JP2024020402A - Pharmaceutical composition comprising oil component dispersion that contains ed-71 and epoxy form thereof in fat/oil - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an epoxy form of (5Z,7E)-(1R,2R,3R)-2-(3-hydroxypropoxy)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol (ED-71) and a method for producing the same.

SOLUTION: A method for producing an ED-71 epoxy form represented by the formula (II) includes a step of oxidizing ED-71. The step of oxidizing ED-71 can be executed through either (a) oxidizing ED-71 with air or (b) using 3-chloroperbenzoic acid for the oxidation of ED-71.

SELECTED DRAWING: Figure 1

COPYRIGHT: (C)2024,JPO&INPIT

Description

The present invention provides (5Z,7E)-(1R,2R,3R)-2-(3-hydroxypropoxy)-9,10-secocholesta-5,7,10(19)-triene-1,3 ,25-triol (hereinafter also referred to as ED-71 or compound 1) and (1R,2R,3R,5Z)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10(19)-secocoresta The present invention relates to a pharmaceutical composition containing -5,10-diene-1,3,25-triol (hereinafter also referred to as ED-71 epoxide), a method for producing the same, and a method for inhibiting oxidation or decomposition of ED-71.

ED-71 (generic name: eldecalcitol) is a synthetic derivative of active vitamin _D3 that has osteogenic activity, and is manufactured and sold as an orally administered osteoporosis therapeutic agent.

ED-71, like other vitamin D derivatives, can be formulated as soft capsules. Patent Document 1 discloses a seamless soft capsule in which a medium chain fatty acid triglyceride (hereinafter also referred to as MCT) solution of ED-71 is encapsulated within a gelatin shell. Patent Document 1 also discloses that by adding an antioxidant such as dl-α-tocopherol to the solution, the production of taxerol and trans forms, which are decomposition products of ED-71, is suppressed. ing.

At present, there are no known commercially available ED-71 preparations other than soft capsules. Patent Document 2 discloses a combination of a strontium salt and a vitamin D derivative that can be applied to osteoporosis, and eldecalcitol is listed as an example of the vitamin D derivative. Moreover, Patent Document 2 describes that the mixture can be made into a tablet. However, the description is only a description of a general tablet, and does not disclose the effects when specific additives other than strontium salt are added to the ED-71 preparation.

Patent Document 3 describes, for example, that after dissolving 1α-(OH)-D ₃ and polyvinylpyrrolidone in ethanol, anhydrous lactose is added, and after stirring, the ethanol is distilled off under reduced pressure, and the resulting reaction product is further pulverized. A 1α-(OH)-D ₃ composition obtained by

Patent Document 4 describes a solid dispersion of ED-71 (a composition in which solid ED-71 and a solid additive are mixed) and an oil dispersion (a composition in which particles of an oil/fat solution of ED-71 are mixed in an excipient). A pharmaceutical composition comprising a composition dispersed in a pharmaceutical composition and a method for making the same is described.

Patent Document 5 describes that a 7,8-epoxide of a specific vitamin D ₃ derivative can be obtained by reacting it with 3-chloroperbenzoic acid.

WO2005/074943A1 CN102688249A WO90/09796A PCT/JP2017/047156 (published as WO2018/124260 on July 5, 2018) Japanese Unexamined Patent Publication No. 58-216179

Edirol (registered trademark) capsules 0.5 μg and 0.75 μg, which are commercially available as osteoporosis treatment agents, are only spherical soft capsules, and there is a need to develop a functionally superior ED-71 formulation with a new formulation. It was getting worse. Additionally, there was a demand for ease of use by making spherical soft capsules non-spherical, making them easier to pinch and less likely to roll. For the convenience of patients who require administration of ED-71, there has been a need to develop a non-spherical ED-71 formulation in a dosage form other than soft capsules.

The present inventors have proceeded with the development of such a formulation manufactured from an oil dispersion in which particles of an oil/fat solution of ED-71 are dispersed in an excipient, and found that ED-71 It has been found that when using an oil dispersion prepared using the oil/fat solution as it is, a formulation of sufficient quality cannot be produced. As a result of further research to solve this problem, we came up with the idea of coating particles of ED-71 oil and fat solution with specific additives, but many of the additives used affect the stability of ED-71. A new issue was discovered: a decrease in In response to this new problem, the present inventors have discovered that it is possible to produce preparations (particularly tablets) of sufficient quality by using hydroxypropylmethylcellulose or hydroxypropylcellulose, which are water-soluble polymers, as additives. We have found that (Patent Document 4).

The present invention was made in view of these circumstances, and its purpose is to provide a novel pharmaceutical composition containing an oil dispersion of ED-71 and a method for producing the same.

The present inventors have newly discovered that in the process of manufacturing tablets containing an oil dispersion of ED-71, a small portion (several percent or less) of ED-71 is converted to ED-71 epoxide. The present inventors conducted further research based on this discovery and completed the present invention.

That is, the present invention more specifically provides the following [1] to [12].
[1] ED-71 and (1R,2R,3R,5Z)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10(19)-secocoresta-5,10-diene-1,3 , 25-triol, the method comprises:
A step of preparing an oil-in-water emulsion containing an oil/fat solution of ED-71 and an aqueous solution of a water-soluble polymer, a step of adhering or adsorbing the oil-in-water emulsion to an excipient, and drying the oil-in-water emulsion. The process of making
including;
The above method, wherein the water-soluble polymer is selected from hydroxypropylmethylcellulose and hydroxypropylcellulose.
[2] The method according to [1], wherein the weight ratio of the oil-in-water emulsion to the excipient is 1:4 to 1:20.
[3] The method according to [1] or [2], wherein the excipient is selected from sugars or sugar alcohols.
[4] The method according to [3], wherein the excipient is mannitol.
[5] ED-71 and (1R,2R,3R,5Z)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10(19)-secocoresta-5,10-diene-1,3 , 25-triol, the pharmaceutical composition comprising:
comprising particles coated with a coating agent comprising a water-soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose in or on the surface of the excipient;
The above pharmaceutical composition, wherein the particles include an oil/fat solution of ED-71.
[6] The pharmaceutical composition according to [5], wherein the excipient is selected from sugars or sugar alcohols. [7] The pharmaceutical composition according to [6], wherein the excipient is mannitol.
[8] The pharmaceutical composition according to any one of [5] to [7], which is a coated tablet coated with an HPMC film.

Furthermore, the present invention provides the following [9] and [10].
[9] A product in which the pharmaceutical composition according to any one of [5] to [8] and an oxygen absorber are hermetically sealed in a package.
[10] The product according to [9], wherein the packaging form is bottle packaging or pillow packaging.

According to the present invention, decomposition of ED-71 caused by contact with additives (change in formulation) can be suppressed in the oil dispersion. Furthermore, ED-71 preparations in various dosage forms other than soft capsules can be manufactured using the oil dispersion.

FIG. 2 is a schematic diagram of a manufacturing flow for manufacturing tablets containing an oil dispersion of ED-71. This is a photograph showing an emulsified state when a 2% aqueous solution of a water-soluble polymer is mixed with medium-chain fatty acid triglyceride. From left: HPMC, HPC, PVP, and POVA-COAT. These are the results of liquid chromatography analysis of the tablets obtained in "[Production Example] Oil Dispersion Tablets". This is an ultraviolet-visible spectrum of ED-71. This is a UV-visible spectrum of ED-71 epoxide (Compound 2).

In the present invention, ED-71 is a compound represented by the following formula (I), preferably the following formula (Ia).

ED-71 can be obtained by preparing (1R, 2R, 3R
)-2-(3-hydroxypropoxy)-cholester-5,7-diene-1,3,25-triol as a starting material, after ultraviolet irradiation and thermal isomerization reaction, purification by reverse phase HPLC, concentration, It can be obtained by crystallizing with ethyl acetate.

In the present invention, ED-71 epoxide is a compound represented by the following formula (II).

In ED-71 epoxide, the steric structure of the epoxy moiety (7 and 8 positions) is not specified, but compounds represented by the following formulas (IIa) and (IIb) in which they are specified, and any proportion thereof The compound represented by the following formula (IIc) mixed with is also included in ED-71 epoxide. As the ED-71 epoxide, any of the compounds represented by the following formulas (IIa) and (IIb), namely (1R, 2R, 3R, 5Z, 7ξ, 8ξ)-2-(3-hydroxypropoxy)-7 ,8-epoxy-9,10(19)-secocholesta-5,10-diene-1,3,25-triol (hereinafter also referred to as compound 2) is preferred.
It is preferable that the steric structure at position 14 in compounds (II), (IIa), (IIb) and (IIc) is the same as in compound (Ia).

ED-71 oil dispersion
PHARMACEUTICAL COMPOSITION CONTAINING ED-71 AND ED-71 EPOXIDE AND METHOD FOR PRODUCING THE SAME TECHNICAL FIELD The present invention relates to an oil dispersion of ED-71 and an oil dispersion containing ED-71 and ED-71 epoxide. As used herein, the ED-71 oil dispersion refers to a composition in which particles of an ED-71 oil/fat solution are dispersed in an excipient. Similarly, an oil dispersion containing ED-71 and ED-71 epoxide refers to a composition in which oil particles containing ED-71 and ED-71 epoxide are dispersed in an excipient.

The present invention provides pharmaceutical compositions comprising such ED-71 and oil dispersions comprising ED-71 epoxide. Specifically, a pharmaceutical composition comprising ED-71 and ED-71 epoxide, comprising a water-soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose in or on the excipient. The pharmaceutical composition comprises particles coated with a coating comprising ED-71 and an oil solution of ED-71 epoxide.

The invention also provides a method for manufacturing such a pharmaceutical composition. Specifically, it is a method for producing a pharmaceutical composition containing ED-71 and ED-71 epoxide, which comprises: (i) producing an oil-in-water emulsion containing an oil/fat solution of ED-71 and an aqueous solution of a water-soluble polymer; (ii) adhering or adsorbing the oil-in-water emulsion to an excipient; and (iii) drying the oil-in-water emulsion, wherein the water-soluble polymer is The method is provided wherein the cellulose is selected from propylmethylcellulose and hydroxypropylcellulose. By this method, oil particles containing ED-71 and ED-71 epoxide are coated with a water-soluble polymer in an excipient, and a formulation using an oil dispersion of ED-71 and ED-71 epoxide can be prepared. (especially tablets). Note that ED-71 epoxide is not contained at the beginning of step (i), or even if it is contained, the content is preferably in a small amount of 0.1% or less, but mainly in step (iii), It is produced by the conversion (oxidation) of ED-71 and is contained in fats and oils. In the pharmaceutical field, a method of impregnating an excipient with an oil solution containing an active ingredient is already known, but it is important to use an oil-in-water emulsion instead of an oil solution, and to Conventionally, there was no known method for drying an oil-in-water emulsion and coating the oil/fat solution with components in the aqueous layer.

Regarding step (i), the fats and oils used in the present invention include medium chain fatty acid triglyceride (hereinafter also referred to as "MCT"), tricaprylin, caproic acid, caprylic acid, capric acid, oleic acid, linoleic acid, linolenic acid, and vegetable oil. Examples include. Here, examples of the vegetable oil include coconut oil, olive oil, rapeseed oil, peanut oil, corn oil, soybean oil, cottonseed oil, grape oil, and safflower oil. Among these, MCT, tricaprylin, caproic acid, caprylic acid, or capric acid, which do not contain unsaturated fatty acids, are preferred, and MCT is particularly preferred.

The concentration of ED-71 in the oil/fat solution in step (i) can be determined as appropriate depending on the target disease or symptom, administration form, administration route, etc., but for example, 0.001 to 0.3% by weight. It is preferably 0.005 to 0.1% by weight, more preferably 0.01 to 0.05% by weight.

An antioxidant may further be added to the fat/oil solution in step (i). Examples of the antioxidant in the present invention include nitrites (e.g., sodium nitrite), sulfites (e.g., sodium sulfite, dry sodium sulfite, sodium bisulfite, sodium pyrosulfite), thiosulfates (e.g., sodium thiosulfate), Alphathioglycerin, 1,3-butylene glycol, thioglycolic acid and its salts (e.g. sodium thioglycolate), thiomalates (e.g. sodium thiomalate), thiourea, thiolactic acid, edetate salts (e.g. sodium edetate) , dichloroisocyanurates (e.g. potassium dichloroisocyanurate), citric acid, cysteine and its salts (e.g. cysteine hydrochloride), benzotriazole, 2-mercaptobenzimidazole, erythorbic acid and its salts (e.g. sodium erythorbate). , ascorbic acid and its ester compounds (e.g. L-ascorbic acid stearate, ascorbic acid palmitate), phospholipids (e.g. soybean lecithin), metal chelating agents and their salts (e.g. ethylenediaminetetraacetic acid, calcium disodium ethylenediaminetetraacetate) , disodium ethylenediaminetetraacetate), tartaric acid and its salts (e.g. Rochelle salt), polyphenols (e.g. catechin), glutathione, dibutylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, natural vitamin E, tocopherol acetate, concentrated mixed tocopherols, Tocopherol congeners (e.g. d-α-tocopherol, dl-α-tocopherol, 5,8-dimethyltocol, 7,8-dimethyltocol, δ-methyltocol, 5,7,8-trimethyltocotrienol, 5,8-dimethyl tocotrienol, 7,8-dimethyltocotrienol, 8-methyltocotrienol), and the like. Among these, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, dl-α-tocopherol, d-α-tocopherol, concentrated mixed tocopherol, ascorbic acid palmitate, L-ascorbic acid stearate, butylated hydroxyanisole, propyl gallate. is preferred, dl-α-tocopherol, dibutylated hydroxytoluene, butylated hydroxyanisole, or propyl gallate is more preferred, and dl-α-tocopherol or dibutylated hydroxytoluene is even more preferred.

The amount of the antioxidant added to the oil and fat solution is not particularly limited, but the amount is below the maximum usage amount that can be used as an antioxidant (for example, the amount approved as described in the Dictionary of Pharmaceutical Additives (Yakuji Nipposha, 2000) An amount below the maximum usage amount of the previous example, an amount below the usage limit stated in the Food Additives Official Standards (Japan Food Additives Association, 1999), etc.) can usually be used.

In a preferred embodiment, dl-α-tocopherol is added to the fat/oil solution at a concentration of 0.01% by weight or more (eg, 1% by weight or more) and 10% by weight or less (eg, 5% by weight or less). The amounts of dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, etc. to be added are also the same as those for dl-α-tocopherol.

The coating material used in the present invention contains a water-soluble polymer. The water-soluble polymer is selected from hydroxypropylmethylcellulose and hydroxypropylcellulose. Although many additives reduce the stability of ED-71 when added to a fat solution of ED-71, hydroxypropylmethylcellulose and hydroxypropylcellulose do not reduce the stability of ED-71. Furthermore, when hydroxypropylmethylcellulose and hydroxypropylcellulose are used, the emulsified state of the oil-in-water emulsion can be maintained for a long period of time.

Here, the fact that the stability of ED-71 does not decrease in the pharmaceutical composition of the present invention can be confirmed by manufacturing tablets from the pharmaceutical composition of the present invention and storing them at 40°C for 1, 3, or 6 months while shielding from light. This is confirmed by examining the residual rate of ED-71 after treatment. The residual rate of ED-71 was determined by high-performance liquid chromatography (measurement wavelength 265 nm) for preserved samples and initial samples.
-71 and its isomer pre form (chemical name: 6Z-(1R,2R,3R)-2-(3-hydroxypropoxy)-9,10-secocholester-5(10),6,8(9) -Triene-1,3,25-triol; herein also referred to as Pre ED-71) peak area is measured and calculated using the following formula.
Ratio of content to labeled amount of ED-71 (%) = (Weighed amount of ED-71 standard product / Total ED-71 peak area in ED-71 standard product) × ED- in initial sample or stored sample 71 Total peak area × (Weight of entire initial sample or stored sample / Weight of sample used for measurement) / Displayed amount × 100
(Total ED-71 peak area = ED-71 peak area + 1.98 x Pre ED-71 peak area)
Survival rate of ED-71 (%) = Ratio of the content to the labeled amount of ED-71 in the stored sample (%) / Ratio of the content to the labeled amount of ED-71 in the initial sample (%) × 100

In addition, the meaning of each term in the above formula is as follows.
・"Displayed amount": Theoretical content per tablet ・"ED-71 standard product": ED-71 drug substance ・"Weighed amount of ED-71 standard product / ED-71 peak in ED-71 standard product "Total area": Weight of ED-71 standard product per unit peak area (value used to calculate the content of ED-71 in the measurement sample from the peak area)

Hydroxypropyl methylcellulose and hydroxypropylcellulose may be of a pharmaceutically acceptable grade.
Hydroxypropyl methylcellulose in the present invention can be purchased from Shin-Etsu Chemical Co., Ltd., for example, under the trade name TC-5.

In addition, in the present invention, hydroxypropylcellulose (HPC) is defined as an ingredient in the Pharmaceutical Excipient Dictionary 2016 (edited by Japan Pharmaceutical Excipients Association; published by Yakuji Nippo Co., Ltd.; ISBN978-4-8408-1329-7). It refers to hydroxypropyl cellulose listed as component number 002303, and is different from the low-substituted hydroxypropyl cellulose listed as component number 002440 in the same dictionary. The hydroxypropyl cellulose used in the present invention has a molar degree of substitution (MS) (indicating the ratio of hydroxy groups in HPC repeating units (glucose rings) being substituted with hydroxypropoxy groups), usually 2 to 3, preferably 2. 5 to 3, more preferably 3. On the other hand, the degree of molar substitution in low-substituted hydroxypropyl cellulose is 0.2 to 0.4. Hydroxypropyl cellulose in the present invention can be purchased, for example, from ISP Japan under the trade name Klucel and from Nippon Soda under the trade name Hydroxypropyl Cellulose.

The coating material in the present invention may contain additives other than the water-soluble polymer, for example, may contain a stabilizer and an antioxidant.

The concentration of the water-soluble polymer in the aqueous solution in step (i) is appropriately determined depending on the amount of ED-71, but is, for example, 1 to 15% by weight, preferably 2 to 10% by weight, and more Preferably it is 3 to 6% by weight, more preferably 4 to 6% by weight, even more preferably 5 to 6% by weight. The aqueous solution in step (i) may contain additives other than the water-soluble polymer, for example, may contain a stabilizer and an antioxidant.

The oil-in-water emulsion can be prepared by a method commonly used in the pharmaceutical field, but it is preferably prepared by a mechanical emulsification method. Mechanical emulsification methods include, for example, chemical stirrers, vortex mixers, homomixers, homogenizers, hydroshares, colloid mills, flow jet mixers, ultrasonic generators, wet grinders using glass beads, membrane emulsifiers using porous membranes, Examples include a method using an electroemulsification device that uses electrical energy. As a homogenizer, for example, T-50 Ultra Turrax (manufactured by IKA) can be used.

The ratio (weight ratio, O/W ratio) of the ED-71 oil solution and the water-soluble polymer aqueous solution may be within a range that allows the preparation of an oil-in-water emulsion, and is usually 1:1.5. to 1:20, preferably 1:2 to 1:20, or 1:2 to 1:4. In a preferred embodiment, when the concentration of the water-soluble polymer in the aqueous solution of the water-soluble polymer is 3 to 6% by weight, 4 to 6% by weight, or 5 to 6% by weight, the oil and fat solution of ED-71 and the water-soluble The ratio of the polymer to the aqueous solution is 1:1.5 to 1:20, 1:2 to 1:20, or 1:2 to 1:4.

The ratio (weight ratio) of the ED-71 oil solution and the water-soluble polymer may be within a range that allows the particles of the ED-71 oil solution to be coated with the water-soluble polymer. The ratio is usually 1:0.05 to 1:10, preferably 1:0.1 to 1:1, or 1:0.1 to 1:0.3. In a preferred embodiment, when the concentration of the water-soluble polymer in the aqueous solution of the water-soluble polymer is 3 to 6% by weight, 4 to 6% by weight, or 5 to 6% by weight, the oil and fat solution of ED-71 and the water-soluble The ratio (weight ratio) to the polymer is 1:0.05 to 1:10, 1:0.1 to 1:1, or 1:0.1 to 1:0.3.
The particles are preferably spherical. The particle size is usually 0.01 to 100 μm, preferably 0.1 to 10 μm.

Regarding step (ii), excipients used in the present invention include, for example, starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch, anhydrous lactose, Examples include sugars or sugar alcohols such as lactose hydrate, fructose, glucose, mannitol, sorbitol, and erythritol, anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, and calcium silicate, preferably sugars or sugar alcohols. , more preferably mannitol, anhydrous lactose, lactose hydrate, and even more preferably mannitol.

The ratio (weight ratio) of the oil-in-water emulsion to the excipient used in step (ii) may vary depending on the type of excipient, etc., but is usually 1:1 to 1:100, preferably 1:4 to The range is 1:20. In particular, when the excipient is mannitol, if the weight ratio is usually in the range of 1:4 to 1:20, it is possible to obtain a preferable granulated powder that can be used for manufacturing preparations such as tablets.

The attachment or adsorption of the oil-in-water emulsion to the excipient can be carried out by methods commonly used in the pharmaceutical field, such as granulation while spraying the emulsion onto the excipient, Examples include a method in which an emulsion is added to the agent and mixed and stirred. Such a method can be carried out using, for example, a high-speed stirring granulator (VG-600CT manufactured by POWREX), a mixing agitator (DM type manufactured by Shinagawa Kogyosho), or the like. Note that adhesion or adsorption also includes impregnation (infiltrating an oil-in-water emulsion into the pores of a porous excipient).

In step (iii), the oil-in-water emulsion adhering to or adsorbing the excipient is dried, thereby removing water from the aqueous solution of the water-soluble polymer, and the oil solution is directly coated with the water-soluble polymer to form particles. is thought to be formed. The oil dispersion thus obtained contains particles containing an oil/fat solution of ED-71, and exhibits good manufacturability (e.g. fluidity and compression moldability) when used in the manufacture of tablets and other preparations. .

Drying of the oil-in-water emulsion can be performed by methods commonly used in the pharmaceutical field, such as fluidized fluid drying, freeze drying, ventilation drying, spray drying, stationary drying, stirring drying, flash drying, and vacuum drying. , microwave drying, and infrared/far-infrared drying. Further, drying may be performed together with heating or cooling. Drying can be performed using, for example, a fluidized bed granulation dryer (WSG-200pro manufactured by POWREX), a vacuum dryer (conical dryer manufactured by Nippon Dryer), or the like.

The pharmaceutical composition of the present invention can be made into oral preparations such as tablets, capsules, granules, and powders. These oral preparations can be manufactured by methods used in the pharmaceutical field. For example, methods for manufacturing tablets include methods i), ii), and iii) below.

i) Tablets are manufactured by mixing an oil dispersion containing ED-71 and ED-71 epoxide with additional additives (excipient 2, disintegrant, lubricant, etc.) and then compression molding.
ii) After mixing the oil dispersion containing ED-71 and ED-71 epoxide with additional additives (excipient 2, binder, etc.), a solvent (e.g. purified water, ethanol, or a mixture thereof) is added. Granulate while adding or spraying. A suitable amount of a lubricant and, if necessary, a disintegrant, etc. are added to the obtained granules, mixed, and then compressed to produce tablets.
iii) After mixing the oil dispersion containing ED-71 and ED-71 epoxide with additional additives (such as Excipient 2), the binder and optionally other additives are dissolved in a solvent (such as purified water , ethanol, or a mixture thereof) is added or sprayed to form granules. After adding and mixing an appropriate amount of a lubricant and, if necessary, a disintegrant, to the obtained granules, tablets are manufactured by compression molding.

Additional additives include, for example, surfactants and pH adjusters to improve drug release, flow agents to improve fluidity during the process, and stabilizers to increase stability. A flavoring agent can be used to add flavor or odor, and a coloring agent can be used to add color. The amount used is usually 0 to 99.999 parts by weight, preferably 50 to 99.5 parts by weight, and more preferably 90 to 99 parts by weight, based on 100 parts by weight of the preparation.

The tablets may also further contain antioxidants as additional additives. The antioxidant can be added at any step in the production methods of i), ii) and iii). For example, in the case of production method i), tablets can be produced by mixing the antioxidant with the oil dispersion together with other additives and then compression molding the mixture. Alternatively, tablets can also be manufactured by preparing an oil dispersion using an oil and fat solution of ED-71 in which an antioxidant has been dissolved in advance, mixing this with other additives, and then compression molding. .

The content of ED-71 in the pharmaceutical composition (preferably tablet) of the present invention is not particularly limited, but in one embodiment, the amount of ED-71 per unit preparation is 0.05 to 5 μg, preferably 0.05 to 5 μg. 5 to 0.75 μg.

Examples of the excipient 2 include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch, lactose hydrate, fructose, glucose, mannitol, and sorbitol. Examples include sugars or sugar alcohols such as, anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, etc. In preferred embodiments, excipient 2 is starch, lactose hydrate, microcrystalline cellulose, or anhydrous calcium hydrogen phosphate.

Examples of the disintegrant include sodium starch glycolate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, and hydroxypropyl starch. The amount of disintegrant used is preferably 0.5 to 25 parts by weight, more preferably 1 to 15 parts by weight, per 100 parts by weight of the preparation.

Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), and gum arabic powder. The amount of binder used is preferably 0.1 to 50 parts by weight, more preferably 0.5 to 40 parts by weight, per 100 parts by weight of the preparation.

Examples of the lubricant include stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, and light anhydrous silicic acid.

Examples of the surfactant include polysorbate 80, polyoxyl stearate 40, lauromacrogol, and the like.

Examples of the pH adjuster include acetic acid, lactic acid, citric acid, malic acid, succinic acid, fumaric acid, tartaric acid, phosphoric acid, and any salt thereof.

Examples of the fluidizing agent include light anhydrous silicic acid, silicon dioxide such as hydrous silicon dioxide, and talc. Here, specific examples of light anhydrous silicic acid include Cylysia 320 (trade name, Fuji Silysia Chemical Co., Ltd.), Aerosil 200 (trade name, Nippon Aerosil Co., Ltd.), and the like.

Stabilizers include, for example, paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; Examples include sorbic acid.

Examples of flavoring agents include sweeteners, acidulants, fragrances, etc. commonly used in the pharmaceutical field.

Any coloring agent may be used as long as it is permitted to be added to pharmaceuticals, such as Food Yellow No. 5 (Sunset Yellow, US Food Yellow No. 6), Food Red No. 2, and Food Blue. Examples include food coloring such as No. 2, food lake coloring, and iron sesquioxide.

Antioxidants include, for example, nitrites (e.g. sodium nitrite), sulfites (e.g. sodium sulfite, dry sodium sulfite, sodium bisulfite, sodium pyrosulfite), thiosulfates (e.g. sodium thiosulfate), alpha-thioglycerin. , 1,3-butylene glycol, thioglycolic acid and its salts (e.g. sodium thioglycolate), thiomalates (e.g. sodium thiomalate), thiourea, thiolactic acid, edetate salts (e.g. sodium edetate), dichlor Isocyanurates (e.g. potassium dichloroisyanurate), citric acid, cysteine and its salts (e.g. cysteine hydrochloride), benzotriazoles, 2-mercaptobenzimidazole, erythorbic acid and its salts (e.g. sodium erythorbate), ascorbic acid and its ester compounds (e.g. L-ascorbic acid stearate, ascorbic palmitate), phospholipids (e.g. soybean lecithin), metal chelating agents and their salts (e.g. ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid calcium disodium, ethylenediaminetetraacetate), disodium acetate), tartaric acid and its salts (e.g. Rochelle's salt), polyphenols (e.g. catechin), glutathione, dibutylated hydroxytoluene, butylated hydroxyanisole, propyl gallate, natural vitamin E, tocopherol acetate, concentrated mixed tocopherols, tocopherol homologs. (For example, d-α-tocopherol, dl-α-tocopherol, 5,8-dimethyltocol, 7,8-dimethyltocol, δ-methyltocol, 5,7,8-trimethyltocotrienol, 5,8-dimethyltocotrienol, 7 , 8-dimethyltocotrienol, 8-methyltocotrienol) and the like. Among these, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, dl-α-tocopherol, d-α-tocopherol, concentrated mixed tocopherol, ascorbic acid palmitate, L-ascorbic acid stearate, butylated hydroxyanisole, propyl gallate. are preferred, dl-α-tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, and propyl gallate are more preferred, and dl-α-tocopherol is even more preferred.
The amount of antioxidant used is preferably 0.001 to 10 parts by weight, more preferably 0.01 to 1 part by weight, per 100 parts by weight of the preparation.

The above additional additives may be used in combination of two or more in an appropriate ratio.

Sugar-coated tablets or film-coated tablets can also be obtained from the tablets by further using suitable coating additives. Examples of coating additives include sugar coating bases, coating agents, enteric film coating bases, sustained release film coating bases, and the like.

Examples of the sugar coating base include sugars or sugar alcohols such as white sugar and erythritol, and one or more types selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. Good too.

Examples of the coating agent include ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, talc, carnauba wax, and paraffin.

Enteric film coating bases include, for example, cellulose polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethyl cellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name), Acrylic acid polymers such as methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Evonik Degussa], methacrylic acid copolymer S [Eudragit S (trade name), Evonik Degussa]; Examples include natural products such as shellac.

Sustained-release film coating bases include, for example, cellulose-based polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), manufactured by Evonik Degussa], ethyl acrylate/methyl methacrylate copolymer suspended Examples include acrylic acid-based polymers such as a cloudy liquid (Eudragit NE (trade name), Evonik Degussa); cellulose acetate, and the like.

Two or more of the above-mentioned coating additives may be used by mixing them in an appropriate ratio.

A water-soluble substance, a plasticizer, etc. may be added to the coating additive as necessary in order to control the elution rate. Water-soluble substances include water-soluble polymers such as hydroxypropyl methylcellulose, sugar alcohols such as mannitol, sugars such as white sugar and anhydrous maltose, sucrose fatty acid esters, polyoxyethylene polyoxypropylene glycol, polysorbate, and sodium lauryl sulfate. One or more surfactants selected from surfactants such as the following can be used. Plasticizers include acetylated monoglyceride, triethyl citrate, triacetin, dibutyl sebacate, dimethyl sebacate, medium chain fatty acid triglyceride, acetyl triethyl citrate, tributyl citrate, acetyl tributyl citrate, dibutyl adipate, oleic acid, oleinol. One or more types selected from the following can be used.

Further, as a method for coating a tablet with the coating additive to form a coating layer, methods commonly used in the pharmaceutical field can be used, such as a pan coating method, a fluid coating method, a rolling coating method, Examples include fluidized rolling coating method. The coating liquid used in these methods is obtained by mixing the coating additive, talc, and a solvent (preferably ethanol or a mixture of ethanol and water). The solid content concentration of such a coating liquid is preferably in the range of 5 to 15% by weight based on the weight of the entire coating liquid.
In a preferred embodiment, the pharmaceutical composition of the invention is a coated tablet coated with an HPMC film.

In formulating the pharmaceutical composition of the present invention, granulation can be carried out using the principles and equipment described in the Examples, as well as extrusion granulation, crushing/sizing, rotary granulation, dry granulation, wet high shear granulation, and fluidized bed granulation.

Examples of granulation equipment based on extrusion granulation include Twin Dome Gran, Basket Reuser, semi-dry/low moisture granulator disc pelleter, semi-dry/small diameter granulator fine disc pelleter, and pelleter double. , and Multigran (manufactured by Dalton), as well as KEX extruder and KRC kneader (manufactured by Kurimoto Iron Works).

Examples of granulation equipment based on the principle of crushing and sizing include the Power Mill (manufactured by Dalton), the granulating machines Fiore F and Randell Mill (manufactured by Tokuju Kosho), and the no-screen granulating machine Nebulasizer (manufactured by Nara Kikai Seisakusho). ), Quick Mill QMY (manufactured by Seishin Enterprises), Roll Granulator (manufactured by Matsubo), New Speed Mill (manufactured by Okada Seiko), MF type granulating machine Osulator, and crushing and grading machine Conivit (all of which are manufactured by Flevit, Switzerland). manufactured by Earth Technica).

Examples of granulation devices based on rotary granulation include Marmerizer (manufactured by Dalton), and centrifugal fluid coating granulators CF and Granulex GX (both manufactured by Freund Sangyo).

Examples of granulation devices based on dry granulation include a roller compactor (manufactured by Freund Sangyo), Pharmapacta (manufactured by Hosokawa Micron), RCP roller compactor (manufactured by Kurimoto Iron Works), and Pharma compactor (manufactured by Matsubo).

Examples of granulation equipment based on the principle of wet high shear granulation include SP Granulator and Spartan Reuser (manufactured by Dalton), Vertical Granulator (manufactured by Powrec), and GEA Aeromatic Fielder Multiprocessor PharmaConnect for Research and Development (manufactured by Powrex). (manufactured by Eurotechno), mixer & granulator (NMG) (manufactured by Nara Kikai Seisakusho), crushing rolling type New Gram Machine SEG (manufactured by Seishin Enterprises), New Speed Kneader (manufactured by Okada Seiko), High Speed Mixer (Advance Series), Dynamic Dryers, Hi-Flex Gural, and microwave granulator dryers (manufactured by Fukae Powtech, sold by Earth Technica), and TM type granulation mixer (manufactured by Nippon Coke Industries) are included.

Examples of granulation equipment based on the principle of fluidized bed granulation include New Marmerizer, swirling fluidized bed, microfluidized bed, swing processor (manufactured by Dalton), Flow Coater Containment, Flow Coater Universal, and Flow Coater FLO. , and Spiraflow SFC (manufactured by Freund Sangyo), Agro Master (manufactured by Hosokawa Micron), GEA Aeromatic Fielder Flex Stream (manufactured by Eurotechno), and Sprued (manufactured by Okawara Seisakusho).

In addition to the principles and equipment described in Examples, mixing is performed using the principles of convection (mechanical stirring), diffusion (rotating container), and kneading/kneading.

Mixing devices based on the convection type (mechanical stirring type) include, for example, mixer agitator NDM type, mixer agitator XDM type, mixer agitator DM type, mixer agitator AM/XDM/DM type for prototype/research use, and mixer agitator twin for laboratory use. Mix, Pug Mixer, Ribbon Mixer, Spartan Mixer, and Paste Mixer (manufactured by Dalton), Cyclomix, and Nauta Mixer (manufactured by Hosokawa Micron), Vertical Mounting MAG-NEO Seal Mixer (manufactured by Magneo Giken), Bottom Type Super Mag mixer, S mixer super mix (manufactured by Satake Kagaku Kikai Kogyo), Julia mixer, ribbon mixer (manufactured by Tokuju Kosho), PX mixer (manufactured by Seishin Enterprises), Loedige mixer (manufactured by Matsubo) , FM mixer RC type, MP mixer (manufactured by Nippon Coke Industries), and Ribocorn (manufactured by Okawara Seisakusho).

Mixing devices based on the diffusion type (container rotation type) include, for example, the GEA Book System IBC Blender, the GEA Book System IBC Blender with NIR Measuring Device (manufactured by Eurotechno), the V-type mixer, and the W-type mixer. machine (manufactured by Tokuju Kosho), V-type mixer (manufactured by Nara Machinery Works), W-type mixer SCM, V-type mixer SVM (manufactured by Seishin Enterprises), capsule rocking mixer (manufactured by Aichi Denki), and An example is Bohle Container Mixer PM (manufactured by Kotobuki Kogyo).

Examples of mixing devices based on the principle of kneading and kneading include Continuous Kneader, Batch Kneader (manufactured by Dalton), T.K. Hivis Mix, T.K. Hivis Dispermix (manufactured by Primix), and Leistritz Extruder. (manufactured by Nara Kikai Seisakusho), and a planetary mixer (manufactured by Asada Tekko).

Other mixing devices include, for example, Conti-TDS (manufactured by Dalton), mixing torque meter ST-3000II process reactor DDL-3000, and stirring simulation MixSim (manufactured by Satake Kagaku Kikai Kogyo).

In addition to the above-mentioned principles, mixing can also be performed using principles such as a fluidized stirring method, a non-stirring method, and a high-speed shearing method.

Tableting is carried out using the principles of single-shot tabletting and rotary tabletting, with rotary tableting being preferred from the standpoint of efficiency.

In addition to the names of tableting machines based on rotary tabletting, in addition to those described in the examples, examples include removable high-speed tablet presser Fette (manufactured by Bosch Packaging Technology), high-speed tablet presser COMPRIMA, and high-speed tablet presser. Machine SYNTHESIS (manufactured by Mutual), rotary press MZ400 (manufactured by Mori Machinery), GEA Cortoa modular tablet press P type, S type, D type, and GEA Pharma System Performa P (manufactured by Eurotechno), Small rotary tablet machines for research and development, small high-speed rotary tablet machines, medium-sized high-speed rotary tablet machines, dual high-speed rotary tablet machines, rotary disc removable water washing rotary tablet machines, and containment tablet machines (manufactured by Kikusui Seisakusho) ), as well as BX type HX type high pressure tablet press, CVX type rotary disc detachable tablet press, X type AP type small tablet press, X type AP medium size tablet press, AP type large size tablet press, and X type One example is the AP type large-format double tablet press (manufactured by Hata Iron Works).

Single-layer tablets can be obtained using the above-mentioned tableting equipment, but multi-layer tablets can be produced using, for example, a GEA Cortoa modular double-layer tablet tablet machine D model (manufactured by Eurotechno) and a multilayer tablet machine (manufactured by Kikusui Seisakusho). It is also possible to manufacture dry-coated tablets using a dry-coated tablet machine (manufactured by Kikusui Seisakusho) and an AP/MS type C-type dry-coated tablet press (manufactured by Hata Iron Works).

In addition to the principles and equipment described in the examples, coating is performed using the principles of pan coating (horizontal pan), pan coating (tilted pan), and air floating method (fluidized bed).

Examples of coating apparatuses based on pan coating (horizontal pan) include Hi-Coater FZ, Aqua Coater AQC Containment, and Aqua Coater AQC (all manufactured by Freund Sangyo).

Examples of coating apparatuses based on the principle of pan coating (tilted pan) include Powrex Coater PRC and Doria Coater DRC (all manufactured by Powrex).

Examples of coating equipment based on the principle of air suspension (fluidized bed) include Glat Powder Coater GPCG SPC, Multiplex, and Composite Fluidized Bed SFP (manufactured by Powrex).

Other coating devices include, for example, a hybridization system (manufactured by Nara Kikai Seisakusho) and a mechano hybrid (manufactured by Nippon Coke Industry Co., Ltd.).

The pharmaceutical compositions of the present invention are useful for treating or preventing diseases or conditions (eg, osteoporosis) that can be treated or prevented by inhibiting bone turnover and improving bone density and strength.

In the present invention, the treatment or prevention of a disease or symptom includes preventing the onset of the disease, suppressing or inhibiting the aggravation or progression of the disease, alleviating one or more symptoms exhibited by an individual suffering from the disease, or suppressing the aggravation or progression of the disease. , treatment or prevention of secondary diseases, etc.

The subject to which the pharmaceutical composition of the present invention is administered is a mammal. The mammal is preferably a human.

Pharmaceutical compositions of the invention are administered to a subject in a therapeutically or prophylactically effective amount. "Amount effective for treatment or prevention" means an amount that has a therapeutic or preventive effect for a specific disease, dosage form, and route of administration, and includes the target species, type of disease, symptoms, gender, age, chronic disease, etc. It will be determined as appropriate depending on the factors. The route of administration is usually oral administration.

The dosage of the pharmaceutical composition of the present invention is appropriately determined depending on the species of the subject, the type of disease, symptoms, sex, age, chronic disease, and other factors. 0.01 to 10 μg, preferably 0.5 to 0.75 μg per day can be administered.

The present invention also relates to a method for treating or preventing a disease or condition, which comprises administering a therapeutically or prophylactically effective amount of the pharmaceutical composition of the present invention to a subject in need thereof.

The term "therapeutically or prophylactically effective amount" in the present invention refers to an amount that exhibits a therapeutic or prophylactic effect for a specific disease or condition, dosage form, and route of administration, and includes the target species, type of disease or condition, symptoms, sex, The amount will be determined as appropriate depending on age, chronic illness, and other factors.

The "subject" in the present invention is, for example, a mammal, preferably a human.

"Administering" in the present invention usually means oral administration.

The "disease or condition" in the present invention includes a disease or condition (eg, osteoporosis) that can be treated or prevented by suppressing bone turnover and improving bone density and bone strength.

As mentioned above, ED-71 epoxide is mainly produced by conversion from ED-71 in step (iii) (drying step) and is present in the oil solution together with ED-71 in the prepared tablets. Furthermore, if the prepared tablets are left as they are, the conversion of ED-71 to ED-71 epoxide will progress gradually, but this process will occur in an airtight container (packaged form) containing an oxygen absorber. This can be reduced by preserving the condition. Accordingly, in one aspect, the invention provides a product in which a pharmaceutical composition of the invention and an oxygen scavenger are hermetically encapsulated within a packaged form.

Examples of oxygen scavengers include Wonder Keep (registered trademark) (Powder Tech), Oxymove (registered trademark) (Nantong Oe Chemical), Modulan (Nippon Kayaku Food Techno), Keepit (Drensey), Wellpack (Taisei), Oxyeater (registered trademark) (Ueno Food Techno), Kepron (Kepron), freshness preservation agent (Toppan Printing), Sansolace (Hiroyo), Sansocut (registered trademark) (Iris Fine Products), Ageless (registered trademark) ZM (Mitsubishi) Gas Kagaku, ZM-1), Everfresh (Torishige Sangyo, QJ-30, etc.), Vitalon PH (Tokiwa Sangyo, PH-100SL, etc.), Secule (registered trademark) (Nisso Resin, AP-250, etc.), etc. , preferably Ageless ZM.

The "packaging form" is one that can be made airtight, and includes, for example, bottle packaging, pillow packaging, blister pack packaging, ampoule packaging, etc., and preferably bottle packaging and pillow packaging. . Furthermore, the pharmaceutical composition of the present invention can be used as it is or in PTP packaging (
Preferably, the intact composition is hermetically sealed in a bottle package, or the PTP-packaged composition is hermetically sealed in a packaging form. Enclosed in pillow packaging.

Examples of the material for the bottle packaging include thermoplastic resin, glass, earthenware, enamel, metal, etc., with thermoplastic resin and glass being preferred. The material for the bottle packaging is not limited to a single layer; for example, it may be made of the same thermoplastic resin or may have a multilayer structure made of multiple types of materials. The lid of the bottle packaging may be in any form as long as it can be made airtight, such as a screw cap. Examples of the material of the lid include thermoplastic resin and metal (eg, iron, tin, stainless steel, etc.), and metal is preferable. Furthermore, when the lid and bottle packaging are made of thermoplastic resin, plastic bottle packaging with a seal (preferably an aluminum seal) is preferred.

"Pillow packaging" refers to a packaging form in which the pharmaceutical composition of the present invention, either as it is or in a PTP-packaged state, is covered with a film in the form of a bag and then made airtight while containing gas. Examples of the material for the pillow packaging include aluminum laminate film, thermoplastic resin, and a combination thereof, with aluminum laminate film being preferred.

"Airtight" means a state in which there is no risk of liquid intrusion during daily handling or under normal storage conditions. Furthermore, airtightness includes a state in which the intrusion of gas is suppressed depending on the degree. In the case of bottle packaging, the degree of airtightness can be quantified using, for example, "closing torque." Examples of the numerical value include 100 to 300 N·cm, preferably 150 to 250 N·cm, and more preferably 200 to 220 N·cm. The airtight state may be a sealed state.

"Hermetically sealed" means a state in which there is no risk of gas or microorganisms entering during daily handling or under normal storage conditions.

Examples of materials for PTP packaging and blister pack packaging include resins such as thermoplastic resins, metals, various paints, and various adhesives, with thermoplastic resins being preferred.

Examples of thermoplastic resins include polyvinyl chloride (PVC), unstretched polypropylene (CPP), polypropylene (PP), polyvinylidene chloride (PVDC), polytrifluorochloroethylene (PCTFE), and cyclic olefin copolymers ( COC), polyethylene (PE; high density, medium density and low density), polycarbonate (PC), polyamide (PA), ethylene-vinyl acetate copolymer (EVA), ethylene-methacrylate copolymer, polystyrene (PS) , polyester (PET), polyacrylic acid (PAA), ethylene-vinyl alcohol copolymer, etc., preferably polyvinyl chloride, unstretched polypropylene, polypropylene, polyvinylidene chloride, polytrifluoroethylene chloride, cyclic These are olefin copolymers and ethylene-vinyl alcohol copolymers. These may be used alone or in combination of two or more. Examples of the lid material for PTP packaging include aluminum foil, a laminate film in which aluminum foil is laminated with a thermoplastic resin film, and the like. A known method may be used to produce the PTP packaging or the blister pack packaging. The packaging material for pillow packaging, PTP packaging, or blister pack packaging in the present invention is not limited to a single layer, but may be in the form of a multilayer film in which a plurality of layers are bonded together. The multilayer film can have a barrier layer that suppresses permeation of oxygen as an outer layer or an intermediate layer, and an absorbent layer that has an oxygen scavenging function as an inner layer or an intermediate layer. Examples of the absorbent layer having an oxygen scavenging function include a resin kneaded with an oxygen scavenger that exhibits the oxygen scavenging function.

Moreover, a packaging form with high light-shielding properties is preferable, such as packaging in a brown glass bottle with a metal cap.

When the pharmaceutical composition and oxygen scavenger of the present invention are hermetically sealed in a package, the gas in the package may be a gas other than oxygen (e.g., nitrogen gas, carbon dioxide gas, helium gas, argon gas, neon gas, Krypton gas, xenon gas, radon gas) may be substituted.

It is difficult to completely eliminate the presence of ED-71 epoxide in the pharmaceutical composition (preferably tablets) of the present invention prepared through a drying step (step (iii)) in which it contacts with air, and Although it is a substance that is allowed to exist, its content is preferably as low as possible from the viewpoint of the effectiveness of ED-71. Specifically, the content is preferably 5% or less, more preferably 2% or less, even more preferably 1.2% or less. A specific example of a preferable content is 0.5%. The lower limit of the content may be, for example, 0.1% or less. In addition, the "content" of ED-71 epoxide is calculated based on the peak area obtained from the 220 nm profile when analyzed by liquid chromatography under the conditions described in Test Example 3 of the following example. Ratio of the content of ED-71 epoxide to the total content of ED-71, ED-71 epoxide, Pre ED-71, which is a thermal isomer of ED-71, and other ED-71 related substances in the pharmaceutical composition (% ) and is calculated using the following formula.
Content of ED-71 epoxide (%) = (A _imp-2 × RRF) / (A _t + A _imp-2 × RRF + A _p × RRF + Σ (A _i × RRF)) × 100
A _t : Peak area of ED-71 A _p : Pre peak area of ED-71 A _imp-2 : Peak area of ED-71 epoxide A _i : Peak area of other ED-71 related substances RRF: Relative to ED-71 Relative sensitivity coefficient; Pre ED-71, 1.79; ED-71 epoxide, 1.72; Other ED-71 related substances, 1.00

In addition, all prior art documents cited in this specification are incorporated herein by reference.

The present invention will be explained in more detail with reference to Examples.

In this example, the following abbreviations are used.
EtOH: ethanol
HPMC: Hydroxypropyl methylcellulose
BHT: dibutylhydroxytoluene
MCT: Medium chain fatty acid triglyceride
HPC: Hydroxypropylcellulose
PVP: Polyvinylpyrrolidone
PVA copolymer: Polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer

Example 1: Mixture change 1
An ethanol solution of ED-71 was prepared by dissolving 50 mg of ED-71 in 2.5 mL of EtOH. 1 g of BHT (Merck) and 2 g of dl-α-tocopherol (special use, Wako Pure Chemical Industries), 97 g of MCT
(O.D.O.C, Nisshin Oilio) to prepare an MCT solution. ED-7 in the prepared MCT solution
0.5 mL of the ethanol solution of 1 was added, and the mixture was stirred with a vortex mixer. Further, the residue was distilled off under reduced pressure to prepare an ED-71 oil and fat solution. 300 mg of hydroxypropyl methylcellulose was added to 150 mg of the prepared ED-71 oil solution to prepare an ED-71 composition (Example 1). Prepared ED-71
The composition was stored in the presence of air in a constant temperature bath adjusted to 60°C, and the residual rate (%) of ED-71 was examined after 14 and 28 days.
As a control substance, the above ED-71 fat solution alone (Control Example 1) was used.
In addition, an ED-71 composition was prepared in the same manner as in Example 1 using the additives (300 mg) listed in Table 1 instead of the hydroxypropyl methylcellulose in Example 1, and the stability at 60°C was determined. The same investigation as in Example 1 was conducted.

The results are shown in Table 1. As is clear from Table 1, the composition of Example 1 is as stable as or more stable than the oil/fat liquid alone of Control Example 1, and is also less stable under high temperature conditions than the compositions of Control Examples 2 to 34. Ta.

Example 2: Mixture change 2
The ED-71 compositions of Example 2 and Control Example 35 were prepared in the same manner as in Example 1, using the additives listed in Table 2 in place of the hydroxypropyl methylcellulose in Example 1, and Stability was investigated in the same manner as in Example 1 and compared with Control Example 1. The results are shown in Table 2. The composition of Example 2 was shown to be as stable as or more stable than Control Example 1, and more stable under high temperature conditions than the compositions of Control Examples 2 to 34 shown in Table 1. Although no decrease in the stability of ED-71 was observed in the composition of Control Example 35, when meglumine was used as an additive, the emulsification state required in the manufacturing process of oil dispersion tablets described below could be improved. Meglumine was found to be unsuitable as an additive for the production of oil dispersion tablets for reasons such as inability to maintain.

[Test Example 1] Emulsion Stabilization Test As described below, in the process of manufacturing oil dispersion tablets, it is necessary to maintain an emulsified state between the MCT solution of ED-71 and the aqueous solution of the water-soluble polymer. Therefore, an emulsion of MCT and a water-soluble polymer was prepared and the emulsion state was investigated.
HPMC (TC-5R, Shin-Etsu Chemical), HPC (SSL, Shin-Etsu Chemical), PVP (K90, BASF), POVA-COAT (F, Daido Kasei Kogyo) were dissolved in purified water, and 2% and 5%, respectively, were dissolved in purified water. An aqueous solution was prepared. 20 mL of each solution was added to a 50 mL plastic centrifuge tube. 10 mL each of medium-chain fatty acid triglyceride colored red by dissolving Oil Red (Oil Red O, Nacalai Tesque) at 0.1 g/L was added thereto.
After emulsifying by stirring with a homogenizer at about 10,000 rpm for 1 minute, the presence or absence of separation of an oil layer at the top of the emulsion was determined after 2 and 24 hours.

The results are shown in Table 3. Furthermore, Fig. 2 shows the emulsified state (photograph) in the centrifuge tube after 24 hours when a 2% aqueous solution of water-soluble polymer was used. HPMC, HPC, and PVA copolymers did not cause separation of water and oil layers, whereas PVP did.

Examples 3-11: Stability of ED-71 during emulsion preparation
An ethanol solution of ED-71 was prepared by dissolving 100 mg of ED-71 in 5.0 mL of EtOH. 1 g of BHT (Merck) and 2 g of dl-α-tocopherol (special use, Wako Pure Chemical Industries) were dissolved in 97 g of MCT (O.D.O.C, Nisshin Oilio) to create an MCT solution. was prepared. 0.5 mL of an ethanol solution of ED-71 was added to the prepared MCT solution and stirred with a vortex mixer to obtain an ED-71 dissolved MCT solution. Each of the water-soluble polymer solutions shown in Table 4 was prepared. The ED-71-dissolved MCT solution and the water-soluble polymer solution were mixed at the ratios shown in Table 5, and stirred for 1 minute at 5400 rpm using a homogenizer to emulsify, thereby preparing an ED-71-containing emulsion. The prepared emulsion containing ED-71 was weighed out so that the amount of ED-71 drug substance was approximately 1 μg, and it was evaporated under reduced pressure in a vacuum dryer, and the obtained sample was used to measure the residual rate (Example 3). ~11). The samples were stored in the presence of air in a constant temperature bath adjusted to 60°C, and the ED-71 content immediately after preparation, and the ED-71 content and residual rate (%) after 14 and 25 days were examined. Each content value was calculated using a sample obtained by weighing the ED-71-dissolved MCT solution so that the amount of ED-71 drug substance was approximately 1 μg and distilling it off under reduced pressure in a vacuum dryer as a standard product. The content value and residual rate of ED-71 were calculated using the following formula.
Content value of ED-71 (%) = Total ED-71 peak area in sample / Total ED-71 peak area in standard product (Total ED-71 peak area = ED-71 peak area + 1.98 x Pre ED- 71 peak areas)
ED-71 residual rate (%) = Average content value of accelerated samples / Average content value of samples immediately after preparation

The results are shown in Table 5. As can be seen from Table 5, it was found that in formulations with a low concentration of water-soluble polymer (1%), there was a large variation in the content value of ED-71. This is thought to be due to the fact that in formulations with a low concentration of water-soluble polymer, separation of the emulsion was observed after preparation, and variations were observed in the weighed amount of ED-71 in the sampled emulsions. For samples with a water-soluble polymer concentration of 5% or 6%, the results showed little variation, and the residual rate of ED-71 after 25 days was over 95%. For formulations with a high concentration of water-soluble polymer (10% or 15%), the variation was small, but the ED-71 residual rate decreased to around 90% in samples after 25 days.
The concentration of the water-soluble polymer solution containing 1% to 15% of HPMC or HPC is preferably 5 to 6% for stabilizing ED-71 in the emulsion.

[Manufacturing example] Oil dispersion tablets
dl-α-tocopherol (Wako Pure Chemical Industries) 0.142 kg and BHT (Merck) 0.284 kg to MCT
(Nissin Oilio) Dissolved in 9.025 kg, here Eldecalcitol (ED-71) 1.1813
After adding 0.078 kg of ethanol (99.5%) (Imazu Pharmaceutical Co., Ltd.) solution, the ethanol was distilled off under reduced pressure (Solution 1).
1.134 kg of hypromellose (HPMC) (TC-5R, Shin-Etsu Chemical) was dissolved in 17.766 kg of purified water (solution 2).
6 kg of Solution 2 was added to 3 kg of Solution 1, and the mixture was stirred for 10 minutes using a homogenizer (T-50 Ultra Turrax manufactured by IKA; rotation speed: 9,600 rpm). This operation was repeated three times to obtain an emulsion.

165.6 kg of mannitol (Merck) sieved through a vibrating sieve with an opening of 850 μm was agitated in a high-speed stirring granulator (POWREX VG-600CT) with a blade of 56 rpm and a cross screw of 1500 rpm, and the emulsion was sprayed. The mixture was added and kneaded for 15 minutes to obtain a granulated powder.

The obtained granulated powder was passed through a wet granulation machine (U-20 made by POWREX) equipped with a 9.5 mm (square hole) screen while operating at 300 rpm, and passed through a fluidized bed granulation dryer ( POWREX WSG-200pro)
and dried (sample 1).

The dried granulated powder was sized by operating a dry granulator (U-20 manufactured by POWREX) equipped with a screen with a diameter of 2 mm at 800 rpm.
The sized product was mixed for 15 minutes with a mixture of 3.0 kg of mannitol and 3.6 kg of croscarmellose sodium (DFE pharma), each sieved through an 850 μm sieve, and then mixed with mannitol, each sieved through an 850 μm sieve. After mixing with a mixture of 6.6 kg and 0.72 kg of calcium stearate (Merck) for 3 minutes (sample 2), it was compressed into tablets using a tablet press (COMPRIMA manufactured by IMA) at a pressure of approximately 7.5 kN (sample 3). . During tabletting, the tablet weight was adjusted so that the eldecalcitol content per tablet was 0.75 μg.

All the obtained tablets were put into a coating machine (PRC-450 manufactured by Powrec), dried by spraying a solution of 6.480 kg of HPMC in water (74.520 kg) at 60°C, and further coated with 4.950 kg of hypromellose and talc ( Merck) 1.350 kg, titanium oxide (Ishihara Sangyo) 2.664 kg, and iron sesquioxide (Kishimi Kasei) 0.036 kg in water (65.167 kg) were sprayed and dried to form tablets coated with two layers of film. (Sample 4; eldecalcitol content per tablet was 0.75 μg).

When preparing tablets with an eldecalcitol content of 0.5 μg per tablet, the second layer contains 4.950 kg of hypromellose, 1.350 kg of talc (Merck), and 2.502 kg of titanium oxide (Ishihara Sangyo).
, a suspension of 0.018 kg of iron sesquioxide (Hisumi Kasei) and 0.180 kg of yellow iron sesquioxide (Hisumi Kasei) in water (65.167 kg) was coated by spraying.
A schematic diagram of the manufacturing flow is shown in Figure 1.

[Test Example 2] Accelerated Stability Test Tablets obtained from "[Production Example] Oil dispersion tablets" (two types with eldecalcitol content per tablet of 0.5 μg and 0.75 μg) were placed in a high-density polyethylene bottle container ( 500 tablets each were put into NC-130 (Shinko Chemical). Close the bottle with a polypropylene cap (SK-200B, Shinko Chemical), store it in a constant temperature bath adjusted to 40℃/75%RH, and measure the survival rate of ED-71 after 1 month, 3 months, and 6 months. I looked into it.

The residual rate of ED-71 was measured by the following method.
Five tablets were placed in a 30 mL centrifuge tube. 7 mL of water:acetonitrile (20:80) was added and ultrasonic irradiation was performed for 30 minutes. Stirring was performed once every 10 minutes during ultrasonic irradiation. The supernatant was filtered through a polytetrafluoroethylene (PTFE) filter with a pore size of 0.20 μm, the first approximately 1 mL was discarded, and the remaining filtrate was used as a sample solution. Separately, a standard solution was prepared using the ED-71 standard product by dissolving it in water:acetonitrile (20:80) to a concentration of approximately 0.6 μg/mL in the same manner as the sample solution preparation. The sample solution and standard solution were measured by high performance liquid chromatography (Waters Alliance, measurement wavelength 265 nm) to quantify the ED-71 content in the sample.

The survival rate of ED-71 was calculated using the following formula.
Residual rate of ED-71 (%) = Ratio of ED-71 content in accelerated sample to labeled amount (%) / Ratio of ED-71 content in unaccelerated sample to labeled amount (%) x 100
The labeled amount is the weight of ED-71 intended to be contained in one tablet (0.5 μg).
or 0.75 μg).

The tablets obtained in "[Production Example] Oil dispersion tablets" were shown to be stable under the acceleration conditions specified in the ICH guidelines (Q1A).

[Test Example 3] Purity Test 20 tablets obtained from "[Production Example] Oil dispersion tablets" were crushed using a small crusher LM-Plus (manufactured by Osaka Chemical Co., Ltd.), and 1.6 g of the crushed sample was weighed out. Ta. 40 mL of a mixed solution of ethyl acetate and hexane mixed at a volume ratio of 1:1 was added, stirred, and subjected to ultrasonic irradiation for 20 minutes. After centrifugation at 3000 rpm for 5 minutes, the supernatant was filtered with a membrane filter (DISMIC-25HP PTFE 0.2 μm HYDROPHILIC, manufactured by ADVANTEC). The filtrate was poured into a solid phase extraction cartridge (InertSep ^™ NH ₂ FF 500 mg/3 mL, manufactured by GL Sciences), washed with 10 mL of a mixed solution of ethyl acetate and hexane at a volume ratio of 1:1, and then washed with 6 mL of ethanol. was passed through and eluted. After the eluted liquid was distilled off to dryness using an evaporator, 100 μL of a mixed solution of water and acetonitrile mixed at a volume ratio of 1:1 was added to redissolve it to obtain a sample solution. For liquid chromatography, ACQUITY UPLC H-Class (manufactured by Waters) was used, and a purity test was conducted under the following analysis conditions.
Column: Kinetex Evo C18 (2.6 μm, 4.6 mm x 100 mm, manufactured by Phenomenex)
Column temperature: 30℃
Mobile phase: water (A) and acetonitrile (B)
Flow rate: 1.0 mL/min Detector: Photodiode array Detection wavelength: 210 nm to 400 nm
Elution method: A concentration gradient was set as shown in Table 7.

The results are shown in Figure 3. In addition to the detection of ED-71 (retention time approximately 10.4 minutes) and its thermal isomer Pre ED-71 (retention time approximately 8.3 minutes), an unknown peak was detected with a retention time of approximately 5.2 minutes. Detected in minutes. This unknown peak was later found to be a peak derived from Compound 2.

[Test Example 4] Measurement of the content of Compound 2 in each step of tablet production The content of Compound 2 was measured for Samples 1 to 4 in the above production example. Samples 3 and 4 were subjected to a purity test in the same manner as in Test Example 3, and samples 1 and 2 were subjected to a purity test in the same manner as in Test Example 3 except that the crushing step was omitted.

The content of Compound 2 was determined from the 220 nm profile obtained from liquid chromatography analysis under the conditions described in Test Example 3. The peak areas of ED-71 and other ED-71 related substances were determined and calculated using the following formula. Note that the peak areas of Compound 2, Pre ED-71, and other ED-71 related substances were corrected by the relative sensitivity factor (RRF) with respect to ED-71.
Content of compound 2 (%) = (A _imp-2 × RRF) / (A _t + A _imp-2 × RRF + A _p × RRF + Σ (A _i × RRF)) × 100
A _t : Peak area of ED-71 A _p : Peak area of Pre ED-71 A _imp-2 : Peak area of compound 2 A _i : Peak area of other related substances RRF: Pre ED-71, 1.79; Compound 2, 1.72; Other related substances, 1.00

The results are shown in Table 8. The content of Compound 2 contained in Sample 1 (dry powder) was 0.5%, and no significant increase was observed in Samples 2 and 3 obtained in subsequent manufacturing steps. Therefore, it was suggested that Compound 2 may be mainly produced up to the drying process.

As shown in the UV-visible spectrum of ED-71 (FIG. 4), ED-71 has a triene structure in its molecule, so its UV absorption is maximized at 265 nm. On the other hand, in the UV-visible spectrum of Compound 2 (FIG. 3), no characteristic peak at 265 nm due to the triene structure of ED-71 was observed. This result suggested that Compound 2 might be a decomposition product of ED-71 in which the triene structure was destroyed. It is known that vitamin _D3 , to which ED-71 belongs, is easily degraded by oxidation. In the drying process, the sample is fluidized by hot air in a drying tower. Samples that remain in the fluidized bed have an increased chance of coming into contact with oxygen in the air, so they can be said to be in an environment that is susceptible to oxidation. From the above, it was presumed that the production of Compound 2 involved oxidation of ED-71 during the manufacturing process.

[Test Example 5] Preparation of Compound 2 by air oxidation of ED-71 and determination of its structure For structure determination, Compound 2 was prepared in large quantities.
A 1:1 mixed solution (10 mL) of ED-71 (60 μg) in water:acetonitrile was added to a vial, and the mixture was vigorously stirred for 16 hours at 30° C. in the atmosphere using a magnetic stirrer to promote oxidation. Since the liquid volume decreased due to volatilization, 3 mL of acetonitrile was additionally added after stirring. As a result of analysis under the same analysis conditions as Test Example 3, Compound 2 and Compound 2 were detected in all of Sample 1 (dry powder), Sample 2 (mixed powder), Sample 3 (uncoated tablet), and Sample 4 (film-coated tablet). Peaks with similar UV-visible spectra were detected at the same retention time. This peak was fractionated, and the structure was determined using a liquid chromatograph mass spectrometer LCMS-IT-TOF (manufactured by Shimadzu Corporation) and a nuclear magnetic resonance apparatus Agilent DD2 600MHz NMR Spectrometer (manufactured by Agilent Technologies).
MS m/z: 529.3528 (M ⁺ -Na)
¹ H-NMR (500 MHz, acetonitrile-d ₃ ) δ: 0.74 (s, 3H), 0.94 (d, 3H), 1.00-1.43 (m, 18H), 1.55-1 .87 (m, 8H), 1.96-1.99 (m, 1H), 2.33 (d, 1H), 2.45 (dd, 1H), 3.18 (dd, 1H), 3. 60-3.64 (m, 1H), 3.64-3.67 (m, 2H), 3.75-3.80 (m, 1H), 3.82 (d, 1H), 4.14- 4.17 (m, 1H), 4.19-4.22 (m, 1H), 5.00 (t, 1H), 5.23 (dd, 1H), 5.36 (t, 1H)

From the molecular weight obtained by LC/MS, it was estimated that Compound 2 was an oxygen adduct of ED-71. Furthermore, the results of various NMR measurements suggested that Compound 2 was an epoxy compound in which oxygen was added to the triene moiety of ED-71. From the above, compound 2 is (1R, 2R, 3R, 5Z, 7ξ, 8ξ)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10(19)-secocholester-5,10-diene- It was identified as 1,3,25-triol.

[Test Example 6] Chemical synthesis of Compound 2 In this test example, proton nuclear magnetic resonance spectra ( ^1H -NMR spectra) were measured in chloroform-d or acetonitrile- _d3 in the presence or absence of tetramethylsilane as an internal standard. Below, measurements were taken using ECP500 (manufactured by JEOL). Further, the purity analysis of the obtained Compound 2 by liquid chromatography was conducted in the same manner as in Test Example 3.

6-1: Method 1

(1R,2R,3R,5Z,7E)-2-(3-hydroxypropoxy)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol (compound 1, 504 3-chloroperbenzoic acid (74.2%, 251.4 mg, 1.08 mmol) was added to a suspension of sodium bicarbonate (170.4 mg, 2.03 mmol) in dichloromethane (15 mL). It was added at -70°C and the temperature was raised to 10°C over 3 hours. The reaction mixture was cooled to -30°C, 3-chloroperbenzoic acid (25.4 mg, 0.109 mmol) was added, and the temperature was raised to around 1°C over 0.5 hours. A 5% aqueous sodium hydrogen carbonate solution (5 mL) was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was extracted with dichloromethane (5 mL). The aqueous layer was extracted again with dichloromethane (10 mL), and the extracts were combined and dried over anhydrous sodium sulfate. The solids were removed by filtration and washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure, and the fraction containing Compound 2 obtained by silica gel chromatography (dichloromethane:ethanol, 1:0→19:1→12:1, v/v) was concentrated. The resulting residue was dissolved in acetone (5 mL) and concentrated to dryness to give (1R, 2R, 3R, 5Z, 7ξ, 8ξ)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10. (19)-Secocholesta-5,10-diene-1,3,25-triol (Compound 2, 342.3 mg, purity 90.4 area %) was obtained. The ¹ H-NMR spectrum of Compound 2 thus obtained matched that of the compound obtained in Test Example 5.

6-2: Method 2

Step 1: ((1R,2R,3R,5Z,7E)-25-hydroxy-1,3-bis[(methoxycarbonyl)oxy]-2-{3-[(methoxycarbonyl)oxy]propoxy}-9, 10-Secocholesta-5,7,10(19)-triene (compound 3))
(1R,2R,3R,5Z,7E)-2-(3-hydroxypropoxy)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol (compounds 1, 4 1-Methylimidazole (3.6 mL, 44.9 mmol) was added to a suspension of .008 g, 8.17 mmol) in dichloromethane (40 mL), and the mixture was cooled in an ice bath. Methyl chloroformate (3.1 mL, 40.8 mmol) was added dropwise to the reaction mixture at 10° C. or below, and after stirring at room temperature for 15 hours, the solvent was distilled off under reduced pressure. Water (40 mL) was added to the residue, and the mixture was extracted with a mixture of heptane (10 mL) and ethyl acetate (30 mL). The extract was washed with water (40 mL) and a saturated aqueous sodium bicarbonate solution (40 mL), passed through diatomaceous earth and anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane:dichloromethane:ethyl acetate, 1:1:0→5:5:2→3:3:2, v/v/v) to obtain compound 3 (5. 3863g) was obtained.

Step 2: ((1R, 2R, 3R, 5Z, 7ξ, 8ξ)-25-hydroxy-1,3-bis[(methoxycarbonyl)oxy]-2-{3-[(methoxycarbonyl)oxy]propoxy}- 7,8-epoxy-9,10-secocholesta-5,10(19)-diene (compound 4))
3-chloroperbenzoic acid (74.2%) was added to a suspension of compound 3 obtained in step 1 (5.3863 g, 8.10 mmol) and sodium hydrogen carbonate (1.3694 g, 16.3 mmol) in dichloromethane (81 mL). , 1.9917g, 8.56mmol) at 0°C,
The mixture was stirred at the same temperature for 3.5 hours. A 5% aqueous sodium hydrogen carbonate solution (40 mL) was added to the reaction mixture, the temperature was raised to room temperature, and then the aqueous layer was removed. The organic layer was passed through diatomaceous earth and anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (heptane: dichloromethane: ethyl acetate, 1:1:0 → 3:3:2 → 1:1:2, v/v/v) to obtain compound 4 (4. 2359g) was obtained.

Step 3: ((1R,2R,3R,5Z,7ξ,8ξ)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10(19)-secocoresta-5,10-diene-1, 3,25-triol (compound 2))
A mixture of Compound 4 obtained in Step 2 (4.1369 g, 6.08 mmol), potassium carbonate (0.8406 g, 6.08 mmol) and methanol (61 mL) was stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane (183 mL) and filtered through silica gel. The silica gel was washed with dichloromethane-methanol (3:1, 100 mL), and the combined filtrates were concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:acetone, 1:0 → 1:1 → 1:2, v/v) to obtain Compound 2 (2.7679 g, purity 97.0 area%). Ta. The ¹ H-NMR spectrum of Compound 2 thus obtained matched that of the compound obtained in Test Example 5.

[Test Example 7] Suppression of increase in Compound 2 in tablets during long-term storage Since Compound 2 is an oxide of ED-71, adding an oxygen scavenger during packaging may reduce the increase in Compound 2 during storage of manufactured tablets. There is a possibility that the increase in Compound 2 can be suppressed. To test this hypothesis, we determined the content of compound 2 for sample 4 (film-coated tablets) after storage in amber glass bottles in the absence and presence of oxygen scavengers at a storage temperature of 25°C and a relative humidity of 75%. was evaluated.

First, sample 4 (500 tablets) was filled into a brown glass bottle (manufactured by Daiichi Glass Co., Ltd., PS-10K (brown)), and the steel cap (manufactured by Araki Kogyo Co., Ltd., No. 10-13 (L)) was closed to make it airtight. state. The content of Compound 2 in Sample 4 after being stored for 19 months at a storage temperature of 25°C and a relative humidity of 75% was measured in the same manner as Test Example 3, and was taken as the content of Compound 2 in the absence of an oxygen scavenger. .
Next, sample 4 (500 tablets) was filled into a brown glass bottle, an oxygen absorber (Mitsubishi Gas Chemical Co., Ltd., Ageless ZM, ZM-1) was added, and the steel cap was closed to make it airtight with a closing torque of 200 to 220 N cm. state. The content of Compound 2 in Sample 4 after being stored for 19 months at a storage temperature of 25° C. and a relative humidity of 75% was measured in the same manner as in Test Example 3, and was taken as the content of Compound 2 in the presence of an oxygen scavenger.

The results are shown in Table 9.

In the absence of oxygen scavenger, compound 2 increased to 1.5%. On the other hand, in the presence of an oxygen scavenger, the amount of Compound 2 was 0.4%, and the addition of the oxygen scavenger suppressed the increase during the storage period.

The present invention makes it possible to provide ED-71 preparations in dosage forms other than soft capsules, in which the decomposition of ED-71 is suppressed.

Claims (8)

ED-71 and (1R,2R,3R,5Z)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10(19)-secocoresta-5,10-diene-1,3,25- A method for producing a pharmaceutical composition comprising a triol, the method comprising:
A step of preparing an oil-in-water emulsion containing an oil/fat solution of ED-71 and an aqueous solution of a water-soluble polymer, a step of adhering or adsorbing the oil-in-water emulsion to an excipient, and drying the oil-in-water emulsion. The process of making
including;
The above method, wherein the water-soluble polymer is selected from hydroxypropylmethylcellulose and hydroxypropylcellulose. The method according to claim 1, wherein the weight ratio of oil-in-water emulsion to excipient is 1:4 to 1:20. 3. A method according to claim 1 or 2, wherein the excipient is selected from sugars or sugar alcohols. 4. The method of claim 3, wherein the excipient is mannitol. ED-71 and (1R,2R,3R,5Z)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10(19)-secocoresta-5,10-diene-1,3,25- A pharmaceutical composition comprising a triol,
The particles include particles coated with a coating agent containing a water-soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose in an excipient or on the surface of the excipient, and the particles are coated with an oil and fat solution of ED-71. The above pharmaceutical composition comprising. Pharmaceutical composition according to claim 5, wherein the excipient is selected from sugars or sugar alcohols. 7. A pharmaceutical composition according to claim 6, wherein the excipient is mannitol. The pharmaceutical composition according to any one of claims 5 to 7, which is a coated tablet coated with an HPMC film.