WO2006075690A1 - Stable medicinal composition - Google Patents

Abstract

To provide a stable medicinal composition containing an EP4 agonist. An aqueous solution containing a dextrin clathrate of methyl 4-{[2-((1R,2R,3R)-3-hydroxy-2-{(1E,3S)-3-hydroxy-4-[3­(methoxymethyl)phenyl]but-1-enyl}-5-oxocyclopentyl)ethyl]­sulfanyl}butanoate, which has EP4 agonistic activity, is mixed with a sugar and optionally with a pH adjustor to regulate the pH to about 3-6.5. The mixture is then freeze-dried. The freeze-dried product obtained is stable during storage and generates no decomposition products. It is hence usable as a higher-quality preparation for injection in clinical practices.

Description

 Stable pharmaceutical composition

 Technical field

 [0001] The present invention relates to (1) methyl 4-{[2 — ((1R, 2R, 3R) -3 hydroxy 1 2- {(IE, 3S) -3 hydroxy 4- [3 (methoxymethyl) phenol] -L] buta-l} 5 oxocyclopentyl) ethyl] sulfar} butanoate, its solvate, or their inclusion compound, and (2) a saccharide, and optionally (3 The present invention relates to a stable pharmaceutical composition containing a pH regulator, a method for producing the same, and a use thereof.

 Background art

 [0002] Methyl 4— {[2— ((1R, 2R, 3R) — 3 Hydroxy 1 — {(IE, 3S) — 3 Hydroxy 4 — [3 (Methoxymethyl) phenol] buta 1 5} -oxocyclopentyl) ethyl] sulfar} butanoate is a compound known as a 5-thia ω-substituted phenyloop rostaglandin Ε derivative with EP4 activity Non-aqueous by dissolving, suspending or emulsifying in a sterile aqueous or non-aqueous solvent together with adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents and solubilizing agents. As an injection for oral administration, it is described that it is used as a prophylactic and acupuncture or therapeutic agent for various diseases such as bone loss diseases (International Publication No. 03980 pamphlet, International Publication No. 01 / 37877 pamphlet). These publications also include methyl 4-{[2— ((1R, 2R, 3R) -3 hydroxy-1- {(IE, 3S) -3 hydroxy-1-4- [3 (methoxymethyl) phenyl] Butter 1 ethyl} 5 oxocyclopentyl) ethyl] sulfar} Produces a sterile solid composition containing butanoate and sterilizes or uses it in sterile distilled water for injection or other solvents for use. It is stated that it may be done.

[0003] On the other hand, it is generally known that a compound having a prostaglandin E (PGE) -like structure is unstable to heat or the like and produces a decomposition product having a prostaglandin A (PGA) -like structure. It has been. Therefore, various techniques are used in pharmaceutical preparations containing compounds having a PGE-like structure (for example, PGE) in order to prevent the formation of PGA-like degradation products. The For example, JP-A-49 66816 discloses that vitamin C or citrate is added to an aqueous solution of cyclodextrin inclusion compound of PGE or cyclodextrin inclusion compound of PGE analog and frozen. A method for drying (see JP-A-49-0666816) Force JP-A-54-103844 describes a method for freeze-drying by adding oligosaccharides to cyclodextrin of PG or a PG-like compound or an aqueous solution of taenoic acid. (See Japanese Patent Laid-Open No. 54-103844). Further, for example, JP-A-57-156460 discloses a stabilizing composition comprising PG or a PG-like compound, cyclodextrin, and oligosaccharide (see JP-A-57-156460). JP-A-240835 describes a PGE1-containing injection composition (see JP-A-11-240835) in which PGE1 is dissolved in sodium citrate Z citrate buffer, sterile filtered and freeze-dried.

 [0004] Methyl 4— {[2— ((1R, 2R, 3R) — 3 Hydroxy 1 — {(IE, 3S) — 3 Hydroxy 4 — [3 (Methoxymethyl) phenol] buta 1 5} oxocyclopentyl) ethyl] sulfar} butanoate has a PGE-like structure in part, but includes the presence or absence of degradation products having a PGA-like structure. There was no report on its chemical stability, and the degradation product was completely unknown.

 [0005] The present inventors have proposed methyl 4-{[2 — ((1R, 2R, 3R) —3hydroxy—2 — {(IE, 3S) —3hydroxy—4— [3 (methoxymethyl) phenol- L] buta-l 1}} 5-oxocyclopentyl) ethyl] sulfar} Butanoate was studied to produce an injectable preparation. As a result, methyl 4-{[2— ((lR , 2R, 3R) — 3 Hydroxy 2 — {(1E, 33) —3—Hydroxy-4 [3- (methoxymethyl) phenyl] butter 1-5} -5-year-old cyclocyclopentyl) ethyl] sulfa In the case of an aqueous solution containing α-cyclodextrin inclusion compound of butanoate or a freeze-dried product manufactured by subjecting it to freeze-drying, a PGA-like structure is formed during the storage period, as in the case of PGE above. It is found that a decomposition product is produced, and in addition to that, a novel decomposition product such as a sulfoxide product is produced. I found it.

[0006] In general, pharmaceuticals are important in terms of safety and effectiveness, and their storage stability is important. Degradation of the main active substance during the storage period, and generation of degradation products accompanying it, should be suppressed as much as possible. It is said that. This means that methyl 4— {[2— ((1R, 2R, 3R) — 3 hydro Xyzy2 {(IE, 3S) — 3 Hydroxy-4 [3- (methoxymethyl) phenol] butter 1-5} -5-year-old xocyclopentyl) ethyl] sulfar} Butanoate The same applies to pharmaceutical preparations, and in order to use it as a pharmaceutical product, it was necessary to suppress the generation of the above-described degradation products during the storage period as much as possible.

[0007] Patent Document 1: International Publication No. 00Z03980 Pamphlet

 Patent Document 2: Pamphlet of International Publication No. 01Z37877

 Patent Document 3: Japanese Patent Laid-Open No. 49-0666816

 Patent Document 4: Japanese Patent Application Laid-Open No. 54-103844

 Patent Document 5: Japanese Patent Application Laid-Open No. 57-156460

 Patent Document 6: Japanese Patent Laid-Open No. 11-240835

 Disclosure of the invention

 Problems to be solved by the invention

[0008] An object of the present invention is to provide methyl 4 {[2 — ((1R, 2R, 3R) -3 hydroxy-2-{(1E, 3S) -3 hydroxy 4- [3 (methoxymethyl) phenol] buta — 1-Yel} 5--Oxocyclopentyl) ethyl] sulfanyl} butanoate is an active ingredient, and produces degradation products during storage, that is, the production of degradation products such as PGA-like structures and sulfoxides. An object of the present invention is to provide a high-quality pharmaceutical composition, particularly an injectable preparation, which is stable in terms of reduction, purity and form.

 Means for solving the problem

[0009] As a result of intensive studies to solve the above problems, the present inventors have found that methyl 4 — {[2— ((1R, 2R, 3R) — 3 hydroxy- 1 2 — {(IE, 3S ) -3 Hydroxy 4- [3 (Methoxymethyl) phenyl] butayl} 5 oxocyclopentyl) ethyl] sulfar} Butanoate _α -cyclodextrin inclusion compound and sugars If necessary, ρΗ adjuster is further added to the aqueous solution, ρΗ is adjusted to the range of about 3 to about 6.5, and the aqueous solution is subjected to lyophilization, thereby generating degradation products during the storage period. It was found that it can be provided as a controlled freeze-dried product. We found that it is possible to provide a stable composition with reduced degradation products by lowering the water content in the lyophilized product. Completed the invention. That is, the present invention

 [I] (1) Methyl 4— {[2— ((1R, 2R, 3R) — 3-Hydroxyl 2— {(IE, 3S) — 3-Hydroxy— 4— [3— (Methoxymethyl) -L] buta-1-ethyl} -5-oxocyclopentyl) ethyl] sulfanyl} butanoate, a solvate thereof, or an inclusion complex thereof, and (2) a saccharide, and if desired (3) a stable pharmaceutical composition comprising a pH regulator;

 [2] The composition according to [1], which is a freeze-dried product;

 [3] The composition according to [1], wherein the inclusion compound is an oc-cyclodextrin inclusion complex

[4] The composition according to [1], wherein the saccharide is lactose or maltose;

 [5] The composition according to the above [4], wherein the saccharide is maltose having a pH of 4.5 to 6.5;

 [6] Methyl 4— {[2— ((1R, 2R, 3R) — 3—Hydroxyl 2— {(IE, 3S) — 3—Hydroxy— 4— [3— (Methoxymethyl) phenol] But-1-ethyl} -5-oxocyclopentyl) ethyl] sulfar} butanoate 500 parts by weight to 500 parts by weight of saccharide per 1 part by weight

The composition according to [1] above, comprising 00 parts by weight;

 [7] The composition according to [1], wherein the pH regulator is one or more selected from organic acids, metal hydroxides, and organic acid metal salts;

 [8] The composition according to [7] above, wherein the pH regulator is (1) citrate and sodium hydroxide, or (2) citrate and sodium citrate;

 [9] (1) Methyl 4— {[2— ((1R, 2R, 3R) — 3-Hydroxy mono 2-— {(IE, 3S) — 3-Hydroxy— 4— [3— (Methoxymethyl) -Ru] buta-1-ethyl} -5-oxocyclopentyl) ethyl] sulfar} butanoate OC-cyclodextrin inclusion compound, and (2) maltose with a pH of 4.5 to 6.5, And (3) a stable pharmaceutical composition comprising citrate and sodium hydroxide;

[10] The composition according to the above [9], which is a freeze-dried product;

[II] Methyl 4— {[2— ((1R, 2R, 3R) — 3-Hydroxyl 2— {(IE, 3S) — 3-Hydoxyl 4-- [3— (Methoxymethyl) phenol ] but one 1-E - le} - 5-Okisoshikurobe pentyl) Echiru] sulfa -. _P H4 to Le} butanoate 1 part by weight of 5 to 6.5 malto The composition according to [9] above, comprising 1000 parts by weight to 10,000 parts by weight;

[12] Methyl 4— {[2— ((1R, 2R, 3R) — 3 Hydroxy 2— {(IE, 3S) — 3 Hydroxy 4 — [3 (Methoxymethyl) phenol] Pig 1 E - le} 5 Okisoshikurobe pentyl) Echiru] sulfa -. _P H4 to Le} butanoate 1 part by weight of 5 to 6. comprising a maltose of 5 contained 5000 parts by the [11] the composition according ;

 [13] The composition according to the above [2] or [10], which is substantially free of water or has a water content of 1% or less;

 [14] After storage at 60 ° C for 2 weeks, methyl 4 {[2 — ((1R, 2R, 3R) — 3 hydroxy

— 2— {(IE, 3S) — 3 Hydroxy 4— [3 (Methoxymethyl) phenol] buta 1

-Le} -5-year-old oxocyclopentyl) ethyl] sulfuryl} butanoate has a residual rate of 85

% Or more of the composition according to [2] or [10] above,

 [15] The stable composition according to [14], wherein the residual ratio is 95% or more;

 [16] After two weeks of storage at 60 ° C, the stable [2]

Or a composition according to [10];

 [17] The composition according to [1], [2], [9] or [10], which is a preparation for injection;

 [18] The above-mentioned [1], [2] which is a prevention, treatment and Z or progression inhibitor of EP4-mediated diseases

[9] or [10]

 [19] The composition of the above-mentioned [18], wherein the EP4-mediated disease is a bone disease;

[20] The composition according to [19] above, wherein the bone disease is vertebral fractures;

[21] An injection container filled with the composition according to [2] or [10] above;

[22] The container according to [21], which is a vial;

 [23] 1 g to 12 g of methyl 4 {[2 — ((1R, 2R, 3R) —3—hydroxy— 2— {(IE, 3S) — 3 hydroxy— 4— [3— (Methoxymethyl) phenol] butter 1-5} -5-year-old cyclocyclopentyl) ethyl] sulfur} butanoate

[24] 2 g, 5 ₈ , 6 g or 10 g of methylol 4— {[2— ((1R, 2R, 3R) — 3 hydroxy 1 2— {(IE, 3S) —3 hydroxy per unit form 1— [3- (methoxymethyl) phenyl] buter 1 ethyl} -5-year-old cyclocyclopentyl) ethyl] sulfur} The container according to the above [23], comprising butanoate;

 [25] (1) Methyl 4-{[2— ((lR, 2R, 3R) —3 Hydroxy-2- {(IE, 3S) — 3-Hydroxy mono 4-— [3 (Methoxymethyl) phenol] buta 1)} 5 oxocyclopentyl) ethyl] sulfanyl} butanoate, a solvate thereof, or an inclusion complex thereof, and (2) a saccharide, and if desired, (3) a pH regulator A method for producing a stable freeze-dried product, characterized by subjecting an aqueous solution having a pH of 3 to 6.5 to freeze-drying;

 [26] (1) Methyl 4— {[2— ((1R, 2R, 3R) — 3 Hydroxy— 2— {(IE, 3S) — 3— Hydroxy 4- [3 (methoxymethyl) phenol] 1-ethyl} 5 oxocyclopentyl) ethyl] sulfanyl} butanoate, its solvate, or inclusion complex thereof, and (2) a saccharide, and optionally (3) a pH regulator An aqueous solution having a pH of 3 to 6.5 containing lyophilized product is subjected to freeze-drying to obtain a freeze-dried product. Methyl 4— {[2— ((1R, 2R, 3R ) — 3 Hydroxy— 2— {(IE, 3S) — 3 —Hydroxy mono 4-— [3 (Methoxymethyl) phenol] butayl 1 5} 5 oxosyl oral pentyl) ethyl] sulfar} butanoate Stabilization method;

[27] Prevention or treatment of an EP4-mediated disease in a mammal, comprising administering an effective amount of the composition described in [1], [2], [9] or [10] to the mammal And Z or progression inhibition methods;

 [28] Use of the composition according to the above [1], [2], [9] or [10] for the prevention and treatment of EP4-mediated diseases and the manufacture of a Z or progression inhibitor;

[29] Per unit form (1) Methyl 4- {[2- ((lR, 2R, 3R) —3 Hydroxy-2 {(IE, 3S) 3 Hydroxy 4 [3 (Methoxymethyl) phenol] butter 1-ethyl} 5—year-old oxocyclopentyl) ethyl] sulfar} butanoate containing 1 μg to 20 g of methyl 4— {[2— ((1R, 2R, 3R) — 3 hydroxy 1 2— {(IE, 3S) — 3 Hydroxy— 4 — [3 (Methoxymethyl) phenol] butayl- 1}} 5 oxoclopentyl) ethyl] sulfuric} _α -cyclodextrin inclusion compound of butanoate, And (2) methyl 4— {[2— ((1R, 2R, 3R) — 3 hydroxy— 2— {(IE, 3S) — 3 hydroxy 1 4— [3 (methoxymethyl) phenol] butane 1 Yell} 5 oxo Cyclopentyl) ethyl] sulfar} butanoate A vial filled with a stable lyophilized product containing 1 to 10 parts by weight of lactose containing 1 to 10 parts by weight of lactose;

[30] Per unit form: (1) Methyl 4- {[2- ((lR, 2R, 3R) —3 Hydroxy-2 {(IE, 3S) 3 Hydroxy 4 [3 (methoxymethyl) phenol] butter 1-ethyl} 5--year-old xocyclopentyl) ethyl] sulfar} butanoate containing 10 μg of methyl 4-— {[2— ((1R, 2R, 3R) — 3 hydroxy 1 2— {(IE , 3S) — 3 Hydroxyl-4-— [3 (Methoxymethyl) phenol] buta-1-ethyl} 5-oxocyclopentyl) ethyl] sulfan} butanoate _α -cyclodextrin inclusion compound, and (2) Methyl 4— {[2— ((1R, 2R, 3R) — 3 Hydroxy 1 — {(IE, 3S) — 3 Hydroxy 4 — [3 (Methoxymethyl) phenol] buta 1 -Le} 5 oxocyclopentyl) ethyl] sulfar} butanoate Filled with a stable lyophilized product containing 5000 parts by weight of lactose and 1% by weight or less of water. 1er;

[31] (1) Methyl 4— {[2— ((1R, 2R, 3R) — 3 Hydroxy— 2— {(IE, 3S) — 3— Hydroxy 1 — [3 (Methoxymethyl) phenol] 1-ethyl} 5 oxocyclopentyl) ethyl] sulfanyl} butanoate, its solvate, or their inclusion complex, and (2) a saccharide, and optionally (3) a rhodium regulator An aqueous solution containing ρ Η of 3 to 6.5; and

 [32] Methyl 4— {[2— ((1R, 2R, 3R) — 3 Hydroxy 2— {(IE, 3S) — 3 Hydroxy 4 — [3 (Methoxymethyl) phenol] butane 1 mL} 5 oxocyclobenzoyl) ethyl] sulfar} butanoate in an aqueous solution according to [31] above, wherein the concentration is 3 μgZmL to 20 μg / mL;

Etc.

(1) Methyl 4— {[2— ((1R, 2R, 3R) — 3 Hydroxy— 2— {(IE, 3S) — 3 Hydroxy— 4— [3 (Methoxymethyl) phenol] 1-butyl} 5 oxocyclopentyl) ethyl] sulfuric} butanoate, its solvate, or their inclusion compounds, and (2) sugars, and optionally (3) pH adjustment A stable pharmaceutical composition containing an agent (hereinafter sometimes abbreviated as the composition of the present invention) is effective. Component Methyl 4- {[2- ((lR, 2R, 3R) — 3 Hydroxy— 2— {(IE, 3S) — 3 —Hydroxy 1 4-— [3 (Methoxymethyl) phenol] butane 1 5} Oxyl oral pentyl) ethyl] sulfar} butanoate (hereinafter sometimes abbreviated as 5-thia PG compound) and saccharides, and optionally a stable pH regulator The composition is not limited by the presence or absence of other additives, the presence or absence of a solvent, the shape of the composition (solid, liquid), etc., as long as it is a composition for medical use.

 [0012] The composition of the present invention is stable. In particular, since it is stable and excellent in both purity and form as described later using “purity stability” and “morphological stability”! It is preferably used as an injectable preparation. The form of the injectable preparation may be a liquid composition generally called a concentrated injection or a concentrated injection, or a solid composition such as a lyophilized product. In the present specification, an injectable preparation means an injectable precursor capable of preparing an injectable preparation that can be administered to a patient by using a solution and Z or a diluting solution at the time of use.

 [0013] When the composition of the present invention is a solid, an injection can be prepared using a diluent after preparing a high-concentration liquid using a solution. Of course, a high-concentration liquid prepared using a solution is also a composition of the present invention. On the other hand, when the composition of the present invention is a liquid, an injection can be prepared by diluting it directly with a diluent. Further, when the composition of the present invention is a liquid, it can be made into a solid composition (lyophilized product) of the present invention by subjecting the raw material to a treatment such as lyophilization. The composition of the present invention is preferably a solid composition, particularly a lyophilized product. In the present specification, the injection may be a liquid injection composition that can be administered parenterally directly to a patient. The injection prepared using the composition of the present invention may be in the form of, for example, an aqueous injection, a non-aqueous injection, a suspension injection, an emulsion injection, an infusion preparation, and the like. The prepared injection can be applied to tissues such as intramuscular, intradermal, subcutaneous, intravenous, intraarterial, intraabdominal, and spinal cord.

[0014] In the present invention, methyl 4-{[2 — ((1R, 2R, 3R) -3 hydroxy 1 2-{(1E, 3S) -3 hydroxy 4- [3 (methoxymethyl) phenol] buta — 1 ethyl} 5— oxocyclopentyl) ethyl] sulfar} butanoate has the formula (I) [0015] [Chemical 1]

 [0016] (where

[0017] [Chemical 2]

 ,,, ...

[0018] represents the α configuration,

[0019] [Chemical 3]

 /

 [0020] represents the j8—configuration. )

 It is a compound shown by these.

[0021] Examples of solvates of 5 thia PG compounds include solvates such as water and alcohol solvents (for example, ethanol). Solvates preferably have low toxicity and water solubility.

[0022] An inclusion complex of 5 thia PG compound or a solvate thereof is a compound obtained by inclusion of a 5 thia PG compound or a solvate thereof as a guest compound into a host compound. Means. Any host compound can be used without particular limitation as long as it is a compound capable of including a 5-thia PG compound or a solvate thereof. For example, monomolecular host compounds (for example, cyclodextrins, crowny compounds, cyclophanes, azacyclophanes, caric suarenes, cyclotriperatrilenes, swelands, capitands, cyclic oligopeptides, etc.), multimolecular host compounds (for example, ), Urea, thiourea, deoxycholic acid, perhydrotriphenylene, trio-thymotide, etc.), high molecular weight host compounds (for example, cellulose, denpun, chitin, chitosan, polyvinyl alcohol, etc.), inorganic host compounds Compound (for example, intercalation compound, zeolite, Hoffman complex, etc.) and the like can be mentioned. Among these host compounds, a monomolecular host compound, particularly a hydrophilic monomolecular host compound is preferred, and cyclodextrin is particularly preferred. Cyclodextrins include hicyclodextrin, 13 _{—Cyclodextrin} , _{Ί —Power} of three types of cyclodextrin In addition to these, some of their hydroxyl groups may be replaced with other functional groups such as alkyl groups, aryl groups, alkoxy groups, amide groups, sulfonic acid groups, etc. You may use the cyclodextrin derivative etc. which were changed into. As the host compound in the present invention, a-cyclodextrin is suitable.

 [0023] In the present invention, the 5 thia PG compound, its solvate, or the inclusion complex thereof is not limited to a substantially pure and single substance, and is acceptable as an active pharmaceutical ingredient. As long as it is within the range, it may contain impurities (for example, by-products derived from the production process, solvents, raw materials, etc., or decomposition products). The content of impurities acceptable as an active pharmaceutical ingredient varies depending on the impurities contained. For example, in the case of 5-thia PG compound a-cyclodextrin inclusion compound, the amount of each related substance is about 1 Preferably, the total amount of related substances is about 4.0% or less, and the water content is about 5.0% or less.

 [0024] 5 Thia PG compound or a solvate thereof may be obtained by a method known per se, for example, the method described in International Publication No. 00/03980, Comprehensive 'Organic' Transformation: A Guide · Thu ^ ~ · Functional · Group · Preparations Yon's, Second 'Edition (Richard C. Larock, John Wiley & Sons Inc., 1999) [Comprehensive Organic Transformations: A Lruide to Functi onal Group Preparations, 2nd Edition (Richard C. Larock , John Wiley

& Sons Inc., 1999)], etc., alone or in combination. In addition, the produced 5-thia mono PG compound or a solvate thereof is obtained by a conventional purification means such as distillation under normal pressure or reduced pressure, high performance liquid chromatography using silica gel or magnesium silicate, thin layer chromatography. It can be purified by mouth matography, column chromatography, washing, recrystallization or the like.

 [0025] The inclusion complex of 5 thia PG compound or a solvate thereof and a host compound is a method known per se from a 5-thia PG compound or a solvate thereof and a host compound. For example, it can be produced by subjecting it to the method described in British Patent Application Publication No. 1351238 and British Patent Application Publication No. 1419221.

[0026] In the present invention, the saccharide is a saccharide generally used in the manufacture of an injectable preparation. If there is no particular limitation, it can be used. For example, glucose, galactose, mannose, lactose, manoleose, palatinose, trenorose, raffinose, enorelose, melethyose and the like are preferred. For example, lactose, maltose and the like are more preferred. For example, maltose is particularly preferred. These saccharides may be crystalline or non-crystalline, and may be hydrated or anhydrous. In particular, these sugars listed in the Japanese Pharmacopoeia, such as lactose, can be 孚 L "'——Hydrogen (4—0— β-Galactopyranosyl- — D—glucopyranose monohydrate) or maltose. For example, maltose monohydrate (4-0- -D-Glucopyranosyl-β-D-glucopyranose monohydrate) is preferred.Manolethose 'monohydrate is sometimes referred to as crystalline manoletose. A maltose of 5 to 6.5 means a maltose in which a pH of a solution obtained by dissolving 1.0 g of maltose in 1 OmL of water is in the range of 4.5 to 6.5. The listed maltose (maltose 'monohydrate) is included in maltose at pH 4.5 to 6.5.

 [0027] The amount of saccharide added in the composition of the present invention is not particularly limited. For example, about 100 parts by weight to about 100000 parts by weight is preferable with respect to 1 part by weight of 5 thia PG compound. About 500 parts by weight to about 50000 parts by weight is more preferable, for example, about 1000 parts by weight to about 10,000 parts by weight is particularly preferable. In particular, it is preferable to cover about 5000 parts by weight of saccharide with respect to 1 part by weight of the 5-char PG compound. These saccharides may be used alone or in combination of two or more.

[0028] In the present invention, as the pH regulator, any pH regulator generally used in the production of injectable preparations can be used without particular limitation. For example, organic acids such as citrate, tartaric acid, oxalic acid, acetic acid, lactic acid (especially divalent or trivalent organic acids (for example, citrate, tartaric acid, oxalic acid, etc.)), for example, hydrochloric acid, phosphoric acid Inorganic acids such as sodium hydroxide, potassium hydroxide, metal hydroxides such as lithium hydroxide (especially hydroxides of alkali metals or alkaline earth metals), such as Organic acid metal salts such as sodium acid, potassium tartrate and sodium acetate (particularly alkali metal or alkaline earth metal salts of divalent or trivalent organic acids) and the like are preferable. These pH regulators may be used alone or in combination of two or more. In the present invention, for example, organic acid metal salts, organic acids, metal hydroxides, or combinations thereof are more preferable. A combination of an organic acid metal salt (such as sodium citrate) and an organic acid (such as citrate), a metal hydroxide (such as sodium hydroxide) and an organic acid (such as citrate) ) Is particularly preferred. In particular, a combination of a metal hydroxide (for example, sodium hydroxide and the like) and an organic acid (for example, citrate) is preferable.

[0029] The amount of the pH regulator added in the composition of the present invention is not particularly limited, but in order to make the composition of the present invention a stable composition, for example, when the composition of the present invention is a liquid, It is preferable to add so that the pH is in the range of about 3 to about 6.5, preferably about 3.5 to about 5, particularly preferably about 4. For example, when the composition of the present invention is a solid, the concentration of 5-thia PG compound is about 1 μg ZmL to about 50 gZmL, more preferably about 3 μg ZmL to about gZmL, and particularly preferably about gZmL to When dissolved with water for injection to a pH of about gZmL (for example, 10 gZO. 6 mL), the pH is about 3 to about 6.5, preferably about 3.5 to about 5, particularly preferably about 4 It is preferable to add an amount that falls within the above range.

[0030] In addition to the saccharides and pH adjusters described above, other additives generally used in the manufacture of injectable preparations may be appropriately added to the composition of the present invention. Examples of such additives include 70 v / v% N-hydroxyethyl lactamide aqueous solution, D sorbitol, D-mannitol, DL-methionine, L-aspartic acid, L-alanin, L-arginine, L-glutamic acid, L Lysine, potassium L-glutamate, sodium L-glutamate, L-cystine, L-cystine, L-histidine, L-methionine, N, N dimethinorea cetamide, ascorbic acid, acetiltliptophan sodium, aminoethyl sulfonic acid, amino acetic acid, gum arabic, Gum arabic powder, alphathioglycerin, albumin, inositol, ethanol, ethylurea, ethylenediamine, sodium edetate, sodium edetate, oleic acid, sodium sodium pellate, carmellose sodium, xylitol, que Disodium phosphate, glycerin, calcium dalconate, sodium dalconate, magnesium dalconate, creatine, chlorobutanol, gentisic acid ethanolamide, succinic acid, sesame oil, sodium chondroitin sulfate, sodium salicylate, diethanolamine, diethylenetriaminepentaacetic acid , Sorbitan sesquioleate, gelatin, gelatino-calyohydrolyzate, sorbitan fatty acid ester, soybean oil, thioglycolic acid, thioglycolic acid Sodium, potassium thiocyanate, sodium thiomalate, sodium thiosulfate, camellia oil, dextran 40, dextran 70, sodium desoxycholate, triethanolamine, sodium formaldehyde, sulfoxylate, nicotinamide, ethyl oxycarboxylate Ptyl parabenzoate, propyl paraoxybenzoate, methyl parabenzoate, hydroxypropylcellulose, castor oil, potassium pyrosulfite, sodium bisulphite, phenol, butylhydroxyl-sol, propylene glycol, heno << phosphate sodium, benzyl Alcohol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene Hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, polysorbate 80, macrogol 400, macrogol 4000, medalmine, sodium methanesulfobenzoate, monoethanolamine, aluminum monostearate, polyoxyl monolaurate Ethylene sorbitan (20E.O.), laccase oil, sodium sulfite, sodium hydrogen sulfite, benzoic acid, sodium benzoate, benzyl benzoate, salt-aluminum, sodium salt, sodium chloride, benzalkonium chloride, chloride Benzetonium, magnesium chloride, zinc chloride, zinc chloride solution, stannous chloride, ferric chloride, arginine hydrochloride, cysteine, lysine hydrochloride, fructose, dried aluminum gel, dried sodium sulfite, dilute hydrochloric acid, highly purified egg yolk lecithin , Calcium carbonate, zinc oxide, calcium bromide Um, sodium bromide, ammonium acetate, sodium acetate, zinc acetate, aluminum hydroxide, refined gelatin, refined soy lecithin, refined soybean oil, refined sucrose, refined egg yolk lecithin, water for injection, calcium carbonate, Lactic acid, ethyl lactate, sodium lactate solution, urea, concentrated glycerin, anhydrous ethanol, anhydrous sodium pyrophosphate, maleic anhydride, anhydrous stannous chloride, anhydrous sodium acetate, sulfuric acid, potassium aluminum sulfate, potassium sulfate, magnesium sulfate, etc. Is mentioned. These additives are generally blended in proportions usually used for injectable preparations. These additives may be used alone or in combination of two or more. It is easy for those skilled in the art to use these additives, as described in Yakuji Nippo Co., Ltd. 2000 “Pharmaceutical Additives Dictionary” (edited by the Japan Pharmaceutical Additives Association). Depending on the purpose, for example, stabilizers, surfactants, buffers, solubilizers, antioxidants, antifoaming agents, tonicity agents, emulsifiers, suspending agents, preservatives, soothing agents, Used as a solubilizer or solubilizer Is possible.

 [0031] The addition amount of other additives in the composition of the present invention is not particularly limited, but in order to give preferable stability to the composition of the present invention, the same index as that of the pH adjuster is used. What is necessary is just to determine the addition amount. Specifically, for example, when the composition of the present invention is a liquid, the pH is in the range of about 3 to about 6.5, preferably about 3.5 to about 5, particularly preferably about 4. It is preferable to add. Also, for example, when the composition of the present invention is a solid, the concentration of 5 thia-PG compound is about: gZmL to about 50 gZmL, more preferably about 3 μgZmL to about 20 μg / m, particularly preferably about 16 pH is about 3 to about 6.5, preferably about 3.5 to about 5, especially when dissolved in water for injection to a microgram ZmL to about 17 g ZmL (eg 10 gZO. 6 mL). It is preferable to add an amount so that it is preferably within the range of about 4.

 [0032] The pH adjuster and other additives are optionally added to the composition of the present invention. If the 5-thia PG compound is stable only by adding a saccharide, the pH adjuster and other additives are added. It is not essential to add any additives. The pros and cons of adding a pH regulator and other additives can be judged as follows. For example, when the composition of the present invention comprising a 5-thia PG compound and a saccharide is a liquid, the pH is about 3 to about 6.5, preferably about 3.5 to about 5, particularly preferably about 4. As long as it is within the range, it is not essential to add a pH regulator or other additives. Also, for example, when the composition of the present invention containing a 5-thia-PG compound and a saccharide is a solid, the concentration of the 5 thia-PG compound is about 1 μgZmL to about gZmL, more preferably about 3 μgZmL to When dissolved in water for injection to a pH of about 20 μgm, particularly preferably about 16 μg / mL to about 17 gZmL (for example, 10 / z gZO. 6 mL), the pH is about 3 to about 6 As long as it is within the range of 5, preferably from about 3.5 to about 5, particularly preferably about 4, it is not essential to add pH adjusting agents or other additives. Specifically, as described in Examples below, when lactose is used as a saccharide and the composition of the present invention which is an aqueous solution is prepared, the pH is in the range of about 4 to about 5. It is not essential to add additives or other additives.

[0033] As described above, the composition of the present invention includes a solid (for example, freeze-dried product) and a liquid (for example, an aqueous solution for producing a freeze-dried product or an aqueous solution in which a freeze-dried product is redissolved). ) However, the degree of stability differs between the two, and the production method and preferred use form thereof also differ. Hereinafter, the case of an aqueous solution (especially an aqueous solution for producing a freeze-dried product) and the case of a freeze-dried product will be specifically described by way of example. In the following description, the “aqueous solution of the present invention” and “ It may be abbreviated as “freeze-dried product”.

 [0034] The aqueous solution of the present invention is obtained by adding (1) 5 thia-PG compound, a solvate thereof, or an inclusion complex thereof, and (2) a saccharide to water as a solvent, and further desired. Prepared by adding (3) pH adjuster and (4) other additives. In the preparation of the aqueous solution of the present invention, addition and mixing operations are carried out according to ordinary pharmaceutical methods. For example, it contains (1) 5 thia PG compounds, solvates or inclusions thereof, (2) sugars, (3) pH regulators, and (4) other additives. When preparing an aqueous solution, each may be weighed, mixed and dissolved in water, or after weighing, may be dissolved in water sequentially without mixing. The order of addition is not particularly limited. It is also possible to prepare the aqueous solution of the present invention by preparing an aqueous solution in which each component is separately dissolved and then mixing the aqueous solutions. In addition, when using an inclusion compound of 5-thia-PG compound or a solvate thereof as a solute, a compound previously prepared as an inclusion compound of 5-thia-PG compound or a solvate thereof must be used. Even if not used, the 5-thia PG compound or a solvate thereof and the host compound can be added separately to form an inclusion complex in an aqueous solution. That is, for example, even a 5-thia PG compound, a host compound, a saccharide, and optionally a pH adjuster separately added to water as a solvent are included in the aqueous solution of the present invention. In addition, naturally, the lyophilized product prepared as described later using the aqueous solution of the present invention is included in the lyophilized product of the present invention.

 [0035] The concentration of the solute in the aqueous solution of the present invention is not particularly limited. For example, the concentration of 5 thia PG compound in the aqueous solution is preferably about 1 μgZmL to about 50 gZmL, and about 3 μgZmL to about 3 μgZmL. More preferred is 20 μg ZmL force. In particular, about 16 gZmL to about 17 g / mL (for example, 10 gZO. 6 mL) is preferable. Preference for sugars, pH regulators, and other additives ヽ The amount of addition is as described above.

[0036] The aqueous solution of the present invention is stable and stable not only in its form but also in terms of purity. In other words, it excels not only in form stability that there is no change in appearance over time, but also in purity stability. It is. Purity stability can be shown, for example, using an index called a residual rate. The survival rate refers to the ratio of the amount of 5-thia PG compound after storage to the amount of 5-thia PG compound before storage. The aqueous solution of the present invention has, for example, a residual ratio of 5 thia-PG compounds of about 80% or more even after storage for 24 hours under conditions of 25 ° C and 60% relative humidity (RH). 80% to about 100%), preferably about 85% or more (about 85% to about 100%), more preferably about 90% or more (about 90% to about 100%), particularly preferably about 93% or more (about 93% or more to about 100%) (purity stability). In particular, aqueous solutions with a high residual rate, for example, the residual rate of 5-lead PG compounds after storage for 24 hours under conditions of 25 ° C and 60% relative humidity (RH) is about 99% or more (about 99% to about 100%). (1) Adjust the pH to about 4 to about 5.5 using crystalline maltose, citrate and sodium citrate as additives, or (2) crystal maltose and citrate. As an additive to adjust the pH to about 3.5 to about 4.5, or (3) adjust the pH to about 4 using crystalline maltose, citrate and sodium hydroxide as additives. Adjust to about 5. In addition, if lactose is used as an additive, the pH is in the range of about 4 to about 5, so that the same effect can be obtained without adding a pH adjusting agent.

[0037] Since the aqueous solution of the present invention is stable, it is sterilized as it is, filled into an appropriate injection container, and if desired, a light-shielding package (for example, an injection container containing the lyophilized product of the present invention). It can also be used as a concentrated injection by applying a light-shielding package, etc., which will be described later). It is preferable to make it a product. In particular, the aqueous solution of the present invention remains in the freeze-dried state since the 5-thia-PG compound, which is an active ingredient, does not decompose rapidly even if it remains in the aqueous solution until it is subjected to freeze-drying after preparation. It is possible to provide an aqueous solution with a high rate.

[0038] The freeze-dried product of the present invention can be produced by filling an injection container with the aqueous solution of the present invention and subjecting it to freeze-drying. The filling amount of the aqueous solution of the present invention into the injection container is not particularly limited, but for example, about 0.5 mL to about 1.5 mL, more preferably about 0.5 mL to about 1. OmL, particularly preferably about 0. It is preferred to charge 6 mL or about 1. OmL, especially about 0.6 mL of aqueous solution. 1 unit for injection (e.g. 1 vial, 1 ampere) The content of the 5-thia PG compound per pull etc. is not particularly limited. For example, it is about 0.1 g to about 20 μg, preferably about 1 μg to about 20 μg, more preferably about 1 μg. Examples include g to about 12 g, particularly preferably about 2 g, about 5 g, about 6 g, and about 10 g. In any process in these steps, a sterilization operation similar to that for general injection ampoules, vials, syringes, and the like can be performed to provide an injection container having sterility. If necessary, before filling into these containers, use a dust filter (eg, 0.45 μm methylcellulose membrane, 0.45 μm nylon 66 membrane, 0.45 μm polyvinylidene fluoride membrane). An operation such as filtration may be performed. Specific sterilization methods used for the sterilization operation include, for example, gas sterilization method, hot water immersion sterilization method, hot water shower sterilization method, filtration sterilization method, irradiation sterilization method (for example, electron beam sterilization method, ultraviolet sterilization method, 0-line sterilization method), high-pressure steam sterilization (autoclave) method and the like. The filtration sterilization method is, for example, after preparing the aqueous solution of the present invention by the above-mentioned method and before filling it into an appropriate container such as an ampoule, a vial, or a syringe, for example, a sterilization filter (e.g., 0. 22 m methylcellulose membrane, 0.22 m nylon 66 membrane, 0.22 m polyvinylidene fluoride membrane, etc.). The gas sterilization method is performed on injection containers such as ampoules, vials, and syringes before filling with the aqueous solution of the present invention. Hot water immersion sterilization method, hot water shower sterilization method, irradiation sterilization method and high-pressure steam sterilization method are prepared by, for example, preparing the aqueous solution of the present invention by the above-mentioned method and placing it in an appropriate container such as an ampoule, vial or syringe. This is done after filling. The autoclaving is preferably performed, for example, under conditions of 100 ° C. to 125 ° C. for 5 minutes to 30 minutes. As the sterilization method in the present invention, for example, a filtration sterilization method, a high-pressure steam sterilization method, and the like are preferred, and a filtration sterilization method (a filtration sterilization method using a filter having a pore size of 0.22 μm) is particularly preferred.

In the present invention, the injection container may be in any form as long as it is sealable and can maintain the sterility of the contents, but is generally filled with an injection preparation or an injection. Vials and ampoules used in are preferred. It is also possible to fill a syringe with a lyophilized solution (eg, distilled water for injection or physiological saline) to obtain a prefilled syringe (double chamber type syringe). These injection containers may be made of any material. For example, glass or plastic is used for vials or ampoules. For example, in the case of a double chamber type syringe, a plastic material is preferable. Further, by combining these materials, for example, a glass container whose inner surface is coated with a plastic material or a plastic container whose inner surface is coated with a glass material can be used.

 [0040] The glass material may be any glass material that can be used in a container for filling pharmaceutical products. When a glass container is used, the inner surface of the container may be coated with silicon or treated with silicon dioxide. Silicon coating is performed using a silicon coating agent (eg, dimethyl silicone oil, methylphenol silicone oil, methyl hydrogen silicone oil, etc.), etc. zm or less, preferably about 15 m to about 50 m or less, by subjecting to a known method such as heat vapor deposition, plasma enhanced chemical vapor deposition, plasma pulse chemical vapor deposition or the like. Is called. The processing of nitric acid silicate is carried out by subjecting it to a known method, for example, a silicoat process, a wave plasma chemical vapor phase process or the like. In addition, glass containers whose inner surfaces have been treated with silicon dioxide in advance (for example, Siricoat ampules, Siricoat vials (made by Shioya Glass, Fuji Glass), Type I plus ampules, Type I plus vials, etc. (made by SCH OTT), etc.) May be used.

 [0041] The plastic material may be any plastic material that can be used in a container for filling pharmaceutical products. For example, polyethylene, polypropylene, polystyrene, polymethylpentene, polyester, polyamide, polycarbonate, or cyclic olefinic compound or crosslinked poly- mer. A polymer hydrocarbon resin of a cyclic hydrocarbon compound can be used without particular limitation.

 [0042] When an ampoule is used as an injection container, a powerful ampoule is filled with the aqueous solution of the present invention, freeze-dried, and then sealed by sealing the opening.

 [0043] When a vial is used as a container for injection, the vial is filled with the aqueous solution of the present invention, and after freeze-drying, the opening is sealed with a rubber stopper, and optionally combined with an aluminum cap or the like. The

[0044] When a syringe (double-chamber one-type syringe) is used as an injection container, such a syringe is filled with the aqueous solution of the present invention in one chamber (for example, the front end side of the syringe) and is freeze-dried. One chamber that remains after attaching (for example, plunger rod side) Fill with a solution for freeze-dried products (e.g., distilled water for injection or physiological saline), seal the tip of the syringe needle with a rubber or plastic part, and fix the plunger rod part. Sealed by sealing with a rubber or plastic gasket or plunger rod.

 A preferable injection container used for filling the aqueous solution of the present invention includes a vial. In particular, glass vials with an inner surface coated with silicon are preferred, especially glass vials.

 [0046] Freeze-drying is performed by the steps of preliminary freeze-drying, vacuum primary drying and secondary drying. Pre-lyophilization is performed at about −50 ° C. to about −40 ° C. for about 2 hours to about 5 hours, preferably at about −50 ° C. to about −45 ° C. for about 2.5 hours to about 4.5 hours. This is done by freezing. Vacuum primary drying is a process performed subsequent to preliminary freeze-drying. The vacuum primary drying is performed by raising the shelf temperature to about 0 ° C to about 20 ° C under a vacuum degree of about 5 Pascals to about 20 Pascals, and at that temperature for about 5 hours to about 10 hours, preferably The temperature is raised to about 0 ° C. to about 15 ° C., and primary drying is performed at that temperature for about 6 hours to about 9 hours. Secondary drying is a process performed subsequent to vacuum primary drying. Secondary drying is performed by raising the temperature from about 0 ° C. to about 20 ° C. to about 25 ° C. to about 55 ° C., preferably from about 35 ° C. to about 50 ° C. Drying at about 5 ° C. to about 15 ° C., preferably about 10 ° C. to about 15 ° C., and drying for about 7 hours to about 10 hours, preferably about 7.5 hours to about 9.5. It takes place over time.

 [0047] The injection container containing the freeze-dried product of the present invention thus produced is provided with a light-shielding package as desired. Such a packaging can be used without particular limitation as long as it is a light-shielding packaging that is generally used. Specifically, bags made of materials that suppress the transmission of light of a specific wavelength, bags made of light-shielding materials such as plastic and aluminum, or shrink packaging using light-shielding plastic (for example, shrink labels) or blister packaging Etc. can be used. These light-shielding packagings can be further improved by using them in combination.

[0048] Since the 5 thia PG compound used in the present invention is a substance that is unstable to light, the injection container containing the lyophilized product of the present invention may be provided with a light-shielding package. preferable. For example, power that can be shielded from light by putting it in a box etc. Especially, it is preferable to apply shrink wrapping (for example, shrink label) using light-shielding plastic.

 [0049] The lyophilized product of the present invention preferably has a low water content, for example, about 2% or less, preferably about 1% or less, more preferably about 0.8% or less, particularly preferably about 0. A water content of 5% or less is preferred. Of course, in the freeze-dried product of the present invention, it is particularly preferable that the moisture content is substantially lower as the moisture content is lower, that is, a product having a detection limit or less. In the lyophilized product of the present invention, the residual ratio of 5 thia PG compound can be increased by lowering the water content.

 [0050] The freeze-dried product of the present invention is stable and excellent in purity stability. The freeze-dried product of the present invention has a residual ratio of 5 thia-PG compounds of about 70% or more (about 70% to about 70% to about 100%), preferably about 75% or more (about 75% to about 100%), more preferably about 80% or more (about 80% to about 100%), particularly preferably about 85% or more (about 85% To about 100%). In other words, since the lyophilized product of the present invention does not rapidly decompose the 5-thia PG compound, which is an active ingredient, after manufacture, the lyophilized product has a high residual rate at clinical sites and is used as an injectable preparation. It is possible to provide. A lyophilized product with a particularly high residual rate, for example, a lyophilized product with a residual rate of 5 thia PG compounds of about 95% or more (about 95% to about 100%) after storage for 2 weeks at 60 ° C To achieve this, (1) a combination of crystalline maltose, succinic acid and sodium succinate as additives, the pH is about 4 to about 4.5, preferably about 4 to about 4.3, particularly preferably about The ability to produce a freeze-dried product using the aqueous solution of the present invention adjusted to 4 to about 4.1, or (2) a combination of crystalline maltose, citrate and sodium hydroxide as additives. A lyophilized product is prepared using the aqueous solution of the present invention having a pH adjusted to about 4 to about 5, preferably about 4 to about 4.6.

[0051] The freeze-dried product of the present invention is also excellent in form stability. The lyophilized product of the present invention, for example, after producing the lyophilized product, does not substantially change its shape even when stored at about 60 ° C. for about 2 weeks, preferably about 4 weeks, and before storage (initial). It has the characteristic of being substantially the same (form stability). Morphological change refers to appearance changes such as shrinkage, thawing, deliquescence, and Z or dissolution of a freeze-dried product over time, for example, spongy, cottony, and Z Or lyophilized cake that is white or extremely light, and has a pale yellow color, it may be crushed, transformed into a yellow color in the shape of cocoon and Z or semi-dissolved over time, etc. Can be mentioned.

 [0052] Hereinafter, a more specific production method of the freeze-dried product of the present invention will be described.

[0053] The freeze-dried product of the present invention is prepared by injection of an appropriate amount of, for example, an OC-cyclodextrin inclusion complex of 5 thia PG compound and a saccharide (for example, crystalline maltose) according to a conventional pharmaceutical method. PH is about 3 to about 6.5, preferably about 3.5 to about 5, particularly preferably by adding a pH adjuster (eg, citrate and sodium hydroxide). Adjust to about 4 and add an appropriate amount of distilled water for injection to adjust the volume, and then sterilize by filtration using a sterilization filter etc. 5 thia-PG compounds per unit form, for example from about 0.1 μg to about g, preferably from about 1 μg to about g, more preferably from about 1 μg to Packed to contain about 12 μg, particularly preferably about 2 g, about 5 g, about 6 g, about 10 g, After the freeze-drying described above, it can be produced by sealing. Here, the unit form refers to a form serving as a unit at the time of dispensing, for example, 1 vial, 1 ampoule or the like.

[0054] In the present invention, the method for stabilizing 5 thia-PG compounds is a method for suppressing the degradation of 5-thia PG compounds in the freeze-dried product of the present invention, and is derived from 5-thia PG compounds. This is a method for suppressing the generation of decomposition products. Specifically, (1) the 5-thia PG compound used for the production of the freeze-dried product is added as an inclusion complex with α-cyclodextrin, and (2) the product is used for the production of the freeze-dried product. Adjusting the pH of the aqueous solution to about 3 to about 6.5, preferably about 3.5 to about 5, particularly preferably about 4 by adding sugars and optionally a pH regulator; and Or (3) by lowering the moisture content of the lyophilized product. By satisfying any of these, preferably all, it becomes possible to more effectively suppress the degradation of the 5-thia PG compound in the lyophilized product.

[0055] The composition of the present invention has a methyl 4 {[2 — ((1R, 2 R, 3R) — 3 hydroxy 1 2— {(IE, 3S) — 3 hydroxy 1 4 — [3- (Methoxymethyl) phenol] buter 1-ethyl} -5-year-old oxocyclopentyl) ethyl] sulfur This is a product that suppresses the formation of tanoate degradation products (hereinafter sometimes simply referred to as degradation products). Here, as the decomposition product, for example, the formula (I—A)

 [Chemical 4]

 [0057] (wherein all symbols have the same meaning as described above), formula (I

[0058] [Chemical 5]

 [0059] (wherein all symbols have the same meaning as described above), formula (I

[0060] [Chemical 6]

 [0061] (wherein all symbols have the same meaning as above), formula (I

[0062] [Chemical 7]

 [0063] (wherein all symbols have the same meaning as above), formula (I

 [0064] [Chemical 8]

[0065] (wherein all symbols have the same meanings as described above), and the like. In particular, the compounds represented by the formulas (I-A) and (I-B) are the main decomposition products. The compounds represented by the formulas (I—A), (I—B), (I—C), (I—D), and (I—E) are methyl 4 {[2 — (( 1R, 2S)-2- {(lE, 3S) — 3Hydroxy-4 [3 (methoxymethyl) phenyl] but-1-enyl} 5-oxocyclopenta-3-en-1-yl) ethyl] sulfur} Butanoate (I—A), Methyl 4 {[2 — ((1R, 2R, 3R) —3 Hydroxy— 2— {(IE, 3S) — 3 Hydroxy— 4— [3— (Methoxymethyl) phenol ] Buta-1 ethyl} 5—oxocyclopentyl) ethyl] sulfier} butanoate (I—B), methyl 4— {[2— ((1R, 2R, 3R) — 3 hydroxy 1 2— {(IE, 3S) — 3 Hydroxyl 4— [3 (Methoxymethyl) phenol] butayl 1}} 5 oxocyclopentyl) ethyl] sulfonyl} butanoate (IC), methyl 4 {[2— ((1R, 2S) — 2— {(IE, 3S) — 3 Hydroxy 4— [3 (Metoki Methyl) phenol] buta-l-l} -5-oxocyclopenter 3-en-1-yl) ethyl] sulfier} butanoate (I-D), methyl 4-{{2- (( lR, 2S)-2- {(lE, 3S) —3 Hydroxy-4 [3 (methoxymethinole) phenol] butter 1 ennenole 5 oxocyclopenta 3 ene 1 yl) ethyl] sulfol} butanoate (I-E). These names are given using ACD / NAME ™ (Advance Chemistry Development), a computer program that mechanically generates IUP AC names.

 [0066] The composition of the present invention, particularly the lyophilized product, can reduce the production of the degradation product as much as possible, and therefore, it is possible to provide an injectable preparation containing a 5-thia PG compound having a high residual rate in the clinical field. Is possible.

[0067] The residual ratio of the 5 thia PG compound in the aqueous solution of the present invention and the lyophilized product of the present invention is determined using a known analysis method (for example, high performance liquid chromatography, gas chromatography, thin layer chromatography, etc.). It can be calculated based on the measured results, but it is particularly preferable to measure using high-speed liquid chromatography. The high performance liquid chromatographic method is performed by a known method. Specifically, it can be carried out by the method described in Examples described later. Using this method, it is possible to calculate the residual ratio of 5-thia-PG compound by measuring the peak area of 5-thia-PG compound before and after storage. [0068] As described above, in the freeze-dried product of the present invention, the generation of decomposition products can be suppressed also by reducing the water content. The water content in the lyophilized product can be measured using a known analysis method (for example, Karl Fischer method). Specifically, it can be carried out by the method described in Examples described later.

 [0069] [Application to pharmaceutical products]

Since the composition of the present invention, particularly the lyophilized product, contains a 5-thia-PG compound having EP4 activity, mammals (eg, humans, non-human animals, eg, monkeys, hidges, udons). , Horses, dogs, cats, rabbits, rats, mice, etc.) can be used as injections for the purpose of preventing, treating, and inhibiting Z or progression of EP4-mediated diseases. Here, the EP4 mediated disease may be any disease in which EP4 is involved in the process of formation, establishment, exacerbation, etc. of the disease, or in the healing process. For example, an immune disease (for example, autoimmunity) Disease (e.g. amyotrophic lateral sclerosis (ALS), multiple sclerosis, Siedalen syndrome, rheumatoid arthritis, systemic lupus erythematosus, etc.), rejection after organ transplantation, etc.), asthma, neuronal cell death , Lung injury, liver injury, acute hepatitis, nephritis, renal failure, hypertension, myocardial ischemia, systemic inflammatory response syndrome, burn pain, sepsis, hemophagocytic syndrome, macrophage activation syndrome, Still disease, Kawasaki disease, burns, systemic granulomas, ulcerative colitis, Crohn's disease, high-site force inemia during dialysis, multiple organ failure, shock, sleep abnormalities, platelet aggregation, bone diseases (e.g., bone dysplasia, Bone loss diseases, etc.). Of these, ulcerative colitis and bone diseases, particularly bone loss diseases are suitable for the application of the composition of the present invention, particularly freeze-dried products. Bone loss diseases refer to diseases in which a decrease in bone mass accompanied by symptoms such as a decrease in bone density and bone tissue occurs. For example, (1) primary osteoporosis (for example, primary osteoporosis associated with aging) Osteoporosis, primary osteoporosis associated with menopause, primary osteoporosis associated with ovariectomy, vertebral fracture, etc.), (2) secondary osteoporosis (eg, darcocorticoid-induced osteoporosis, hyperthyroidism) Osteoporosis, fixation-induced osteoporosis, heparin-induced osteoporosis, immunosuppression-induced osteoporosis, osteoporosis due to renal failure, inflammatory osteoporosis, osteoporosis associated with Cushing syndrome, rheumatic osteoporosis, etc.), (3) cancer bone metastasis , Hypercalcemia, Beige's disease, bone defect (alveolar bone defect, mandible bone defect, childhood sudden bone defect) And the like, and bone diseases such as osteonecrosis. Furthermore, the composition of the present invention, particularly the lyophilized product, can be used for bone formation after bone surgery (for example, bone formation after fracture, bone formation after bone transplantation, bone formation after artificial joint surgery, spinal fusion) It can be used as an injection for the purpose of 'promoting healing' and subsequent bone formation and other bone formation after bone reconstruction. It can also be used for bone graft replacement therapy.

 [0070] Among the above-mentioned bone loss diseases, the most preferable disease for the application of the composition of the present invention, particularly the freeze-dried product, is vertebral fracture.

[0071] The composition of the present invention, particularly a lyophilized product, is in a form that can be administered to a patient using a lysing solution and z or a diluting solution for the purpose of prevention, treatment and Z or progression inhibition of the above-mentioned diseases. That is, it is administered in vivo after it is made into an injection. Here, the solution and the Z or diluent may be any aqueous solution that can be injected into a living body, preferably intravenously, such as distilled water for injection, physiological saline, sugar solution, and other general-purpose infusions. .

 [0072] The daily dose of an injection prepared using the composition of the present invention, particularly a lyophilized product, varies depending on the degree of symptoms; age, sex, body weight of administration subject; Although not particularly limited, for example, when used as an injection for the purpose of prophylaxis, treatment and Z or progression inhibition of EP4-mediated diseases, the daily dose is about 4 ng to about 0.36 g per kg of patient body weight. It is preferred to administer 5 thia PG compound. In particular, when administered intravenously as a therapeutic agent for vertebral fractures, it is preferable to administer about 0.12 g of 5 thia PG compound per lkg of patient body weight as a daily dose. As a more specific administration method in the case of intravenous infusion as a therapeutic agent for vertebral fracture, for example, about 0.12 g of 5 thia-PG compound per 1 kg of patient's body weight is divided twice a day. For example, a method of instilling with 4 hours of force in the afternoon and afternoon for 2 hours.

[0073] Injectables prepared using the composition of the present invention, particularly lyophilized products, include other drugs such as phosphodiesterase 4 inhibitors, bisphosphonate preparations, vitamin D preparations, calcium preparations, estrogen preparations, calcitonin preparations, isoflavones. Formulations, anabolic steroids, vitamin K preparations, cathebsin K inhibitors, HMG—CoA reductase inhibitors, parathyroid hormone, growth factors, caspase 1 inhibitors, PTHrP derivatives, meta-oral proteinase inhibitors, farnesoids X receptor agonist, estrogen agonist, progesterone agonist It may be used in combination with drugs. The administration method of these drugs used in combination is not particularly limited, and it may be oral administration or parenteral administration.

 [0074] Phosphodiesterase inhibitors (PDE4) include, for example, cilomilast, oral flumilast, arofylline, OPC-6535, ONO-6126, IC-485, AWD-12-281, CC- 10004, CC-1088, KW-4490, Iirimilast, ZK-117137, ΥΜ-976, BY-61-9987, CC-7085, CDC-998, MEM-1414, ND-1251, Bayl9-8004, D-4396, PD-168787, Atizolam, Cipamfylline, Rolipram, NIK-616, SCH-351591, V-11294A and the like.

 [0075] Bisphosphonate preparations include, for example, alendronate sodium hydrate, inbandronic acid, incadronate disodium, etidronate disodium ), Onoreno << Dolonate, Clodronate sodium hydrate, Zoledronic acid, Tiludronate disodium, Neridronate, Pamidronate Examples include sodium (Pamidronate disodium), pyridronate, minodronic acid hydrate, risedronate sodium hydrate, YM175, and the like.

 [0076] Vitamin D preparations include, for example, alphacalcidol, falecalcitriol, strength lucitriol, 1α, 25-dihydroxycholecalciferol, dihydrotaxosterol, ST-630, KDR, ST-630, ED- 71, Mouth Cartolol (Ro44-7190), Tacalcitol, Maxacalcitol and the like.

 [0077] Examples of calcium preparations include calcium chloride, calcium gluconate, calcium glycerophosphate; calcium lactate, L-aspartate cane -aspartat e), d¾asic calcium phosphate, and the like.

[0078] Estrogen preparations include, for example, Estradiol (Estradiol cypionate, Estradiol cypionate, KEstradiol dipropionate), KEstradiol enanthate), Estradiol hexahexahydrobenzoate (Estradiol hexah) ydrobenzoate), Estradiol phenylpropionate, Estradiol undecanoate, Estradiol valerate, Estrone, Ethynyl estradio 1 ), Mestranol and the like.

[0079] Calcitonin preparations include, for example, calcitonin, salmon calcitonin (STH-32, SMC20-51), -tricalcitonin (chicken calcitonin; MCI-536), secalciferol , Elcatonin, TJN-135 and the like.

 [0080] Examples of the isoflavone preparation include ipriflavone and the like.

[0081] Anabolic steroids include, for example, oxymetholone, stanozolol, nandrolone decanoate, nandrolone phenylpropionate, cyclohexenorepropionate nand Ron (Nandrolone cyclohexylpropionate), acetic acid Meanoron (Metenolone acetate entrance female Tanoron (Mestanolone), e Chino Les Lisbon no Honoré (Ethylestrenol), and the like Kanoresuteron (Calustero n _e).

 [0082] Examples of vitamin K preparations include menatetrenone, ph ytonadione, and the like.

[0083] Examples of the cathebucin K inhibitor include ONO-5334 and the like.

[0084] HMG—CoA reductase inhibitors include, for example, pravastatin (sodium) (prava statin (sodium)), simvastatin, flupastatin (sodium) (fluvastat in (sodium)), cerivastatin (sodium) ) (Cerivastatin (sodium)), itapastatin (itav astatin), atonorevastatin (calcores hydrate) (atorvastatin (calcium hydrate)), oral pastatin (lovastatin), pitapastatin (calcium) (pitavastatin (calcium)), ZD -45 22 etc.

 [0085] Parathyroid hormones include, for example, dried thyroid, lepotyroxine sodium, di-aged P liothyronine sodium, ~ 7 ° η propylthiouracil, thiamazole (thiamazole) and the like.

[0086] Examples of growth factors include fibroblast growth factor (FGF) and vascular endothelial growth factor (VE). GF), hepatocyte growth factor (HGF), insulin-like growth factor and the like.

[0087] Examples of the caspase 1 inhibitor include nitroflubiprofen and prarnacasan.

 [0088] Examples of the PTHrP derivative include hPTHrP, RS-66271, and the like.

[0089] Examples of meta-oral proteinase inhibitors include ONO-4817.

[0090] Examples of the agonist of the farnesoid X receptor include SR-45023A.

[0091] Examples of the estrogen agonist include TSE-424, WJ-713 / MPA, lasofoxifene tartrate, estradiol, teriparatide acetate, and osaterone acetate.

[0092] Examples of progesterone agonists include trimegestone.

[0093] The above concomitant drugs are illustrative and are not limited thereto.

[0094] The other drugs may be administered in combination of any two or more. The drugs used in combination include not only those found so far, but also those found in the future based on the above-mentioned mechanism.

[0095] [Toxicity]

 Since the 5-thia PG compound used in the present invention has a sufficiently low toxicity, the composition of the present invention, particularly a lyophilized product, can be used safely as a pharmaceutical product. In addition, the composition of the present invention, in particular the lyophilized product, can minimize the generation of a decomposed product whose toxicity has not been confirmed as a result of storage, thereby reducing the risk of exposure to the living body of 5-thia PG compounds. Can be reduced.

 The invention's effect

 [0096] Since the pharmaceutical composition provided by the present invention, in particular the freeze-dried product, is stable, the production of degradation products during the storage period is suppressed as much as possible. As an injectable preparation, it can be clinically provided in a safe state without degrading quality.

 BEST MODE FOR CARRYING OUT THE INVENTION

[0097] Hereinafter, the present invention will be described in detail with reference to examples, but the present invention is not limited thereto.

[0098] Also, the scope of the present invention is not deviated! [0099] [Example 1]

Methyl 4— {[2— ((1R, 2R, 3R) — 3-Hydroxyl 2— {(IE, 3S) — 3-Hydroxy— 4-— [3- (Methoxymethyl) phenol] buta 1 Preparation of aqueous solution containing _α -cyclodextrin inclusion compound of —ethyl}-5-oxocyclopentyl) ethyl] sulfar} butanoate

 1—1: Maltose prescription

 [Formulation 1— 1— 1] Content: 10 g / vial, additive: maltose

 In water for injection, methyl 4— {[2— ((1R, 2R, 3R) — 3-hydroxyl 2— {(IE, 3S)

— 3-Hydroxy mono 4-— [3- (Methoxymethyl) phenol] butane 1-ethyl} — 5-oxocyclopentyl) ethyl] sulfar} Butanoate _α -cyclodextrin inclusion compound ( 9. 7mg: Methyl 4— {[2— ((1R, 2R, 3R) — 3—Hydroxy— 2— {(IE, 3S) — 3-Hydroxy mono 4— [3— (Methoxymethyl) phenol] 1-ethyl} -5-oxocyclopentyl) ethyl] sulfar} butanoate 2 mg) and crystalline maltose (10 g) were added to make 120 mL with water for injection. After preparing a uniform solution, the solution was filtered through a sterile filter (0.22 m membrane manufactured by Deyurapore) to produce the aqueous solution of the present invention. The solution in each aqueous solution was clear and colorless. In addition, 3 lots were manufactured with this formulation, and the pH after filtration of each aqueous solution was 6.00 (Lot A-1), 6.00 (Lot A-2), 5.58 (Lot A-3) Met.

[0100] [Formulation 1-1-2] Content: 10 g / vial, Additives: Maltose, Quenic acid

In water for injection, methyl 4— {[2— ((1R, 2R, 3R) — 3—hydroxy 1 2— {(IE, 3S) — 3-hydroxy 1 4— [3— (methoxymethyl) phenol] Butylate 1-ethyl} — 5-oxocyclopentyl) ethyl] sulfar} butanoate inclusion compound of _α -cyclodextrin (9.7 mg: methyl 4- {{2- ((1R, 2R, 3R ) — 3—Hydroxy— 2— {(IE, 3S) — 3 —Hydroxy 1 —— [3 — (Methoxymethyl) phenol] buta 1 —ethyl} — 5 —oxocyclopentyl) ethyl] sulfa- Add 2 mg) and crystalline maltose (10 g) as butanoate, adjust the pH by adding an appropriate amount of citrate aqueous solution of various concentrations (0.5N, 0.05N, 0.01N) and use water for injection. 120 mL. After preparing a uniform solution, the solution was filtered through a sterile filter (0.22 m membrane manufactured by Deyurapore) to produce the aqueous solution of the present invention. The solution in each aqueous solution was clear and colorless. In addition, 6 lots were manufactured with this formulation, and p after filtration of each aqueous solution. H is 4.40 (Lot B—l), 5.32 (Lot B—2), 3.75 (Lot B—3), 3.16 (Lot B —4), 3.72 (Lot B— 5), 3.69 (Lot B 6).

[0101] [Formulation 1-1-3] Content: 10 / z g / vial, additives: maltose, citrate, sodium citrate

Methyl 4- {[2- ((lR, 2R, 3R) — 3 Hydroxy 1 — {(IE, 3S) — 3 Hydroxy 4 — [3 (Methoxymethyl) phenol] porcine 1 5} oxocyclopentyl) ethyl] sulfar} butanoate _α -cyclodextrin inclusion compound (9.7 mg: methyl 4— {[2— ((1R, 2R, 3R) — 3 hydroxy— 2 — {(IE, 3S) — 3 Hydroxy 4- [3 (Methoxymethyl) phenol] butayl} 5 oxocyclopentyl) syl] sulfan} butanoate as 2 mg), crystalline maltose (10 g ) And 0.01N aqueous citrate solution (10 mL), and an appropriate amount of 0.05N aqueous sodium citrate solution was added to adjust the pH to 120 mL with water for injection. After forming a uniform solution, the solution was filtered through a sterile filter (0.22 / zm membrane manufactured by Deyurapore) to produce the aqueous solution of the present invention. The solubility of each aqueous solution was clear and colorless. Three lots were manufactured with this formulation, and ρΗ after filtration of each aqueous solution was 4.12 (Lot C-1), 4.58 (Lot C 2), 5.06 (Pot C 3). there were.

 [0102] [Formulation 1 1 4] Content: 10 g / vial, additives: maltose, citrate, sodium hydroxide

In water for injection, methyl 4— {[2— ((1R, 2R, 3R) — 3 hydroxy 1 2— {(IE, 3S) — 3 hydroxy 1 4— [3 (methoxymethyl) phenol] porcine 1 5} oxocyclopentyl) ethyl] sulfar} butanoate _α -cyclodextrin inclusion compound (9.7 mg: methyl 4— {[2— ((1R, 2R, 3R) — 3 hydroxy— 2 — {(IE, 3S) — 3 Hydroxy 4- [3 (Methoxymethyl) phenol] butayl} 5 oxocyclopentyl) syl] sulfan} butanoate as 2 mg), crystalline maltose (10 g ) And 0.01N aqueous citrate solution (10 mL), and an appropriate amount of 0.05N aqueous sodium hydroxide solution was added to adjust the pH to 120 mL with water for injection. After forming a uniform solution, the solution was filtered through a sterile filter (0.22 m membrane manufactured by Deyurapore) to produce the aqueous solution of the present invention. The solubility of each aqueous solution was clear and colorless. In addition, 4 lots were manufactured with this prescription and each The pH after filtration of the aqueous solution was 4.11 (Lot D-1), 4.58 (Lot D2), 5.09 (Lot D-3), 5.72 (Lot D-4).

 1 2: Lactose prescription

 [Formulation 1 2— 1] Content: 10 gZ vial, additive: lactose

Methyl 4- {[2- ((lR, 2R, 3R) — 3 Hydroxy 1 — {(IE, 3S) — 3 Hydroxy 4 — [3 (Methoxymethyl) phenol] porcine 1 5} oxocyclopentyl) ethyl] sulfar} butanoate _α -cyclodextrin inclusion compound (9.4 mg: methyl 4— {[2— ((1R, 2R, 3R) — 3 hydroxy— 2 — {(IE, 3S) — 3 Hydroxy 4- [3 (Methoxymethyl) phenol] butayl} 5 oxocyclopentyl) ethyl] sulfar} butanoate 2 mg) and lactose (10 g) In addition, it was made up to 120 mL with water for injection. After preparing a uniform solution, the solution was filtered through a sterile filter (0.22 m membrane manufactured by Deyurapore) to produce the aqueous solution of the present invention (Lot E). The aqueous solution was clear and colorless, and the pH showed a value of about 4 to about 5.

[0103] [Formulation 1-2-2] Content: 100 gZ vial, additive: lactose

In water for injection, methyl 4— {[2— ((1R, 2R, 3R) — 3 hydroxy 1 2— {(IE, 3S) — 3 hydroxy 1 4— [3 (methoxymethyl) phenol] porcine 1 }} 5 oxocyclopentyl) ethyl] sulfar} butanoate _α -cyclodextrin inclusion compound (94 mg: methyl 4- {[2— ((1R, 2R, 3R) — 3 hydroxy-2— { (IE, 3S) — 3 Hydroxy 4- [3 (Methoxymethyl) phenol] butayl} 5 oxocyclopentyl) ethyl] sulfar} butanoate 20 mg) and lactose (10 g) The volume was made up to 120 mL using water for injection. After preparing a uniform solution, the solution was filtered through a sterile filter (0.22 m membrane manufactured by Deyurapore) to produce the aqueous solution of the present invention (Lot F). The aqueous solution was clear and colorless, and the pH showed a value of about 4 to about 5.

[Example 2]

The aqueous solution prepared in Example 1 was filled in 0.6 mL portions in silicon-coated glass vials and stored for 24 hours under conditions of 25 ° C. and 60% relative humidity (RH). Methyl 4— {[2— ((1R, 2R, 3R) — 3 Hydroxy 1— {(IE, 3S) — 3 Hydroxy 4— [3 (Methoxymethyl) phenol in each vial after storage ] Buta—1}} 5 oxocyclo [Pentyl) ethyl] sulfanyl} butanoate was measured under the following conditions to evaluate the residual ratio.

 [Evaluation method of survival rate]

 The remaining rate evaluation method is described below. The following notation shall conform to the general rules of the Japanese Pharmacopoeia. For example, the description “accurately” means that the force is precisely applied up to that digit, and the description “about” means a range of ± 10%.

(1) Preparation of sample solution and standard solution

<Preparation of sample solution>

 For each of the three specimens, add the internal standard solution 2 described below to the methyl 4- {{2- ((1 R, 2R, 3R)-3 hydroxy 1 2- {(IE, 3S) -3 hydroxy 1 4- [3- (methoxymethyl) phenol] butayl 1} 5-year-old oxocyclopentyl) ethyl] sulfar} The concentration ratio of butanoate and butyl 4-hydroxybenzoate is the same as the standard solution described below Mixed. A sample solution was prepared by collecting 0.4 mL of each of these three samples and mixing them.

<Preparation of standard solution>

 Methyl 4— {[2— ((1R, 2R, 3R) — 3 Hydroxy 1 — {(IE, 3S) — 3 Hydroxy 4 — [3 (Methoxymethyl) phenol] buta-1 } 5 oxocyclopentyl) ethyl] sulfar} About 25 mg of butanoate was weighed and dissolved in methanol to make exactly lOOmL. Accurately 4 mL of this solution was added, and 4 mL of the internal standard solution 1 described later was accurately added, and methanol was added to make exactly 10 mL. When this solution was used, it was diluted 2 times with water and used (methyl 4- {{2-((1R, 2R, 3R)-3-hydroxy-l 2- {(IE, 3S)-3 hydroxy- 4- [3 (Methoxymethyl) phenol] buta-l} 5 oxocloclopentyl) ethyl] sulfar} butanoate concentration: 5 gZmL, internal standard concentration: approx. S / z gZmD o

<Preparation of internal standard solution 1>

 30 mg of 4 hydroxybutyl benzoate was weighed and methanol was added to make 200 mL (4 hydroxybutyl benzoate concentration: 150 g / mL).

<Preparation of internal standard solution 2> 4 mL of the internal standard solution 1 was applied accurately, and methanol was added to make exactly 1 mL (4 hydroxybutyl benzoate concentration: 6 μg / mL).

 (2) High performance liquid chromatograph

 The sample solution was subjected to high performance liquid chromatography under the following conditions.

<Test conditions>

Detector: UV spectrophotometer (measurement wavelength: 210 nm);

Column: A stainless steel tube with an inner diameter of 4.6 mm and a length of 15 cm is packed with 5 μm Otadecyl Silylated Silica Gel for Liquid Chromatography (for example, YMC-Pack ODS A302 etc.); Column temperature: constant temperature around 50 ° C;

Mobile phase: water Z-acetonitrile Z methanol mixed solvent (water: acetonitrile: methanol = 58

: 25: 17);

Flow rate: 1. OmL / ^;

Analysis time: 40 minutes (standard solution 20 minutes);

Estimated retention time: methyl 4- {[2- ((lR, 2R, 3R) — 3 hydroxy— 2— {(IE, 3 S) — 3 hydroxy— 4— [3 (methoxymethyl) phenol] pig — 1 ethyl} 5 oxocyclopentyl) ethyl] sulfar} butanoate: about 15 minutes, internal standard: about 18 minutes.

 (3) Calculation of survival rate

 Methyl 4 1 {[2— ((1R, 2R, 3R) — 3 Hydroxy 2— {(IE, 3S) — 3 Hydroxy 1 4— [3— ( Methoxymethyl) phenyl] butayl} -5 oxocyclopentyl) ethyl] sulfur} butanoate peak area ratio.

 [Result]

The obtained results are shown in Tables 1 to 4 below. In the table, the pH before storage (after filtration) and the pH after storage are described together, and the pH after storage is indicated as “-” for those not measured. When crystalline maltose is used alone as an additive and the pH is in the range of about 5.5 to about 6.5, 5 thia-PG compounds at 25 ° C and 60% relative humidity (RH) The survival rate after 24-hour storage was about 94% to about 100% (Table 1). In addition, crystalline malting as an additive When using a combination of toose and citrate and adjusting the pH to about 3.5 to about 5.5, the 25-thia-PG compound under conditions of 25 ° C, 60% relative humidity (RH) 24 The residual rate after storage for about 97% to about 100% (Table 2). In addition, when crystalline maltose, citrate and sodium citrate are used in combination as an additive and the pH is adjusted to about 4 to about 5.5, the 5-thia-PG compound at 25 ° C and 60% relative humidity The residual rate after storage for 24 hours under the conditions of (RH) was about 99% to about 100% (Table 3). Furthermore, when a combination of crystalline maltose, citrate, and sodium hydroxide is used as an additive, and the pH is adjusted to about 4 to about 6, the 5-thia-PG compound at 25 ° C, 60% The residual rate after storage for 24 hours under conditions of relative humidity (RH) was about 98% to about 100% (Table 4).

[0107] [Table 1]

[0108] [Table 2] Table

[0109] [Table 3]

[0110] [Table 4] Lot number D ™ 1 D— 2 D ™ 3 D ~ 4

 4.11 4 i 5.09 '/ after filtration

 PH after storage 4.08 4.57 5.05 5.S6

 Survival rate (%) 09.1 100.3 987 Θ8.5

[0111] [Example 3]

Methyl 4— {[2— ((1R, 2R, 3R) — 3—Hydroxyl 2 — {(IE, 3S) — 3—Hydroxy—4— [3- (Methoxymethyl) phenol] buta 1 Preparation of freeze-dried product containing _α -cyclodextrin inclusion compound of —ethyl}-5-oxocyclopentyl) ethyl] sulfar} butanoate

 3—1: Maltose prescription

 [Formulation 3— 1— 1] Content: 10 g / vial, additive: maltose

 Methyl 4-{[2— ((1R, 2R, 3R) — 3-hydroxyl 2— {(IE, 3S)

— 3-Hydroxy mono 4-— [3- (Methoxymethyl) phenol] butane 1-ethyl} — 5-oxocyclopentyl) ethyl] sulfar} Butanoate _α -cyclodextrin inclusion compound ( 9. 7mg: Methyl 4— {[2— ((1R, 2R, 3R) — 3-Hydroxy— 2— {(IE, 3S) — 3-Hydroxy mono 4-— [3- (Methoxymethyl) phenol] 1-ethyl} -5-oxocyclopentyl) ethyl] sulfar} butanoate 2 mg) and crystalline maltose (10 g) were added to make 120 mL with water for injection. After preparing a uniform solution (pH 5.66), the solution was filtered through a sterile filter (0.22 m membrane manufactured by Deyurapore), and 0.6 mL was filled in a silicon-coated glass vial. The vial was cooled to below −40 ° C. to freeze the solution, then gradually warmed at about 20 Pascal vacuum and dried at 10 ° C. for 7 hours. Thereafter, the lyophilized product (lot a-1) of the present invention was produced by final drying at 45 ° C. The appearance of the lyophilized product was a white mass or powder.

[0112] [Formulation 3 -1-2] Content: 10 g / vial, additives: maltose, citrate

Methyl 4-{[2— ((1R, 2R, 3R) — 3-Hydroxy 1-{(IE, 3S) — 3-Hydroxy 1- 4-] [3- (Methoxymethyl) phenol] Butane 1-ethyl} — 5-oxocyclopentyl) ethyl] sulfar} butanoate inclusion compound of _α -cyclodextrin (9.7 mg: methyl 4-{[2— ((1R, 2R, 3R ) — 3—Hydroxy— 2— {(IE, 3S) — 3 Hydroxy 4- [3 (Methoxymethyl) phenol] butayl} 5 oxocyclopentyl) ethyl] sulfar} butanoate as 2 mg), crystalline maltose (10 g) and 0.01 N citrate The pH was adjusted (pH 3.64) by adding an aqueous solution (10 mL), and adjusted to 120 mL using water for injection. After forming a uniform solution, the solution was filtered through a sterile filter (0.22 / zm membrane manufactured by Deyurapore), and 0.6 mL was filled in a silicon-coated glass vial. The vial was cooled to below 40 ° C to freeze the solution, then gradually warmed at about 20 Pascal vacuum and dried at 10 ° C for 7 hours. Thereafter, the lyophilized product (lot b-1) of the present invention was produced by final drying at 45 ° C. The appearance of the freeze-dried product was a white lump or powder.

 [0113] [Formulation 3-1-3] Content: 10 g / vial, additives: maltose, citrate, sodium citrate

Methyl 4- {[2- ((lR, 2R, 3R) — 3 Hydroxy 1 — {(IE, 3S) — 3 Hydroxy 4 — [3 (Methoxymethyl) phenol] porcine 1 5} oxocyclopentyl) ethyl] sulfar} butanoate _α -cyclodextrin inclusion compound (9.7 mg: methyl 4— {[2— ((1R, 2R, 3R) — 3 hydroxy— 2 — {(IE, 3S) — 3 Hydroxy 4- [3 (Methoxymethyl) phenol] butayl} 5 oxocyclopentyl) syl] sulfan} butanoate as 2 mg), crystalline maltose (10 g ) And 0.01N aqueous citrate solution (10mL), and then adjust the pH with an appropriate amount of 0.05N aqueous sodium citrate solution (pH 4.07, pH 4.53, pH 5.09). The volume was 120 mL. After forming a uniform solution, the solution was filtered with a sterile filter (0.22 m membrane manufactured by Deyurapore), and 0.6 mL each was filled into a silicon-coated glass vial. The vial was cooled to 40 ° C or lower to freeze the solution, and then gradually heated at a vacuum of about 20 Pascal and dried at 10 ° C for 7 hours. After that, the final product is dried at 45 ° C, and the freeze-dried product of the present invention (the lot is distinguished by ρ ろ 過 before filtration: lot c-1 (ρΗ4.07), lot c-2 (pH 4.53), lot c- 3 (pH 5.09)) was produced. The appearance of the freeze-dried product was a white lump or powder.

[0114] [Formulation 3—1 4] Content: 10 g / vial, Additives: Maltose, citrate, sodium hydroxide Methyl 4- {[2- ((lR, 2R, 3R) — 3-Hydroxy 1- {(IE, 3S) — 3-Hydroxy 1- 4-] [3- (Methoxymethyl) phenol] Butylate 1-ethyl} — 5-oxocyclopentyl) ethyl] sulfar} butanoate inclusion compound of _α -cyclodextrin (9.7 mg: methyl 4- {{2- ((1R, 2R, 3R ) — 3—Hydroxy— 2— {(IE, 3S) — 3 —Hydroxy 1 —— [3 — (Methoxymethyl) phenol] buta 1 —ethyl} — 5 —oxocyclopentyl) ethyl] sulfa- }} 2 mg as butanoate), crystalline maltose (10 g) and 0.01N aqueous citrate solution (10 mL), and adjust the pH by adding an appropriate amount of 0.05N aqueous sodium hydroxide solution (pH 4.07, pH 4.54 and pH 5.04) and adjusted to 120 mL with water for injection. After forming a uniform solution, the solution was filtered through a sterile filter (0.22 m membrane manufactured by Deyurapore), and 0.6 mL each was filled into a silicon-coated glass vial. The vial was cooled to below −40 ° C. to freeze the solution, and then gradually heated at a vacuum of about 20 Pascal and dried at 10 ° C. for 7 hours. Then, freeze-dried product of the present invention by final drying at 45 ° C (Lot is distinguished by ρΗ before filtration: Lot d-1 (ρΗ4.07), Lot d-2 (pH 4.54), Lot d-3 (pH 5.04)) was produced. The appearance of the lyophilized product was a white mass or powder.

 [Example 4]

 The lyophilized product produced in Example 3 was (1) 1 week at 60 ° C, (2) 2 weeks at 60 ° C, and (3) 3 weeks at 60 ° C. (4) Stored for 1 month at 40 ° C and 75% relative humidity (RH). For each sample after storage and before storage (Initial: initial), (a) Appearance, (b) Appearance when redissolved, (c) pH when redissolved, (d) Water content, and (e) Residual Each item of rate was evaluated using the following evaluation methods.

[Evaluation methods]

 (a) Appearance

The appearance of the freeze-dried product before and after storage was observed.

 (b) Appearance when re-dissolved

The lyophilized product before and after storage was dissolved in 0.6 mL of water for injection and the appearance was observed.

(c) pH during redissolution The lyophilized product before and after storage was dissolved in 0.6 mL of water for injection and the pH was measured.

(d) Moisture content

The moisture content in the lyophilized product before storage was measured by the Karl-Fisher method (volume method) using the following test conditions.

<Test conditions>

Equipment: Moisture analyzer (Mitsubishi Chemical) CA-06

Method: Capacity method (KF)

Reagents: Dehydrated solvent (GEX), Karl Fischer reagent (SS—X) 3 mg (Mitsubishi Chemical)

 (e) Survival rate

Using the lyophilized product before and after storage as a specimen, methyl 4- {{2- ((1R, 2R, 3R)-3 hydroxy- 1 2- {(IE, 3S)] by the measurement method described in Example 2 — 3 Hydroxy — 4-— [3 (Methoxymethyl) phenol] buta-1-ethyl} 5-oxocyclopentyl) ethyl] sulfanyl} butanoate was measured. For each of the three specimens, the sample solution was prepared by adding an appropriate amount of water and the internal standard solution 2 described later, and methyl 4 {[2— ((1R, 2R, 3R) -3 hydroxy-1 2- { (IE, 3S) -3 Hydroxy 4- [3- (Methoxymethyl) phenol] Butter 1-Ear} 5-Year-Cyclocyclopentyl) Ethyl] Sulfa-l} Butanoate and Butyl 4-Hydroxybenzoate Were mixed in such a way as to be the same as the above standard solution, and 0.4 mL of each of these three samples was collected and mixed.

[Result]

The results obtained are shown in Tables 5 to 9 below (Table 5 initial; Table 6: 60 ° C, 1 week; Table 7: 60 ° C, 2 weeks; Table 8: 60 ° C, 4 weeks; Table 9: 40 ° C, 75% RH, for 1 month). When a freeze-dried product is produced using an aqueous solution containing crystalline maltose alone as an additive (when no pH regulator is added to the aqueous solution: lot a-1), the condition is 2 weeks at 60 ° C. The residual rate of 5 thia-PG compounds in the frozen product after storage was about 85% to about 100% (Table 7). O In addition, crystalline maltose and citrate were combined as additives to adjust the pH. When a freeze-dried product is produced using an aqueous solution adjusted to about 3.5 to about 4 (lot b-1), The residual rate of 5 thia PG compounds in the lyophilized product after storage for 2 weeks was about 90% to about 100% (Table 7). Furthermore, crystalline maltose, combining Kuen acid and sodium Kuen acid as an additive, if you produce a lyophilizate using an aqueous solution with an adjusted _P H of about 4 to about 5.5 (Lot c-l, Lot c 2 In lot c3), the residual ratio of 5 thia PG compound in the lyophilized product after storage for 2 weeks at 60 ° C. was about 92% to about 100% (Table 7). Furthermore, when freeze-dried products are produced using an aqueous solution in which crystalline maltose, citrate and sodium hydroxide are combined as additives and the pH is adjusted to about 4 to about 5.5 (lot d-l, In lot d-2 and lot d-3), the residual ratio of 5 thia PG compounds in the lyophilized product after storage for 2 weeks at 60 ° C was about 93% to about 100% (Table 1). 7). Regarding the appearance and appearance at the time of re-dissolution, no change due to storage was observed in any specimen. Of the lyophilized products studied, the lyophilized products (lots of about 95% to about 100%) that had a particularly good residual rate of 5 thia-PG compounds after storage for 2 weeks at 60 ° C. cl, lot d-1 and lot d-2) are stable even after long-term storage.For example, the survival rate is about 92% to about 100% even after storage for 4 weeks at 60 ° C. Shown (Table 8). In addition, the lyophilized product showed good results in the residual rate after storage for 1 month under the conditions of 40 ° C and 75% RH. Especially as additives, crystalline maltose, citrate and citrate Freeze-dried products (lot c 1, lot c 2, lot c 3) manufactured using an aqueous solution adjusted to a pH of about 4 to about 5.5, combined with sodium, and crystalline maltose and citrate as additives. Good results were obtained with the lyophilized product (Lot d-1) produced using an aqueous solution with pH adjusted to about 4 by combining sodium hydroxide and sodium hydroxide (Table 9).

[Table 5]

[0117] [Table 6]

 [0119] [Table 8]

[0120] [Table 9] 40; 75% RH 1 month storage

[0121] [Example 5]

[Formulation 5— 1— 1] Content: 500 / zg / vial, Additive: Maltose or lactose Injectable water, methyl 4- {[2- ((lR, 2R, 3R) — 3 hydroxy 1 2— {(IE , 3S) — 3 Hydroxy 4- [3 (Methoxymethyl) phenol] butane 1}} 5 oxocyclopentyl) ethyl] sulfur} Butanoate _α -cyclodextrin inclusion compound (480 mg: Methyl 4— {[2— ((lR, 2R, 3R) —3 Hydroxy-2-— {(IE, 3S) — 3 Hydroxy 4-— [3 (Methoxymethyl) phenol] butane 1 1) 5 LOOmg) and crystalline maltose (10 g) or lactose (10 g) were added as oxocyclopentyl) ethyl] sulfar} butanoate, and made up to 120 mL with water for injection. After forming a uniform solution, the solution was filtered through a sterile filter (0.22 m membrane manufactured by Deyurapore), and 0.6 mL was filled in a silicon glass vial. The vial was cooled to below 40 ° C to freeze the solution, then gradually warmed at a vacuum of about 20 Pascals and dried at 10 ° C for 7 hours. After that, freeze-dried products were produced by final drying at 45 ° C. The appearance of the lyophilized product was white and cracked in the cake. When maltose was used alone as an additive, the pH of the aqueous solution before filtration showed a value around 7.

[0122] [Example 6]

 The freeze-dried product produced in Example 5 is stored for (1) 60 ° C for 1 week, (2) 60 ° C for 2 weeks, and (3) 60 ° C for 3 weeks. did. (A) Appearance, (b) Appearance when redissolved, (c) pH when redissolved, (d) Moisture content, and (e) Residual rate for each sample after storage and sample before storage (Initial: initial) Each item was evaluated using the evaluation method described in Example 4.

[result] The results obtained are shown in Table 10 to Table 13 below (Table 10: Initial; Table 11: 60 ° C, 1 week; Table 12: 60. C, 2 weeks; Table 13: 60 ° C, 4 weeks). It was. Regarding the appearance and re-dissolution appearance, no change due to storage was observed in any specimen. Regarding the residual rate, those with a pH of 6.5 or less (pH when redissolved), that is, those using lactose showed better results.

[0123] [Table 10] 1 U Initia

[0124] [Table 11]

 Table 11 60¾, 1 遛 閒

 Lot No. 1 Appearance • ft; '仓 fl H Mamoru pM remaining rate

 White 'fflfl 6.46 992 Mart's 1 White' crack 774 96,1

[0125] [Table 12]

[Example 7]

 7—1: Lactose prescription

 [Formulation 7—1 1] Content: 10 gZ vial, additive: lactose

In water for injection, methyl 4-{[2-((lR, 2R, 3R) — 3 hydroxy 1 2— {(IE, 3S) — 3 hydroxy 1 4— [3 (methoxymethyl) phenol] porcine 1 5} oxocyclopentyl) ethyl] sulfar} butanoate _α -cyclodextrin inclusion compound (9.4mg: methyl 4-{[2— ((1R, 2R, 3R) — 3 hydroxy-2— {(IE, 3S) — 3-Hydroxy mono 4- [3- (methoxymethyl) phenol] butane 1-ethyl} —5-oxocyclopentyl) ethyl] sulfar} butanoate 2 mg) and lactose (10 g) The volume was made up to 120 mL using water for injection. After forming a uniform solution, the solution was filtered through a sterile filter (0.22 / zm membrane manufactured by Deyurapore), and 0.6 mL was filled in a silicon-coated glass vial. The vial was cooled to below −40 ° C. to freeze the solution, then gradually warmed at a vacuum of about 20 pascals and dried at 10 ° C. for 7 hours. Thereafter, the lyophilized product of the present invention was produced by final drying at 45 ° C. The appearance of the freeze-dried product was a white lump or powder, and the water content was 1%.

 [Prescription 7-1-2] Content: 100 gZ vial, additive: lactose

In water for injection, methyl 4— {[2— ((1R, 2R, 3R) — 3—hydroxy 1 2— {(IE, 3S) — 3-hydroxy 1 4— [3— (methoxymethyl) phenol] pigs one 1-E - le} - 5-Okiso cyclopentyl) Echiru] sulfa - Le} butanoate _alpha - cyclodextrin clathration compound (94 mg: methyl 4- {[2- ((1R, 2R, 3R) - 3-Hydroxy— 2— {(IE, 3S) — 3-Hydroxy mono 4-— [3- (methoxymethyl) phenol] butane 1-ethyl} — 5-oxocyclopentyl) ethyl] sulfuric} Carrotate 20 mg) and lactose (10 g) as butanoate, and make up to 120 mL with water for injection. After forming a uniform solution, the solution was filtered through a sterile filter (0.22 / zm membrane manufactured by Deyurapore), and 0.6 mL was filled in a silicon-coated glass vial. The vial was cooled to below −40 ° C. to freeze the solution, then gradually warmed at a vacuum of about 20 pascals and dried at 10 ° C. for 7 hours. Thereafter, the lyophilized product of the present invention was produced by final drying at 45 ° C. The appearance of the freeze-dried product was a white lump or powder, and the water content was 1%.

7-2: Maltose prescription

 [Formulation 7—2-1] Content: 10 g / vial, additives: maltose, citrate, sodium hydroxide

In water for injection, methyl 4— {[2— ((1R, 2R, 3R) — 3—hydroxy 1 2— {(IE, 3S) — 3-hydroxy 1 4— [3— (methoxymethyl) phenol] Butylate 1-ethyl} — 5-oxocyclopentyl) ethyl] sulfar} butanoate inclusion compound of _α -cyclodextrin (9.7 mg: methyl 4- {{2- ((1R, 2R, 3R ) — 3—Hydroxy— 2— {(IE, 3S) — 3 Hydroxy 4- [3 (Methoxymethyl) phenol] butayl} 5 oxocyclopentyl) ethyl] sulfar} butanoate 2 mg) and crystalline maltose (lOg) were added, and citrate aqueous solution was added. And an aqueous solution of sodium hydroxide and sodium hydroxide were added to adjust the pH to about 4.0, and 120 mL was prepared using water for injection. After forming a uniform solution, the solution was filtered through a sterile filter (0.22 m membrane manufactured by Deyurapore), and 0.6 mL each was filled into a silicon-coated glass vial. The vial was cooled to below −40 ° C. to freeze the solution, then gradually heated to a vacuum of about 20 Pascals and dried at 10 ° C. for 7 hours. Then, the freeze-dried product of the present invention was produced by final drying at 45 ° C. The appearance of the lyophilized product was a white mass or powder, and the water content was 0.7%.

Industrial applicability

 The composition of the present invention, particularly a lyophilized product, is useful for the prevention, treatment and Z or progression inhibition of bone loss diseases such as vertebral fractures, etc. Methyl 4 {[2-((1R, 2R, 3R) — 3 Hydroxy— 2— {(IE, 3S) — 3 Hydroxy— 4 — [3 — (Methoxymethyl) phenol] butter 1 -ethyl 5--5-year-old oxocyclopentyl) ethyl] sulfar} butanoate Therefore, it can be provided to the clinic in a safe state without deteriorating the quality while maintaining a high residual ratio of active ingredients, and its applicability as a pharmaceutical is extremely high.

Claims

The scope of the claims

 [I] (1) Methyl 4— {[2— ((1R, 2R, 3R) — 3-Hydroxy 1- 2 — {(IE, 3S) — 3-Hydroxy 4-- [3— (Methoxymethyl) [Fuel] butane 1-ethyl} — 5-oxocyclobenthyl) ethyl] sulfanyl} butanoate, its solvate, or their inclusion complex, and (2) a saccharide, and A stable pharmaceutical composition comprising (3) a pH regulator as desired.

 [2] The composition according to claim 1, which is a freeze-dried product.

 [3] The composition according to claim 1, wherein the inclusion compound is an ex-cyclodextrin inclusion complex.

 [4] The composition according to claim 1, wherein the saccharide is lactose or maltose.

 [5] The composition according to claim 4, wherein the saccharide is maltose having a pH of 4.5 to 6.5.

 [6] Methyl 4— {[2— ((1R, 2R, 3R) — 3—Hydroxyl 2— {(IE, 3S) — 3—Hydroxy 4 — [3— (Methoxymethyl) phenol] 1. The composition according to claim 1, comprising 500 parts by weight to 50,000 parts by weight of a saccharide with respect to 1 part by weight of butanoate but 1-ethyl} -5-oxocyclopentyl) ethyl] sulfar} butanoate. .

[7] The composition according to claim 1, wherein the pH regulator is one or more selected from organic acids, metal hydroxides and organic acid metal salts.

[8] The composition according to claim 7, wherein the pH adjuster is (1) citrate and sodium hydroxide, or (2) citrate and sodium taenate.

[9] (1) Methyl 4— {[2— ((1R, 2R, 3R) — 3-Hydroxy mono 2-— {(IE, 3S) — 3-Hydroxy mono 4-— [3— (Methoxymethyl) [Fuyl] butane 1-ethyl} -5-oxocyclobenzoyl) ethyl] sulfar} butanoate inclusion compound of _α -cyclodextrin, and (2) maltose of ρ 6.4.5 to 6.5 A stable pharmaceutical composition comprising (3) citrate and sodium hydroxide.

[10] The composition according to claim 9, which is a freeze-dried product.

[II] Methyl 4— {[2— ((1R, 2R, 3R) — 3—Hydroxyl 2— {(IE, 3S) — 3—Hydroxy 4 — [3— (Methoxymethyl) phenol] pigs - 1 E - le} - 5-O Kiso cyclopentyl) Echiru] sulfa _-. Η4 Ρ to Le} butanoate 1 part by weight 5 to 6.5 maltose 10. The composition according to claim 9, comprising 1000 parts by weight to 10,000 parts by weight.

[12] Methyl 4— {[2— ((1R, 2R, 3R) — 3 Hydroxy 1 — {(IE, 3S) — 3 Hydroxy 4 — [3 (Methoxymethyl) phenol] buta 1 E - le} 5 O Kiso cyclopentyl) Echiru] sulfa -. _P H4 to Le} butanoate 1 part by weight of 5 to 6. 5 maltose comprising 5000 parts by weight composition in the range 11 according claims.

[13] Claim 2 or 2 which is substantially free of moisture or has a moisture content of 1% or less

10. The composition according to 10.

 [14] Methyl 4— {[2— ((1R, 2R, 3R) — 3 Hydroxy 1 2 after storage at 60 ° C for 2 weeks

 {(IE, 3S) 3 Hydroxy 4 [3 (methoxymethyl) phenol] butter 1 -ethyl} 5-oxocyclopentyl) ethyl] sulfur} Butanoate residual rate is more than 85% A composition according to claim 2 or 10.

[15] The stable composition according to claim 14, wherein the residual ratio is 95% or more.

[16] The composition according to claim 2 or 10, which has a form substantially the same as the initial form after storage at 60 ° C for 2 weeks.

[17] The composition according to claim 1, 2, 9, or 10, which is a preparation for injection.

[18] The prevention, treatment, and Z or progression inhibitor of EP4 mediated diseases 1, 2,

The composition according to 9 or 10.

[19] The composition according to claim 18, wherein the EP4-mediated disease is a bone disease.

[20] The composition according to claim 19, wherein the bone disease is a vertebral fracture.

[21] An injection container filled with the composition according to claim 2 or 10.

[22] The container according to claim 21, which is nominal.

 [23] 1 to 12 g of methyl 4— {[2— ((1R, 2R, 3R) — 3 Hydroxy 2— {(1E, 3S) — 3 Hydroxy 4— [3 The container according to claim 21, comprising (methoxymethyl) phenol] butane 1} -5-year-old cyclocyclopentyl) ethyl] sulfur} butanoate.

[24] 2 / zg, 5 / zg, 6 ₈ or 10 ₈ methyl per unit form 4— {[2— ((1R, 2R, 3R) — 3 hydroxy 1 2— {(IE, 3S) — 3 Hydroxy 4- [3- (Methoxymethyl) phenol] butayl 1}} 5-oxocyclopentyl) ethyl] sulfar} buta 24. The container according to claim 23, comprising noate.

[25] (1) Methyl 4— {[2— ((1R, 2R, 3R) — 3-Hydroxy mono 2-— {(IE, 3S) — 3-Hydoxy 4-- [3-— (Methoxymethyl) [Fuel] butane 1-ethyl} -5-oxocyclobenzoyl) ethyl] sulfanyl} butanoate, a solvate thereof, or an inclusion complex thereof, and (2) a saccharide, and (3) A method for producing a stable freeze-dried product, which comprises subjecting an aqueous solution having a pH force of S3 to 6.5 containing a pH regulator to freeze-drying as desired.

 [26] (1) Methyl 4— {[2— ((1R, 2R, 3R) — 3-Hydroxy mono 2-— {(IE, 3S) — 3-Hydoxy 4-- [3-— (Methoxymethyl) [Fuel] butane 1-ethyl} -5-oxocyclobenzoyl) ethyl] sulfanyl} butanoate, a solvate thereof, or an inclusion complex thereof, and (2) a saccharide, and (3) Methyl 4- {[2 in freeze-dried product, characterized in that (3) freeze-dried product is obtained by subjecting aqueous solution of pH power ^ ~ 6.5 containing pH regulator to freeze-drying. — ((1R, 2R, 3R) — 3—Hydroxy 1 2 — {(IE, 3S) — 3 —Hydroxy 1 4 — [3 — (Methoxymethyl) phenol] butane 1—Er} —Oxocyclopentyl) ethyl] sulfar} Butanoate stabilization method.

 [27] A method for preventing, treating, and inhibiting Z or progression of an EP4-mediated disease in a mammal, comprising administering an effective amount of the composition according to claim 1, 2, 9, or 10 to the mammal .

 [28] Use of the composition according to claim 1, 2, 9 or 10 for the prevention, treatment and production of Z or progression inhibitor of EP4-mediated diseases.

[29] Per unit form (1) Methyl 4— {[2— ((1R, 2R, 3R) — 3-Hydroxy 1 2— {(IE, 3S) — 3—Hydroxy— 4— [3— ( Methoxymethyl) phenol] buta-1-ethyl} -5-oxocyclopentyl) ethyl] sulfar} butanoate containing 1 μg to 20 μg of methyl 4-{{2 ((1R, 2R, 3R) — 3—Hydroxyl 2— {(IE, 3S) — 3 —Hydroxy— 4 — [3 — (Methoxymethyl) phenol] buta 1 —ethyl} — 5 —oxocyclopentyl) Ethyl] sulfuric} OC-cyclodextrin inclusion compound of butanoate, and (2) methyl 4-— {[2— ((1R, 2R, 3R) — 3-hydroxy-1- 2— {(IE, 3S) — 3 —Hydroxy-1 4- [3- (methoxymethyl) phenol] but-1-yl} — 5-oxo Mouth pentyl) ethyl] sulfar} butanoate A vial filled with a stable lyophilized product containing 1 to 1000 parts by weight of lactose and 1% by weight or less of water.

 Per unit form, (1) Methyl 4- {[2- ((lR, 2R, 31¾—3—Hydroxy-2-— {(IE, 3S) — 3 Hydroxy 4 — [3 (Methoxymethyl) phenol] buta — 1 ethyl} -5-oxocyclopentyl) ethyl] sulfar} butanoate containing 10 μg of methyl 4— {[2— ((1R, 2R, 3R) — 3 hydroxy 1 2— {( IE, 3S) — 3 Hydroxy-4

[3 (Methoxymethyl) phenyl] buter 1-ethyl} 5-year-old oxocyclopentyl) ethyl] sulfar} butanoate _α -cyclodextrin inclusion compound, and (2) methyl 4- {[2— ((1R, 2R, 3R) — 3 Hydroxy 2— {(IE, 3S) — 3 Hydroxy — 4— [3 (Methoxymethyl) phenol] buta- 1 -ell} 5 oxo Cyclopentyl) ethyl] sulfanyl} butanoate A vial filled with a stable lyophilized product containing 1 part by weight of lactose containing 5000 parts by weight of lactose and having a water content of 1% or less.