Anti-aggregation agent, pharmaceutical composition and medical device using the same

Abstract

This aggregation inhibitory agent contains, as an aggregation inhibitory component, at least one selected from the group consisting of polyoxyethylene cetyl ether, polyoxyethylene sorbitan fatty acid esters, and polyoxyethylene polyoxypropylene glycol having an average molecular weight of 3000-13000. The present invention can prevent aggregation of a poorly water-soluble agent caused by a silicone oil within a container having an inner wall treated with the silicone oil.

Description

[Technical Field]

[0001] The present invention relates to an anti-aggregation agent, and a pharmaceutical composition and a medical device using the same. [Background technology]

[0002] When a poorly water-soluble drug, such as aripiprazole hydrate, used to treat schizophrenia, is administered as an injection, the drug is dispersed in water in advance to form an aqueous suspension, which is then injected directly into the patient, or the drug is made into a powder or cake-like solid (e.g., lyophilized product) which is suspended in water before use and then injected into the patient. Here, the aqueous suspension or solid (e.g., lyophilized product) is stored and distributed in a vial or a so-called prefilled syringe, such as a double-chamber syringe. When contained in a vial, it is extracted using a commonly used syringe and administered to the patient before use.

[0003] In the pre-filled syringe and the general-purpose syringe, the inner wall of the syringe is silicone-treated (specifically, silicone oils such as silicone oil and silicone oil derivatives are applied) to improve the sliding property inside the syringe. In addition, the inner wall of the vial may also be silicone-treated for the purpose of improving water repellency.

[0004] However, when silicone oils are present on the inner walls of syringes (prefilled syringes, general-purpose syringes) or vials, they can contaminate aqueous suspensions or lyophilized products contained therein. It has been pointed out that when silicone oils are contaminated and resuspended in an aqueous dispersion medium, poorly water-soluble drugs aggregate in the suspension, increasing the particle size of the drug in the resuspension. Drugs with increased particle size exhibit a dissolution profile different from that of the drug itself (i.e., the drug before the silicone oils were mixed in), which can affect the efficacy of poorly water-soluble drugs, such as by varying the sustained release rate. This can also lead to clogging of the device when used as an injection, or physical irritation at the injection site due to increased particle size.

[0005] In response to this, Patent Document 1 proposes that the shape of the drug cake contained in the prefilled syringe (medical device) is devised to prevent the cake from coming into contact with the inner surface of the syringe, thereby suppressing the aggregation of aripiprazole caused by silicone oil. Furthermore, Patent Document 2 proposes that the amount of silicone oil relative to the amount of aripiprazole used is adjusted within a predetermined range to suppress the aggregation of aripiprazole caused by silicone oil. All of these technologies aim to suppress the aggregation of aripiprazole by reducing the amount of silicone oil mixed in.

[0006] However, even if the above-mentioned technology is used, it is still not possible to completely avoid the contamination of silicone oils, and it is difficult to say that aggregation can be sufficiently suppressed when suspending poorly water-soluble drugs. Further technological development is desired to prevent aggregation in suspensions of poorly water-soluble drugs. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] Patent No. 5980215 [Patent Document 2] Patent No. 5575269 Summary of the Invention [Problem to be solved by the invention]

[0008] The present invention addresses the above-mentioned problems, and its object is to provide an anti-aggregation agent that can properly suspend a poorly water-soluble drug stored in the presence of silicone oils in an aqueous dispersion medium and prevent the drug from aggregating, as well as a pharmaceutical composition and a medical device using the same. [Means for solving the problem]

[0009] The present invention provides an anti-agglomeration agent for preventing a poorly water-soluble drug from aggregating due to silicone oils, comprising: The anti-aggregating agent contains, as an anti-aggregating component, at least one selected from the group consisting of polyoxyethylene cetyl ether, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene polyoxypropylene glycol having an average molecular weight of 3,000 to 13,000.

[0010] The present invention also relates to a pharmaceutical composition comprising a poorly water-soluble drug and the above-mentioned anti-aggregating agent in the presence of a silicone oil.

[0011] In one embodiment of the pharmaceutical composition of the present invention, the anti-aggregation agent contains the anti-aggregation component in a ratio of 2 to 40 parts by mass per 100 parts by mass of the drug.

[0012] In one embodiment of the pharmaceutical composition of the present invention, the silicone oil is derived from the inner wall of a container whose inner wall is treated with silicone oil.

[0013] In one embodiment, the pharmaceutical composition of the present invention is obtained by lyophilization.

[0014] The present invention also provides a medical device comprising a container whose inner wall is treated with silicone oil, The medical device contains a pharmaceutical composition containing a poorly water-soluble drug and the anti-aggregating agent according to claim 1 in the container.

[0015] In one embodiment, the medical device of the present invention has the form of a pre-filled syringe.

[0016] In one embodiment of the medical device of the present invention, the anti-aggregation agent contains the anti-aggregation component in a ratio of 2 to 40 parts by mass per 100 parts by mass of the drug. [Effects of the Invention]

[0017] According to the present invention, even if silicone oils are applied to the inner wall of the container constituting the medical device, it is possible to prevent the poorly water-soluble drug stored in the container from aggregating and increasing in particle size when suspended in an aqueous dispersion medium. As a result, the dissolution profile of the poorly water-soluble drug itself used does not deviate significantly from the dissolution profile of the drug when not in contact with silicone oils, and it is possible to obtain substantially the same sustained release properties and efficacy. DETAILED DESCRIPTION OF THE INVENTION

[0018] The present invention will be described in detail below.

[0019] (1) Anti-aggregating agent The anti-agglomerating agent of the present invention is a composition used to prevent poorly water-soluble drugs from aggregating due to silicone oils.

[0020] (Silicone oils) The term "silicone oil" used in this specification includes the silicone oil and silicone oil derivatives that can be used in medical applications, and their combinations.More specifically, silicone oil can be exemplified by dimethylpolysiloxane.More specifically, silicone oil derivative can be exemplified by the silicone oil derivatives that part of the side chain and / or end of silicone is replaced with polyoxyalkylene group or vinyl group.

[0021] The average molecular weight of the silicone constituting the silicone oil is not necessarily limited, but is preferably 10 to 100,000,000, more preferably 100 to 10,000,000, and even more preferably 200 to 10,000.

[0022] (Poorly water-soluble drugs) The term "poorly water-soluble drug" as used herein includes drugs classified as "slightly soluble," "slightly soluble," "very slightly soluble," or "practically insoluble" as defined in the Japanese Pharmacopoeia. More specifically, "poorly water-soluble drug" includes, for example, drugs that dissolve within 30 minutes when 1 g or 1 mL of the solute (drug) is added to a solvent (water) and vigorously shaken for 30 seconds every 5 minutes at 20±5°C, in a solvent (water) volume of 30 mL or more but less than 100 mL, 100 mL or more but less than 1000 mL, 1000 mL or more but less than 10,000 mL, or 10,000 mL or more of water.

[0023] Examples of poorly water-soluble drugs include, but are not limited to, aripiprazole, candesartan, ezetimibe, atorvastatin, tolvaptan, sorafenib, paclitaxel, adriamycin, camptothecin, cisplatin, daunomycin, pinorubin, methotrexate, mitomycin C, etoposide, gefitinib, irinotecan hydrochloride, topotecan hydrochloride, docetaxol, vinblastine sulfate, vincristine sulfate, vindesine sulfate, teniposide, vinorelbine tartrate, busulfan, carboquone, thiotepa, and cyclophosphamide. , melphalan, estramustine sodium phosphate, mechlorethamine oxide hydrochloride, ifosfamide, ranimustine, nimustine hydrochloride, bleomycin hydrochloride, peplomycin sulfate, zinostatin stimaraate, actinomycin D, aclarubicin hydrochloride, doxorubicin hydrochloride, idarubicin hydrochloride, amrubicin hydrochloride, daunorubicin hydrochloride, pirarubicin, epirubicin hydrochloride, valrubicin, mercaptopurine, fludarabine phosphate, cladribine, fluorouracil, tegafur, cytarabine, gemcitabine hydrochloride, cytarabine ocfosfate, capesi Tabine, lentinan, oxaliplatin, xifluridine, carmofur, enocitabine, nedaplatin, carboplatin, fadrozole hydrochloride, anastrozole, exemestane, bicalutamide, flutamide, tamoxifen citrate, toremifene citrate, tretinoin, pentostatin, L-asparaginase, dacarbazine, procarbazine hydrochloride, mitoxantrone hydrochloride, sobuzoxane, trastuzumab, rituximab, imatinib mesylate, 5-fluoro-2'-deoxyuridine, asclepiad, carbocriline, quinolespan, krestin Picibanil, hydrocortisone, hydrocortisone acetate, prednisolone, methylprednisolone, prednisolone acetate, hydrocortisone acetate propionate, prednisolone valerate, dexamethasone, betamethasone, triamcinolone, clobetasone acetate, clobetasol propionate, fluocinonide, dexamethasone acetate, betamethasone valerate, triamcinolone acetonide, aspirin, salicylic acid, acetaminophen, methyl salicylate, glycol salicylate, mefenamic acid, flufenamic acid, indomethacin, diclofenac,Ketoprofen, ibuprofen, flurbiprofen, fenprofen, bufexamac, piroxicam, oxyphenbutazone, mepirizole, ibuprofen piconol, clidanac, phenylbutazone, naproxen, glycyrrhizin, glycyrrhetinic acid, azulene, camphor, thymol, l-menthol, tolfenamic acid, sazapyrine, alclofenac, diclofenac, suprofen, loxoprofen, acemetacin, metiazinic acid, protizinic acid, sulindac, pranoprofen, fentiazac, diflunisal, tiaprofen Enic acid, oxaprozin, felbinac, bufexamac, dipcaine hydrochloride, ethyl aminobenzoate, procaine hydrochloride, lidocaine, tetracaine hydrochloride, lidocaine hydrochloride, tecaine, benzyl alcohol, pramoxine hydrochloride, catacaine hydrochloride, butanicaine hydrochloride, piperocaine hydrochloride, chlorobutanol, barbital, amobarbital, amobarbital sodium, phenobarbital, phenobarbital sodium, secobarbital sodium, pentobarbital calcium, hexobarbital, triclophos, bromvaleriluria Benzyl alcohol, glutethimide, methaqualone, perlapine, nitrazepam, estazolam, flurazepam hydrochloride, flunitrazepam, estazolam, chloramphenicol, cefmetazole, bacitracin, penicillin, cephalexin, tetracycline, streptomycin, nystatin, erythromycin, fradiomycin sulfate, tolnaftate, tocopheryl acetate, nicotinic acid benzyl ester, tolazoline, verapamil, caffeine, cyclandelate, acetylcholine, tocopheryl nicotinate, nifedipine, dipyridamole, prenylamine Lactate, efloxate, phenytoin, phenacemide, ethylphenacemide, ethotoin, primidone, fenesuximide, nitrazeban, clonazeban, carbamazepine, clozobazone, fenopropamate, diphenhydramine, metaquizine, digoxin, digotoxin, cobidecarenone, phenytoin, disopyramide, polythiazide, spironolactone, chlorthalidone, deserpidine, meptame, reserpine, meptamate, prostaglandin F2α danazol, mepitiostane, and pharmaceutically acceptable salts and hydrates thereof.and derivatives thereof.

[0024] (Agglutination prevention ingredient) The anti-aggregating agent of the present invention contains an anti-aggregating component, examples of which include polyoxyethylene cetyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene polyoxypropylene glycol having an average molecular weight of 3,000 to 13,000, and combinations thereof.

[0025] Polyoxyethylene sorbitan fatty acid esters are obtained by esterification of polyoxyethylene sorbitan with long-chain fatty acids (e.g., lauric acid, stearic acid, palmitic acid, oleic acid, etc.), and are also called polysorbates. Specific examples of polyoxyethylene sorbitan fatty acid esters include polysorbate 20 (Tween 20), polysorbate 40 (Tween 40), polysorbate 60 (Tween 60), polysorbate 80 (Tween 80), polysorbate 85 (Tween 85), and polysorbate 120, as well as combinations thereof.

[0026] The polyoxyethylene polyoxypropylene glycol having an average molecular weight of 3,000 to 13,000 is a Pluronic (registered trademark) type polyoxyethylene polyoxypropylene glycol, preferably a polyoxyethylene polyoxypropylene glycol having an average molecular weight of 5,500 to 12,500. Specific examples of such polyoxyethylene polyoxypropylene glycol include polyoxyethylene (160) polyoxypropylene (30) glycol.

[0027] The average molecular weight of polyoxyethylene polyoxypropylene glycol in this specification means the weight average molecular weight, which is measured by, for example, GPC (gel permeation chromatography).

[0028] (Other ingredients) The anti-aggregating agent of the present invention preferably consists solely of the anti-aggregating component, but may contain other components in addition to the anti-aggregating component as long as the effects of the present invention are not impaired. There are no particular limitations on the other components, and known additives can be used. When other components are contained, the content of the anti-aggregating component in the anti-aggregating agent of the present invention is preferably 50% by mass or more, more preferably 80% by mass or more, and even more preferably 90% by mass or more.

[0029] The anti-aggregation agent of the present invention is prepared, for example, in the form of a pharmaceutical composition mixed with a poorly water-soluble drug, and is contained in a container whose inner wall is treated with silicone oil, thereby preventing aggregation of the drug in the presence of the silicone oil.

[0030] (2) Pharmaceutical composition The pharmaceutical composition of the present invention comprises the above-mentioned poorly water-soluble drug and anti-aggregating agent in the presence of silicone oil.Here, the term "in the presence of silicone oil" used in this specification includes the state that silicone oil and the above-mentioned poorly water-soluble drug and anti-aggregating agent are completely or partially mixed, and the state that silicone oil and the above-mentioned poorly water-soluble drug and anti-aggregating agent are not mixed, but are at least in contact with the above-mentioned poorly water-soluble drug and anti-aggregating agent.

[0031] The silicone oil in the pharmaceutical composition of the present invention is preferably derived from the inner wall of a container whose inner wall is treated with silicone oil.Here, the term "inner wall treated with silicone oil" used in this specification refers to the state in which silicone oil is applied to the inner wall (inner surface) of the container.For example, when the container is a syringe, a predetermined amount of silicone oil is applied to the inner wall of the syringe (syringe barrel and plunger), and the silicone oil can function as a lubricant for the plunger that slides in the syringe barrel and the stopper (sealing stopper) located at its tip.When the container is a vial, by applying silicone oil to the inner wall, it can reduce the possibility of the content (e.g., drug solution) filled in the vial remaining in the vial when it is discharged to the outside.In other words, it is not necessary to predetermine the amount of pharmaceutical composition to be filled in the vial in consideration of such remaining.

[0032] The amount of silicone oil applied to the inner wall of the container is not necessarily limited. For example, if the container is a syringe, the amount is sufficient to maintain the sliding properties of the syringe. Alternatively, if the container is a vial, the amount is sufficient to allow the contents of the vial to be efficiently discharged.

[0033] The pharmaceutical composition of the present invention contains a poorly water-soluble drug and an anti-aggregation agent in coexistence, and therefore can prevent aggregation of the poorly water-soluble drug when such a pharmaceutical composition is suspended in an aqueous dispersion medium described below, even if silicone oils are applied to the inner wall of a container containing them and are mixed with or come into contact with them.

[0034] In the pharmaceutical composition of the present invention, the anti-aggregation agent is preferably contained in an amount of 2 to 40 parts by mass of the anti-aggregation component per 100 parts by mass of the poorly water-soluble drug. More preferably, the anti-aggregation component is contained in an amount of 3 to 30 parts by mass of the anti-aggregation component per 100 parts by mass of the poorly water-soluble drug. When the content of the anti-aggregation component is 2 parts by mass or more per 100 parts by mass of the poorly water-soluble drug, aggregation of the poorly water-soluble drug in an aqueous dispersion medium can be efficiently suppressed, even in the presence of silicone oils. When the content of the anti-aggregation component is 40 parts by mass or less per 100 parts by mass of the poorly water-soluble drug, dissolution of a portion of the poorly water-soluble drug due to the influence of an excessive amount of the anti-aggregation component, which results in a change in the dissolution property of the drug, can be avoided.

[0035] Alternatively, the content of the anti-aggregation component may be set based on the amount of silicone oils present in the pharmaceutical composition. In one embodiment, the content of the anti-aggregation component is preferably 0.4 to 500 parts by mass, more preferably 1.0 to 50 parts by mass, per 1 part by mass of silicone oils. When the content of the anti-aggregation component is 0.4 parts by mass or more per 1 part by mass of silicone oils, aggregation of a poorly water-soluble drug in an aqueous dispersion medium can be efficiently suppressed even in the presence of silicone oils. When the content of the anti-aggregation component is 500 parts by mass or less per 1 part by mass of silicone oils, it is possible to avoid a situation in which a portion of the poorly water-soluble drug dissolves due to the influence of an excessive amount of the anti-aggregation component, resulting in a change in the dissolution property of the drug.

[0036] When the silicone oils present in the pharmaceutical composition originate from silicone oils applied to the inner wall of the container that holds the pharmaceutical composition, not all of the silicone oils applied to the inner wall of the container actually get mixed into the pharmaceutical composition. However, the amount of silicone oils present in the pharmaceutical composition can be determined by assuming that all of the silicone oils applied to the inner wall of the container get mixed into the pharmaceutical composition, and then setting the content of the aggregation-preventing component.

[0037] The amount of silicone oils present in the pharmaceutical composition can be measured by extracting the silicone oils with an appropriate solvent (e.g., methyl isobutyl ketone) and quantifying the amount by, for example, inductively coupled plasma (ICP) emission spectrometry or atomic absorption spectrometry.

[0038] (Other additives) The pharmaceutical composition of the present invention may contain other additives in addition to the above-mentioned poorly water-soluble drug and anti-aggregating agent.

[0039] Other additives include, but are not necessarily limited to, other suspending agents, excipients, buffers, pH adjusters, and lubricants, and combinations thereof.

[0040] Examples of other suspending agents include cetylpyridinium chloride, gelatin, casein, lecithin, dextran, glycerol, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene castor oil derivatives, polyethylene glycols, dodecyltrimethylammonium bromide, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, hydroxypropylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, magnesium aluminum silicate, triethanolamine, polyvinyl alcohol, poloxamer, poloxamine, and charged phospholipids, and combinations thereof.

[0041] Examples of excipients include mannitol, sucrose, maltose, xylitol, glucose, starch, and sorbitol, and combinations thereof.

[0042] Examples of buffering agents include sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, and tris(hydroxymethyl)aminomethane (Tris), and combinations thereof.

[0043] Examples of pH adjusters include basic pH adjusters, and acidic pH adjusters such as hydrochloric acid and acetic acid; and basic pH adjusters such as sodium hydroxide, potassium hydroxide, calcium carbonate, magnesium oxide, and magnesium hydroxide.

[0044] Examples of lubricants include stearic acid, sodium stearyl fumarate, magnesium stearate, calcium stearate, sucrose fatty acid esters, polyethylene glycol, light anhydrous silicic acid, hydrogenated oils, glycerin fatty acid esters, and talc, and combinations thereof.

[0045] The other additives can be added in appropriate amounts selected by those skilled in the art within a range that does not impair the efficacy of the poorly water-soluble drug and the effects of the anti-aggregation agent of the present invention.

[0046] (shape and condition) The pharmaceutical composition of the present invention may be in any form or state as long as it contains the above-mentioned components. For example, it may be a solid lyophilized product obtained by lyophilizing a suspension in which the above-mentioned components are dissolved or dispersed in an aqueous dispersion medium, or a liquid suspension in which the components are suspended in an aqueous dispersion medium. Preferably, the pharmaceutical composition of the present invention is obtained by lyophilization.

[0047] (3) Medical devices The medical device of the present invention comprises a container whose inner wall is treated with silicone oil.

[0048] The container that constitutes the medical device of the present invention can be, for example, sealed from the outside.The example of the container includes pre-filled syringe and vial, and preferably pre-filled syringe.The specific example of pre-filled syringe includes the single-chamber syringe that is composed of one syringe barrel and one plunger, and the syringe that contains the contents in a state of being separated into multiple compartments (chambers) (for example, the double-chamber syringe that has two compartments).

[0049] When the medical device of the present invention is a prefilled syringe, it is preferable that the container has a double-chamber syringe configuration in which a solid material containing at least a poorly water-soluble drug is contained in one compartment and an aqueous dispersion medium is contained in the other compartment. In this case, the anti-aggregating agent and, if necessary, the other additives contained in the pharmaceutical composition may be contained in the solid material or the aqueous dispersion medium.

[0050] This type of medical device in the form of a double-chamber syringe preserves the poorly water-soluble drug in a solid state until use, thereby maintaining the drug's stability. Furthermore, when the aqueous dispersion medium is added to the solid to suspend it at the time of use, the aqueous dispersion medium is already contained, providing high convenience. Furthermore, this configuration maintains the coexistence of the poorly water-soluble drug and the anti-aggregation agent during suspension. Therefore, even if silicone oils are added to the inner wall of the syringe to enhance sliding properties, aggregation of the poorly water-soluble drug in the suspension can be prevented. This ensures that the dissolution profile of the poorly water-soluble drug itself does not deviate significantly from the dissolution profile of the drug when not in contact with silicone oils, thereby achieving substantially the same sustained-release properties and efficacy. Furthermore, concerns about clogging within the device and physical irritation at the patient's injection site due to increased particle size are eliminated.

[0051] The material of the container constituting the medical device of the present invention is not particularly limited, and examples thereof include glass; and thermoplastic resins such as olefin-based resins (polyethylene, polypropylene, etc.) and cycloolefin polymers (COP).

[0052] The aqueous dispersion medium is water or a mixture of water and ethanol. Usually, water (water for injection) is used as the aqueous dispersion medium. As mentioned above, the aqueous dispersion medium may contain an anti-aggregating agent and other additives (especially other suspending agents and / or pH adjusters). [Example]

[0053] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited to these examples.

[0054] In all examples and comparative examples, test suspensions were prepared according to the procedures described below, and the volume average particle diameter of the particles contained in the resulting suspensions was measured.

[0055] This procedure seems different from the assumed procedure when using the medical device of the present invention, in which a poorly water-soluble drug and an anti-aggregating agent are placed in a container containing silicone oil, and then suspended in an aqueous dispersion medium.However, the two procedures have in common the fact that a poorly water-soluble drug is suspended in an aqueous dispersion medium in the presence of silicone oil.Therefore, the following procedure can be evaluated in the same way as the example or the corresponding comparative example when suspending a poorly water-soluble drug as assumed in the medical device of the present invention.

[0056] The volume-average particle size of particles contained in the test suspensions obtained in each Example, Comparative Example, and Reference Example was measured by the following method. After allowing the obtained test suspensions to stand at room temperature for 5 minutes, the particle size (volume-average particle size) of particles contained in the test suspension (a) (using a circulation cell and water as the measurement medium) was measured using a laser diffraction / scattering particle size distribution analyzer (HORIBA, Ltd. (LA-950)) (this result is referred to as "before ultrasonic treatment (a)"). Next, the test suspension (a) was ultrasonically treated for 1 minute using an ultrasonic generator attached to the particle size distribution analyzer, and the particle size of particles contained in the test suspension (b) after the ultrasonic treatment was measured in the same manner (this result is referred to as "after ultrasonic treatment (b)").

[0057] Example 1: Test Suspensions Containing Aripiprazole (Example 1-1-1: Preparation and evaluation of test suspension using polyoxyethylene cetyl ether) Aripiprazole hydrate as a poorly water-soluble drug, carboxymethylcellulose sodium, mannitol, and sodium dihydrogen phosphate monohydrate were added to purified water to give the following concentrations to prepare an aripiprazole suspension. Aripiprazole hydrate: 30% by mass (as anhydrous substance) Sodium carboxymethylcellulose: approximately 1.248% by mass Mannitol: Approximately 6.24% by mass Sodium dihydrogen phosphate monohydrate: approximately 0.111% by mass

[0058] To 1 g of this aripiprazole suspension, polyoxyethylene cetyl ether was added as an anti-aggregating agent in an amount equivalent to 4 parts by weight per 100 parts by weight of aripiprazole contained in the suspension, and the mixture was stirred. 1% silicone oil emulsion (Dow Corning® 365, 35% Dimethicone NF Elusion, manufactured by DuPont; hereinafter simply referred to as "1% silicone oil emulsion") was added to this suspension so that the silicone oil contained in the suspension was 0.05 parts by weight per 100 parts by weight of aripiprazole, and the mixture was stirred to obtain a test suspension (E1-1-1). The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 1.

[0059] (Examples 1-1-2 to 1-1-7: Preparation and evaluation of test suspensions using polyoxyethylene cetyl ether) Test suspensions (E1-1-2) to (E1-1-7) were prepared by adding 1% silicone oil emulsion to the test suspension (E1-1-1) (before ultrasonic treatment) obtained in Example 1-1-1 so that the amount of silicone oil contained in the suspension was the amount shown in Table 1 per 100 parts by mass of aripiprazole, and test suspensions (E1-1-2) to (E1-1-7) were obtained. For each test suspension, the particle size of the particles contained in the test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b). The results are shown in Table 1.

[0060] (Reference Example 1-1: Preparation and evaluation of test suspension using polyoxyethylene cetyl ether) Test suspension (R1-1) was prepared in the same manner as in Example 1-1-1, except that 1% silicone oil emulsion was not included, and test suspension (R1-1) was obtained.For this test suspension, the particle size of the particles contained in the test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b).The results are shown in Table 1.

[0061] [Table 1]

[0062] (Example 1-2-1: Preparation and evaluation of test suspension using polyoxyethylene cetyl ether) A test suspension (E1-2-1) was prepared in the same manner as in Example 1-1-1, except that 1 g of the aripiprazole suspension prepared in Example 1-1-1 was added with polyoxyethylene cetyl ether as an anti-aggregating agent in an amount equivalent to 20 parts by mass relative to 100 parts by mass of aripiprazole contained in the suspension, and the test suspension (E1-2-1) was obtained.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 2.

[0063] (Examples 1-2-2 to 1-2-7: Preparation and evaluation of test suspensions using polyoxyethylene cetyl ether) A 1% silicone oil emulsion was added to the test suspension (E1-2-1) (before ultrasonic treatment) obtained in Example 1-2-1 so that the amount of silicone oil contained in the suspension was the amount shown in Table 2 per 100 parts by mass of aripiprazole, and the mixture was stirred to obtain test suspensions (E1-2-2) to (E1-2-7). The particle size of the particles contained in each test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b). The results are shown in Table 2.

[0064] (Reference Example 1-2: Preparation and evaluation of test suspension using polyoxyethylene cetyl ether) A test suspension (R1-2) was obtained in the same manner as in Example 1-2-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 2.

[0065] [Table 2]

[0066] (Example 1-3-1: Preparation and evaluation of test suspension using polyoxyethylene (160) polyoxypropylene (30) glycol) A test suspension (E1-3-1) was obtained in the same manner as in Example 1-1-1, except that polyoxyethylene (160) polyoxypropylene (30) glycol (average molecular weight 8905) was added as an anti-aggregating agent to 1 g of the aripiprazole suspension prepared in Example 1-1-1 in an amount equivalent to 4 parts by mass per 100 parts by mass of aripiprazole contained in the suspension. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 3.

[0067] (Examples 1-3-2 to 1-3-7: Preparation and evaluation of test suspensions using polyoxyethylene (160) polyoxypropylene (30) glycol) A 1% silicone oil emulsion was added to the test suspension (E1-3-1) (before ultrasonic treatment) obtained in Example 1-3-1 so that the amount of silicone oil contained in the suspension was the amount shown in Table 3 per 100 parts by mass of aripiprazole, and the mixture was stirred to obtain test suspensions (E1-3-2) to (E1-3-7). The particle size of the particles contained in each test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b). The results are shown in Table 3.

[0068] (Reference Example 1-3: Preparation and evaluation of test suspension using polyoxyethylene (160) polyoxypropylene (30) glycol) A test suspension (R1-3) was obtained in the same manner as in Example 1-3-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 3.

[0069] [Table 3]

[0070] (Example 1-4-1: Preparation and evaluation of test suspension using polyoxyethylene (160) polyoxypropylene (30) glycol) A test suspension (E1-4-1) was obtained in the same manner as in Example 1-1-1, except that 1 g of the aripiprazole suspension prepared in Example 1-1-1 was added with polyoxyethylene (160) polyoxypropylene (30) glycol (average molecular weight 8905) as an anti-aggregating agent in an amount equivalent to 20 parts by mass per 100 parts by mass of aripiprazole contained in the suspension. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 4.

[0071] (Examples 1-4-2 to 1-4-7: Preparation and evaluation of test suspensions using polyoxyethylene (160) polyoxypropylene (30) glycol) A 1% silicone oil emulsion was added to the test suspension (E1-4-1) (before ultrasonic treatment) obtained in Example 1-4-1 so that the amount of silicone oil contained in the suspension was the amount shown in Table 4 per 100 parts by mass of aripiprazole, and the mixture was stirred to obtain test suspensions (E1-4-2) to (E1-4-7). The particle size of the particles contained in each test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b). The results are shown in Table 4.

[0072] (Reference Example 1-4: Preparation and evaluation of test suspension using polyoxyethylene (160) polyoxypropylene (30) glycol) Test suspension (R1-4) was obtained in the same manner as in Example 1-4-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 4.

[0073] [Table 4]

[0074] (Example 1-5-1: Preparation and evaluation of test suspension using polysorbate 20) A test suspension (E1-5-1) was obtained in the same manner as in Example 1-1-1, except that 1 g of the aripiprazole suspension prepared in Example 1-1-1 was added with polysorbate 20 as an anti-aggregating agent in an amount equivalent to 4 parts by mass per 100 parts by mass of aripiprazole contained in the suspension.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 5.

[0075] (Examples 1-5-2 to 1-5-7: Preparation and evaluation of test suspensions using polysorbate 20) Test suspension (E1-5-1) (before ultrasonic treatment) obtained in Example 1-5-1 was added with 1% silicone oil emulsion so that the amount of silicone oil contained in the suspension was the amount shown in Table 5 per 100 parts by mass of aripiprazole, and the mixture was stirred to obtain test suspensions (E1-5-2) to (E1-5-7). For each test suspension, the particle size of the particles contained in the test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b). The results are shown in Table 5.

[0076] (Reference Example 1-5: Preparation and evaluation of test suspension using polysorbate 20) Test suspension (R1-5) was obtained in the same manner as in Example 1-5-1, except that 1% silicone oil emulsion was not added.For this test suspension, the particle size of the particles contained in the test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b).The results are shown in Table 5.

[0077] [Table 5]

[0078] (Example 1-6-1: Preparation and evaluation of test suspension using polysorbate 20) A test suspension (E1-6-1) was obtained in the same manner as in Example 1-1-1, except that 1 g of the aripiprazole suspension prepared in Example 1-1-1 was added with 20 parts by mass of polysorbate 20 as an anti-aggregating agent relative to 100 parts by mass of aripiprazole contained in the suspension.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 6.

[0079] (Examples 1-6-2 to 1-6-7: Preparation and evaluation of test suspensions using polysorbate 20) Test suspension (E1-6-1) (before ultrasonic treatment) obtained in Example 1-6-1 was added with 1% silicone oil emulsion so that the amount of silicone oil contained in the suspension was the amount shown in Table 6 per 100 parts by mass of aripiprazole, and the mixture was stirred to obtain test suspensions (E1-6-2) to (E1-6-7). For each test suspension, the particle size of the particles contained in the test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b). The results are shown in Table 6.

[0080] (Reference Example 1-6: Preparation and evaluation of test suspension using polysorbate 20) Test suspension (R1-6) was obtained in the same manner as in Example 1-6-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 6.

[0081] [Table 6]

[0082] (Example 1-7-1: Preparation and evaluation of test suspension using polysorbate 80) A test suspension (E1-7-1) was obtained in the same manner as in Example 1-1-1, except that 1 g of the aripiprazole suspension prepared in Example 1-1-1 was added with polysorbate 80 as an anti-aggregating agent in an amount equivalent to 4 parts by mass per 100 parts by mass of aripiprazole contained in the suspension.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 7.

[0083] (Examples 1-7-2 to 1-7-7: Preparation and evaluation of test suspensions using polysorbate 80) Test suspension (E1-7-1) (before ultrasonic treatment) obtained in Example 1-7-1 was added with 1% silicone oil emulsion so that the amount of silicone oil contained in the suspension was the amount shown in Table 7 per 100 parts by mass of aripiprazole, and the mixture was stirred to obtain test suspensions (E1-7-2) to (E1-7-7). For each test suspension, the particle size of the particles contained in the test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b). The results are shown in Table 7.

[0084] (Reference Example 1-7: Preparation and evaluation of test suspension using polysorbate 80) Test suspension (R1-7) was obtained in the same manner as in Example 1-7-1, except that 1% silicone oil emulsion was not added.For this test suspension, the particle size of the particles contained in the test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b).The results are shown in Table 7.

[0085] [Table 7]

[0086] (Example 1-8-1: Preparation and evaluation of test suspension using polysorbate 80) A test suspension (E1-8-1) was obtained in the same manner as in Example 1-1-1, except that 1 g of the aripiprazole suspension prepared in Example 1-1-1 was added with 20 parts by mass of polysorbate 80 as an anti-aggregating agent relative to 100 parts by mass of aripiprazole contained in the suspension.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 8.

[0087] (Examples 1-8-2 to 1-8-7: Preparation and evaluation of test suspensions using polysorbate 80) Test suspension (E1-8-1) (before ultrasonic treatment) obtained in Example 1-8-1 was added with 1% silicone oil emulsion so that the amount of silicone oil contained in the suspension was the amount shown in Table 8 per 100 parts by mass of aripiprazole, and the mixture was stirred to obtain test suspensions (E1-8-2) to (E1-8-7). For each test suspension, the particle size of the particles contained in the test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b). The results are shown in Table 8.

[0088] (Reference Example 1-8: Preparation and evaluation of test suspension using polysorbate 80) Test suspension (R1-8) was obtained in the same manner as in Example 1-8-1, except that 1% silicone oil emulsion was not added.For this test suspension, the particle size of the particles contained in the test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b).The results are shown in Table 8.

[0089] [Table 8]

[0090] (Comparative Example 1-1-1: Preparation and Evaluation of Test Suspension (Blank) Not Containing Anti-Aggregating Agent) A test suspension (C1-1-1) was obtained in the same manner as in Example 1-1-1, except that no anti-aggregating agent was added to 1 g of the aripiprazole suspension prepared in Example 1-1-1.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 9.

[0091] (Comparative Examples 1-1-2 to 1-1-7: Preparation and Evaluation of Test Suspensions (Blanks) Not Containing Anti-Aggregating Agent) To the test suspension (C1-1-1) (before ultrasonic treatment) obtained in Comparative Example 1-1-1, 1% silicone oil emulsion was added so that the amount of silicone oil contained in the suspension was the amount shown in Table 9 per 100 parts by mass of aripiprazole, and the mixture was stirred to obtain test suspensions (C1-1-2) to (C1-1-7). For each test suspension, the particle size of the particles contained in the test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b). The results are shown in Table 9.

[0092] (Comparative Reference Example 1-1: Preparation and Evaluation of Test Suspensions Containing No Anti-flocculant) Test suspension (CR1-1) was obtained in the same manner as in Comparative Example 1-1-1, except that 1% silicone oil emulsion was not added.For this test suspension, the particle size of the particles contained in the test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b).The results are shown in Table 9.

[0093] [Table 9]

[0094] (Comparative Example 1-2-1: Preparation and Evaluation of Test Suspension Using Sodium Lauryl Sulfate) A test suspension (C1-2-1) was obtained in the same manner as in Example 1-1-1, except that sodium lauryl sulfate was added to 1 g of the aripiprazole suspension prepared in Example 1-1-1 in an amount equivalent to 20 parts by weight per 100 parts by weight of aripiprazole contained in the suspension instead of the anti-aggregating agent.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 10.

[0095] (Comparative Reference Example 1-2: Preparation and Evaluation of Test Suspension Using Sodium Lauryl Sulfate) A test suspension (CR1-2) was obtained in the same manner as in Comparative Example 1-2-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 10.

[0096] [Table 10]

[0097] (Comparative Example 1-3-1: Preparation and Evaluation of Test Suspension Using Sodium Lauroyl Sarcosinate) A test suspension (C1-3-1) was obtained in the same manner as in Example 1-1-1, except that sodium lauroyl sarcosinate was added to 1 g of the aripiprazole suspension prepared in Example 1-1-1 in an amount equivalent to 20 parts by weight per 100 parts by weight of aripiprazole contained in the suspension instead of an anti-aggregating agent.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 11.

[0098] (Comparative Examples 1-3-2 to 1-3-7: Preparation and Evaluation of Test Suspensions Using Sodium Lauroyl Sarcosinate) Test suspension (C1-3-1) (before ultrasonic treatment) obtained in Comparative Example 1-3-1 was added with 1% silicone oil emulsion so that the amount of silicone oil contained in the suspension was the amount shown in Table 11 per 100 parts by mass of aripiprazole, and the mixture was stirred to obtain test suspensions (C1-3-2) to (C1-3-7). For each test suspension, the particle size of the particles contained in the test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b). The results are shown in Table 11.

[0099] (Comparative Reference Example 1-3: Preparation and Evaluation of Test Suspension Using Sodium Lauroyl Sarcosinate) A test suspension (CR1-3) was obtained in the same manner as in Comparative Example 1-3-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 11.

[0100] [Table 11]

[0101] (Comparative Example 1-4-1: Preparation and evaluation of test suspension using polyoxyethylene (20) polyoxypropylene (20) glycol) A test suspension (C1-4-1) was obtained in the same manner as in Example 1-1-1, except that 1 g of the aripiprazole suspension prepared in Example 1-1-1 was replaced with 4 parts by mass of polyoxyethylene (20) polyoxypropylene (20) glycol (average molecular weight approximately 2000 (less than 3000)) per 100 parts by mass of aripiprazole contained in the suspension instead of the anti-aggregating agent, and 1% silicone oil emulsion was not added. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 12. Note that the test suspension (C1-4-1) lost fluidity and eventually solidified.

[0102] [Table 12]

[0103] (Comparative Example 1-5-1: Preparation and evaluation of test suspension using Macrogol 400) A test suspension (C1-5-1) was obtained in the same manner as in Example 1-1-1, except that instead of an anti-aggregating agent, Macrogol 400 was added in an amount equivalent to 4 parts by mass per 100 parts by mass of aripiprazole contained in the suspension to 1 g of the aripiprazole suspension prepared in Example 1-1-1, and 1% silicone oil emulsion was not added. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 13. Note that the test suspension (C1-5-1) lost fluidity and eventually solidified.

[0104] [Table 13]

[0105] (Comparative Example 1-6-1: Preparation and evaluation of test suspension using Macrogol 400) A test suspension (C1-6-1) was obtained in the same manner as in Example 1-1-1, except that 1 g of the aripiprazole suspension prepared in Example 1-1-1 was supplemented with macrogol 400 in an amount equivalent to 20 parts by weight per 100 parts by weight of aripiprazole contained in the suspension instead of the anti-aggregating agent, and 1% silicone oil emulsion was not added. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 14. Note that the test suspension (C1-6-1) lost fluidity and eventually solidified.

[0106] [Table 14]

[0107] As is clear from Tables 1 to 14 above, the test suspensions prepared in the above examples were able to adequately prevent aggregation of aripiprazole by the anti-aggregation agent, even though they contained silicone oil.

[0108] Example 2: Test Suspensions Containing Ezetimibe (Example 2-1-1: Preparation and evaluation of test suspension using polyoxyethylene cetyl ether) An ezetimibe suspension was prepared by adding ezetimibe as a poorly water-soluble drug, sodium carboxymethylcellulose, mannitol, and sodium dihydrogen phosphate monohydrate to purified water to the concentrations shown below. Ezetimibe: 30% by weight Sodium carboxymethylcellulose: approximately 1.248% by mass Mannitol: Approximately 6.24% by mass Sodium dihydrogen phosphate monohydrate: approximately 0.111% by mass

[0109] To 1 g of this ezetimibe suspension, polyoxyethylene cetyl ether was added as an anti-aggregating agent in an amount equivalent to 4 parts by mass per 100 parts by mass of ezetimibe contained in the suspension, and the mixture was stirred. 1% silicone oil emulsion was added to this suspension so that the silicone oil contained in the suspension was 0.5 parts by mass per 100 parts by mass of ezetimibe, and the mixture was stirred to obtain a test suspension (E2-1-1). The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 15.

[0110] (Example 2-1-2: Preparation and evaluation of test suspension using polyoxyethylene cetyl ether) In the test suspension (E2-1-1) (before ultrasonic treatment) obtained in Example 2-1-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts for 100 mass parts of ezetimibe, and then stirred to obtain test suspension (E2-1-2).For this test suspension, measure the particle size of the particles contained in the test suspension before ultrasonic treatment (a) and after ultrasonic treatment (b).Results are shown in Table 15.

[0111] (Reference Example 2-1: Preparation and evaluation of test suspension using polyoxyethylene cetyl ether) Test suspension (R2-1) was obtained in the same manner as in Example 2-1-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 15.

[0112] [Table 15]

[0113] (Example 2-2-1: Preparation and evaluation of test suspension using polyoxyethylene (160) polyoxypropylene (30) glycol) A test suspension (E2-2-1) was obtained in the same manner as in Example 2-1-1, except that polyoxyethylene (160) polyoxypropylene (30) glycol (average molecular weight 8905) was added as an anti-aggregating agent to 1 g of the ezetimibe suspension prepared in Example 2-1-1 in an amount equivalent to 4 parts by mass per 100 parts by mass of ezetimibe contained in the suspension. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 16.

[0114] (Example 2-2-2: Preparation and evaluation of test suspension using polyoxyethylene (160) polyoxypropylene (30) glycol) In the test suspension (E2-2-1) (before ultrasonic treatment) obtained in Example 2-2-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts per 100 mass parts of ezetimibe, and then stirred to obtain test suspension (E2-2-2).For this test suspension, the particle size of the particles contained in the test suspension before ultrasonic treatment (a) and after ultrasonic treatment (b) is measured.Results are shown in Table 16.

[0115] (Reference Example 2-2: Preparation and evaluation of test suspension using polyoxyethylene (160) polyoxypropylene (30) glycol) Test suspension (R2-2) was obtained in the same manner as in Example 2-2-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 16.

[0116] [Table 16]

[0117] (Example 2-3-1: Preparation and evaluation of test suspension using polysorbate 20) A test suspension (E2-3-1) was obtained in the same manner as in Example 2-1-1, except that 1 g of the ezetimibe suspension prepared in Example 2-1-1 was added with polysorbate 20 as an anti-aggregating agent in an amount equivalent to 4 parts by mass per 100 parts by mass of ezetimibe contained in the suspension. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 17.

[0118] (Example 2-3-2: Preparation and evaluation of test suspension using polysorbate 20) In the test suspension (E2-3-1) (before ultrasonic treatment) obtained in Example 2-3-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts for 100 mass parts of ezetimibe, and then stirred to obtain test suspension (E2-3-2).For this test suspension, measure the particle size of the particles contained in the test suspension before ultrasonic treatment (a) and after ultrasonic treatment (b).Results are shown in Table 17.

[0119] (Reference Example 2-3: Preparation and evaluation of test suspension using polysorbate 20) Test suspension (R2-3) was obtained in the same manner as in Example 2-3-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 17.

[0120] [Table 17]

[0121] (Example 2-4-1: Preparation and evaluation of test suspension using polysorbate 20) A test suspension (E2-4-1) was obtained in the same manner as in Example 2-1-1, except that 1 g of the ezetimibe suspension prepared in Example 2-1-1 was added with 20 parts by mass of polysorbate 20 as an anti-aggregating agent relative to 100 parts by mass of ezetimibe contained in the suspension. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 18.

[0122] (Example 2-4-2: Preparation and evaluation of test suspension using polysorbate 20) In the test suspension (E2-4-1) (before ultrasonic treatment) obtained in Example 2-4-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts per 100 mass parts of ezetimibe, and then stirred to obtain test suspension (E2-4-2).For this test suspension, the particle size of the particles contained in the test suspension before ultrasonic treatment (a) and after ultrasonic treatment (b) is measured.Results are shown in Table 18.

[0123] (Reference Example 2-4: Preparation and evaluation of test suspension using polysorbate 20) Test suspension (R2-4) was obtained in the same manner as in Example 2-4-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 18.

[0124] [Table 18]

[0125] (Example 2-5-1: Preparation and evaluation of test suspension using polysorbate 80) A test suspension (E2-5-1) was obtained in the same manner as in Example 2-1-1, except that 1 g of the ezetimibe suspension prepared in Example 2-1-1 was added with polysorbate 80 as an anti-aggregating agent in an amount equivalent to 4 parts by mass per 100 parts by mass of ezetimibe contained in the suspension. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 19.

[0126] (Example 2-5-2: Preparation and evaluation of test suspension using polysorbate 80) In the test suspension (E2-5-1) (before ultrasonic treatment) obtained in Example 2-5-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts per 100 mass parts of ezetimibe, and then stirred to obtain test suspension (E2-5-2).For this test suspension, measure the particle size of the particles contained in the test suspension before ultrasonic treatment (a) and after ultrasonic treatment (b).Results are shown in Table 19.

[0127] (Reference Example 2-5: Preparation and evaluation of test suspension using polysorbate 80) Test suspension (R2-5) was obtained in the same manner as in Example 2-5-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 19.

[0128] [Table 19]

[0129] (Example 2-6-1: Preparation and evaluation of test suspension using polysorbate 80) A test suspension (E2-6-1) was obtained in the same manner as in Example 2-1-1, except that 1 g of the ezetimibe suspension prepared in Example 2-1-1 was added with polysorbate 80 as an anti-aggregating agent in an amount equivalent to 20 parts by mass per 100 parts by mass of ezetimibe contained in the suspension. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 20.

[0130] (Example 2-6-2: Preparation and evaluation of test suspension using polysorbate 80) In the test suspension (E2-6-1) (before ultrasonic treatment) obtained in Example 2-6-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts per 100 mass parts of ezetimibe, and then stirred to obtain test suspension (E2-6-2).For this test suspension, measure the particle size of the particles contained in the test suspension before ultrasonic treatment (a) and after ultrasonic treatment (b).Results are shown in Table 20.

[0131] (Reference Example 2-6: Preparation and evaluation of test suspension using polysorbate 80) Test suspension (R2-6) was obtained in the same manner as in Example 2-6-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 20.

[0132] [Table 20]

[0133] (Comparative Example 2-1-1: Preparation and Evaluation of Test Suspension (Blank) Not Containing Anti-Aggregating Agent) A test suspension (C2-1-1) was obtained in the same manner as in Example 2-1-1, except that no anti-aggregating agent was added to 1 g of the ezetimibe suspension prepared in Example 2-1-1. The particle sizes of the particles contained in this test suspension were measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 21.

[0134] (Comparative Example 2-1-2: Preparation and Evaluation of Test Suspension (Blank) Not Containing Anti-Aggregating Agent) In the test suspension (C2-1-1) (before ultrasonic treatment) obtained in Comparative Example 2-1-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts per 100 mass parts of ezetimibe, and then stirred to obtain test suspension (C2-1-2).For this test suspension, measure the particle size of the particles contained in the test suspension before ultrasonic treatment (a) and after ultrasonic treatment (b).Results are shown in Table 21.

[0135] (Comparative Reference Example 2-1: Preparation and evaluation of test suspension containing no anti-flocculant) A test suspension (CR2-1) was obtained in the same manner as in Comparative Example 2-1-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 21.

[0136] [Table 21]

[0137] (Comparative Example 2-2-1: Preparation and evaluation of test suspension using polyoxyethylene (20) polyoxypropylene (20) glycol) Test suspension (C2-2-1) was prepared in the same manner as in Example 2-1-1, except that polyoxyethylene (20) polyoxypropylene (20) glycol (average molecular weight approximately 2000 (less than 3000)) was added to 1 g of the ezetimibe suspension prepared in Example 2-1-1 in an amount equivalent to 4 parts by mass per 100 parts by mass of ezetimibe contained in the suspension instead of the anti-aggregating agent. However, this test suspension (C2-2-1) had already lost its fluidity and solidified, and obvious aggregation was observed by visual inspection, so the particle size (before ultrasonic treatment (a) and after ultrasonic treatment (b)) was not measured (Table 22).

[0138] (Comparative Example 2-2-2: Preparation and evaluation of test suspension using polyoxyethylene (20) polyoxypropylene (20) glycol) In the test suspension (C2-2-1) (before ultrasonic treatment) obtained in comparative example 2-2-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts for 100 mass parts of ezetimibe, and then stirred to prepare test suspension (C2-2-2).However, this test suspension (C2-2-2) has already lost the fluidity of suspension and solidified, and there is obvious aggregation in visual observation, so the particle size (before ultrasonic treatment (a) and after ultrasonic treatment (b)) is not measured (Table 22).

[0139] (Comparative Reference Example 2-2: Preparation and Evaluation of Test Suspension Using Polyoxyethylene (20) Polyoxypropylene (20) Glycol) A test suspension (CR2-2) was obtained in the same manner as in Comparative Example 2-2-1, except that 1% silicone oil emulsion was not added. The particle size of the test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 22. The test suspension (CR2-2) lost fluidity and was partially solidified.

[0140] [Table 22]

[0141] (Comparative Example 2-3-1: Preparation and evaluation of test suspension using Macrogol 400) A test suspension (C2-3-1) was prepared in the same manner as in Example 2-1-1, except that 1 g of the ezetimibe suspension prepared in Example 2-1-1 was supplemented with macrogol 400 instead of the anti-aggregating agent in an amount equivalent to 4 parts by mass relative to 100 parts by mass of ezetimibe contained in the suspension, and 1% silicone oil emulsion was not added. However, this test suspension (C2-3-1) had already lost its fluidity and solidified, and obvious aggregation was observed visually, so the particle size (before ultrasonic treatment (a) and after ultrasonic treatment (b)) was not measured (Table 23).

[0142] (Comparative Example 2-3-2: Preparation and evaluation of test suspension using Macrogol 400) In the test suspension (C2-3-1) (before ultrasonic treatment) obtained in comparative example 2-3-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts for 100 mass parts of ezetimibe, and then stirred to prepare test suspension (C2-3-2).However, this test suspension (C2-3-2) has already lost the fluidity of suspension and solidified, and there is obvious aggregation in visual observation, so the particle size (before ultrasonic treatment (a) and after ultrasonic treatment (b)) is not measured (Table 23).

[0143] (Comparative Reference Example 2-3: Preparation and evaluation of test suspension using Macrogol 400) A test suspension (CR2-3) was obtained in the same manner as in Comparative Example 2-3-1, except that 1% silicone oil emulsion was not added. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 23. Note that test suspension (CR2-3) lost fluidity and was partially solidified.

[0144] [Table 23]

[0145] As is clear from Tables 15 to 23 above, the test suspensions prepared in the above examples were able to adequately prevent aggregation of ezetimibe by the anti-aggregating agent, even though they contained silicone oil.

[0146] Example 3: Test suspensions containing tolvaptan (Example 3-1-1: Preparation and evaluation of test suspension using polyoxyethylene cetyl ether) Tolvaptan suspension was prepared by adding tolvaptan as a poorly water-soluble drug, sodium carboxymethylcellulose, mannitol, and sodium dihydrogen phosphate monohydrate to purified water to the concentrations shown below. Tolvaptan: 30% by mass Sodium carboxymethylcellulose: approximately 1.248% by mass Mannitol: Approximately 6.24% by mass Sodium dihydrogen phosphate monohydrate: approximately 0.111% by mass

[0147] To 1 g of this tolvaptan suspension, polyoxyethylene cetyl ether was added as an anti-aggregating agent in an amount equivalent to 4 parts by mass per 100 parts by mass of tolvaptan contained in the suspension, and the mixture was stirred. A 1% silicone oil emulsion was added to this suspension so that the silicone oil content in the suspension was 0.5 parts by mass per 100 parts by mass of tolvaptan, and the mixture was stirred to obtain a test suspension (E3-1-1). The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 24.

[0148] (Example 3-1-2: Preparation and evaluation of test suspension using polyoxyethylene cetyl ether) A 1% silicone oil emulsion was added to the test suspension (E3-1-1) (before ultrasonic treatment) obtained in Example 3-1-1 so that the silicone oil content in the suspension was 5 parts by mass per 100 parts by mass of tolvaptan, and the mixture was stirred to obtain test suspension (E3-1-2).The particle size of the particles contained in this test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b).The results are shown in Table 24.

[0149] (Reference Example 3-1: Preparation and evaluation of test suspension using polyoxyethylene cetyl ether) Except that 1% silicone oil emulsion was not added, test suspension (R3-1) was obtained in the same manner as in Example 3-1-1.The particle size of the particles contained in this test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b).The results are shown in Table 24.

[0150] [Table 24]

[0151] (Example 3-2-1: Preparation and evaluation of test suspension using polyoxyethylene (160) polyoxypropylene (30) glycol) A test suspension (E3-2-1) was prepared in the same manner as in Example 3-1-1, except that polyoxyethylene (160) polyoxypropylene (30) glycol (average molecular weight 8905) was added as an anti-aggregating agent to 1 g of the tolvaptan suspension prepared in Example 3-1-1 in an amount equivalent to 4 parts by mass per 100 parts by mass of tolvaptan contained in the suspension. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 25.

[0152] (Example 3-2-2: Preparation and evaluation of test suspension using polyoxyethylene (160) polyoxypropylene (30) glycol) A 1% silicone oil emulsion was added to the test suspension (E3-2-1) (before ultrasonic treatment) obtained in Example 3-2-1 so that the silicone oil content in the suspension was 5 parts by mass per 100 parts by mass of tolvaptan, and the mixture was stirred to obtain test suspension (E3-2-2).The particle size of the particles contained in this test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b).The results are shown in Table 25.

[0153] (Reference Example 3-2: Preparation and evaluation of test suspension using polyoxyethylene (160) polyoxypropylene (30) glycol) Test suspension (R3-2) was obtained in the same manner as in Example 3-2-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 25.

[0154] [Table 25]

[0155] (Example 3-3-1: Preparation and evaluation of test suspension using polysorbate 20) A test suspension (E3-3-1) was prepared in the same manner as in Example 3-1-1, except that 1 g of the tolvaptan suspension prepared in Example 3-1-1 was supplemented with polysorbate 20 as an anti-aggregating agent in an amount equivalent to 4 parts by mass per 100 parts by mass of tolvaptan contained in the suspension. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 26.

[0156] (Example 3-3-2: Preparation and evaluation of test suspension using polysorbate 20) A 1% silicone oil emulsion was added to the test suspension (E3-3-1) (before ultrasonic treatment) obtained in Example 3-3-1 so that the silicone oil content in the suspension was 5 parts by mass per 100 parts by mass of tolvaptan, and the mixture was stirred to obtain test suspension (E3-3-2).The particle size of the particles contained in this test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b).The results are shown in Table 26.

[0157] (Reference Example 3-3: Preparation and evaluation of test suspension using polysorbate 20) Test suspension (R3-3) was obtained in the same manner as in Example 3-3-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 26.

[0158] [Table 26]

[0159] (Example 3-4-1: Preparation and evaluation of test suspension using polysorbate 80) A test suspension (E3-4-1) was prepared in the same manner as in Example 3-1-1, except that 1 g of the tolvaptan suspension prepared in Example 3-1-1 was supplemented with polysorbate 80 as an anti-aggregating agent in an amount equivalent to 4 parts by mass per 100 parts by mass of tolvaptan contained in the suspension. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 27.

[0160] (Example 3-4-2: Preparation and evaluation of test suspension using polysorbate 80) A 1% silicone oil emulsion was added to the test suspension (E3-4-1) (before ultrasonic treatment) obtained in Example 3-4-1 so that the silicone oil content in the suspension was 5 parts by mass per 100 parts by mass of tolvaptan, and the mixture was stirred to obtain test suspension (E3-4-2).The particle size of the particles contained in this test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b).The results are shown in Table 27.

[0161] (Reference Example 3-4: Preparation and evaluation of test suspension using polysorbate 80) Test suspension (R3-4) was obtained in the same manner as in Example 3-4-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 27.

[0162] [Table 27]

[0163] (Comparative Example 3-1-1: Preparation and Evaluation of Test Suspension (Blank) Not Containing Anti-flocculant) A test suspension (C3-1-1) was obtained in the same manner as in Example 3-1-1, except that no anti-aggregating agent was added to 1 g of the tolvaptan suspension prepared in Example 3-1-1. The particle sizes of the particles contained in this test suspension were measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 28.

[0164] (Comparative Example 3-1-2: Preparation and evaluation of test suspension (blank) containing no anti-aggregating agent) A 1% silicone oil emulsion was added to the test suspension (C3-1-1) (before ultrasonic treatment) obtained in Comparative Example 3-1-1 so that the silicone oil content in the suspension was 5 parts by mass per 100 parts by mass of tolvaptan, and the mixture was stirred to obtain test suspension (C3-1-2). The particle size of the particles contained in this test suspension was measured before ultrasonic treatment (a) and after ultrasonic treatment (b). The results are shown in Table 28.

[0165] (Comparative Reference Example 3-1: Preparation and evaluation of test suspension containing no anti-flocculant) A test suspension (CR3-1) was obtained in the same manner as in Comparative Example 3-1-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 28.

[0166] [Table 28]

[0167] As is clear from Tables 24 to 28 above, the test suspensions prepared in the above examples were able to appropriately prevent aggregation of tolvaptan by the anti-aggregating agent, even though they contained silicone oil.

[0168] Example 4: Test suspension containing sofenib tosylate (Example 4-1-1: Preparation and evaluation of test suspension using polyoxyethylene cetyl ether) Sofenibut tosylate as a poorly water-soluble drug, sodium carboxymethylcellulose, mannitol, and sodium dihydrogen phosphate monohydrate were added to purified water to give the following concentrations to prepare a sofenibut tosylate suspension. Sofenib tosylate: 30% by mass Sodium carboxymethylcellulose: approximately 1.248% by mass Mannitol: Approximately 6.24% by mass Sodium dihydrogen phosphate monohydrate: approximately 0.111% by mass

[0169] To 1 g of this sofenib tosylate suspension, polyoxyethylene cetyl ether was added as an anti-aggregating agent in an amount equivalent to 4 parts by mass per 100 parts by mass of sofenib tosylate contained in the suspension, and then stirred.To this suspension, 1% silicone oil emulsion was added so that the silicone oil contained in the suspension was 0.5 parts by mass per 100 parts by mass of sofenib tosylate, and then stirred to obtain test suspension (E4-1-1).For this test suspension, the particle size of the particles contained in the test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 29.

[0170] (Example 4-1-2: Preparation and evaluation of test suspension using polyoxyethylene cetyl ether) In the test suspension (E4-1-1) (before ultrasonic treatment) obtained in Example 4-1-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts per 100 mass parts of sofenib tosylate, and then stirred to obtain test suspension (E4-1-2).For this test suspension, measure the particle size of the particles contained in the test suspension before ultrasonic treatment (a) and after ultrasonic treatment (b).Results are shown in Table 29.

[0171] (Reference Example 4-1: Preparation and evaluation of test suspension using polyoxyethylene cetyl ether) Test suspension (R4-1) was obtained in the same manner as in Example 4-1-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 29.

[0172] [Table 29]

[0173] (Example 4-2-1: Preparation and evaluation of test suspension using polyoxyethylene (160) polyoxypropylene (30) glycol) A test suspension (E4-2-1) was obtained in the same manner as in Example 4-1-1, except that 1 g of the sofenib tosylate suspension prepared in Example 4-1-1 was supplemented with polyoxyethylene (160) polyoxypropylene (30) glycol (average molecular weight 8905) as an anti-aggregating agent in an amount equivalent to 4 parts by mass per 100 parts by mass of sofenib tosylate contained in the suspension. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 30.

[0174] (Example 4-2-2: Preparation and evaluation of test suspension using polyoxyethylene (160) polyoxypropylene (30) glycol) In the test suspension (E4-2-1) (before ultrasonic treatment) obtained in Example 4-2-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts per 100 mass parts of sofenib tosylate, and then stirred to obtain test suspension (E4-2-2).For this test suspension, measure the particle size of the particles contained in the test suspension before ultrasonic treatment (a) and after ultrasonic treatment (b).Results are shown in Table 30.

[0175] (Reference Example 4-2: Preparation and evaluation of test suspension using polyoxyethylene (160) polyoxypropylene (30) glycol) Test suspension (R4-2) was obtained in the same manner as in Example 4-2-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 30.

[0176] [Table 30]

[0177] (Example 4-3-1: Preparation and evaluation of test suspension using polysorbate 20) A test suspension (E4-3-1) was obtained in the same manner as in Example 4-1-1, except that 1 g of the sofenib tosylate suspension prepared in Example 4-1-1 was supplemented with 4 parts by mass of polysorbate 20 as an anti-aggregating agent relative to 100 parts by mass of sofenib tosylate contained in the suspension. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 31.

[0178] (Example 4-3-2: Preparation and evaluation of test suspension using polysorbate 20) In the test suspension (E4-3-1) (before ultrasonic treatment) obtained in Example 4-3-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts per 100 mass parts of sofenib tosylate, and then stirred to obtain test suspension (E4-3-2).For this test suspension, the particle size of the particles contained in the test suspension before ultrasonic treatment (a) and after ultrasonic treatment (b) is measured.Results are shown in Table 31.

[0179] (Reference Example 4-3: Preparation and evaluation of test suspension using polysorbate 20) Test suspension (R4-3) was obtained in the same manner as in Example 4-3-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 31.

[0180] [Table 31]

[0181] (Example 4-4-1: Preparation and evaluation of test suspension using polysorbate 80) A test suspension (E4-4-1) was obtained in the same manner as in Example 4-1-1, except that 1 g of the sofenib tosylate suspension prepared in Example 4-1-1 was added with polysorbate 80 as an anti-aggregating agent in an amount equivalent to 4 parts by mass per 100 parts by mass of sofenib tosylate contained in the suspension. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 32.

[0182] (Example 4-4-2: Preparation and evaluation of test suspension using polysorbate 80) In the test suspension (E4-4-1) (before ultrasonic treatment) obtained in Example 4-4-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts per 100 mass parts of sofenib tosylate, and then stirred to obtain test suspension (E4-4-2).For this test suspension, the particle size of the particles contained in the test suspension before ultrasonic treatment (a) and after ultrasonic treatment (b) is measured.Results are shown in Table 32.

[0183] (Reference Example 4-4: Preparation and evaluation of test suspension using polysorbate 80) Test suspension (R4-4) was obtained in the same manner as in Example 4-4-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 32.

[0184] [Table 32]

[0185] (Comparative Example 4-1-1: Preparation and Evaluation of Test Suspension (Blank) Not Containing Anti-Aggregating Agent) A test suspension (C4-1-1) was obtained in the same manner as in Example 4-1-1, except that no anti-aggregating agent was added to 1 g of the sofenib tosylate suspension prepared in Example 4-1-1. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 33.

[0186] (Comparative Example 4-1-2: Preparation and evaluation of test suspension (blank) containing no anti-aggregating agent) In the test suspension (C4-1-1) (before ultrasonic treatment) obtained in comparative example 4-1-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts per 100 mass parts of sofenib tosylate, and then stirred to obtain test suspension (C4-1-2).For this test suspension, measure the particle size of the particles contained in the test suspension before ultrasonic treatment (a) and after ultrasonic treatment (b).Results are shown in Table 33.

[0187] (Comparative Reference Example 4-1: Preparation and Evaluation of Test Suspensions Containing No Anti-flocculant) A test suspension (CR4-1) was obtained in the same manner as in Comparative Example 4-1-1, except that 1% silicone oil emulsion was not added.The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment.The results are shown in Table 33.

[0188] [Table 33]

[0189] (Comparative Example 4-2-1: Preparation and Evaluation of Test Suspension Using Sodium Lauroyl Sarcosinate) A test suspension (C4-2-1) was prepared in the same manner as in Example 4-1-1, except that sodium lauroyl sarcosinate was added to 1 g of the tolvaptan suspension prepared in Example 4-1-1 in an amount equivalent to 4 parts by mass per 100 parts by mass of sofenib tosylate contained in the suspension instead of the anti-aggregating agent. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 34.

[0190] (Comparative Example 4-2-2: Preparation and evaluation of test suspension using sodium lauroyl sarcosinate) In the test suspension (C4-2-1) (before ultrasonic treatment) obtained in comparative example 4-2-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts per 100 mass parts of sofenib tosylate, to obtain test suspension (C4-2-2).For this test suspension, before ultrasonic treatment (a) and after ultrasonic treatment (b), the particle size of the particles contained in the test suspension is measured.Results are shown in Table 34.

[0191] (Comparative Reference Example 4-2: Preparation and Evaluation of Test Suspension Using Sodium Lauroyl Sarcosinate) A test suspension (CR4-2) was obtained in the same manner as in Comparative Example 4-2-1, except that 1% silicone oil emulsion was not added. The particle size of the test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 34. The test suspension (CR4-2) lost fluidity and was partially solidified.

[0192] [Table 34]

[0193] (Comparative Example 4-3-1: Preparation and evaluation of test suspension using polyoxyethylene (20) polyoxypropylene (20) glycol) A test suspension (C4-3-1) was prepared in the same manner as in Example 4-1-1, except that polyoxyethylene (20) polyoxypropylene (20) glycol (average molecular weight approximately 2000 (less than 3000)) was added to 1 g of the tolvaptan suspension prepared in Example 4-1-1 in an amount equivalent to 4 parts by mass per 100 parts by mass of sofenib tosylate contained in the suspension instead of the anti-aggregating agent. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 35.

[0194] (Comparative Example 4-3-2: Preparation and evaluation of test suspension using polyoxyethylene (20) polyoxypropylene (20) glycol) In the test suspension (C4-3-1) (before ultrasonic treatment) obtained in comparative example 4-3-1, 1% silicone oil emulsion is added, so that the silicone oil contained in this suspension is 5 mass parts per 100 mass parts of sofenib tosylate, and then stirred to obtain test suspension (C4-3-2).For this test suspension, measure the particle size of the particles contained in the test suspension before ultrasonic treatment (a) and after ultrasonic treatment (b).Results are shown in Table 35.

[0195] (Comparative Reference Example 4-3: Preparation and evaluation of test suspension using polyoxyethylene (20) polyoxypropylene (20) glycol) A test suspension (CR4-3) was obtained in the same manner as in Comparative Example 4-3-1, except that 1% silicone oil emulsion was not added. The particle size of the particles contained in this test suspension was measured before (a) and after (b) ultrasonic treatment. The results are shown in Table 35. Note that the test suspension (CR4-3) lost fluidity and was partially solidified.

[0196] [Table 35]

[0197] As is clear from Tables 29 to 35 above, the test suspensions prepared in the above examples were able to adequately prevent aggregation of sofenibut tosylate by the anti-aggregating agent, even though they contained silicone oil.

[0198] This shows that the anti-aggregation agents used in the above examples are useful for preventing aggregation of poorly water-soluble drugs such as aripiprazole, ezetimibe, tolvaptan, and sorafenib tosylate when the drugs are suspended in an aqueous dispersion medium in the presence of silicone oils.Furthermore, it is also useful to have such an anti-aggregation agent coexist with poorly water-soluble drugs in medical devices including containers whose inner walls are treated with silicone oils. [Industrial Applicability]

[0199] The present invention is useful in the fields of manufacturing pharmaceuticals and medical devices, for example.

Claims

1. An anti-agglomeration agent for preventing a poorly water-soluble drug from aggregating due to silicone oils, An anti-flocculating agent comprising, as an anti-flocculating component, at least one selected from the group consisting of polyoxyethylene cetyl ether, polyoxyethylene sorbitan fatty acid ester, and polyoxyethylene polyoxypropylene glycol having an average molecular weight of 3,000 to 13,000.

2. A pharmaceutical composition contained in a double-chamber syringe having two compartments, A lyophilized product of aripiprazole is contained in one compartment of the double-chamber syringe, an aqueous dispersion medium is contained in another compartment of the double-chamber syringe; The inner wall of the double-chamber syringe is treated with silicone oil, A pharmaceutical composition comprising the anti-aggregating agent according to claim 1 contained in the freeze-dried product or the aqueous dispersion medium.

3. 3. The pharmaceutical composition according to claim 2, wherein the anti-aggregation agent contains the anti-aggregation component in a ratio of 2 to 40 parts by mass per 100 parts by mass of the aripiprazole.

4. A medical device comprising a double-chamber syringe whose inner wall is treated with silicone oil, A medical device comprising a container containing the pharmaceutical composition according to claim 2 or 3.

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