WO2020004541A1 - Pharmaceutical composition comprising oil component dispersion that contains ed-71 and epoxy form thereof in fat/oil - Google Patents

Abstract

The present invention provides a method for producing a pharmaceutical composition comprising ED-71 and an epoxy form thereof, said method comprising a step for preparing an oil-in-water type of emulsion comprising a fat/oil solution of (5Z,7E)-(1R,2R,3R)-2-(3-hydroxypropoxy)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol (ED-71) and an aqueous solution of a water-soluble polymer. The water-soluble polymer is selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose.

Description

Pharmaceutical composition containing oil dispersion containing ED-71 and its epoxy compound in fats and oils

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

ED-71 (generic name: eldecalcitol) is a synthetic derivative of active vitamin D ₃ with bone formation action, which is manufactured and sold as a therapeutic agent for osteoporosis by oral administration.

@ ED-71, like other vitamin D derivatives, can be formulated as soft capsules. Patent Literature 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 in a gelatin skin. Patent Literature 1 also discloses that the addition of an antioxidant such as dl-α-tocopherol to the solution suppresses the production of decomposed products of ED-71, a taxosterol compound and a trans compound. ing.

At present, there are no known ED-71 preparations other than soft capsules that are commercially available. Patent Literature 2 discloses a combination of a strontium salt and a vitamin D derivative applicable to osteoporosis, and mentions eldecalcitol as an example of the vitamin D derivative. Patent Document 2 describes that the mixture can be made into a tablet. However, the description is merely a description as a general tablet, and does not disclose the effect of adding a specific additive other than a strontium salt to the ED-71 formulation.

Patent Document 3 discloses that, for example, a reaction product obtained by dissolving 1α- (OH) -D ₃ and polyvinylpyrrolidone in ethanol, adding anhydrous lactose, stirring and distilling off ethanol under reduced pressure is further pulverized. A 1α- (OH) -D ₃ composition obtained by the above method is described.

Patent Document 4 discloses a solid dispersion of ED-71 (a composition in which solid ED-71 and a solid additive are mixed) and an oil dispersion (particles of a fat solution of ED-71 in an excipient). And a method for producing the same.

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

WO2005 / 074943A1 CN102688249A WO90 / 09796A PCT / JP2017 / 047156 (released as WO2018 / 124260 on July 5, 2018) JP-A-58-216179

0.5 μg and 0.75 μg of Edirol (registered trademark) capsules that are commercially available as therapeutic agents for osteoporosis are only spherical soft capsules, and development of a functionally superior ED-71 formulation using a new formulation is required. Had been. Further, by making the spherical soft capsule non-spherical, there has been a demand for usability such that the soft capsule is more easily pinched and hard to roll. For the convenience of patients who need to administer ED-71, development of a non-spherical ED-71 formulation other than soft capsules has been required.

The present inventors have proceeded with the development of a formulation prepared from an oil dispersion in which particles of a fat solution of ED-71 are dispersed in an excipient as such a formulation. It has been found that the use of an oil dispersion prepared using the oil / fat solution as it is cannot produce a preparation of sufficient quality. As a result of further research to solve this problem, the idea of coating the particles of the ED-71 oil and fat solution with a specific additive was obtained, but the stability of the ED-71 depends on many of the additives used. A new problem has been found that is reduced. In order to solve this new problem, the present inventors have made it possible to produce a sufficiently high-quality preparation (particularly, a tablet) by using a water-soluble polymer such as hydroxypropylmethylcellulose or hydroxypropylcellulose as an additive. (Patent Document 4).

The present invention has been made in view of such circumstances, and an object of the present invention is to provide a novel pharmaceutical composition containing an ED-71 oil dispersion and a method for producing the same.

The present inventors have newly found that only a small portion (several percent or less) of ED-71 is converted to ED-71 epoxide in the process of producing a tablet containing an oil dispersion of ED-71. The present inventors have further studied 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) -secocholesta-5,10-diene-1,3 A process for the preparation of a pharmaceutical composition comprising, 25-triol,
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;
The step of attaching or adsorbing the oil-in-water emulsion to the excipient, and the step of drying the oil-in-water emulsion,
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 and the excipient is from 1: 4 to 1:20.
[3] The method according to [1] or [2], wherein the excipient is selected from sugar 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) -secocholesta-5,10-diene-1,3 A pharmaceutical composition comprising, 25-triol,
In the vehicle or on the surface of the vehicle, comprising particles coated with a coating agent containing a water-soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose,
The above-mentioned pharmaceutical composition, wherein the particles comprise a fat solution of ED-71.
[6] The pharmaceutical composition according to [5], wherein the excipient is selected from sugar 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.

Further, 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 scavenger 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, it is possible to suppress the decomposition of ED-71 caused by the contact with the additive (change in blending) in the oil dispersion. In addition, ED-71 preparations in various dosage forms other than soft capsules can be produced using the oil dispersion.

It is a schematic diagram of a production flow for producing a tablet containing an oil dispersion of ED-71. 3 is a photograph showing an emulsified state when a 2% aqueous solution of a water-soluble polymer is mixed with a medium-chain fatty acid triglyceride. From left, HPMC, HPC, PVP, and POVA-COAT. It is the analysis result by the liquid chromatography of the tablet obtained by "[Production example] oil-dispersion tablet." It is an ultraviolet-visible spectrum of ED-71. It is an ultraviolet-visible spectrum of ED-71 epoxide (compound 2).

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

ED-71 can be prepared, for example, according to the method described in JP-A-10-72432 by using (1R, 2R, 3R) -2- (3-hydroxypropoxy) -cholesta-5,7-diene-1,3,25-. Using triol as a starting material, it can be obtained by purifying by reverse phase HPLC after ultraviolet irradiation and thermal isomerization reaction, concentrating, and crystallizing with ethyl acetate.

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

In the ED-71 epoxide, the stereochemistry of the epoxy moiety (positions 7 and 8) is not specified, but the compounds represented by the following formulas (IIa) and (IIb) in which they are specified, The compound represented by the following formula (IIc) mixed with the above is also included in the ED-71 epoxide. As the ED-71 epoxide, any of the compounds represented by the following formulas (IIa) and (IIb), that is, (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.
The stereo at position 14 in compounds (II), (IIa), (IIb) and (IIc) is preferably the same as that of compound (Ia).

Oil dispersion of ED-71
Pharmaceutical compositions comprising an ED-71 and ED-71 epoxide and TECHNICAL FIELD The present invention relates to oil dispersion comprising oil dispersion and ED-71 and ED-71 epoxide of ED-71. In the present specification, the oil dispersion of ED-71 refers to a composition in which particles of a fat or oil solution of ED-71 are dispersed in an excipient. Similarly, the oil dispersion containing ED-71 and ED-71 epoxide refers to a composition in which particles of fats and oils containing ED-71 and ED-71 epoxide are dispersed in an excipient.

The present invention provides a pharmaceutical composition comprising such an oil dispersion containing ED-71 and ED-71 epoxide. Specifically, a pharmaceutical composition containing ED-71 and ED-71 epoxide, wherein a water-soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose is added to or on the surface of an excipient. Comprising ED-71 and an ED-71 epoxide in a fat or oil solution.

The present invention also provides a method for producing such a pharmaceutical composition. Specifically, the present invention relates to a method for producing a pharmaceutical composition containing ED-71 and ED-71 epoxide, wherein (i) an oil-in-water emulsion containing an oil / fat solution of ED-71 and an aqueous solution of a water-soluble polymer. Preparing, (ii) attaching or adsorbing the oil-in-water emulsion to an excipient, and (iii) drying the oil-in-water emulsion, wherein the water-soluble polymer is hydroxy. The method provided above is selected from propylmethylcellulose and hydroxypropylcellulose. According to this method, the oil and fat particles containing ED-71 and ED-71 epoxide are coated with the water-soluble polymer in the excipient, and the formulation using the oil dispersion of ED-71 and ED-71 epoxide is obtained. (Especially tablets) can be produced. The ED-71 epoxide is not contained at the start of the step (i), or even if it is contained, it is preferably a small amount of not more than 0.1%, but mainly in the step (iii) It is produced by conversion (oxidation) of ED-71 and is contained in fats and oils. In the field of formulation, a method of impregnating an oil or fat solution containing an active ingredient with an excipient is already known, but using an oil-in-water emulsion instead of an oil or fat solution, or after attaching or adsorbing to an excipient. A method of drying an oil-in-water emulsion and coating the oil-fat solution with the components in the aqueous layer has not heretofore been known.

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 And the like. Here, examples of the vegetable oil include coconut oil, olive oil, rapeseed oil, peanut oil, corn oil, soybean oil, cottonseed oil, grape oil, safflower oil, and the like. Among these, MCT, tricaprylin, caproic acid, caprylic acid, or capric acid containing no unsaturated fatty acid is preferable, and MCT is particularly preferable.

The concentration of ED-71 in the fat or oil solution in step (i) can be appropriately determined according to the disease or condition to be treated, the dosage form, the administration route, etc., for example, 0.001 to 0.3% by weight. , Preferably 0.005 to 0.1% by weight, more preferably 0.01 to 0.05% by weight.

抗 An antioxidant may be further added to the fat or oil solution in the step (i). Examples of the antioxidant in the present invention include nitrite (eg, sodium nitrite), sulfite (eg, sodium sulfite, dried sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfite), thiosulfate (eg, sodium thiosulfate), Alpha thioglycerin, 1,3-butylene glycol, thioglycolic acid and its salts (eg, sodium thioglycolate), thiomalate (eg, sodium thiomalate), thiourea, thiolactic acid, edetate (eg, sodium edetate) , Dichloroisocyanurate (eg, potassium dichlorisocyanurate), citric acid, cysteine and its salts (eg, cysteine hydrochloride), benzotriazole, 2-mercaptobenzimidazole, erythorbic acid and its salts (eg, erysol) Sodium), ascorbic acid and its ester compounds (eg, L-ascorbic acid stearic acid ester, ascorbic acid palmitate), phospholipids (eg, soybean lecithin), metal chelators and salts thereof (eg, ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid) Disodium calcium acetate, disodium ethylenediaminetetraacetate), tartaric acid and its salts (eg, Rochelle salt), polyphenols (eg, catechin), glutathione, dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, natural vitamin E, tocopherol acetate, Concentrated and mixed tocopherols, tocopherol homologs (eg, d-α-tocopherol, dl-α-tocopherol, 5,8-dimethyltocol, 7,8-dimethyltocol, - methyl DOO call, 5,7,8- trimethyl-tocotrienol, 5,8-dimethyl-tocotrienol, 7,8-dimethyl-tocotrienol, 8-methyl-tocotrienol), and the like. Among them, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, dl-α-tocopherol, d-α-tocopherol, concentrated mixed tocopherol, ascorbic acid palmitate, stearic L-ascorbic acid ester, butylhydroxyanisole, propyl gallate Are preferred, dl-α-tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, or propyl gallate are more preferred, and dl-α-tocopherol or dibutylhydroxytoluene is even more preferred.

The amount of the antioxidant added to the fat or oil solution is not particularly limited, but is not more than the maximum amount that can be used as an antioxidant (for example, the approval described in the Pharmaceutical Additives Encyclopedia (Yakuji Nippo, 2000)) Normally, the maximum amount of use or less as described in the precedent example, or the amount of use or less as described in the Official Specification of Food Additives (Japan Food Additives Association, 1999) can be used.

In a preferred embodiment, dl-α-tocopherol is added to the fat or 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 addition amounts of dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate and the like are the same as those for dl-α-tocopherol described above.

被覆 The coating agent 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. When hydroxypropylmethylcellulose and hydroxypropylcellulose are used, the emulsified state of the oil-in-water emulsion can be maintained for a long time.

Here, the fact that the stability of ED-71 in the pharmaceutical composition of the present invention does not decrease means that tablets are produced from the pharmaceutical composition of the present invention and stored at 40 ° C. for 1, 3, or 6 months under light shielding. After that, it is confirmed by examining the residual ratio of ED-71. The residual ratio of ED-71 was determined for the preserved sample and the initial sample by high performance liquid chromatography (measuring wavelength: 265 nm) and ED-71 and its isomer pre-form (chemical name: 6Z- (1R, 2R, 3R)) -2- (3-hydroxypropoxy) -9,10-secocholesta-5 (10), 6,8 (9) -triene-1,3,25-triol; also referred to herein as Pre ED-71) Is measured and calculated by the following formula.
Content ratio (%) to the indicated amount of ED-71 = (weighed amount of ED-71 standard product / total ED-71 peak area in ED-71 standard product) x ED- in initial sample or stored sample 71 total peak area x (weight of initial sample or stored sample / weight of sample used for measurement) / display amount x 100
(Total ED-71 peak area = ED-71 peak area + 1.98 x Pre ED-71 peak area)
Residual rate of ED-71 (%) = ratio of content to indicated amount of ED-71 in stored sample (%) / ratio of content to indicated amount of ED-71 in initial sample (%) x 100

The meaning of each term in the above formula is as follows.
-"Displayed amount": theoretical content per tablet-"ED-71 standard": API of ED-71-"Measured amount of ED-71 standard / ED-71 peak in ED-71 standard" Total area ": Weight of ED-71 standard product per unit peak area (value for calculating ED-71 content in measurement sample from peak area)

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

In the present invention, hydroxypropylcellulose (HPC) is defined as a component in the Pharmaceutical Excipients Dictionary 2016 (edited by the Japan Pharmaceutical Excipients Association; published by Yakuji Nippo, Inc .; ISBN978-4-8408-1329-7). This refers to hydroxypropylcellulose listed as number 23303, which is different from the low-substituted hydroxypropylcellulose listed as component number 24440 in the same encyclopedia. In the hydroxypropylcellulose used in the present invention, the degree of molar substitution (MS) (indicating the ratio of the hydroxy group of the repeating unit (glucose ring) of the HPC to the hydroxypropoxy group) is usually 2-3, preferably 2. 5 to 3, more preferably 3. On the other hand, the molar substitution degree of the low-substituted hydroxypropylcellulose is 0.2 to 0.4. The hydroxypropyl cellulose in the present invention can be purchased, for example, from ASP Japan under the trade name Klucel and from Nippon Soda under the trade name hydroxypropyl cellulose.

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

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

油 The oil-in-water emulsion can be prepared by a method generally used in the field of pharmaceutical preparation, but is preferably prepared by a mechanical emulsification method. The mechanical emulsification method includes, for example, a chemical stirrer, a vortex mixer, a homomixer, a homogenizer, a hydroshear, a colloid mill, a flow jet mixer, an ultrasonic generator, a wet mill using glass beads, a membrane emulsifier using a porous membrane, Examples thereof include a method using an electroemulsifying apparatus using electric energy. As the homogenizer, for example, T-50 @ Ultra @ Turrax (manufactured by IKA) can be used.

The ratio (weight ratio, o / w ratio) of the oil / fat solution of ED-71 to the aqueous solution of the water-soluble polymer may be within a range in which an oil-in-water emulsion can be prepared, and is usually 1: 1.5. １ ： 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 ED-71 oil-fat solution and the water-soluble The ratio of polymer to aqueous solution is from 1: 1.5 to 1:20, 1: 2 to 1:20, or 1: 2 to 1: 4.

The ratio (weight ratio) of the fat / oil solution of ED-71 to the water-soluble polymer may be within a range in which the particles of the fat / oil solution of ED-71 can be coated with the water-soluble polymer. It 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 ED-71 oil-fat solution 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 from 0.01 to 100 μm, preferably from 0.1 to 10 μm.

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

The ratio (weight ratio) of the oil-in-water emulsion and the excipient used in the step (ii) may vary depending on the type of the excipient and the like, 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 producing a preparation such as a tablet.

The adhesion or adsorption of the oil-in-water emulsion to the excipient can be carried out by a method generally used in the field of pharmaceutical preparations, for example, a method of granulating the excipient by spraying the emulsion, shaping, A method of adding an emulsion to the agent and mixing and stirring. Such a method can be performed using, for example, a high-speed stirring granulator (VG-600CT manufactured by POWREX), a mixing stirrer (DM type manufactured by Shinagawa Kogyosho), or the like. The adhesion or adsorption includes impregnation (infiltration of an oil-in-water emulsion into pores with a porous excipient).

In step (iii), the oil-in-water emulsion adhering or adsorbed to the excipient is dried, whereby water is removed from the aqueous solution of the water-soluble polymer, and the oil-fat solution is directly coated with the water-soluble polymer. Is considered to be formed. The oil dispersion thus obtained contains particles containing an ED-71 oil / fat solution, and exhibits good productivity (eg, fluidity and compression moldability) when used in the production of tablets and other preparations. .

Drying of the oil-in-water emulsion can be performed by a method generally used in the field of pharmaceutical preparations, for example, fluidized drying, freeze drying, air drying, spray drying, standing drying, stirring drying, flash drying, and vacuum drying. , Microwave drying, and infrared / far infrared drying. Drying may be performed together with heating or cooling. Drying can be performed using, for example, a fluidized bed granulating dryer (WSG-200pro manufactured by POWREX), a vacuum dryer (Conical Dryer manufactured by Nippon Dryer), or the like.

医 薬 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 produced by a method used in the field of pharmaceuticals. For example, the method for producing a tablet includes the following methods i), ii) and iii).

i) Tablets are prepared by mixing the ED-71 and the oil dispersion containing the 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.), the solvent (eg, purified water, ethanol, or a mixture thereof) is added. Granulate while adding or spraying. A tablet is produced by adding an appropriate amount of a lubricant and, if necessary, a disintegrant and the like to the obtained granules, mixing and then compression-molding.
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 mixed with a solvent (eg, purified water). , Ethanol, or a mixture thereof), and granulation is performed while adding or spraying a liquid obtained by dispersing or dissolving the resulting mixture. A tablet is produced by adding an appropriate amount of a lubricant and, if necessary, a disintegrant or the like to the obtained granules and mixing the resulting mixture, followed by compression molding.

Additional additives include, for example, surfactants and pH adjusters to improve drug release, stabilizing agents to improve fluidity during the process, and stabilizing agents to increase stability. A flavoring agent can be used for the purpose of adding taste and smell, and a coloring agent can be used for the purpose of adding color. The amount of these to be used is generally 0 to 99.999 parts by weight, preferably 50 to 99.5 parts by weight, more preferably 90 to 99 parts by weight, based on 100 parts by weight of the preparation.

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

Although the content of ED-71 in the pharmaceutical composition (preferably tablet) of the present invention is not particularly limited, in one embodiment, the amount of ED-71 per unit preparation is 0.05 to 5 μg, preferably 0.1 to 0.1 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, perforated starch, lactose hydrate, fructose, glucose, mannitol, sorbitol And sugar alcohols, anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate and the like. In a preferred embodiment, excipient 2 is a starch, lactose hydrate, microcrystalline cellulose, or anhydrous calcium hydrogen phosphate.

Examples of the disintegrant include sodium starch glycolate, carboxymethylcellulose, carboxymethylcellulose calcium, sodium carboxymethylstarch, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropylstarch and the like. The amount of the disintegrant to be used is preferably 0.5 to 25 parts by weight, more preferably 1 to 15 parts by weight, based on 100 parts by weight of the preparation.

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

Lubricants include, for example, stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, light anhydrous silicic acid, and the like.

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 salts thereof.

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

Examples of the stabilizer include 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; Sorbic acid.

As a flavoring agent, for example, sweeteners, sour agents, flavors, and the like usually used in the field of pharmaceutical preparations can be mentioned.

Any coloring agent may be used as long as it is permitted to be added to pharmaceutical products, for example, Food Yellow No. 5 (Sunset Yellow, US Food Yellow No. 6), Food Red No. 2, Food Blue Food dyes such as No. 2, food lake dyes, iron sesquioxide and the like.

Examples of the antioxidant include nitrite (eg, sodium nitrite), sulfite (eg, sodium sulfite, dried sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfite), thiosulfate (eg, sodium thiosulfate), alpha thioglycerin 1,3-butylene glycol, thioglycolic acid and its salts (eg, sodium thioglycolate), thiomalate (eg, sodium thiomalate), thiourea, thiolactic acid, edetate (eg, sodium edetate), dichlor Isocyanurate (eg, potassium dichlorocyanurate), citric acid, cysteine and its salts (eg, cysteine hydrochloride), benzotriazole, 2-mercaptobenzimidazole, erythorbic acid and its salts (eg, sodium erythorbic acid) ), Ascorbic acid and its ester compounds (eg, L-ascorbic acid stearic acid ester, ascorbic acid palmitate), phospholipids (eg, soybean lecithin), metal chelators and salts thereof (eg, ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid calcium salt). Sodium, disodium ethylenediaminetetraacetate), tartaric acid and its salts (eg, Rochelle salt), polyphenols (eg, catechin), glutathione, dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, natural vitamin E, tocopherol acetate, concentrated mixed tocopherol And tocopherol homologs (eg, d-α-tocopherol, dl-α-tocopherol, 5,8-dimethyltocol, 7,8-dimethyltochol, δ-methyltoco Le, 5,7,8- trimethyl-tocotrienol, 5,8-dimethyl-tocotrienol, 7,8-dimethyl-tocotrienol, 8-methyl-tocotrienol), and the like. Among them, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, dl-α-tocopherol, d-α-tocopherol, concentrated mixed tocopherol, ascorbic acid palmitate, stearic L-ascorbic acid ester, butylhydroxyanisole, propyl gallate Dl-α-tocopherol, dibutylhydroxytoluene, butylhydroxyanisole and propyl gallate are more preferred, and dl-α-tocopherol is even more preferred.
The amount of the antioxidant to be used is preferably 0.001 to 10 parts by weight, more preferably 0.01 to 1 part by weight, based on 100 parts by weight of the preparation.

The additional additives may be used as a mixture of two or more kinds at an appropriate ratio.

糖 Sugar-coated tablets or film-coated tablets can also be obtained from tablets by using a suitable coating additive. Examples of the coating additive include a sugar coating base, a coating agent, an enteric film coating base, a sustained release film coating base, and the like.

Examples of the sugar-coating base include sugars such as sucrose and erythritol and sugar alcohols. Further, one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like are used in combination. Is also good.

Examples of the coating agent include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, paraffin and the like.

Examples of the enteric film coating base include cellulose-based polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name); Acrylic polymers such as Evonik Degussa Co., Ltd., methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Evonik Degussa Co., Ltd.], and methacrylic acid copolymer S [Eudragit S (trade name), Evonik Degussa Company]; Natural products such as shellac are exemplified.

Examples of the sustained-release film coating base include cellulosic polymers such as ethylcellulose; aminoalkyl methacrylate copolymer RS (Eudragit RS (trade name), Evonik Degussa), and ethyl acrylate / methyl methacrylate copolymer suspension. An acrylic acid-based polymer such as a suspension [Eudragit NE (trade name), Evonik Degussa]; cellulose acetate;

コ ー テ ィ ン グ The above-mentioned coating additives may be used by mixing two or more kinds thereof at an appropriate ratio.

水溶 To the coating additive, a water-soluble substance, a plasticizer, etc. may be added as needed to adjust the dissolution rate. Water-soluble substances include water-soluble polymers such as hydroxypropylmethylcellulose, sugar alcohols such as mannitol, sugars such as sucrose and anhydrous maltose, sucrose fatty acid esters, polyoxyethylene polyoxypropylene glycol, polysorbate, and sodium lauryl sulfate. One or more selected from surfactants and the like 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 selected from such as can be used.

Further, as a method of coating the tablet with the coating additive to form a coating layer, a general method in the field of pharmaceuticals can be used, for example, a pan coating method, a fluid coating method, a rolling coating method, The fluid tumbling coating method may be used. 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 of such a coating solution is preferably in the range of 5 to 15% by weight based on the total weight of the coating solution.
In a preferred embodiment, the pharmaceutical composition of the present invention is a coated tablet coated with an HPMC film.

In the formulation of the pharmaceutical composition of the present invention, granulation is, in addition to the principle and apparatus described in the examples, extrusion granulation, crushing and sizing, rotary granulation, dry granulation, wet high shear granulation, And fluidized bed granulation.

Granulation devices based on extrusion granulation include, for example, twin dome granules, basket louvers, semi-dry / low-moisture granulator disk pelleters, semi-dry / small-diameter granulators, fine disk pelleters, and pelletizer doubles. , And Multigran (all from Dalton), and KEX Extruder and KRC Kneader (all from Kurimoto).

Examples of granulators based on the principle of crushing and sizing include power mills (made by Dalton), sieving machines Fiore F and Landel mills (manufactured by Tokuju Kosakusho), and no-screen sizing machines Nebula Sizer (manufactured by Nara Machine Works) ), Quick Mill QMY (manufactured by Seishin Enterprise), Roll Granulator (manufactured by Matsubo), New Speed Mill (manufactured by Okada Seiko), MF Type Granulator Oscillator and Crusher Granulator (Conibit) Manufactured by Earth Technica).

造 Examples of the granulating apparatus based on rotary granulation include a marmellaizer (made by Dalton), a centrifugal flow coating granulator CF and Granulex GX (all made by Freund Corporation).

造 Examples of a granulating apparatus based on dry granulation include, for example, a roller compactor (manufactured by Freund Corporation), a Pharma compactor (manufactured by Hosokawa Micron), an RCP roller compactor (manufactured by Kurimoto Iron Works), and a pharmaceutical compactor (manufactured by Matsubo).

Examples of granulating devices based on wet high shear granulation include SP Granulator and Spartan Luzer (above, manufactured by Dalton), Vertical Granulator (manufactured by Powrex), Pharma Connect for GEA Aeromatic Fielder Multiprocessor R & D ( Eurotechno), Mixer & Granulator (NMG) (Nara Machinery), Crushing and Rolling Type New Grass Machine SEG (Seisin Enterprise), New Speed Kneader (Okada Seiko), High Speed Mixer (Advanced Series), Dynamic Dryers, high-flex granules, and microwave granulator dryers (both sold by Fukae Powtech, sold by Earth Technica), and TM-type granulating mixers (manufactured by Nippon Coke Industries).

Examples of a granulating apparatus based on fluidized bed granulation include a pulverizer, a swirling fluidized bed, a microfluidized bed, a swing processor (above, manufactured by Dalton), a flow coater containment, a flow coater Universal, and a flow coater FLO. And Spiral Flow SFC (from Freund Corporation), Agromaster (from Hosokawa Micron), GEA Aeromatic Fielder Flexstream (from Eurotechno), and Sprude (Okawara Seisakusho).

In addition to the principles and apparatuses described in the examples, the mixing is performed according to each principle of a convection type (mechanical stirring type), a diffusion type (container rotating type), and a kneading / kneader.

Mixing devices based on the principle of convection (mechanical stirring) include, for example, a mixing stirrer NDM type, a mixing stirrer XDM type, a mixing stirrer DM type, a mixing stirrer AM / XDM / DM type for prototype and research, and a mixing stirrer twin for a laboratory. Mix, Pug Mixer, Ribbon Mixer, Spartan Mixer, and Paste Mixer (Made by Dalton), Cyclo Mix, and Nauta Mixer (Made by Hosokawa Micron), Vertical Mount MAG-NEO Seal Mixer (Magneo Giken), Bottom Type Super Mag Mixer and S Mixer Super Mix (all made by Satake Chemical Machinery), Julia Mixer and Ribbon Mixer (all made by Tokuju Kogyo), PX Mixer (made by Seishin Enterprise), Ledige Mixer (made by Matsubo) , FM mixer RC type, and MP mixer (Nippon Coke Industry) Ribocone (Okawara Seisakusho Co., Ltd.) and the like in beauty.

Examples of the mixing device based on the diffusion type (container rotation type) include a GEA book system IBC blender, a GEA book system IBC blender with an NIR measuring device (all manufactured by Eurotechno), a V-type mixer, and a W-type mixer. Machines (manufactured by Tokuju Kosakusho), V-type mixers (manufactured by Nara Machinery Works), W-type mixers SCM, and V-type mixers SVM (all manufactured by Seishin Enterprises), capsule locking mixers (made by Aichi Electric), and Bohle container mixer PM (manufactured by Kotobuki Kogyo).

Mixing devices based on kneading and kneading are, for example, continuous kneaders, batch kneaders (above, manufactured by Dalton), TK Hibismix, and TK hibisdispermix (above, manufactured by Primix), Leistritz extruder (Manufactured by Nara Machinery) and a planetary mixer (manufactured by Asada Tekko).

{Other mixing devices include, for example, Conti-TDS (manufactured by Dalton) and mixing torque meter ST-3000II} process reactor DDL 3000, and stirring simulation MixSim (all manufactured by Satake Chemical Machinery Co., Ltd.).

の 他 In addition to the above-described principles, mixing can also be performed based on principles such as a fluid stirring type, a non-stirring type, and a high-speed shearing type.

Tabletting is performed according to each principle of single-shot tableting and rotary tableting, but rotary tableting is preferred from the viewpoint of efficiency.

Examples of tableting devices based on rotary tableting include, in addition to those described in the examples, detachable high-speed tableting machine Fette (manufactured by Bosch Packaging Technology), high-speed tableting machine COMPRIMA, and high-speed tableting machine. Machine SYNTHESIS (Mutual), rotary press MZ400 (Mori Machinery), GEA Coltoa module type tablet press P, S, D, and GEA Pharma System Performer P (Made by Eurotechno), Small rotary tablet machine for research and development, small high-speed rotary tablet machine, medium-sized high-speed rotary tablet machine, double high-speed rotary tablet machine, rotary-table detachable flush rotary tablet machine, and containment tablet machine (Kikusui Seisakusho) ), BX type HX type compression tableting machine, CVX type rotary table detachable tableting machine, X type AP type small tableting machine, X type AP type medium size tableting machine, AP type large tableting machine, and X type AP type large-sized double tableting (Manufactured by HataTetsuko office), and the like.

A single-layer tablet can be obtained with the above-described tableting apparatus. It is also possible to produce a dry-coated tablet using a dry-pressed tablet machine (manufactured by Kikusui Seisakusho) and an AP / MS type C-type dry-pressed tableting machine (manufactured by Hata Iron Works).

In addition to the principles and devices described in the examples, coating is performed by each principle of pan coating (horizontal pan), pan coating (inclined pan), and air floating type (fluidized bed).

Examples of the coating apparatus based on コ ー テ ィ ン グ pan coating (horizontal pan) include High Coater FZ, Aqua Coater AQC Containment, and Aqua Coater AQC (all manufactured by Freund Corporation).

Examples of the coating apparatus based on pan coating (inclined pan) include a Porec coater PRC and a doria coater DRC (all manufactured by Powrex).

{As a coating apparatus based on an air-floating type (fluidized bed), for example, a Glatt powder coater {GPCG} SPC, multiplex, and composite fluidized bed} SFP (all manufactured by Powrex) can be mentioned.

Other coating apparatuses include, for example, a hybridization system (manufactured by Nara Kikai Seisakusho), and a mechano hybrid (manufactured by Nippon Coke E).

The pharmaceutical composition of the present invention is useful for treating or preventing a disease or condition (eg, osteoporosis) that can be treated or prevented by suppressing bone turnover and improving bone density and strength.

In the present invention, treatment or prevention of a disease or symptom includes prevention of onset of the disease, suppression or inhibition of exacerbation or progression, reduction of one or more symptoms exhibited by an individual suffering from the disease, or suppression of exacerbation or progression. , Secondary disease treatment or prevention, and the like.

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

(4) The pharmaceutical composition of the present invention is administered to a subject in an amount effective for treatment or prevention. “Therapeutically or prophylactically effective amount” means an amount that produces a therapeutic or prophylactic effect for a particular disease, mode of administration and route of administration, and includes the species, type of disease, symptom, gender, age, chronic disease, other Is appropriately determined in accordance with the element of. The route of administration is usually oral.

The dose of the pharmaceutical composition of the present invention is appropriately determined according to the species, type of disease, symptom, sex, age, chronic disease, and other factors of the subject. 0.01 to 10 μg, preferably 0.5 to 0.75 μg per day.

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 means an amount that produces a therapeutic or prophylactic effect for a specific disease or condition, administration form and administration route, and is the species of the subject, the type of the disease or condition, the condition, the sex, It is appropriately determined according to age, chronic disease, 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 that can be treated or prevented by suppressing bone turnover to improve bone density and strength (eg, osteoporosis).

の 通 り As mentioned above, the ED-71 epoxide is produced mainly by conversion from ED-71 in step (iii) (drying step) and is present in the prepared tablets in a fat solution together with ED-71. When the prepared tablets are left as they are, the conversion of ED-71 to ED-71 epoxide progresses more gradually, but the progress is made in a container (packaging form) in which an oxygen scavenger is coexistent. It can be suppressed by saving in the state. Thus, in one aspect, the present invention provides a product in which the pharmaceutical composition of the present invention and the oxygen scavenger are hermetically enclosed in a packaged form.

Examples of the oxygen scavenger include Wonder Keep (registered trademark) (Powder Tech), Oxymove (registered trademark) (Nantong Oe Chemical), Modulan (Nippon Kayaku Food Techno), Keypit (Drainy), Wellpack (Taisei), Oxytor (registered trademark) (Ueno Food Techno), Keplon (Keplon), freshness preservative (Toppan Printing), Sansoles (Hakuyo), Sansocut (registered trademark) (Iris Fine Products), Ageless (registered trademark) ZM (Mitsubishi) Gas Chemistry, ZM-1), Everfresh (Tori Shigeki, QJ-30, etc.), Vitalon PH (Tokiwa Sangyo, PH-100SL, etc.), SEQUEL (registered trademark) (Nisso resin, AP-250, etc.) , Preferably Ageless ZM.

The “packing form” can be in an airtight state and includes, for example, bottle packaging, pillow packaging, blister pack packaging, and ampoule packaging, and is preferably bottle packaging and pillow packaging. . In addition, the pharmaceutical composition of the present invention is packaged as it is or in a PTP package (press-through pack packaging) and hermetically sealed in a package form. Preferably, the composition as it is is hermetically sealed in a bottle package. Or the PTP packaged composition is hermetically sealed in a pillow package.

As the material of the bottle packaging, for example, thermoplastic resin, glass, pottery, enamel, metal and the like can be mentioned, and thermoplastic resin and glass are preferable. The material of the bottle packaging is not limited to a single-layer material. For example, the same thermoplastic resin or a multi-layer structure made of a plurality of types of materials may be used. The lid portion of the bottle packaging may be in any form as long as it can be made airtight, and includes, for example, a screw cap. Examples of the material of the lid include a thermoplastic resin and a metal (eg, iron, tin, stainless steel, etc.), and preferably a metal. When the lid and bottle packaging are made of a 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 as it is or in a PTP package is covered in a bag shape with a film, and is then kept in an air-tight state with a gas still contained. As a material of the pillow packaging, for example, an aluminum laminated film, a thermoplastic resin, or the like, or a combination thereof can be mentioned, and an aluminum laminated film is preferable.

"Airtight" means that there is no danger of liquid intrusion in daily handling or in normal storage conditions. Airtightness includes a state in which gas intrusion is suppressed depending on the degree. In the case of bottle packaging, the degree of airtightness can be quantified by using, for example, “closing torque”. The numerical value is, for example, 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.

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

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

Examples of the thermoplastic resin include polyvinyl chloride (PVC), unstretched polypropylene (CPP), polypropylene (PP), polyvinylidene chloride (PVDC), poly (chlorotrifluoroethylene) (PCTFE), and cyclic olefin copolymer ( COC), polyethylene (PE; high, medium 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, poly (ethylene trifluoride) chloride, cyclic An olefin copolymer and an ethylene-vinyl alcohol copolymer. These may be used alone or in combination of two or more. Examples of the lid material of the PTP packaging include an aluminum foil, a laminated film obtained by laminating an aluminum foil with a thermoplastic resin film, and the like. A known method may be used as a method for producing the PTP package or the blister pack package. The packaging material of the pillow packaging, the PTP packaging, or the blister pack packaging in the present invention is not limited to a single layer, but may be a multilayer film in which a plurality of layers are laminated. The multilayer film has an outer layer or an intermediate layer having a barrier layer for suppressing oxygen permeation, and may have an inner layer or an intermediate layer having an absorbing layer having a deoxygenation function. The absorbing layer having a deoxidizing function includes, for example, a resin in which a deoxidizing agent having a deoxidizing function is kneaded.

Further, a packaging form having a high light-shielding property is preferable, and examples thereof include a brown glass bottle packaging with a metal cap.

When the pharmaceutical composition and the oxygen scavenger of the present invention are sealed in a package in an airtight state, a gas other than oxygen (for example, nitrogen gas, carbon dioxide gas, helium gas, argon gas, neon gas, (Krypton gas, xenon gas, radon gas).

ED-71 epoxide is difficult to completely eliminate its presence in the pharmaceutical composition (preferably tablet) of the present invention prepared through a drying step (step (iii)) in contact with air, Although it is a substance that is allowed to be present, the content thereof is preferably small from the viewpoint of the effectiveness of ED-71. Specifically, the content is preferably 5% or less, more preferably 2% or less, and further 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. The “content” of the 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 in the following Examples. 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 analogs (%) in the pharmaceutical composition ) And is calculated by 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 : peak area of Pre ED-71 A _imp-2 : peak area of ED-71 epoxide A _i : peak area of other ED-71 analog RRF: relative to ED-71 Relative sensitivity coefficient; Pre ED-71, 1.79; ED-71 epoxide, 1.72; Other ED-71 analogs, 1.00

All prior art documents cited in the present specification are incorporated herein by reference.

The present invention will be described in more detail with reference to examples.

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

Example 1: Composition change 1
50 mg of ED-71 was dissolved in 2.5 mL of EtOH to prepare an ethanol solution of ED-71. 1 g of BHT (Merck) and 2 g of dl-α-tocopherol (Wako Pure Chemical Industries, Ltd.) were dissolved in 97 g of MCT (ODOC, Nisshin Oilio) to prepare an MCT solution. Was prepared. 0.5 mL of an ethanol solution of ED-71 was added to the prepared MCT solution, and the mixture was stirred with a vortex mixer. Further, the mixture 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 / fat solution to prepare an ED-71 composition (Example 1). The prepared ED-71 composition was stored in a thermostat adjusted to 60 ° C. in the presence of air, and the residual ratio (%) of ED-71 was examined after 14 days and 28 days.
As a control, the above ED-71 oil / fat solution alone (Control Example 1) was used.
An ED-71 composition was prepared in the same manner as in Example 1, except that the additives (300 mg) described in Table 1 were used instead of the hydroxypropylmethylcellulose of Example 1, and the stability at 60 ° C was measured. The examination was performed in the same manner as in Example 1.

The results are shown in Table 1. As is evident from Table 1, the composition of Example 1 was as stable as or higher than the oil and fat solution of Comparative Example 1 alone, and was more stable than the compositions of Comparative Examples 2 to 34 under high temperature conditions. Was.

Example 2: Composition change 2
Using the additives described in Table 2 in place of the hydroxypropyl methylcellulose of Example 1, the ED-71 compositions of Example 2 and Control Example 35 were prepared in the same manner as in Example 1, and at 60 ° C. The stability was examined as in Example 1 and compared to Control 1. The results are shown in Table 2. The composition of Example 2 was shown to be more stable than or equal to Control Example 1 and more stable than the compositions of Control Examples 2-34 shown in Table 1 under high temperature conditions. Although the stability of ED-71 was not reduced in the composition of Comparative Example 35, when meglumine was used as an additive, the emulsified state required in the production process of the oil dispersion tablet described below was obtained. It has been found that meglumine is not suitable as an additive for the production of oil dispersion tablets because it cannot be maintained.

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

Table 3 shows the results. FIG. 2 shows the emulsified state (photograph) in the centrifuge tube after 24 hours when a 2% aqueous solution of a water-soluble polymer was used. Separation of the water layer and the oil layer did not occur in HPMC, HPC, and PVA copolymer, whereas separation occurred in PVP.

Examples 3 to 11: Stability of ED-71 at the time of emulsion preparation 100 mg of ED-71 was dissolved in 5.0 mL of EtOH to prepare an ethanol solution of ED-71. 1 g of BHT (Merck) and 2 g of dl-α-tocopherol (Wako Pure Chemical Industries, Ltd.) and 97 g of MCT (ODOC, Nisshin Oilio) were dissolved in MCT solution. Was prepared. To the prepared MCT solution was added 0.5 mL of an ED-71 ethanol solution, and the mixture was stirred with a vortex mixer to obtain an ED-71 dissolved MCT solution. Water-soluble polymer solutions shown in Table 4 were prepared. An ED-71-containing emulsion was prepared by mixing the ED-71-dissolved MCT solution and the water-soluble polymer solution in the proportions shown in Table 5 and stirring the mixture at 5400 rpm for 1 minute using a homogenizer. The prepared ED-71-containing emulsion was weighed so as to be about 1 μg as the ED-71 drug substance amount, and was distilled off under reduced pressure with a vacuum dryer, and the obtained sample was used for residual ratio measurement (Example 3). ~ 11). The sample was stored in a thermostat adjusted to 60 ° C. in the presence of air, and the ED-71 content value immediately after preparation, the ED-71 content value after 14 days and 25 days after, and the residual ratio (%) were examined. Each content value was calculated by weighing the ED-71-dissolved MCT solution so that the amount of the ED-71 drug substance was about 1 μg, and distilling off the sample under reduced pressure with a vacuum dryer as a standard product. The content value and residual rate of ED-71 were determined by the following formulas.
ED-71 content value (%) = total ED-71 peak area in the sample / total ED-71 peak area in the standard (total ED-71 peak area = ED-71 peak area + 1.98 x Pre ED- 71 peak area)
Residual rate of ED-71 (%) = average content value of accelerated sample / average content value of sample immediately after preparation

The results are shown in Table 5. As can be seen from Table 5, the formulation (1%) with a low concentration of the water-soluble polymer showed a large variation in the ED-71 content value. This is considered to be due to the fact that in the formulation having a low concentration of the water-soluble polymer, the emulsion was separated after the preparation, and that the weighed amount of ED-71 in the sampled emulsion varied. Samples with a water-soluble polymer concentration of 5% or 6% showed a small variation in the results, and the residual ratio of ED-71 after 25 days was 95% or more. The ED-71 residual ratio decreased to around 90% in the sample after 25 days, although the variation was small in the formulation having a high concentration of the water-soluble polymer (10% or 15%).
As a concentration of the water-soluble polymer solution containing 1% to 15% of HPMC or HPC, 5 to 6% is preferable for stabilizing the ED-71 in the emulsion.

[Production Example] Oil dispersion tablet dl-α-tocopherol (Wako Pure Chemical Industries) 0.142 kg and BHT (Merck) 0.284 kg were dissolved in MCT (Nissin Oilio) 9.025 kg, and erdecalcitol (ED-71) was dissolved therein. After adding a solution of 1.1813 g of ethanol (99.5%) (Imazu Pharmaceutical) (0.078 kg), ethanol was distilled off under reduced pressure (solution 1).
1.134 kg of hypromellose (HPMC) (TC-5R, Shin-Etsu Chemical Co., Ltd.) 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 with a homogenizer (T-50 Ultra Turrax manufactured by IKA; rotation speed 9,600 rpm) for 10 minutes. This operation was repeated three times to obtain an emulsion.

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

The obtained granulated powder is sieved with a wet granulator (POWREX U-20) equipped with a 9.5 mm (square hole) screen at 300 rpm to obtain a fluidized bed granulating dryer ( It was transferred to 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 having 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) sieved through a 850 μm sieve, respectively, and further sieved through a 850 μm sieve. After mixing with a mixture of 6.6 kg and calcium stearate (Merck) 0.72 kg for 3 minutes (sample 2), the mixture was tabletted with a tableting machine (COMPRIMA manufactured by IMA) at a pressure of about 7.5 kN to obtain tablets (sample 3). . At the time of tableting, the tablet weight was adjusted so that the erdecalcitol content per tablet was 0.75 μg.

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

When preparing tablets with an erdecalcitol content of 0.5 μg per tablet, the second layer is 4.950 kg of hypromellose, 1.350 kg of talc (Merck), 2.502 kg of titanium oxide (Ishihara Sangyo), and 2.502 kg of iron sesquioxide (Kishimi) A suspension of 0.018 kg of Kasei) and 0.180 kg of yellow iron sesquioxide (Kishi Kasei) (65.167 kg) was spray-coated.
FIG. 1 shows a schematic diagram of the manufacturing flow.

[Test Example 2] Accelerated stability test The tablets obtained in [[Production Example] oil-dispersed tablets] (two kinds of tablets having an eldecalcitol content of 0.5 µg and 0.75 µg per tablet) were placed in a high-density polyethylene bottle container ( NC-130, Shinko Chemical). Close the bottle with a polypropylene cap (SK-200B, Shinko Chemical) and store it in a thermostatic chamber adjusted to 40 ° C / 75% RH. After 1 month, 3 months, and 6 months, the residual ratio of ED-71 Was examined.

The residual ratio 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 the mixture was irradiated with ultrasonic waves for 30 minutes. During ultrasonic irradiation, stirring was performed once every 10 minutes. The supernatant was filtered through a polytetrafluoroethylene (PTFE) filter having a pore size of 0.20 μm, the first about 1 mL was discarded, and the remaining filtrate was used as a sample solution. Separately, an ED-71 standard product was dissolved in water: acetonitrile (20:80) to a concentration of about 0.6 μg / mL, and a standard solution was prepared in the same manner as in the preparation of the sample solution. The sample solution and the standard solution were measured by a high performance liquid chromatography method (Alliance, manufactured by Waters, measurement wavelength: 265 nm), and the ED-71 content in the sample was quantified.

The residual ratio of ED-71 was determined by the following formula.
Residual rate of ED-71 (%) = ratio of ED-71 content in accelerated sample to indicated amount (%) / ratio of ED-71 content in unaccelerated sample to indicated amount (%) x 100
The indicated amount refers to the weight (0.5 μg or 0.75 μg) of ED-71 intended to be contained per tablet.

錠 剤 The tablets obtained in “[Production Example] Oil-dispersed tablets” were shown to be stable under the acceleration conditions defined in the ICH guidelines (Q1A).

[Test Example 3] Purity test Twenty tablets obtained in "[Production example] oil dispersion tablet" were crushed by a small crusher LM-Plus (manufactured by Osaka Chemical Co., Ltd.), and 1.6 g of the crushed sample was weighed. Was. 40 mL of a mixed solution of ethyl acetate and hexane mixed at a volume ratio of 1: 1 was added, stirred, and irradiated with ultrasonic waves 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 injected 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 mixed at a volume ratio of 1: 1 and then washed with 6 mL of ethanol. And eluted. The eluted liquid was evaporated and evaporated to dryness using an evaporator, and then 100 μL of a mixed solution of water and acetonitrile mixed at a volume ratio of 1: 1 was added to redissolve to obtain a sample solution. The purity test was performed by liquid chromatography using ACQUITY UPLC H-Class (manufactured by Waters) under the following analysis conditions.
Column: Kinetex Evo C18 (2.6 μm, 4.6 mm × 100 mm, manufactured by Phenomenex)
Column temperature: 30 ° C
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: The concentration gradient was set as shown in Table 7.

The results are shown in FIG. In addition to the detection of ED-71 (retention time: about 10.4 minutes) and its thermal isomer Pre @ ED-71 (retention time: about 8.3 minutes), unknown peaks were observed at a retention time of about 5.2. Minutes detected. This unknown peak was later found to be a peak derived from compound 2.

Test Example 4 Measurement of 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 Examples. 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 grinding step was omitted.

The content of Compound 2 was determined from the 220 nm profile obtained by liquid chromatography analysis under the conditions described in Test Example 3, from the ED-71, Pred, which is a thermal isomer of Compound 2 and ED-71 in the sample solution. The peak areas of ED-71 and other ED-71 analogs were determined and calculated by the following formula. The peak areas of Compound 2, Pre ED-71, and other ED-71 analogs were corrected by the relative sensitivity coefficient (RRF) for 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 (dried powder) was 0.5%, and no remarkable increase was observed in Samples 2 and 3 obtained in the subsequent production steps. Therefore, it was suggested that compound 2 may have been formed mainly by the drying step.

As shown in the ultraviolet-visible spectrum of ED-71 (FIG. 4), since ED-71 has a triene structure in the molecule, the ultraviolet absorption becomes maximum at 265 nm. On the other hand, in the ultraviolet-visible spectrum of Compound 2 (FIG. 3), a characteristic peak at 265 nm due to the triene structure of ED-71 was not observed. This result suggested that Compound 2 may be a decomposition product of ED-71 in which the triene structure was destroyed. It is known that vitamin D ₃ to which ED-71 belongs is easily decomposed by oxidation. In the drying step, the sample is in a fluidized state by hot air in the drying tower. It can be said that the sample staying in the fluidized bed is in an environment susceptible to oxidation because the chance of contact with oxygen in the air increases. From the above, it was presumed that the oxidation of ED-71 during the production process was involved in the production of compound 2.

[Test Example 5] Preparation of compound 2 by air oxidation of ED-71 and determination of its structure Compound 2 was prepared in a large amount for structure determination.
A mixed solution (10 mL) of ED-71 (60 μg) in water: acetonitrile = 1: 1 was added to the vial, and the mixture was vigorously stirred with a magnetic stirrer at 30 ° C. for 16 hours under open air to promote oxidation. Since the mixture was volatilized and the amount of liquid decreased, 3 mL of acetonitrile was additionally added after stirring. As a result of analysis under the same analysis conditions as in Test Example 3, compound 2 detected in all of sample 1 (dry powder), sample 2 (mixed powder), sample 3 (uncoated tablet) and sample 4 (film-coated tablet) At the same retention time, a peak having an equivalent ultraviolet-visible spectrum was detected. The peak was collected, 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 600 MHz 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 oxygenated form of ED-71. Further, the results of various NMR measurements suggested that Compound 2 was an epoxy compound in which oxygen was added to the triene site of ED-71. From the above, Compound 2 was converted to (1R, 2R, 3R, 5Z, 7ξ, 8ξ) -2- (3-hydroxypropoxy) -7,8-epoxy-9,10 (19) -secocholesta-5,10-diene- It was identified as 1,3,25-triol.

In the chemical synthesis this test example of Test Example 6] Compound 2, proton nuclear magnetic resonance spectra ^{(1 H-NMR} spectra) is, in chloroform -d or acetonitrile -d _3, the presence or absence tetramethylsilane as the internal standard Below, it measured using ECP500 (made by JEOL). Further, the purity analysis of the obtained compound 2 by liquid chromatography was performed 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 0.4 mg, 1.03 mmol) and 3-chloroperbenzoic acid (74.2%, 251.4 mg, 1.08 mmol) in a suspension of sodium bicarbonate (170.4 mg, 2.03 mmol) in dichloromethane (15 mL). At -70 ° C, 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 mixture was heated to room temperature, and extracted with dichloromethane (5 mL). The aqueous layer was extracted again with dichloromethane (10 mL), and the combined extracts were dried over anhydrous sodium sulfate. The solid was 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 obtained 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) -Secocolesta-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 obtained was consistent with 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 .008 g, 8.17 mmol) in dichloromethane (40 mL) was added with 1-methylimidazole (3.6 mL, 44.9 mmol) and cooled in an ice bath. To the reaction mixture, methyl chloroformate (3.1 mL, 40.8 mmol) was added dropwise at 10 ° C. or lower, and the mixture was stirred at room temperature for 15 hours, and then 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 solution of sodium hydrogen carbonate (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 give compound 3 (5. 3863 g).

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 (5.3683 g, 8.10 mmol) obtained in Step 1 and sodium hydrogen carbonate (1.3694 g, 16.3 mmol) in dichloromethane (81 mL). 1.9917 g, 8.56 mmol) at 0 ° C. and 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 mixture was heated to room temperature, and 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 give compound 4 (4. 2359 g) were obtained.

Step 3: ((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)
A mixture of compound 4 (4.1369 g, 6.08 mmol) obtained in step 2, potassium carbonate (0.8406 g, 6.08 mmol) and methanol (61 mL) was stirred at room temperature for 3 hours. The reaction was diluted with dichloromethane (183 mL) and filtered over silica gel. The silica gel was washed with dichloromethane-methanol (3: 1, 100 mL), and the filtrates were combined and concentrated under reduced pressure. The obtained residue is 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%). Was. The ¹ H-NMR spectrum of Compound 2 obtained was consistent with the compound obtained in Test Example 5.

[Test Example 7] Inhibition of increase in compound 2 in tablets during long-term storage Since compound 2 is an oxide of ED-71, it can occur during storage of manufactured tablets by adding an oxygen scavenger during packaging. There is a possibility that an increase in compound 2 can be suppressed. To test this hypothesis, the content of Compound 2 in Sample 4 (film coated tablets) after storage at 25 ° C. and 75% relative humidity in a brown glass bottle in the absence and presence of an oxygen scavenger Was evaluated.

First, a sample 4 (500 tablets) was filled in a brown glass bottle (manufactured by Daiichi Glass Co., Ltd., PS-10K (brown)), and a steel cap (manufactured by Araki Industry Co., Ltd., No. 10-13 (L)) was closed and airtight. State. The content of Compound 2 in Sample 4 after storage 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 determined 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 scavenger (manufactured by Mitsubishi Gas Chemical Company, Ageless ZM, ZM-1) was added, the steel cap was closed, and the container was airtight with a stopper torque of 200 to 220 N · cm. State. The content of Compound 2 in Sample 4 after storage 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 defined as the content of Compound 2 in the presence of an oxygen scavenger.

The results are shown in Table 9.

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

According to the present invention, it is possible to provide an ED-71 preparation in a dosage form other than a soft capsule, in which the decomposition of ED-71 is suppressed.

Claims (8)

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

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