JP2022065053A - 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 a method for producing a formulation of new dosage form and the formulation, useful for a patient who needs to be administered with an osteoporosis treatment agent, (5Z,7E)-(1R,2R,3R)-2-(3-hydroxypropoxy)-9,10-secocholesta-5,7,10(19)-triene-1,3,25-triol (ED-71).

SOLUTION: The present invention provides a method for producing a pharmaceutical composition comprising ED-71 and an epoxy form thereof, the method comprising a step for preparing an oil-in-water emulsion comprising a fat/oil solution of ED-71 and an aqueous solution of a water-soluble polymer, wherein the water-soluble polymer is selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose.

SELECTED DRAWING: Figure 1

COPYRIGHT: (C)2022,JPO&INPIT

Description

In the present invention, (5Z, 7E)-(1R, 2R, 3R) -2- (3-hydroxypropoxy) -9,10-secocholester-5,7,10 (19) -trien-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) -secocolesta 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, 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 D3 having a bone-forming action, and is manufactured and sold as a therapeutic agent for osteoporosis by oral administration.

ED-71 can be formulated as a soft capsule like other vitamin D derivatives. 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 in a gelatin agent skin. Patent Document 1 also discloses that the production of taxosterols and transs, which are decomposition products of ED-71, is suppressed by adding an antioxidant such as dl-α-tocopherol to the solution. ing.

At present, there are no known commercially available ED-71 preparations other than soft capsules. Patent Document 2 discloses a mixture of a strontium salt and a vitamin D derivative that can be applied to osteoporosis, and erdecalcitol is mentioned as an example of the vitamin D derivative. Further, Patent Document 2 describes that the combination drug can be made into a tablet. However, the description is merely a description as a general tablet, and the effect when a specific additive other than the strontium salt is added to the ED-71 preparation is not disclosed.

In Patent Document 3, for example, 1α- (OH) _-D3 and polyvinylpyrrolidone are dissolved in ethanol, anhydrous lactose is added, and after stirring, ethanol is distilled off under reduced pressure to further pulverize the reaction product obtained. The 1α- (OH) _-D3 composition obtained by the above is described.

In Patent Document 4, a solid dispersion of ED-71 (a composition in which a solid ED-71 and a solid additive are mixed) and an oil dispersion (particles of an oil / fat solution of ED-71 are contained in an excipient. A pharmaceutical composition containing the composition dispersed in (1) and a method for producing the same are described.

Patent Document 5 describes that 7,8-epoxide can be obtained by reacting a specific vitamin D3 derivative with ₃ -chloroperbenzoic acid.

WO2005 / 074943A1 CN10268829A WO90 / 09996A PCT / JP2017 / 0471156 (Released as WO2018 / 124260 on July 5, 2018) Japanese Unexamined Patent Publication No. 58-216179

The EDILOL® capsules 0.5 μg and 0.75 μg, which are commercially available as therapeutic agents for osteoporosis, are only spherical soft capsules, and it is required to develop a functionally superior ED-71 formulation by a new formulation. Was being done. Further, by making the spherical soft capsule non-spherical, there is a demand for usability such that it becomes easier to pinch and it becomes difficult to roll. For the convenience of patients who need to administer ED-71, it has been required to develop a non-spherical ED-71 preparation in a dosage form other than soft capsules.

As such a preparation, the present inventors have proceeded with the development of a preparation prepared from an oil dispersion in which particles of an oil / fat solution of ED-71 are dispersed in an excipient. It has been found that when an oil dispersion prepared by using the oil-and-fat solution of No. 1 as it is is used, it is not possible to produce a preparation of sufficient quality. As a result of repeated research to solve this problem, we came up with the idea of coating the particles of the oil and fat solution of ED-71 with a specific additive, but the stability of ED-71 depends on many of the additives used. A new challenge has been found in which In response to this new problem, the present inventors have made it possible to produce a pharmaceutical product (particularly a tablet) of sufficient quality by using hydroxypropylmethyl cellulose or hydroxypropyl cellulose, which is a water-soluble polymer, 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 oil dispersion of ED-71 and a method for producing the same.

The present inventors have newly found that a small part (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. Based on this discovery, the present inventors further studied 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-A method for producing a pharmaceutical composition containing triol.
Step of preparing an oil-in-water emulsion containing an oil-and-fat solution of ED-71 and an aqueous solution of a water-soluble polymer,
A step of adhering or adsorbing an oil-in-water emulsion to an excipient, and a step of drying an oil-in-water emulsion,
Including
Here, the method, wherein the water-soluble polymer is selected from hydroxypropylmethyl cellulose and hydroxypropyl cellulose.
[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) -secocholester-5,10-diene-1,3 , 25-Triol-containing pharmaceutical composition.
Particles coated with a coating agent containing a water-soluble polymer selected from hydroxypropylmethyl cellulose and hydroxypropyl cellulose are contained in the excipient or on the surface of the excipient.
The pharmaceutical composition containing the oil-and-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 and the oxygen scavenger according to any one of [5] to [8] are encapsulated in an airtight state in a package form.
[10] The product according to [9], wherein the packaging form is bottle packaging or pillow packaging.

According to the present invention, in the oil dispersion, decomposition of ED-71 due to contact with the additive (formulation change) can be suppressed. Further, the oil dispersion can be used to produce ED-71 preparations in various dosage forms other than soft capsules.

It is the schematic of the manufacturing flow for manufacturing the tablet containing the oil dispersion of ED-71. It is a photograph showing the 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 an analysis result by liquid chromatography of the tablet obtained in "[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).

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

For ED-71, for example, according to the method described in JP-A No. 10-72432, (1R, 2R, 3R) -2- (3-hydroxypropoxy) -cholester-5,7-diene-1,3,25- It can be obtained by using triol as a starting material, subjecting it to ultraviolet irradiation and a thermal isomerization reaction, purifying it by reverse phase HPLC, concentrating it, and crystallizing it with ethyl acetate.

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

In the ED-71 epoxide, the sterics of the epoxy moieties (positions 7 and 8) have not been identified, but the compounds represented by the following formulas (IIa) and (IIb) in which they have been identified, and any proportions thereof. The compound represented by the following formula (IIc) mixed with ED-71 epoxide is also included in the ED-71 epoxide. The ED-71 epoxide is 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) -secocholester-5,10-diene-1,3,25-triol (hereinafter, also referred to as compound 2) is preferable.
It is preferable that the 14-position steric in the compounds (II), (IIa), (IIb) and (IIc) is the same as that of the compound (Ia), respectively.

Oil dispersion of ED-71
Pharmaceutical Compositions Containing ED-71 and ED-71 Epoxides and Methods for Producing The Invention The present invention relates to an oil dispersion of ED-71 and an oil dispersion containing ED-71 and ED-71 epoxides. In the present specification, the oil dispersion of ED-71 refers to a composition in which particles of an oil / fat 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 oil and fat containing ED-71 and ED-71 epoxide are dispersed in an excipient.

The present invention provides a pharmaceutical composition comprising an oil dispersion containing such ED-71 and ED-71 epoxides. Specifically, it is a pharmaceutical composition containing ED-71 and ED-71 epoxide, and a water-soluble polymer selected from hydroxypropylmethyl cellulose and hydroxypropyl cellulose is applied to the excipient or the surface of the excipient. The pharmaceutical composition comprises particles coated with a coating agent comprising, said particles comprising a fat solution of ED-71 and ED-71 epoxide.

The present invention also provides a method for producing such a pharmaceutical composition. Specifically, it is a method for producing a pharmaceutical composition containing ED-71 and ED-71 epoxide, and (i) 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 preparing, (ii) adhering or adsorbing the oil-in-water emulsion to the excipient, and (iii) drying the oil-in-water emulsion, wherein the water-soluble polymer is hydroxy. The method is provided, which is selected from propylmethylcellulose and hydroxypropylcellulose. By this method, particles of fats and oils containing ED-71 and ED-71 epoxide are coated on a water-soluble polymer in an excipient, and a preparation using an oil dispersion of ED-71 and ED-71 epoxide is used. (Especially tablets) can be manufactured. The ED-71 epoxide is not contained at the start of the step (i), or even if it is contained, the content is preferably a small amount of 0.1% or less, but mainly in the 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-and-fat solution containing an active ingredient is already known, but an oil-in-water emulsion instead of the oil-and-fat solution is used, and after adhering or adsorbing to the excipient. A method of drying an oil-in-water emulsion and coating the oil-and-fat solution with the components in the aqueous layer has not been known so far.

Regarding step (i), the fats and oils used in the present invention include medium-chain fatty acid triglyceride (hereinafter, also referred to as “MCT”), tricaprylic acid, caproic acid, caprylic acid, caproic acid, oleic acid, linoleic acid, linolenic acid, and vegetable oil. And so on. Here, examples of the vegetable oil include palm oil, olive oil, rapeseed oil, peanut oil, corn oil, soybean oil, cottonseed oil, grape oil, safflower oil and the like. Of these, MCT, tricapriline, caproic acid, caprylic acid, or capric acid, which do not contain unsaturated fatty acids, are preferable, and MCT is particularly preferable.

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

An antioxidant may be further added to the oil / fat solution in the step (i). Examples of the antioxidant in the present invention include nitrite (eg, sodium nitrite), sulfite (eg, sodium sulfite, dry sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfate), thiosulfate (eg, sodium thiosulfate), and the like. Alpha thioglycerin, 1,3-butylene glycol, thioglycolic acid and its salts (eg sodium thioglycolate), thiolinate (eg sodium thioappleate), thiourea, thiolactic acid, edetate (eg sodium edetate) , Dichlorisocyanurate (eg, potassium dichlorisocyanurate), citric acid, cysteine and its salts (eg, cysteine hydrochloride), benzotriazole, 2-mercaptobenzimidazole, erythorbic acid and its salts (eg, sodium erythorbinate). , Ascorbic acid and its ester compounds (eg L-ascorbic acid stearate, palmitate ascorbic acid), phospholipids (eg soy lecithin), metal chelating agents and salts thereof (eg ethylenediamine tetraacetic acid, ethylenediamine tetraacetate disodium disodium). , Ethylenediamine disodium tetraacetate), tartaric acid and its salts (eg Rochelle salt), polyphenols (eg catechin), glutathione, dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, natural vitamin E, tocopherol acetate, concentrated mixed tocopherols, Tocopherol homologues (eg 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 can be mentioned. Among these, tocopherol acetate, dibutylhydroxytoluene, natural vitamin E, dl-α-tocopherol, d-α-tocopherol, concentrated mixed tocopherol, ascorbic acid palmitate, stearic acid L-ascorbic acid ester, butylhydroxyanisole, propyl dieticoate. Is preferable, dl-α-tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, or propyl dioxide is more preferable, and dl-α-tocopherol or dibutylhydroxytoluene is even more preferable.

The amount of the antioxidant added to the oil / fat solution is not particularly limited, but the amount is equal to or less than the maximum amount that can be used as an antioxidant (for example, the approval described in the Encyclopedia of Pharmaceutical Additives (Yakuji Nippo Co., Ltd., 2000)). Usually, an amount less than or equal to the maximum amount used in the previous example or less than the usage limit amount described in the Food Additives Official Regulations (Japan Food Additives Association, 1999) can be usually used.

In a preferred embodiment, dl-α-tocopherol is added to the fat and oil solution at a concentration of 0.01% by weight or more (for example, 1% by weight or more) and 10% by weight or less (for example, 5% by weight or less). The amount of dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate and the like added is also the same as that of the above-mentioned dl-α-tocopherol.

The coating agent used in the present invention contains a water-soluble polymer. The water-soluble polymer is selected from hydroxypropylmethylcellulose and hydroxypropylcellulose. Many additives reduce the stability of ED-71 when added to a solution of ED-71, but hydroxypropylmethyl cellulose and hydroxypropyl cellulose do not reduce the stability of ED-71. When hydroxypropylmethyl cellulose and hydroxypropyl cellulose 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 means that tablets are produced from the pharmaceutical composition of the present invention, and the tablets are shielded from light and stored at 40 ° C. for 1, 3, or 6 months. It is confirmed by examining the residual rate of ED-71 after the above. The residual ratio of ED-71 is determined by high performance liquid chromatography (measurement wavelength 265 nm) for the preserved sample and the initial sample, ED-71 and its isomer preform (chemical name: 6Z- (1R, 2R, 3R)). -2- (3-Hydroxypropoxy) -9,10-secocholesta-5 (10), 6,8 (9) -trien-1,3,25-triol; also referred to herein as Pre ED-71) The peak area of is measured and calculated by the following formula.
Ratio of content to labeled amount of ED-71 (%) = (Weighing amount of ED-71 standard product / Total ED-71 peak area in ED-71 standard product) × ED- in initial sample or storage sample 71 Total peak area x (weight of initial sample or whole stored sample / weight of sample used for measurement) / displayed amount x 100
(Total ED-71 peak area = ED-71 peak area + 1.98 x Pre ED-71 peak area)
ED-71 residual rate (%) = ratio of content to labeled amount of ED-71 in preserved sample (%) / ratio of content to labeled amount of ED-71 in initial sample (%) x 100

The meaning of each term in the above formula is as follows.
・ "Indication amount": Theoretical content per tablet ・ "ED-71 standard product": ED-71 drug substance ・ "Weighing 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 for calculating the content of ED-71 in the measurement sample from the peak area)

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

Further, in the present invention, hydroxypropyl cellulose (HPC) is a component in the Pharmaceutical Additives Dictionary 2016 (edited by the Japan Pharmaceutical Additives Association; published by: Yakuji Nippo Co., Ltd .; ISBN978-4-8408-1329-7). It refers to hydroxypropyl cellulose listed as No. 002303, which is different from the low-substituted hydroxypropyl cellulose listed as component No. 002440 in the same encyclopedia. In the hydroxypropyl cellulose used in the present invention, the degree of substitution (MS) (indicating the rate at which the hydroxy group of the HPC repeating unit (glucose ring) is replaced with a hydroxypropoxy group) is usually 2 to 3, preferably 2. 5 to 3, more preferably 3. On the other hand, the degree of molar substitution in the low degree of substitution hydroxypropyl cellulose 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.

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

The concentration of the water-soluble polymer in the aqueous solution in the 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. It is preferably 3 to 6% by weight, more preferably 4 to 6% by weight, and even more preferably 5 to 6% by weight. The aqueous solution in step (i) may contain additives other than the water-soluble polymer, and may contain, for example, a stabilizer or an antioxidant.

The oil-in-water emulsion can be prepared by a method generally 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, hydroshears, colloid mills, flow jet mixers, ultrasonic generators, wet grinders using glass beads, membrane emulsifiers using porous membranes, etc. A method using an electric emulsifying device or the like using electric energy can be mentioned. 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 the range in which an oil-in-water emulsion can be prepared, and is usually 1: 1.5. It is ~ 1:20, preferably 1: 2 ~ 1:20, or 1: 2 ~ 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, it is water-soluble with the oil-and-fat solution of ED-71. 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 oil-and-fat solution of ED-71 to the water-soluble polymer may be as long as the particles of the oil-and-fat solution of ED-71 can be covered 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, it is water-soluble with the oil-and-fat solution of ED-71. 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.

With respect to step (ii), the excipients used in the present invention include, for example, starches such as corn starch, potato starch, wheatco starch, rice starch, partially pregelatinized starch, pregelatinized starch, perforated starch, anhydrous lactose, and the like. Examples thereof include sugars or sugar alcohols such as lactose hydrate, fructose, starch, mannitol, sorbitol, and erythritol, anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, and the like, preferably sugars or sugar alcohols. , More preferably mannitol, anhydrous lactose, lactose hydrate, still more preferably mannitol.

The ratio (weight ratio) of the oil-in-water emulsion used in the step (ii) to the excipient 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, a preferable granulated powder that can be used for producing a preparation such as a tablet can be obtained.

Adsorption or adsorption of the oil-in-water emulsion to the excipient can be performed by a method generally used in the pharmaceutical field, for example, a method of granulating while spraying the emulsion on the excipient, shaping. Examples thereof include 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 stirring machine (DM type manufactured by Shinagawa Machinery Works Co., Ltd.), or the like. The adhesion or adsorption also includes impregnation (infiltration of an oil-in-water emulsified solution into the pores in a porous excipient).

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

The oil-in-water emulsion can be dried by a method generally used in the field of formulation, for example, fluid drying, freeze drying, aeration drying, spray drying, static drying, stirring drying, air flow drying, vacuum drying. , Microwave drying, infrared / far infrared drying, etc. 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 an oral preparation such as tablets, capsules, granules and powders. These oral preparations can be produced by the methods used in the pharmaceutical field. For example, as a method for producing a tablet, the following methods i), ii) and iii) can be mentioned.

i) Tablets are produced by mixing the 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.), add a solvent (eg, purified water, ethanol, or a mixture thereof). Granulate while adding or spraying. Tablets are produced by adding an appropriate amount of lubricant, a disintegrant if necessary, a disintegrant, and the like to the obtained granulated product, mixing them, and then compression-molding them.
iii) The oil dispersion containing ED-71 and ED-71 epoxide is mixed with an additional additive (such as Excipient 2), followed by a binder and, if necessary, other additives as a solvent (eg, purified water). , Ethanol, or a mixture thereof), and granulate while adding or spraying the solution obtained by dispersing or dissolving. Tablets are produced by adding an appropriate amount of lubricant and, if necessary, a disintegrant, and mixing them to the obtained granulated product, and then compression molding.

Additional additives include, for example, surfactants and pH regulators for the purpose of improving drug release, fluidizers for the purpose of improving fluidity during the process, and stabilization for the purpose of increasing stability. An agent can be used, a flavoring agent for the purpose of adding a taste or odor, and a colorant for the purpose of adding a color. The amount of these to be used is usually 0 to 99.99 parts by weight, preferably 50 to 99.5 parts by weight, and more preferably 90 to 99 parts by weight with respect to 100 parts by weight of the pharmaceutical product.

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

The content of ED-71 in the pharmaceutical composition (preferably tablets) 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. It is 5 to 0.75 μg.

Excipients 2 include, for example, starches such as corn starch, horse belly starch, wheatco starch, rice starch, partially pregelatinized starch, pregelatinized starch, and perforated starch, lactose hydrate, fructose, glucose, mannitol, and sorbitol. Examples thereof include sugars such as sugars or sugar alcohols, anhydrous calcium hydrogen phosphate, crystalline cellulose, starched calcium carbonate, calcium silicate and the like. In a preferred embodiment, Excipient 2 is starch, lactose hydrate, crystalline cellulose, or anhydrous calcium hydrogen phosphate.

Examples of the disintegrant include sodium starch glycolate, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidone, low degree of substitution hydroxypropyl cellulose, hydroxypropyl starch and the like. The amount of the disintegrant 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 pharmaceutical product.

Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, 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.

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

Examples of the surfactant include polysorbate 80, polyoxyl 40 stearate, 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 hydrous silicon dioxide, and talc. Here, specific examples of the light anhydrous silicic acid include Siricia 320 (trade name, Fuji Silysia Chemical Ltd.), Aerosil 200 (trade name, Nippon Aerosil Co., Ltd.) and the like.

Stabilizers include, for example, paraoxybenzoic acid esters such as methylparaben, propylparaben; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol; benzalconium chloride; phenols such as phenols and cresols; Examples include sorbic acid.

Examples of the flavoring agent include sweeteners, acidulants, and fragrances that are usually used in the pharmaceutical field.

The colorant may be any colorant as long as it is permitted to be added to pharmaceutical products, for example, Edible Yellow No. 5 (Sunset Yellow, US Edible Yellow No. 6), Edible Red No. 2, and Edible Blue. Examples include food coloring such as No. 2, food coloring, iron sesquioxide, and the like.

Examples of the antioxidant include nitrite (eg sodium nitrite), sulfite (eg sodium sulfate, dry sodium sulfite, sodium hydrogen sulfite, sodium pyrosulfate), thiosulfate (eg sodium thiosulfate), alpha thioglycerin. , 1,3-butylene glycol, thioglycolic acid and its salts (eg sodium thioglycolate), thioalinate (eg sodium thioappleate), thiourea, thiolactic acid, edetate (eg sodium edetate), dichlor Isocyanurate (eg potassium dichloruisianurate), citric acid, cysteine and its salts (eg cysteine hydrochloride), benzotriazole, 2-mercaptobenzimidazole, erythorbic acid and its salts (eg sodium erythorbic acid), ascorbic acid. And their ester compounds (eg L-ascorbic acid stearate, palmitate ascorbic acid), phospholipids (eg soy lecithin), metal chelating agents and salts thereof (eg ethylenediamine tetraacetic acid, ethylenediamine tetraacetate calcium disodium, ethylenediamine tetratetra. Disodium acetate), tartrate acid and its salts (eg Rochelle salt), polyphenols (eg catechin), glutathione, dibutylhydroxytoluene, butylhydroxyanisole, propyl ascorbic acid, natural vitamin E, tocopherol acetate, concentrated mixed tocopherols, tocopherol homologues. (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, butylhydroxyanisole, propyl castorate. Is preferable, dl-α-tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, and propyl ascorbic acid are more preferable, and dl-α-tocopherol is even more preferable.
The amount of the antioxidant 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 pharmaceutical product.

The above-mentioned additional additives may be used by mixing two or more kinds at an appropriate ratio.

From the tablets, sugar-coated tablets or film-coated tablets can also be obtained by using a more 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 or sugar alcohols, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like. May be good.

Examples of the coating agent include ethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl 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, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name), Evonik Degusa], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Evonik Degusa], methacrylic acid copolymer S [Eudragit S (trade name), Evonik Degusa] and other acrylic acid polymers; Natural products such as cellac can be mentioned.

Examples of the sustained-release film coating base include cellulose-based polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Ebonic Degusa], ethyl acrylate / methyl methacrylate copolymer suspension. Acrylic acid-based polymers such as turbid liquid [Eudragit NE (trade name), Ebonic Degusa]; cellulose acetate and the like can be mentioned.

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

A water-soluble substance, a plasticizer, or the like may be added to the coating additive as needed to control the elution 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, acetyltriethyl citrate, tributyl citrate, acetyltributyl citrate, dibutyl adipate, oleic acid, oleinol. One or more selected from the above can be used.

Further, as a method for forming a coating layer by coating a tablet with the coating additive, a method generally used in the pharmaceutical field can be used, for example, a pan coating method, a fluid coating method, a rolling coating method, and the like. The flow rolling coating method can be mentioned. The coating liquid used in these methods is obtained by mixing the above-mentioned 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 with respect to the total weight of the coating liquid.
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, in addition to the principle / apparatus described in the examples, granulation includes extrusion granulation, crushing / sizing, rotary granulation, dry granulation, wet high shear granulation, and the like. And it can be carried out by each principle of fluidized bed granulation.

Examples of granulators based on extrusion granulation include twin dome granules, basket crowners, semi-dry / low-moisture granulator disc peretters, semi-dry / small-diameter granulators fine disc peretters, and peretter doubles. , And Multigran (above, made by Dalton), and KEX Extruda and KRC Nida (above, Kurimoto Iron Works).

Examples of granulators based on crushing and sizing include power mills (made by Dalton), sizing machines Fiore F and Randell mills (all made by Tokuju Kosakusho), and no-screen sizing machines Nebula Sizer (manufactured by Nara Machinery Co., Ltd.). ), Quick Mill QMY (manufactured by Seishin Corporation), Roll Granulator (manufactured by Matsubo), New Speed Mill (manufactured by Okada Seiko), and MF type sizing machine Oscillator and crushing sizing machine Conibit (above, Swiss Frebit) Manufactured and sold at EarthTechnica).

Examples of the granulator based on the principle of rotary granulation include Malmölizer (manufactured by Dalton), centrifugal flow coating granulator CF and Granulex GX (manufactured by Freund Industries).

Examples of the granulator based on the dry granulation principle include a roller compactor (manufactured by Freund Sangyo), a pharma compactor (manufactured by Hosokawa Micron), an RCP roller compactor (manufactured by Kurimoto, Ltd.), and a pharma compactor (manufactured by Matsubo).

Granulators based on wet high shear granulation include, for example, SP Granulator and Spartan Luzer (above, Dalton), Vertical Granulator (Paurek), GEA Aeromatic Fielder Multiprocessor Pharma Connect (Pharma Connect for Research and Development). Eurotechno), Mixer & Granulator (NMG) (Nara Machinery Co., Ltd.), Crushing Rolling New Gramachine SEG (Seishin Corporation), New Speed Kneader (Okada Seiko), High Speed Mixer (Advance Series), Dynamic Examples include dryers, high flex glural, and microwave granulator dryers (above, manufactured by Fukae Pautech, sold by EarthTechnica), and TM-type granulation mixers (manufactured by Nippon Coke Industries).

As a granulation device based on the principle of fluidized bed granulation, for example, a pneumulmerizer, a swirling fluidized bed, a minute amount fluidized bed, a swing processor (all manufactured by Dalton), a flow coater containment, a flow coater Universal, and a flow coater FLO. , And Spiraflow SFC (Freund Sangyo), Agromaster (Hosokawa Micron), GEA Aeromatic Fielder Flexstream (Eurotechno), and Sprud (Okawara Seisakusho).

In addition to the principles and devices described in the examples, mixing is performed by a convection type (mechanical stirring type), a diffusion type (container rotation type), and a kneading / kneader principle.

Mixing devices based on the convection type (mechanical stirring type) include, for example, a mixing stirrer NDM type, a mixing stirrer XDM type, a mixing stirrer DM type, a prototype / research mixing stirrer AM / XDM / DM type, and a laboratory mixing stirrer twin. Mix, Pug Mixer, Ribbon Mixer, Spartan Mixer, and Paste Mixer (Dalton), Cyclomix, and Nauta Mixer (Hosokawa Micron), Vertical Mounting MAG-NEO Seal Mixer (Magneo Giken), Bottom Type Super Mag Mixer, S Mixer Super Mix (above, made by Satake Kagaku Kikai Kogyo), Julia Mixer, and Ribbon Mixer (above, manufactured by Tokuju Kosakusho), PX Mixer (manufactured by Seishin Co., Ltd.), Ladyge Mixer (manufactured by Matsubo) , FM mixer RC type, MP mixer (above, manufactured by Nippon Coke Industries), and ribocorn (manufactured by Okawara Seisakusho).

Mixing devices based on the diffusion type (rotary container type) include, for example, the GEA book system IBC blender, the GEA book system IBC blender with NIR measuring device (all manufactured by Eurotechno), the V-type mixer, and the W-type mixing device. Machine (above, manufactured by Tokuju Kosakusho), V-type mixer (manufactured by Nara Machinery Co., Ltd.), W-type mixer SCM, and V-type mixer SVM (above, manufactured by Seishin Corporation), capsule locking mixer (manufactured by Aichi Electric), and Bole container mixer PM (manufactured by Kotobuki Kogyo) can be mentioned.

Mixing devices based on the principle of kneading and kneading include, for example, continuous kneader, batch kneader (above, made by Dalton), T.K. hibis mix, and T.K. hibis disper mix (above, made by Primix), and Lystritz extruder. (Manufactured by Nara Machinery Co., Ltd.) and Planetary Mixer (manufactured by Asada Iron Works).

Examples of other mixing devices include Conti-TDS (manufactured by Dalton), mixing torque meter ST-3000II process reactor DDL / 3000, and stirring simulation MixSim (manufactured by Satake Chemical Machinery Co., Ltd.).

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

Locking is performed by the principles of single-shot locking and rotary locking, but rotary locking is preferable from the viewpoint of efficiency.

In addition to the names described in the examples, the names of the tableting devices based on the rotary tableting principle include, for example, the removable high-speed tableting machine Fette (manufactured by Bosch Packaging Technology), the high-speed tableting machine COMPRIMA, and the high-speed tableting machine. Machine SYNTHESIS (Mutual), Rotary Press MZ400 (Mori Machinery), GEA Coltoa Module Tableting Machine P-type, S-type, D-type, and GEA Pharma System Performer P (above, 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 disk desorption / washing rotary tablet machine, and containment tablet machine (all manufactured by Kikusui Seisakusho) ), And BX type HX type high pressure tableting machine, CVX type rotating disk removable 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 compound tableting machine (above, manufactured by Hata Iron Works) can be mentioned.

Single-layer tablets can be obtained with the above-mentioned tableting device. For example, a GEA Coltoa module type double-layer tablet locking machine D type (manufactured by Eurotechno) and a multi-layer tablet machine (manufactured by Kikusui Seisakusho) can be used to obtain multi-layer tablets. Nucleated tablets can also be manufactured using a nucleated tablet machine (manufactured by Kikusui Seisakusho) and an AP / MS type C type nucleated tableting machine (manufactured by Hata Iron Works).

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

Examples of the coating device based on the pan coating (horizontal pan) include the high coater FZ, the aqua coater AQC containment, and the aqua coater AQC (all manufactured by Freund Industries).

Examples of the coating device based on the pan coating (tilted pan) include the Paulek coater PRC and the Doria coater DRC (all manufactured by Paulek).

Examples of the coating device based on the air floating type (fluidized bed) include a glatt powder coater GPCG SPC, a multiplex, and a composite fluidized bed SFP (all manufactured by Paulec).

Examples of other coating devices include a hybridization system (manufactured by Nara Machinery Co., Ltd.) and a mechano hybrid (manufactured by Nippon Corksue Co., Ltd.).

The pharmaceutical composition of the present invention is useful for the treatment or prevention of diseases or symptoms (eg, osteoporosis) that can be treated or prevented by suppressing bone turnover and improving bone density and bone strength.

In the present invention, for the treatment or prevention of a disease or symptom, prevention, exacerbation or suppression or inhibition of the onset of the disease, alleviation or exacerbation or suppression of the progression of one or more symptoms exhibited by an individual suffering from 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. Mammals are preferably humans.

The pharmaceutical composition of the present invention is administered to a subject in an amount effective for treatment or prevention. "Effective amount for treatment or prevention" means an amount that has a therapeutic or prophylactic effect for a specific disease, dosage form and route of administration, and refers to the target species, type of disease, symptoms, gender, age, chronic disease, etc. It is determined as appropriate according to the factors of. The route of administration is usually oral administration.

The dose of the pharmaceutical composition of the present invention is appropriately determined according to the species of subject, the type of disease, symptoms, sex, age, chronic disease, and other factors, and is usually ED-71 for human adults. As a result, 0.01 to 10 μg, preferably 0.5 to 0.75 μg, can be administered per day.

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

The "therapeutically or prophylactically effective amount" in the present invention means an amount that exerts a therapeutic or prophylactic effect for a specific disease or symptom, administration form and administration route, and means a target species, disease or symptom type, symptom, sex, etc. It will be decided as appropriate according to age, chronic illness, and other factors.

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

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

Examples of the "disease or symptom" in the present invention include a disease or symptom (for example, osteoporosis) that can be treated or prevented by suppressing bone turnover and improving bone density and bone strength.

As described above, the ED-71 epoxide is produced by conversion from ED-71 mainly in the step (iii) (drying step) and is present in the oil solution together with ED-71 in the prepared tablets. Further, if the prepared tablet is left as it is, the conversion from ED-71 to ED-71 epoxide progresses further gradually, but the progress is airtight in a container (packaging form) in which an oxygen scavenger coexists. It can be suppressed by saving it in the state. Therefore, in one aspect, the present invention provides a product in which the pharmaceutical composition of the present invention and the oxygen scavenger are encapsulated in an airtight state in a package form.

Examples of oxygen scavengers include Wonder Keep (registered trademark) (Powder Tech), Oxymove (registered trademark) (Nandori Oe Chemical), Modulan (Nippon Kayaku Food Techno), Keypit (Drency), Welpack (Taisei), etc. Oxyter (registered trademark) (Ueno Food Techno), Keplon (Keplon), Freshness preservative (Toppan Printing), Sansoles (Hiroyo), Sansokat (registered trademark) (Iris Fine Products), Ageless (registered trademark) ZM (Mitsubishi) Gas Chemical, ZM-1), Everfresh (Torishige Sangyo, QJ-30, etc.), Vitalon PH (Tokiwa Sangyo, PH-100SL, etc.), Secure (registered trademark) (Nisso Resin, AP-250, etc.), etc. , Preferably ageless ZM.

The "packaging form" can be in an airtight state, and examples thereof include bottle packaging, pillow packaging, blister pack packaging, ampoule packaging, and the like, and bottle packaging and pillow packaging are preferable. .. Further, the pharmaceutical composition of the present invention is encapsulated as it is or in PTP packaging (press-through pack packaging) in an airtight state, and preferably, the composition as it is is contained in a bottle package in an airtight state. The composition is sealed in or PTP packaged in an airtight state in a pillow package.

Examples of the material of the bottle packaging include thermoplastic resin, glass, pottery, spinach, metal and the like, and thermoplastic resin and glass are preferable. The material of the bottle packaging is not limited to a single layer, and for example, the same thermoplastic resin may be used or a multi-layer structure made of a plurality of types of materials may be used. The lid of the bottle packaging may be in any form as long as it can be kept airtight, and examples thereof include a screw cap. Examples of the material of the lid include thermoplastic resin and metal (for example, iron, tinplate, stainless steel, etc.), and metal is preferable. When the lid and the bottle packaging are made of thermoplastic resin, plastic bottle packaging with a seal (preferably an aluminum seal) is preferable.

The "pillow packaging" means a packaging form in which the pharmaceutical composition of the present invention is packaged as it is or in a blister pack, covered in a bag shape with a film, and then airtightly contained with gas. Examples of the material of the pillow packaging include an aluminum laminated film, a thermoplastic resin, and the like, or a combination thereof, and an aluminum laminated film is preferable.

"Airtight" means a state in which there is no risk of liquid intrusion during daily handling or normal storage conditions. Further, the airtightness includes a state in which the invasion of gas is suppressed to some extent. 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.

"Sealed" means a condition in which there is no risk of gas or microbial invasion during routine handling or normal storage conditions.

Examples of the material of the PTP packaging and the blister pack packaging include resins such as thermoplastic resins, metals, various paints, various adhesives and the like, and thermoplastic resins are preferable.

Examples of the thermoplastic resin include polyvinyl chloride (PVC), unstretched polypropylene (CPP), polypropylene (PP), polyvinylidene chloride (PVDC), polyvinylidene chloride (PCTFE), and cyclic olefin copolymer (Cyclic olefin copolymer). 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 and the like, preferably polyvinyl chloride, unstretched polypropylene, polypropylene, polyvinylidene chloride, polyethylene trifluoride, cyclic. It is 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 for PTP packaging include aluminum foil and a laminated film obtained by laminating an aluminum foil with a film made of a thermoplastic resin. As a method for producing PTP packaging or blister pack packaging, a known method may be used. The packaging material for pillow packaging, PTP packaging, or blister pack packaging in the present invention is not limited to a single-layer packaging material, and may be in the form of a multi-layer film in which a plurality of layers are bonded together. The multilayer film has a barrier layer that suppresses the permeation of oxygen in the outer layer or the intermediate layer, and can have an absorption layer having a deoxidizing function as the inner layer or the intermediate layer. Examples of the absorption layer having an oxygen scavenging function include a resin kneaded with an oxygen scavenger that exerts an oxygen scavenging function.

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

When the pharmaceutical composition and the deoxidizing agent of the present invention are sealed in the package form in an airtight state, the gas in the package form is a gas other than oxygen (for example, nitrogen gas, carbon dioxide gas, helium gas, argon gas, neon gas, etc.). It may be replaced with krypton gas, xenon gas, radon gas).

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 contact with air, and also. Although it is a substance that is allowed to exist, its content 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, still more preferably 1.2% or less. Specific examples of the preferred content include 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 of the following Examples. Ratio of ED-71 epoxide content to total content of ED-71, ED-71 epoxide, Pre ED-71, a thermal isomer of ED-71, and other ED-71 related substances in the pharmaceutical composition (%) ), And is calculated by the following formula.
ED-71 epoxide content (%) = (A _imp-2 x RRF) / (At + A _{imp-2 x} RRF + _Ap x RRF + Σ (A _i x RRF)) x 100
At: Peak area of ED-71 _Ap : 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: For 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 herein 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 Methyl Cellulose
BHT: Dibutylhydroxytoluene
MCT: Medium-chain fatty acid triglyceride
HPC: Hydroxypropyl Cellulose
PVP: Polyvinylpyrrolidone
PVA copolymer: polyvinyl alcohol / acrylic acid / methyl methacrylate copolymer

Example 1: Formulation change 1
An ethanol solution of ED-71 was prepared by dissolving 50 mg of ED-71 in 2.5 mL of EtOH. Dissolve 1 g of BHT (Merck) and 2 g of dl-α-tocopherol (special use, Wako Pure Chemical Industries, Ltd.) in 97 g of MCT (ODOC, Nisshin Oillio) to dissolve MCT solution. Was prepared. 0.5 mL of 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 / fat solution. The ED-71 composition (Example 1) was prepared by adding 300 mg of hydroxypropylmethylcellulose to 150 mg of the prepared ED-71 oil / fat solution. The prepared ED-71 composition was stored in a constant temperature bath adjusted to 60 ° C. in the presence of air, and the residual rate (%) of ED-71 was examined after 14 days and 28 days.
As a control, the above-mentioned ED-71 oil / fat solution alone (Control Example 1) was used.
Further, the ED-71 composition was prepared in the same manner as in Example 1 by using the additive (300 mg) shown in Table 1 instead of the hydroxypropylmethylcellulose of Example 1, and the stability at 60 ° C. was improved. The same examination as in Example 1 was carried out.

The results are shown in Table 1. As is clear from Table 1, the composition of Example 1 is as stable as or better than the oil and fat solution of Control Example 1 alone, and is more stable under high temperature conditions than the compositions of Control Examples 2-34. rice field.

Example 2: Formulation change 2
Using the additives shown in Table 2 in place of hydroxypropylmethylcellulose 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. Stability was examined 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 better than Control Example 1 and more stable under high temperature conditions than the compositions of Control Examples 2-34 shown in Table 1. Although the composition of Control Example 35 did not show any decrease in the stability of ED-71, when meglumine was used as an additive, the emulsified state required in the manufacturing process of the oil dispersion tablet described later was observed. 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 will be described later, it is necessary to maintain the emulsified state of the MCT solution of ED-71 and the aqueous solution of the water-soluble polymer in the process of producing the oil dispersion tablet. Therefore, an emulsified solution 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) are dissolved in purified water, and 2% and 5%, respectively. An aqueous solution was prepared. 20 mL of each solution was added to each of the plastic 50 mL centrifuge tubes. Oil Red (Oil Red O, Nacalai Tesque) was dissolved at 0.1 g / L, and 10 mL each of medium-chain fatty acid triglycerides colored red was added.
After emulsifying with a homogenizer at about 10,000 rpm for 1 minute, it was determined whether or not the oil layer was separated on the upper part of the emulsified solution after 2 hours and 24 hours.

The results are shown in Table 3. 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. HPMC, HPC, and PVA copolymer did not separate the water layer from the oil layer, 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. Dissolve 1 g of BHT (Merck) and 2 g of dl-α-tocopherol (special use, Wako Pure Chemical Industries, Ltd.) in 97 g of MCT (ODOC, Nisshin Oillio) to dissolve MCT solution. Was prepared. 0.5 mL of ethanol-dissolved solution of ED-71 was added to the prepared MCT solution, and the mixture was stirred with a vortex mixer to prepare an ED-71-dissolved MCT solution. The water-soluble polymer solutions shown in Table 4 were prepared respectively. The ED-71-dissolved MCT solution and the water-soluble polymer solution were mixed at the ratios shown in Table 5 and emulsified by stirring at 5400 rpm for 1 minute using a homogenizer to prepare an ED-71-containing emulsion. The prepared ED-71-containing emulsion was weighed to an ED-71 drug substance amount of about 1 μg, distilled under reduced pressure in a vacuum dryer, and the obtained sample was used for measuring the residual ratio (Example 3). ~ 11). The sample was stored in a constant temperature bath adjusted to 60 ° C. in the presence of air, and the content value of ED-71 immediately after preparation, the content value of ED-71 after 14 days and 25 days, and the residual rate (%) 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 approximately 1 μg, and using a sample that was distilled under reduced pressure in a vacuum dryer as a standard product. The content value and residual rate of ED-71 were calculated by the following formula.
ED-71 content value (%) = 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 area)
ED-71 survival rate (%) = 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, it was found that the content value of ED-71 varied widely in the formulation (1%) with a low concentration of water-soluble polymer. It is considered that this is because the emulsion was separated after preparation in the formulation having a low concentration of the water-soluble polymer, and the weighed amount of ED-71 in the sampled emulsion was uneven. In the sample with a water-soluble polymer concentration of 5% or 6%, the variation in the results was small, and the residual rate of ED-71 after 25 days was 95% or more. Although the variation was small in the formulation with a high concentration of water-soluble polymer (10% or 15%), the residual rate of ED-71 decreased to around 90% in the sample after 25 days.
The concentration of the water-soluble polymer solution containing 1% to 15% HPMC or HPC is preferably 5 to 6% for stabilization of ED-71 in the emulsion.

[Manufacturing example] Oil dispersion tablet
Dissolve 0.142 kg of dl-α-tocopherol (Wako Pure Chemical Industries, Ltd.) and 0.284 kg of BHT (Merck) in 9.025 kg of MCT (Nissin Oillio), where 1.1813 g of ethanol (99.5%) of eldecalcitol (ED-71) is dissolved. ) (Imazu Pharmaceutical Industries, Ltd.) (0.078 kg) After adding the solution, 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 3 times to obtain an emulsion.

Spray the emulsion while stirring 165.6 kg of mannitol (Merck) sieved with 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 of 56 rpm and a cross screw of 1500 rpm. It was added and kneaded for 15 minutes to obtain granulated powder.

While sieving the obtained granulated powder while operating a wet granulator (POWREX U-20) with a 9.5 mm (square hole) screen at 300 rpm, a fluidized bed granulator dryer ( Transferred to POWREX WSG-200pro) and dried (Sample 1).

For the dried granulated powder, a dry granulator (U-20 manufactured by POWREX) set with a screen having a diameter of 2 mm was operated at 800 rpm to perform granulation.
The sizing product was mixed with a mixture of 3.0 kg of mannitol sieved through a sieve with an opening of 850 μm and 3.6 kg of croscarmellose sodium (DFE pharma) for 15 minutes, and further sieved with a sieve of 850 μm with an opening. After mixing with a mixture of 6.6 kg and 0.72 kg of calcium stearate (Merck) for 3 minutes (Sample 2), tablets were tableted with a tableting machine (COMPRIMA manufactured by IMA) at a pressure of about 7.5 kN (Sample 3). .. At the time of tableting, the tablet weight was adjusted so that the eldecalcitol content per tablet was 0.75 μg.

All the obtained tablets were placed in a coating machine (PRC-450 manufactured by Paulek), sprayed with a solution of HPMC 6.480 kg of water (74.520 kg) and dried at 60 ° C., and further, hypromellose 4.950 kg and talc (Tark). Merck) 1.350 kg, titanium oxide (Ishihara Sangyo) 2.664 kg, and iron sesquioxide (Hypromellose) 0.036 kg water (65.167 kg) suspension sprayed to dry and coated with two layers of film. Obtained (Sample 4; Eldecalcitol content per tablet is 0.75 μg).

When preparing tablets with an eldecalcitol content of 0.5 μg per tablet, the second layer is hypromellose 4.950 kg, talck (Merck) 1.350 kg, titanium oxide (Ishihara Sangyo) 2.502 kg, iron sesquioxide (Suspension). Chemicalization) 0.018 kg and yellow iron sesquioxide (Shinmi Kasei) 0.180 kg water (65.167 kg) suspension was sprayed and coated.
A schematic diagram of the manufacturing flow is shown in FIG.

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

The residual rate of ED-71 was measured by the following method.
Five tablets were placed in a 30 mL centrifuge tube. Water: 7 mL of acetonitrile (20:80) was added and ultrasonically irradiated for 30 minutes. During ultrasonic irradiation, stirring was performed once every 10 minutes. The supernatant was filtered through a polytetrafluoroethylene (PTFE) filter with a pore size of 0.20 μm, the first 1 mL was discarded, and the remaining filtrate was used as a sample solution. Separately, using the ED-71 standard product, the solution 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 standard solution were measured by high performance liquid chromatography (Waters Alliance, measurement wavelength 265 nm), and the ED-71 content in the sample was quantified.

The survival rate of ED-71 was calculated by the following formula.
ED-71 residual rate (%) = 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 refers to the weight (0.5 μg or 0.75 μg) of ED-71 intended to be contained in one tablet.

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 in "[Production Example] Oil Dispersion Tablets" were crushed with a small crusher LM-Plus (manufactured by Osaka Chemical Co., Ltd.), and 1.6 g of the crushed sample was weighed. rice field. 40 mL of a mixed solution of ethyl acetate and hexane in a 1: 1 volume ratio was added, stirred, and irradiated with ultrasonic waves for 20 minutes. After centrifugation at 3000 rpm for 5 minutes, the supernatant was filtered through a membrane filter (DISMIC-25HP PTFE 0.2 μm HYDROPHILIC, manufactured by ADVANTEC). The filtrate is injected into a solid-phase extraction cartridge (InertSep ^TM NH ₂ FF 500 mg / 3 mL, manufactured by GL Sciences), washed with 10 mL of a mixed solution of ethyl acetate and hexane in a 1: 1 volume ratio, and then 6 mL of ethanol. The liquid was passed and eluted. The eluted liquid was distilled off and dried by an evaporator, and then 100 μL of a mixed solution in which water and acetonitrile were mixed at a volume ratio of 1: 1 was added and redissolved to prepare a sample solution. For liquid chromatography, ACQUITY UPLC H-Class (manufactured by Waters) was used, and a purity test was performed under the following analytical conditions.
Column: Kinex 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 velocity: 1.0 mL / min Detector: Photodiode array Detection wavelength: 210 nm-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), an unknown peak has a retention time of about 5.2. 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 in 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 the same purity test as in Test Example 3, and Sample 1 and Sample 2 were subjected to the same purity test as in Test Example 3 except that the pulverization step was omitted.

The content of compound 2 is Pre, which is a thermal isomer of ED-71, compound 2 and ED-71 in the sample solution from the 220 nm profile obtained from the analysis by liquid chromatography under the conditions described in Test Example 3. The peak areas of ED-71 and other ED-71 related substances were obtained and calculated by the following formula. The peak areas of compound 2, Pre ED-71, and other ED-71 related substances were corrected by the relative sensitivity coefficient (RRF) with respect to ED-71.
Compound 2 content (%) = (A _imp-2 x RRF) / (At + A _{imp-2 x} RRF + _Ap x RRF + Σ (A _i x RRF)) x 100
At: Peak area of ED-71 Ap: 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 significant increase was observed in samples 2 to 3 obtained in the subsequent production process. Therefore, it was suggested that compound 2 may have been produced mainly by the drying step.

As shown in the ultraviolet-visible spectrum of ED-71 (FIG. 4), ED-71 has a triene structure in the molecule, so that ultraviolet absorption is maximized 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. From this result, it was suggested that compound 2 may be a decomposition product of ED-71 in which the triene structure was destroyed. Vitamin D3 _, to which ED-71 belongs, is known to be easily decomposed by oxidation. In the drying step, the sample is in a fluidized state with hot air in the drying column. It can be said that the sample staying in the fluidized bed is in an environment susceptible to oxidation because it has more opportunities to come into contact with oxygen in the air. From the above, it was presumed that the oxidation of ED-71 in the production process was involved in the formation of compound 2.

[Test Example 5] Preparation of compound 2 by air oxidation of ED-71 and its structure determination In order to determine the structure, a large amount of compound 2 was prepared.
A water: acetonitrile = 1: 1 mixed solution (10 mL) of ED-71 (60 μg) was added to the vial, and the mixture was vigorously stirred with a magnetic stirrer at 30 ° C. for 16 hours with a magnetic stirrer to promote oxidation. Since it 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, the compound 2 detected in all of Sample 1 (dried powder), Sample 2 (mixed powder), Sample 3 (uncoated tablet) and Sample 4 (film-coated tablet). Peaks with equivalent UV-visible spectra were detected for the same retention time. This peak was fractionated, and the structure was determined by a liquid chromatograph mass spectrometer LCMS-IT-TOF (manufactured by Shimadzu Corporation) and a nuclear magnetic resonance apparatus Agent DD2 600 MHz NMR Spectrometer (manufactured by Agilent Technologies).
MS m / z: 529.3528 (M ⁺ -Na)
^{1 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, compound 2 was presumed to be an oxygen adduct of ED-71. Moreover, from the results of various NMR measurements, it was suggested that compound 2 is an epoxy body in which oxygen is added to the triene site of ED-71. Based on the above, compound 2 was designated as (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.

[Test Example 6] Chemical synthesis of compound 2 In this test example, the proton nuclear magnetic resonance spectrum ( ¹ H-NMR spectrum) is present or absent as an internal standard in chloroform-d or acetonitrile-d ₃ . Below, it was measured using ECP500 (manufactured by JEOL). Further, the purity analysis of the obtained compound 2 by liquid chromatography was carried out in the same manner as in Test Example 3.

6-1: Method 1

(1R, 2R, 3R, 5Z, 7E) -2- (3-Hydroxypropoxy) -9,10-Secocolesta-5,7,10 (19) -Triene-1,3,25-Triol (Compound 1,504) .4 mg, 1.03 mmol) and sodium hydrogen carbonate (170.4 mg, 2.03 mmol) in dichloromethane (15 mL) suspension with 3-chloroperbenzoic acid (74.2%, 251.4 mg, 1.08 mmol). The mixture was added at −70 ° C. and heated 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), the extracts were combined and 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 then concentrated to dryness (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 the obtained compound 2 was in agreement 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-Secocolester-5,7,10 (19) -triene (Compound 3))
(1R, 2R, 3R, 5Z, 7E) -2- (3-Hydroxypropoxy) -9,10-Secocolesta-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 dichloromethane (40 mL) of .008 g, 8.17 mmol) and cooled in an ice bath. Methyl chloroformate (3.1 mL, 40.8 mmol) was added dropwise to the reaction mixture at 10 ° C. or lower, the mixture was stirred at room temperature for 15 hours, and the solvent was distilled off under reduced pressure. Water (40 mL) was added to the residue, and the mixture was extracted with a mixed solution of heptane (10 mL) and ethyl acetate (30 mL). The extract was washed with water (40 mL) and saturated aqueous sodium hydrogen carbonate 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), and compound 3 (5. 3863 g) was obtained.

Step 2: ((1R, 2R, 3R, 5Z, 7ξ, 8ξ) -25-hydroxy-1,3-bis [(methoxycarbonyl) oxy] -2- {3-[(methoxycarbonyl) oxy] epoxy}- 7,8-Epoxy-9,10-Secocolesta-5,10 (19) -diene (Compound 4))
3-Chloroperbenzoic acid (74.2%) in a dichloromethane (81 mL) suspension of compound 3 (5.3863 g, 8.10 mmol) and sodium hydrogen carbonate (1.3694 g, 16.3 mmol) obtained in step 1. 1.9917 g, 8.56 mmol) was added at 0 ° C., and 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), and compound 4 (4. 2359 g) 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 (4.1369 g, 6.08 mmol), potassium carbonate (0.8406 g, 6.08 mmol) and methanol (61 mL) obtained in step 2 was stirred at room temperature for 3 hours. The reaction 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 filtrates were combined and 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%). rice field. The ¹ H-NMR spectrum of the obtained compound 2 was in agreement with the compound obtained in Test Example 5.

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

First, sample 4 (500 tablets) is filled in 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)) is closed to make it airtight. I made it into a state. The content of compound 2 in sample 4 after storage at a storage temperature of 25 ° C. and a relative humidity of 75% for 19 months was measured in the same manner as in Test Example 3 and used as the content of compound 2 in the absence of an oxygen scavenger. ..
Next, sample 4 (500 tablets) is filled in a brown glass bottle, an oxygen scavenger (Ageless ZM, ZM-1 manufactured by Mitsubishi Gas Chemical Company, Inc.) is added, the steel cap is closed, and the sealing torque is 200 to 220 N · cm. I made it into a state. The content of compound 2 in sample 4 after storage at a storage temperature of 25 ° C. and a relative humidity of 75% for 19 months was measured in the same manner as in Test Example 3 and used 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 the oxygen scavenger, the amount of compound 2 was 0.4%, and the addition of the oxygen scavenger could suppress the increase during the storage period.

INDUSTRIAL APPLICABILITY 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)

ED-71 and (1R, 2R, 3R, 5Z) -2- (3-hydroxypropoxy) -7,8-epoxy-9,10 (19) -secocholester-5,10-diene-1,3,25- A method for producing a pharmaceutical composition containing triol.
Step of preparing an oil-in-water emulsion containing an oil-and-fat solution of ED-71 and an aqueous solution of a water-soluble polymer,
A step of adhering or adsorbing an oil-in-water emulsion to an excipient, and a step of drying an oil-in-water emulsion,
Including
Here, the method, wherein the water-soluble polymer is selected from hydroxypropylmethyl cellulose and hydroxypropyl cellulose. The method according to claim 1, wherein the weight ratio of the oil-in-water emulsion to the excipient is 1: 4 to 1:20. The method of claim 1 or 2, wherein the excipient is selected from sugars or sugar alcohols. 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) -secocholester-5,10-diene-1,3,25- A pharmaceutical composition containing triol,
Particles coated with a coating agent containing a water-soluble polymer selected from hydroxypropylmethyl cellulose and hydroxypropyl cellulose are contained in the excipient or on the surface of the excipient.
The pharmaceutical composition containing the oil-and-fat solution of ED-71. The pharmaceutical composition according to claim 5, wherein the excipient is selected from sugars or sugar alcohols. The 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.

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