aqueous water-soluble binder solution of (1). it can.

(3) Preparation of granulated product When the water-soluble excipient, disintegrant and starch are contained, the starch is charged into a granulator and mixed. Subsequently, granulation is carried out while spraying the aqueous suspension of (2). Examples of the granulation method include fluidized bed granulation, rolling granulation, rolling fluidized bed granulation, agitation granulation, and the like.
(4) Drying of granulated product The granulated product of (3) is dried under reduced pressure or normal pressure. This drying is preferably performed so that the loss on drying value observed with an infrared moisture meter is, for example, within about 5% by weight, preferably within about 3% by weight.

(5) Blending of lubricant The dried granulated product of (4) can be tableted as it is, but it is more preferable to tablet after blending the lubricant. Examples of the lubricant include magnesium stearate, talc, hydrogenated oil, stearic acid, calcium stearate, glyceryl behenate, glyceryl stearate, sodium stearyl fumarate and the like. The blending amount of the lubricant is, for example, about 0.3 to about 3% by weight, preferably about 0.5 to about 1.5% by weight based on the total weight of the tablet. The blending of the lubricant can be carried out by adding the lubricant to the dried granulated product of (4) and mixing it. As the mixing device, for example, a tumbler blender (Tumble Blender), a V blender (V Blender), a double cone (Double Cone), a bin tumbler (Bin Tumbler), or the like can be used.

(6) Tableting The mixture of (5) is tableted into a tablet by a conventional method. As the tableting device, for example, a tablet press, a rotary tableting machine or the like can be used. Examples of the tableting pressure include 2000 to 15000 N, and examples of preferable tablet hardness include about 40 to about 200 N.

(7) Film coating The tablet of (6) can be film-coated if necessary. Examples of coating agents include base materials (water-soluble film agents) such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and polyvinylpyrrolidone, and polyethylene glycol, propylene glycol, triacetin, triethyl citrate, glycerin, glycerin fatty acid ester, polyethylene glycol, and the like. A combination with a plasticizer may be used. Moreover, you may add additives, such as titanium oxide (light-shielding agent) and mannitol, as needed. Examples of the coating apparatus include a perforated coating pan system such as Hicoater (Freund Sangyo) and Aqua Coater (Freund Sangyo).
Preferred amounts of the water-soluble film agent, plasticizer, and light-shielding agent include the following:
Water-soluble film agent: 1 to 5% by weight based on the total amount of the preparation
Plasticizer: 0 to 1% by weight based on the total amount of the preparation
Light-shielding agent: 0.2 to 2% by weight based on the total amount of the preparation.

(8) Drying of tablet The tablet of (7) is dried under reduced pressure or normal pressure. This drying is preferably performed so that the loss on drying value observed with an infrared moisture meter is, for example, within about 5% by weight, preferably within about 3% by weight.

Manufacturing method 2
(1) Preparation of water-soluble binder aqueous solution A water-soluble binder aqueous solution is prepared in the same manner as in Production Method 1 (1).
(2) Preparation of granulated product When the crystalline isoxazole derivative of formula 1, water-soluble excipient, disintegrant and starch are contained, the starch is charged into a granulator and mixed. Subsequently, granulation is carried out while spraying the aqueous solution (1). As a granulation method, it can carry out similarly to the granulation of (3) of the manufacturing method 1.
(3) Drying of granulated product, blending of lubricant, tableting, film coating and tablet drying In the same manner as in (4) to (8) of Production Method 1, tablets can be produced.

Manufacturing method 3
(1) Preparation of Granulated Product When a crystalline isoxazole derivative of formula 1 is added, a water-soluble excipient, a disintegrant and starch, the starch is charged into a granulator and mixed. Then granulate while spraying purified water. As a granulation method, it can carry out similarly to the granulation of (3) of the manufacturing method 1.
(2) Drying of granulated product, blending of lubricant, tableting, film coating, and drying of tablet Tablets can be produced in the same manner as (4) to (8) of Production Method 1.

Examples Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1
Preparation of β-type crystals 4.0 g of the isoxazole derivative of Formula 1 was added to 40.0 g of 2-propanol, and the crystals were completely dissolved at 50 ° C. At the same temperature, 70 g of water was added and stirred, and seed crystals of β-type crystals were added. At the same temperature, 30 g of water was added dropwise over 25 minutes, and the mixture was further stirred for 35 minutes. The mixture was gradually cooled to 25 ° C. over 55 minutes and stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration. The obtained crystal was washed with a 10% 2-propanol aqueous solution and then dried under reduced pressure to obtain 3.88 g (yield 97%) of β-type crystal of the isoxazole derivative of Formula 1 as a needle-like crystal.

Example 2
Preparation of β-type crystals 250 g of α-type crystals of the isoxazole derivative of Formula 1 were added to 500 g of toluene and 187.5 g of 2-propanol, and the crystals were completely dissolved at 60 ° C. The solution was filtered and washed with 62.5 g of 2-propanol. The filtrate and the washing solution were combined, and 231 g of hexane was added dropwise to this solution at 50 ° C. A seed crystal of β-type crystal was added, and further 2013 g of hexane was added dropwise, stirred at the same temperature for 30 minutes, allowed to cool, and stirred at 20-30 ° C. for 1 hour. The precipitated crystals were collected by filtration. The obtained crystals were washed with 1 L of hexane and then dried under reduced pressure to obtain 237.5 g (yield 95%) of β-form crystals of the isoxazole derivative of formula 1 as needle crystals.

Example 3
Preparation of β-type crystals To 12.5 g (25.4 mmol) of the isoxazole derivative phosphate of formula 1 was added 56.3 g of water, 93.8 g of 2-propanol, and 93.8 g of toluene, and heated to 30 ° C to completely dissolve the crystals. I let you. To this solution, 41.3 g (19.5 mmol) of 5% aqueous sodium carbonate solution was added dropwise at the same temperature, and the mixture was further stirred for 30 minutes and then separated. To the organic layer was added 0.1 g of activated carbon, and the mixture was stirred at 30 ° C. for 30 minutes. The activated carbon was filtered, and the activated carbon was washed with 28.2 g of 2-propanol. The resulting solution was concentrated under reduced pressure until the total amount was 82.4 g, 282 g of 2-propanol was added, and the mixture was again concentrated under reduced pressure until the total amount was 75.5 g. To the obtained solution, 34.5 g of 2-propanol was added (the amount of residual toluene in the solution was measured by gas chromatography and found to be 0.22% with respect to 2-propanol). To this solution, 175 g of water and 1.3 g of toluene were further added at 50 ° C., cooled to 43 ° C., 6 mg of seed crystals of β-type crystals were added, and 75 g of water was added dropwise to precipitate crystals. The mixture was further kept at 43 ° C. for 1 hour, then cooled to 0 ° C., kept at 0 ° C. for 1 hour, and the precipitated crystals were collected by filtration. The obtained crystal was washed with 60 g of 10% 2-propanol aqueous solution and then dried under reduced pressure to obtain 9.8 g (24.9 mmol, yield 98%) of β-type crystal of the isoxazole derivative of formula 1.

Reference example 1
Preparation of α-form crystal 40 g of water was added to 2.0 g (4.1 mmol) of the phosphate salt of the isoxazole derivative of Formula 1, and dissolved by heating to 50 ° C. After incubating at the same temperature for 1 minute, it was immediately cooled to 30 ° C. and the crystals were collected by filtration. The obtained crystals were dried under reduced pressure to obtain 1.22 g (3.1 mmol, yield 76%) of α-type crystals of the isoxazole derivative of Formula 1 as scaly crystals.

Example 4
Powder X-ray diffraction powder X-ray diffraction pattern of β-type crystal and α-type crystal was measured using Cu · Kα with an X-ray diffractometer RINT 2500V (manufactured by Rigaku Corporation). The value of the diffraction angle (2θ) in this powder X-ray diffraction represents a standard accuracy and is about ± 0.1. Table 1 shows the diffraction angle (2θ) and relative intensity in powder X-ray diffraction of the β-type crystal of Example 1. The diffraction angle (2θ) and relative intensity in powder X-ray diffraction of the α-type crystal of Reference Example 1 are as shown in Table 2.
Table 1
2θ (°) Relative strength (%)
6.1 100
14.1 55
16.0 74
18.5 36
20.0 43
25.4 39
Table 2
2θ (°) Relative strength (%)
5.8 35
11.8 100
20.3 38
20.6 44
22.7 70
23.8 52
27.4 43

Test example 1
Crystallization method of dry air flow of crystal -1
The crystal was put into an AO jet mill (manufactured by Seishin Enterprise Co., Ltd.), and airflow pulverization was performed at an indentation pressure of 0.49 MPa and a pulverization pressure of 0.49 MPa. Table 3 shows the fixed amount inside the apparatus when 7 g each of α-type crystal and β-type crystal was manually charged at a charging speed of about 10 to 20 g / hour. It has been confirmed that the charging speed does not significantly affect the amount of fixing.
Table 3
Crystal sticking amount
α-type crystal 2.06g
β-type crystal 0.00g
From the above results, it can be seen that although the α-type crystal is fixed in the apparatus in a considerable amount during the airflow pulverization, the β-type crystal is hardly fixed in the apparatus during the airflow pulverization.

Test example 2
Crystalline dry-air pulverization method-2
The crystals were put into a jet ohm JOM0101 type (manufactured by Seishin Enterprise Co., Ltd.), and air flow pulverization was performed at 0.44 MPa to 0.49 MPa indentation pressure and pulverization pressure (indentation pressure and pulverization pressure were set the same). Table 4 shows the particle size distribution of the pulverized product when α-type crystals and β-type crystals are manually charged at a charging rate of about 1 to 2 kg / hour. A laser diffraction particle size distribution meter (dry measurement) was used for the particle size distribution measurement. Further, it has been confirmed that it is necessary to repeatedly pulverize or increase the pulverization pressure to make finer powder.
Table 4
α-type crystal β-type crystal
Throughput 950g 900g
Under-sieving D50% particle size 27.6μm 4.7μm
Under-sieving D 90% particle size 79.3μm 10.2μm
Based on the above results, α-type crystals cannot be pulverized to a particle size that can be formulated in one pulverization, but β-type crystals can be obtained as a pulverized product with a significantly smaller particle size than α-type crystals. It turns out that it can grind | pulverize to the suitable particle diameter.

Test example 3
Method for dry air flow crushing of crystals-3
The number of pulverization times and the working time required to pulverize α-type crystals into a particle size that can be formulated were examined. The crystal was put into a jet ohil and airflow grinding was performed. Table 5 shows the recovery rate and working time of the pulverized product when the base crystal is manually charged at a charging speed of about 1 to 2 kg / hour. It has been confirmed that the pulverization pressure does not significantly affect the amount of fixing.
When the α-type crystals were repeatedly pulverized until the particle size was the same as that of the β-type crystal pulverized product, 6 repeated pulverizations were required.
Table 5
α-type crystal β-type crystal
Crushing pressure 0.80 MPa 0.44 MPa
Repeat grinding 6 times None (only once)
Processing volume 10kg 9kg
Recovery rate 82% 99%
Working time 70 hours 10 hours
As described above, the β-type crystal was able to obtain a pulverized product at a lower pulverization pressure and without requiring repeated pulverization. As a result, the recovery rate was also superior to the α-type crystal. In addition, the work time was significantly reduced. Thus, the grinding efficiency of β-type crystals is remarkably excellent.

Test example 4
Method for wet high-pressure pulverization of crystals The crystals were put together with water into a microfluidizer M110Y type (manufactured by Mizuho Kogyo Co., Ltd.) and subjected to high-pressure pulverization. Table 6 shows the particle size distribution when crystals are added. Here, the α-type crystal was solidified during the pulverization. Further, the moisture content of the solidified α-type crystal was about 80%, and the water used for the suspension was completely taken up. The particle size distribution was measured by dispersing in water using an agate mortar. A laser diffraction particle size distribution meter (wet measurement) was used for the particle size distribution measurement.

Table 6
α-type crystal β-type crystal
Crushing pressure 100 MPa 100 MPa
Amount of treatment (active substance / water) 40g / 150g 20g / 75g
Treatment time 6 minutes (solidification) 7 minutes Under-sieving D50% particle size 26.1 μm 1.7 μm
Under-sieving D 90% particle size 58.1μm 3.2μm
As mentioned above, α-type crystals are aggregated and solidified, so only those that are unsuitable for preparations are given. On the other hand, β-type crystal wet pulverized products can be transferred to the next step of preparation or dried. It was found that it can be pulverized to a small particle size.

Formulation Example 1
Tablet (20mg tablet)
In accordance with the following formulation, mannitol, corn starch and croscarmellose sodium are charged into a fluid bed granulator and spray granulated with a binding solution in which a poorly water-soluble active ingredient is dispersed and suspended in a water-soluble polymer binder solution. The granulated product was blended with magnesium stearate and compressed into tablets (20 mg tablets).
Table 7
Ingredient Content (mg)
Isoxazole derivative of formula 1 (β-type crystal) 20
Mannitol 66
Corn starch 28
Croscarmellose sodium 6
Hydroxypropyl methylcellulose 4
Magnesium stearate 1
Total 125mg

Formulation Example 2
Tablet (40mg tablet)
In accordance with the following formulation, mannitol, corn starch and croscarmellose sodium are charged into a fluid bed granulator and spray granulated with a binding solution in which a poorly water-soluble active ingredient is dispersed and suspended in a water-soluble polymer binder solution. The granulated product was mixed with magnesium stearate and compressed into tablets (40 mg tablets).
Table 8
Ingredient Content (mg)
Isoxazole derivative of formula 1 (β-type crystal) 40
Mannitol 132
Cornstarch 56
Croscarmellose sodium 12
Hydroxypropyl methylcellulose 8
Magnesium stearate 2
250mg total

Formulation Example 3
The uncoated tablet prepared in Film-coated Tablet Formulation Example 1 was charged into HiCoater HCT30N (Freund Sangyo) and coated so that the coating amount was 3 mg to obtain a film-coated tablet (20 mg tablet) having the formulation shown in the table below. .
Table 9
Ingredient Content (mg)
Bare tablets prepared in Production Example 1 125
Hydroxypropyl methylcellulose 2.13
Macrogol 400 0.21
Titanium oxide 0.66
Carnauba wax
Total 128mg

Formulation Example 4
Tablet (20mg tablet)
In accordance with the following formulation, poorly water-soluble active ingredients, mannitol, corn starch and croscarmellose sodium are charged into a fluid bed granulator, spray granulated with a water-soluble polymer binder solution, and the resulting granulated product is stearic acid. After blending magnesium, the tablets were tableted to produce tablets (20 mg tablets).
Table 10
Ingredient Content (mg)
Isoxazole derivative of formula 1 (β-type crystal) 20
Mannitol 66
Corn starch 28
Croscarmellose sodium 6
Hydroxypropyl methylcellulose 4
Magnesium stearate 1
Total 125mg

Formulation Example 5
Tablet (40mg tablet)
In accordance with the following formulation, mannitol, corn starch and croscarmellose sodium are charged into a fluid bed granulator and spray granulated with a binding solution in which a poorly water-soluble active ingredient is dispersed and suspended in a water-soluble polymer binder solution. The granulated product was mixed with magnesium stearate and compressed into tablets (40 mg tablets).
Table 11
Ingredient Content (mg)
Isoxazole derivative of formula 1 (β-type crystal) 40
Mannitol 169
Cornstarch 19
Croscarmellose sodium 12
Hydroxypropyl methylcellulose 8
Magnesium stearate 2
250mg total

Formulation Example 6
Tablet (40mg tablet)
In accordance with the following formulation, lactose, corn starch and croscarmellose sodium are charged into a fluidized bed granulator and spray granulated with a binding solution in which a poorly water-soluble active ingredient is dispersed and suspended in a water-soluble polymer binder solution. The granulated product was mixed with magnesium stearate and compressed into tablets (40 mg tablets).
Table 12
Ingredient Content (mg)
Isoxazole derivative of formula 1 (β-type crystal) 40
Lactose 169
Cornstarch 19
Croscarmellose sodium 12
Hydroxypropyl methylcellulose 8
Magnesium stearate 2
250mg total

Formulation Example 7
Tablet (40mg tablet)
In accordance with the following formulation, mannitol, corn starch and croscarmellose sodium are charged into a fluid bed granulator and spray granulated with a binding solution in which a poorly water-soluble active ingredient is dispersed and suspended in a water-soluble polymer binder solution. The granulated product was mixed with magnesium stearate and compressed into tablets (40 mg tablets).
Table 13
Ingredient Content (mg)
Isoxazole derivative of formula 1 (β-type crystal) 40
Mannitol 132
Cornstarch 56
Croscarmellose sodium 12
Hydroxypropyl cellulose 8
Magnesium stearate 2
250mg total

Comparative formulation example
Tablets (bare tablets) containing water-soluble excipients less than 2.5 times the weight of poorly water-soluble drugs
In accordance with the following formulation, mannitol, corn starch and croscarmellose sodium are charged into a fluid bed granulator and spray granulated with a binding solution in which a poorly water-soluble active ingredient is dispersed and suspended in a water-soluble polymer binder solution. The granulated product was mixed with magnesium stearate and compressed into tablets (40 mg tablets).
Table 14
Ingredient Content (mg)
Isoxazole derivative of formula 1 (β-type crystal) 40
Mannitol 52
Cornstarch 22
Croscarmellose sodium 6
Hydroxypropyl methylcellulose 4
Magnesium stearate 1
Total 125mg

Test Example 5
The dissolution test of the tablets prepared in dissolution test formulation examples 1 to 3 and the comparative formulation example was carried out under the following conditions according to the second method of dissolution test method of Japanese Pharmacopoeia.
Test solution: Diluted McIlvaine buffer (pH 3.5)
Paddle rotation speed: 50 rpm, test solution: 900 ml
The dissolution test results for one tablet are shown below in terms of dissolution rate (%).
Table 15

The tablet of Formulation Example 1 (20 mg tablet) had an elution rate of 85% or more in 15 minutes and showed extremely good dissolution properties.
The tablet of formulation example 2 (40 mg tablet) was prepared in twice the amount of the formulation of formulation example 1, but the dissolution rate at 15 minutes was 78%. Compared with the dissolution rate of Formulation Example 1, the dissolution rate at 15 minutes was in the range of ± 10%, and it was revealed that the dissolution behavior was equivalent.
The film coating agent of Formulation Example 3 was obtained by subjecting the tablets of Formulation Example 1 to film coating, and the dissolution rate after 15 minutes was 86%, which was the same value as Formulation Example 1. It was considered that the dissolution rate did not change.
The comparative formulation example is a formulation in which a water-soluble excipient is blended less than 2.5 times with respect to a poorly water-soluble drug, but the dissolution rate after 15 minutes is 65%. It was considered that the dissolution was clearly inferior to the preparation.

INDUSTRIAL APPLICABILITY According to the present invention, an oral preparation having a good dissolution property of an isoxazole derivative that is useful as a therapeutic agent for autoimmune diseases, inflammatory diseases and the like can be provided.

Claims (18)

(1) In powder X-ray diffraction, diffraction angles (2θ): 3 -[(1S) showing main peaks at 6.1, 14.1, 16.0, 18.5, 20.0 and 25.4 degrees ) -1- (2-fluoro-biphenyl-4-yl) ethyl] -5 - {[amino (morpholin-4-yl) methylene] amino} crystal isoxazole, 2.5 against (2) (1) An oral preparation containing a water-soluble excipient, (3) a disintegrating agent, and (4) a water-soluble binder, in an amount of 100 to 100 times by weight. 3 -[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole crystals under sieving D50% particle size The oral preparation according to claim 1, which is 20 µm or less. 3 -[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole crystals under sieving D50% particle size The oral preparation according to claim 1, which is 10 µm or less. 3 -[(1S) -1- (2-fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole crystals under sieving D50% particle size The oral preparation according to claim 1, which is 7 µm or less. Each content is the following weight ratios with respect to the formulation whole quantity, The oral formulation in any one of Claims 1-4 .
3 -[(1S) -1- (2-Fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole crystals : 1-25%
Water-soluble excipient: 35-90%
Disintegrant: 1-40%
Water-soluble binder: 0.5-10%. Each content is the following weight ratios with respect to the formulation whole quantity, The oral formulation in any one of Claims 1-4 .
3 -[(1S) -1- (2-Fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole crystals : 1-25%
Water-soluble excipient: 50-90%
Disintegrant: 2 to 35%,
Water-soluble binder: 1-5%.   The oral preparation according to any one of claims 1 to 6, wherein the water-soluble excipient is lactose, mannitol, erythritol, xylitol or a mixture thereof.   The oral preparation according to any one of claims 1 to 7, wherein the disintegrant is croscarmellose sodium, carboxymethyl starch sodium, crospovidone, carmellose calcium, low-substituted hydroxypropylcellulose, starch or a mixture thereof.   The oral preparation according to any one of claims 1 to 8, wherein the water-soluble binder is hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, pullulan or a mixture thereof.   It is a tablet, The oral formulation in any one of Claims 1-9.   The oral preparation according to claim 10, which is film-coated. The oral preparation according to claim 11, wherein the film coating has the following composition.
Water-soluble film agent: 1 to 5% by weight based on the total amount of the preparation
Plasticizer: 0 to 1% by weight based on the total amount of the preparation
Light-shielding agent: 0.2 to 2% by weight based on the total amount of the preparation   The therapeutic agent or preventive agent of an autoimmune disease or an inflammatory disease containing the oral formulation in any one of Claims 1-12. The manufacturing method of the oral formulation in any one of Claims 1-10 including the following process.
(1) Mixing a water-soluble excipient and a disintegrant to prepare a mixture,
(2) 3-[(1S) -1- (2-Fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole crystals as water-soluble binder A suspension is prepared by dispersing in an aqueous solution of
(3) Prepare a granulated product by spraying the suspension of (2) onto the mixture of (1), and
(4) Compress the granulated product of (3). The manufacturing method of the oral formulation in any one of Claims 1-10 including the following process.
(1) 3-[(1S) -1- (2-Fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole crystals , water-soluble shaping Mixing the agent and disintegrant to prepare a mixture,
(2) preparing an aqueous solution of a water-soluble binder,
(3) Prepare a granulated product by spraying the aqueous solution of (2) onto the mixture of (1), and
(4) Compress the granulated product of (3). The manufacturing method of the oral formulation in any one of Claims 1-10 including the following process.
(1) 3-[(1S) -1- (2-Fluorobiphenyl-4-yl) ethyl] -5-{[amino (morpholin-4-yl) methylene] amino} isoxazole crystals , water-soluble shaping Mixing the agent, disintegrant and water-soluble binder to prepare a mixture;
(2) spraying water on the mixture of (1) to prepare a granulated product, and
(3) Compress the granulated product of (2).   Furthermore, a film coating is given, The manufacturing method of the oral formulation in any one of Claims 14-16 characterized by the above-mentioned. The method for producing an oral preparation according to claim 17, wherein the film coating has the following composition.
Water-soluble film agent: 1 to 5% by weight based on the total amount of the preparation,
Plasticizer: 0 to 1% by weight relative to the total amount of the preparation,
Light-shielding agent: 0.2 to 2% by weight based on the total amount of the preparation.