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TWI784997B - Pharmaceutical composition comprising solid dispersion and oil dispersion of ED-71 - Google Patents

Pharmaceutical composition comprising solid dispersion and oil dispersion of ED-71 Download PDF

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TWI784997B
TWI784997B TW106146225A TW106146225A TWI784997B TW I784997 B TWI784997 B TW I784997B TW 106146225 A TW106146225 A TW 106146225A TW 106146225 A TW106146225 A TW 106146225A TW I784997 B TWI784997 B TW I784997B
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water
oil
soluble polymer
solution
pharmaceutical composition
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TW201834661A (en
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倉崎和貴
髙野隆介
松岡慶宏
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日商中外製藥股份有限公司
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    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
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    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
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Abstract

根據本發明，提供抑制ED-71氧化的方法，包含調製於溶劑中含有(5Z,7E)-(1R,2R,3R)-2-(3-羥基丙氧基)-9,10-開環膽甾-5,7,10(19)-三烯-1,3,25-三醇(ED-71)與水溶性高分子或鹼性化合物的混合溶液的步驟，及由所得混合溶液去除溶劑的步驟，以及提供抑制ED-71分解的方法，包含調製由ED-71的油脂溶液與水溶性高分子的水溶液所形成之水中油型乳化液的步驟，此處前述水溶性高分子選擇自羥丙基甲基纖維素及羥丙基纖維素。 According to the present invention, there is provided a method for inhibiting the oxidation of ED-71, comprising preparing a solvent containing (5Z,7E)-(1R,2R,3R)-2-(3-hydroxypropoxy)-9,10-ring Process for a mixed solution of cholesta-5,7,10(19)-triene-1,3,25-triol (ED-71) and a water-soluble polymer or basic compound, and removal of the solvent from the resulting mixed solution and providing a method for inhibiting the decomposition of ED-71, including the step of preparing an oil-in-water emulsion formed by an oil solution of ED-71 and an aqueous solution of a water-soluble polymer, where the aforementioned water-soluble polymer is selected from hydroxyl Propyl methyl cellulose and hydroxypropyl cellulose.

Description

包含ED-71的固體分散體與油分散體的醫藥組合物 Pharmaceutical composition comprising solid dispersion and oil dispersion of ED-71

本發明係關於包含(5Z,7E)-(1R,2R,3R)-2-(3-羥基丙氧基)-9,10-開環膽甾-5,7,10(19)-三烯-1,3,25-三醇((5Z,7E)-(1R,2R,3R)-2-(3-hydroxypropyloxy)-9,10-secocholesta-5,7,10(19)-trien-1,3,25-triol)(以下，亦稱為ED-71)的醫藥組合物及其製造方法、抑制ED-71的氧化或分解的方法等。 The present invention relates to compounds comprising (5Z,7E)-(1R,2R,3R)-2-(3-hydroxypropoxy)-9,10-ring-opened cholesta-5,7,10(19)-triene -1,3,25-triol ((5Z,7E)-(1R,2R,3R)-2-(3-hydroxypropyloxy)-9,10-secocholesta-5,7,10(19)-trien-1 ,3,25-triol) (hereinafter also referred to as ED-71), a pharmaceutical composition, a method for producing the same, a method for inhibiting the oxidation or decomposition of ED-71, and the like.

ED-71(一般名：艾地骨化醇(eldecalcitol))為具有骨形成作用的活性型維生素D3的合成衍生物，作為經由經口投藥的骨質疏鬆症治療劑被製造販賣。 ED-71 (common name: eldecalcitol) is a synthetic derivative of active vitamin D 3 having a bone-forming effect, and is manufactured and marketed as an orally administered osteoporosis therapeutic agent.

ED-71與其他的維生素D衍生物同樣地，可製劑化作為軟膠囊劑。專利文獻1中揭示，將ED-71的中鏈脂肪酸三酸甘油酯(以下亦稱為MCT)溶液封入明膠劑皮內的無縫軟膠囊。再者，專利文獻1亦揭示藉由於該溶液添加dl-α-生育酚等抗氧化劑，能抑制ED-71的分解物之速甾醇(tachysterol)及反式體的生成。 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 enclosed in a gelatin skin. Furthermore, Patent Document 1 also discloses that by adding an antioxidant such as dl- α -tocopherol to the solution, the generation of tachysterol and the trans-isomer of the decomposition product of ED-71 can be suppressed.

目前，未知有軟膠囊以外的ED-71製劑市售商品。專利文獻2中揭示，可適用於骨質疏鬆症的鍶鹽與維生素D衍生物的合劑，作為維生素D衍生物的一例列舉艾地骨化醇。再者，專利文獻2中，揭示該合劑可做成錠劑。然而，其記載僅為作為一般性錠劑的記載，未揭示於ED-71製劑中調配鍶鹽以外的特定添加劑的效果。 At present, there are no commercial products of ED-71 preparations other than soft capsules. Patent Document 2 discloses a mixture of a strontium salt and a vitamin D derivative applicable to osteoporosis, and idecalcitol is cited as an example of the vitamin D derivative. Furthermore, in Patent Document 2, it is disclosed that the mixture can be made into lozenges. However, this description is only a description of a general lozenge, and does not disclose the effects of compounding specific additives other than strontium salts in the ED-71 preparation.

專利文獻3中，揭示例如，將1α-(OH)-D3 及聚乙烯基吡咯烷酮溶解於乙醇後，添加無水乳糖，攪拌後將乙醇減壓餾除所得反應生成物，進一步粉碎可得1α-(OH)-D3 組合物。 [先前技術文獻] [專利文獻]Patent Document 3 discloses, for example, that after dissolving 1α-(OH) -D3 and polyvinylpyrrolidone in ethanol, adding anhydrous lactose, stirring, and distilling off ethanol under reduced pressure to obtain a reaction product, which can be further pulverized to obtain 1α- (OH)-D 3 composition. [Prior Art Document] [Patent Document]

[專利文獻1] WO2005/074943A1 [專利文獻2] CN102688249A [專利文獻3] WO90/09796A[Patent Document 1] WO2005/074943A1 [Patent Document 2] CN102688249A [Patent Document 3] WO90/09796A

作為骨質疏鬆症治療劑之市售EDIROL(註冊商標)膠囊0.5μg及同藥品的0.75μg，僅為球形軟膠囊劑，冀求藉由新的製劑之功能性優異的ED-71製劑的開發。再者，將球形的軟膠囊製成非球形時，具有更容易捏取，或者不易轉動之關於使用性的需要存在。為了必須投藥ED-71的患者的便利性，冀求軟膠囊以外的劑型的非球形ED-71製劑的開發。 本發明者們，對於該等製劑，進行由使固體的ED-71與固體的添加劑混合的固體分散體(solid dispersion)所製造的製劑，以及由使ED-71的油脂溶液的粒子分散於賦形劑中的油分散體(oil dispersion)所製造的製劑的開發時，發現以下的課題。 首先，由固體分散體製造製劑的開發中，發現固體的ED-71的安定性低，因此提高其安定性為必要的課題。 再者，由油分散體製造製劑的開發中，發現使用將ED-71的油脂溶液直接使用所調製的油分散體時，無法製造充分品質的製劑的課題。進一步地，為了解決該課題重複調查的結果，雖可考慮將ED-71的油脂溶液藉由特定的添加劑被覆，而由於使用添加劑多，發現ED-71的安定性降低的新課題。 Commercially available EDIROL (registered trademark) capsules 0.5 μg and the same drug 0.75 μg as a therapeutic agent for osteoporosis are only spherical soft capsules, and the development of ED-71 formulations with excellent functionality through new formulations is desired. Furthermore, when the spherical soft capsule is made into a non-spherical shape, there is a need for ease of handling or difficulty in rotation. For the convenience of patients who must administer ED-71, the development of non-spherical ED-71 preparations in dosage forms other than soft capsules is desired. For these preparations, the present inventors carried out preparations produced by mixing solid ED-71 with solid additives, and dispersing particles of an oil solution of ED-71 in an excipient. During the development of formulations produced by oil dispersion (oil dispersion) in the vehicle, the following problems were found. First, in the development of preparations produced from solid dispersions, it was found that the stability of solid ED-71 was low, and therefore improvement of the stability was a necessary subject. Furthermore, in the development of preparations produced from oil dispersions, it was found that when oil dispersions prepared by directly using the oil and fat solution of ED-71 were used, there was a problem that preparations of sufficient quality could not be produced. Furthermore, as a result of repeated investigations to solve this problem, it is conceivable to coat the oil solution of ED-71 with a specific additive, but a new problem of lowering the stability of ED-71 was found due to the use of many additives.

本發明有鑑於該等狀況，其目的係提供於軟膠囊以外的各種劑型的ED-71製劑中，抑制ED-71分解的手段。 In view of these circumstances, the present invention aims to provide means for inhibiting the decomposition of ED-71 in ED-71 preparations in various dosage forms other than soft capsules.

本發明者們，為了解決上述課題而致力調查的結果，發現關於固體分散體，ED-71的分解為氧化所導致者，進一步地，發現該氧化藉由使用不具抗氧化作用的羥丙基甲基纖維素等水溶性高分子或美洛明(Meglumine)、L-精胺酸、及焦磷酸四鉀等鹼性化合物作為添加劑，而顯著地受到抑制。 The inventors of the present invention, as a result of diligent investigations to solve the above-mentioned problems, have found that the decomposition of ED-71 is caused by oxidation in solid dispersions. Water-soluble polymers such as base cellulose or basic compounds such as Meglumine, L-arginine, and tetrapotassium pyrophosphate are used as additives, which are significantly inhibited.

再者關於油分散體，發現藉由使用水溶性高分子之羥丙基甲基纖維素或羥丙基纖維素作為添加劑，能夠製造充分品質的製劑(特別是錠劑)，進一步地發現不引起ED-71的安定性降低。 Furthermore, with regard to oil dispersions, it was found that by using hydroxypropylmethylcellulose or hydroxypropylcellulose as an additive of a water-soluble polymer, preparations (especially tablets) of sufficient quality could be produced, and it was further found that it did not cause The stability of ED-71 has been reduced.

本發明者們基於上述發現進一步地重複調查，完成本發明。 Based on the above-mentioned findings, the inventors of the present invention further conducted investigations and completed the present invention.

亦即，本發明係更具體地提供以下的[1]~[12]者。 That is, the present invention provides the following [1] to [12] more specifically.

[1]一種抑制ED-71氧化的方法，包含調製於溶劑中含有(5Z,7E)-(1R,2R,3R)-2-(3-羥基丙氧基)-9,10-開環膽甾-5,7,10(19)-三烯-1,3,25-三醇(ED-71)及水溶性高分子或鹼性化合物的混合溶液的步驟，以及由所得混合溶液去除溶劑的步驟。 [1] A method for inhibiting the oxidation of ED-71, comprising preparing (5Z,7E)-(1R,2R,3R)-2-(3-hydroxypropoxy)-9,10-cyclopentadiene in a solvent Process for a mixed solution of ster-5,7,10(19)-triene-1,3,25-triol (ED-71) and a water-soluble polymer or basic compound, and the process for removing solvent from the resulting mixed solution step.

[2]如[1]記載的方法，ED-71與添加劑的重量比係1：50~1：5000。 [2] As described in [1], the weight ratio of ED-71 to additives is 1:50~1:5000.

[3]如[1]或[2]記載的方法，水溶性高分子選擇自羥丙基甲基纖維素、聚氧乙烯聚氧丙烯二醇、聚乙二醇、磺基丁基醚-β-環糊精、聚乙烯基己內醯胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物、甲基丙烯酸胺基烷基酯共聚物、羥丙基纖維素、乙基纖維素、蔗糖脂肪酸酯、聚乙烯基吡咯烷酮、聚維酮(copovidone)、聚氧乙烯 硬化蓖麻油、2-羥基丙基-β-環糊精、D-α-生育酚聚乙二醇琥珀酸、聚氧乙烯硬化蓖麻油、糊精、阿拉伯膠、羥丙基甲基纖維素-乙酸琥珀酸酯、鹼處理明膠、甲基纖維素、聚乙烯醇(polyvinyl Alcohol)、聚乙烯醇‧丙烯酸‧甲基丙烯酸甲酯共聚物(polyvinyl alcohol-acrylic acid-methyl methcarylate)、α化澱粉、羥乙基纖維素、及卵磷脂粉末，鹼性化合物選擇自美洛明、L-精胺酸、及焦磷酸四鉀。 [3] As described in [1] or [2], the water-soluble polymer is selected from hydroxypropyl methylcellulose, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, sulfobutyl ether- β - Cyclodextrin, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer, hydroxypropyl cellulose, ethyl cellulose, sucrose Fatty acid esters, polyvinylpyrrolidone, copovidone, polyoxyethylene hardened castor oil, 2-hydroxypropyl- β -cyclodextrin, D- α -tocopheryl polyethylene glycol succinic acid, polyoxyethylene Vinyl hardened castor oil, dextrin, gum arabic, hydroxypropylmethylcellulose-acetate succinate, alkali-treated gelatin, methylcellulose, polyvinyl alcohol, polyvinyl alcohol‧acrylic acid‧methacrylic acid Methyl ester copolymer (polyvinyl alcohol-acrylic acid-methyl methcarylate), alpha starch, hydroxyethyl cellulose, and lecithin powder, the basic compound is selected from melomin, L-arginine, and tetrapotassium pyrophosphate .

[4]一種包含ED-71的醫藥組合物，係藉由調製於溶劑中含有ED-71及水溶性高分子或鹼性化合物的混合溶液，由該混合溶液去除溶劑所製造者，其中，水溶性高分子選擇自羥丙基甲基纖維素、聚氧乙烯聚氧丙烯二醇、聚乙二醇、磺基丁基醚-β-環糊精、聚乙烯基己內醯胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物、甲基丙烯酸胺基烷基酯共聚物、羥丙基纖維素、乙基纖維素、蔗糖脂肪酸酯、聚乙烯基吡咯烷酮、聚維酮(copovidone)、聚氧乙烯硬化蓖麻油、2-羥基丙基-β-環糊精、D-α-生育酚聚乙二醇琥珀酸、聚氧乙烯硬化蓖麻油、糊精、阿拉伯膠、羥丙基甲基纖維素-乙酸琥珀酸酯、鹼處理明膠、甲基纖維素、聚乙烯醇、聚乙烯醇‧丙烯酸‧甲基丙烯酸甲酯共聚物、α化澱粉、羥乙基纖維素、及卵磷脂粉末，鹼性化合物選擇自美洛明、L-精胺酸、及焦磷酸四鉀。 [4] A pharmaceutical composition containing ED-71, prepared by preparing a mixed solution containing ED-71 and a water-soluble polymer or basic compound in a solvent, and removing the solvent from the mixed solution, wherein the water-soluble The permanent polymer is selected from hydroxypropyl methylcellulose, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, sulfobutyl ether- β -cyclodextrin, polyvinylcaprolactam-polyvinyl acetate Ester-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer, hydroxypropyl cellulose, ethyl cellulose, sucrose fatty acid ester, polyvinylpyrrolidone, povidone (copovidone), Polyoxyethylene Hardened Castor Oil, 2-Hydroxypropyl- β -Cyclodextrin, D- α -Tocopheryl Polyethylene Glycol Succinate, Polyoxyethylene Hardened Castor Oil, Dextrin, Gum Arabic, Hydroxypropyl Methyl Cellulose-acetate succinate, alkali-treated gelatin, methyl cellulose, polyvinyl alcohol, polyvinyl alcohol‧acrylic acid‧methyl methacrylate copolymer, alpha starch, hydroxyethyl cellulose, and lecithin powder, The basic compound is selected from melomine, L-arginine, and tetrapotassium pyrophosphate.

[5]如[4]記載的醫藥組合物，ED-71與添加劑的重量比係1：50~1：5000。 [5] The pharmaceutical composition as described in [4], wherein the weight ratio of ED-71 to the additive is 1:50 to 1:5000.

[6]一種包含ED-71的醫藥組合物的製造方法，該方包含調製包含ED-71的油脂溶液與水溶性高分子的水溶液之水中油型乳化液的步驟，使水中油型乳化液附著或吸附於賦形劑的步驟，以及使水中油型乳化液乾燥的步驟，其中，前述水溶性高分子選擇自羥丙基甲基纖維素及羥丙基纖維素。 [6] A method for producing a pharmaceutical composition comprising ED-71, comprising the step of preparing an oil-in-water emulsion comprising an oil solution of ED-71 and an aqueous solution of a water-soluble polymer, and allowing the oil-in-water emulsion to adhere to the Or the step of adsorbing to an excipient, and the step of drying the oil-in-water emulsion, wherein the water-soluble polymer is selected from hydroxypropylmethylcellulose and hydroxypropylcellulose.

[7]如[6]記載的方法，水中油型乳化液與賦形劑的重量比為1：4~1：20。 [7] As described in [6], the weight ratio of the oil-in-water emulsion to the excipient is 1:4~1:20.

[8]如[6]或[7]記載的方法，賦形劑係選自糖或糖醇類。 [8] The method according to [6] or [7], wherein the excipient is selected from sugars or sugar alcohols.

[9]一種包含ED-71的醫藥組合物，其於賦形劑中或賦形劑表面包含以含有選擇 自羥丙基甲基纖維素及羥丙基纖維素之水溶性高分子的被覆劑所被覆的粒子，該粒子包含ED-71的油脂溶液。 [9] A pharmaceutical composition comprising ED-71, which is contained in or on the surface of an excipient to contain the selected Particles coated with hydroxypropylmethylcellulose and a water-soluble polymer coating agent of hydroxypropylcellulose, the particles contain an oil solution of ED-71.

[10]如[9]記載的醫藥組合物，其為以HPMC膜所包覆的包覆錠。 [10] The pharmaceutical composition according to [9], which is a coated tablet coated with an HPMC film.

[11]一種抑制ED-71分解的方法，包含調製包含ED-71的油脂溶液及水溶性高分子的水溶液所形成之水中油型乳化液的步驟，其中，前述水溶性高分子選擇自羥丙基甲基纖維素及羥丙基纖維素。 [11] A method for inhibiting the decomposition of ED-71, comprising the step of preparing an oil-in-water emulsion formed by an oil solution containing ED-71 and an aqueous solution of a water-soluble polymer, wherein the aforementioned water-soluble polymer is selected from hydroxypropyl methylcellulose and hydroxypropylcellulose.

[12]如[11]記載的方法，進一步包含將所得之水中油型乳化液進行乾燥的步驟。 [12] The method according to [11], further comprising the step of drying the obtained oil-in-water emulsion.

根據本發明，能夠於固體分散體及油分散體中抑制ED-71的分解。再者可製造使用固體分散體及油分散體之軟膠囊以外的種種劑型的ED-71製劑。 According to the present invention, the decomposition of ED-71 can be suppressed in solid dispersion and oil dispersion. Furthermore, various dosage forms of ED-71 preparations other than soft capsules using solid dispersion and oil dispersion can be produced.

圖1為製造包含ED-71的油分散體的錠劑的製造流程概略圖。 FIG. 1 is a schematic diagram of a manufacturing process for manufacturing lozenges containing an oil dispersion of ED-71.

圖2為顯示水溶性高分子的2%水溶液與中鏈脂肪酸三酸甘油酯混合之際的乳化狀態的影像。由左起為HPMC、HPC、PVP、及POVA-COAT。 Fig. 2 is an image showing an emulsified state when a 2% aqueous solution of a water-soluble polymer is mixed with a medium-chain fatty acid triglyceride. From the left are HPMC, HPC, PVP, and POVA-COAT.

[用於實施本發明的態樣] [Aspects for Carrying Out the Invention]

本發明中，ED-71為下述式(I)所示化合物。 In the present invention, ED-71 is a compound represented by the following formula (I).

Figure 106146225-A0305-02-0007-2
Figure 106146225-A0305-02-0007-2

ED-71，例如可根據日本特開平10-72432號所記載的方法，以(1R,2R,3R)-2-(3-羥基丙氧基)膽甾醇-5,7-二烯-1,3,25-三醇作為起始物質，經紫外線照射及熱異構化反應後，以逆相HPLC精製、濃縮後，以乙酸乙酯使其結晶化而可製得。 ED-71, for example, can be prepared as (1R,2R,3R)-2-(3-hydroxypropoxy)cholesterol-5,7-diene-1, 3,25-triol is used as the starting material, after ultraviolet irradiation and thermal isomerization reaction, purified by reverse phase HPLC, concentrated, and crystallized with ethyl acetate.

I. ED-71的固體分散體 I. Solid Dispersion of ED-71

I-1. 抑制ED-71氧化的方法 I-1. Method for inhibiting oxidation of ED-71

本發明的第一態樣係關於ED-71的固體分散體。本說明書中，ED-71固體分散體意指使固體的ED-71與固體的添加劑混合的組合物。如後述的實施例所示，可知ED-71於保存中因氧化而分解。本發明係提供抑制該等方式之ED-71的因氧化而分解的方法。本方法包含將ED-71與選擇自水溶性高分子及鹼性化合物的添加劑混合的步驟，調製於溶劑中包含ED-71與水溶性高分子或鹼性化合物的混合溶液，自該混合溶液去除溶劑的步驟。藉由將ED-71與添加劑混合，使ED-71的氧化受到抑制。 The first aspect of the invention concerns solid dispersions of ED-71. In this specification, the ED-71 solid dispersion means a composition in which solid ED-71 and solid additives are mixed. As shown in the Examples described later, it was found that ED-71 was decomposed by oxidation during storage. The present invention provides a method for suppressing the decomposition of ED-71 in the above-mentioned forms due to oxidation. This method comprises the step of mixing ED-71 with additives selected from water-soluble polymers and basic compounds, preparing a mixed solution containing ED-71 and water-soluble polymers or basic compounds in a solvent, and removing Solvent step. By mixing ED-71 with additives, the oxidation of ED-71 is inhibited.

ED-71氧化的抑制，藉由將本發明的方法實施所得之ED-71的固體分散體以遮光7日或14日保存於60℃後，調查ED-71的殘存率而予以確認。與不含添加劑的ED-71的標準品比較，該固體分散體中的ED-71的殘存率高，則判斷ED-71氧化受到抑制。ED-71的殘存率，關於保存樣品及初期樣品，係測定藉 由高速液體層析法(測定波長265)之ED-71與其異構物之前體(化學名：6Z-(1R,2R,3R)-2-(3-羥基丙氧基)-9,10-開環膽甾-5(10),6,8(9)-三烯-1,3,25-三醇；本說明書中亦稱為pre ED-71)的峰面積，藉由以下的計算式算出。 The inhibition of ED-71 oxidation was confirmed by observing the residual rate of ED-71 after storing the solid dispersion of ED-71 obtained by carrying out the method of the present invention at 60° C. for 7 or 14 days in the dark. When the remaining rate of ED-71 in this solid dispersion is high compared with the standard product of ED-71 containing no additive, it is judged that the oxidation of ED-71 is suppressed. The residual rate of ED-71, regarding the preserved samples and the initial samples, was measured by ED-71 and its isomer precursor (chemical name: 6Z-(1R,2R,3R)-2-(3-hydroxypropoxy)-9,10- The peak area of ring-opened cholesta-5(10),6,8(9)-triene-1,3,25-triol; also referred to as pre ED-71 in this specification, is calculated by the following formula figured out.

ED-71的殘存率(%)=保存樣品中的ED-71的峰面積合計/初期樣品中的ED-71峰面積合計×100 The remaining rate of ED-71 (%) = the total peak area of ED-71 in the preserved sample / the total peak area of ED-71 in the initial sample × 100

(ED-71峰面積合計=ED-71峰面積+1.98×pre ED-71的峰面積) (The total peak area of ED-71=the peak area of ED-71+1.98×the peak area of pre ED-71)

本發明所使用的水溶性高分子，亦可為以往未知具有抗氧化作用者，例如，可列舉羥丙基甲基纖維素、聚氧乙烯聚氧丙烯二醇(polyoxyethylene polyoxypropylene glycol)、聚乙二醇、磺基丁基醚-β-環糊精、聚乙烯基己內醯胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物、甲基丙烯酸胺基烷基酯共聚物、羥丙基纖維素、乙基纖維素、蔗糖脂肪酸酯、聚乙烯基吡咯烷酮、聚維酮(copovidone)、聚氧乙烯硬化蓖麻油、2-羥基丙基-β-環糊精、D-α-生育酚聚乙二醇琥珀酸、聚氧乙烯硬化蓖麻油、糊精、阿拉伯膠、羥丙基甲基纖維素-乙酸琥珀酸酯、鹼處理明膠、甲基纖維素、聚乙烯醇、聚乙烯醇‧丙烯酸‧甲基丙烯酸甲酯共聚物、α化澱粉、羥乙基纖維素、及卵磷脂粉末等製劑上容許的水溶性高分子。較佳態樣中，水溶性高分子，係選自磺基丁基醚-β-環糊精、聚乙二醇、蔗糖脂肪酸酯(F-160)、D-α-生育酚聚乙二醇琥珀酸、羥丙基甲基纖維素-乙酸琥珀酸酯、聚乙烯醇、聚氧乙烯硬化蓖麻油、糊精、聚乙烯基吡咯烷酮K90、羥丙基甲基纖維素、羥乙基纖維素、2-羥基丙基-β-環糊精、羥丙基纖維素、聚氧乙烯聚氧丙烯二醇、聚維酮、乙基纖維素、甲基丙烯酸胺基烷基酯共聚物、甲基纖維素、及聚乙烯基吡咯烷酮K30。更佳態樣中，水溶性高分子係選自羥丙基甲基纖維素-乙酸琥珀酸酯、聚乙烯醇、聚氧乙烯硬化蓖麻油40、糊精、聚乙烯基吡咯烷酮K90、羥丙基甲基纖維素、羥乙基纖維素、2-羥丙基-β-環糊精、聚氧乙烯聚氧丙烯二醇101、羥丙基纖維素、聚氧乙烯聚氧丙烯二醇F68、聚維酮、乙基纖維 素、甲基丙烯酸胺基烷基酯共聚物E100、甲基纖維素、及聚乙烯基吡咯烷酮K30。該等可單獨或組合2種以上使用。 The water-soluble macromolecule used in the present invention may also be one that has previously been unknown to have an antioxidant effect, for example, hydroxypropyl methylcellulose, polyoxyethylene polyoxypropylene glycol (polyoxyethylene polyoxypropylene glycol), polyethylene glycol Alcohol, sulfobutyl ether- β -cyclodextrin, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer, hydroxypropyl Cellulose, ethyl cellulose, sucrose fatty acid esters, polyvinylpyrrolidone, copovidone, polyoxyethylene hardened castor oil, 2-hydroxypropyl- β -cyclodextrin, D- α -tocopherol Polyethylene glycol succinic acid, polyoxyethylene hardened castor oil, dextrin, gum arabic, hydroxypropyl methylcellulose-acetate succinate, alkali-treated gelatin, methylcellulose, polyvinyl alcohol, polyvinyl alcohol‧ Acrylic acid‧methyl methacrylate copolymer, α -starch, hydroxyethyl cellulose, and lecithin powder are water-soluble polymers allowed in formulations. In a preferred form, the water-soluble polymer is selected from sulfobutyl ether- β -cyclodextrin, polyethylene glycol, sucrose fatty acid ester (F-160), D- α -tocopheryl polyethylene glycol Alcohol succinate, hydroxypropylmethylcellulose-acetate succinate, polyvinyl alcohol, polyoxyethylene hardened castor oil, dextrin, polyvinylpyrrolidone K90, hydroxypropylmethylcellulose, hydroxyethylcellulose , 2-hydroxypropyl- β -cyclodextrin, hydroxypropyl cellulose, polyoxyethylene polyoxypropylene glycol, povidone, ethyl cellulose, aminoalkyl methacrylate copolymer, methyl Cellulose, and polyvinylpyrrolidone K30. In a more preferred form, the water-soluble polymer is selected from the group consisting of hydroxypropyl methylcellulose-acetate succinate, polyvinyl alcohol, polyoxyethylene hardened castor oil 40, dextrin, polyvinylpyrrolidone K90, hydroxypropyl Methyl cellulose, hydroxyethyl cellulose, 2-hydroxypropyl- β -cyclodextrin, polyoxyethylene polyoxypropylene glycol 101, hydroxypropyl cellulose, polyoxyethylene polyoxypropylene glycol F68, poly Vitone, ethyl cellulose, aminoalkyl methacrylate copolymer E100, methyl cellulose, and polyvinylpyrrolidone K30. These can be used individually or in combination of 2 or more types.

本發明所使用的鹼性化合物，亦可為以往未知具有抗氧化作用者，例如，可列舉美洛明、L-精胺酸、及焦磷酸四鉀等製劑上容許的鹼性化合物。較佳態樣中，鹼性化合物為美洛明或L-精胺酸。該等可單獨或組合2種以上使用。 The basic compounds used in the present invention may also be those that have not been known to have antioxidative effects. For example, basic compounds allowed in preparations such as melomin, L-arginine, and tetrapotassium pyrophosphate can be mentioned. In a preferred aspect, the basic compound is melomin or L-arginine. These can be used individually or in combination of 2 or more types.

作為上述態樣中使用的添加劑，較佳為水溶性高分子。 As the additive used in the above aspect, a water-soluble polymer is preferable.

ED-71與添加劑的混合，能夠以製劑領域中一般使用的方法進行。作為該等方法，例如，可列舉於水或有機溶劑等溶劑中使ED-71及添加劑溶解或懸濁後，去除溶劑的方法，溶融混練法等。藉由該等的混合，多數的情況，形成添加劑均勻地存在於ED-71中，或ED-71均勻地存在於添加劑中的固體分散體。較佳地，本發明使用ED-71均勻地存在於添加劑中的固體分散體。 The mixing of ED-71 and additives can be carried out by a method generally used in the pharmaceutical field. Such methods include, for example, a method of dissolving or suspending ED-71 and additives in a solvent such as water or an organic solvent, and then removing the solvent, a melt-kneading method, and the like. By such mixing, in many cases, the additive is uniformly present in ED-71, or a solid dispersion in which ED-71 is uniformly present in the additive is formed. Preferably, the present invention uses a solid dispersion in which ED-71 is uniformly present in the additive.

使用溶劑的方法中，亦可為ED-71及添加劑之至少1種係不溶解於該溶劑之懸濁狀態，但較佳為ED-71及添加劑二者皆溶解於該溶劑。亦即，較佳態樣中，混合係藉由調製使ED-71與水溶性高分子或鹼性化合物溶解於溶劑之混合溶液，自該混合溶液去除溶劑。 In the method using a solvent, at least one of ED-71 and the additive may be in a suspended state in which the solvent does not dissolve, but it is preferable that both ED-71 and the additive are dissolved in the solvent. That is, in a preferred aspect, the mixing is by preparing a mixed solution in which ED-71 and a water-soluble polymer or a basic compound are dissolved in a solvent, and removing the solvent from the mixed solution.

本發明所使用的溶劑，只要為製劑上容許者即可，例如，可列舉乙酸、丙酮、乙腈、苯甲醚、苯、1-丁醇、2-丁醇、乙酸丁酯、t-丁基甲基醚、四氯化碳、氯苯、氯仿、異丙苯、環己烷、1,2-二氯乙烷、1,2-二氯乙烯、二氯甲烷、1,2-二甲氧基乙烷、N,N-二甲基乙醯胺、N,N-二甲基甲醯胺、二甲基亞碸、1,4-二噁烷、乙醇、2-乙氧基乙醇、乙酸乙酯、乙二醇、乙醚、甲酸乙酯、甲醯胺、甲酸、庚烷、己烷、乙酸異丁酯、乙酸異丙酯、甲醇、2-甲氧基乙醇、乙酸甲酯、異戊醇、甲基丁基酮、甲基環己烷、己烷-2-酮、乙酸異戊酯、甲基乙基酮、甲基異丁基酮、2-甲基-1-丙醇、N-甲基吡咯烷酮、硝基甲烷、戊烷、 戊醇、丙醇、異丙醇、乙酸丙酯、吡啶、環丁碸、四氫呋喃、四氫萘、甲苯、1,1,1-三氯乙烷、1,1,2-三氯乙烯、及二甲苯。較佳態樣中，溶劑為1-丁醇、2-丁醇、乙醇、2-乙氧基乙醇、乙二醇、甲醇、2-甲氧基乙醇、異戊醇、2-甲基-1-丙醇、戊醇、丙醇、及異丙醇等醇，更佳為乙醇。該等可單獨或組合2種以上使用。再者，醇亦可為與水混和之含水醇(例如含水乙醇)。 The solvent used in the present invention may be any solvent as long as it is acceptable in the formulation, for example, acetic acid, acetone, acetonitrile, anisole, benzene, 1-butanol, 2-butanol, butyl acetate, t-butylmethyl Ether, carbon tetrachloride, chlorobenzene, chloroform, cumene, cyclohexane, 1,2-dichloroethane, 1,2-dichloroethylene, dichloromethane, 1,2-dimethoxyethane Alkane, N,N-dimethylacetamide, N,N-dimethylformamide, dimethylsulfide, 1,4-dioxane, ethanol, 2-ethoxyethanol, ethyl acetate , ethylene glycol, diethyl ether, ethyl formate, formamide, formic acid, heptane, hexane, isobutyl acetate, isopropyl acetate, methanol, 2-methoxyethanol, methyl acetate, isoamyl alcohol, Methyl butyl ketone, methyl cyclohexane, hexane-2-one, isoamyl acetate, methyl ethyl ketone, methyl isobutyl ketone, 2-methyl-1-propanol, N-methyl Basepyrrolidone, nitromethane, pentane, Pentanol, propanol, isopropanol, propyl acetate, pyridine, cyclobutane, tetrahydrofuran, tetrahydronaphthalene, toluene, 1,1,1-trichloroethane, 1,1,2-trichloroethylene, and xylene. In a preferred aspect, the solvent is 1-butanol, 2-butanol, ethanol, 2-ethoxyethanol, ethylene glycol, methanol, 2-methoxyethanol, isoamyl alcohol, 2-methyl-1 Alcohols such as propanol, pentanol, propanol, and isopropanol, more preferably ethanol. These can be used individually or in combination of 2 or more types. Furthermore, the alcohol may also be a water-containing alcohol (eg, water-containing ethanol) mixed with water.

溶劑的去除，能夠以製劑領域中一般使用的方法進行。做為該等方法，例如，可列舉減壓餾除、凍結乾燥、噴霧乾燥、流動層乾燥、加熱乾燥、對不良溶劑中的沉澱法、送風乾燥、自然乾燥等，較佳為減壓餾除。 Removal of the solvent can be performed by a method generally used in the pharmaceutical field. Such methods include, for example, vacuum distillation, freeze drying, spray drying, fluidized bed drying, heat drying, precipitation in a poor solvent, air drying, natural drying, etc., preferably vacuum distillation .

該等方式所得之混合物中，多數的情況成為ED-71分散於固體的添加劑中的狀態，或固體的添加劑分散於ED-71中的狀態。此處的分散狀態，意指其他成分幾乎均勻地存在於成為母材的成分中。一態樣中，混合物中的ED-71與添加劑的重量比為1：0.01~1：100000，較佳為1：0.1~1：10000，更佳為1：1~1：8000，進一步更佳為1：50~1：5000。別的態樣中，混合物中的ED-71與添加劑的重量比為1：1~1：0000，例如，1：10~1：0000、1：100~1：0000、或1：1000~1：10000。作為混合物中的ED-71與添加劑的重量比的具體例，例如，可列舉1：1、1：10、1：100、1：1000、1：4000及1：10000，較佳為1：1000及1：4000。作為別的較佳具體例，可列舉1：10000。ED-71的重量比添加劑的重量更少的態樣中，多數的情況是成為ED-71分散於固體的添加劑中的狀態。 In the mixture obtained by these methods, in many cases, ED-71 is dispersed in a solid additive, or a solid additive is dispersed in ED-71. The dispersed state here means that the other components are almost uniformly present in the components to be the base material. In one aspect, the weight ratio of ED-71 in the mixture to the additive is 1:0.01~1:100000, preferably 1:0.1~1:10000, more preferably 1:1~1:8000, and even more preferably 1:50~1:5000. In another aspect, the weight ratio of ED-71 in the mixture to the additive is 1:1~1:0000, for example, 1:10~1:0000, 1:100~1:0000, or 1:1000~1 : 10000. Specific examples of the weight ratio of ED-71 and additives in the mixture include, for example, 1:1, 1:10, 1:100, 1:1000, 1:4000 and 1:10000, preferably 1:1000 And 1:4000. As another preferable specific example, 1:10000 is mentioned. In the aspect in which the weight of ED-71 is smaller than the weight of the additive, ED-71 is dispersed in the solid additive in many cases.

I-2. 包含ED-71的醫藥組合物 I-2. Pharmaceutical compositions comprising ED-71

使用根據上述方法、藉由將ED-71與添加劑混合使ED-71的氧化受到抑制的混合物(亦即固體分散體)，能夠製造包含ED-71的醫藥組合物。因此，本發明為提供包含ED-71的醫藥組合物，係藉由調製於溶劑中包含ED-71與水溶性高分子或鹼性化合物的混合溶液，自該混合溶液去除溶劑所製造之醫藥組合物。本發明之一態樣中，ED-71分散於選擇自水溶性高分子及鹼性化合物的添加劑中。本 發明的醫藥組合物中，藉由將ED-71與添加劑混合，使ED-71的氧化受到抑制。 A pharmaceutical composition comprising ED-71 can be produced using a mixture (ie, a solid dispersion) in which the oxidation of ED-71 is inhibited by mixing ED-71 with an additive according to the above method. Therefore, the present invention provides a pharmaceutical composition comprising ED-71, which is a pharmaceutical combination prepared by preparing a mixed solution comprising ED-71 and a water-soluble polymer or a basic compound in a solvent, and removing the solvent from the mixed solution. things. In one aspect of the present invention, ED-71 is dispersed in additives selected from water-soluble polymers and basic compounds. Book In the pharmaceutical composition of the invention, the oxidation of ED-71 is inhibited by mixing ED-71 with additives.

本發明的醫藥組合物中的ED-71的含量雖無特別限定，一態樣中，作為每單位製劑的ED-71的量為0.05~5μg，較佳為0.5~0.75μg。 Although the content of ED-71 in the pharmaceutical composition of the present invention is not particularly limited, in one aspect, the amount of ED-71 per unit preparation is 0.05-5 μg, preferably 0.5-0.75 μg.

ED-71與添加劑的混合物(ED-71的固體分散體)，係藉由上述I-1所記載的方法調製。本發明之水溶性高分子及鹼性化合物，係如I-1所記載。再者，本發明的醫藥組合物中的ED-71與添加劑的重量比，一態樣中為1：0.01~1：100000，較佳為1：0.1~1：10000，更佳為1：1~1：8000，進一步更佳為1：50~1：5000。別的態樣中，混合物中的ED-71與添加劑的重量比為1：1~1：10000，例如，1：10~1：10000，1：100~1：10000，或1：1000~1：10000。作為混合物中的ED-71與添加劑的重量比的具體例，例如，可列舉1：1、1：10、1：100、1：1000、1：4000及1：10000，較佳為1：1000及1：4000。作為別的較佳具體例，可列舉1：10000。 The mixture of ED-71 and additives (solid dispersion of ED-71) was prepared by the method described in the above-mentioned I-1. The water-soluble polymer and basic compound of the present invention are as described in I-1. Furthermore, the weight ratio of ED-71 to additives in the pharmaceutical composition of the present invention is in one aspect 1:0.01~1:100000, preferably 1:0.1~1:10000, more preferably 1:1 ~1:8000, further preferably 1:50~1:5000. In another aspect, the weight ratio of ED-71 in the mixture to the additive is 1:1~1:10000, for example, 1:10~1:10000, 1:100~1:10000, or 1:1000~1 : 10000. Specific examples of the weight ratio of ED-71 and additives in the mixture include, for example, 1:1, 1:10, 1:100, 1:1000, 1:4000 and 1:10000, preferably 1:1000 And 1:4000. As another preferable specific example, 1:10000 is mentioned.

本發明的醫藥組合物能夠為錠劑、膠囊劑、顆粒劑、散劑等經口劑。該等經口劑，可藉由使用製劑領域中所使用的方法製造。例如作為錠劑的製造方法，可列舉以下的i)、ii)及iii)的方法。 The pharmaceutical composition of the present invention can be oral preparations such as tablets, capsules, granules, and powders. These oral preparations can be produced by using methods used in the field of pharmaceutical preparations. For example, as a manufacturing method of a tablet, the following i), ii) and iii) methods are mentioned.

i)將ED-71與添加劑的混合物與賦形劑、崩解劑、潤滑劑等追加的添加劑一起混合後，經由壓縮成型，製造錠劑。 i) After mixing the mixture of ED-71 and additives with additional additives such as excipients, disintegrants, and lubricants, compression molding was performed to produce tablets.

ii)將ED-71與添加劑的混合物與賦形劑、結合劑等追加的添加劑混合後，邊添加或噴霧溶劑(例如，精製水、乙醇、或其混合液)同時造粒。所得造粒物中，添加適量的潤滑劑、視需要之崩解劑等混合後，經由壓縮成型，製造錠劑。 ii) After mixing the mixture of ED-71 and additives with additional additives such as excipients and binders, granulation is performed while adding or spraying a solvent (for example, purified water, ethanol, or a mixture thereof). The obtained granules are mixed with an appropriate amount of lubricants and disintegrants if necessary, and then compression molded to produce lozenges.

iii)將ED-71與添加劑的混合物與賦形劑混合後，添加或噴霧將結合劑及視需要之其他添加劑分散或溶解於溶劑(例如，精製水、乙醇、或其混合液)所得之液，同時造粒。所得造粒物中，添加適量的潤滑劑、視需要之崩解劑等混合後，經由壓縮成型，製造錠劑。 iii) After mixing the mixture of ED-71 and additives with excipients, add or spray the solution obtained by dispersing or dissolving the binder and other additives if necessary in a solvent (for example, purified water, ethanol, or a mixture thereof) , while granulating. The obtained granules are mixed with an appropriate amount of lubricants and disintegrants if necessary, and then compression molded to produce lozenges.

作為水溶性高分子及鹼性化合物以外的追加的添加劑，除了賦形 劑、崩解劑、結合劑及潤滑劑之外，例如，可各別使用以使藥物的釋放性提升為目的之界面活性劑、pH調整劑等，以使步驟中的流動性佳為目的之流動化劑，以提升安定性為目的之安定化劑，以加入口味或味道為目的之矯味矯臭劑，以加入顏色為目的之著色劑。該等的使用量，對於製劑100重量份，通常為0~99.999重量份，較佳為50~99.5重量份，更佳為90~99重量份。 As additional additives other than water-soluble polymers and basic compounds, in addition to excipient In addition to agents, disintegrants, binders, and lubricants, for example, surfactants, pH adjusters, etc. for the purpose of improving drug release can be used separately to improve fluidity in the process. Fluidizers, stabilizers for the purpose of improving stability, flavoring and odorants for the purpose of adding taste or taste, and coloring agents for the purpose of adding color. The amount used is usually 0 to 99.999 parts by weight, preferably 50 to 99.5 parts by weight, and more preferably 90 to 99 parts by weight, based on 100 parts by weight of the preparation.

作為賦形劑，例如，可列舉玉蜀黍澱粉、馬鈴薯澱粉、小麥澱粉、米澱粉、部分α化澱粉、α化澱粉、多孔澱粉等澱粉類，乳糖水合物、果糖、葡萄糖、甘露醇、山梨糖醇等糖或糖醇類，無水磷酸氫化鈣，結晶纖維素，沉降碳酸鈣，矽酸鈣等。較佳態樣中，賦形劑為澱粉類、乳糖水合物、結晶纖維素、或無水磷酸氫鈣。 Examples of excipients include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, porous starch, lactose hydrate, fructose, glucose, mannitol, and sorbitol. Such as sugar or sugar alcohols, anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, etc. In a preferred aspect, the excipient is starch, lactose hydrate, crystalline cellulose, or anhydrous calcium hydrogen phosphate.

作為崩解劑，例如，可列舉澱粉乙醇酸鈉、羧甲基纖維素、羧甲基纖維素鈣、羧甲基澱粉鈉、交聯羧甲基纖維素鈉(croscarmellose sodium)、交聯聚維酮、低取代度羥丙基纖維素、羥丙基澱粉等。崩解劑的使用量，對於製劑100重量份，較佳為0.5~25重量份，進一步較佳為1~15重量份。 As the disintegrant, for example, sodium starch glycolate, carboxymethylcellulose, carmellose calcium, carboxymethylstarch sodium, croscarmellose sodium, croscarmellose Ketones, low-substituted hydroxypropyl cellulose, hydroxypropyl starch, etc. 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 preparation.

作為結合劑，例如，可列舉羥丙基纖維素、羥丙基甲基纖維素、甲基纖維素、聚維酮(聚乙烯吡咯烷酮)、阿拉伯膠粉末等。結合劑的使用量，對於製劑100重量份，較佳為0.1~50重量份，進一步較佳為0.5~40重量份。 Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, povidone (polyvinylpyrrolidone), gum arabic powder and the like. The usage-amount of the binder is preferably 0.1-50 parts by weight, more preferably 0.5-40 parts by weight with respect to 100 parts by weight of the preparation.

作為潤滑劑，例如，可列舉硬脂酸、硬脂酸鎂、硬脂酸鈣、滑石、蔗糖脂肪酸酯、富馬酸硬脂醯鈉、輕質無水矽酸等。 As a lubricant, stearic acid, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, sodium stearyl fumarate, light anhydrous silicic acid etc. are mentioned, for example.

作為界面活性劑，例如，可列舉聚山梨醇酯80、硬脂酸聚烴氧酯40、聚桂醇(Lauromacrogol)等。 As a surfactant, polysorbate 80, polyoxyl stearate 40, lauromacrogol, etc. are mentioned, for example.

作為pH調整劑，例如，可列舉乙酸、乳酸、檸檬酸、蘋果酸、琥珀酸、富馬酸、酒石酸、磷酸、以及該等任一者之鹽。 Examples of the pH adjuster include acetic acid, lactic acid, citric acid, malic acid, succinic acid, fumaric acid, tartaric acid, phosphoric acid, and salts of any of these.

作為流動化劑，例如，可列舉輕質無水矽酸、含水二氧化矽等二 氧化矽，滑石等。此處，作為輕質無水矽酸的具體例，例如可列舉Sylysia 320(商品名，富士Silysia化學公司)、Aerosil 200(商品名，日本Aerosil公司)等。 As the fluidizing agent, for example, light anhydrous silicic acid, hydrous silica, etc. Silicon oxide, talc, etc. Here, specific examples of light anhydrous silicic acid include Sylysia 320 (trade name, Fuji Silysia Chemical Co., Ltd.), Aerosil 200 (trade name, Nippon Aerosil Corporation), and the like.

作為安定化劑，例如可列舉羥苯甲酸甲酯(methylparaben)、羥苯甲酸丙酯等對羥苯甲酸(paraoxybenzoic acid)酯；氯丁醇、苯甲醇、苯基乙醇等醇；苯札氯銨(benzalkonium chloride)；酚、甲酚等酚類；硫柳汞(thimerosal)；去水乙酸；及山梨酸。 Examples of stabilizers include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol, and phenylethanol; and benzalkonium chloride. (benzalkonium chloride); phenols such as phenol and cresol; thimerosal; anhydroacetic acid; and sorbic acid.

作為矯味矯臭劑，例如，可列舉製劑領域中通常使用之甜味料、酸味料、香料等。 As the flavoring and flavoring agent, for example, sweeteners, sour flavorants, fragrances and the like generally used in the field of pharmaceutical preparations may be mentioned.

作為著色劑，只要為容許添加於醫藥品者，任何者皆可，例如可列舉食用黃色5號(Sunset yellow，美國的食用黃色6號)、食用紅色2號、食用藍色2號等食用色素，食用沉澱色素，三氧化二鐵等。 As the coloring agent, any one is acceptable as long as it is allowed to be added to pharmaceuticals, for example, food colorings such as food yellow No. 5 (Sunset yellow, US food yellow No. 6), food red No. 2, food blue No. 2, etc. , edible precipitated pigment, ferric oxide, etc.

再者，錠劑亦可進一步包含作為追加添加劑之抗氧化劑。抗氧化劑於i)、ii)及iii)的製造法中可於任意步驟添加。例如，i)的製造法的情況，抗氧化劑與其他添加劑一起與混合物混合後，經由壓縮成型，可製造錠劑。 Furthermore, the lozenge may further contain an antioxidant as an additional additive. The antioxidant may be added at any step in the production methods of i), ii) and iii). For example, in the case of the production method of i), after the antioxidant is mixed with the mixture together with other additives, the tablet can be produced by compression molding.

作為抗氧化劑，例如，可列舉亞硝酸鹽(例如亞硝酸鈉)、亞硫酸鹽(例如亞硫酸鈉、乾燥亞硫酸鈉、亞硫酸氫鈉、焦亞硫酸鈉)、硫代硫酸鹽(例如硫代硫酸鈉)、α硫甘油、1,3-丁二醇、硫醇基乙酸及其鹽(例如硫醇基乙酸鈉)、硫基蘋果酸鹽(例如巰基蘋果酸鈉)、硫脲、硫代乳酸、依地酸鹽(例如依地酸鈉)、二氯異三聚氰酸鹽(例如二氯異三聚氰酸鉀)、檸檬酸、半胱胺酸及其鹽(例如鹽酸半胱胺酸)、苯并三唑、2-巰基苯并咪唑、異抗壞血酸及其鹽(例如異抗壞血酸鈉)、抗壞血酸及其酯化合物(例如：L-抗壞血酸硬脂酸酯、棕櫚酸抗壞血酸)、磷脂質(例如大豆卵磷脂)、金屬螯合劑及其鹽(例如乙二胺四乙酸、乙二胺四乙酸鈣二鈉、乙二胺四乙酸二鈉)、酒石酸及其鹽(例如羅謝爾鹽)、多酚類(例如兒茶素)、穀胱甘肽、二丁基羥基甲苯、丁基羥基苯甲醚、沒食子酸丙酯、天然維生 素E、乙酸生育酚、濃縮混合生育酚、生育酚同系物(例如d-α-生育酚、dl-α-生育酚、5,8-二甲基母育酚(5,8-dimethyl tocol)、7,8-二甲基母育酚、δ-甲基母育酚、5,7,8-三甲基參雙鍵生殖酚(5,7,8-trimethyl tocotrienol)、5,8-二甲基參雙鍵生殖酚、7,8-二甲基參雙鍵生殖酚、8-甲基參雙鍵生殖酚)等。其等之中，較佳為乙酸生育酚、二丁基羥基甲苯、天然維生素E、dl-α-生育酚、d-α-生育酚、濃縮混合生育酚、棕櫚酸抗壞血酸、L-抗壞血酸硬脂酸酯、丁基羥基苯甲醚、沒食子酸丙酯，更佳為dl-α-生育酚、二丁基羥基甲苯、丁基羥基苯甲醚、沒食子酸，進一步更佳為dl-α-生育酚。 Examples of antioxidants include nitrites (such as sodium nitrite), sulfites (such as sodium sulfite, dry sodium sulfite, sodium bisulfite, sodium pyrosulfite), thiosulfates (such as sodium thiosulfate), α Thioglycerol, 1,3-butanediol, thioglycolic acid and its salts (such as sodium thioglycolate), thiomalate (such as sodium thiomalate), thiourea, thiolactic acid, edetic acid Salts (such as sodium edetate), dichloroisocyanurates (such as potassium dichloroisocyanurate), citric acid, cysteine and its salts (such as cysteine hydrochloride), benzo Triazoles, 2-mercaptobenzimidazole, erythorbic acid and its salts (such as sodium erythorbate), ascorbic acid and its ester compounds (such as L-ascorbyl stearate, ascorbyl palmitate), phospholipids (such as soybean lecithin ), metal chelating agents and their salts (such as ethylenediaminetetraacetic acid, edetate calcium disodium, edetate disodium), tartaric acid and its salts (such as Rochelle salt), polyphenols ( e.g. catechin), glutathione, dibutylhydroxytoluene, butylated hydroxyanisole, propyl gallate, natural vitamin E, tocopheryl acetate, concentrated mixed tocopherols, tocopherol homologues (e.g. d- α -tocopherol, dl- α -tocopherol, 5,8-dimethyl tocol (5,8-dimethyl tocol), 7,8-dimethyl tocol, δ-methyl tocol Phenol, 5,7,8-trimethyl tocotrienol (5,7,8-trimethyl tocotrienol), 5,8-dimethyl tocotrienol, 7,8-dimethyl tocotrienol Tocopherol, 8-methyl ginseng double bond tocopherol), etc. Among them, tocopheryl acetate, dibutyl hydroxytoluene, natural vitamin E, dl- α -tocopherol, d- α -tocopherol, concentrated mixed tocopherol, ascorbic acid palmitate, L-stearyl ascorbate are preferred Ester, butyl hydroxyanisole, propyl gallate, more preferably dl- α -tocopherol, dibutyl hydroxytoluene, butyl hydroxyanisole, gallic acid, further preferably dl - Alpha -tocopherol.

抗氧化劑的使用量，對於製劑100重量份，較佳為0.001~10重量份，進一較佳為0.01~1重量份。 The amount of the antioxidant used is preferably 0.001-10 parts by weight, more preferably 0.01-1 part by weight, based on 100 parts by weight of the preparation.

上述追加的添加劑，亦可2種以上以適合的比例混合使用。 The above-mentioned additional additives may be used in combination of two or more kinds in an appropriate ratio.

錠劑進一步使用適當的包覆用添加劑，可製得糖衣包覆錠或膜包覆錠。作為包覆用添加劑，可列舉糖衣基劑、包覆劑、腸溶性膜包覆基劑、緩釋性膜包覆基劑等。 Tablets can be prepared with sugar-coated tablets or film-coated tablets by further using appropriate coating additives. Examples of coating additives include sugar-coating bases, coating agents, enteric film-coating bases, sustained-release film-coating bases, and the like.

作為糖衣基劑，例如可列舉白糖、赤蘚醇等糖或糖醇，進一步地，亦可併用由滑石、沉降碳酸鈣、明膠、阿拉伯膠、聚三葡萄糖、卡那巴蠟等所選出1種或2種以上。 Sugar-coating bases include, for example, sugars such as sucrose and erythritol, or sugar alcohols, and further, one selected from talc, precipitated calcium carbonate, gelatin, acacia, polyglucose, and carnauba wax may be used in combination. or 2 or more.

作為膜包覆劑，例如，可列舉乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素、蟲膠、滑石、卡那巴蠟、石蠟等。 Examples of the film coating agent include ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, shellac, talc, carnauba wax, paraffin wax and the like.

作為腸溶性膜包覆基劑，例如可列舉酞酸羥丙基甲基纖維素、羥丙基甲基纖維素-乙酸琥珀酸酯、羧甲基乙基纖維素、乙酸酞酸纖維素等纖維素系高分子；甲基丙烯酸共聚物L[EUDRAGIT L(商品名)，Evonik Degussa公司]、甲基丙烯酸共聚物LD[EUDRAGIT L-30 D55(商品名)，Evonik Degussa公司]、甲基丙烯酸共聚物S[EUDRAGIT S(商品名)，Evonik Degussa公司]等丙烯酸系高分 子；蟲膠等天然物等。 Examples of enteric film-coating bases include fibers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose-acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate. Plain polymer; methacrylic acid copolymer L [EUDRAGIT L (trade name), Evonik Degussa company], methacrylic acid copolymer LD [EUDRAGIT L-30 D55 (trade name), Evonik Degussa company], methacrylic acid copolymer Material S [EUDRAGIT S (trade name), Evonik Degussa company] and other acrylic high scores sub; natural products such as shellac, etc.

作為緩釋性膜包覆基劑，例如可列舉乙基纖維素等纖維素系高分子；甲基丙烯酸胺基烷基酯共聚物RS[EUDRAGIT RS(商品名)，Evonik Degussa公司]、丙烯酸乙酯‧甲基丙烯酸甲酯共聚物懸濁液[EUDRAGIT NE(商品名)，Enovik Degussa公司]等丙烯酸系高分子；乙酸纖維素等。 As the sustained-release film coating base agent, for example, cellulose-based polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [EUDRAGIT RS (trade name), Evonik Degussa company], ethyl acrylate, etc. Ester‧methyl methacrylate copolymer suspension [EUDRAGIT NE (trade name), Enovik Degussa Company] and other acrylic polymers; cellulose acetate, etc.

上述包覆用添加劑，亦可將其2種以上以適當的比例混合使用。 The above additives for coating may be used by mixing two or more of them in an appropriate ratio.

包覆用添加劑中，為了溶出速度的調節，根據需要亦可添加水溶性物質、可塑劑等。水溶性物質中，可使用自羥丙基甲基纖維素等水溶性高分子類、甘露醇等糖醇類、白糖或無水麥芽糖等糖類、蔗糖脂肪酸酯、聚氧乙烯聚氧丙烯二醇、聚山梨醇酯、月桂基硫酸鈉等界面活性劑中選擇1種以上。可塑劑中，可使用自乙醯化單甘油酯、檸檬酸三乙酯、三乙酸甘油酯、癸二酸二丁酯、癸二酸二甲酯、中鏈脂肪酸三酸甘油酯、乙醯檸檬酸三乙酯、檸檬酸三丁酯、乙醯檸檬酸三丁酯、己二酸二丁酯、油酸、油醇等選擇1種以上。 To the coating additives, water-soluble substances, plasticizers, etc. may be added as needed for the purpose of adjusting the dissolution rate. Among the water-soluble substances, water-soluble polymers such as hydroxypropyl methylcellulose, sugar alcohols such as mannitol, sugars such as white sugar or anhydrous maltose, sucrose fatty acid esters, polyoxyethylene polyoxypropylene glycol, One or more surfactants such as polysorbate and sodium lauryl sulfate are selected. Among plasticizers, self-acetylated monoglycerides, triethyl citrate, glyceryl triacetate, dibutyl sebacate, dimethyl sebacate, medium-chain fatty acid triglycerides, acetylated lemon Select one or more of triethyl citrate, tributyl citrate, acetyl tributyl citrate, dibutyl adipate, oleic acid, and oleyl alcohol.

再者，作為將錠劑以前述包覆用添加劑包覆、形成包覆層的方法，可使用製劑領域中一般的方法，例如，可列舉缽式包覆法、流動包覆法、轉動包覆法、流動轉動包覆法。該等方法中所使用的包覆液，可藉由混合前述包覆用添加劑、滑石及溶劑(較佳為乙醇或乙醇與水的混合物)獲得。該等包覆液的固形分濃度，對於包覆液全體的重量，較佳為5~15重量%的範圍。 In addition, as a method of coating the tablet with the above-mentioned coating additive to form a coating layer, a general method in the field of pharmaceutical preparations can be used, for example, a bowl coating method, a flow coating method, a spin coating method, etc., can be used. method, flow rotation coating method. The coating solution used in these methods can be obtained by mixing the aforementioned additives for coating, talc and a solvent (preferably ethanol or a mixture of ethanol and water). The solid content concentration of these coating liquids is preferably in the range of 5 to 15% by weight with respect to the weight of the entire coating liquid.

本發明的醫藥組合物的製劑化中，除了實施例所記載的原理、裝置以外，造粒可藉由押出造粒、破碎‧整粒、迴轉造粒、乾式造粒、濕式高剪斷造粒、及流動層造粒的各原理進行。 In the formulation of the pharmaceutical composition of the present invention, in addition to the principles and devices described in the examples, granulation can be achieved by extrusion granulation, crushing‧sizing, rotary granulation, dry granulation, and wet high-shear granulation. Granulation, and the principles of fluidized bed granulation.

作為押出造粒為原理的造粒裝置，例如可列舉雙圓頂造粒(twin dome granulator)、籃式造粒機(basket granulator)、半乾式/低水分造粒機碟式製粒機、半乾式/小徑造粒機精細-碟式製粒機、雙押出製粒機、及多功能造粒機(以上為 Dalton公司製)，以及KEX擠出機及KRC捏合機(以上為栗本鐵工所製)。 As a granulation device based on the principle of extrusion granulation, for example, a twin dome granulator, a basket granulator, a semi-dry/low-moisture granulator, a disc granulator, a semi-dry granulator, etc. Dry/small-diameter granulator fine-disc granulator, double-extrusion granulator, and multi-functional granulator (above is Dalton Co., Ltd.), and KEX extruder and KRC kneader (the above are manufactured by Kurimoto Iron Works).

作為破碎‧整粒為原理的造粒裝置，例如可列舉Power Mill(Dalton公司製)、整粒機Fiore F及Roundel Mill(以上德壽工作所製)、No-screen整粒機Nebulasizer(奈良機械製作所製)、QUICK MILL QMY(SEISHIN企業製)、Roll Granulator(MATSUBO製)、NEW SPEED MILL(岡田精工製)、以及MF型整粒機Oscillator及破碎整粒機ConiWitt(以上，瑞士福來畢德公司製，Earth Technica販賣)。 As a granulation device based on the principle of crushing and granulation, for example, Power Mill (manufactured by Dalton Corporation), granulator Fiore F and Roundel Mill (manufactured by Tokushou Works), No-screen granulator Nebulasizer (Nara Machinery) Seisakusho), QUICK MILL QMY (manufactured by Seishin Corporation), Roll Granulator (manufactured by MATSUBO), NEW SPEED MILL (manufactured by Okada Seiko), and MF-type Oscillator and ConiWitt (above, Swiss Flat Manufactured by the company, sold by Earth Technica).

作為迴轉造粒為原理的造粒裝置，例如可列舉Marumerizer(Dalton製)、以及離心流動包覆造粒機CF及GRANUREX GX(以上，FREUND產業製)。 Examples of the granulator based on the principle of rotary granulation include Marumerizer (manufactured by Dalton), and centrifugal flow coating granulator CF and GRANUREX GX (above, manufactured by Freund Sangyo).

作為乾式造粒為原理的造粒裝置，例如可列舉Roller Compactor(FREUND產業製)、Pharmapaktor(HOSOKAWA MICRON製)、RCP Roller Compactor(栗本鐵工所製)、以及Pharma Compactor(MATSUBO製)。 Examples of granulation devices based on the principle of dry granulation include Roller Compactor (manufactured by Freund Sangyo), Pharmapaktor (manufactured by HOSOKAWA MICRON), RCP Roller Compactor (manufactured by Kurimoto Iron Works), and Pharma Compactor (manufactured by MATSUBO).

作為濕式高剪斷為原理的造粒裝置，例如可列舉SP Granulator及Spartan Granulator(以上，Dalton製)、Vertical Granulator(Powrex製)、GEA Aeromatic Fielder Multiprocessor調查開發用Pharma Compactor(EUROTECHNO製)、Mixer及Granulator(NMG)(奈良機械製作所製)、破碎轉動式New-Gra Machine SEG(SEISHIN企業製)、New Speed Kneader(岡田精工製)、High Speed Mixer(Advance series)、Dynamic Granulator、High Flex Granulator、及Microwave Granulator Dryer(以上，深江Powtech製，Earth Technica販賣)、以及TM型造粒Mixer(日本Coke工業製)。 Examples of granulators based on the principle of wet high shear include SP Granulator and Spartan Granulator (manufactured by Dalton), Vertical Granulator (manufactured by Powrex), Pharma Compactor for research and development of GEA Aeromatic Fielder Multiprocessor (manufactured by EUROTECHNO), Mixer and Granulator (NMG) (manufactured by Nara Machinery Manufacturing Co., Ltd.), crushing and rotating New-Gra Machine SEG (manufactured by SEISHIN Corporation), New Speed Kneader (manufactured by Okada Seiko), High Speed Mixer (Advance series), Dynamic Granulator, High Flex Granulator, And Microwave Granulator Dryer (above, manufactured by Fukae Powtech, sold by Earth Technica), and TM type Granulator Mixer (manufactured by Japan Coke Industry).

作為流動層造粒為原理的造粒裝置，例如可列舉New Marumerizer、旋回流動層、微少量流動層、及Swing Processor(以上，Dalton製)、Flow Coater Containment、Flow Coater Universal、Flow Coater FL0、及SPIR-A-FLOW SFC(以上，Freund產業製)、Agglomaster(Hosokawa Micron製)、GEA Aeromatic Fielder Flex Stream(Euro Techno製)、以及SPRUDE(大川原製作所)。 As a granulation device based on the principle of fluidized bed granulation, for example, New Marumerizer, revolving fluidized bed, small amount of fluidized bed, and Swing Processor (above, manufactured by Dalton), Flow Coater Containment, Flow Coater Universal, Flow Coater FL0, and SPIR-A-FLOW SFC (above, manufactured by Freund Industries), Agglomaster (manufactured by Hosokawa Micron), GEA Aeromatic Fielder Flex Stream (manufactured by Euro Techno), and SPRUDE (Okawara Seisakusho).

除了實施例所記載的原理、裝置之外，混合係藉由對流式(機械攪拌式)、擴散式(容器迴轉式)、以及捏和‧揉合的各原理進行。 In addition to the principles and devices described in the examples, the mixing system is carried out by the principles of convection (mechanical stirring), diffusion (container rotation), and kneading/kneading.

作為對流式(機械攪拌式)為原理的混合裝置，例如可列舉混合攪拌機NDM型、混合攪拌機XDM型、混和攪拌機DM型、試作‧研究用混和攪拌機AM‧XDM‧DM型、實驗室用混合攪拌機Swing Mix、Pug Mixer、Ribbon Mixer、Spartan Mixer、及Paste Mixer(以上，Dalton製)、Cyclomix、及Nauta Mixer(以上，Hosokawa Micron製)、直立安裝之MAG-NEO Seal Mixer(MAGNEO技研製)、底面型Supermag Mixer、及S Mixer Super Mixer(以上，佐竹化學機械工業製)、Julia Mixer及Ribbon混合機(以上德壽工作所製)、PX Mixer(SEISHIN企業製)、Loedige Mixer(Matsubo製)、FC Mixer RC型、及MP Mixer(以上，Nippon Coke工業製)、以及RIBOCONE(大川原製作所製)。 Mixing devices based on the principle of convection (mechanical stirring), such as mixing mixer NDM type, mixing mixer XDM type, mixing mixer DM type, prototype‧research mixing mixer AM‧XDM‧DM type, laboratory mixing mixer Swing Mixer, Pug Mixer, Ribbon Mixer, Spartan Mixer, and Paste Mixer (above, made by Dalton), Cyclomix, and Nauta Mixer (above, made by Hosokawa Micron), vertically installed MAG-NEO Seal Mixer (manufactured by MAGNEO Technology), bottom surface Type Supermag Mixer, and S Mixer Super Mixer (manufactured by Satake Chemical Machinery Industry Co., Ltd.), Julia Mixer and Ribbon Mixer (manufactured by Tokusu Works Co., Ltd. above), PX Mixer (manufactured by Seishin Corporation), Loedige Mixer (manufactured by Matsubo), FC Mixer RC type, MP Mixer (above, manufactured by Nippon Coke Industry), and RIBOCONE (made by Okawara Seisakusho).

作為擴散式(容器迴轉式)為原理的混合裝置，例如可列舉GEA Buck System IBC Blender、及GEA Buck System附NIR測定裝置IBC Blender(以上，Eurotechno製)、V型混合機、及W型混合機(以上，德壽工作所製)、V型Mixer(奈良機械製作所製)、W型混合機SCM、及V型混合機SVM(以上，SEISHIN企業製)、Capsule Rocking Mixer(愛知電機製)、以及Bohle Container Mixer(壽工業製)。 As a mixing device based on the diffusion type (container rotary type), for example, GEA Buck System IBC Blender, and GEA Buck System with NIR measurement device IBC Blender (above, manufactured by Eurotechno), V-type mixer, and W-type mixer (above, manufactured by Tokushou Works Co., Ltd.), V-type Mixer (manufactured by Nara Machinery Manufacturing Co., Ltd.), W-type Mixer SCM, and V-type Mixer SVM (above, manufactured by Seishin Corporation), Capsule Rocking Mixer (made by Aichi Denki), and Bohle Container Mixer (manufactured by Kotobuki Industry).

作為捏和‧揉合為原理的混合裝置，例如可列舉Continuous Kneader、及Batch Kneader(以上，Dalton製)、T.K.HIVIS MIX、及T.K.HIVIS DISPER MIX(以上，Primix製)、Leistritz Extruder(奈良機械製作所製)、以及Planetary Mixer(淺田鐵工製)。 As a mixing device based on the principle of kneading and kneading, for example, Continuous Kneader, and Batch Kneader (above, manufactured by Dalton), T.K.HIVIS MIX, and T.K.HIVIS DISPER MIX (above, manufactured by Primix), Leistritz Extruder (above, manufactured by Nara Machinery Co., Ltd.) Manufactured), and Planetary Mixer (manufactured by Asada Iron Works).

作為其他的混合裝置，例如可列舉Conti-TDS(Dalton製)、及Mixing Meter ST-3000II Process Reactor DDL3000、及攪拌Simulatton MixSim(以上，佐竹化學機械工業製)。 Examples of other mixing devices include Conti-TDS (manufactured by Dalton), Mixing Meter ST-3000II Process Reactor DDL3000, and stirring Simulatton MixSim (above, manufactured by Satake Chemical Machinery Co., Ltd.).

上述的各原理以外，亦可藉由流動式攪拌、無攪拌式、及高速剪斷式等原理混合。 In addition to the above-mentioned principles, it can also be mixed by the principles of flow stirring, non-stirring, and high-speed shearing.

打錠，雖可藉由單次式打錠及迴轉式打錠的各原理進行，以效率性的觀點而言，較佳為迴轉式打錠。 Ingot ingot can be carried out by the principles of single ingot ingot and rotary ingot ingot, but from the viewpoint of efficiency, rotary ingot ingot is preferred.

作為迴轉式打錠為原理的打錠裝置，除了實施例記載者以外，例如可列舉拆裝式高速打錠機Fette(Bosch Packaging Technology製)、高速打錠機COMPRIMA、及高速打錠機SYNTHESIS(以上，Mutual製)、Rotary Press MZ400(Mori Machinary製)、GEA Courtoy Module型打錠機P型、S型、D型、及GEA Pharma System Performa P(以上，Euro Techno製)、研究開發用小型迴轉式錠劑機、小型高速迴轉式錠劑機、中型高速迴轉式錠劑機、複式高速迴轉式錠劑機、迴轉盤拆裝水洗迴轉式錠劑機、及Containment錠劑機(以上，菊水製作所製)、以及BX型HX型強押打錠機、CVX型迴轉盤拆裝式打錠機、X型AP型小型打錠機、X型AP型中型打錠機、AP型大型打錠機、及X型AP型大型複式打錠機(以上，畑鐵工所製)。 As the ingot device based on the principle of rotary ingot, in addition to those described in the embodiments, for example, detachable high-speed ingot machine Fette (manufactured by Bosch Packaging Technology), high-speed ingot machine COMPRIMA, and high-speed ingot machine SYNTHESIS ( The above, manufactured by Mutual), Rotary Press MZ400 (manufactured by Mori Machinary), GEA Courtoy Module ingot machines P-type, S-type, D-type, and GEA Pharma System Performa P (above, manufactured by Euro Techno), small rotary for research and development Tablet machine, small high-speed rotary tablet machine, medium-sized high-speed rotary tablet machine, compound high-speed rotary tablet machine, rotary table disassembly and washing rotary tablet machine, and Containment tablet machine (above, Kikusui Manufacturing Co., Ltd. system), and BX type HX strong pressure ingot machine, CVX rotary disc disassembly type ingot machine, X type AP small ingot machine, X type AP medium ingot machine, AP large ingot machine, And X-type AP large-scale compound ingot machine (above, manufactured by Hata Iron Works).

上述的打錠裝置雖可製得單層錠，例如使用GEA Courtoy Module行二層錠打錠機D型(Euro Techno製)、及多層錠劑機(菊水製作所製)等可製造多層錠，使用有核錠劑機(菊水製作所製)、及AP‧MS型C型有核打錠機(畑鐵工所製)等亦可製造有核錠。 Although the above-mentioned ingot making device can produce single-layer ingots, for example, a two-layer ingot ingot machine D-type (manufactured by Euro Techno) using a GEA Courtoy Module, and a multi-layer ingot machine (manufactured by Kikusui Seisakusho) can be used to manufacture multi-layer ingots. Nucleated tablet machine (manufactured by Kikusui Seisakusho) and AP‧MS C-type nuclear ingot machine (manufactured by Hata Iron Works) can also produce nuclear ingots.

除了實施例記載的原理、裝置之外，包覆是藉由缽式包覆(水平缽)、缽式包覆(傾斜缽)、及空氣浮游式(流動層)的各原理進行。 In addition to the principle and apparatus described in the examples, coating is carried out by the respective principles of bowl-type coating (horizontal bowl), bowl-type coating (inclined bowl), and air floating type (fluidized bed).

作為缽式包覆(水平缽)為原理的包覆裝置，例如可列舉HICOATER FZ、AQUA COATER AQC Containment、及AQUA COATER AQC(以上，Freund產業製)。 Examples of coating devices based on the principle of bowl-type coating (horizontal bowl) include HICOATER FZ, AQUA COATER AQC Containment, and AQUA COATER AQC (manufactured by Freund Sangyo).

作為盤包覆(傾斜盤)為原理的包覆裝置，例如可列舉Powrex Coater PRC、 及Tri Coater DRC(以上，Powrex製)。 As a coating device based on the principle of disk coating (swash plate), for example, Powrex Coater PRC, and Tri Coater DRC (above, manufactured by Powrex).

作為空氣浮游式(流動層)為原理的包覆裝置，例如可列舉Grant Powder Coater GPCG SPC、Multiplex、及複合型流動層SFP(以上，Powrex製)。 Examples of coating devices based on the air floating type (fluidized layer) principle include Grant Powder Coater GPCG SPC, Multiplex, and composite fluidized layer SFP (above, manufactured by Powrex).

作為其他的包覆裝置，例如可列舉Hybridization System(奈良機械製作所製)、及Mechano Hybrid(以上，Nippon Coke工業製)。 Examples of other coating devices include Hybridization System (manufactured by Nara Machinery Manufacturing Co., Ltd.) and Mechano Hybrid (above, manufactured by Nippon Coke Industries).

本發明的醫藥組合物，藉由抑制骨代謝轉換而改善骨密度及骨強度，對於可治療或預防的疾病或症狀(例如骨質疏鬆症)的治療或預防是有用的。 The pharmaceutical composition of the present invention improves bone density and bone strength by inhibiting bone metabolic turnover, and is useful for the treatment or prevention of treatable or preventable diseases or symptoms (such as osteoporosis).

本發明中，疾病或症狀的治療或預防，包含該疾病的發病的預防、增惡或進行的抑制或阻礙、罹患該疾病的個體所呈現的一個以上的症狀的減輕或者增惡或進行的抑制、二次性疾病的治療或預防等。 In the present invention, the treatment or prevention of a disease or a symptom includes prevention of onset, progression or suppression or inhibition of the disease, and alleviation or progression or suppression of one or more symptoms in an individual suffering from the disease. , Treatment or prevention of secondary diseases, etc.

本發明的醫藥組合物所投藥的對象為哺乳動物。哺乳動物較佳為人類。 The subject to which the pharmaceutical composition of the present invention is administered is a mammal. The mammal is preferably a human.

本發明的醫藥組合物，以治療或預防的有效量投藥於對象。「治療或預防的有效量」意味，關於特定的疾病、投藥形態及投藥途徑顯示治療或預防效果的量，根據對象物種、疾病種類、症狀、性別、年齡、慢性病、其他要素而適宜決定。投藥途徑，通常為經口投藥。 The pharmaceutical composition of the present invention is administered to a subject in a therapeutically or prophylactically effective amount. "Therapeutic or prophylactic effective amount" means an amount that exhibits a therapeutic or prophylactic effect with respect to a specific disease, administration form, and administration route, and is appropriately determined depending on the target species, disease type, symptom, sex, age, chronic disease, and other factors. The route of administration is usually oral administration.

本發明的醫藥組合物的投藥量，根據對象物種、疾病種類、症狀、性別、年齡、慢性病、其他要素而適宜決定，對於人類成人，通常，作為ED-71為每1日可投藥0.01~10μg，較適宜為0.5~0.75μg。 The dose of the pharmaceutical composition of the present invention is appropriately determined depending on the target species, disease type, symptom, sex, age, chronic disease, and other factors. For human adults, usually, 0.01 to 10 μg per day can be administered as ED-71 , preferably 0.5~0.75μg.

再者，本發明係關於包含將本發明的醫藥組合物的治療或預防有效量，投藥於有其必要的對象之疾病或症狀的治療或預防用的方法。 Furthermore, the present invention relates to methods for treating or preventing diseases or symptoms comprising administering a therapeutically or preventively effective amount of the pharmaceutical composition of the present invention to a subject in need thereof.

本發明之「治療或預防有效量」意味，關於特定的疾病或症狀、投藥形態及投藥途徑顯示治療或預防效果的量，根據對象物種、疾病或症狀的種類、症狀、性別、年齡、慢性病、其他要素而適宜決定。 The "therapeutically or prophylactically effective dose" of the present invention means an amount that exhibits a therapeutic or preventive effect on a specific disease or symptom, administration form, and administration route, depending on the target species, type of disease or symptom, symptom, sex, age, chronic disease, other factors as appropriate.

本發明之「對象」，例如為哺乳動物，較佳為人類。 The "subject" of the present invention is, for example, a mammal, preferably a human.

本發明之「投藥」，通常意味經口投藥。 "Administration" in the present invention generally means oral administration.

作為本發明之「疾病或症狀」，可列舉經由抑制骨代謝轉換而改善骨密度或骨強度而可治療或預防的疾病或症狀(例如骨質疏鬆症)。 The "disease or symptom" of the present invention includes diseases or symptoms that can be treated or prevented by inhibiting bone metabolic turnover to improve bone density or bone strength (eg, osteoporosis).

II. ED-71的油分散體 II. Oil Dispersion of ED-71

II-1. 包含ED-71的醫藥組合物及其製造方法 II-1. Pharmaceutical composition comprising ED-71 and its production method

本發明的第二態樣，是關於ED-71的油分散體。本說明書中，ED-71的油分散體意指，ED-71的油脂溶液粒子分散於賦形劑中的組合物。 The second aspect of the present invention relates to an oil dispersion of ED-71. In this specification, the oil dispersion of ED-71 means a composition in which ED-71 fat solution particles are dispersed in a vehicle.

本發明係提供包含該等ED-71的油分散體的醫藥組合物。具體而言，提供包含ED-71的醫藥組合物，該醫藥組合物包含於賦形劑中或賦形劑的表面，包含以含有自羥丙基甲基纖維素及羥丙基纖維素選擇之水溶性高分子的被覆劑所被覆的粒子，該粒子包含ED-71的油脂溶液。 The present invention provides pharmaceutical compositions comprising the oil dispersions of the ED-71. Specifically, there is provided a pharmaceutical composition comprising ED-71, the pharmaceutical composition being contained in or on the surface of an excipient, comprising a compound selected from hydroxypropylmethylcellulose and hydroxypropylcellulose Particles coated with a water-soluble polymer coating agent, the particles contain an oil solution of ED-71.

再者，本發明提供該等醫藥組合物的製造方法。具體而言，提供包含ED-71的醫藥組合物的製造方法，該方法包含(i)調製包含ED-71的油脂溶液與水溶性高分子的水溶液之水中油型乳化液的步驟，(ii)使水中油型乳化液附著或吸附於賦形劑的步驟，及(iii)使水中油型乳化液乾燥的步驟，此處前述水溶性高分子為選擇自羥丙基甲基纖維素及羥丙基纖維素。經由該方法，於賦形劑中成為ED-71的油脂溶液粒子被水溶性高分子被覆的狀態，可製造使用ED-71的油分散體的製劑(特別是錠劑)。製劑領域中，雖已知將包含有效成分的油脂溶液含浸於賦形劑的方法，但不使用油脂溶液而使用水中油型乳化液，再者使經附著或吸附於賦形劑的水中油型乳化液乾燥，以水層中的成分被覆油脂溶液的方法則為以往所未知。 Furthermore, the present invention provides methods for producing the pharmaceutical compositions. Specifically, there is provided a method for producing a pharmaceutical composition comprising ED-71, the method comprising (i) preparing an oil-in-water emulsion comprising an oil solution of ED-71 and an aqueous solution of a water-soluble polymer, (ii) The step of attaching or adsorbing the oil-in-water emulsion to the excipient, and (iii) the step of drying the oil-in-water emulsion, where the aforementioned water-soluble polymer is selected from hydroxypropylmethylcellulose and hydroxypropyl base cellulose. By this method, the oil and fat solution particles of ED-71 are coated with the water-soluble polymer in the excipient, and preparations (especially tablets) using the oil dispersion of ED-71 can be produced. In the field of pharmaceutical preparations, although a method of impregnating an excipient with an oil solution containing an active ingredient is known, an oil-in-water emulsion is used instead of an oil solution, and an oil-in-water emulsion attached or adsorbed to an excipient is used. The method of drying the emulsion and coating the oil and fat solution with the components in the water layer was not known in the past.

關於步驟(i)，作為本發明使用的油脂，可列舉中鏈脂肪酸三酸甘油酯(以下亦記為「MCT」)、三辛酸甘油酯(tricaprylin)、己酸、辛酸、癸酸、油 酸、亞麻油酸、次亞麻油酸、植物油等。此處，作為植物油，可列舉椰子油、橄欖油、菜籽油、落花生油、玉米油、大豆油、棉籽油、葡萄籽油、紅花油等。其等之中，較佳為不含不飽和脂肪酸之MCT、三辛酸甘油酯、己酸、辛酸、或癸酸，特佳為MCT。 As for the step (i), examples of 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, oil acid, linoleic acid, linoleic acid, vegetable oil, etc. Here, coconut oil, olive oil, rapeseed oil, groundnut oil, corn oil, soybean oil, cottonseed oil, grapeseed oil, safflower oil, etc. are mentioned as vegetable oil. Among them, MCT, tricaprylic acid glyceride, caproic acid, caprylic acid, or capric acid that do not contain unsaturated fatty acids are preferred, and MCT is particularly preferred.

步驟(i)之油脂溶液中的ED-71的濃度，可根據成為對象之疾病或症狀、投藥形態、投藥途徑等而適宜決定，例如0.001~0.3重量%，較佳為0.005~0.1重量%，更佳為0.01~0.05重量%。 The concentration of ED-71 in the oil solution in step (i) can be appropriately determined according to the target disease or symptom, administration form, administration route, etc., for example, 0.001~0.3% by weight, preferably 0.005~0.1% by weight, More preferably, it is 0.01 to 0.05% by weight.

步驟(i)之油脂溶液，進一步地亦可添加抗氧化劑。作為本發明之抗氧化劑，例如，可列舉亞硝酸鹽(例如亞硝酸鈉)、亞硫酸鹽(例如亞硫酸鈉、乾燥亞硫酸鈉、亞硫酸氫鈉、焦亞硫酸鈉)、硫代硫酸鹽(例如硫代硫酸鈉)、α硫甘油、1,3-丁二醇、硫醇基乙酸及其鹽(例如硫醇基乙酸鈉)、硫基蘋果酸鹽(例如硫基蘋果酸鈉)、硫脲、硫代乳酸、依地酸鹽(例如依地酸鈉)、二氯異三聚氰酸鹽(例如二氯異三聚氰酸鉀)、檸檬酸、半胱胺酸及其鹽(例如鹽酸半胱胺酸)、苯并三唑、2-巰基苯并咪唑、異抗壞血酸及其鹽(例如異抗壞血酸鈉)、抗壞血酸及其酯化合物(例如：L-抗壞血酸硬脂酸酯、棕櫚酸抗壞血酸)、磷脂質(例如大豆卵磷脂)、金屬螯合劑及其鹽(例如乙二胺四乙酸、乙二胺四乙酸鈣二鈉、乙二胺四乙酸二鈉)、酒石酸及其鹽(例如羅謝爾鹽)、多酚類(例如兒茶素)、穀胱甘肽、二丁基羥基甲苯、丁基羥基苯甲醚、沒食子酸丙酯、天然維生素E、乙酸生育酚、濃縮混合生育酚、生育酚同系物(例如d-α-生育酚、dl-α-生育酚、5,8-二甲基母育酚、7,8-二甲基母育酚、δ-甲基母育酚、5,7,8-三甲基參雙鍵生殖酚、5,8-二甲基參雙鍵生殖酚、7,8-二甲基參雙鍵生殖酚、8-甲基參雙鍵生殖酚)等。其等之中，較佳為乙酸生育酚、二丁基羥基甲苯、天然維生素E、dl-α-生育酚、d-α-生育酚、濃縮混合生育酚、棕櫚酸抗壞血酸、L-抗壞血酸硬脂酸酯、丁基羥基苯甲醚、沒食子酸丙酯，更佳為dl-α-生育酚、二丁基羥基甲苯、丁基羥基 苯甲醚、沒食子酸，進一步更佳為dl-α-生育酚。 The oil solution of step (i) can further add antioxidants. As the antioxidant of the present invention, for example, nitrite (such as sodium nitrite), sulfite (such as sodium sulfite, dry sodium sulfite, sodium bisulfite, sodium metabisulfite), thiosulfate (such as sodium thiosulfate ), alpha thioglycerol, 1,3-butanediol, thioglycolic acid and its salts (e.g. sodium thioglycolate), thiomalate (e.g. sodium thiomalate), thiourea, thiolactic acid , edetate (such as sodium edetate), dichloroisocyanurate (such as potassium dichloroisocyanurate), citric acid, cysteine and its salts (such as cysteine hydrochloride ), benzotriazole, 2-mercaptobenzimidazole, erythorbic acid and its salts (such as sodium erythorbate), ascorbic acid and its ester compounds (such as: L-ascorbyl stearate, ascorbyl palmitate), phospholipids ( such as soybean lecithin), metal chelating agents and their salts (such as ethylenediaminetetraacetic acid, edetate calcium disodium, edetate disodium), tartaric acid and its salts (such as Rochelle salt), Polyphenols (e.g. catechins), glutathione, dibutylhydroxytoluene, butylated hydroxyanisole, propyl gallate, natural vitamin E, tocopheryl acetate, mixed tocopherol concentrate, tocopherols Homologues (e.g. d- α -tocopherol, dl- α -tocopherol, 5,8-dimethyltocol, 7,8-dimethyltocol, δ-methyltocol, 5, 7,8-trimethylparaffinic tocopherol, 5,8-dimethylparaffinic tocopherol, 7,8-dimethylparaffinic tocopherol, 8-methylparaffinic tocopherol, etc. . Among them, tocopheryl acetate, dibutyl hydroxytoluene, natural vitamin E, dl- α -tocopherol, d- α -tocopherol, concentrated mixed tocopherol, ascorbic acid palmitate, L-stearyl ascorbate are preferred Ester, butyl hydroxyanisole, propyl gallate, more preferably dl- α -tocopherol, dibutyl hydroxytoluene, butyl hydroxyanisole, gallic acid, further preferably dl - Alpha -tocopherol.

對於油脂溶液的抗氧化劑的添加量，雖無特別限定，通常可使用作為抗氧化劑能夠使用之最大使用量以下的量(例如，醫藥品添加事典(藥事日報社，2000)所記載之承認前例的最大使用量以下，食品添加物公定書(日本食品添加物協會，1999)所記載之使用限制量以下的量等)。 Although there is no particular limitation on the amount of antioxidant added to the oil solution, generally an amount below the maximum amount that can be used as an antioxidant can be used (for example, the approved previous example recorded in the Pharmaceutical Addition Code (Yakuji Ilbo, 2000) The amount below the maximum usage amount of the food additives, the amount below the usage limit amount recorded in the Food Additives Official Document (Japan Food Additives Association, 1999), etc.).

較佳態樣中，dl-α-生育酚於油脂溶液中以0.01重量%以上(例如1重量%以上)、10重量%以下(例如5重量%以下)的濃度添加。關於二丁基羥基甲苯、丁基羥基苯甲醚、沒食子酸丙酯等的添加量，皆與上述dl-α-生育酚相同。 In a preferred aspect, dl- α -tocopherol is added to the 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 addition amounts of dibutyl hydroxytoluene, butyl hydroxyanisole, propyl gallate, etc. are the same as those of dl- α -tocopherol mentioned above.

本發明使用之被覆劑，包含水溶性高分子。水溶性高分子選擇自羥丙基甲基纖維素及羥丙基纖維素。多數的添加劑，添加於ED-71的油脂溶液時使ED-71的安定性降低，但羥丙基甲基纖維素及羥丙基纖維素則不使ED-71的安定性降低。再者，使用羥丙基甲基纖維素及羥丙基纖維素的情況，可歷經長期維持水中油型乳化液的乳化狀態。 The coating agent used in the present invention includes a water-soluble polymer. The water-soluble polymer is selected from hydroxypropyl methylcellulose and hydroxypropyl cellulose. Most additives will reduce the stability of ED-71 when added to the oil solution of ED-71, but hydroxypropyl methylcellulose and hydroxypropyl cellulose will not reduce the stability of ED-71. Furthermore, when hydroxypropylmethylcellulose and hydroxypropylcellulose are used, the emulsified state of the oil-in-water emulsion can be maintained over a long period of time.

此處本發明的醫藥組合物中ED-71的安定性不降低，係經由將由本發明的醫藥組合物製造錠劑，將其遮光於40℃保存1、3或6個月後，調查ED-71的殘存率而予以確認。ED-71的殘存率，係針對保存樣品及初期樣品，經由高速液體層析法(測定波長265nm)測定ED-71及其異構物之前體(化學名：6Z-(1R,2R,3R)-2-(3-羥基丙氧基)-9,10-開環膽甾-5(10),6,8(9)-三烯-1,3,25-三醇；本說明書中亦稱為pre ED-71)的峰面積，藉由以下的計算式算出。 Here, the stability of ED-71 in the pharmaceutical composition of the present invention does not decrease, which is obtained by making lozenges from the pharmaceutical composition of the present invention and storing them at 40° C. for 1, 3, or 6 months with shading, and then investigating ED-71. The survival rate of 71 was confirmed. The residual rate of ED-71 is determined by high-speed liquid chromatography (measurement wavelength 265nm) for the preserved samples and initial samples. ED-71 and its isomer precursor (chemical name: 6Z-(1R, 2R, 3R) -2-(3-Hydroxypropoxy)-9,10-cyclocholesta-5(10),6,8(9)-triene-1,3,25-triol; also known as is the peak area of pre ED-71), calculated by the following calculation formula.

對於ED-71的表示量之含量比(%)=(ED-71標準品的秤取量/ED-71標準品中的ED-71峰面積合計)×初期樣品或保存樣品中的ED-71峰面積合計×(初期樣品或保存樣品全體的重量/測定時使用的樣品的重量)/表示量×100 For the expressed amount of ED-71 content ratio (%)=(weighed amount of ED-71 standard product/sum of ED-71 peak area in ED-71 standard product)×ED-71 in initial sample or preserved sample Total peak area × (weight of the initial sample or the entire stored sample / weight of the sample used for measurement) / indicated amount × 100

(ED-71峰面積合計=ED-71峰面積+1.98×pre ED-71的峰面積) (The total peak area of ED-71=the peak area of ED-71+1.98×the peak area of pre ED-71)

ED-71的殘存率(%)=對於保存樣品中的ED-71的表示量之含量比(%)/對於初期 樣品中的ED-71的表示量之含量比(%)×100 The remaining rate of ED-71 (%)=the content ratio (%) of the indicated amount of ED-71 in the preserved sample/for the initial stage The content ratio of the expressed amount of ED-71 in the sample (%)×100

又，上述式中各用語的意義係如下所述。 In addition, the meaning of each term in the said formula is as follows.

‧「表示量」：每1錠的理論含量 ‧"Indicated Amount": Theoretical content per 1 ingot

‧「ED-71標準品」：ED-71的原藥 ‧"ED-71 standard product": the original drug of ED-71

‧「ED-71標準品的秤取量/ED-71標準品中的ED-71峰面積合計」：每單位峰面積之ED-71標準品的重量(由峰面積用於算出測定樣品中的ED-71之含量的值) ‧"Weighed amount of ED-71 standard product/sum of ED-71 peak area in ED-71 standard product": the weight of ED-71 standard product per unit peak area (the peak area is used to calculate the ED-71 content value)

羥丙基甲基纖維素及羥丙基纖維素，只要為製劑上容許等級者即可。 Hydroxypropylmethyl cellulose and hydroxypropyl cellulose should just be what is acceptable grade on a formulation.

本發明之羥丙基甲基纖維素，例如，可為商品名TC-5之自信越化學工業購入。 The hydroxypropylmethylcellulose of the present invention is commercially available under the trade name TC-5 from Shinetsu Chemical Industry, for example.

再者，本發明中，羥丙基纖維素(HPC)，意指醫藥品添加物事典2016(編集：日本醫藥品添加物協會；發行：藥事日報社股份公司；ISBN978-4-8408-1329-7)中，作為成分編號002303所收錄的羥丙基纖維素，與同事典中作為成分編號002440所收錄的低取代度羥丙基纖維素為不同之物。本發明使用之羥丙基纖維素中，莫耳取代度(MS)(顯示HPC的重複單元(葡萄糖環)的羥基經取代為羥丙氧基的比例)通常為2~3，較佳為2.5~3，更佳為3。另一方面，低取代度羥丙基纖維素中之莫耳取代度為0.2~0.4。本發明之羥丙基纖維素，例如可以商品名Klucel自ISP Japan、以及商品名羥丙基纖維素自日本曹達分別購入。 Furthermore, in the present invention, hydroxypropyl cellulose (HPC) refers to the Codex of Pharmaceutical Additives 2016 (edited by: Japan Association of Pharmaceutical Additives; issued by: Yaoji Daily Co., Ltd.; ISBN978-4-8408-1329 In -7), the hydroxypropyl cellulose included in the ingredient number 002303 is different from the low-substituted hydroxypropyl cellulose included in the ingredient number 002440 in the Codex. In the hydroxypropyl cellulose used in the present invention, the molar degree of substitution (MS) (showing the ratio of the hydroxyl group of the repeating unit (glucose ring) of HPC replaced by hydroxypropoxy) is usually 2~3, preferably 2.5 ~3, more preferably 3. On the other hand, the molar substitution degree in low-substitution hydroxypropyl cellulose is 0.2-0.4. The hydroxypropyl cellulose of the present invention can be purchased, for example, from ISP Japan under the trade name Klucel and from Nippon Soda under the trade name hydroxypropyl cellulose.

本發明之被覆劑，亦可包含水溶性高分子以外的添加劑，例如，亦可包含安定化劑或抗氧化劑。 The coating agent of the present invention may contain additives other than water-soluble polymers, for example, stabilizers or antioxidants.

步驟(i)之水溶液中的水溶性高分子的濃度，可根據ED-71的量而適宜決定，例如1~15重量%，較佳為2~10重量%，更佳為3~6重量%，更佳為4~6重量%，進一步更佳為5~6重量%。步驟(i)之水溶液，亦可包含水溶性高分子以外的添加劑，例如，亦可包含安定化劑或抗氧化劑。 The concentration of the water-soluble polymer in the aqueous solution of step (i) can be appropriately determined according to the amount of ED-71, for example, 1-15% by weight, preferably 2-10% by weight, more preferably 3-6% by weight , more preferably 4 to 6% by weight, further preferably 5 to 6% by weight. The aqueous solution in step (i) may contain additives other than water-soluble polymers, for example, stabilizers or antioxidants.

水中油型乳化液，可經由製劑領域中一般所使用的方法調製，較佳係經由機械性乳化法調製。機械性乳化法，例如，可列舉使用化學攪拌機、漩渦混合機、均質混合機、均質機、水剪切(hydroshear)、膠體研磨、流體噴射式混合機、超音波產生機、使用玻璃珠粒的濕式粉碎機、使用多孔質膜的膜乳化機、使用電性能量的電乳化裝置的方法。作為均質機，例如可使用T-50 Ultra Turrax(IKA製)。 The oil-in-water emulsion can be prepared by a method generally used in the formulation field, preferably by a mechanical emulsification method. Mechanical emulsification methods include, for example, chemical mixers, vortex mixers, homomixers, homogenizers, hydroshears, colloid mills, fluid jet mixers, ultrasonic generators, and methods using glass beads. Methods of wet pulverizer, membrane emulsifier using porous membrane, and electro-emulsification device using electrical energy. As a homogenizer, for example, T-50 Ultra Turrax (manufactured by IKA) can be used.

ED-71的油脂溶液與水溶性高分子的水溶液的比率(重量比，o/w比)，只要為可調製水中油型乳化液的範圍即可，通常1：1.5~1：20，較佳為1：2~1：20，或1：2~1：4。較佳態樣中，水溶性高分子的水溶液中的水溶性高分子的濃度為3~6重量%、4~6重量%、或5~6重量%的情況，ED-71的油脂溶液與水溶性高分子的水溶液的比率為1：1.5~1：20、1：2~1：20、或1：2~1：4。 The ratio (weight ratio, o/w ratio) of the oil solution of ED-71 to the aqueous solution of the water-soluble polymer is sufficient as long as it is within the range that can prepare an oil-in-water emulsion, usually 1:1.5~1:20, preferably 1:2~1:20, or 1:2~1:4. In a preferred aspect, when the concentration of the water-soluble polymer in the aqueous solution of the water-soluble polymer is 3 to 6% by weight, 4 to 6% by weight, or 5 to 6% by weight, the oil solution of ED-71 and the water-soluble The ratio of the aqueous solution of the permanent polymer is 1:1.5~1:20, 1:2~1:20, or 1:2~1:4.

再者，ED-71的油脂溶液與水溶性高分子的比率(重量比)，只要能夠成為ED-71的油脂溶液的粒子被水溶性高分子所被覆的狀態的範圍即可，通常1：0.05~1：10，較佳為1：0.1~1：1、或1：0.1~1：0.3。較佳態樣中，水溶性高分子的水溶液中的水溶性高分子的濃度為3~6重量%、4~6重量%、或5~6重量%的情況，ED-71的油脂溶液與水溶性高分子的比率(重量比)為1：0.05~1：10、1：0.1~1：1、或1：0.1~1：0.3。 Furthermore, the ratio (weight ratio) of the fat solution of ED-71 to the water-soluble polymer is within the range as long as the particles of the fat solution of ED-71 are coated with the water-soluble polymer, usually 1:0.05 ~1:10, preferably 1:0.1~1:1, or 1:0.1~1:0.3. In a preferred aspect, when the concentration of the water-soluble polymer in the aqueous solution of the water-soluble polymer is 3 to 6% by weight, 4 to 6% by weight, or 5 to 6% by weight, the oil solution of ED-71 and the water-soluble The ratio (weight ratio) of the permanent polymer is 1:0.05 to 1:10, 1:0.1 to 1:1, or 1:0.1 to 1:0.3.

該粒子，較佳為球形。其粒子徑，通常為0.01~100μm，較佳為0.1~10μm。 The particles are preferably spherical. The particle size thereof is usually 0.01 to 100 μm, preferably 0.1 to 10 μm.

關於步驟(ii)，作為本發明使用的賦形劑，例如，玉蜀黍澱粉、馬鈴薯澱粉、小麥澱粉、米澱粉、部分α化澱粉、α化澱粉、多孔澱粉等澱粉類，無水乳糖、乳糖水合物、果糖、葡萄糖、甘露醇、山梨糖醇、赤蘚醇等糖或糖醇類，無水磷酸氫化鈣，結晶纖維素，沉降碳酸鈣，矽酸鈣等，較佳為糖或糖醇，進一步較佳為甘露醇、無水乳糖、乳糖水合物，進一步較佳為甘露醇。 Regarding step (ii), as excipients used in the present invention, for example, starches such as corn starch, potato starch, wheat starch, rice starch, partially gelatinized starch, gelatinized starch, porous starch, anhydrous lactose, lactose hydrate , fructose, glucose, mannitol, sorbitol, erythritol and other sugars or sugar alcohols, anhydrous calcium hydrogen phosphate, crystalline cellulose, precipitated calcium carbonate, calcium silicate, etc., preferably sugar or sugar alcohols, further Preferably, it is mannitol, anhydrous lactose, and lactose hydrate, More preferably, it is mannitol.

步驟(ii)中使用的水中油型乳化液與賦形劑的比率(重量比)，可根據賦形劑的種類等而變化，通常為1：1~1：100，較佳為1：4~1：20的範圍。特別地，賦形劑為甘露醇的情況，重量比通常為1：4~1：20的範圍，則能夠得到適用於錠劑等製劑的製造中的造粒末。 The ratio (weight ratio) of the oil-in-water emulsion used in step (ii) to the excipient can vary depending on the type of excipient, etc., and is usually 1:1~1:100, preferably 1:4 ~1:20 range. In particular, when the excipient is mannitol, the weight ratio is usually in the range of 1:4 to 1:20, and a granulated powder suitable for the production of preparations such as tablets can be obtained.

水中油型乳化液對於賦形劑的附著或吸附，能夠經由製劑領域中一般所使用的方法進行，例如，可列舉於賦形劑中噴霧乳化液同時造粒的方法、於賦形劑添加乳化液混合攪拌的方法等。該等方法，例如，可使用高速攪拌造粒機(POWREX製VG-600CT)、混合攪拌機(品川工業所製DM型)等進行。又，附著或吸附，亦包含含浸(於多孔質的賦形劑中，使水中油型乳化液浸潤於孔內)。 The attachment or adsorption of the oil-in-water emulsion to the excipient can be carried out by methods generally used in the field of formulations, for example, the method of spraying the emulsion in the excipient while granulating, adding emulsification to the excipient, etc. The method of liquid mixing and stirring, etc. These methods can be performed using, for example, a high-speed stirring granulator (VG-600CT manufactured by POWREX), a mixing mixer (DM type manufactured by Shinagawa Kogyo Co., Ltd.), and the like. In addition, attachment or adsorption also includes impregnation (soaking oil-in-water emulsion into pores in a porous vehicle).

步驟(iii)中，使附著或吸附於賦形劑的水中油型乳化液乾燥，咸信藉此自水溶性高分子的水溶液去除水，形成使油脂溶液直接以水溶性高分子所被覆的粒子。該等方式所得之油分散體，包含含有ED-71的油脂溶液的粒子，使用於錠劑等製劑的製造的情況，顯示良好的製造性(例如，流動性或壓縮成型性)。 In step (iii), the oil-in-water emulsion attached or adsorbed to the excipient is dried, and it is believed that water is removed from the aqueous solution of the water-soluble polymer to form particles in which the oil solution is directly coated with the water-soluble polymer . The oil dispersion obtained in this way contains particles of an oil solution containing ED-71 and exhibits good manufacturability (for example, fluidity and compression moldability) when used in the manufacture of preparations such as tablets.

水中油型乳化液的乾燥，可經由製劑領域中一般使用的方法進行，例如，可列舉流動乾燥、凍結乾燥、通氣乾燥、噴霧乾燥、靜置乾燥、攪拌乾燥、氣流乾燥、真空乾燥、微波乾燥、紅外線‧遠紅外線乾燥等。再者，乾燥，亦可與加熱或冷卻一起進行。乾燥，例如可使用流動層造粒乾燥機(POWREX製WSG-200pro)、真空乾燥機(日本乾燥機製Conical Dryer)等進行。 Drying of the oil-in-water emulsion can be carried out by a method generally used in the pharmaceutical field, for example, flow drying, freeze drying, air drying, spray drying, static drying, stirring drying, airflow drying, vacuum drying, microwave drying , infrared ‧ far infrared drying, etc. Furthermore, drying can also 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 Japan Drying Co., Ltd.), or the like.

本發明的醫藥組合物，可作為錠劑、膠囊劑、顆粒劑、散劑等經口劑。該等經口劑，可經由製劑領域中使用的方法製造。例如作為錠劑的製造方法，可列舉以下的i)、ii)、及iii)的方法。 The pharmaceutical composition of the present invention can be used as oral preparations such as tablets, capsules, granules, and powders. These oral preparations can be produced by methods used in the pharmaceutical field. For example, as a manufacturing method of a tablet, the following methods of i), ii) and iii) are mentioned.

i)將ED-71的油分散體與追加的添加劑(賦形劑、崩解劑、潤滑劑等)一起混合後，經由壓縮成型，製造錠劑。 i) After mixing the oil dispersion of ED-71 with additional additives (excipients, disintegrants, lubricants, etc.), compression molding was performed to manufacture lozenges.

ii)將ED-71的油分散體與追加的添加劑(賦形劑、結合劑等)混合後，添加或噴霧溶劑(例如，精製水、乙醇、或其混合液)同時造粒。所得造粒物中，添加適量的潤滑劑、視需要之崩解劑等混合後，經由壓縮成型，製造錠劑。 ii) After mixing the oil dispersion of ED-71 with additional additives (excipients, binders, etc.), adding or spraying a solvent (for example, purified water, ethanol, or a mixture thereof) to granulate. The obtained granules are mixed with an appropriate amount of lubricants and disintegrants if necessary, and then compression molded to produce lozenges.

iii)將ED-71的油分散體與追加的添加劑(賦形劑等)混合後，將結合劑及視需要之其他添加劑分散或溶解於溶劑(例如，精製水、乙醇、或其混合液)所得之液邊添加或噴霧，同時造粒。所得造粒物中，添加適量的潤滑劑、視需要之崩解劑等混合後，經由壓縮成型，製造錠劑。 iii) After mixing the oil dispersion of ED-71 with additional additives (excipients, etc.), disperse or dissolve the binder and other additives if necessary in a solvent (for example, purified water, ethanol, or a mixture thereof) The obtained liquid is added or sprayed and granulated at the same time. The obtained granules are mixed with an appropriate amount of lubricants and disintegrants if necessary, and then compression molded to produce lozenges.

作為追加的添加劑，例如，可各別使用以使藥物的釋放性提升為目的之界面活性劑、pH調整劑等，以使步驟中的流動性佳為目的之流動化劑，以提升安定性為目的之安定化劑，以加入口味或味道為目的之矯味矯臭劑，以加入顏色為目的之著色劑。 As additional additives, for example, surfactants, pH regulators, etc. for the purpose of improving drug release, and fluidizers for the purpose of improving fluidity in the process can be used to improve stability. Stabilizers for the purpose, flavoring and odorants for the purpose of adding taste or taste, and coloring agents for the purpose of adding color.

再者，錠劑，亦可進一步包含抗氧化劑作為追加的添加劑。抗氧化劑於i)、ii)及iii)的製造法中可於任意步驟添加。例如，i)的製造法的情況，抗氧化劑與其他添加劑一起與油分散體混合後，經由壓縮成型，可製造錠劑。再者，使用預先溶解抗氧化劑的ED-71的油脂溶液調製油分散體，將其與其他的添加劑混合物後，經由壓縮成型，亦可製造錠劑。 Furthermore, the lozenge may further contain an antioxidant as an additional additive. The antioxidant may be added at any step in the production methods of i), ii) and iii). For example, in the case of the production method of i), after the antioxidant and other additives are mixed with the oil dispersion, compression molding can be used to produce tablets. Furthermore, an oil dispersion is prepared by using a fat solution of ED-71 in which an antioxidant has been dissolved in advance, and after mixing it with other additives, compression molding can also be used to manufacture lozenges.

賦形劑、崩解劑、結合劑、潤滑劑、界面活性劑、pH調整劑、流動化劑、安定化劑、矯味矯臭劑、及著色劑，可使用上述I-2所記載者。再者，抗氧化劑，可使用上述者。 Excipients, disintegrants, binders, lubricants, surfactants, pH regulators, fluidizers, stabilizers, flavoring agents, and coloring agents can be those described in I-2 above. In addition, as an antioxidant, the one mentioned above can be used.

上述追加的添加劑，亦可以適宜的比例混合2種以上使用。 The above-mentioned additional additives may be used by mixing two or more kinds in an appropriate ratio.

由錠劑，進一步使用適當的包覆用添加劑，可製得糖衣包覆錠或膜包覆錠。包覆用添加劑，可使用上述I-2所記載者。較佳態樣中，本發明的醫藥組合物為以HPMC膜包覆的包覆錠。 From the lozenges, sugar-coated or film-coated lozenges can be prepared by further using appropriate coating additives. As the additives for coating, those described in the above-mentioned I-2 can be used. In a preferred aspect, the pharmaceutical composition of the present invention is a coated tablet coated with an HPMC film.

本發明的醫藥組合物的製造中，造粒、混合、打錠、及包覆，可 經由上述I-2所記載的原理、裝置進行。 In the manufacture of the pharmaceutical composition of the present invention, granulation, mixing, tableting, and coating can be It is carried out via the principle and apparatus described in the above-mentioned I-2.

本發明的醫藥組合物，經由抑制骨代謝轉換而改善骨密度及骨強度，對於可治療或預防的疾病或症狀(例如骨質疏鬆症)的治療或預防是有用的。 The pharmaceutical composition of the present invention improves bone density and bone strength by inhibiting bone metabolic turnover, and is useful for the treatment or prevention of treatable or preventable diseases or symptoms (such as osteoporosis).

本發明中，疾病或症狀的治療或預防，包含該疾病的發病的預防、增惡或進行的抑制或阻礙、罹患該疾病的個體呈現的一個以上的症狀的減輕或者增惡或進行的抑制、二次性疾病的治療或預防等。 In the present invention, the treatment or prevention of a disease or symptom includes prevention of the onset of the disease, suppression or inhibition of its progression or progress, alleviation or progression or suppression of one or more symptoms presented by an individual suffering from the disease, Treatment or prevention of secondary diseases, etc.

本發明的醫藥組合物所投藥的對象為哺乳動物。哺乳動物較佳為人類。 The subject to which the pharmaceutical composition of the present invention is administered is a mammal. The mammal is preferably a human.

本發明的醫藥組合物，以治療或預防的有效量投藥於對象。「治療或預防的有效量」意味，關於特定的疾病、投藥形態及投藥途徑顯示治療或預防效果的量，根據對象物種、疾病種類、症狀、性別、年齡、慢性病、其他要素而適宜決定。投藥途徑，通常為經口投藥。 The pharmaceutical composition of the present invention is administered to a subject in a therapeutically or prophylactically effective amount. "Therapeutic or prophylactic effective amount" means an amount that exhibits a therapeutic or prophylactic effect with respect to a specific disease, administration form, and administration route, and is appropriately determined depending on the target species, disease type, symptom, sex, age, chronic disease, and other factors. The route of administration is usually oral administration.

本發明的醫藥組合物的投藥量，根據對象物種、疾病種類、症狀、性別、年齡、慢性病、其他要素而適宜決定，對於人類成人，通常，作為ED-71為每1日可投藥0.01~10μg，較適宜為0.5~0.75μg。 The dose of the pharmaceutical composition of the present invention is appropriately determined depending on the target species, disease type, symptom, sex, age, chronic disease, and other factors. For human adults, usually, 0.01 to 10 μg per day can be administered as ED-71 , preferably 0.5~0.75μg.

再者，本發明係關於包含將本發明的醫藥組合物的治療或預防有效量，投藥於有其必要的對象之疾病或症狀的治療或預防用的方法。 Furthermore, the present invention relates to methods for treating or preventing diseases or symptoms comprising administering a therapeutically or preventively effective amount of the pharmaceutical composition of the present invention to a subject in need thereof.

本發明之「治療或預防有效量」意味，關於特定的疾病或症狀、投藥形態及投藥途徑顯示治療或預防效果的量，根據對象物種、疾病或症狀的種類、症狀、性別、年齡、慢性病、其他要素而適宜決定。 The "therapeutically or prophylactically effective dose" of the present invention means an amount that exhibits a therapeutic or preventive effect on a specific disease or symptom, administration form, and administration route, depending on the target species, type of disease or symptom, symptom, sex, age, chronic disease, other factors as appropriate.

本發明之「對象」，例如為哺乳動物，較佳為人類。 The "subject" of the present invention is, for example, a mammal, preferably a human.

本發明之「投藥」，通常意味經口投藥。 "Administration" in the present invention generally means oral administration.

作為本發明之「疾病或症狀」，可列舉經由抑制骨代謝轉換而改善骨密度或骨強度而可治療或預防的疾病或症狀(例如骨質疏鬆症)。 The "disease or symptom" of the present invention includes diseases or symptoms that can be treated or prevented by inhibiting bone metabolic turnover to improve bone density or bone strength (eg, osteoporosis).

II-2. 抑制ED-71分解的方法 II-2. Methods of inhibiting the decomposition of ED-71

本發明進一步地提供抑制ED-71分解的方法，包含調製包含ED-71的油脂溶液與水溶性高分子的水溶液所形成之水中油型乳化液的步驟，此處前述水溶性高分子選擇自羥丙基甲基纖維素及羥丙基纖維素。 The present invention further provides a method for inhibiting the decomposition of ED-71, comprising the step of preparing an oil-in-water emulsion formed by an oil solution containing ED-71 and an aqueous solution of a water-soluble polymer, wherein the aforementioned water-soluble polymer is selected from hydroxyl Propyl methyl cellulose and hydroxypropyl cellulose.

本發明之調製包含ED-71的油脂溶液與水溶性高分子的水溶液所形成之水中油型乳化液的步驟，與上述II-1所記載之包含ED-71的醫藥組合物的製造方法中之步驟(i)相同。ED-71的油脂溶液咸信於水中油型乳化液中成為被水溶性高分子覆蓋的狀態。本方法就不使油脂溶液中的ED-71的安定性降低，能夠製造ED-71油分散體或使用其之醫藥組合物之觀點而言，為有用的。 The step of preparing the oil-in-water emulsion formed by the oil solution containing ED-71 and the aqueous solution of the water-soluble polymer according to the present invention is the same as the method for producing the pharmaceutical composition containing ED-71 described in II-1 above. Step (i) is the same. The oil solution of ED-71 is believed to be in a state of being covered with water-soluble polymers in the oil-in-water emulsion. This method is useful from the viewpoint of being able to produce an ED-71 oil dispersion or a pharmaceutical composition using the same without reducing the stability of ED-71 in an oil and fat solution.

又，本說明書中所引用的全部先前技術文獻，係以參照併入本說明書。 In addition, all the prior art documents cited in this specification are incorporated in this specification by reference.

本發明藉由實施例進一步詳細說明。 The present invention is further described in detail through examples.

[實施例] [Example]

本實施例中，使用以下簡略符號。 In this embodiment, the following abbreviated symbols are used.

EtOH：乙醇 EtOH: ethanol

HPMC：羥丙基甲基纖維素 HPMC: Hydroxypropylmethylcellulose

THF：四氫呋喃 THF: Tetrahydrofuran

BHT：二丁基羥基甲苯 BHT: Butylated Hydroxytoluene

MCT：中鏈脂肪酸三酸甘油酯 MCT: medium-chain fatty acid triglycerides

HPC：羥丙基纖維素 HPC: Hydroxypropyl Cellulose

PVP：聚乙烯基吡咯烷酮 PVP: polyvinylpyrrolidone

PVA copolymer：聚乙烯基醇‧丙烯酸‧甲基丙烯酸甲酯共聚物 PVA copolymer: polyvinyl alcohol‧acrylic acid‧methyl methacrylate copolymer

A. 固體分散體 A. Solid dispersion

參考例A1~A3 Reference example A1~A3

使ED-71溶解於EtOH(乙醇(99.5)試藥特級，今津藥品工業)，調製EtOH溶液(0.1mg/mL)。將其分注100μL於玻璃管中，減壓下餾除溶劑，獲得經乾燥的ED-71。將其單獨(對照例A1)、或脫氧劑(Pharmakeep KD-20，三菱氣體化學)存在下(參考例A1)、吸濕劑(Silica Gel(中粒狀，藍色)，和光純藥工業製)存在下(參考例A2)、或脫氧劑及吸濕劑存在下(參考例A3)的條件，於大氣存在下封入鋁袋(Lamizip，AS One)遮光，保存於經調整為60℃的恆溫槽內，7日後及14日後調查ED-71的殘存率(%)。 ED-71 was dissolved in EtOH (ethanol (99.5) reagent special grade, Imatsu Pharmaceutical Co., Ltd.) to prepare an EtOH solution (0.1 mg/mL). 100 μL of this was dispensed into a glass tube, and the solvent was distilled off under reduced pressure to obtain dried ED-71. It was used alone (comparative example A1), or in the presence of a deoxidizer (Pharmakeep KD-20, Mitsubishi Gas Chemical) (reference example A1), a hygroscopic agent (Silica Gel (medium granular, blue), manufactured by Wako Pure Chemical Industries, Ltd. ) in the presence of (Reference Example A2), or in the presence of deoxidizers and hygroscopic agents (Reference Example A3), sealed in an aluminum bag (Lamizip, AS One) in the presence of air to shield it from light, and stored at a constant temperature adjusted to 60°C In the tank, the survival rate (%) of ED-71 was investigated after 7 days and 14 days.

ED-71的殘存率，係經由以下的方法測定。 The survival rate of ED-71 was measured by the following method.

在置入ED-71的上述玻璃管中，分注EtOH 100μL及乙腈400μL，以移液進行攪拌者作為樣本溶液。另外，於空的玻璃管中分注樣本調製中所使用的ED-71 EtOH溶液(0.1mg/mL)100μL，添加乙腈400μL，以移液進行攪拌者作為標準溶液。將樣本溶液及標準溶液以高速液體層析法(Waters製Alliance，測定波長265nm)測定，求出樣品溶液的ED-71峰面積及pre ED-71的峰面積。 Into the above-mentioned glass tube placed in ED-71, 100 μL of EtOH and 400 μL of acetonitrile were dispensed, and what was stirred by pipetting was used as a sample solution. Separately, 100 μL of ED-71 EtOH solution (0.1 mg/mL) used for sample preparation was dispensed into an empty glass tube, and what was added with 400 μL of acetonitrile and stirred by pipetting was used as a standard solution. The sample solution and the standard solution were measured by high-speed liquid chromatography (Alliance manufactured by Waters, measurement wavelength: 265 nm), and the peak area of ED-71 and the peak area of pre ED-71 of the sample solution were determined.

經由以下的計算式求出ED-71的殘存率。 The survival rate of ED-71 was calculated|required by the following calculation formula.

ED-71的殘存率(%)=加速樣本溶液中的ED-71面積合計/未加速樣本溶液中的ED-71峰面積合計 The residual rate of ED-71 (%)=the total area of ED-71 in the accelerated sample solution/the total peak area of ED-71 in the unaccelerated sample solution

(ED-71峰面積合計=ED-71峰面積+1.98×pre ED-71的峰面積) (The total peak area of ED-71=the peak area of ED-71+1.98×the peak area of pre ED-71)

結果示於第A1表。由第A1表可知，ED-71的分解原因為氧，ED-71於脫氧劑存在下顯示安定化。 The results are shown in Table A1. It can be seen from Table A1 that the decomposition cause of ED-71 is oxygen, and ED-71 is stabilized in the presence of a deoxidizer.

Figure 106146225-A0305-02-0029-34
Figure 106146225-A0305-02-0029-34
Figure 106146225-A0305-02-0030-35
Figure 106146225-A0305-02-0030-35

實施例A1 Example A1

將15mg的ED-71溶解於100mL的EtOH(HPLC級，和光純藥工業)。於樣品容器秤量水溶性高分子之HPMC(TC-5R，信越化學工業)375mg，溶解於10mL的70v/v%EtOH(水與EtOH為容積比30：70的混合物)，調製添加劑溶液。將ED-71乙醇溶液20μL與添加劑溶液80μL於1mL玻璃管內混合，然後減壓下餾除溶劑，乾燥，獲得實施例A1的組合物。本組合物每管直立排列96孔管架，於大氣存在下置入鋁袋遮光，保存於經調整為60℃的恆溫槽內，7日後及14日後調查ED-71的殘存率。 15 mg of ED-71 was dissolved in 100 mL of EtOH (HPLC grade, Wako Pure Chemical Industries). Weigh 375 mg of water-soluble polymer HPMC (TC-5R, Shin-Etsu Chemical Co., Ltd.) in a sample container, dissolve it in 10 mL of 70v/v% EtOH (a mixture of water and EtOH at a volume ratio of 30:70), and prepare an additive solution. Mix 20 μL of ED-71 ethanol solution and 80 μL of additive solution in a 1 mL glass tube, then distill off the solvent under reduced pressure and dry to obtain the composition of Example A1. Each tube of this composition is arranged upright in a 96-well tube rack, placed in an aluminum bag for shading in the presence of the atmosphere, and stored in a constant temperature bath adjusted to 60°C. The residual rate of ED-71 was investigated after 7 days and 14 days.

除了使用70v/v% EtOH替代添加劑溶液以外，與實施例A1同樣的方式調製對照例A2，與實施例A1同樣的方式調查ED-71的殘存率。 Except for using 70v/v% EtOH instead of the additive solution, Comparative Example A2 was prepared in the same manner as in Example A1, and the remaining rate of ED-71 was investigated in the same manner as in Example A1.

結果示於第A2表。由第A2表明顯可知，ED-71於高溫條件下，HPMC的存在下相較於單獨的情況更為安定。 The results are shown in Table A2. It is evident from Table A2 that ED-71 is more stable in the presence of HPMC at high temperature than alone.

Figure 106146225-A0305-02-0030-36
Figure 106146225-A0305-02-0030-36

實施例A2~A6 Embodiment A2~A6

使用第A3表記載的水溶性高分子替代實施例A1的HPMC，以與實施例A1同樣的方法，製備ED-71組合物，與實施例A1同樣方式調查於60℃的安定性，與對照例A2比較。結果示於第A3表。實施例A2~A6的組合物之任一者相較於對照例A2於高溫條件下均顯示安定。 Use the water-soluble polymer described in Table A3 to replace the HPMC of Example A1, prepare the ED-71 composition in the same way as in Example A1, and investigate the stability at 60°C in the same way as in Example A1. A2 comparison. The results are shown in Table A3. Any one of the compositions of Examples A2-A6 is stable under high temperature conditions compared with Control Example A2.

Figure 106146225-A0305-02-0031-37
Figure 106146225-A0305-02-0031-37

實施例A7~A19 Embodiment A7~A19

使用EtOH替代實施例A1的70v/v%EOH，且使用第A4表顯示的水溶性高分子替代HPMC，以與實施例A1同樣的方法製得實施例A7~A19的ED-71組合物。再者，與對照例A2同樣方式，調製不含水溶性高分子的對照例A3。該等樣品中的ED-71於60℃的安定性與實施例A1同樣方式調查。結果示於第A4表。實施例A7~A19的組合物之任一者相較於對照，於高溫條件下均顯示安定。 EtOH was used to replace 70v/v%EOH in Example A1, and the water-soluble polymer shown in Table A4 was used to replace HPMC, and the ED-71 composition of Examples A7 to A19 was prepared in the same manner as in Example A1. Furthermore, in the same manner as in Comparative Example A2, Comparative Example A3 not containing a water-soluble polymer was prepared. The stability of ED-71 in these samples at 60° C. was investigated in the same manner as in Example A1. The results are shown in Table A4. Compared with the control, any of the compositions of Examples A7-A19 showed stability under high temperature conditions.

Figure 106146225-A0305-02-0031-38
Figure 106146225-A0305-02-0031-38
Figure 106146225-A0305-02-0032-39
Figure 106146225-A0305-02-0032-39

Figure 106146225-A0305-02-0032-40
Figure 106146225-A0305-02-0032-40
Figure 106146225-A0305-02-0033-41
Figure 106146225-A0305-02-0033-41

實施例20~A28 Embodiment 20~A28

使用50v/v%EtOH(水與EtOH以容積比50：50混和者)替代實施例A1的70v/v%EOH，且使用第A5表顯示的水溶性高分子替代HPMC，以與實施例A1同樣的方法製得實施例A20~A28的ED-71組合物。再者，與對照例A2同樣方式，調製不含水溶性高分子的對照例A4。該等樣品中的ED-71於60℃的安定性與實施例A1同樣方式調查。結果示於第A5表。實施例A20~A28的組合物之任一者相較於對照，於高溫條件下均顯示安定。 Use 50v/v%EtOH (water and EtOH mixed at a volume ratio of 50:50) to replace the 70v/v%EOH in Example A1, and use the water-soluble polymer shown in Table A5 to replace HPMC, to be the same as in Example A1 The method for making the ED-71 composition of embodiment A20～A28. Furthermore, in the same manner as in Comparative Example A2, Comparative Example A4 not containing a water-soluble polymer was prepared. The stability of ED-71 in these samples at 60° C. was investigated in the same manner as in Example A1. The results are shown in Table A5. Compared with the control, any one of the compositions of Examples A20-A28 showed stability under high temperature conditions.

Figure 106146225-A0305-02-0033-42
Figure 106146225-A0305-02-0033-42
Figure 106146225-A0305-02-0034-43
Figure 106146225-A0305-02-0034-43

實施例A29 Example A29

使用THF(HPLC級，和光純藥工業)替代實施例A1的70v/v%EtOH，且使用卵磷脂粉末(化學用，Nacalai Tesque)替代HPMC，以與實施例A1同樣的方法製得實施例A29的ED-71組合物。再者，與對照例A2同樣方式，調製不含水溶性高分子的對照例A5。該等樣品中的ED-71於60℃的安定性與實施例A1同樣方式調查。結果示於第A6表。實施例A29的組合物相較於對照，於高溫條件下顯示安定。 Use THF (HPLC grade, Wako Pure Chemical Industries) to replace the 70v/v%EtOH of Example A1, and use lecithin powder (for chemistry, Nacalai Tesque) to replace HPMC, to prepare Example A29 in the same way as Example A1 Composition of ED-71. Furthermore, in the same manner as in Comparative Example A2, Comparative Example A5 containing no water-soluble polymer was prepared. The stability of ED-71 in these samples at 60° C. was investigated in the same manner as in Example A1. The results are shown in Table A6. Compared with the control, the composition of Example A29 is stable under high temperature conditions.

Figure 106146225-A0305-02-0034-44
Figure 106146225-A0305-02-0034-44

實施例A30及A31 Embodiments A30 and A31

使用的A7表顯示的鹼性化合物替代實施例A1的HMPC，以與實施例A1同樣的方法製得實施例A30及A31的ED-71組合物。所調製的ED-71組合物於60℃的安定性與實施例A1同樣方式調查，與對照例A2比較。結果示於第A7表。實施例A30及A31的組合物之任一者相較於對照，於高溫條件下均顯示安定。 The basic compound shown in Table A7 was used instead of the HMPC of Example A1, and the ED-71 compositions of Examples A30 and A31 were prepared in the same manner as in Example A1. The stability of the prepared ED-71 composition at 60°C was investigated in the same manner as in Example A1, and compared with Control Example A2. The results are shown in Table A7. Any one of the compositions of Examples A30 and A31 was stable under high temperature conditions compared with the control.

Figure 106146225-A0305-02-0034-45
Figure 106146225-A0305-02-0034-45
Figure 106146225-A0305-02-0035-46
Figure 106146225-A0305-02-0035-46

實施例A32 Example A32

使用50v/v%EtOH替代實施例A1的70v/v%EOH，且使用焦磷酸四鉀(食品添加等級，太平化學產業)作為鹼性化合物替代HPMC，以與實施例A1同樣的方法製得實施例A32的ED-71組合物。所調製的ED-71組合物於60℃的安定性與實施例A1同樣方式調查，與對照例A4比較。結果示於第A8表。實施例A32的組合物相較於對照，於高溫條件下顯示安定。 Use 50v/v%EtOH to replace the 70v/v%EOH of Example A1, and use tetrapotassium pyrophosphate (food additive grade, Taiping Chemical Industry) as the basic compound to replace HPMC, and make the same method as Example A1 The ED-71 composition of Example A32. The stability of the prepared ED-71 composition at 60° C. was investigated in the same manner as in Example A1, and compared with Control Example A4. The results are shown in Table A8. Compared with the control, the composition of Example A32 is stable under high temperature conditions.

Figure 106146225-A0305-02-0035-47
Figure 106146225-A0305-02-0035-47

實施例A33~A38 Embodiment A33~A38

使15mg的ED-71溶解於100mL的EtOH(HPLC級，和光純藥工業)，調製ED-71溶解EtOH溶液。個別於樣品容器秤量750mg的水溶性高分子之羥丙基甲基纖維素(TC-5R，信越化學工業)、鹼性化合物之美洛明(Merck)，使其溶解於20mL的70v/v%EtOH(水與EtOH經以容積比30：70混合者)，各自稀釋成為37.5mg/mL~0.0375mg/mL的濃度，調製添加劑溶液。ED-71原藥量與添加劑量的比以成為如第A9表所示方式，將ED-71溶解EtOH溶液與添加劑溶液分注於離心管，調製ED-71溶解添加劑溶液。所調製的ED-71溶解添加劑溶液，以ED-71原藥量成為3μg的方式，各自分注於1mL玻璃管內，然後減壓下餾除溶劑，獲得真空乾燥組 合物(實施例A33~A38)。本組合物每管直立排列96孔管架，於大氣存在下置入鋁袋遮光，保存於經調整為60℃的恆溫槽內，7日後調查ED-71的殘存率。又，經由以下的計算式求出ED-71的殘存率。 15 mg of ED-71 was dissolved in 100 mL of EtOH (HPLC grade, Wako Pure Chemical Industries, Ltd.) to prepare an ED-71 dissolved EtOH solution. Separately weigh 750 mg of water-soluble polymer hydroxypropyl methylcellulose (TC-5R, Shin-Etsu Chemical Co., Ltd.) and basic compound merlomin (Merck) in a sample container, and dissolve them in 20 mL of 70v/v% EtOH (Water and EtOH are mixed at a volume ratio of 30:70), each diluted to a concentration of 37.5mg/mL~0.0375mg/mL to prepare an additive solution. The ratio of the ED-71 original drug amount to the additive amount is as shown in Table A9, and the ED-71 dissolved EtOH solution and the additive solution are dispensed into centrifuge tubes to prepare the ED-71 dissolved additive solution. The prepared ED-71 dissolving additive solution was dispensed into 1 mL glass tubes so that the amount of ED-71 original drug became 3 μg, and then the solvent was distilled off under reduced pressure to obtain a vacuum-dried composition. compound (embodiment A33～A38). Each tube of this composition is arranged upright in a 96-hole tube rack, placed in an aluminum bag for shading in the presence of the atmosphere, and stored in a constant temperature tank adjusted to 60°C. After 7 days, the residual rate of ED-71 was investigated. Moreover, the survival rate of ED-71 was calculated|required by the following calculation formula.

ED-71的殘存率(%)=加速樣本溶液中的ED-71峰面積合計/未加速樣本溶液中的ED-71峰面積合計(ED-71峰面積合計=ED-71峰面積+1.98×pre ED-71的峰面積) The residual rate of ED-71 (%)=the total peak area of ED-71 in the accelerated sample solution/the total peak area of ED-71 in the unaccelerated sample solution (the total peak area of ED-71=the peak area of ED-71+1.98× Peak area of pre ED-71)

再者，不使用添加劑溶液所調製的ED-71溶解EtOH溶液，以ED-71原藥量成為3μg的方式各自分注於1mL玻璃管內，然後減壓下餾除溶劑，獲得真空乾燥組合物(對照例A6)，以與實施例A33~A38同樣的方式調查ED-71的殘存率。 Furthermore, ED-71 prepared without using an additive solution was dissolved in an EtOH solution, and each was dispensed into a 1 mL glass tube so that the amount of the original drug of ED-71 became 3 μg, and then the solvent was distilled off under reduced pressure to obtain a vacuum-dried composition. (Comparative Example A6), the survival rate of ED-71 was investigated in the same manner as in Examples A33 to A38.

結果示於第A10表。由第A10表清楚可知，ED-71於高溫條件下，即使為任一添加比例，相較於單獨的情況，與羥丙基甲基纖維素或美洛明的共存下為更安定。再者，可觀察到添加劑的添加比例越高，ED-71殘存率越高的傾向。 The results are shown in Table A10. It can be clearly seen from Table A10 that under high temperature conditions, ED-71 is more stable in the coexistence of hydroxypropyl methylcellulose or melomin, even at any addition ratio, than alone. Furthermore, it was observed that the higher the addition ratio of the additive, the higher the ED-71 remaining rate tended to be.

實施例A39~A41 Embodiment A39~A41

使用EtOH替代實施例A33~A38的70v/v%EOH，且使用水溶性高分子之聚乙烯基吡咯烷酮(K-30，BASF)替代羥丙基甲基纖維素或美洛明作為添加劑，以與實施例A33~A38同樣的方法製得ED-71組合物(實施例A39~A41)。該等樣品中的ED-71於60℃的安定性與實施例A33~A38同樣方式調查。結果示於第A11表。ED-71於高溫條件下，即使為任一添加比例，相較於單獨的情況，與聚乙烯基吡咯烷酮的共存下為更安定。再者，可觀察到添加劑的添加比例越高，ED-71殘存率越高的傾向。 Use EtOH to replace the 70v/v%EOH of Examples A33~A38, and use polyvinylpyrrolidone (K-30, BASF) of a water-soluble polymer to replace hydroxypropyl methylcellulose or melomin as an additive, to be compatible with Embodiment A33～A38 same method makes ED-71 composition (embodiment A39～A41). The stability of ED-71 in these samples at 60°C was investigated in the same manner as in Examples A33-A38. The results are shown in Table A11. Under high temperature conditions, ED-71 is more stable in the coexistence of polyvinylpyrrolidone than alone, even at any addition ratio. Furthermore, it was observed that the higher the addition ratio of the additive, the higher the ED-71 remaining rate tended to be.

Figure 106146225-A0305-02-0036-48
Figure 106146225-A0305-02-0036-48
Figure 106146225-A0305-02-0037-49
Figure 106146225-A0305-02-0037-49

Figure 106146225-A0305-02-0037-50
Figure 106146225-A0305-02-0037-50

Figure 106146225-A0305-02-0037-51
Figure 106146225-A0305-02-0037-51
Figure 106146225-A0305-02-0038-52
Figure 106146225-A0305-02-0038-52

B. 油分散體 B. Oil dispersion

實施例B1：調配變化1 Example B1: Deployment Variation 1

使50mg的ED-71溶解於2.5mL的EtOH，調製ED-71的乙醇溶解液。將BHT(Merck)1g及dl-α-生育酚(特殊用，和光純藥工業)2g，溶解於97g的MCT(O.D.O.C，日清Oillio)中調製MCT液。所調製的MCT液中加入ED-71的乙醇溶解液0.5mL，以漩渦混合機攪拌。進一步於減壓下餾除，調製ED-71油脂溶液。所調製的ED-71油脂溶液150mg中加入羥丙基甲基纖維素300mg，調製ED-71組合物(實施例B1)。所調製的ED-71組合物於大氣存在下保存於經調整為60℃的恆溫槽內，14日後及28日後調查ED-71殘存率(%)。 50 mg of ED-71 was dissolved in 2.5 mL of EtOH to prepare an ethanol solution of ED-71. Dissolve 1 g of BHT (Merck) and 2 g of dl- α -tocopherol (for special use, Wako Pure Chemical Industry) in 97 g of MCT (ODOC, Nissin Oillio) to prepare MCT solution. Add 0.5 mL of ED-71 ethanol solution to the prepared MCT solution, and stir with a vortex mixer. Further distilled off under reduced pressure to prepare ED-71 oil solution. 300 mg of hydroxypropylmethylcellulose was added to 150 mg of the prepared ED-71 oil solution to prepare an ED-71 composition (Example B1). The prepared ED-71 composition was stored in a thermostat adjusted to 60° C. in the presence of air, and the remaining rate (%) of ED-71 was investigated after 14 days and 28 days.

作為對照物係使用上述ED-1油脂溶液單獨(對照例B1)。 As a control system, the above-mentioned ED-1 oil solution was used alone (comparative example B1).

再者，使用第B1表記載的添加劑(300mg)替代實施例B1的羥丙基甲基纖維素，以與實施例B1同樣的方法製作ED-71組合物，與實施例B1同樣的方式調查60℃的安定性。 Furthermore, using the additive (300 mg) described in Table B1 instead of the hydroxypropyl methylcellulose in Example B1, the ED-71 composition was prepared in the same manner as in Example B1, and the investigation was carried out in the same manner as in Example B1. ℃ stability.

結果示於第B1表。由第B1表清楚可知，實施例B1的組合物與對照例B1的油脂液單獨為同等或其以上的安定，再者，相較於對照例B2~B34的組合物，於高溫條件下為安定。 The results are shown in Table B1. It can be clearly seen from Table B1 that the composition of Example B1 and the oil solution of Comparative Example B1 alone are stable at the same level or above. Furthermore, compared with the compositions of Comparative Examples B2~B34, they are stable under high temperature conditions. .

Figure 106146225-A0305-02-0038-53
Figure 106146225-A0305-02-0038-53
Figure 106146225-A0305-02-0039-54
Figure 106146225-A0305-02-0039-54

Figure 106146225-A0305-02-0039-55
Figure 106146225-A0305-02-0039-55
Figure 106146225-A0305-02-0040-56
Figure 106146225-A0305-02-0040-56

Figure 106146225-A0305-02-0040-57
Figure 106146225-A0305-02-0040-57

實施例B2：調配變化2 Example B2: Deployment Variation 2

使用第B2表記載的添加劑替代實施例B1的羥丙基甲基纖維素，以與實施例B1同樣的方法，製作實施例B2及對照例B35的ED-71組合物，與實施例B1同樣的方式調查60℃的安定性，與對照例B1比較。結果示於第B2表。實施例B2的組合物與對照例B1為同等或其以上的安定，再者，相較於第B1表所示的對照例B2~B34的組合物於高溫條件下顯示安定。又，雖然對照例35的組合物中未觀察到ED-71的安定性降低，但由於使用美洛明作為添加劑的情況，於後述的油分散體錠劑的製造過程中，無法維持必要的乳化狀態等理由，判定美洛明不適合作為油分散體錠劑製造用添加劑。 Use the additive described in the table B2 to replace the hydroxypropyl methylcellulose of embodiment B1, with the same method as embodiment B1, make the ED-71 composition of embodiment B2 and comparative example B35, same as embodiment B1 Investigate the stability at 60°C by way of comparison with Control Example B1. The results are shown in Table B2. The composition of Example B2 is as stable as or more stable than that of Comparative Example B1, and moreover, compared with the compositions of Comparative Examples B2 to B34 shown in Table B1, it is stable under high temperature conditions. Also, although no decrease in the stability of ED-71 was observed in the composition of Comparative Example 35, due to the use of melomin as an additive, the necessary emulsification could not be maintained during the production of oil dispersion tablets described later. Due to the state and other reasons, it is judged that melomin is not suitable as an additive for the manufacture of oil dispersion lozenges.

Figure 106146225-A0305-02-0041-58
Figure 106146225-A0305-02-0041-58

[試驗例]乳化物安定化試驗 [Test Example] Emulsion Stabilization Test

如後述方式，油分散體錠劑的製造過程中，必需維持ED-71的MCT溶液與水溶性高分子的水溶液的乳化狀態。此處，調製MCT與水溶性高分子的乳化液，調查乳化狀態。 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 during the production of oil dispersion tablets. Here, an emulsion of MCT and a water-soluble polymer was prepared, and the emulsified state was investigated.

將HPMC(TC-5R，信越化學)、HPC(SSL，信越化學)、PVP(K90，BASF)、POVA-COAT(F，大同化成工業製)溶解於精製水，個別調製2%及5%的水溶液。各液20mL個別加至塑膠製的50mL離心管。對其加入各10mL的以0.1g/L溶解的油紅(Oil red O，Nacalai Tesque)著色為紅色之中鏈脂肪酸三酸甘油酯。 Dissolve HPMC (TC-5R, Shin-Etsu Chemical), HPC (SSL, Shin-Etsu Chemical), PVP (K90, BASF), POVA-COAT (F, Daido Chemical Co., Ltd.) in purified water, and prepare 2% and 5% aqueous solution. Add 20mL of each solution to a 50mL centrifuge tube made of plastic. To this was added 10 mL each of Oil red (Oil red O, Nacalai Tesque) dissolved at 0.1 g/L to be colored in red medium-chain fatty acid triglycerides.

以均質機於約10,000rpm攪拌1分鐘使其乳化後，判定2小時後及24小時後的 乳化液的上部的油層分離的有無。 Stir at about 10,000rpm with a homogenizer for 1 minute to emulsify, and determine the 2 hours and 24 hours after Presence or absence of oil layer separation in the upper part of the emulsion.

結果示於第B3表。再者，使用水溶性高分子的2%水溶液時之24小時候的離心管內的乳化狀態(照相)示於圖2。相對於HPMC、HPC、及PVA共聚物中不產生水層與油層的分離，PVP則產生分離。 The results are shown in Table B3. Furthermore, the emulsified state (photograph) in the centrifuge tube at 24 hours when using a 2% aqueous solution of a water-soluble polymer is shown in FIG. 2 . Compared with HPMC, HPC, and PVA copolymers, there is no separation of water layer and oil layer, but PVP produces separation.

Figure 106146225-A0305-02-0042-59
Figure 106146225-A0305-02-0042-59

-：不分離，+：分離 -: no separation, +: separation

實施例B3~B11：乳化物調製時之ED-71的安定性 Examples B3~B11: Stability of ED-71 during emulsion preparation

將100mg的ED-71溶解於5.0mL的EtOH，調製ED-71的乙醇溶解液。將BHT(Merck)1g及dl-α-生育酚(特殊用，和光純藥工業)2g，溶解於97g的MCT(O.D.O.C，日清Oillio)中，調製MCT液。所調製的MCT液中加入ED-71的乙醇溶解液0.5mL，以漩渦混合機攪拌，作為ED-71溶解MCT液。分別調製示於第B4表的水溶性高分子溶液。以第B5表記載的比例混合ED-71溶解MCT液及水溶性高分子溶液，使用均質機以5400rpm攪拌1分鐘使其乳化，調製含有ED-71的乳化物。所調製的含有ED-71的乳化物以作為ED-71原藥量成為1μg的方式秤取，以真空乾燥機減壓餾除，所得樣品使用於殘存率測定(實施例B3~B11)。樣本於大氣存在下保存於經調整為60℃的恆溫槽內，調查調製後即刻的ED-71含量值、14日後及25日後的ED-71含量值及殘存率(%)。又，各含量值係將ED-71溶解MCT液以作為ED-71原藥量成為1μg的方式秤取，以經真空乾燥機餾除的樣品作為標準品算出。ED-71的含量值及殘存率，係經由以下的計算式求出。 100 mg of ED-71 was dissolved in 5.0 mL of EtOH to prepare an ethanol solution of ED-71. Dissolve 1 g of BHT (Merck) and 2 g of dl- α -tocopherol (for special use, Wako Pure Chemical Industries) in 97 g of MCT (ODOC, Nissin Oillio) to prepare an MCT solution. To the prepared MCT solution, 0.5 mL of ethanol solution of ED-71 was added, stirred with a vortex mixer, and dissolved as ED-71 MCT solution. The water-soluble polymer solutions shown in Table B4 were prepared respectively. Mix ED-71-dissolved MCT solution and water-soluble polymer solution at the ratio described in Table B5, stir at 5400 rpm for 1 minute to emulsify using a homogenizer, and prepare an emulsion containing ED-71. The prepared emulsion containing ED-71 was weighed so that the amount of the original drug of ED-71 was 1 μg, distilled off under reduced pressure in a vacuum dryer, and the obtained samples were used for the determination of the residual rate (Examples B3 to B11). The samples were stored in a thermostat adjusted to 60°C in the presence of the atmosphere, and the ED-71 content immediately after preparation, 14 and 25 days later, and the remaining rate (%) of ED-71 were investigated. In addition, each content value calculated|required that the ED-71 dissolved MCT liquid was weighed so that the amount of ED-71 raw material might become 1 microgram, and the sample distilled off by the vacuum dryer was used as a standard substance. The content value and remaining rate of ED-71 were calculated|required by the following calculation formula.

ED-71的含量值(%)=樣本中的ED-71面積合計/標準品中的ED-71峰面積合計(ED-71峰面積合計=ED-71峰面積+1.98×pre ED-71的峰面積) The content value of ED-71 (%)=the total area of ED-71 in the sample/the total peak area of ED-71 in the standard (the total peak area of ED-71=the peak area of ED-71+1.98×pre ED-71 Peak area)

ED-71的殘存率(%)=加速樣本中的含量值平均/調製後即刻的樣本的含量值平均 Survival rate of ED-71 (%) = average content value in accelerated samples/average content value of samples immediately after modulation

結果示於第B5表。由第B5表可知，水溶性高分子的濃度低的配方(1%)中，ED-71的含量值的偏差大。咸信原因在於水溶性高分子的濃度低的配方中，可觀察到調製後乳化物的分離，取樣的乳化物中的ED-71的秤取量可觀察到偏差。水溶性高分子的濃度為5%或6%的樣品中，結果的偏差小，且25日後的ED-71殘存率為任一者皆顯示95%以上。水溶性高分子的濃度高的配方(10%或15%)中雖然偏差小，但25日後的樣品中ED-71殘存率降低為90%前後。 The results are shown in Table B5. It can be seen from Table B5 that the ED-71 content has a large variation in the formulation with a low concentration of water-soluble polymer (1%). The cause is believed to be that in formulations with a low concentration of the water-soluble polymer, separation of the emulsion after preparation was observed, and deviations were observed in the weighed amount of ED-71 in the sampled emulsion. In samples with a water-soluble polymer concentration of 5% or 6%, the variation in the results was small, and the ED-71 residual rate after 25 days was 95% or higher for either. In the formulation with a high concentration of water-soluble polymer (10% or 15%), although the deviation was small, the residual rate of ED-71 in the sample after 25 days decreased to around 90%.

作為含有1%~15%HPMC或HPC的水溶性高分子溶液的濃度，5~6%於ED-71的乳化物中的安定化之故為較佳。 As the concentration of the water-soluble polymer solution containing 1%~15% HPMC or HPC, 5~6% in the emulsion of ED-71 is better for stabilization.

Figure 106146225-A0305-02-0043-60
Figure 106146225-A0305-02-0043-60

Figure 106146225-A0305-02-0043-61
Figure 106146225-A0305-02-0043-61
Figure 106146225-A0305-02-0044-63
Figure 106146225-A0305-02-0044-63

[製造例]油分散體錠劑 [Manufacturing example] Oil dispersion tablet

將dl-α-生育酚(和光純藥工業)0.142kg及BHT(Merck)0.284kg溶解於MCT(日清Oillio)9.025kg，對其加入艾地骨化醇(Eldecalcitol)(ED-71)1.1813g之乙醇(99.5%)(今津藥品工業)(0.078kg)溶液後，減壓下餾除乙醇(溶液1)。 Dissolve 0.142 kg of dl-α-tocopherol (Wako Pure Chemical Industry) and 0.284 kg of BHT (Merck) in 9.025 kg of MCT (Nissin Oillio), and add 1.1813 kg of Eldecalcitol (ED-71) to it g of ethanol (99.5%) (Imazu Pharmaceutical Co., Ltd.) (0.078kg) solution, and distill off ethanol under reduced pressure (solution 1).

將Hypromellose(HPMC)(TC-5R，信越化學工業)1.134kg溶解於精製水17.766kg(溶液2)。 1.134 kg of Hypromellose (HPMC) (TC-5R, Shin-Etsu Chemical Co., Ltd.) was dissolved in 17.766 kg of purified water (solution 2).

3kg的溶液1中加入6kg的溶液2，以均質機(IKA~T-50 Ultra Turrax；迴轉數 9600rpm)攪拌10分鐘。此操作重複3次獲得乳化液。 Add 6kg of solution 2 to 3kg of solution 1, and use a homogenizer (IKA~T-50 Ultra Turrax; number of revolutions) 9600rpm) stirring for 10 minutes. This operation was repeated 3 times to obtain an emulsion.

經以篩孔850μm的振動器過篩的甘露醇(Merck)165.6kg於高速攪拌造粒機(POWREX製VG-600CT)中，以槳葉56rpm、十字螺桿1500rpm的條件，邊攪拌下，邊噴霧添加乳化液，練合15分鐘，獲得造粒末。 Mannitol (Merck) 165.6 kg sieved by a vibrator with a mesh size of 850 μm was sprayed while stirring in a high-speed stirring granulator (VG-600CT manufactured by POWREX) under the conditions of 56 rpm of the paddle and 1500 rpm of the cross screw. Add emulsified liquid, knead for 15 minutes, and obtain granulated powder.

所得造粒末，於設置9.5mm(方孔)之篩之濕式整粒機(POWREX製U-20)以300rpm運轉同時過篩，移~流動層造粒乾燥機(POWREX製WSG-200pro)，乾燥。 The obtained granulated powder is sieved in a wet granulator (U-20 manufactured by POWREX) with a sieve of 9.5 mm (square hole) while running at 300 rpm, and transferred to a fluidized bed granulation dryer (WSG-200pro manufactured by POWREX) ,dry.

對於經乾燥的造粒末，於經設置直徑2mm的篩之乾式整粒機(POWREX製U-20)以800rpm運轉，整粒。 The dried granulated powder was sized by operating at 800 rpm in a dry granulator (U-20 manufactured by POWREX) provided with a sieve with a diameter of 2 mm.

整粒品係各別以篩孔850μm的篩過篩之甘露醇3.0kg及交聯羧甲基纖維素鈉(DFE pharma)3.6kg的混合物混合15分鐘，進一步地，各別與以孔徑850μm的篩過篩之甘露醇6.6kg及硬脂酸鈣(Merck)0.72kg的混合物混合3分鐘後，以約7.5kN的壓力，於打錠機(IMA製COMPRIMA)打錠作為錠劑。打錠時，以每1錠的艾地骨化醇含量成為0.75μg的方式調整錠劑重量。 The whole grain strains were respectively mixed with a mixture of 3.0 kg of mannitol and 3.6 kg of croscarmellose sodium (DFE pharma) sieved through a sieve with a sieve of 850 μm for 15 minutes, and further, respectively mixed with a sieve with a sieve of 850 μm A mixture of 6.6 kg of mannitol sieved and 0.72 kg of calcium stearate (Merck) was mixed for 3 minutes, and then tableted in a tableting machine (COMPRIMA manufactured by IMA) with a pressure of about 7.5 kN as lozenges. When tableting, the weight of the tablet was adjusted so that the content of idecalcitol per one tablet became 0.75 μg.

所得錠劑全部投入包覆機(POWREX製PRC-450)內，於60℃，噴霧HPMC 6.480kg的水(74.520kg)溶液後乾燥，進一步地，噴霧Hypromellose 4.950kg、滑石(Merck)1.350kg、氧化鈦(石原產業)2.644kg、及三氧化二鐵(癸巳化成)0.036kg的水(65.167kg)懸濁液後乾燥，獲得2層膜包覆的錠劑(每1錠的艾地骨化醇含量為0.75μg)。 All the tablets obtained were put into a coating machine (PRC-450 manufactured by POWREX), and dried after spraying 6.480 kg of HPMC in water (74.520 kg) solution at 60° C. Titanium oxide (Ishihara industry) 2.644kg, and the water (65.167kg) suspension liquid of 0.036kg of ferric oxide (Kaisi chemical industry) is dried after, obtains the lozenge (every 1 lozenge of idecalcification of 1 lozenge) of coating Alcohol content is 0.75 μg).

又，調製每1錠的艾地骨化醇含量為0.5μg的錠劑時，第2層為Hypromellose 4.950kg、滑石(Merck)1.350kg、氧化鈦(石原產業)2.502kg、三氧化二鐵(癸巳化成)0.018kg、及黃色三氧化二鐵(癸巳化成)0.180kg的水(65.167kg)懸濁液噴霧包覆。 Also, when preparing a lozenge with an idecalcitol content of 0.5 μg per lozenge, the second layer was composed of 4.950 kg of Hypromellose, 1.350 kg of talc (Merck), 2.502 kg of titanium oxide (Ishihara Sangyo), and 2.502 kg of ferric oxide ( The water (65.167kg) suspension of 0.018kg of Guisi Chemical Industry) and 0.180kg of yellow ferric oxide (Kuisi Chemical Industry) was spray coated.

製造流程概略圖示於圖1。 A schematic diagram of the manufacturing process is shown in Fig. 1 .

[試驗例]加速安定性試驗 [Test example] Accelerated stability test

『[製造例]油分散體錠劑』中所得錠劑(每1錠的艾地骨化醇含量為0.5μg及0.75μg之2種類)於高密度聚乙烯瓶容器(NC-130，伸晃化學)各投入500錠。以聚丙烯蓋(SK-200B，伸晃化學)將瓶栓閉，保存於經調整為40℃/75%RH的恆溫槽內，1個月後、3個月後、及6個月後調查ED-71殘存率。 Tablets obtained in "[Manufacturing Example] Oil Dispersion Tablets" (two types with idecalcitol content of 0.5 μg and 0.75 μg per tablet) were placed in high-density polyethylene bottle containers (NC-130, Shinko Chemical Co., Ltd. ) into 500 ingots each. Close the bottle with a polypropylene cap (SK-200B, Shinko Chemical), store it in a constant temperature tank adjusted to 40°C/75%RH, and investigate ED after 1 month, 3 months, and 6 months -71 survival rate.

ED-71的殘存率，係經由以下的方法測定。 The survival rate of ED-71 was measured by the following method.

將錠劑5錠投入30mL的離心管。加入水：乙腈(20：80)7mL後超音波照射30分鐘。超音波照射中，每10分鐘進行1次攪拌。上清部分以孔徑0.2μm的聚四氟乙烯(PTFE)膜過濾，廢棄最初的約1mL，其餘的濾液作為樣本溶液。另外，使用ED-71標準品，以成為約0.6μg/mL的濃度的方式以水：乙腈(20：80)溶解，與樣品溶液的調製為同樣的方法調製標準溶液。樣本溶液及標準溶液以高速液體層析法(Waters製Alliance，測定波長265nm)測定，求出樣本中ED-71的含量。 Put 5 lozenges into a 30mL centrifuge tube. After adding water: acetonitrile (20:80) 7mL, ultrasonic irradiation was performed for 30 minutes. During ultrasonic irradiation, stirring was performed every 10 minutes. The supernatant was filtered through a polytetrafluoroethylene (PTFE) membrane with a pore size of 0.2 μm, the first about 1 mL was discarded, and the remaining filtrate was used as the sample solution. In addition, using ED-71 standard substance, it dissolved in water: acetonitrile (20:80) so that the concentration may become about 0.6 microgram/mL, and prepared the standard solution by the same method as preparation of the sample solution. The sample solution and standard solution were measured by high-speed liquid chromatography (Alliance manufactured by Waters, measurement wavelength: 265 nm), and the content of ED-71 in the sample was determined.

經由以下的計算式求出ED-71的殘存率。 The survival rate of ED-71 was calculated|required by the following calculation formula.

ED-71的殘存率(%)=相對於表示量之加速樣品中的ED-71含量比(%)/相對於表示量之未加速樣品中的ED-71含量比(%)×100 Residual rate of ED-71 (%) = ED-71 content ratio in the accelerated sample relative to the indicated amount (%) / ED-71 content ratio in the non-accelerated sample relative to the indicated amount (%) × 100

又，表示量意指每一錠中企圖含有的ED-71的重量(0.5μg或0.75μg)。 In addition, the indicated amount means the weight (0.5 μg or 0.75 μg) of ED-71 intended to be contained in one tablet.

Figure 106146225-A0305-02-0046-64
Figure 106146225-A0305-02-0046-64

『[製造例]油分散體錠劑』中所得錠劑，於ICH規範(Q1A)所規定的加速條件中，顯示為安定。 The tablet obtained in "[Manufacture Example] Oil dispersion tablet" showed stability under the accelerated conditions stipulated in the ICH specification (Q1A).

[產業上可利用性] [industrial availability]

根據本發明，可使ED-71的分解受到抑制，提供軟膠囊以外的劑型的ED-71製劑。 According to the present invention, the decomposition of ED-71 can be suppressed, and ED-71 preparations in dosage forms other than soft capsules can be provided.

Figure 106146225-A0305-02-0001-1
Figure 106146225-A0305-02-0001-1

Claims (12)

一種抑制ED-71的氧化的方法，包含調製於溶劑中含有(5Z,7E)-(1R,2R,3R)-2-(3-羥基丙氧基)-9,10-開環膽甾-5,7,10(19)-三烯-1,3,25-三醇(ED-71)與水溶性高分子、鹼性化合物、磺基丁基醚-β-環糊精、蔗糖脂肪酸酯、2-羥丙基-β-環糊精、或卵磷脂粉末的混合溶液的步驟，以及由所得混合溶液去除溶劑的步驟。 A method for inhibiting the oxidation of ED-71, comprising preparing (5Z,7E)-(1R,2R,3R)-2-(3-hydroxypropoxy)-9,10-cyclocholesterol- 5,7,10(19)-triene-1,3,25-triol (ED-71) and water-soluble polymer, basic compound, sulfobutyl ether-β-cyclodextrin, sucrose fatty acid a step of a mixed solution of ester, 2-hydroxypropyl-β-cyclodextrin, or lecithin powder, and a step of removing the solvent from the resulting mixed solution. 如申請專利範圍第1項所述之方法，其中，ED-71與水溶性高分子、鹼性化合物、磺基丁基醚-β-環糊精、蔗糖脂肪酸酯、2-羥丙基-β-環糊精、或卵磷脂粉末的重量比係1：50~1：5000。 The method described in Item 1 of the scope of the patent application, wherein ED-71 is mixed with water-soluble polymers, basic compounds, sulfobutyl ether-β-cyclodextrin, sucrose fatty acid ester, 2-hydroxypropyl- The weight ratio of β-cyclodextrin or lecithin powder is 1:50~1:5000. 如申請專利範圍第1或2項所述之方法，其中，水溶性高分子選擇自羥丙基甲基纖維素、聚氧乙烯聚氧丙烯二醇、聚乙二醇、聚乙烯基己內醯胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物、甲基丙烯酸胺基烷基酯共聚物、羥丙基纖維素、乙基纖維素、聚乙烯基吡咯烷酮、聚維酮(copovidone)、聚氧乙烯硬化蓖麻油、D-α-生育酚聚乙二醇琥珀酸、糊精、阿拉伯膠、羥丙基甲基纖維素-乙酸琥珀酸酯、鹼處理明膠、甲基纖維素、聚乙烯醇、聚乙烯醇‧丙烯酸‧甲基丙烯酸甲酯共聚物、α化澱粉、及羥乙基纖維素，鹼性化合物選擇自美洛明、L-精胺酸、及焦磷酸四鉀。 The method described in item 1 or 2 of the scope of the patent application, wherein the water-soluble polymer is selected from hydroxypropyl methylcellulose, polyoxyethylene polyoxypropylene glycol, polyethylene glycol, polyvinyl caprolactam Amine-polyvinyl acetate-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer, hydroxypropyl cellulose, ethyl cellulose, polyvinylpyrrolidone, povidone (copovidone), Polyoxyethylene hardened castor oil, D-alpha-tocopherol macrogol succinate, dextrin, gum arabic, hydroxypropylmethylcellulose-acetate succinate, alkali-treated gelatin, methylcellulose, polyethylene Alcohol, polyvinyl alcohol‧acrylic acid‧methyl methacrylate copolymer, alpha starch, and hydroxyethyl cellulose, and the basic compound is selected from melomin, L-arginine, and tetrapotassium pyrophosphate. 一種醫藥組合物，其係包含ED-71之醫藥組合物，係藉由調製於溶劑中含有ED-71及水溶性高分子、鹼性化合物、磺基丁基醚-β-環糊精、蔗糖脂肪酸酯、2-羥丙基-β-環糊精、或卵磷脂粉末的混合溶液，由該混合溶液去除溶劑所製造者，其中，水溶性高分子選擇自羥丙基甲基纖維素、聚氧乙烯聚氧丙烯二醇、聚乙二醇、聚乙烯基己內醯胺-聚乙酸乙烯酯-聚乙二醇接枝共聚物、甲基丙烯酸胺基烷基酯共聚物、羥丙基纖維素、乙基纖維素、聚乙烯基吡咯烷酮、聚維酮(copovidone)、聚氧乙烯硬化蓖麻油、D-α-生育酚聚乙二醇琥珀酸、糊精、 阿拉伯膠、羥丙基甲基纖維素-乙酸酯琥珀酸酯、鹼處理明膠、甲基纖維素、聚乙烯醇、聚乙烯醇‧丙烯酸‧甲基丙烯酸甲酯共聚物、α化澱粉、及羥乙基纖維素，鹼性化合物選擇自美洛明、L-精胺酸、及焦磷酸四鉀。 A pharmaceutical composition, which is a pharmaceutical composition containing ED-71, by preparing a solvent containing ED-71 and a water-soluble polymer, a basic compound, sulfobutyl ether-β-cyclodextrin, sucrose A mixed solution of fatty acid ester, 2-hydroxypropyl-β-cyclodextrin, or lecithin powder, manufactured by removing the solvent from the mixed solution, wherein the water-soluble polymer is selected from hydroxypropylmethylcellulose, Polyoxyethylene polyoxypropylene glycol, polyethylene glycol, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, aminoalkyl methacrylate copolymer, hydroxypropyl Cellulose, ethyl cellulose, polyvinylpyrrolidone, copovidone, polyoxyethylene hardened castor oil, D-alpha-tocopherol macrogol succinate, dextrin, Gum Arabic, hydroxypropylmethylcellulose-acetate succinate, alkali-treated gelatin, methylcellulose, polyvinyl alcohol, polyvinyl alcohol‧acrylic acid‧methyl methacrylate copolymer, alpha starch, and Hydroxyethyl cellulose, alkaline compound selected from melomin, L-arginine, and tetrapotassium pyrophosphate. 如申請專利範圍第4項所述之醫藥組合物，其中，ED-71與水溶性高分子、鹼性化合物、磺基丁基醚-β-環糊精、蔗糖脂肪酸酯、2-羥丙基-β-環糊精、或卵磷脂粉末的重量比係1：50~1：5000。 The pharmaceutical composition as described in Item 4 of the scope of the patent application, wherein ED-71 is mixed with water-soluble polymers, basic compounds, sulfobutyl ether-β-cyclodextrin, sucrose fatty acid ester, 2-hydroxypropyl The weight ratio of base-β-cyclodextrin or lecithin powder is 1:50~1:5000. 一種方法，其係包含ED-71的醫藥組合物之製造方法，該方法包含調製包含ED-71的油脂溶液與水溶性高分子的水溶液之水中油型乳化液的步驟，使水中油型乳化液附著或吸附於賦形劑的步驟，以及使水中油型乳化液乾燥的步驟，其中，前述水溶性高分子選擇自羥丙基甲基纖維素及羥丙基纖維素。 A method, which is a method for producing a pharmaceutical composition comprising ED-71, the method comprising the step of preparing an oil-in-water emulsion comprising an oil solution of ED-71 and an aqueous solution of a water-soluble polymer, and making the oil-in-water emulsion The step of attaching or adsorbing to the excipient, and the step of drying the oil-in-water emulsion, wherein the aforementioned water-soluble polymer is selected from hydroxypropylmethylcellulose and hydroxypropylcellulose. 如申請專利範圍第6項所述之方法，其中，水中油型乳化液與賦形劑的重量比為1：4~1：20。 The method described in item 6 of the patent application, wherein the weight ratio of the oil-in-water emulsion to the excipient is 1:4~1:20. 如申請專利範圍第6或7項所述之方法，其中，賦形劑係選自糖或糖醇類。 The method as described in claim 6 or 7, wherein the excipient is selected from sugars or sugar alcohols. 一種醫藥組合物，其係包含ED-71之醫藥組合物，其於賦形劑中或賦形劑表面包含以含有選擇自羥丙基甲基纖維素及羥丙基纖維素之水溶性高分子的被覆劑所被覆的粒子，該粒子包含ED-71的油脂溶液。 A pharmaceutical composition, which is a pharmaceutical composition comprising ED-71, which is contained in the excipient or on the surface of the excipient to contain a water-soluble polymer selected from hydroxypropylmethylcellulose and hydroxypropylcellulose The particles coated with the coating agent, the particles contain the oil solution of ED-71. 如申請專利範圍第9項所述之醫藥組合物，其為以HPMC膜所包覆的包覆錠。 The pharmaceutical composition as described in item 9 of the scope of the patent application is a coated tablet coated with HPMC film. 一種抑制ED-71分解之方法，包含調製包含ED-71的油脂溶液及水溶性高分子的水溶液所形成之水中油型乳化液的步驟，其中，前述水溶性高分子選擇自羥丙基甲基纖維素及羥丙基纖維素。 A method for inhibiting the decomposition of ED-71, comprising the step of preparing an oil-in-water emulsion formed by an oil solution containing ED-71 and an aqueous solution of a water-soluble polymer, wherein the aforementioned water-soluble polymer is selected from hydroxypropylmethyl Cellulose and hydroxypropyl cellulose. 如申請專利範圍第11項所述之方法，進一步包含將所得之水中油型乳化液進行乾燥的步驟。 The method described in claim 11 of the patent application further includes the step of drying the obtained oil-in-water emulsion.
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