JP7291138B2 - Pharmaceutical composition containing oil dispersion containing ED-71 and its epoxy form in fat - Google Patents

Description

The present invention provides (5Z,7E)-(1R,2R,3R)-2-(3-hydroxypropoxy)-9,10-seccocholester-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)-seccocholesta 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 inhibiting oxidation or decomposition of ED-71, and the like.

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

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

Currently, there are no known commercially available ED-71 formulations other than soft capsules. Patent Document 2 discloses a combination drug of a strontium salt and a vitamin D derivative that can be applied to osteoporosis, and eldecalcitol is mentioned as an example of the vitamin D derivative. Moreover, Patent Document 2 describes that the combination can be made into a tablet. However, the description is nothing more than a description of a general tablet, and does not disclose the effect of adding a specific additive other than a strontium salt to the ED-71 formulation.

In Patent Document 3, for example, after dissolving 1α-(OH)-D ₃ and polyvinylpyrrolidone in ethanol, anhydrous lactose is added, and after stirring, the reaction product obtained by distilling off ethanol under reduced pressure is further pulverized. 1α-(OH) _-D3 compositions obtained by

In Patent Document 4, 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) A pharmaceutical composition, including a composition dispersed in a liquid, is described, as well as methods for making the same.

US Pat. No. 6,200,001 describes that certain vitamin D ₃ derivatives are reacted with 3-chloroperbenzoic acid to give their 7,8-epoxides.

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

Edirol (registered trademark) capsules 0.5 μg and 0.75 μg, which are commercially available as a therapeutic agent for osteoporosis, are only spherical soft capsules. had been In addition, there is a demand for ease of use, such as making spherical soft capsules non-spherical to make them easier to pick up and less likely to roll. For the convenience of patients requiring administration of ED-71, there has been a need to develop non-spherical ED-71 formulations other than soft capsules.

As such a formulation, the present inventors have developed a formulation manufactured from an oil dispersion in which particles of an oil solution of ED-71 are dispersed in an excipient. A problem was found that a preparation of sufficient quality could not be produced by using an oil dispersion prepared by using the oil-fat solution of No. 2 as it is. As a result of further research to solve this problem, we came up with the idea of coating the particles of the ED-71 oil solution with a specific additive. A new problem was found that the In response to this new problem, the present inventors have found that it is possible to produce preparations (especially tablets) of sufficient quality by using hydroxypropylmethylcellulose or hydroxypropylcellulose, which are water-soluble polymers, as an additive. (Patent Document 4).

The present invention has been made in view of such circumstances, and an object thereof 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 portion (several % or less) of ED-71 is converted to ED-71 epoxide in the process of producing tablets containing an oil dispersion of ED-71. Based on this discovery, the inventors have 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)-seccocholester-5,10-diene-1,3 ,25-triol, comprising:
A step of preparing an oil-in-water emulsion containing a fat solution of ED-71 and an aqueous solution of a water-soluble polymer;
a step of attaching or adsorbing the oil-in-water emulsion to an excipient, and a 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 to the excipient is 1:4 to 1:20.
[3] The method of [1] or [2], wherein the excipient is selected from sugars or sugar alcohols.
[4] The method of [3], wherein the excipient is mannitol.
[5] ED-71 and (1R,2R,3R,5Z)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10(19)-seccocholester-5,10-diene-1,3 ,25-triol, comprising:
comprising particles coated in the excipient or on the surface of the excipient with a coating agent comprising a water-soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose;
The above pharmaceutical composition, wherein the particles comprise a fat solution of ED-71.
[6] The pharmaceutical composition of [5], wherein the excipient is selected from sugars or sugar alcohols.
[7] The pharmaceutical composition of [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 HPMC film.

Furthermore, the present invention provides the following [9] and [10].
[9] A product in which the pharmaceutical composition according to any one of [5] to [8] and an oxygen scavenger are hermetically enclosed in a packaging form.
[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 decomposition of ED-71 due to contact with additives (formulation change) in an oil dispersion. In addition, the oil dispersion can be used to produce ED-71 preparations in various dosage forms other than soft capsules.

1 is a schematic diagram of a manufacturing flow for manufacturing tablets containing an oil dispersion of ED-71. FIG. 1 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. Fig. 3 shows the results of liquid chromatography analysis of the tablets obtained in "[Production Example] Oil Dispersion Tablets". UV-visible spectrum of ED-71. UV-visible spectrum of ED-71 epoxide (compound 2).

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

ED-71 can be prepared by (1R,2R,3R)-2-(3-hydroxypropoxy)-cholester-5,7-diene-1,3,25- It can be obtained by using a triol as a starting material, purifying it with reversed-phase HPLC after ultraviolet irradiation and thermal isomerization, concentrating it, and crystallizing it with ethyl acetate.

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

In ED-71 epoxide, the stereo of the epoxy moieties (positions 7 and 8) is not specified, but the compounds represented by the following formulas (IIa) and (IIb) in which they are specified, and any ratio thereof Also included in the ED-71 epoxides are compounds represented by the following formula (IIc) mixed with: As the ED-71 epoxide, any of the compounds represented by the following formulas (IIa) and (IIb), namely (1R,2R,3R,5Z,7ξ,8ξ)-2-(3-hydroxypropoxy)-7 ,8-epoxy-9,10(19)-seccocholester-5,10-diene-1,3,25-triol (hereinafter also referred to as compound 2) is preferred.
The 14-position configuration in compounds (II), (IIa), (IIb) and (IIc) is preferably the same as in compound (Ia).

Oil dispersion of ED-71
FIELD OF THE INVENTION The present invention relates to oil dispersions of ED-71 and oil dispersions containing ED-71 and ED-71 epoxide. As used herein, an 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, an oil dispersion containing ED-71 and ED-71 epoxide refers to a composition in which oil particles containing ED-71 and ED-71 epoxide are dispersed in an excipient.

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

The present invention also provides methods of making such pharmaceutical compositions. Specifically, a method for producing a pharmaceutical composition containing ED-71 and ED-71 epoxide, comprising: (i) preparing an oil-in-water emulsion containing an oil-fat solution of ED-71 and an aqueous solution of a water-soluble polymer; (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 hydroxyl The method is provided, wherein the cellulose is selected from propylmethylcellulose and hydroxypropylcellulose. By this method, oil particles containing ED-71 and ED-71 epoxide in the excipient are coated with a water-soluble polymer, and a formulation using an oil dispersion of ED-71 and ED-71 epoxide (especially tablets) can be manufactured. ED-71 epoxide is not present at the beginning of step (i) or, if present, preferably in a small amount of 0.1% or less, but mainly in step (iii): It is produced by the conversion (oxidation) of ED-71 and is contained in fats and oils. In the field of formulations, a method of impregnating an excipient with a fat solution containing an active ingredient is already known. A method for drying an oil-in-water emulsion and coating an oil-and-fat solution with components in the water layer has not been known in the past.

Regarding step (i), fats and oils used in the present invention include medium-chain fatty acid triglycerides (hereinafter also referred to as "MCT"), tricaprylin, caproic acid, caprylic acid, capric acid, oleic acid, linoleic acid, linolenic acid, vegetable oil etc. Here, the vegetable oils 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, which does not contain unsaturated fatty acids, are preferred, and MCT is particularly preferred.

The concentration of ED-71 in the oil/fat solution in step (i) can be appropriately determined according to the target disease or symptom, dosage form, administration route, etc., and is, 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.

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

The amount of antioxidant to be added to the oil solution is not particularly limited, but the amount below the maximum amount that can be used as an antioxidant Usually, the maximum amount used in the previous example or less, or the amount less than the usage limit amount described in the Food Additives Standards (Japan Food Additives Association, 1999) can be used.

In a preferred embodiment, dl-α-tocopherol is added to the fat solution at a concentration of 0.01% by weight or more (eg, 1% by weight or more) and 10% by weight or less (eg, 5% by weight or less). The amounts of dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate and the like to be added are the same as those for 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 oil solutions of ED-71, but hydroxypropylmethylcellulose and hydroxypropylcellulose do not reduce the stability of ED-71. Moreover, when hydroxypropylmethylcellulose and hydroxypropylcellulose are used, the emulsified state of the oil-in-water emulsion can be maintained for a long period of time.

Here, the fact that the stability of ED-71 in the pharmaceutical composition of the present invention does not decrease is confirmed by producing tablets from the pharmaceutical composition of the present invention and storing them at 40° C. for 1, 3, or 6 months, protected from light. This is confirmed by examining the residual rate of ED-71 after The residual rate of ED-71 was determined by high-performance liquid chromatography (measurement wavelength: 265 nm) for stored samples and initial samples. -2-(3-hydroxypropoxy)-9,10-seccocholester-5(10),6,8(9)-triene-1,3,25-triol; also referred to herein as Pre ED-71) is calculated by the following formula.
Ratio of ED-71 content to the indicated amount (%) = (measured amount of ED-71 standard / total ED-71 peak area in ED-71 standard) x ED- in initial sample or stored sample Total 71 peak areas x (weight of initial sample or total sample/weight of sample used for measurement)/labeled 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 ED-71 content to the labeled amount in the preserved sample (%) / ratio of ED-71 content to the labeled amount in the initial sample (%) x 100

In addition, the meaning of each term in the above formula is as follows.
・"Display amount": Theoretical content per tablet ・"ED-71 standard product": ED-71 drug substance Area total": Weight of ED-71 standard per unit peak area (value for calculating the content of ED-71 in the measurement sample from the peak area)

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

Further, in the present invention, hydroxypropyl cellulose (HPC) is defined as an ingredient It refers to hydroxypropyl cellulose listed as No. 002303, and is different from low-substituted hydroxypropyl cellulose listed as ingredient number 002440 in the same encyclopedia. In the hydroxypropyl cellulose used in the present invention, the molar degree of substitution (MS) (indicating the ratio of the hydroxy groups of the repeating units (glucose rings) of HPC substituted with hydroxypropoxy groups) is usually 2 to 3, preferably 2.5. 5 to 3, more preferably 3. On the other hand, the molar substitution degree in low substituted hydroxypropyl cellulose is 0.2 to 0.4. Hydroxypropyl cellulose in the present invention can be purchased, for example, from ISP Japan under the trade name of Klucel and from Nippon Soda under the trade name of hydroxypropyl cellulose.

The coating agent in the present invention may contain additives other than the water-soluble polymer, such as stabilizers and antioxidants.

The concentration of the water-soluble polymer in the aqueous solution in step (i) is appropriately determined according to the amount of ED-71. Preferably 3 to 6 wt%, more preferably 4 to 6 wt%, even more preferably 5 to 6 wt%. The aqueous solution in step (i) may contain additives other than the water-soluble polymer, such as stabilizers and antioxidants.

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

The ratio (weight ratio, o/w ratio) between the oil solution of ED-71 and the aqueous solution of the water-soluble polymer may be within a range where an oil-in-water emulsion can be prepared, and is usually 1:1.5. ~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 3-6% by weight, 4-6% by weight, or 5-6% by weight, the fat solution of ED-71 and the water-soluble The ratio of the polymer to the aqueous solution is 1:1.5 to 1:20, 1:2 to 1:20, or 1:2 to 1:4.

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

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

The ratio (weight ratio) between the oil-in-water emulsion and the excipient used in step (ii) may vary depending on the type of excipient, but is usually 1:1 to 1:100, preferably 1:4 to It is in the range of 1:20. In particular, when the excipient is mannitol, a preferred granulated powder that can be used in the production of formulations such as tablets can be obtained if the weight ratio is usually in the range of 1:4 to 1:20.

Adhesion or adsorption of the oil-in-water emulsion to the excipient can be performed by a method commonly used in the pharmaceutical field, for example, a method of granulating while spraying the emulsion onto the excipient, an excipient For example, an emulsified liquid is added to the agent and mixed and stirred. Such a method can be carried out using, for example, a high-speed stirring granulator (VG-600CT manufactured by POWREX), a mixing stirrer (DM type manufactured by Shinagawa Kogyosho), and the like. The attachment or adsorption also includes impregnation (infiltration of the pores of a porous excipient with an oil-in-water emulsion).

In step (iii), the oil-in-water emulsion adhered or adsorbed to the excipient is dried, thereby removing water from the aqueous solution of the water-soluble polymer, and the oil-fat solution is directly coated with the water-soluble polymer. is thought to be formed. The oil dispersion obtained in this manner contains particles containing an oil solution of ED-71, and exhibits good manufacturability (e.g., fluidity and compression moldability) when used in the production of formulations such as tablets. .

Drying of the oil-in-water emulsion can be carried out by methods commonly used in the pharmaceutical field, such as fluidized drying, freeze drying, air drying, spray drying, static drying, stirring drying, flash drying, and vacuum drying. , microwave drying, infrared/far infrared drying, and the like. Drying may also be performed with heating or cooling. Drying can be performed using, for example, a fluid bed granulator dryer (POWREX WSG-200pro), a vacuum dryer (Nippon Dryer Conical Dryer), or the like.

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

i) Tablets are produced by mixing an oil dispersion containing ED-71 and ED-71 epoxide with additional excipients (excipient 2, disintegrants, lubricants, etc.) followed by compression molding.
ii) After mixing the oil dispersion containing ED-71 and ED-71 epoxide with additional additives (excipient 2, binders, etc.), a solvent (e.g., purified water, ethanol, or mixtures thereof) is added. Granulate while adding or spraying. Appropriate amounts of a lubricant and, if necessary, a disintegrant are added to the resulting granules, mixed, and then compression-molded to produce tablets.
iii) After mixing an oil dispersion comprising ED-71 and ED-71 epoxide with additional additives (such as Excipient 2), the binder and optionally other additives are added to a solvent (e.g., purified water , ethanol, or a mixture thereof) and granulate while adding or spraying a liquid obtained by dispersing or dissolving it. A suitable amount of lubricant and, if necessary, a disintegrant are added to the resulting granules, mixed, and then compressed to produce tablets.

Additional additives include, for example, surfactants and pH modifiers to improve drug release, fluidizers to improve fluidity during the process, and stabilizers to increase stability. A flavoring agent can be used for the purpose of adding taste or 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, per 100 parts by weight of the preparation.

The tablets may also contain antioxidants as additional excipients. The antioxidant can be added at any step in the manufacturing processes 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 and then compressing the mixture. Tablets can also be produced by preparing an oil dispersion using an oil-and-fat solution of ED-71 in which an antioxidant has been dissolved in advance, mixing this with other additives, and then compressing. .

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

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

Disintegrants include, for example, sodium starch glycolate, carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylstarch sodium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, hydroxypropyl starch and the like. The amount of disintegrant used is preferably 0.5 to 25 parts by weight, more preferably 1 to 15 parts by weight, per 100 parts by weight of the preparation.

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

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

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

pH adjusters include, for example, acetic acid, lactic acid, citric acid, malic acid, succinic acid, fumaric acid, tartaric acid, phosphoric acid, and any salts thereof.

Fluidizing agents include, for example, light silicic anhydride, silicon dioxide such as hydrous silicon dioxide, and talc. Specific examples of the light anhydrous silicic acid include Silicia 320 (trade name, Fuji Silysia Chemical Co., Ltd.) and Aerosil 200 (trade name, Nippon Aerosil Co., Ltd.).

Examples of stabilizers 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; Sorbic acid can be mentioned.

Flavoring agents include, for example, sweeteners, acidulants, flavoring agents and the like that are commonly used in the pharmaceutical field.

Any coloring agent may be used as long as it is permitted to be added to pharmaceuticals. food dyes such as No. 2, food lake dyes, iron sesquioxide, and the like;

Antioxidants include, for example, nitrites (e.g. sodium nitrite), sulfites (e.g. sodium sulfite, dry sodium sulfite, sodium bisulfite, sodium pyrosulfite), thiosulfates (e.g. sodium thiosulfate), alpha thioglycerin , 1,3-butylene glycol, thioglycolic acid and its salts (eg sodium thioglycolate), thiomalates (eg sodium thiomalate), thiourea, thiolactic acid, edetates (eg sodium edetate), dichlor Isocyanurates (eg potassium dichlorocyanurate), citric acid, cysteine and its salts (eg cysteine hydrochloride), benzotriazole, 2-mercaptobenzimidazole, erythorbic acid and its salts (eg sodium erythorbate), ascorbic acid and its ester compounds (e.g. L-ascorbic acid stearate, palmitate ascorbic acid), phospholipids (e.g. soybean lecithin), metal chelating agents and their salts (e.g. ethylenediaminetetraacetic acid, calcium disodium ethylenediaminetetraacetate, ethylenediaminetetraacetic acid Acetate Disodium), Tartaric Acid and Its Salts (e.g. Rochelle Salt), Polyphenols (e.g. Catechin), Glutathione, Dibutyl Hydroxytoluene, Butyl Hydroxyanisole, Propyl Gallate, Natural Vitamin E, Tocopherol Acetate, Concentrated Mixed Tocopherols, Tocopherol Congeners (e.g. d-α-tocopherol, dl-α-tocopherol, 5,8-dimethyltocopherol, 7,8-dimethyltocohol, δ-methyltocopherol, 5,7,8-trimethyltocotrienol, 5,8-dimethyltocotrienol, 7 , 8-dimethyl tocotrienol, 8-methyl tocotrienol) and the like. Among these, tocopherol acetate, dibutyl hydroxytoluene, natural vitamin E, dl-α-tocopherol, d-α-tocopherol, concentrated mixed tocopherols, ascorbic palmitate, L-ascorbyl stearate, butyl hydroxyanisole, propyl gallate is preferred, dl-α-tocopherol, dibutylhydroxytoluene, butylhydroxyanisole and propyl gallate are more preferred, and dl-α-tocopherol is even more preferred.
The amount of antioxidant used is preferably 0.001 to 10 parts by weight, more preferably 0.01 to 1 part by weight, per 100 parts by weight of the preparation.

Two or more of the above additional additives may be mixed at an appropriate ratio and used.

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

Examples of sugar-coating bases include sugars and sugar alcohols such as sucrose and erythritol, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. may be used in combination. good too.

Coating agents include, for example, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, shellac, talc, carnauba wax, paraffin and the like.

Examples of enteric film coating bases include cellulosic polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name); Evonik Degussa], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Evonik Degussa], methacrylic acid copolymer S [Evonik Degussa]; Examples include natural products such as shellac.

Examples of sustained release film coating bases include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Evonik Degussa]; acrylic acid-based polymer such as turbid solution [Eudragit NE (trade name), Evonik Degussa]; cellulose acetate;

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

If necessary, a water-soluble substance, a plasticizer, or the like may be added to the coating additive to adjust the dissolution rate. Water-soluble substances include water-soluble polymers such as hydroxypropyl methylcellulose, sugar alcohols such as mannitol, sugars such as sucrose and anhydrous maltose, sucrose fatty acid esters, polyoxyethylene polyoxypropylene glycol, polysorbate, and sodium lauryl sulfate. It is possible to use one or more selected from surfactants such as Plasticizers include acetylated monoglycerides, triethyl citrate, triacetin, dibutyl sebacate, dimethyl sebacate, medium chain fatty acid triglycerides, acetyltriethyl citrate, tributyl citrate, acetyltributyl citrate, dibutyl adipate, oleic acid, oleinol and the like can be used.

In addition, as a method for forming a coating layer by coating the tablet with the coating additive, a general method in the pharmaceutical field can be used. Fluidized tumbling coating methods can be mentioned. The coating liquid used in these methods is obtained by mixing the coating additive, talc, and a solvent (preferably ethanol or a mixture of ethanol and water). The solid content concentration of such a coating liquid is preferably in the range of 5 to 15% by weight based on the total weight of the coating liquid.
In a preferred embodiment, the pharmaceutical composition of the present invention is a coated tablet coated with HPMC film.

In formulating the pharmaceutical composition of the present invention, granulation, in addition to the principles and devices described in the Examples, includes extrusion granulation, crushing/sizing, rotary granulation, dry granulation, wet high-shear granulation, and fluid bed granulation principles.

Granulators based on the principle of extrusion granulation include, for example, twin dome gran, basket granulator, semi-dry/low-moisture granulator disk pelleter, semi-dry/small diameter granulator fine disc pelleter, and pelleter double. , and Multigran (manufactured by Dalton), and KEX Extruder and KRC Kneader (manufactured by Kurimoto, Ltd.).

Examples of granulating equipment based on the principle of crushing and sizing include Power Mill (manufactured by Dalton), sizing machines Fiore F and Randel Mill (manufactured by Tokuju Kosakusho), and no-screen sizing machine Nebula Cizer (manufactured by Nara Machinery Works). ), Quick Mill QMY (manufactured by Seishin Enterprises), Roll Granulator (manufactured by Matsubo), New Speed Mill (manufactured by Okada Seiko), Oscillator MF Oscillator, and Conibit Crusher and Granulator (Switzerland). manufactured by Earth Technica).

Granulators based on the principle of rotary granulation include, for example, Marumerizer (manufactured by Dalton), centrifugal fluid coating granulator CF and Granulex GX (manufactured by Freund Corporation).

Examples of the granulation apparatus based on dry granulation include roller compactor (manufactured by Freund Corporation), Pharmapactor (manufactured by Hosokawa Micron), RCP roller compactor (manufactured by Kurimoto, Ltd.), and Pharmacompactor (manufactured by Matsubo).

Examples of granulation equipment based on the principle of wet high-shear granulation include SP Granulator and Spartan Reuzer (manufactured by Dalton), Vertical Granulator (manufactured by Powrex), GEA Aeromatic Fielder Multiprocessor PharmaConnect for research and development ( Eurotechno), Mixer & Granulator (NMG) (Nara Machinery), Crushing Rolling Type Newgra Machine SEG (Seishin Enterprise), New Speed Kneader (Okada Seiko), High Speed Mixer (Advanced Series), Dynamic Drier, Hiflex Gral, and Microwave Granulator Drier (all of which are manufactured by Fukae Powtech and sold by Earth Technica), and TM type granulating mixer (manufactured by Nippon Coke Kogyo Co., Ltd.).

Granulators based on the principle of fluidized bed granulation include, for example, Pneumarmerizer, swirling fluidized bed, minute fluidized bed, and swing processor (manufactured by Dalton), flow coater containment, flow coater universal, and flow coater FLO. , and Spiraflow SFC (manufactured by Freund Corporation), Agromaster (manufactured by Hosokawa Micron), GEA Aeromatic Fielder Flexstream (manufactured by Eurotechno), and Sprued (manufactured by Okawara Seisakusho).

Mixing is performed according to the principles and devices described in the Examples, as well as the principles of convection (mechanical stirring), diffusion (container rotation), and kneading/kneading.

Examples of mixing devices based on the convection type (mechanical stirring type) include the mixing stirrer NDM type, the mixing stirrer XDM type, the mixing stirrer DM type, the mixing stirrer AM/XDM/DM type for trial and research, and the mixing stirrer twin for laboratory use. Mix, Pag Mixer, Ribbon Mixer, Spartan Mixer, and Paste Mixer (manufactured by Dalton), Cyclomix, and Nauta Mixer (manufactured by Hosokawa Micron), Vertical Mounted MAG-NEO Seal Mixer (manufactured by Magneo Giken), Bottom Type Super Mag Mixer, S Mixer Super Mix (manufactured by Satake Chemical Machinery Industry), Julia Mixer, and Ribbon Mixer (manufactured by Tokuju Kosakusho), PX Mixer (manufactured by Seishin Enterprise), Redige Mixer (manufactured by Matsubo) , FM mixer RC type, and MP mixer (manufactured by Nippon Coke Co., Ltd.), and Ribocon (manufactured by Okawara Seisakusho).

Examples of mixing devices based on the principle of diffusion type (container rotation type) include GEA Book System IBC Blender, GEA Book System IBC Blender with NIR measurement device (manufactured by Eurotechno), V-type mixer, and W-type mixer. machine (manufactured by Tokuju Kosakusho), V-type mixer (manufactured by Nara Machinery Works), W-type mixer SCM, and V-type mixer SVM (manufactured by Seishin Enterprises), capsule locking mixer (manufactured by Aichi Electric), and Bohle Container Mixer PM (manufactured by Kotobuki Kogyo Co., Ltd.) can be mentioned.

Mixing devices based on kneading and kneading principles include, for example, continuous earth kneaders and batch kneaders (manufactured by Dalton), T.K. Hivismix and T.K. Hivis Dispermix (manufactured by Primix), Leistritz Extruder. (manufactured by Nara Machinery Works) and a planetary mixer (manufactured by Asada Iron Works).

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

In addition to the above principles, mixing can also be performed by fluidized stirring, non-stirring, and high-speed shearing principles.

Tableting is performed according to the principles of single-shot tableting and rotary tableting, with rotary tableting being preferred from the viewpoint of efficiency.

In addition to those described in the examples, the name of the tableting apparatus based on the principle of rotary tableting includes, for example, a detachable high-speed tableting machine Fette (manufactured by Bosch Packaging Technology), a high-speed tableting machine COMPRIMA, and a high-speed tableting machine. machine SYNTHESIS (Mutual), rotary press MZ400 (Mori Machinery), GEA Coltor modular tableting machine P, S and D, and GEA Pharma System Performa P (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, detachable rotary tablet machine with water washing, and containment tablet machine (manufactured by Kikusui Seisakusho) ), BX-type HX-type high-pressure tableting machine, CVX-type rotating disk detachable tableting machine, X-type AP small-sized tableting machine, X-type AP medium-sized tableting machine, AP-type large-sized tableting machine, and X-type The AP type large double tablet press (manufactured by Hata Iron Works Co., Ltd.) is exemplified.

Single-layer tablets can be obtained with the above-mentioned tableting machine. Alternatively, dry-coated tablets can be manufactured using a dry-coated tableting machine (manufactured by Kikusui Seisakusho) and an AP/MS type C-type dry-coated tableting machine (manufactured by Hata Iron Works).

Coating is carried out by the principles of pan coating (horizontal pan), pan coating (inclined pan), and air floating (fluidized bed) in addition to the principles and devices described in the examples.

Coating equipment based on pan coating (horizontal pan) includes, for example, Hicoater FZ, Aquacoater AQC Containment, and Aquacoater AQC (manufactured by Freund Corporation).

Coating equipment based on the principle of pan coating (inclined pan) includes, for example, Powrex Coater PRC and Doria Coater DRC (manufactured by Powrex).

Coating equipment based on the air floating type (fluidized bed) principle includes, for example, Glatt Powder Coater GPCG SPC, Multiplex, and Combined Fluidized Bed SFP (manufactured by Powrex).

Other coating apparatuses include, for example, Hybridization System (manufactured by Nara Machinery Works) and Mechanohybrid (manufactured by Nippon Coke Industry).

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

In the present invention, treatment or prevention of a disease or condition includes prevention of onset, suppression or inhibition of exacerbation or progression of the disease, alleviation of one or more symptoms exhibited by an individual suffering from the disease, or suppression of exacerbation or progression. , treatment or prevention of secondary diseases, etc.

Subjects to whom the pharmaceutical composition of the present invention is administered are mammals. The mammal is preferably human.

The pharmaceutical compositions of the invention are administered to a subject in a therapeutically or prophylactically effective amount. The term "therapeutically or prophylactically effective amount" means an amount that has a therapeutic or prophylactic effect for a particular disease, dosage form and administration route, and includes target species, type of disease, symptoms, sex, age, chronic disease, etc. is appropriately determined according to the elements of The route of administration is usually oral administration.

The dosage of the pharmaceutical composition of the present invention is appropriately determined according to the target species, disease type, symptoms, sex, age, chronic disease, and other factors. 0.01 to 10 μg, preferably 0.5 to 0.75 μg, can be administered as a daily dose.

The present invention also relates to a method for treating or preventing a disease or condition comprising 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" as used in the present invention means an amount that exhibits a therapeutic or prophylactic effect for a specific disease or symptom, dosage form and administration route. It is determined appropriately according to age, chronic disease, and other factors.

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

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

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

As mentioned above, the ED-71 epoxide is mainly generated in step (iii) (drying step) by conversion from ED-71 and is present in the oil solution along with ED-71 in the prepared tablets. In addition, when the prepared tablet is left as it is, the conversion of ED-71 to ED-71 epoxide proceeds gradually. It can be suppressed by saving in the state. Accordingly, in one aspect, the invention provides an article of manufacture in which a pharmaceutical composition of the invention and an oxygen scavenger are hermetically enclosed within a packaging form.

Examples of oxygen scavengers include Wonderkeep (registered trademark) (Powdertech), Oxymove (registered trademark) (Nantong Ohe Chemical), Moduran (Nippon Kayaku Food Techno), Keepit (Drency), Wellpack (Taisei), Oxiter (Registered Trademark) (Ueno Food Techno), Capron (Capron), Freshness Keeping Agent (Toppan Printing), Sansoles (Hakuyo), Sanso Cut (Registered Trademark) (Iris Fine Products), Ageless (Registered Trademark) ZM (Mitsubishi Gas Kagaku, ZM-1), Everfresh (Torishige Sangyo, QJ-30, etc.), Vitalon PH (Tokiwa Sangyo, PH-100SL, etc.), Secur (registered trademark) (Nisso resin, AP-250, etc.), etc. , preferably Ageless ZM.

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

Examples of materials for bottle packaging include thermoplastic resins, glass, pottery, porcelain enamel, and metals, with thermoplastic resins and glass being preferred. The material of the bottle packaging is not limited to a single-layered one. For example, even if the same thermoplastic resin is used, it may have a multi-layered structure made of a plurality of types of materials. The cap of the bottle packaging may be of any form as long as it can be made airtight, for example, a screw cap. Examples of materials for the lid include thermoplastic resins and metals (eg, iron, tinplate, stainless steel, etc.), preferably metals. Also, when the lid and bottle packaging are made of thermoplastic resin, plastic bottle packaging with a seal (preferably an aluminum seal) is preferred.

“Pillow packaging” means a form of packaging in which the pharmaceutical composition of the present invention as it is or in a PTP-packaged state is covered with a film in the form of a bag, and then airtightly filled with gas. Materials for the pillow packaging include, for example, an aluminum laminate film, a thermoplastic resin, or a combination thereof, preferably an aluminum laminate film.

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

The term "sealed" means a state in which there is no risk of invasion of gas or microorganisms during routine handling or normal storage conditions.

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

Examples of thermoplastic resins include polyvinyl chloride (PVC), unstretched polypropylene (CPP), polypropylene (PP), polyvinylidene chloride (PVDC), polytrifluoroethylene (PCTFE), and cyclic olefin copolymers ( COC), polyethylene (PE; high density, medium density and low density), polycarbonate (PC), polyamide (PA), ethylene-vinyl acetate copolymer (EVA), ethylene-methacrylate copolymer, polystyrene (PS) , polyester (PET), polyacrylic acid (PAA), ethylene-vinyl alcohol copolymer, etc., preferably polyvinyl chloride, unstretched polypropylene, polypropylene, polyvinylidene chloride, polytrifluoroethylene chloride, cyclic olefin copolymers and ethylene-vinyl alcohol copolymers. These may be used alone or in combination of two or more. Examples of lid materials for PTP packaging include aluminum foil and laminated films obtained by laminating aluminum foil with films made of thermoplastic resin. A known method may be used as a method for producing PTP packaging or blister pack packaging. The packaging material for pillow packaging, PTP packaging, or blister pack packaging in the present invention is not limited to a single layer, and may be a multi-layered film in which multiple layers are pasted together. The multilayer film may have a barrier layer that suppresses permeation of oxygen as an outer layer or an intermediate layer, and an absorption layer having a deoxidizing function as an inner layer or an intermediate layer. As an absorption layer having a deoxidizing function, for example, there is a resin into which a deoxidizing agent that exerts a deoxidizing function is kneaded.

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

When enclosing the pharmaceutical composition and the oxygen scavenger of the present invention in an airtight state in the packaging form, the gas in the packaging form is replaced with a gas other than oxygen (for example, nitrogen gas, carbon dioxide gas, helium gas, argon gas, neon gas, krypton gas, xenon gas, radon gas).

It is difficult to completely eliminate the presence of ED-71 epoxide in the pharmaceutical composition (preferably tablet) of the present invention prepared through a drying step (step (iii)) in contact with air, and Although it is a substance that is allowed to exist, its content is preferably as small as possible from the viewpoint of the efficacy of ED-71. Specifically, the content is preferably 5% or less, more preferably 2% or less, further preferably 1.2% or less. A specific example of a preferred content is 0.5%. The lower limit of the content may be, for example, 0.1% or less. The "content" of ED-71 epoxide is calculated based on the peak area obtained from the profile at 220 nm when analyzed by liquid chromatography under the conditions described in Test Example 3 of the following Examples. ED-71 epoxide content ratio (% ) and is calculated by the following formula.
ED-71 epoxide content (%) = (A _imp-2 x RRF)/(A _t + A _imp-2 x RRF + A _p x RRF + Σ (A _i x RRF)) x 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 analogues RRF: relative to ED-71 Relative sensitivity factors; Pre ED-71, 1.79; ED-71 epoxide, 1.72; other ED-71 analogues, 1.00

All prior art documents cited herein are hereby incorporated by reference.

EXAMPLES The present invention will be described in more detail by way of examples.

In this example, the following abbreviations are used.
EtOH: ethanol
HPMC: Hydroxypropyl methylcellulose
BHT: dibutyl hydroxytoluene
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. 1 g of BHT (Merck) and 2 g of dl-α-tocopherol (special use, Wako Pure Chemical Industries) were dissolved in 97 g of MCT (O.D.O.C., Nisshin OilliO) to obtain 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, it was distilled off under reduced pressure to prepare an ED-71 oil/fat solution. 300 mg of hydroxypropylmethylcellulose 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 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 ED-71 fat solution alone (Control Example 1) was used.
An ED-71 composition was prepared in the same manner as in Example 1 using the additive (300 mg) shown in Table 1 instead of hydroxypropylmethylcellulose in Example 1, and the stability at 60 ° C. It was investigated in the same manner as in Example 1.

Table 1 shows the results. As is clear from Table 1, the composition of Example 1 is as stable as or more stable than the fat liquid alone of Control Example 1, and is more stable than the compositions of Control Examples 2 to 34 under high temperature conditions. rice field.

Example 2: Formulation change 2
The ED-71 compositions of Example 2 and Control Example 35 were prepared in the same manner as in Example 1 using the additives listed in Table 2 instead of the hydroxypropylmethylcellulose of Example 1, and Stability was investigated 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 as stable or more stable than Control 1 and more stable under high temperature conditions than the compositions of Controls 2-34 shown in Table 1. Although no decrease in the stability of ED-71 was observed in the composition of Control Example 35, when meglumine was used as an additive, an emulsified state required in the production process of oil dispersion tablets described later was obtained. It was found that meglumine is not suitable as an excipient for the production of oil dispersion tablets, for reasons such as the inability to maintain.

[Test Example 1] Emulsion Stabilization Test As described later, it is necessary to maintain an emulsified state between the MCT solution of ED-71 and the aqueous solution of the water-soluble polymer in the process of producing oil dispersion tablets. Therefore, an emulsified liquid of MCT and water-soluble polymer was prepared, and the emulsified state was investigated.
HPMC (TC-5R, Shin-Etsu Chemical), HPC (SSL, Shin-Etsu Chemical), PVP (K90, BASF), POVA-COAT (F, manufactured by Daido Kasei) were dissolved in purified water, and 2% and 5%, respectively, were added. An aqueous solution was prepared. 20 mL of each solution was added to a plastic 50 mL centrifuge tube. 10 mL each of red-colored medium-chain fatty acid triglycerides obtained by dissolving 0.1 g/L of Oil Red (Oil Red O, Nacalai Tesque) was added thereto.
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 top of the emulsified liquid after 2 hours and 24 hours was determined.

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

Examples 3-11: Stability of ED-71 during emulsion preparation
An ethanol solution of ED-71 was prepared by dissolving 100 mg of ED-71 in 5.0 mL of EtOH. 1 g of BHT (Merck) and 2 g of dl-α-tocopherol (special use, Wako Pure Chemical Industries) were dissolved in 97 g of MCT (O.D.O.C., Nisshin OilliO) to obtain 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 to prepare an ED-71-dissolved MCT solution. Each of the water-soluble polymer solutions shown in Table 4 was prepared. An ED-71-dissolved MCT solution and a water-soluble polymer solution were mixed at the ratio 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 so that the amount of ED-71 drug substance was about 1 μg, and it was distilled off under reduced pressure using a vacuum dryer, and the obtained sample was used for residual rate measurement (Example 3 ~11). The samples were stored in a constant temperature bath adjusted to 60°C in the presence of air, and the ED-71 content immediately after preparation, and the ED-71 content and residual rate (%) after 14 and 25 days were examined. Each content value was calculated using a sample obtained by weighing the ED-71-dissolved MCT solution so that the amount of the ED-71 drug substance was approximately 1 μg and distilling off under reduced pressure using a vacuum dryer as a standard product. The content value and residual rate of ED-71 were obtained by the following formulas.
ED-71 content value (%) = total ED-71 peak area in sample / total ED-71 peak area in standard (ED-71 total peak area = ED-71 peak area + 1.98 x Pre ED- 71 peak areas)
ED-71 residual 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 formulation with a low water-soluble polymer concentration (1%) had large variations in the content of ED-71. This is probably because the formulation with a low concentration of water-soluble polymer showed separation of the emulsion after preparation, and the variation in the weighed amount of ED-71 in the sampled emulsion was observed. Samples with a water-soluble polymer concentration of 5% or 6% showed little variation in the results, and the ED-71 residual rate after 25 days was more than 95%. The ED-71 residual rate decreased to around 90% in the samples after 25 days, although the variation was small in the formulations with high concentration of water-soluble polymer (10% or 15%).
The concentration of the water-soluble polymer solution containing 1%-15% HPMC or HPC is preferably 5-6% for stabilizing ED-71 in emulsion.

[Manufacturing example] Oil dispersion tablets
0.142 kg of dl-α-tocopherol (Wako Pure Chemical Industries) and 0.284 kg of BHT (Merck) were dissolved in 9.025 kg of MCT (Nissin OilliO), and 1.1813 g of eldecalcitol (ED-71) was dissolved in ethanol (99.5%). ) (Imazu Yakuhin Kogyo) (0.078 kg) was added, and 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 for 10 minutes with a homogenizer (IKA T-50 Ultra Turrax; rotation speed 9,600 rpm). This operation was repeated three times to obtain an emulsified liquid.

165.6 kg of mannitol (Merck) sieved through a vibrating sieve with a mesh size of 850 μm was placed in a high-speed stirring granulator (VG-600CT manufactured by POWREX) while stirring at a blade speed of 56 rpm and a cross screw of 1500 rpm while spraying the emulsion. It was added and kneaded for 15 minutes to obtain granulated powder.

The obtained granulated powder was sieved while operating at 300 rpm with a wet granulator (POWREX U-20) set with a 9.5 mm (square hole) screen, and passed through a fluid bed granulator dryer ( WSG-200pro manufactured by POWREX) 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 sieved product was mixed with a mixture of 3.0 kg mannitol and 3.6 kg croscarmellose sodium (DFE pharma), each sieved through a 850 μm sieve, for 15 minutes, and then mixed with mannitol, each sieved through a 850 μm sieve. After mixing with a mixture of 6.6 kg and 0.72 kg of calcium stearate (Merck) for 3 minutes (Sample 2), tableting was performed using a tableting machine (IMA COMPRIMA) at a pressure of about 7.5 kN to form tablets (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 Powrex) and dried by spraying a solution of 6.480 kg of HPMC in water (74.520 kg) at 60°C. A water (65.167 kg) suspension of 1.350 kg of Merck), 2.664 kg of titanium oxide (Ishihara Sangyo), and 0.036 kg of iron sesquioxide (Kisumi Kasei) was sprayed and dried to form a two-layer film-coated tablet. (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 was 4.950 kg of hypromellose, 1.350 kg of talc (Merck), 2.502 kg of titanium oxide (Ishihara Sangyo), 2.502 kg of iron sesquioxide (Kimi Kasei) 0.018 kg and yellow ferric oxide (Kisumi Kasei) 0.180 kg water (65.167 kg) suspension was sprayed to coat.
A schematic diagram of the manufacturing flow is shown in FIG.

[Test Example 2] Accelerated stability test Tablets obtained in "[Manufacturing Example] Oil dispersion tablets" (two types of eldecalcitol content per tablet: 0.5 μg and 0.75 μg) were placed in high-density polyethylene bottle containers ( NC-130, Shinko Kagaku), 500 tablets each were put. The bottle was capped with a polypropylene cap (SK-200B, Shinko Kagaku) and stored in a constant temperature bath adjusted to 40°C/75% RH. examined.

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

The residual rate of ED-71 was determined 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 that is intended to be contained in one tablet.

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

[Test Example 3] Purity test 20 tablets obtained in "[Production Example] Oil dispersion tablets" were pulverized with a small pulverizer LM-Plus (manufactured by Osaka Chemical Co., Ltd.), and 1.6 g of the pulverized sample was weighed. rice field. 40 mL of a mixed solution of ethyl acetate and hexane at a volume ratio of 1:1 was added, stirred, and subjected to ultrasonic irradiation for 20 minutes. After centrifugation at 3000 rpm for 5 minutes, the supernatant was filtered through a membrane filter (DISMIC-25HP PTFE 0.2 μm HYDROPHILIC, manufactured by ADVANTEC). The filtrate was poured into a solid-phase extraction cartridge (InertSep ^™ NH ₂ FF 500 mg/3 mL, manufactured by GL Sciences), washed with 10 mL of a mixed solution of ethyl acetate and hexane at a volume ratio of 1:1, and then washed with 6 mL of ethanol. was passed through and eluted. After the eluted liquid was distilled off and dried by an evaporator, 100 μL of a mixed solution of water and acetonitrile mixed at a volume ratio of 1:1 was added to re-dissolve to obtain a sample solution. ACQUITY UPLC H-Class (manufactured by Waters) was used for liquid chromatography, and a purity test was performed 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: A concentration gradient was set as shown in Table 7.

The results are shown in FIG. ED-71 (retention time about 10.4 minutes) and its thermal isomer Pre ED-71 (retention time about 8.3 minutes) were detected, and an unknown peak with a retention time of about 5.2 minutes was detected. detected in minutes. 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 example. Samples 3 and 4 were subjected to the purity test in the same manner as in Test Example 3, and samples 1 and 2 were subjected to the purity test in the same manner as in Test Example 3, except that the pulverization step was omitted.

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

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

As shown in the UV-visible spectrum of ED-71 (FIG. 4), ED-71 has a triene structure in its molecule, so that UV absorption is maximized at 265 nm. On the other hand, in the UV-visible spectrum of Compound 2 (FIG. 3), no characteristic peak at 265 nm attributed to the triene structure of ED-71 was observed. This result suggested the possibility that compound 2 was a degradation product of ED-71 in which the triene structure was destroyed. Vitamin _D3 , to which ED-71 belongs, is known to be susceptible to oxidation. In the drying process, the sample is fluidized by hot air in the drying tower. Since the samples staying in the fluidized bed have more chances to come into contact with oxygen in the air, it can be said that they are in an environment susceptible to oxidation. From the above, it was presumed that the production of compound 2 involved oxidation of ED-71 during the production process.

[Test Example 5] Preparation of Compound 2 by Air Oxidation of ED-71 and Structure Determination A large amount of Compound 2 was prepared for structure determination.
A mixed solution (10 mL) of ED-71 (60 μg) in water:acetonitrile=1:1 was added to the vial and vigorously stirred with a magnetic stirrer at 30° C. for 16 hours in the open atmosphere to promote oxidation. After stirring, an additional 3 mL of acetonitrile was added because the amount of liquid decreased due to volatilization. As a result of analysis under the same analytical conditions as in Test Example 3, compound 2 and compound 2 were detected in all of sample 1 (dry powder), sample 2 (mixed powder), sample 3 (uncoated tablet) and sample 4 (film-coated tablet). Peaks with equivalent UV-vis spectra at identical retention times were detected. This peak was fractionated and the structure was determined with 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, compound 2 was presumed to be an oxygen adduct 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 is (1R,2R,3R,5Z,7ξ,8ξ)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10(19)-seccocholester-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) was measured in chloroform-d or acetonitrile-d ₃ in the presence or absence of tetramethylsilane as an internal standard. Below, it was measured using ECP500 (manufactured 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-seccocholesta-5,7,10(19)-triene-1,3,25-triol (Compound 1, 504 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). 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 hydrogencarbonate solution (5 mL) was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was extracted with dichloromethane (5 mL). The aqueous layer was extracted again with dichloromethane (10 mL), and the extracts were combined and dried over anhydrous sodium sulfate. Solids were removed by filtration and washed with dichloromethane (10 mL). The filtrate was concentrated under reduced pressure, and the fraction containing compound 2 obtained by silica gel chromatography (dichloromethane:ethanol, 1:0→19:1→12:1, v/v) was concentrated. The resulting residue was dissolved in acetone (5 mL) and concentrated to dryness to give (1R,2R,3R,5Z,7ξ,8ξ)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10 (19)-Seccocholesta-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 agreed 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-seccocholester-5,7,10(19)-triene (compound 3))
(1R,2R,3R,5Z,7E)-2-(3-hydroxypropoxy)-9,10-seccocholester-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. Methyl chloroformate (3.1 mL, 40.8 mmol) was added dropwise to the reaction mixture at 10° C. or lower, and after stirring at room temperature for 15 hours, the solvent was distilled off under reduced pressure. Water (40 mL) was added to the residue, and the mixture was extracted with a mixture of heptane (10 mL) and ethyl acetate (30 mL). The extract was washed with water (40 mL) and saturated aqueous sodium hydrogencarbonate solution (40 mL), passed through diatomaceous earth and anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The resulting 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-seccocholester-5,10(19)-diene (compound 4))
3-chloroperbenzoic acid (74.2% , 1.9917 g, 8.56 mmol) was added at 0° C. and stirred at the same temperature for 3.5 hours. A 5% aqueous sodium hydrogencarbonate solution (40 mL) was added to the reaction mixture and 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 resulting 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).

Step 3: ((1R,2R,3R,5Z,7ξ,8ξ)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10(19)-seccocholester-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 through silica gel. The silica gel was washed with dichloromethane-methanol (3:1, 100 mL) and the combined filtrates were concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane:acetone, 1:0→1:1→1:2, v/v) to obtain compound 2 (2.7679 g, purity 97.0 area %). rice field. The ¹ H-NMR spectrum of Compound 2 obtained agreed 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, by adding an oxygen absorber during packaging, it may occur during storage of the manufactured tablets There is a possibility that the increase of compound 2 can be suppressed. To test this hypothesis, for sample 4 (film-coated tablets), the content of compound 2 after storage in brown glass bottles in the absence and presence of oxygen scavengers at a storage temperature of 25°C and a relative humidity of 75% evaluated.

First, sample 4 (500 tablets) is filled in a brown glass bottle (manufactured by Daiichi Glass Co., Ltd., PS-10K (brown)), and a steel cap (manufactured by Araki Kogyo Co., Ltd., No. 10-13 (L)) is 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 defined as the content of Compound 2 in the absence of the oxygen scavenger. .
Next, fill a brown glass bottle with sample 4 (500 tablets), add an oxygen absorber (manufactured by Mitsubishi Gas Chemical Co., Ltd., Ageless ZM, ZM-1), close the steel cap and airtight with a capping 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 the oxygen scavenger.

Table 9 shows the results.

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 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 soft capsules, in which the decomposition of ED-71 is suppressed.

Claims (8)

ED-71 and (1R,2R,3R,5Z)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10(19)-seccocholester-5,10-diene-1,3,25- A method for producing a product in which a pharmaceutical composition containing a triol and an oxygen scavenger are hermetically enclosed in a packaging form ,
A step of preparing an oil-in-water emulsion containing a fat solution of ED-71 and an aqueous solution of a water-soluble polymer;
Adhering or adsorbing the oil-in-water emulsion to an excipient ,
drying the oil-in-water emulsion; and
ED-71 and (1R,2R,3R,5Z)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10(19)-seccocholesta-5,10-diene- obtained in the previous step A step of enclosing a pharmaceutical composition containing 1,3,25-triol in an oxygen scavenger and a packaging form in an airtight state
including
The above method, wherein the water-soluble polymer is selected from hydroxypropylmethylcellulose and hydroxypropylcellulose. The method according to claim 1, wherein the weight ratio of oil-in-water emulsion to excipient is from 1:4 to 1:20. 3. A method according to claim 1 or 2, wherein the excipient is selected from sugars or sugar alcohols. 4. The method of claim 3, wherein the excipient is mannitol. ED-71 and (1R,2R,3R,5Z)-2-(3-hydroxypropoxy)-7,8-epoxy-9,10(19)-seccocholester-5,10-diene-1,3,25- A product in which a pharmaceutical composition containing a triol and an oxygen scavenger are hermetically enclosed in a packaging form ,
comprising particles coated in the excipient or on the surface of the excipient with a coating agent comprising a water-soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose;
The above product , wherein the particles comprise a fat solution of ED-71. 6. A product according to claim 5, wherein the excipients are selected from sugars or sugar alcohols. 7. The product of Claim 6, wherein the excipient is mannitol. The product according to any one of claims 5 to 7, which is a coated tablet coated with HPMC film.

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