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    • 专利摘要:
    The present invention relates to a sustained-release formulation comprising a metastin derivative and a lactic polymer having a weight average molecular weight of about 5,000 to about 40,000 or a salt thereof. The sustained-release formulation of the present invention slowly and stably releases compound (I) or a salt thereof over a long period of time and exerts medicinal effects of compound (I) or a salt thereof over a long period of time. Furthermore, the sustained-release formulation of the present invention, which improves patient's convenience by reducing frequency of administration, is an excellent formulation as a clinical medicine.
    公开号:AU2011270093A1
    申请号:U2011270093
    申请日:2011-06-23
    公开日:2013-01-10
    发明作者:Tomomichi Futo；Seitaro Mizukami；Naoyuki Murata；Hikaru Taira
    申请人:Takeda Pharmaceutical Co Ltd；
    IPC主号:A61K38-08
    专利说明:
    WO 2011/162413 PCT/JP2011/064992 DESCRIPTION SUSTAINED-RELEASE FORMULATION 5 1. TECHNICAL FIELD [0001] The present invention relates to a novel sustained-release formulation and the like which can effectively treat cancer and the like. 10 2. BACKGROUND OF THE INVENTION [0002] As a stable metastin derivative having an excellent metastin-like activity, for example, a compound described in Patent Literature 1 is known. Furthermore, as a sustained-release formulation containing metastin or a derivative thereof, for 15 example, the formulation described in Patent Literature 2 is known. [Citation List] [Patent Literature] [0003] [Patent Literature 1] W02007/72997 20 [Patent Literature 2] W002/85399 3. SUMMARY OF THE INVENTION [Problem to be solved by the Invention] [0004] 25 To obtain benefits from reduction of side effects by requiring no high dosage amount in order to obtain medicinal effects, an improvement of patient's convenience and overcoming pain by reduction of frequency of administration as well as WO 2011/162413 PCT/JP2011/064992 -2 producing medicinal effects over a long period of time, it is desired to develop a sustained-release formulation being capable of slowly releasing a metastin derivative over a long period of time and having excellent properties as a clinical medicine. It is particularly desired to develop a formulation which gives stable and sustained 5 release of compound (I) or a salt thereof over a long period of time. [Solution to the Problem] [0005] The present inventors conducted intensive studies with a view to solving the aforementioned problems, and as a result, found that a sustained-release formulation 10 which contains a metastin derivative or a salt thereof and a lactic acid polymer having a weight average molecular weight of about 5,000 to about 40,000 or a salt thereof according to the present application has excellent properties required for a clinical medicine in medicinal effects, safety, stability, dosage amount, dosage form and usage, and finally achieved the present invention. 15 More specifically, the present invention relates to the following sustained release formulation and a method for producing the same. [1] A sustained-release formulation comprising a compound represented by Formula: Ac-D-Tyr-Hyp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH 2 (I) 20 (in the specification, sometimes simply referred to as compound (I)) or a salt thereof, and a lactic acid polymer having a weight average molecular weight of about 5,000 to about 40,000 or a salt thereof; [2] The sustained-release formulation according to item [1] above, wherein the weight average molecular weight of the lactic acid polymer or a salt thereof is 25 about 13,000 to about 17,000; [3] The sustained-release formulation according to item [1] or [2], which is a 3 to 6-month sustained-release formulation; [4] The sustained-release formulation according to any one of items [1] to [3] above, which is a therapeutic or prophylactic agent for cancer; WO 2011/162413 PCT/JP2011/064992 -3 [5] The sustained-release formulation according to any one of items [1] to [4] above, which is a parenteral agent; and [6] A method for treating or preventing cancer comprising administering an effective amount of the sustained-release formulation according to any of items [1] to 5 [5] above to a mammal; [7] A method for producing the sustained-release formulation according to any of items [1] to [5] above, comprising subjecting (1) a W/O/W emulsion obtained by emulsifying a W/O emulsion composed of an internal water phase containing compound (I) or a salt thereof, and an oil phase 10 containing the lactic acid polymer or a salt thereof, or (2) an O/W emulsion obtained by emulsifying an oil phase containing compound (I) or a salt thereof and the lactic acid polymer or a salt thereof; to an in-water drying method; [8] The method according to item [7], comprising subjecting an O/W 15 emulsion obtained by emulsifying an oil phase containing compound (I) or a salt thereof and the lactic acid polymer or a salt thereof, to an in-water drying method. Furthermore, the present invention also relates to a sustained-release formulation and therapeutic method according to the following aspects. [9] A sustained-release formulation comprising compound (I) or a salt thereof 20 and a lactic acid polymer having a weight average molecular weight of about 5,000 to about 40,000 or a salt thereof, which is used such that compound (I) or a salt thereof is administered to a patient in a dose of about 0.01 to about 4 mg/kg body weight at intervals of once 3 weeks or more (preferably, 1 month); [10] A sustained-release formulation comprising compound (I) or a salt 25 thereof and a lactic acid polymer having a weight average molecular weight of about 5,000 to about 40,000 or a salt thereof, which is used such that compound (I) or a salt thereof is administered to a patient in a dose of about 0.03 to about 12 mg/kg body weight at intervals of once 2 months or more (preferably, 3 months); [11] A sustained-release formulation comprising compound (I) or a salt 30 thereof and a lactic acid polymer having a weight average molecular weight of about WO 2011/162413 PCT/JP2011/064992 -4 5,000 to about 40,000 or a salt thereof, which is used such that compound (I) or a salt thereof is administered to a patient in a dose of about 0.06 to about 24 mg/kg body weight at intervals of once 4 months or more (preferably, 6 months); [12] The sustained-release formulation according to any of items [9] to [11] 5 above produced by a method using (1) a W/O/W emulsion or (2) an O/W emulsion; [13] The sustained-release formulation according to any of items [1] to [5] and [9] to [12] above for use in treating or preventing cancer (for example, lung cancer, stomach cancer, liver cancer, pancreatic cancer, large bowel cancer, rectal cancer, colon cancer, prostatic cancer, ovary cancer, uterine cervix cancer, breast 10 cancer, kidney cancer, bladder cancer, brain tumor), a pancreatic disease (for example, acute or chronic pancreatitis, pancreatic cancer), chorioma, hydatidiform mole, invasive mole, miscarriage, fetus hypogenesis, anomaly of saccharometabolism, lipidosis and abnormal childbirth; [14] The sustained-release formulation according to item [13] above, which is 15 a microcapsule formulation; and [15] A method for treating or preventing cancer (for example, lung cancer, stomach cancer, liver cancer, pancreatic cancer, large bowel cancer, rectal cancer, colon cancer, prostatic cancer, ovary cancer, uterine cervix cancer, breast cancer, kidney cancer, bladder cancer, brain tumor), a pancreatic disease (for example, acute 20 or chronic pancreatitis), chorioma, hydatidiform mole, invasive mole, miscarriage, fetus hypogenesis, anomaly of saccharometabolism, lipidosis and abnormal childbirth, comprising: administering an effective amount of the sustained-release formulation according to item [13] or [14] above to a mammal. [Advantageous Effects of Invention] 25 [0006] The sustained-release formulation of the present invention slowly and stably releases compound (I) or a salt thereof over a long period of time (e.g., 3 weeks or more) and also exerts medicinal effects of compound (I) or a salt thereof over a long period of time. Furthermore, the sustained-release formulation of the present 30 invention provides improved patient's convenience by reducing frequency of administration, and is an excellent formulation as a clinical medicine.
    WO 2011/162413 PCT/JP2011/064992 -5 4. MODE FOR CARRYING OUT THE INVENTION [0007] The present invention will be more specifically described below. 5 [0008] The present invention provides a sustained-release formulation containing a metastin derivative (in the specification, sometimes simply referred to as compound (I)) represented by the following formula: Ac-D-Tyr-Hyp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH 2 (I) 10 (SEQ ID NO: 1) or a salt thereof. [0009] Compound (I) to be used in the present invention may be present in the form of a salt. As the salt formed with compound (I), a pharmacologically acceptable 15 salt is particularly preferable. Examples of such a salt include salts with inorganic acids (for example, hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid); salts with organic acids (for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid); salts with inorganic 20 bases (for example, alkali metal salts such as a sodium salt and potassium salt; alkaline earth metal salts such as a calcium salt and a magnesium salt; an aluminium salt, an ammonium salt) and salts with organic bases (for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N,N-dibenzylethylenediamine). 25 Preferable examples of the salts formed with compound (I) that can be used in the present invention include salts with acetic acid. [0010] Compound (I) or a salt thereof to be used in the present invention can be produced by a known peptide synthesis method, and more specifically, produced by WO 2011/162413 PCT/JP2011/064992 -6 the method described in W02007/72997. [0011] The sustained-release formulation of the present invention contains a lactic acid polymer having a weight average molecular weight of about 5,000 to about 5 40,000 (in the specification, sometimes simply referred to as a lactic acid polymer) or a salt thereof in addition to compound (I) or a salt thereof. [0012] In the present invention, the lactic acid polymer refers to a polymer consisting of lactic acid alone. 10 The weight average molecular weight of the lactic acid polymer or a salt thereof to be used in the present invention is about 5,000 to about 40,000, preferably about 5,000 to about 30,000, further preferably about 6,000 to about 20,000 and further more preferably about 13,000 to about 17,000. The polydispersity of the lactic acid polymer or a salt thereof (weight average 15 molecular weight/number average molecular weight) is preferably about 1.2 to about 4.0 and further preferably about 1.5 to about 3.5. The weight average molecular weight and the polydispersity used in the specification refer to values obtained by gel permeation chromatographic (GPC) measurement. The weight average molecular weight and the content of each 20 polymer are polystyrene-equivalent weight average molecular weight, which is obtained by GPC measurement using, for example, a mono disperse polystyrene as a standard substance, and the content of each polymer calculated from this, respectively. The weight average molecular weight and the content of each polymer can be measured, for example, by a high-speed GPC apparatus (HLC-8120 25 GPC manufactured by Tosoh Corporation). As a column, Super H4000 x 2 and Super H2000 (each manufactured by Tosoh Corporation) can be used. As a mobile phase, tetrahydrofuran can be used and the flow rate can be set to 0.6 mL/min. As a detection method, a differential refractive index can be used. Note that as the lactic acid polymer and a salt thereof, a commercially 30 available product can be used.
    WO 2011/162413 PCT/JP2011/064992 -7 [0013] In the present invention, the lactic acid polymer may be present in the form of a salt. Examples of the salt include salts with inorganic bases (e.g., an alkali metal such as sodium and potassium, an alkaline earth metal such as calcium and 5 magnesium) and organic bases (e.g., an organic amine such as triethylamine, a basic amino acid such as arginine) or salts with transition metals (e.g., zinc, iron, copper) and complex salts. [0014] The sustained-release formulation of the present invention is, for example, 10 produced by mixing compound (I) or a salt thereof and a lactic acid polymer or a salt thereof, and, if necessary, molding thus-obtained mixture. The amount of compound (I) or a salt thereof to be used is, for example, about 0.01 to about 50% (w/w) relative to a lactic acid polymer or a salt thereof, and preferably about 0.1 to about 30% (w/w). 15 [0015] Now, the method for producing a sustained-release formulation according to the present invention will be more specifically described below. [0016] (1) Method for producing rod-form molding and the like 20 [0017] (1-a) A lactic acid polymer or a salt thereof is dissolved in an organic solvent (preferably dichloromethane, etc.) and an aqueous solution of compound (I) or a salt thereof is added and then emulsified. The resulting emulsion is dried in a vacuum 25 to obtain powder having compound (I) or a salt thereof and the lactic acid polymer or a salt thereof uniformly dispersed therein. The powder is warmed and cooled to obtain moldings of disk form, film form, rod form and the like. The warming temperature is, for example, about 50 to about 100'C and cooling temperature is, for example, about 0 to about 40'C. The amount of compound (I) or a salt thereof to 30 be used varies depending upon the type of compound (I) or a salt thereof, desired WO 2011/162413 PCT/JP2011/064992 -8 pharmacological effect and duration of the effect, etc.; however, it is, for example, about 0.01 to about 50% (w/w) relative to the lactic acid polymer or a salt thereof, preferably about 0.1 to about 30% (w/w), and particularly preferably about 1 to about 20% (w/w). 5 [0018] (1-b) A lactic acid polymer or a salt thereof is dissolved in an organic solvent (preferably dichloromethane, etc.) and compound (I) or a salt thereof is uniformly dispersed. The resulting dispersion is dried in a vacuum to obtain powder of the 10 lactic acid polymer or a salt thereof in which compound (I) or a salt thereof is uniformly dispersed. The powder was warmed and cooled to obtain moldings of disk form, film form, rod form and the like. The warming temperature, cooling temperature and amount of compound (I) or a salt thereof to be used are the same as described in the above section (1-a). 15 [0019] (2) Method for producing microcapsule (also referred to as microsphere) (2-a) In-water drying method Microcapsules are produced by subjecting (i) a W (internal water phase)/O (oil phase)/W (external water phase) emulsion, which is obtained by emulsifying a W 20 (internal water phase)/O (oil phase) emulsion composed of an internal water phase containing compound (I) or a salt thereof and an oil phase containing a lactic acid polymer or a salt thereof, or (ii) an 0 (oil phase)/W (external water phase) emulsion, which is obtained by emulsifying an oil phase containing compound (I) or a salt thereof and a lactic acid polymer or a salt thereof, to an in-water-drying method. 25 [0020] The above emulsion (i), that is, the W/O emulsion composed of an internal water phase containing compound (I) or a salt thereof and an oil phase containing a lactic acid polymer or a salt thereof, is produced as follows. First, compound (I) or a salt thereof is dissolved, dispersed or suspended in 30 water to produce the internal water phase. The concentration of compound (I) or a WO 2011/162413 PCT/JP2011/064992 -9 salt thereof in water is, for example, 0.001 to 90% (w/w) and preferably 0.01 to 80% (w/w). The amount of compound (I) or a salt thereof to be used varies depending upon the type of compound (I) or a salt thereof, desired pharmacological effect, 5 duration of the effect and the like; it is, for example, about 0.01 to about 50% (w/w) relative to a lactic acid polymer or a salt thereof, preferably about 0.1 to about 30% (w/w) and further preferably about 1 to about 20% (w/w). If necessary, to enhance uptake of compound (I) or a salt thereof in a microcapsule, a drug retaining substance such as gelatin, agar, sodium alginate, 10 polyvinyl alcohol or basic amino acid (for example, arginine, histidine, lysine), may be added to an internal water phase. The amount of the drug retaining substance to be added is usually about 0.01 to about 10 fold by weight relative to compound (I) or a salt thereof. The internal water phase may be once lyophilized into powder and thereafter 15 dissolved by adding water so as to obtain an appropriate concentration and then put in use. Separately, a lactic acid polymer or a salt thereof is dissolved in an organic solvent to produce an oil phase. Examples of the organic solvent include halogenated hydrocarbons (for 20 example, dichloromethane, chloroform, chloroethane, trichloroethane, carbon tetrachloride), fatty acid esters (for example, ethyl acetate, butyl acetate) and aromatic hydrocarbons (for example, benzene, toluene, xylene). Among others, dichloromethane is preferable. The concentration of a lactic acid polymer or a salt thereof in an organic 25 solvent varies depending upon the type and weight average molecular weight of the lactic acid polymer or a salt thereof and the type of organic solvent; usually, a value expressed by the formula: [weight of a lactic acid polymer or a salt thereof /(weight of an organic solvent + weight of a lactic acid polymer or a salt thereof)] (x 100%) 30 is about 0.01 to about 90% (w/w) and preferably about 0.01 to about 70% (w/w).
    WO 2011/162413 PCT/JP2011/064992 -10 The oil phase desirably contains no insoluble matter. To the organic solvent solution (oil phase) of a lactic acid polymer or a salt thereof thus obtained, an aqueous solution, dispersion or suspension (internal water phase) of compound (I) or a salt thereof is added, dispersed and emulsified by a 5 homomixer, etc., to produce a W/O emulsion. When the W/O emulsion is produced at room temperature (about 19 to 25'C), the resulting W/O emulsion changes with the passage of time to a state (e.g., gelatinous state), which is unfavorable to secondary emulsification (later described). In this case, it is sometimes difficult to produce microcapsules in high yield (the 10 yield used herein refers to a ratio of the weight of compound (I) or a salt thereof contained in microcapsules to the weight of compound (I) or a salt thereof used for a W/O emulsion). To prevent such a change, it is preferred that the temperature of a W/O emulsion produced is controlled to be 3 PC or more (preferably 31 to 33'C). 15 [0021] On the other hand, the above emulsion (ii), that is, the oil phase containing compound (I) or a salt thereof and a lactic acid polymer or a salt thereof, is produced as follows. First, an organic solvent solution of a lactic acid polymer or a salt thereof is 20 produced. As the organic solvent, the same organic solvent used for producing the above W/O emulsion is used. The concentration of a lactic acid polymer or a salt thereof in an organic solvent solution varies depending upon the type and weight average molecular weight of the lactic acid polymer or a salt thereof and the type of organic solvent; 25 usually, a value expressed by the formula: [weight of a lactic acid polymer or a salt thereof/(weight of an organic solvent + weight of a lactic acid polymer or a salt thereof)] (x 100%) is about 0.01 to about 70% (w/w) and preferably about 1 to about 60% (w/w). Next, compound (I) or a salt thereof is dissolved or suspended in the organic WO 2011/162413 PCT/JP2011/064992 - 11 solvent solution of a lactic acid polymer or a salt thereof to prepare an oil phase. The oil phase can be produced also by dissolving or suspending a solution, which is prepared by dissolving compound (I) or a salt thereof in an alcohol, in the organic solvent solution of a lactic acid polymer or a salt thereof Examples of the alcohol 5 for dissolving compound (I) or a salt thereof include methanol. The amount of compound (I) or a salt thereof to be used may be selected such that the ratio of compound (I) or a salt thereof relative to a lactic acid polymer or a salt thereof is similar to that employed in producing the (i) W/O emulsion above. [0022] 10 Subsequently, the above (i) W/O emulsion or (ii) oil phase is added to an external water phase, dispersed and emulsified (secondary emulsification) by a homomixer, etc. to produce an emulsion (hereinafter, the emulsion obtained from the W/O emulsion is sometimes referred to as a W/O/W emulsion, whereas the emulsion obtained from the (ii) oil phase is sometimes referred to as an O/W emulsion). 15 The amount of external water phase to be used is usually about 1 to about 10,000 fold by volume relative to the W/O emulsion or oil phase, preferably about 10 to about 5,000 fold by volume and particularly preferably about 50 to about 1,000 fold by volume. To the external water phase, an emulsifier is usually added. As the 20 emulsifier, any emulsifier can be used as long as it can usually form a stable W/O/W emulsion or O/W emulsion. Examples thereof include an anionic surfactant, a nonionic surfactant, a polyoxyethylene castor oil derivative, polyvinylpyrrolidone, polyvinyl alcohol, carboxymethylcellulose, lecithin, gelatin and hyaluronic acid. Among others, polyvinyl alcohol is preferable. The concentration of an emulsifier 25 in an external water phase is usually about 0.001 to about 20% (w/w), preferably about 0.01 to about 10% (w/w) and particularly preferably about 0.05 to about 5% (w/w). [0023] The W/O/W emulsion or O/W emulsion (hereinafter, these each may 30 sometimes simply be referred to as an emulsion) thus obtained is subjected to an in water-drying method to remove an organic solvent contained in the emulsion. In WO 2011/162413 PCT/JP2011/064992 - 12 this manner, microcapsules can be produced. [0024] Furthermore, other than the method using the aforementioned W/0/W emulsion or O/W emulsion, there is a production method in which an S (solid 5 phase)/O (oil phase) emulsion, which is composed of a solid phase containing compound (I) or a salt thereof and a lactic acid polymer or a salt thereof, is subjected to an in-water-drying method. [0025] First, a lactic acid polymer or a salt thereof is dissolved in an organic solvent. 10 In the resulting organic solvent solution, compound (I) or a salt thereof is dispersed. At this time, the amounts of compound (I) or a salt thereof and lactic acid polymer or a salt thereof to be used may be selected such that the ratio of compound (I) or a salt thereof to the lactic acid polymer or a salt thereof becomes the same as in producing the above (i) W/O emulsion. Furthermore, to uniformly disperse compound (I) or a 15 salt thereof in the organic solvent, for example, ultrasonic irradiation, a turbine-form stirrer or a homogenizer, is used. Next, the S/0 emulsion thus prepared is further added to an external water phase and dispersed and emulsified by use of, for example, ultrasonic irradiation, a turbine-form stirrer or a homogenizer to produce an emulsion (hereinafter sometimes 20 referred to as an S (solid phase)/O (oil phase)/W (water phase) emulsion). Thereafter, the oil-phase solvent is vaporized to produce microcapsules. At this time, the volume of the water phase is generally selected from about 1 fold to about 10,000 fold of the oil phase by volume, further preferably about 10 fold to about 5,000 fold and particularly preferably about 50 fold to about 1,000 fold. 25 To the external water phase, an emulsifier as mentioned above may be added. The amount of external water phase to be added and the type and concentration of emulsifier to be added to the external water phase are the same as those employed in producing the above W/0/W emulsion. The S/0/W emulsion thus obtained is subjected to an in-water-drying method 30 to remove an organic solvent. In this manner, microcapsules can be produced.
    WO 2011/162413 PCT/JP2011/064992 - 13 [0026] The microcapsules obtained by using a W/0/W emulsion, an O/W emulsion, an S/O/W emulsion were separated by centrifugation, sieving or filtration, and then, if necessary, washed with distilled water to remove an emulsifier, etc. attached to the 5 surface of microcapsules. Thereafter, the microcapsules are dispersed in distilled water, etc., lyophilized, and, if necessary, warmed to further remove water and an organic solvent in the microcapsule. Warming may be performed under reduced pressure. As the conditions for a warming step, heat dry is performed at a temperature, which is not less than a glass-transition temperature of the lactic acid 10 polymer or a salt thereof used herein and at which microcapsule particles are not adhered to each other. Preferably, heat dry is performed in the temperature range from the glass-transition temperature of a lactic acid polymer or a salt thereof to a temperature higher by about 30'C thereof. The glass-transition temperature used herein refers to a medium point of the temperatures obtained by measuring using a 15 differential scanning calorimeter at a temperature raising rate of 10 to 20*C/minute. [0027] (2-b) Phase separation method When microcapsules are produced by this method, a coacervation agent is gradually added under stirring to the W/O emulsion described in the above (2-a) "in 20 water-drying method". In this manner, microcapsules are precipitated and solidified. The amount of coacervation agent is selected from about 0.01 to about 1,000 fold of oil phase volume, preferably about 0.05 to about 500 fold and particularly preferably about 0.1 to about 200 fold. The coacervation agent is not particularly limited as long as it is a polymer 25 compound, a mineral-oil based compound or a vegetable-oil based compound, etc. that is miscible with an organic solvent and does not dissolve a biodegradable polymer of the present invention. Specific examples thereof that may be used include silicon oil, sesame oil, soybean oil, corn oil, cotton seed oil, coconut oil, linseed oil, mineral oil, n-hexane and n-heptane. These may be used as a mixture of 30 two types or more. After the microcapsules thus obtained are separated, they are repeatedly WO 2011/162413 PCT/JP2011/064992 -14 washed with heptane, etc. to remove the coacervation agent except a physiologically active substance and a composition formed of a biodegradable polymer of the present invention and dried under reduced pressure. Alternatively, washing is performed in the same manner as described in the above (2-a) "in-water-drying method", followed 5 by lyophilizing and warm-drying. [0028] (2-c) Spray drying method When microcapsules are produced by this method, the W/O emulsion described in the above (2-a) "in-water-drying method" is sprayed by a nozzle in a 10 dehydration chamber of a spray drier to volatilize the organic solvent within micro liquid drops within an extremely short time to produce microcapsules. Examples of the nozzle include a two-fluid nozzle type, a pressure nozzle type and a rotation disk type. Thereafter, if necessary, washing is performed in the same manner as described in the above (2-a) "in-water-drying method" and thereafter may be 15 lyophilized and further dried by warming. As the dosage form other than the aforementioned microcapsule, microparticles may be mentioned, which are obtained by drying the W/O emulsion described in the above (2-a) "in-water-drying method", for example, by a rotary evaporator, into a solid, while vaporizing an organic solvent and water by controlling 20 the degree of vacuum, and thereafter pulverizing by a jet mill, etc. Furthermore, the microparticles pulverized are washed in the same manner as described in the above (2-a) "in-water-drying method" and thereafter may be lyophilized and further dried by warming. [0029] 25 In dispersing the microcapsules produced in the above section (2-a), (2-b) or (2-c) in distilled water, etc., an aggregation preventing agent may be added in order to prevent aggregation of particles. Examples of the aggregation preventing agent include water soluble polysaccharides such as mannitol, lactose, glucose, a starch (for example, cornstarch) and hyaluronic acid or an alkali metal salt thereof; proteins 30 such as glycine, fibrin and collagen; and inorganic salts such as sodium chloride and sodium hydrogenphosphate. Among others, mannitol is preferable. The amount WO 2011/162413 PCT/JP2011/064992 - 15 of aggregation preventing agent to be used is preferably about 2 to about 100 parts by weight relative to microcapsule (100 parts by weight) and further preferably about 10 to about 25 parts by weight. Furthermore, microcapsules may be warmed and then cooled in the same 5 manner as described in the case of the above (1-a) to obtain moldings of disk form, film form and rod form, etc. [0030] The content of compound (I) or a salt thereof in a microcapsule is not particularly limited; however, the content of a 3-month sustained-release formulation 10 is, for example, 4% or more to 10% or less and preferably 6% or more to 10% or less. Furthermore, the content of a 6-month sustained-release formulation is, for example, 4% or more to 18% or less, preferably 6% or more to 16% or less and more preferably 7% or more to 10% or less. [0031] 15 Of the various production methods mentioned above, a production method, which includes subjecting an O/W emulsion obtained by emulsifying an oil phase containing compound (I) or a salt thereof and a lactic acid polymer or a salt thereof, to an in-water drying method is preferred, in view of the sustained release period of the sustained-release formulation of the present invention. 20 [0032] In various production methods as mentioned above, in dissolving a lactic acid polymer or a salt thereof in an organic solvent, zinc oxide may be added to the organic solvent. The amount of zinc oxide to be used is, for example, about 0.01 to about 100 25 parts by weight relative to a lactic acid polymer (100 parts by weight), preferably about 0.1 to about 20 parts by weight. Furthermore, the particle size of zinc oxide is usually about 0.001 to about 10 pm and preferably about 0.005 to about 1 pm. Likewise, the sustained-release formulation obtained by using zinc oxide has 30 excellent properties, such as "high uptake rate of a drug", "ability to persistently WO 2011/162413 PCT/JP2011/064992 -16 release a drug over a long period of time", etc. In producing the sustained-release formulation of the present invention, compound (I) or a salt thereof may be dissolved in an aqueous solution of a volatile salt, for example, ammonium acetate, lyophilized and then put in use. 5 The lyophilized product of compound (I) or a salt thereof obtained by treating with ammonium acetate in this way has a small particle size and excellent operability, and thus advantageous in producing a sustained-release formulation. [0033] The sustained-release formulation of the present invention thus obtained, if 10 desired, may appropriately contain pharmaceutically acceptable additives (for example, a stabilizer, a preservative, a soothing agent). Examples of the dosage form of the sustained-release formulation of the present invention include parenteral agents (for example, an injection, an implantation, a suppository) and oral administration agents (for example, a solid formulation such as a capsule agent, a 15 tablet, a granule and a powder; liquid formulation such as a syrup, an emulsion and a suspension). Examples of the stabilizer include human serum albumin and polyethylene glycol. Examples of the preservative include benzyl alcohol and phenol. Examples of the soothing agent include benzalkonium chloride and procaine hydrochloride. In the sustained-release formulation of the present 20 invention, the content of compound (I) or a salt thereof can be usually and appropriately selected within the range of about 0.01 to about 33% (w/w) relative to the total sustained-release formulation. [0034] The sustained-release formulation of the present invention is excellent in that 25 a blood drug concentration of compound (I) or a salt thereof is stable in a sustained release period. [0035] The sustained-release formulation of the present invention is preferably a parenteral agent and further preferably an injection. For example, when the 30 sustained-release formulation is in the form of microcapsules, the microcapsules are WO 2011/162413 PCT/JP2011/064992 -17 used in combination with a dispersant (e.g., a surfactant such as Tween 80 and HCO 60; and a polysaccharide such as carboxymethylcellulose, sodium alginate and hyaluronic acid), a preservative (e.g., methylparaben and propylparaben) and an isotonic agent (e.g., sodium chloride, mannitol, sorbitol and glucose) etc. to prepare 5 an aqueous suspension. In this manner, a sustained-release injection can be obtained. Furthermore, a sustained-release injection can be obtained also by dispersing microcapsules in a vegetable oil such as sesame oil and corn oil or in the vegetable oil to which a phospholipid such as lecithin is added, or in a medium chain triglyceride (e.g., Miglyol 812) to obtain an oily suspension. 10 When the sustained-release formulation is, for example, in the form of microcapsules, the particle size of microcapsules that are used as a suspension injection may be satisfactory if it satisfies the polydispersity and the range passing through a syringe needle. As an average particle size thereof, for example, the range of about 0.1 to about 300 pm may be mentioned. The average particle size 15 thereof preferably falls within the range of about 1 to about 150 pm and particularly preferably about 2 to about 100 pm. The aforementioned microcapsules are aseptically treated by a method of performing the whole production steps in aseptic conditions, a method of sterilizing with gamma ray and a method of adding an aseptic agent. The method is not 20 particularly limited. [0036] Since the sustained-release formulation of the present invention is low in its toxicity, it can be safely administered orally or parenterally to mammals (for example, human, monkey, hamadryas, chimpanzee, pig, cow, sheep, horse, dog, cat, 25 mouse, rat). [0037] The sustained-release formulation of the present invention can be used for treating or preventing all diseases in which a physiological activity of metastin is involved. In particular, the sustained-release formulation of the present invention 30 can be effectively used in treating or preventing cancer (for example, lung cancer, stomach cancer, liver cancer, pancreatic cancer, large bowel cancer, rectal cancer, WO 2011/162413 PCT/JP2011/064992 - 18 colon cancer, prostatic cancer, ovary cancer, uterine cervix cancer, breast cancer, kidney cancer, bladder cancer, brain tumor), a pancreatic disease (for example, acute or chronic pancreatitis), chorioma, hydatidiform mole, invasive mole, miscarriage, fetus hypogenesis, anomaly of saccharometabolism, lipidosis and abnormal 5 childbirth. The sustained-release formulation of the present invention is particularly useful as a therapeutic agent or prophylactic agent for cancer (preferably prostatic cancer). [0038] 10 The dose of the sustained-release formulation of the present invention can be appropriately selected depending upon the type and content of an active ingredient, i.e., compound (I) or a salt thereof, dosage form, duration of release, a subject for administration, administration route, administration purpose, target disease and symptom, etc.; however, the dose may be satisfactory as long as the active ingredient 15 can be maintained in a living body in a pharmaceutically effective concentration in a desired duration. For example, in the therapy for an adult cancer patient, when the sustained-release formulation of the present invention is administered, for example, via injection for an about 1-month sustained-release, compound (I) or a salt thereof is used in an amount of, for example, within the range of about 0.01 to about 4 mg/kg 20 body weight, and preferably about 0.03 to 0.6 mg/kg body weight per administration. Furthermore, when the sustained-release formulation of the present invention is administered via injection for an about 3-month sustained-release, compound (I) or a salt thereof is used in an amount of, for example, within the range of about 0.03 to about 12 mg/kg body weight, and preferably about 0.09 to about 1.8 mg/kg body 25 weight per administration. Moreover, when the sustained-release formulation of the present invention is administered via injection for an about 6-month sustained release, compound (I) or a salt thereof is used in an amount of, for example, within the range of about 0.06 to about 24 mg/kg body weight, and preferably about 0.18 to about 3.6 mg/kg body weight per administration. The administration frequency is, 30 for example, once per month, once per 3 months, once per 6 months and can be appropriately selected depending upon the content of compound (I) or a salt thereof, dosage form, duration of release, a target disease and a subject for administration, WO 2011/162413 PCT/JP2011/064992 - 19 etc. As the sustained-release formulation of the present invention, preferably a 1 to 8-month sustained-release formulation (that is, a formulation slowly releasing compound (I) or a salt thereof during the period of I to 8 months), more preferably a 1 to 6-month sustained-release formulation, further preferably a 3 to 6-month 5 sustained release formulation and further more preferably a 6-month sustained release formulation is used. [0039] Furthermore, the sustained-release formulation of the present invention can be used in combination with other medicines (hereinafter, simply referred to as a 10 combined medicine) for various diseases for which compound (I) or a salt thereof pharmaceutically effectively works, in particular, medicinal agents such as a chemotherapeutic agent, a hormonal therapeutic agent and an immunotherapeutic agent for cancer treatment. In such cases, the administration periods of the sustained-release formulation of the present invention and the combined medicine 15 are not limited. They can be administered to a subject for administration simultaneously or at a time interval. The dosage amount of combined medicine can be appropriately selected based on clinical dosage amount. Furthermore, a blending ratio of the sustained-release formulation of the present invention and a combined medicine can be appropriately selected depending upon a subject for administration, 20 administration route, target disease, symptom and combination, etc. [0040] Examples of the chemotherapeutic agent include alkylating agents (for example, cyclophosphamide, ifosfamide, nimustine, ranimustine, carboquone), antimetabolites (for example, methotrexate, 5-fluorouracil, tegafur, carmofur, UFT, 25 doxifluridine, cytarabine, enocitabine, mercaptopurine, mercaptopurine riboside, thioguanine), anticancer antibiotic substances (for example, mitomycin, adriamycin, daunorubicin, epirubicin, pirarubicin, idarubicin, bleomycin, peplomycin, actinomycin) and plant-derived anticancer agents (for example, vincristine, vinblastine, vindesine, etoposide, camptothecine, irinotecan), cisplatin, carboplatin, 30 nedaplatin, paclitaxel, docetaxel and estramustine. [0041] WO 2011/162413 PCT/JP2011/064992 - 20 Examples of the hormonal therapeutic agent include, adrenocortical hormones (for example, prednisolone, prednisone, dexamethasone, cortisone acetate), estrogens (for example, estradiol, ethinylestradiol, fosfestrol, chlorotrianisene), antiestrogen (for example, epitiostanol, mepitiostane, tamoxifen, clomiphene), progesterons (for 5 example, hydroxyprogesterone caproate, dydrogesterone, medroxyprogesterone, norethisterone, norethindrone) and LHRH derivatives (for example, leuprorelin acetate). Examples of the immunotherapeutic agent include microbial or bacterial components (for example, a muramyldipeptide derivative, picibanil), polysaccharides 10 having an immunological-enhancing activity (for example, lentinan, sizofiran, krestin), cytokines obtained by a genetic engineering approach (for example, interferon, interleukin 2(IL-2), interleukin 12 (IL-12), tumor necrosis factor (TNF)) and colony stimulating factors (for example, granulocyte colony stimulating factor, erythropoietin). 15 [0042] Furthermore, medicines that are confirmed to have an effect of ameliorating cachexia in animal models or clinical practice; more specifically, cyclooxygenase inhibitors (for example, indomethacin) [Cancer Research, Vol. 49, pages 5935 to 5939, 1989], progesterone derivatives (for example, megesterol acetate)[Journal of 20 Clinical Oncology, Vol. 12, pages 213 to 225, 1994], glucocorticosteroids (for example, dexamethasone), metoclopramide based medicines, tetrahydrocannabinol based medicines (literatures are the same as mentioned above), fat metabolism improving agents (for example, eicosapentaenoic acid)[British Journal of Cancer, Vol. 68, pages 314 to 318, 1993], growth hormone, IGF-1, or antibodies against a 25 factor of inducing cachexia, i.e., TNF-c, LIF, IL-6, oncostatin M can be used in combination with the sustained-release formulation of the present invention. [0043] Other than these, general medicines for use in treating or preventing diseases of the placenta and pancreas can be used as combined medicines. Examples of such 30 medicines include an anti-inflammatory agent, an antipyretic/analgesic agent, an antibacterial agent, an antiviral agent and a hormonal agent that are clinically used in WO 2011/162413 PCT/JP2011/064992 - 21 general. [0044] In the specification, when bases and amino acids, etc. are expressed by abbreviations, they are expressed based on IUPAC IUB Commission on Biochemical 5 Nomenclature or conventional abbreviations routinely used in the art. Examples thereof are as follows. When an optical isomer of an amino acid is conceivably present, unless otherwise specified, an L-form amino acid is shown. Ac acetyl AzaGly azaglycine 10 Hyp trans-4-hydroxyproline Leu leucine Thr threonine Arg(Me) : No-methyl arginine Phe phenylalanine 15 Tyr :tyrosine Trp tryptophan Asn asparagine 5. EXAMPLES 20 [0045] The present invention will be more specifically explained below by way of Examples and Test Examples; however, the present invention is not limited thereto. Except for the active component, substances described in, e.g., the Japanese Pharmacopeia, 15th revision, Japanese Standards for Pharmaceutical Ingredients, or 25 adaptive substances listed in the standard for pharmaceutical additive 2003 were used as components (i.e., additives) for the prescriptions described as Examples below. [0046] WO 2011/162413 PCT/JP2011/064992 - 22 Example 1 A lactic acid polymer (weight average molecular weight Mw: 6,500, number average molecular weight Mn: 2,800, Mw/Mn ratio: 2.3; manufactured by Wako Pure Chemical Industries Ltd.) (7.0417 g) was dissolved in dichloromethane (13.186 5 g). This solution (15.56 g) was weighed and blended with a solution prepared by dissolving an acetate of compound (I) (0.7406 g) in methanol (2.819 g) to obtain an oil phase. Subsequently, the oil phase was poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) solution (1 liter), which was previously adjusted to about 18*C, and 10 emulsified by use of a turbine-form homomixer (manufactured by Tokushukika) to prepare an O/W emulsion (evolution of turbine: about 7,000 rpm). The O/W emulsion was stirred for about 3 hours (in-water-drying step) and sieved by use of a 75 pim standard sieve, and then, microspheres were collected by centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, 15 manufactured by Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.855 g) was added. The mixture was lyophilized by a lyophilizer (DF-OIH, ULVAC) to obtain microcapsule powder. The content of compound (I) in the resulting microcapsule 20 powder was 8.1%. [0047] Example 2 A lactic acid polymer (weight average molecular weight Mw: 8,000, number average molecular weight Mn: 3,400, Mw/Mn ratio: 2.4; manufactured by Wako 25 Pure Chemical Industries Ltd.) (7.0530 g) was dissolved in dichloromethane (13.269 g). This solution (15.82 g) was weighed and blended with a solution prepared by dissolving an acetate of compound (I) (0.7398 g) in methanol (2.832 g) to obtain an oil phase. Subsequently, the oil phase was poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry 30 Co., Ltd.) solution (1 liter), which was previously adjusted to about 18*C, and emulsified by use of a turbine-form homomixer (manufactured by Tokushukika) to WO 2011/162413 PCT/JP2011/064992 - 23 prepare an O/W emulsion (evolution of turbine: about 7,000 rpm). The O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 pm standard sieve, and then, microspheres were collected by centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5 5DL, manufactured by Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.866 g) was added. The mixture was lyophilized by a lyophilizer (DF-O1H, ULVAC) to obtain microcapsule powder. The content of compound (I) in the 10 resulting microcapsule powder was 8.4%. [0048] Example 3 A lactic acid polymer (weight average molecular weight Mw: 10,000, number average molecular weight Mn: 4,000, Mw/Mn ratio: 2.5; manufactured by Wako 15 Pure Chemical Industries Ltd.) (7.0405 g) was dissolved in dichloromethane (13.184 g). This solution (15.54 g) was weighed and blended with a solution prepared by dissolving an acetate of compound (I) (0.7397 g) in methanol (2.82 g) to obtain an oil phase. Subsequently, the oil phase was poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) 20 solution (1 liter), which was previously adjusted to about 18'C, and emulsified by use of a turbine-form homomixer (manufactured by Tokushukika) to prepare an O/W emulsion (evolution of turbine: about 7,000 rpm). The O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 pm standard sieve, and then, microspheres were collected by centrifugation (rotation 25 rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.840 g) was added. The mixture was lyophilized by a lyophilizer (DF-01H, ULVAC) to obtain microcapsule powder. 30 The content of compound (I) in the resulting microcapsule powder was 8.6%. [0049] WO 2011/162413 PCT/JP2011/064992 - 24 Example 4 A lactic acid polymer (weight average molecular weight Mw: 11,800, number average molecular weight Mn: 4,900, Mw/Mn ratio: 2.4; manufactured by Wako Pure Chemical Industries Ltd.) (13.3028 g) was dissolved in dichloromethane (24.15 5 g). This solution (15.60 g) was weighed and blended with a solution prepared by dissolving an acetate of compound (I) (0.7417 g) in methanol (2.83 g) to obtain an oil phase. Subsequently, the oil phase was poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) solution (1 liter), which was previously adjusted to about 18'C, and emulsified by 10 use of a turbine-form homomixer (manufactured by Tokushukika) to prepare an O/W emulsion (evolution of turbine: about 7,000 rpm). The O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 ptm standard sieve, and then, microspheres were collected by centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by 15 Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.852 g) was added. The mixture was lyophilized by a lyophilizer (DF-01H, ULVAC) to obtain microcapsule powder. The content of compound (I) in the resulting microcapsule powder was 8.6%. 20 [0050] Example 5 A lactic acid polymer (weight average molecular weight Mw: 8,000, number average molecular weight Mn: 3,400, Mw/Mn ratio: 2.4; manufactured by Wako Pure Chemical Industries Ltd.) (13.3374 g) was dissolved in dichloromethane (24.47 25 g). This solution (15.54 g) was weighed and blended with an aqueous solution prepared by dissolving an acetate of compound (I) (0.7450 g) in distilled water (0.60 g) and emulsified by a small homogenizer (KINEMATICA) to form a W/O emulsion (rotation rate: about 10,000 rpm, 30 sec). Subsequently, the W/O emulsion was adjusted to 32*C and poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, 30 manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) solution (1 liter), which was previously adjusted to about 18'C, and subjected to secondary WO 2011/162413 PCT/JP2011/064992 - 25 emulsification using a turbine-form homomixer (manufactured by Tokushukika) to obtain a W/O/W emulsion (evolution of turbine: about 7,000 rpm). The W/O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 pm standard sieve, and then, microspheres were collected by 5 centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.872 g) was added. The mixture was lyophilized by a lyophilizer (DF-01H, 10 ULVAC) to obtain microcapsule powder. The content of compound (I) in the resulting microcapsule powder was 7.2%. [0051] Example 6 A lactic acid polymer (weight average molecular weight Mw: 10,000, number 15 average molecular weight Mn: 4,000, Mw/Mn ratio: 2.5; manufactured by Wako Pure Chemical Industries Ltd.) (13.3334 g) was dissolved in dichloromethane (24.30 g). This solution (15.90 g) was weighed and blended with an aqueous solution prepared by dissolving an acetate of compound (I) (0.7554 g) in distilled water (0.60 g) and emulsified by a small homogenizer (KINEMATICA) to form a W/O emulsion 20 (rotation rate: about 10,000 rpm, 30 sec). Subsequently, the W/O emulsion was adjusted to 32'C and poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) solution (1 liter), which was previously adjusted to about 18'C, and subjected to secondary emulsification using a turbine-form homomixer (manufactured by Tokushukika) to 25 obtain a W/O/W emulsion (evolution of turbine: about 7,000 rpm). The W/O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 ptm standard sieve, and then, microspheres were collected by centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by Hitachi, Ltd.). This was dispersed again in distilled water 30 and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol WO 2011/162413 PCT/JP2011/064992 - 26 (0.864 g) was added. The mixture was lyophilized by a lyophilizer (DF-01H, ULVAC) to obtain microcapsule powder. The content of compound (I) in the resulting microcapsule powder was 7.2%. [0052] 5 Example 7 A lactic acid polymer (weight average molecular weight Mw: 11,800, number average molecular weight Mn: 4,900, Mw/Mn ratio: 2.4; manufactured by Wako Pure Chemical Industries Ltd.) (13.2307 g) was dissolved in dichloromethane (24.74 g). This solution (15.57 g) was weighed and blended with an aqueous solution 10 prepared by dissolving an acetate of compound (I) (0.7589 g) in distilled water (0.60 g) and emulsified by a small homogenizer (KINEMATICA) to form a W/O emulsion (rotation rate: about 10,000 rpm, 30 sec). Subsequently, the W/O emulsion was adjusted to 32'C and poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) solution (1 liter), 15 which was previously adjusted to about 18'C, and subjected to secondary emulsification using a turbine-form homomixer (manufactured by Tokushukika) to obtain a W/O/W emulsion (evolution of turbine: about 7,000 rpm). The W/O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 ptm standard sieve, and then, microspheres were collected by 20 centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.845 g) was added. The mixture was lyophilized by a lyophilizer (DF-01H, 25 ULVAC) to obtain microcapsule powder. The content of compound (I) in the resulting microcapsule powder was 6.8%. [0053] Example 8 A lactic acid polymer (weight average molecular weight Mw: 6,500, number 30 average molecular weight Mn: 2,800, Mw/Mn ratio: 2.3; manufactured by Wako Pure Chemical Industries Ltd.) (6.2666 g) was dissolved in dichloromethane (10.975 WO 2011/162413 PCT/JP2011/064992 - 27 g). This solution (13.20 g) was weighed and blended with a solution prepared by dissolving an acetate of compound (I) (1.4825 g) in methanol (5.61 g) to obtain an oil phase. Subsequently, the oil phase was poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) 5 solution (1 liter), which was previously adjusted to about 18*C, and emulsified by use of a turbine-form homomixer (manufactured by Tokushukika) to prepare an O/W emulsion (evolution of turbine: about 7,000 rpm). The O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 Pm standard sieve, and then, microspheres were collected by centrifugation (rotation 10 rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.851 g) was added. The mixture was lyophilized by a lyophilizer (DF-OIH, ULVAC) to obtain microcapsule powder. 15 The content of compound (I) in the resulting microcapsule powder was 16.4%. [0054] Example 9 A lactic acid polymer (weight average molecular weight Mw: 8,000, number average molecular weight Mn: 3,400, Mw/Mn ratio: 2.4; manufactured by Wako 20 Pure Chemical Industries Ltd.) (6.2621 g) was dissolved in dichloromethane (10.948 g). This solution (13.22 g) was weighed and blended with a solution prepared by dissolving an acetate of compound (I) (1.4795 g) in methanol (5.60 g) to obtain an oil phase. Subsequently, the oil phase was poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) 25 solution (1 liter), which was previously adjusted to about 18'C, and emulsified by use of a turbine-form homomixer (manufactured by Tokushukika) to prepare an O/W emulsion (evolution of turbine: about 7,000 rpm). The O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 Pim standard sieve, and then, microspheres were collected by centrifugation (rotation 30 rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to WO 2011/162413 PCT/JP2011/064992 - 28 wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.854 g) was added. The mixture was lyophilized by a lyophilizer (DF-01H, ULVAC) to obtain microcapsule powder. The content of compound (I) in the resulting microcapsule powder was 16.4%. 5 [0055] Example 10 A lactic acid polymer (weight average molecular weight Mw: 10,000, number average molecular weight Mn: 4,000, Mw/Mn ratio: 2.5; manufactured by Wako Pure Chemical Industries Ltd.) (6.2617 g) was dissolved in dichloromethane (10.971 10 g). This solution (13.18 g) was weighed and blended with a solution prepared by dissolving an acetate of compound (I) (1.4775 g) in methanol (5.63 g) to obtain an oil phase. Subsequently, the oil phase was poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) solution (1 liter), which was previously adjusted to about 18*C, and emulsified by 15 use of a turbine-form homomixer (manufactured by Tokushukika) to prepare an O/W emulsion (evolution of turbine: about 7,000 rpm). The O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 pm standard sieve, and then, microspheres were collected by centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by 20 Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.848 g) was added. The mixture was lyophilized by a lyophilizer (DF-01H, ULVAC) to obtain microcapsule powder. The content of compound (I) in the resulting microcapsule powder was 15.5%. 25 [0056] Example 11 A lactic acid polymer (weight average molecular weight Mw: 11,800, number average molecular weight Mn: 4,900, Mw/Mn ratio: 2.4; manufactured by Wako Pure Chemical Industries Ltd.) (13.3028 g) was dissolved in dichloromethane (24.15 30 g). This solution (13.46 g) was weighed and blended with a solution prepared by dissolving an acetate of compound (I) (1.4821 g) in methanol (5.75 g) to obtain an oil WO 2011/162413 PCT/JP2011/064992 - 29 phase. Subsequently, the oil phase was poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) solution (1 liter), which was previously adjusted to about 18'C, and emulsified by use of a turbine-form homomixer (manufactured by Tokushukika) to prepare an O/W 5 emulsion (evolution of turbine: about 7,000 rpm). The O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 pm standard sieve, and then, microspheres were collected by centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to 10 wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.857 g) was added. The mixture was lyophilized by a lyophilizer (DF-0 1 H, ULVAC) to obtain microcapsule powder. The content of compound (I) in the resulting microcapsule powder was 13.3%. [0057] 15 Example 12 A lactic acid polymer (weight average molecular weight Mw: 8,000, number average molecular weight Mn: 3,400, Mw/Mn ratio: 2.4; manufactured by Wako Pure Chemical Industries Ltd.) (13.3374 g) was dissolved in dichloromethane (24.47 g). This solution (13.42 g) was weighed and blended with an aqueous solution 20 prepared by dissolving an acetate of compound (I) (1.4892 g) in distilled water (1.20 g) and emulsified by a small homogenizer (KINEMATICA) to form a W/O emulsion (rotation rate: about 10,000 rpm, 30 sec). Subsequently, the W/O emulsion was adjusted to 32'C and poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) solution (1 liter), 25 which was previously adjusted to about 18'C, and subjected to secondary emulsification using a turbine-form homomixer (manufactured by Tokushukika) to obtain a W/O/W emulsion (evolution of turbine: about 7,000 rpm). The W/0/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 pm standard sieve, and then, microspheres were collected by 30 centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by Hitachi, Ltd.). This was dispersed again in distilled water WO 2011/162413 PCT/JP2011/064992 - 30 and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.878 g) was added. The mixture was lyophilized by a lyophilizer (DF-01H, ULVAC) to obtain microcapsule powder. The content of compound (I) in the 5 resulting microcapsule powder was 13.1%. [0058] Example 13 A lactic acid polymer (weight average molecular weight Mw: 10,000, number average molecular weight Mn: 4,000, Mw/Mn ratio: 2.5; manufactured by Wako 10 Pure Chemical Industries Ltd.) (13.3334 g) was dissolved in dichloromethane (24.30 g). This solution (13.38 g) was weighed and blended with an aqueous solution prepared by dissolving an acetate of compound (I) (1.4866 g) in distilled water (1.21 g) and emulsified by a small homogenizer (KINEMATICA) to form a W/O emulsion (rotation rate: about 10,000 rpm, 30 sec). Subsequently, the W/O emulsion was 15 adjusted to 32'C and poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) solution (1 liter), which was previously adjusted to about 18*C, and subjected to secondary emulsification using a turbine-form homomixer (manufactured by Tokushukika) to obtain a W/O/W emulsion (evolution of turbine: about 7,000 rpm). The W/O/W 20 emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 pm standard sieve, and then, microspheres were collected by centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to wash away free substances, etc. The collected 25 microspheres were redispersed in a small amount of distilled water and mannitol (0.885 g) was added. The mixture was lyophilized by a lyophilizer (DF-01H, ULVAC) to obtain microcapsule powder. The content of compound (I) in the resulting microcapsule powder was 12.6%. [0059] 30 Example 14 A lactic acid polymer (weight average molecular weight Mw: 11,800, number WO 2011/162413 PCT/JP2011/064992 -31 average molecular weight Mn: 4,900, Mw/Mn ratio: 2.4; manufactured by Wako Pure Chemical Industries Ltd.) (13.2307 g) was dissolved in dichloromethane (24.74). This solution (13.43 g) was weighed and blended with an aqueous solution prepared by dissolving an acetate of compound (I) (1.4900 g) in distilled water (1.21 5 g) and emulsified by a small homogenizer (KINEMATICA) to form a W/O emulsion (rotation rate: about 10,000 rpm, 30 sec). Subsequently, the W/O emulsion was adjusted to 32'C and poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) solution (1 liter), which was previously adjusted to about 18'C, and subjected to secondary 10 emulsification using a turbine-form homomixer (manufactured by Tokushukika) to obtain a W/O/W emulsion (evolution of turbine: about 7,000 rpm). The W/O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 pm standard sieve, and then, microspheres were collected by centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 15 5DL, manufactured by Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.885 g) was added. The mixture was lyophilized by a lyophilizer (DF-01H, ULVAC) to obtain microcapsule powder. The content of compound (I) in the 20 resulting microcapsule powder was 13.0%. [0060] Example 15 A lactic acid polymer (weight average molecular weight Mw: 14,300, number average molecular weight Mn: 5,400, Mw/Mn ratio: 2.7; manufactured by Wako 25 Pure Chemical Industries Ltd.) (6.24 g) was dissolved in dichloromethane (10.92 g). This solution (13.28 g) was weighed and blended with a solution prepared by dissolving an acetate of compound (I) (1.3619 g) in methanol (5.73 g) to obtain an oil phase. Subsequently, the oil phase was poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) 30 solution (1 liter), which was previously adjusted to about 18"C, and emulsified by use of a turbine-form homomixer (manufactured by Tokushukika) to prepare an O/W WO 2011/162413 PCT/JP2011/064992 - 32 emulsion (evolution of turbine: about 7,000 rpm). The O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 Pim standard sieve, and then, microspheres were collected by centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by 5 Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.740 g) was added. The mixture was lyophilized by a lyophilizer (DF-O1H, ULVAC) to obtain microcapsule powder. The content of compound (I) in the resulting microcapsule powder was 15.1%. 10 [0061] Example 16 A lactic acid polymer (weight average molecular weight Mw: 16,000, number average molecular weight Mn: 6,000, Mw/Mn ratio: 2.7; manufactured by Wako Pure Chemical Industries Ltd.) (6.26 g) was dissolved in dichloromethane (10.98 g). 15 This solution (13.27 g) was weighed and blended with a solution prepared by dissolving an acetate of compound (I) (1.3627 g) in methanol (5.61 g) to obtain an oil phase. Subsequently, the oil phase was poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) solution (1 liter), which was previously adjusted to about 18'C, and 20 emulsified by use of a turbine-form homomixer (manufactured by Tokushukika) to prepare an O/W emulsion (evolution of turbine: about 7,000 rpm). The O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 pm standard sieve, and then, microspheres were collected by centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 25 5DL, manufactured by Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.740 g) was added. The mixture was lyophilized by a lyophilizer (DF-O1H, ULVAC) to obtain microcapsule powder. The content of compound (I) in the 30 resulting microcapsule powder was 15.7%. [0062] WO 2011/162413 PCT/JP2011/064992 - 33 Example 17 A lactic acid polymer (weight average molecular weight Mw: 14,300, number average molecular weight Mn: 5,400, Mw/Mn ratio: 2.7; manufactured by Wako Pure Chemical Industries Ltd.) (7.02 g) was dissolved in dichloromethane (13.18 g). 5 This solution (15.64 g) was weighed and blended with a solution prepared by dissolving an acetate of compound (I) (0.6799 g) in methanol (5.57 g) to obtain an oil phase. Subsequently, the oil phase was poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) solution (1 liter), which was previously adjusted to about 18'C, and emulsified by 10 use of a turbine-form homomixer (manufactured by Tokushukika) to prepare an O/W emulsion (evolution of turbine: about 7,000 rpm). The O/W emulsion was stirred for about 3 hours (in-water-drying method step) and sieved by use of a 75 pm standard sieve, and then, microspheres were collected by centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by 15 Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.740 g) was added. The mixture was lyophilized by a lyophilizer (DF-01H, ULVAC) to obtain microcapsule powder. The content of compound (I) in the resulting microcapsule powder was 8.4%. 20 [0063] Example 18 A lactic acid polymer (weight average molecular weight Mw: 16,000, number average molecular weight Mn: 6,000, Mw/Mn ratio: 2.7; manufactured by Wako Pure Chemical Industries Ltd.) (7.01 g) was dissolved in dichloromethane (13.11 g). 25 This solution (15.50 g) was weighed and blended with a solution prepared by dissolving an acetate of compound (I) (0.6870 g) in methanol (5.61 g) to obtain an oil phase. Subsequently, the oil phase was poured in a 0.1% (w/w) aqueous polyvinyl alcohol (EG-40, manufactured by Nippon Synthetic Chemical Industry Co., Ltd.) solution (1 liter), which was previously adjusted to about 18'C, and emulsified by 30 use of a turbine-form homomixer (manufactured by Tokushukika) to prepare an O/W emulsion (evolution of turbine: about 7,000 rpm). The O/W emulsion was stirred WO 2011/162413 PCT/JP2011/064992 - 34 for about 3 hours (in-water-drying method step) and sieved by use of a 75 ptm standard sieve, and then, microspheres were collected by centrifugation (rotation rate: about 2,500 rpm, 5 min) using a centrifuge (HIMAC CR 5DL, manufactured by Hitachi, Ltd.). This was dispersed again in distilled water and further centrifuged to 5 wash away free substances, etc. The collected microspheres were redispersed in a small amount of distilled water and mannitol (0.768 g) was added. The mixture was lyophilized by a lyophilizer (DF-OlH, ULVAC) to obtain microcapsule powder. The content of compound (I) in the resulting microcapsule powder was 9.2%. [0064] 10 Comparative Example 1 In the case where a solution mixture of a solution prepared by dissolving a lactic acid polymer in dichloromethane and an aqueous solution prepared by dissolving an acetate of compound (II) (Ac-D-Tyr-D-Trp-Asn-Thr-Phe-AzaGly-Leu Arg(Me)-Trp-NH 2 ) (SEQ ID NO: 2) in distilled water, is allowed to suspend by a 15 mini-mixer, the solution mixture is gelatinized. Therefore, a W/O emulsion cannot be obtained. [0065] Test Example 1 The microcapsule powder (9.6 mg as a free compound (I)) of Example 15 was 20 dispersed in a dispersion medium (0.9 mL) (a solution in which carboxymethylcellulose (5.50 mg), polysorbate 80 (0.90 mg) and mannitol (45.0 mg) were dissolved) and subcutaneously administered to the dorsal portions of rats by means of a 22G injection needle. In a predetermined time interval after the administration, blood was sampled from the caudal vein and the concentration of 25 compound (I) in the plasma was measured. As a result, sustained release of compound (I) over a period of about 22 weeks was demonstrated. [0066] Test Example 2 The microcapsule powder (9.6 mg as a free compound (I)) of Example 16 was 30 dispersed in a dispersion medium (0.9 mL) (a solution in which WO 2011/162413 PCT/JP2011/064992 - 35 carboxymethylcellulose (5.50 mg), polysorbate 80 (0.90 mg) and mannitol (45.0 mg) were dissolved) and subcutaneously administered to the dorsal portions of rats by means of a 22G injection needle. In a predetermined time interval after the administration, blood was sampled from the caudal vein and the concentration of 5 compound (I) in the plasma was measured. As a result, sustained release of compound (I) over a period of about 24 weeks was demonstrated. [0067] Test Example 3 The microcapsule powder (9.6 mg as a free compound (I)) of Example 17 was 10 dispersed in a dispersion medium (0.9 mL) (a solution in which carboxymethylcellulose (5.50 mg), polysorbate 80 (0.90 mg) and mannitol (45.0 mg) were dissolved) and subcutaneously administered to the dorsal portions of rats by means of a 22G injection needle. In a predetermined time interval after the administration, blood was sampled from the caudal vein and the concentration of 15 compound (I) in the plasma was measured. As a result, sustained release of compound (I) over a period of about 22 weeks was demonstrated. [0068] Test Example 4 The microcapsule powder (4.8 mg as a free compound (I)) of Example 5 was 20 dispersed in a dispersion medium (0.9 mL) (a solution in which carboxymethylcellulose (5.50 mg), polysorbate 80 (0.90 mg) and mannitol (45.0 mg) were dissolved) and subcutaneously administered to the dorsal portions of rats by means of a 22G injection needle. In a predetermined time interval after the administration, blood was sampled from the caudal vein and the concentration of 25 compound (I) in the plasma was measured. As a result, sustained release of compound (I) over a period of about 15 weeks was demonstrated. [0069] Test Example 5 The microcapsule powder (4.8 mg as a free compound (I)) of Example 6 was 30 dispersed in a dispersion medium (0.9 mL) (a solution in which WO 2011/162413 PCT/JP2011/064992 -36 carboxymethylcellulose (5.50 mg), polysorbate 80 (0.90 mg) and mannitol (45.0 mg) were dissolved) and subcutaneously administered to the dorsal portions of rats by means of a 22G injection needle. In a predetermined time interval after the administration, blood was sampled from the caudal vein and the concentration of 5 compound (I) in the plasma was measured. As a result, sustained release of compound (I) over a period of about 15 weeks was demonstrated. [0070] Test Example 6 The microcapsule powder (4.8 mg as a free compound (I)) of Example 7 was 10 dispersed in a dispersion medium (0.9 mL) (a solution in which carboxymethylcellulose (5.50 mg), polysorbate 80 (0.90 mg) and mannitol (45.0 mg) were dissolved) and subcutaneously administered to the dorsal portions of rats by means of a 22G injection needle. In a predetermined time interval after the administration, blood was sampled from the caudal vein and the concentration of 15 compound (I) in the plasma was measured. As a result, sustained release of compound (I) over a period of about 18 weeks was demonstrated. 6. INDUSTRIAL APPLICABILITY [0071] 20 The sustained-release formulation of the present invention slowly and stably releases a metastin derivative over a long period of time and also exerts medicinal effects of the metastin derivative over a long period of time. Furthermore, the sustained-release formulation of the present invention can reduce the administration frequency, thereby improving convenience of patients and can be used as a clinical 25 medicine.
    权利要求:
    Claims (7)
    [1] 2. The sustained-release formulation according to claim 1, wherein the weight 10 average molecular weight of the lactic acid polymer or a salt thereof is about 13,000 to about 17,000.
    [2] 3. The sustained-release formulation according to claim 1, which is a 3 to 6 month sustained-release formulation. 15
    [3] 4. The sustained-release formulation according to claim 1, which is a therapeutic or prophylactic agent for cancer.
    [4] 5. The sustained-release formulation according to claim 1, which is a parenteral 20 agent.
    [5] 6. A method for treating or preventing cancer comprising administering an effective amount of the sustained-release formulation according to clam 1 to a mammal. 25
    [6] 7. A method for producing the sustained-release formulation according to claim 1, comprising subjecting (1) a W/O/W emulsion obtained by emulsifying a W/O emulsion composed of WO 2011/162413 PCT/JP2011/064992 - 38 an internal water phase containing a compound represented by Formula: Ac-D-Tyr-Hyp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH 2 or a salt thereof, and an oil phase containing the lactic acid polymer or a salt thereof, or 5 (2) an O/W emulsion obtained by emulsifying an oil phase composed of a compound represented by Formula: Ac-D-Tyr-Hyp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH 2 or a salt thereof and the lactic acid polymer or a salt thereof; to an in-water drying method. 10
    [7] 8. The method according to claim 7, comprising subjecting an O/W emulsion obtained by emulsifying an oil phase containing a compound represented by Formula: Ac-D-Tyr-Hyp-Asn-Thr-Phe-AzaGly-Leu-Arg(Me)-Trp-NH 2 15 or a salt thereof and the lactic acid polymer or a salt thereof, to an in-water drying method.
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    法律状态:
    2015-06-25| MK1| Application lapsed section 142(2)(a) - no request for examination in relevant period|
    优先权:
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    JP2010144792||2010-06-25||
    JP2010-144792||2010-06-25||
    PCT/JP2011/064992|WO2011162413A1|2010-06-25|2011-06-23|Sustained-release formulation|
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