WO2003002095A1 - O/w type microemulsion preparation - Google Patents

Abstract

A microemulsion preparation which enables a drug to be more effectively utilized biologically. The O/W type microemulsion preparation comprises (1) a sparingly water-soluble drug, (2) an oil, (3) a hydrophilic surfactant, and (4) an oleophilic surfactant having an HLB of 4.0 to 9.0, and (5) water.

Description

 Description ozw type mic mouth emulsion formulation

 The present invention relates to a novel oZw-type pre-composition containing a drug dissolved in an oil phase and a novel ozw-type mic-mouth emulsion formulation. Background art

 Poorly water-soluble drugs, despite having strong pharmacological effects, have low water solubility (solubility or dissolution rate), such as bioavailability when administered orally. ) Decreased, and the metabolic effect was greatly affected, and the variability increased, often failing to achieve the expected therapeutic effect. Therefore, conventionally, in order to improve the solubility of the poorly water-soluble drug, a pulverizing technique such as pulverization, solid dispersion, and OZW type emulsion has been used (Panayiotis P. et al. Constantinides: Revi ew L ipid Microemu lsions for Imp roving Dr ug D issolutionand Oral Ab sorption: Phy sica 1 and Biopha rma ceutical Aspect s. P ha rm. Re s., 12, 1561—1572 (1995 )). In the case of pulverization or solid dispersion, there are many cases where drug agglomeration occurs and it is difficult to ensure stability. Also, oZw emulsions improve solubility by completely dissolving poorly soluble drugs in the oil phase, thereby improving bioavailability, but the stability of the emulsion itself is not sufficient In many cases, further improvement is desired.

The microemulsion is an oil-Z water system stabilized by the surface phase of a surfactant. In the case of the OZW type, the oil phase particles are smaller than the emulsion and the thermodynamics It is also stable. Formulations utilizing such microemers / solutions include Mikuguchi emulsion containing cyclosporin (Japanese Unexamined Patent Publication No. 2-121929, Zh on g-Ga ogaoeta 1-Phy sicoch em ical characterization a ndevaluationofa micro emu lsionsyst em fororaldeliveryofcycl osporin A. Int. , WA R itschel: Micro emu lsions for imp rovedpeptideabsorptio nfr om thegastrointestinaltr act.Meth.Find.Ep.Clin.Pharma col., 13, 205-220 (1991)) However, the development of preparations that can further improve bioavailability and preparations that can be applied to various drugs is awaited.

 In addition, since the external phase of the o / w type microemulsion is water, considering the stability of the microemulsion itself, the development of a pre-emulsion OZ w-type mic mouth emulsion that does not contain water for clinical application is also considered. Is desired. Disclosure of the invention

 The present invention comprises (1) a poorly water-soluble drug, (2) an oil, (3) a hydrophilic surfactant, and (4) a lipophilic surfactant having an HLB value of 4.0 to 9.0. An OZW type (oil-in-water type) provides a pre-emulsion composition.

 Further, the present invention provides (1) a poorly water-soluble drug, (2) an oil, (3) a hydrophilic surfactant, (4) a lipophilic surfactant having an HLB value of 4.0 to 9.0, And (5) To provide an OZW type mic mouth emulsion formulation comprising water.

 In the pre-O / W type microphone mouth emulsion composition and the OZW type microemulsion preparation of the present invention, the weight ratio of the hydrophilic surfactant to the lipophilic surfactant may be 9: 1 to 5: 5. preferable.

In the OZW type microemulsion preparation according to the present invention, the HLB value of the lipophilic surfactant is preferably 4.0 to 6.0. Preferably, the lipophilic surfactant is diglyceryl monooleate. Before the o / w type mic mouth emulsion of the present invention, in the composition oZw type mic mouth emulsion formulation, the lipophilic surfactant is diglyceryl monooleate, diglyceryl monoisostearate, sorbitan monooleate, Preferably, it is selected from the group consisting of sorbitan sesquioleate, sorbitan trioleate, sorbitan monoisostearate, polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene (2) nourphenyl ether. More preferably, the lipophilic surfactant is selected from the group consisting of diglyceryl monooleate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate.

 In the pre-o / w-type mic-mouth emollient composition and the oZw-type mic-mouth emulsion formulation of the present invention, the hydrophilic surfactant preferably has an HLB value of 11.5 to: 17.5, and 11. More preferably, it is 5 to 15.6. Preferably, the hydrophilic surfactant freshener is a polyoxyethylene hydrogenated castor oil.

In the OZW-type mic-mouth emulsion pre-composition and the 〇 / W-type mic-mouth emulsion formulation of the present invention, the hydrophilic surfactant is monococo oil fatty acid polyoxyethylene (20) sorbitan, monopalmitate polyoxyethylene (20) Sorbitan, polyoxyethylene monooleate (20) sorbitan, polyoxyethylene monolaurate (6) sorbite, polyoxyethylene tetraoleate (30) sorbite, polyoxyethylene tetraoleate (40) sorbite, polyoxyethylene tetraoleate (60) sorbitol, polyoxyethylene (40) hard castor oil, polyoxyethylene (50) hardened castor oil, polyoxyethylene (60) hardened castor oil, polyethylene glycol monolaurate (1010), polyoxyethylene ( 4.2) Lauryl ether , Polyoxyethylene (9) lauryl ether, polyoxyethylene (7.5) nourphenyl ether, polyoxyethylene (10) nouryl phenyl ether, hexaglyceryl monolaurate, deglyceryl monooleate It is preferable to be selected from a group. The hydrophilic surfactant is polyoxyethylene monopalmitate (20) sonorebitan, polyoxetylene monooleate (20) sonorebitan, polyoxyethylene (40) hard castor oil, polyoxyethylene (50) Hard ^ f danger castor Oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (4.2) lauryl ether, polyoxyethylene (9) lauryl ether, hexaglyceryl monolaurate, deglyceryl monooleate Is more preferable.

 The oZw-type pre-emulsion emulsion and the 〇 / w-type microemulsion preparation of the present invention may further contain a solubilizer for poorly water-soluble drugs. Ethanol is preferred as a solubilizer.

 The disclosure of Japanese Patent Application No. 2001-196873, which is the application on which the priority claimed by the present application is based, is incorporated herein by reference in its entirety.

BEST MODE FOR CARRYING OUT THE INVENTION

 Each term used in the present specification has the following meaning unless otherwise specified.

 “Consisting of” means that other components and components may be included. For example, “consisting of A, B, and C” means that A, B, and C are included, but D and E may or may not be included.

 "Micro-emulsion (hereinafter also referred to as" ME ")" is an optically transparent or semi-transparent oil Z water system stabilized by the interfacial phase of a surfactant active agent. is there. For example, the largest dimension (eg, diameter) of a particle or droplet is about 1

50 nm (1500 angstroms) or less, for example, generally 10 ~: L Emulsion which is 00 nm is included. O / W microemulsions are monophasic and thermodynamically stable. Since the particles are small, the absorption of the active ingredient is good. “O / W type microemulsion” means an oil-in-water type microemulsion.

"OZW type microemulsion pre-composition" refers to a composition which is in contact with an aqueous phase, for example, added to an aqueous phase before administration, or in vivo after administration (for example, after oral administration, such as in the stomach and small intestine). A composition capable of forming an O / W type microemulsion when contacted with water in the living body is used in the so-called self-emulsifying type (Self Emu 1 sifying Drug De livery System) OZWs ^ My Completely spontaneous oZw microemulsification Not only the case, but also includes a composition capable of forming an oZw type mic mouth emulsion when added to the aqueous phase and stirred.

 "Poorly water-soluble drug" refers to a drug that is hardly soluble in water (the amount of water required to dissolve 1 g or 1 ml of the drug must be 100 ml or more and less than 1000 ml), and a drug that is extremely poorly soluble (100 Om 1 or more) Includes general substances such as drugs that are almost insoluble (requires less than 10000m1) and almost insoluble (requires 1000 Oml or more). For example, oily drugs, fat-soluble drugs, and the like can be mentioned. It also includes drugs that can be dissolved in the oil phase by using solubilizers such as ethanol, anhydrous ethanol, propylene glycol, macrogol, and glycerin. For example, a drug having a LogD (water-octanol partition coefficient) of 2 or more can be used. In the present invention, any drug can be used as long as it is sparingly soluble, very sparingly soluble, or hardly soluble in water. Ninorebutazone, phenacetin, dipyridamone, canolebamazepine, sulfamethoxazonole, tenorefenadine, spironolatone, furosemide, indomethacin, hydrocortisone, -fuedipin, snorefaxazole, fometoidin, dexamethasone, dexamethasone Drugs such as AG-041R, ER-1039, B0-653, and CP-060S.

 "Oil" includes fats and oils widely used in pharmaceutical preparations, foods, and food additives, and includes both unsaturated fatty acids (fatty acids with one or more double bonds in the fatty acid molecule) and saturated fatty acids . For example, vegetable oils (soy oil, safflower oil, sunflower oil, corn oil, cottonseed oil, sesame oil, rapeseed oil, peanut oil, olive oil, etc.), medium-chain fatty acid triglycerides, tricaprylin, caprylic acid 'capric triglyceride, short Chain fatty acid triglyceride, oleic acid, ethyl oleate, linoleic acid, linolenic acid, lecithin and the like. Among them, panaceto 810 (triglyceride of caprylic acid / capric acid, C8: 85%, C10: 15%, Nippon Oil & Fats), orethyl oleate, tributylin, triacetin, olive oil, oleic acid, etc. are preferred. .

"Hydrophilic surfactant" is a surfactant having a high affinity for water. As long as the hydrophilic surfactant has an HLB value in the range of 9.0 to 20.0, it can be generally used without limitation. In general, polyoxyethylene monooleate (15) glyceryl (HLB value: 14.5), hexaglyceryl monolaurate (HLB value: 14.5), decaglyceryl monolaurate (HLB value: 15.5), decaglyceryl monooleate (HLB value: 12.0), decaglyceryl monolinoleate (HLB value: 12.0), decaglyceryl monoisostearate (HLB value: 12.0), polyoxyethylene monococonut fatty acid (20) sorbitan ( HLB value: 16.9), polyoxyethylene monopalmitate (20) sorbitan (HLB value: 15.6), polyoxyethylene monostearate (20) sorbitan (HLB value: 14.9), monooleic acid Polyoxyethylene (20) sorbitan (HLB value: 15.0), polyoxyethylene monoisostearate (20) sorbitan (HLB value: 15.0), polyoxyethylene monolaurate (6) Solvit (HLB value: 15.5), polyoxyethylene tetraoleate (30) sorbit (HLB value: 11.5), polyoxyethylene tetraoleate (40) sorbite (HLB value: 12) 5), polyoxyethylene tetraoleate (60) sorbitol (HLB value: 14.0), polyoxyethylene (40) castor oil (HLB value: 12.5), polyoxyethylene (50) castor oil (HLB value) : 14.0), polyoxyethylene (60) castor oil (HLB value: 14.0), polyoxyethylene (40) hydrogenated castor oil (HLB value: 12.5), polyoxyethylene (50) hydrogenated castor oil ( HLB value: 13.5), polyoxyethylene (60) hydrogenated castor oil (HLB value: 14.0), polyethylene glycol monolaurate (10 EO) (HLB value: 12.5), polyethylene glycol monostearate ( 40EO) (HLB value: 17.5), polyoxyethylene (4.2) Lauryl ether (HLB value: 11.5), polyoxyethylene (9) lauryl ether (HLB value: 14.5), polyoxyethylene (10) oleyl ether (HLB value: 14.2) ◦), polyoxyethylene (7.5) nonylphenol ether (HLB value: 14.0), polyoxyethylene (10) non-norrefinolenoether (HLB value: 16.5), polyoxyethylene (10 ) Octyl / Refenyl ether (HLB value: 16.5), polyoxyethylene (10) stearyl Min (HLB value: 14.0), Polyoxyethylene (15) Oleylamine (HLB value: 15.5), Polyoxyethylene (8) Stearyl propylene diamine

(HLB value: 15.5), polyoxyethylene (4) Hydrophilicity such as sodium lauryl ether phosphate (HLB value: 13.0) with an HLB value in the range of 11.5 to 17.5 Surfactants are preferred. Further, those having an HLB value of 11.5 to 15.6 are preferable, and among them, polyoxyethylene having an HLB value of about 12.5 is preferable.

(40) Hardened castor oil (eg, HCO-40 (trade name), Nikko Chemicals), polyoxyethylene (40) Castor oil (eg, CO-40TX (trade name), Nikko Chemicals), polyoxyethylene tetraoleate (40) Sorbit (for example, GO-440 (trade name), Nikko Chemicals), polyethylene glycol monolaurate (10EO) (for example, MYL-10 (trade name), Nikko Chemicals, HLB value: 12.5), etc. Is particularly preferred. In addition, mono-coconut oil polyoxyethylene (20) sorbitan, polyoxyxylene (monopalmitate) (20) sorbitan, polyoxyethylene (monooleate) (20) sonorevitan, polyoxyethylene monolaurate (6) sorbit, tetraoleic acid Polyoxyethylene

(30) Sonorebit, polyoxyethylene tetraoleate (40) Sorbit, polyoxyethylene tetraoleate (60) Sorbit, polyoxyethylene

(40) Hardened castor oil, polyoxyethylene (50) Hardened castor oil, polyoxyethylene (60) Hardened castor oil, polyethylene glycol monolaurate (10 EO), polyoxyethylene (4.2) lauryl ether, polyoxy ethylene

(9) lauryl ether, polyoxyethylene (7.5) nonylphenyl etherate, polyoxyethylene (10) noninolephenineoleatenole, hexaglyceryl monolaurate, decaglyceryl monooleate, etc. Polyoxyethylene monopalmitate (20) sorbitan, polyoxyethylene monooleate (20) sorbitan, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, poly Preferred are oxyethylene (4.2) laurino ether, polyoxyethylene (9) peryl ether, hexaglyceryl monolaurate, and deglyceryl monooleate. Here, the HLB (Hy drophile—Lipophi 1 e Balance) value is a numerical expression of the balance between the relative strength of hydrophilicity and lipophilicity of a surfactant molecule. The HLB of the nonionic surfactant is calculated by the following equation:

 HLB = 20 (1-S / A)

 A: Acid value of raw fatty acid

 S: Saponification value of Estenolle

 “Lipophilic surfactants” are surfactants that have a high affinity for oil. One of the features of the present invention is to use a lipophilic surfactant having an HLB value in the range of 4.0 to 9.0. If it is within this range, it can generally be used without limitation, for example, glyceryl monoisostearate (HLB value: 4.0), diglyceryl monooleate (HLB value: 5.5), diglyceryl monoisostearate (HLB value: 5.5), tetraglycerinole monooleate (HLB value: 6.0), sorbitan monooleate (HLB value: 5.0), sorbitan sesquioleate (HLB value: 3.7), trio Sorbitan maleate (HLB value: 4.0), Sorbitan monoisostearate (HLB value: 5.0), Sorbitan sesquiisostearate (HLB value: 4.5), Polyoxyethylene (5) Hardened castor oil (HLB g :: 6.0), polyoxyethylene (2) nonylphenyl ether (HLB value: 4.5), polyethylene glycol monooleate (2EO) (HLB value: 4.5), HLB value is 4. Lipophilic range of 0-6.0 Surfactants are preferred, HLB value among about 5.5 Monoorein diglyceryl (e.g., DGMO- C

(Trade name), Nikko Chemicals), diglyceryl monoisostearate (eg, DGMIS (trade name), Nikko Chemicals) and the like are preferable. In addition, diglyceryl monooleate, diglyceryl monoisostearate, sorbitan monooleate, sonorebitan sesquioleate, sorbitan trioleate, sonorebitan monoisostearate, polyoxyethylene (5) hard castor oil, polyoxyethylene (2) Noel phenyl ether and the like are preferable, and among them, diglyceryl monooleate, sorbitan monooleate, sorbitan sesquioleate and sonorebitan trioleate are preferable. The average particle size of the micromouth emulsion obtained from the oZw-type microphone mouth emulsion pre-emulsion composition of the present invention or the oZw-type microphone mouth emulsion formulation of the present invention is preferably about 150 nm or less, more preferably about 100 nm or less. nm or less, particularly preferably about 50 nm or less, and more preferably about 5 nm or more. The average particle size of the microemulsion can be determined using, for example, a dynamic light scattering particle size distribution meter as in the following examples.

 In the OZW-type mic-mouth emulsion pre-composition according to the present invention, in the O / W-type mic-mouth emulsion formulation, it is generally desirable that the drug concentration be as high as possible. ◦. 25 mg / m 1 to 75 mg Zm 1, preferably 2.5 mg / m 1 to 7 S mg Zm 1

Further, the weight ratio of the hydrophilic surfactant to the lipophilic surfactant can be used in the range of about 9 _: 1 to about 1: 9. Preferably from about 9: 1 to about 5: 5, more preferably from about 9 ::! To 8: 2, particularly preferably about 9: 1.

 The amount of water contained in the OZW type mic-mouth emulsion formulation of the present invention is preferably 0 to 80%, more preferably 25 to 80%, particularly preferably 5 to 80% based on the total weight of the composition. 0 to 80%. By adjusting the amount of water contained, it is also possible to select forms such as gels, pastes, and creams.

The OZW-type mic-mouth emulsion composition of the present invention may contain one or more other types of oils, hydrophilic surfactants, lipophilic surfactants, and diluents. May be included. For example, a thickener, a diluent, an antioxidant, a stabilizer, a buffer, a seasoning, a fragrance and the like can be mentioned. For example, when topical application is intended, a thickener may be used, and known pharmaceutically acceptable polymer materials, inorganic thickeners and the like can be used. Examples of the diluent include purified water, normal water, physiological saline, phosphate buffer and the like. Antioxidants include ascorbyl palmitate, butylhydroxydisole (BHA), butylhydroxytoluene (BHT), and tocopherol. Stabilizers include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, sorbic acid, potassium sorbate, sodium propionate, methyl parahydroxybenzoate, ethyl parahydroxybenzoate, butyl parahydroxybenzoate, paratyl benzoate and paraoxybenzoate Isopropyl, etc. No. Buffers include citrate, sodium citrate, sodium citrate, acetic acid, sodium acetate, tartaric acid, sodium tartrate, sodium bicarbonate, sodium carbonate, citrate, sodium citrate, phosphoric acid, and dihydrogen phosphate. Thorium, disodium phosphate, potassium dihydrogen phosphate, dipotassium phosphate and the like. Seasonings include sodium L-aspartate, DL-alanine, L-glutamic acid, L-glutamate, 5'-sodium inosinate, sodium citrate, monosodium succinate, disodium succinate, sodium tartrate, sodium lactate , Sodium fumarate, acetic acid, glacial acetic acid, lactic acid, tartaric acid, fumaric acid, citric acid, darconodelta ratatone, saccharin sodium, disodium glycyrrhizinate, trisodium glycyrrhizinate, D-xylose, D-sorbitol, etc. . Examples of the fragrance include orange essence, sugar freno, chocolate freno, drink freno, noni-la-freino, fruit flavor, heart water, menthol, and the like. All are known compounds that are pharmaceutically acceptable.

 By mixing a poorly water-soluble drug with an oil, a hydrophilic bioactive surfactant, and a lipophilic surfactant, the OZW pre-emulsion composition of the present invention can be obtained. The order of mixing these components is not particularly limited, but when a solubilizing agent is used, it is preferable to dissolve the drug in the solubilizing agent and then mix the remaining components.

 By mixing a poorly water-soluble drug with an oil, a hydrophilic surfactant, a lipophilic surfactant, and water, the OZW type microemulsion preparation of the present invention can be obtained. The mixing method is not particularly limited, but the stirring may be performed using a stirrer or the like. The order in which the components are mixed is not particularly limited, but when a solubilizing agent is used, it is preferable to dissolve the drug in the solubilizing agent and then mix it with the other components. Also, it is preferable to add water last. The OZW-type microemulsion preparation of the present invention can also be obtained by bringing the OZW-type microemulsion pre-composition of the present invention into contact with moisture.

The route of administration of the oZw-type microemulsion pre-emulsion composition or the oZw-type microemulsion preparation of the present invention is not particularly limited. Oral administration or parenteral administration (intravenous administration) Administration, intramuscular administration, subcutaneous administration, intraperitoneal administration, transdermal administration, transmucosal administration, enteral administration, nasal administration, pulmonary administration, etc.).

 Further, the pre-oZw type microemulsion composition of the present invention may be administered as it is and brought into contact with water in a living body, or may be administered as a microemulsion by bringing it into contact with water immediately before use. .

 The O / W-type micromouth emulsion pre-composition or the O / W-type microemulsion preparation of the present invention may be administered as it is, but in various forms depending on the efficacy of the drug as an active ingredient, etc. It can be administered. For example, unit doses may be enclosed in capsules or the like, or creams, pastes, lotions, gels, ointments, compresses, knops, plasters, aerosols, sprays, skin patches, eye drops, lotions, gels It may be administered in the form of a preparation or the like.

Example

 The present invention will be described more specifically with reference to the following Examples, but the present invention is not limited to these Examples.

 In the following examples, unless otherwise specified, statistical processing of particle size distribution and pharmacokinetic parameters was performed using the unpaired t-test for comparison between two groups, and comparison for three or more groups. Performed multiple comparisons by the Tukey method.

 (Example 1)

It is a poorly soluble drug represented by the following formula. (S) — (1) 1 2 — (3,5-di-tert-ptinole 14-hydroxyphenyl)-3-[3 — [N-methyl-N— [2- (3,4-Methylenedioxyphenoxy) ethyl] amino] propyl] fumarate salt of 1,1,3-thiazolidine-14one (hereinafter also referred to as “CP-06S fumarate” ) Were used to examine the physical properties of the O / W type microphone mouth emulsion of the present invention and the effect of promoting absorption from the digestive tract of rats. CP-060S Fumarate

CP-06 OS fumarate is a compound described in JP-A-10-287672, and is expected to be useful as a therapeutic agent for ischemic heart disease 2-phenyl-1,3-thiazolidine. 4 It is a one-one compound.

 1. Experimental materials and reagents

 CP-060 S fumarate (Lot No. V617A30) was manufactured by Chugai Pharmaceutical Co., Ltd. by the method described in JP-A-10-287672.

 Other laboratory equipment and chemicals are shown below.

 • PE-50 polyethylene tube (trade name): Intramedic • SP-10 polyethylene tube (trade name): Natsume Seisakusho

 • HPLC system: Waters

 · HPLC column (D e V e 10 s i 1 ODS HG-5 (trade name), 4.6 x 150 mm): No Neo Chemical

 "-HPLC column (YMC A-312 (trade name)): YMC

 • Methyl alcohol for HPL C: Pure Chemical

 • Dynamic light scattering particle size distribution analyzer NI COMP C370 (trade name): P art i c 1 e s i z i n g s y s t ems

 • Trifluoroacetic acid: PI ECE

 'Sodium heparin Note 1000 (product name): Nopo

 • Saline (Otsuka Raw Food Injection (brand name)): Otsuka Pharmaceutical Factory ·

.Anhydrous ethanol: Wako Pure Chemical Industries • EOO (Ethyl oryl oleate): Nikko Chemicals

• Panase one door 8 1 0 (trade name), (force prills acid, capric acid _{triglyceride, C 8: 8 5%,} C 10: 1 5%): NOF

 Triester F810 (trade name), (force prillic acid. Capric triglyceride): Nikko Chemicals

 • HCO-40 (trade name), (polyoxyethylene (40) hydrogenated castor oil): Nikko Chemicals

 • DGMO—C (trade name), (diglycerol monooleate!) :) Nikko Chemicals

 The other reagents were of a special grade.

 2. Laboratory animals

Seven-week-old male SD rats were obtained from Japan SLC, Inc., temperature 24 ± 2 ° C, humidity 55 ± 10%, ventilation rate 10 to 30 times, Z time, lighting time 5 B temple to 19 Pre-breeding for 1 week under free-water feeding (tap water, feed CE-2 (trade name, Japan Tale)) in a constant temperature animal breeding room, 8 weeks old (body weight 2 248 ₈ to 27 6 _§) ) And then used for experiments.

 3. Experimental method

 (1) Preparation of OZW type ME containing CP-600S fumarate and evaluation of physical properties (i) Preparation of O / W type ME containing CP-0600S fumarate

Ethanol was added to CP-0600S fumarate, and sonication was performed to dissolve it to a concentration of 300 mg / m1. In a glass vial, dissolve HCO-40 (270 μ1) and DGMO-C (301) melted by heating to 50 ° C, and stir at room temperature for about 10 minutes using a stirrer. And then add oil (150 μl of either ΕΟΟ or Panacetate 8 or Triester F810) and 300 mg / 1 CP-600S fumarate in ethanol (1 50 ^ 1) was added, and the mixture was similarly stirred for 10 minutes. To this was added PBS (final concentration of a mixture of 10 mM phosphate buffer and 15 OmM sodium chloride, pH 6.8) (24001), and the mixture was stirred for 2 hours. OZW-type ME containing various CII-600S fumarate shown in the following was prepared. Processing- 1 processing- processing- — £ —

 Dangdang-4 Prescription-5

(No oil) t? Nn MR, VrblU Mcno colu mt) v oiut ion;

CP-060S in 5¾Manni tol 3000

 (1.2mg / ml)

 CP-060S in EtOH 150 150 150 150

 (300mg / ml)

 Oil 150 150 150

 HCO-40 270 270 270 270

 DGMO 30 30 30 30

 PBS 2550 2400 2400 2400

 Unit: l In addition, an oil-free formulation was prepared by adding PBS (150 1) instead of oil (Formulation 1 1).

Add the 5% D-water solution of mannitol (3 ml) to CP-06 OS fumarate (3.6 mg), dissolve by sonication, and dissolve 5% D of CP-06 OS fumarate. —Prepared an aqueous solution of mannitol (1.2 _{mg /} ml) (Prescription 1 5) ₀

 (ii) Physical property evaluation of O / W type ME containing CP-060S fumarate

 Each CP-060S fumarate-containing O / W ME and oil-free formulation was diluted appropriately with PBS (pH 6.8), and the particle size distribution was measured using a dynamic light scattering particle size analyzer NIC OM PC 370. It measured using. The ME, the oil-free preparation and the aqueous solution were appropriately diluted with ethanol, and the CP-06 OS fumarate content was measured using a Waters HPLC system under the following conditions.

 (H PLC condition)

 · Column: YMC A— 312 (ODS)

 • Eluent: 70% methanol 0.1% trifluoroacetic acid

 • Detection wavelength: UV234 nm

 • fe: 1 m 1 / m 1 n

• Injection volume: 50 1

Table 2 en Solvent g Surfactant content (¾) CP-060S charge measurement CP-060S particle size distribution.

 Content tt) HCO-40 DGMO concentration (mg / ml) Concentration (mg / ml) Recovery ft) Peak-1 (nm; Peak-2 (nm) Formulation 5 D-mannitol 5 1. 1.13 94.5

 Formula 1 EtOH 10 9 1 15 11.1 74.1 17.3 (100 ¾)

 Formula 2 EOO / EtOH 515 9 1 15 13.1 87.1 20.6 (93.4¾) 65.0 (6.6¾) Formula 3 P810 / EtOH 515 9 1 15 11.3 75.3 23.0 ± 11.5

Formula 4 F810 / Et0H 515 9 1 15 11.7 77.7 35.2 (99.3¾) 107.1 (0.7¾)

(i i i) result

 Each CP—060 S Humalai 1, encapsulated OZW ME, oil-free formulation and 5% D

—CP- 060 S fumarate content in aqueous mannitol solution and CP— 060

Table 2 shows the particle size distributions of the OZW type ME with S fumarate and the suspension. Regarding the particle size distribution, most of the formulations (93.4 to 100%) have particle sizes of 17.3 to 35.2 nm, and O / W type ME with small particle size can be prepared. It was confirmed that.

 The solubility (concentration actually measured) of CP-060S fumarate in OZW type ME is 11.3mg / ml-13.1mgZml, and water of CP-060S fumarate (5% mannitol) Aqueous solution) 1.13 mg / m 1 approx.

It was shown that it could be dissolved up to 10 times or more.

 (2) Absorption evaluation of O / W ME containing CP-060S fumarate in rats

 (i) Animal treatment

 Heparin lock (approximately 50 IU / m1 normal saline) -treated PE-50 tube was inserted into the femoral artery of rats that had been fasted for 16 hours and had free water supply to prepare for blood collection. For intraduodenal (id) administration, a PE-50 tube was inserted from the stomach to a site 1 cm beyond the pylorus. The pylorus was ligated from above the force neuron with a silk thread to prevent reflux of the administered drug solution. All of the above operations were performed under ether anesthesia.After the operation was completed, the rats were fixed in a ballman cage, and approximately 2 hours after the operation, each O-W ME containing CP-060S fumarate was administered. .

 (ii) Dosage solution formulation and dosage

 Rats were administered i.d. over 30 seconds from a force-uration tube inserted into the duodenum with the five CP-060S fumarate administration solutions shown in Table 1. At the time of administration, the amount of the administered solution was set to 1 OmgZkg based on the actually measured CP-060S fumarate content obtained in 3. (1) above.

 (i i i) Blood collection and plasma separation

Blood is collected through the arterial tension tube before administration and at 2, 5, 10, 20, 30 minutes, 1, 2, 4, 6, 8, and 24 hours after administration. I went. The collected blood was centrifuged at 4 ° C. and 10,000 rpm for 3 minutes, and the obtained plasma was subjected to quantification.

 (i v) Extraction and quantification of CP—060 S from rat plasma

 Plasma was added to IN Na ΟΗ (50 ^ 1), distilled water (1 ml) and ether (5 ml), respectively, and shaken at room temperature for 10 minutes. After centrifugation at 4 ° C · 3000 rpm for 5 minutes, the entire amount of ether was collected. The solvent was distilled off from the obtained ether layer with nitrogen gas and evaporated to dryness, then redissolved in 0.1% trifluoroacetic acid-70% methanol (100 ^ 1), and the Waters HP LC system was used. Was used to quantify CP-060S.

 (H PLC condition)

 Column: Develosil ODS HG—5 (trade name) Eluent: 62% methanolic 0.1% trifluoroacetic acid

 Detection wavelength: UV234 nm

 Flow; ^: 1 m 1 / m i n

 · Injection volume: 50 1

 (V) Data analysis

 The area under the plasma concentration curve (AUC) was calculated by the trapezoidal method from the obtained changes in the concentration of CP-060S in plasma, and the absorption rate constant and average residence time (MRT) were calculated using the analysis software Wi n Using No n 1 in, they were obtained by a compartment model analysis and a moment analysis, respectively.

Table 3 shows the results.

CO

In Table 3 above, each data is expressed as the average of 3 to 4 cases ± 3.

 (V i) result

 As shown in Table 3, in the case of O / W type ME, when the surfactant was HCO-40 and DGMO-1C, EOO (Formulation 2), P810 (Formulation 3), F810 (Formulation Using any of the three types of oils in 4), the time to reach the maximum plasma concentration of CP-060S (Tmax) is about the same as or longer than that of the aqueous solution, and it is the same as or more than that of the aqueous solution in 1 to 2 hours. Plasma CP-600S concentration (Cma X) reached 508.1 ± 188.7-594.5 ± 174. lng / ml.

 In contrast, for an oil-free formulation containing HCO-40 and DGMO but no oil (Formulation 1), the Cmax was 43.5.4 ± 62.4 ng / m1 in 2 hours. Only reached.

 Furthermore, the OUC of ME is 2.1 to 2.2 times and that of MRT is 1.3 to 1.6 times of O / W type ME compared to aqueous solution (Formulation 5) and oil-free formulation (Formulation 1). Was growing. Thus, when CP-060S fumarate was administered into the duodenum as an O / W-type ME, the AUC doubled and the MRT increased 1.5-fold, resulting in improved absorption.

(Example 2)

It is a poorly soluble drug represented by the following formula (3S, 4S) -7-hydroxy-3- (4-hydroxyphenyl) -13-methyl-4-1 [4,4,5,5,5 — Pentafluor mouth pentylsulfiel) Noel] Tiochroman (hereinafter referred to as “ER-103 9”) was used to examine the physical properties of OZW-type ME and its absorption from the gastrointestinal tract of rats. ER- 1039

ER-1039 is an estrogen receptor antagonist described in JP-T-2000-507620, and is a thiochroman compound expected to be a novel orally administrable therapeutic agent for breast cancer hormone.

 1. Experimental materials and reagents

 ER-1039 (Lot No. V806K29)

It was produced by Chugai Pharmaceutical Co., Ltd. by the method described in JP-A-7620.

 Other experimental instruments and chemicals were the same as in Example 1 except for the following.

 PEG200 (brand name): Pure chemistry

 Gum arabic (Gum a r a b i c): S i gma

 Triptyline (trade name), Tributyldariceride: Tokyo Danisei Kogyo

 'Olive Oil: Nikko Chemicals

 Oleic acid: Wako Pure Chemical Industries

 MGO (trade name), Monodariseride oleate: Nikko Chemicals

 Perex OT-P (trade name), di (2-ethylhexyl) sodium sulfosuccinate: Kao

 . Methanol for HP LC: Pure Chemical

 2. Laboratory animals

Seven-week-old male SD rats were obtained from Japan SLC, and temperature 24 ± 2 ° (: Humidity 55 ± 10%, ventilation rate 10-30 times, lighting time 5-5-19 hours In the breeding room, under free water feeding (tap water, feed CE-2 (CLEA Japan)) The animals were preliminarily reared for 1 week to reach the age of 8 weeks (body weight: 228 g to 275 g), and then used for experiments. 3. Experimental method

 (1) Preparation and physical property evaluation of O / W type ME and aqueous solution containing ER-1039.

 Add ER-1039 (35 Omg) with ethanol and calcine, and sonicate 1

It was dissolved to a concentration of 0 Omg / m1. In a glass vial, HCO-40 (350-630 mg) melted by heating to 50 ° C and one of DGMO-C, PELEX OT-P or MGO (70-350 mg) are collected. The mixture was stirred at room temperature for about 10 minutes using a stirrer. In addition, various oils (Tributyr

1 n, Panassate 810, EOO, Olive oil, or oleic acid (35 Omg) and l O Omg / m 1 concentration of E R—1039 ethanol solution

(35 Omg) was added, and the mixture was similarly stirred for 10 minutes. PBS (pH 6.8, 5.6 ml) was added thereto, and the mixture was stirred for 2 hours to prepare an OZW-type ME containing ER-1039 having the following formulation.

 ER-1039 was dissolved in a solution of PEG200: ethanol: distilled water = 6: 1: 3 (v / v) to a concentration of 5 mg / ml to obtain an ER-1039 aqueous solution.

 Note that three samples were used for the aqueous solution, and that for Formulations 2, 3, and 4

Two samples, Formulations 1, 5, and 6, were prepared.

 (ER-1039-containing OZW ME formulation)

 [Prescription_1]

 ER-1039 ethanol solution 5% 350 mg

Tr i b u t y r i n 5% 35 Omg

DGMO 5% 35 Omg

HCO— 40 5% 35 Omg

PBS (pH6.8) 80% 5.6ml

[Prescription_2]

ER— 1039 Ethanol solution 5% 35 Omg Nonassate 810 5% 35 Omg DGMO 5% 35 Omg

HCO-40 5% 35 Omg

PBS (pH 6.8) 80% 5.6 ml

[Prescription 1 3]

 ER-1039 Ethanol solution 5% 35 Omg

EOO 5% 35 Omg

DGMO. 5% 35 Omg

HCO-40 5% 35 Omg

PBS (pH 6.8) 80% 5.6 ml t prescription 1 4]

 ER-1039 ethanol solution 5% 35 Omg

EOO 5% 35 Omg Perex OT—P 5% 35 Omg

HCO-40 5% 35 Omg

PBS (pH 6.8) 80% 5.6 ml

[: Prescription—5]

 ER-1039 Ethanol ^ "-Solution 5% 35 Omg Olive oil 5% 35 Omg

DGMO 5% 35 Omg

HCO-40 5% 35 Omg

PBS (pH6.8) 80% 5.6ml

1: Prescription 1.6]: Comparative example

 ER-1039 Ethano,-Solution 5% 35 Omg Oleic acid 5% 35 Omg

MGO 1% 7 Omg

HCO-40 9% 63 Omg

PBS (pH 6.8) 80% 5.6 ml (ii) Physical property evaluation

 Each OZW-ME sample containing ER-1039 was diluted appropriately with PBS (pH 6.8), and the particle size distribution was measured using a dynamic light scattering particle size distribution analyzer NI COMP C370. In addition, each ER-1039-containing OZW ME sample solution was diluted appropriately with ethanol, and the ER-1039 concentration was measured under the following conditions using a Waters HPLC system.

 (H PLC condition)

 • Column: Develosil ODS HG-5 (trade name) • Eluent: 60% acetate trinole 0.1% trifluoroacetic acid • Detection wavelength: UV230nm

 • Flow velocity: 1 m1 / min

 • Injection volume: 50 z 1

The results are shown in Tables 4 to 10.

Table 4

 Aqueous solution

 PEG200: EtOH: D.W.ER-1039 concentration Turbidity

 Mean soil SD (mg / nl) 650 thigh

 Sanfuru 1D: 1: o

 Sanfu 'n 6: 1: 3 5.93 ± 0.52

 Sample 3 6: 1: 3 5 16 ± 0.56

Prescription 1

 (Tributyrin: DGM0-C: HCO-40) ER-1039 concentration mm. Gaussian¾i distribution

 Mean soil SD (mg / ml) 650 thigh Mean soil SD (nm) Chi-square

 5: 5: 5 6.08 ± 0.64 0.585 13.2 ± 5.9 1.52 to

 ^ Table 6

 Prescription 2

 (Λ · Nase -1 "810: DGM0-C: HC0-40) ER-1039 concentration Dodge Gaussian particle size distribution

 Mean ± SD (mg / tii) OOUlMl Mean soil SDwim) Chi-square

 Sa '' '5: 5: 5 6.32 ± 0.56 0.288 11.7 ± 6.2 1.07

 Sail 2 5: 5: 5 6.64 ± 0.73 0.444 11.2 ± 8.0 2.57 Table 7

 Prescription 3

 (E00: DGM0-C: HC0-40) ER-1039 concentration Turbidity Gaussian particle size distribution NIC0MP particle size distribution

 Mean ± SD (mg / in!) 650 clothing Mean-sat SD (Ran) Chi-square Peak-l (iira) Peak-2 (nm) Peak- 3 (nm) Sample 1 5: 5: 5 5.26 ± 0.21 17.27 50.1 ± 20.8 2.09

SanfuΑ2 5: 5: 5 6.02 ± 0.61 37.86 55.3 ± 36.7 6.16 73.3 (67.0¾) 446.3 (32.9¾)

Table 8

 Prescription 4

 (E00: he're'nox 0T-P: 11C0-40) 'ER-1039 concentration Turbidity Gaussian particle size distribution

 Mean soil S'D (mg / ml) 650nm Mean ± SD (nm) Chi-square

 Sample 1 5: 5: 5 5.56 ± 0.31 0.0045 11.9 ± 2.1 1.68

 Sanfu 'n 5: 5: 5 5.15 ± 0.35 0.0000 11.8 ± 5.2 2.72

Table 9

 Prescription 5

 (Olive oil: DGMO-C: HCO-40) ER-1039 concentration Turbidity Gaussian particle size distribution

t _ Mean ± SD (fflg / ml) 650nin Mean soil SD (measurement) _Chi square.

 5: 5: 5 6.15 Sat 0.35 0.232 15.3 ± 5.3 1.41 Table 10

 Prescription 6

 (Oleic acid: MGO: HCO-40) ER-1039 concentration Turbidity Gaussian particle size distribution NIC0MP particle size distribution

 Meaner SD (m_g / ml) 650nm Mean soil SD (nra) _Chi square Peak- l (nm) _Peak-2 (nm) Peak-3 (nm)

5: 1: 9 7.59 ± 0.81-26.63 97.8 ± 61.8 15.94 71.1 (70.6¾) 375.6 (29.4¾)

(i i i) result

 As is clear from Tables 5 to 10, according to the OZW type ME of the present invention, ER-1039 could be dissolved up to a concentration of about 6 mgZml.

 Regarding the particle size distribution, when the surfactant is DGMO-C and HCO-40 and Tributyrin, Panassate 810 or olive oil is used as the oil (preparation_1, 2, 5), and the surfactant Is Perex OT-P and HCO-40 and EOO is used as the oil (Formulation 1-4), it has a normal distribution, and the particle size is 11.2 ± 8.0 to 15.3 Sat 5.3 nm Was within the range. Therefore, it was confirmed that these formulations yielded very small OZW-type MEs.

 Also, when the surfactant is DGMO and HCO-40 and EOO is used as the oil (Formulation 13), and when the surfactant is MGO and HCO-40 and oleic acid is used as the oil ( In Formula 1-6), no normal distribution was observed, and two peaks were found. However, particles of 73.3 nm and 71.1] 1111 contained 67.0% and 70.6%, which were large. The portion was a small particle of 10 ° nm or less.

 (2) Absorption evaluation of O / W ME containing ER-1 039 in rats

 (i) Preparation of OZW ME containing ER-1 039, aqueous solution suspension

 The ER-1039-containing O / W-type ME was prepared in the same manner as the above-mentioned ER-1039 O / W-type ME of Formulations 1 and 3 of 3. (1) (i).

 The ER-1039 aqueous solution was prepared in the same manner as in 3. (1) (i) above.

 The ER-1039 suspension was prepared by suspending ER-1039 to a concentration of 5 mg / ml in a 5% arabia gum solution.

 The resulting ME, aqueous solution, and suspension were stored at 4 ° C until the in V i v o experiment.

 (ii) Animal treatment

 —Early and night fasted—Freely water-fed rat femoral arteries were introduced into a heparin lock (about 5 OU / m1—saline) -treated PE-50 tube under ether anesthesia to prepare for blood collection. . After the operation, the rats were fixed in a ballman cage and left for at least 2 hours to awaken.

 (iiii) administration

Approximately 2 hours after the operation, drug administration was started. ER_1039 ER-1039-containing 〇ZW-type ME, aqueous solutions and suspensions were each administered into the stomach using a rat probe for intragastric use. At the time of administration, the amount of the administered solution was set to 20 mgZkg based on the actually measured ER_1039 content obtained in 3. (1) above. ,

 (i v) Blood sampling

 Immediately before the drug administration, blood (300 μI) was collected from the kayule inserted into the femoral artery of each rat.

 In addition, approximately 301 blood samples were collected at 5, 15, 30 minutes, 1, 2, 4, 6, 8, and 24 hours after drug administration. The probed blood was centrifuged at 4 ° C. at 100 000 rpm for 3 minutes, and the obtained plasma was subjected to quantification. Plasma was stored at _80 ° C until used for quantification.

 (V) Extraction and quantification of ER-1039 from rat plasma

Rat plasma (50 μl) in ethanol (50 μl), 1. 3. (Interna 1 standard, internal standard) (ICI 18 2,780, 10 μg / ml, 10 μl) and acetone (5001) were added and mixed, followed by centrifugation at room temperature at 15,000 rpm for 5 minutes. After collecting the entire amount of the supernatant, the supernatant was evaporated to dryness using nitrogen gas. The Zan查, immediately before the measurement, was re-dissolved by adding 6 0% § Se Tonitoriru (5 0 _beta 1), at room temperature, for 5 minutes centrifugation at 1 5 000 r pm, the resulting supernatant Was subjected to LCZMS (liquid chromatography / mass spectrum) under the following conditions. A mixture of rat plasma and ethanol was treated in the same manner to obtain a blank. Ethanol solutions of ER-1039 at various concentrations were used as standard solutions.

 Conditions for measuring ER—10 39 concentration by LC / MS

 • L C: UMA (trade name) (MichromBiorResouurces.Inc., Auburn, CA)

 • MS: QUATTRO (trade name) (VG Biotech., Manchestre, UK)

 • Ionization method: AP c I +

• Column: D evelosil OD S—UG—3 (brand name) 1. 5 mmX 100 mm and OD S -UG 51.5 mmX 10 mm (Nomura Chemical)

 • Eluent: A; 50% Me CN—0.1% TFA, B; 90% MeCN-0.1% TFA

 Time (minutes): 0 → 1 ~ 6, 5 → 7 ~ 1 1 5

 (%): 25 · 75 to 75 → 00 100.25 • Flow rate: 100 1 / i n

 • Detection wavelength: UV21 5 nm

 • Injection volume: 10 / ^ 1

 (v i) Data analysis

 From the obtained changes in plasma ER-1 039 concentration, the AUC was calculated by the trapezoidal method, and the absorption rate constant (ka) and mean residence time (MRT) were determined using the analysis software Win Non 1 in, respectively. It was determined by a component model analysis and a moment analysis.

Table 11 shows the results.

Solution suspension formula-2 (Hana 1 810 / Ver.) Method 3 (ΪΟΟ / DG O)

 Mean S. D. Mean S. D. Mean S. D. Mean S. D.

Tmax (hr) 3.2 1.10 4.5 1.00 2.00 0.00 2.00 0.00

Cmax (ng / ffll) 314.18 84.69 165.53 14.98 590.86 104.99 468.28 68.39 bo

 CO AUC (nfi * hr / ml) 2351.30 363.27 1720.42 292.71 3173.47 273.54 2645.01'809.59

 Absolute B.A. (¾) 14.30 2.21 10.46 1.78 19.30 1.66 16.09 4.92

Relative BA (¾) 100 15.45 73.17 12.45 134.97 11.63 112.49 34.43

In Table 11 above, each data is represented by the average soil S.D. of five cases.

 (V i i) results.

 When rats were orally administered ER-1039 aqueous solution, the concentration of ER-1039 in the peripheral plasma reached Cmax 314.2 ± 84.7 ng / m 1 in 3.2 ± 1.1 hours. The AUC is 23351 ± 363.3 ngxhr / m1, and the absolute bioavailability calculated from the ratio of the ER_1039 concentration in peripheral plasma to the AUC after intravenous administration is 14.3 ± 2 It was 2%.

 When administered orally as a suspension, the ER-1039 concentration in peripheral plasma reached Cmax 165.5 ± 15. On gZml in 4.5 ± 1.0 hours. The AU C is 172.4 Sat 292.7 ng X hr / 1 and the absolute bioavailability is 10.5 Sat 1.8. /. Met. The relative bioavailability (Relativi ebiioavaiilabiliti) for the ER-1039 aqueous solution was 73.2 ± 12.5%.

 On the other hand, when administered orally as O / W-type ME (Formulations 1 and 3), the concentration of ER-1039 in peripheral plasma in Formulation 2 was reduced to Cma X 590.9 ± 15.0 ngZm 1 in 2 hours. Reached. AUC is 313.5 ± 273.5 ng X hr / m1, absolute bioavailability is 19.3 ± 1.7%, relative bioavailability to ER-1039 aqueous solution is 135 0 ± 1 1.6%. In Formulation 1, ER_1039 concentration in peripheral plasma reached Cma X 468.3 ± 68.4 ng / ml in 2 hours. AUC is 265.0 ± 809.6 ng X hr / m1, with absolute bioavailability of 16.1 ± 4.9% and relative bioavailability of 112.5 ± 34.4% Met.

Thus, when ER-1039 is orally administered as O / W-type ME, Tma X is 1.6 to 2.7 times less than when administered as an aqueous solution, and 2.5 minutes as a suspension. 1-3.8 times lower than the above, and the absorption rate was increased. In addition, the Cmax X AUC (relative bioavailability) was 1.7-fold and 1.3-fold higher than that of a solution administered as an aqueous solution in Formulation 1 (Panasate 810), respectively. 3.6 times and 1.8 times of the solution, respectively. The ratio was 1. 4 times, 1.1 times, 2.8 times and 1.5 times that of the suspension, and a promoting effect on the absorbed amount was also observed.

(Example 3)

 Using CP-060S fumarate used in Example 1, absorption of the microemulsion (ME) pre-composition from the digestive tract of rats was examined.

 1. Experimental materials and reagents

 As in Example 1, CP-060S fumarate (Lot No. V6 17 A30) was produced by Chugai Pharmaceutical Co., Ltd. by the method described in JP-A-10-287672.

 Unless otherwise stated, the same experimental instruments and chemicals as those used in Examples 1 and 2 were used.

 2. Laboratory animals

 7-week-old male SD rats were obtained from SLC Japan, temperature 24 ± 2 ° C, humidity 55 ± 10%, ventilation rate 10-30 times / hour, lighting time 5: 00-19: 00 8 weeks old (body weight 235.6 g-261.2 g) after pre-breeding for 1 week under free water feeding (tap water, feed CE-2 (CLEA Japan)) in a constant temperature and constant humidity animal breeding room After that, it was used for the experiment.

 3. Experimental method

 (1) Preparation and physical property evaluation

 (i) Preparation

 (a) Preparation of O / W type ME pre-composition containing CP-060 S fumarate

Ethanol was added to CP-060S fumarate and sonicated to dissolve to a concentration of 6 Omg / m1. In a glass vial, DGMO-C, PANASATE 810 or EOO, and 50 in the amounts indicated below, respectively. HCO-40 heated and melted in C, and ethanol solution of CP-06 OS fumarate (60 mg / m 1) were separated and added, and the mixture was stirred for about 10 minutes at room temperature using a stirrer. Thus, an O / W type ME pre-composition containing CP-060S fumarate was prepared. (CP-060 Formulation of OZW type ME pre-composition containing fumarate)

 [Prescription 1 1]

 Panacet 810 5% 60 Omg

DGMO-C 1% 12 Omg

HCO-40 9% 108 Omg

CP—060 S ethanol solution 5% 6.00 mg

[Prescription 1 2]

 EOO 5% 60 Omg

DGMO-C 1% 12 Omg

HCO-40 9% 108 Omg

CP— O 60 S ethanol solution 5% 6 O Omg

(b) Preparation of O / W type ME containing CP-06 Os fumarate

 Add 9.6 ml of PBS (pH 6.8) to the OZW type ME pre-composition (2400 mg) containing each of the above CP-060S fumarate and stir at room temperature for about 2 hours using a stirrer. An OZW-type ME containing CP-060S fumarate of the formula was prepared.

 [Prescription 1 3]

 Panacet 810 5% D 0 O mg

DGMO-C 1% 12 Omg

HCO-40 9% 108 Omg

CP—060 Sethanol solution 5% 600 mg

PBS (pH 6.8) 80% 9.6 ml

[Prescription 1 4]

 EOO 5% 600 mg

DGMO-C 1% 12 Omg

HCO-40 9% 108 Omg

CP-060 S Etano ^ "-solution 5% 600 mg

PBS (pH 6.8) 80% 9.6 ml

(c) Preparation of CP-060 S fumarate aqueous solution 5% D-mannitol aqueous solution (32 ml) was added to CP-060S fumarate (40mg) and sonicated to completely dissolve. 5% D-mannitol containing CP-060S fumarate was added. An aqueous solution (1.25mg / m1) was obtained.

 (i i) Physical property evaluation

 9.6 ml of PBS (pH 6.8) was added to each OZW ME pre-composition (240 Omg) containing each CP-060 S fumarate, and the mixture was stirred at room temperature for about 2 hours using a stirrer to completely emulsify. After being appropriately diluted with PBS, the particle size distribution was measured using a dynamic light scattering particle size distribution analyzer NI COMP C370. Similarly, the O / W type ME containing CP-060S fumarate was appropriately diluted with PBS and the particle size distribution was measured.

 In addition, the OZW type ME pre-composition containing each CP-060S fumarate emulsified by adding PBS (pH 6.8) was added. After diluting the mannitol aqueous solution of 060S fumarate 50, 200, 800 and 3200 times with the mobile phase, use the Waters HP LC system under the following conditions. The 060 S content was measured.

 (H PLC condition)

 • Column: YMC A—312 (ODS)

 • Eluent: 70% methanol 0.1% trifluoroacetic acid

 · Detection wavelength: UV234 nm

 • Flow velocity: 1 m1 / min

 • Injection volume: 50 μ1

Table 12 shows the results.

Table 12

 TYF '0 / W ME composition (w / w¾) Gaussian particle size distribution NICOMP particle size distribution CP-060S content

 Λ'Nasset E00 DGM0-CHC0-40 CP-060S PBS Mean soil SDOua) Chi-square Peak-1 (nn) Peak-2 (nm) and charge rate

810 in EtOH (pH6.8) (πικ / ral, (¾)) O Formula 3 (ME) 5 1 9 5 80 20.7 ± 17.9 318.75 35.4 (92.4¾) 783.0 (7.7¾) 3.20 (89.6) *

 Formula 1 (pre-ME composition) 5 1 9 5 13.1 ± 9.8 5.57 32.0 (97.4¾) 894.9 (2.7¾) 15.90 (91.1) * Formula 4 (ME) 5 1 9 5 80 i 14.2 16.4 30.0 (97.9¾) 194.4 (2.2%) 3.48 (108.4) * Formula 2 (pre-ME composition) 5 1 9 5 20.8 ± 14.0 4.68 32.4 (98.2¾) 196.6 (1.7%) 16.99 (106.8) *

* Prepared concentration of CP-060S Prescription 3 (Α'Naceto 810): 3.57 mg / ml, Prescription 1 (Λ '«-T 810): 17.46 mg / ml

Formula 4 (E00): 3.21 mg / Bil, Formula 2 (EO0): 15.91 mg / ml

(i i i) result

 As shown in Table 12, the content of CP-060S in the O / W type ME pre-composition and the aqueous solution of mannitol was almost the same as the charged amount.

 On the other hand, regarding the particle size distribution, none of the particles was normally distributed, and two peaks were observed.Particles with a force of 30.0 to 35.4 nm were 92.4 to 98.2%, and the majority were 50 nm. The following small particles were found.

 (2) Absorption evaluation of OZW-type ME pre-composition containing CP-060S fumarate in rats

 (i) Animal treatment

 16 hours fasting · Heparin lock (approximately 50 IU / m 1-saline) PE-50 tube was inserted into the large J3 aorta of the rats which had been freely supplied with water under anesthesia anesthesia to prepare for blood collection. Was. After the operation, the rats were fixed in a poleman cage and left for at least 2 hours to awaken.

 (ii) Dosage solution formulation

 About 2 hours after the end of the operation, the OZW-type ME pre-composition containing CP-060S fumarate, the O / W-type ME and an aqueous solution of mannitol were administered to the stomach of rats using a sonde into the rat for 1 μs. The formulation of the administration solution is the same as the formulation used in 3. (1) above.

 At the time of administration, the amount of the administration solution was set to 1 OmgZkg based on the actually measured CP-060S fumarate content obtained in 3. (1) above. For the O / W type ME pre-composition, 4 times volume of PBS (pH 6.8) was continuously administered.

 (i i i) Blood sampling

 Immediately before drug administration, 500 μl of force-neutral blood inserted into the femoral artery was collected.

Further, blood was collected at about 500 μl each at 5, 10, 20, 30 minutes, 1, 2, 4, 6, 8, and 24 hours after drug administration. The collected blood was centrifuged at 10,000 rpm at 4 ° C. for 3 minutes, and the obtained plasma was subjected to quantification. Stored at 180 ° C until used for quantification. (iv) Extraction and quantification of CP-O60S from rat plasma INN aOH (50 μl), distilled water (1 ml) and ether (5 ml) were added to plasma (Ι Ο ΟμΙ), respectively. And shaken at room temperature for 10 minutes. After centrifugation at 4 ° C · 3000 rpm for 5 minutes, the entire amount of ether was collected. The obtained ether layer was evaporated to dryness by distilling off the solvent with nitrogen gas, then redissolved in 0.1% trifluoroacetic acid-70% methanol (100 μl), and the Waters HP LC CP_600S was quantified using the system.

 (HPLC conditions)

 • Column: D e V e 1 o s i 1 OD S HG— 5

 · Eluate: 62% methanol 0.1% trifluoroacetic acid

 • Detection wavelength: UV234 nm

 • Flow velocity: 1 m1 / min

 • Injection volume: 5 0 1

 (ν) Data analysis

 From the obtained plasma CP-0600S concentration transition, the AUC was calculated by the trapezoidal method, and the absorption rate constant (ka) and average residence time (MRT) were determined using the analysis software Wi n Non 1 in It was determined by compartment model / V ^ analysis and moment analysis.

 The results are shown in Tables 13 and 14.

Table 13

 ΡΚ Λ. LAMETER 5% D-MANN :: Toll solution Formulation 3 (ME) Formulation 1 (ME pre-composition)

 Mean S. D. Mean S.D. Mean S.D.

Tmax (hr) 0.36 0.08 1.60 0.55 1.80 0.45

Cmax (ng / ml) 290.79 129.76 247.35 65.08 290.79 129.76

MRT (hr) 2.8 0.4 3.48 1.53 2.82 0.13 ka (hr ^-1 ) 5.47 3.05 0.70 0.23 0.59 0.05

AUC (ng x hr / il) 1108.74 442.84 1279.46 352.41 1280.00 313.85

Relative B.A. (¾) 100 .39.94 115.40 31.79 115.45 28.31

Relative BA (¾) 100.00 27.54 100.04 24.53 Table 14

In Tables 13 and 14 above, each data is represented by the average soil S.D. of five cases.

 (V i) result

When administered orally as an aqueous mannitol solution, the concentration of CP-060S in the peripheral plasma reached Cmax 290.8 ± 129.8 ng / ml in 0.36 ± 0.08 hours. The absorption rate constant ka was 5.5 soil 3.1 hr- ¹ and the AUC was 1108.7 ± 442.8 ng X hr / m1.

 When Panassate 810 was used as the oil, the OZW-ME (formulation 3) reached Cmax x 247.4, 65.1 ng / ml in 1.6 hours for 0.6 hours.

& Was 0.70 hr—AUC was 1279.5 ± 352.4 ng X hr / 1 and the relative bioavailability for solution administration was 11.5.4 ± 31.8%. In the case of the OZW type ME pre-composition (formulation 1), Cmax reached 299.8 ± 129.8ngZml in 1.8 ± 0.5 hours. . ka is 0. 59 ± 0 at 05h r one ^1, 11 (:. is 1280. a 0 ± 313 9 ng X hr / m 1, the relative biological for solution Contact Yopi O / W type ME administration The availability was 115.5 ± 28.3% and 100.0 ± 24.5%, respectively.

On the other hand, when EOO was used as the oil, the O / W ME (formulation 4) reached Cma 191.4 ± 85.7 ng gZml in 2 hours. ka is 0.43 ± 0.06 hr—AUC is 126.7 ± 697.6 ng X hr Zm1, and the relative bioavailability for solution administration is 11.2 ± 62.9% Met. In the case of the OZW type ME pre-composition (formulation 2), Cmax reached 261.0 ± 36.8 ng / ml in 2 hours. ka is 0.41 hr— ¹ and AU C is 15567.9 ± 5 72.4 ng Xh rZm 1, with relative bioavailabilities for solution / O / W ME administration of 141.4 ± 51.6% and 123.8 ± 45, respectively.

2%.

 Thus, MRT when CP-060S fumarate was orally administered as an O / W-type ME pre-composition was higher than that when mannitol solution was administered, similar to OZW-type ME. Had improved. Furthermore, the relative bioavailability upon administration of the O / W-type ME pre-composition was improved as compared with the administration of the mannitol solution, as with the OZW-type ME administration. Thus, it is suggested that the OZW-type ME prosthetic product is a dosage form that can become an O / W-type ME in the gastrointestinal tract and improve the absorbability of the poorly soluble conjugate. Was.

(Example 4)

 Using nine types of poorly soluble drugs, the dispersibility (emulsification rate) and particle size of the O / W type ME pre-composition and drug solubility were examined.

 1. Experimental materials and reagents

 The following drugs were used:

 • Chloram feniconole (Chloramphinicol, molecular weight 323.1, Lot No. 106H0971, Sigma)

 • Disoviramide (Disopyramide, molecular weight 339.5, Lot No. 47H1400, Sigma)

 • Ibuprofen (I bup rofen, molecular weight 206.3, Lot No. DLL 3680, Wako)

 • Ketoprofen (Ketoprofen, molecular weight 254.3, LotNo. 126H1330, Sigma)

 Tamoxifen (Tamo x ifen, molecular weight 371.5, Lot No. 28H 1033, Sigma)

 • Testosterone (Testostelone, molecular weight 288.4, Lot No. GE 01, Tokyo Chemical Industry)

• Tolbutamid, molecular weight 270.3 Lot N o. 47H1030, Sigma)

 • (+) — 1— (2,2-Jetoxyshetyl)-3-(4-Methylphenyl) aminocarbonylmethyl 13-(N, 1- (4-methylphenyl) ゥ raid) Indolin-2-one (AG— 041 R, molecular weight 544.6, Lot No. R5F01, manufactured by Chugai Pharmaceutical Co., Ltd.)

 • 4, 6—Jittery Petit 1, 2, 2—n—Pentin 5—Hidden. Mouth Kissy 2,3-Dihydrobenzofuran (BO-653, molecular weight 388.6, Lot No. R7 I02, manufactured by Chugai Pharmaceutical Co., Ltd.)

 AG-041R is an indoline-21-one compound described in W094 / 19322, which is useful as a CCK-B // gastrin receptor antagonist, and is represented by the following formula. It is expected to be useful as a cartilage formation promoter (WO00Z4 4722).

AG— 041 R

Me

BO-653 is a dihydrobenzofuran-based compound described in WO 94/08930 and is represented by the following formula. It is expected as a therapeutic agent for arteriosclerosis. BO- 6 5 3

Other experimental instruments and chemicals used were the same as in Example 1. 2. Experimental method

 (1) Preparation of O / W type ME pre-composition of various drugs

 An ethanol solution of each drug was prepared by sonication at the concentrations shown below. To a glass vial, add DGMO-C, Panassate 810 or EOO, HCO-40 melted by heating to 60 ° C, and an ethanol solution of each drug, in the amounts shown in the formula below. After that, the mixture was stirred at room temperature for 10 minutes using a stirrer to prepare an OZW-type ME pre-composition containing each drug.

 Also, since BO-653 is an oily substance, a study was also conducted on how to treat all the oil as BO-653. In this case, add ethanol (30 Omg) to BO-653 (1200 mg), dissolve and prepare an 80% BO-653 ethanol solution, and then add 1.6 times, 4 times, and 20 times with ethanol. A 50%, 20%, and 4% solution of BO-653 ethanol was prepared by diluting it twice.

 -AG-0.41 R: 30 Omg / m 1 (final concentration 75 mg Zm 1)

 • BO— 653: 30 Omg / m1, 90 Omg m1 (final concentration 75 mg / m1, 225 mg / m1) '• I buprofen: l O Omg / m1, 300 mg / m1 (final concentration 25 mgZml , 75 m gZm 1)

-Ke toprofen: 100mg / m1, 30 Omg / m1 (final concentration

 • Te st o st e ro n e: l O Omg / m 1 (final concentration 25 mg / m 1)

• Tamo xifen: 10 Omg / ui 1 (final concentration 25mg / m 1) To lbut am ide 100 mg / m 1 (final concentration 25 mg / m

1)

 • Disopyramide: 100mgZml, 30Omg / ml (final concentration 25mg / TSX1, 75mg / 1)

 * Ch lor r amp h e nic o 1: 6 D ./mgZm l, 200 mg ml (final concentration 16.7 mg / ml, 50 mg / m 1)

 (Prescription 1 1)

 Panacet 810 5% 150 mg DGMO 1% 3 Omg HCO-40 9% 27 Omg Drug ethanol solution 5% 15 Omg

(Prescription 1 2)

 Nonassate 810 5% 150 mg DGMO 5% 15 Omg HCO-40 5% 15 Omg Drug ethanol solution 5% 150 mg

(Prescription 1 3)

 EOO 5% 150 mg DGMO 1% 3 Omg HCO-40 9% 27 Omg Drug ethanol solution 5% 150 mg

(Prescription 1: BO-653 2% (ratio to prescription weight))

 BO-653 0.4% 12mg EtOH 9.6% 288mg DGMO 1.0% 3 Omg

HCO-40 9.0% 27 Omg (Prescription 1: BO-653 10 ° / (Ratio to prescription weight))

BO-653 2.0% 6 Omg E t OH 8.0% 24 Omg D GMO 1.0% 3 Omg

 HCO-40 9.0% 27 Omg

 (Prescription 6: BO—653 25% (ratio to prescription weight))

 BO-653 5.0% 15 Omg

 E t OH 5.0% 15 Omg

 DGMO 1.0% 3 Omg

 HCO-40 9.0% 27 Omg

 (2) Evaluation of physical properties of OZW ME pre-composition containing drug

 (i) Dispersibility

 PBS (pH 6.8, 2.4 m1) is added to the O / W-type ME pre-composition containing drug (60 Omg), and the mixture is stirred at room temperature at a rate of 130 to 15 ° rpm to obtain its dispersibility (milk Rate). Specifically, the time required for the uniformity to be visually observed was measured and defined as the emulsification time.

 The results are shown in Tables 15 to 24.

 (ii) Particle size measurement

 After the drug-containing O / W-type ME was completely emulsified in (i) above, it was appropriately diluted with PBS (pH 6.8), and the particle size was measured with a dynamic light scattering particle size distribution analyzer. The results are shown in Tables 15 to 24.

 (iiii) Drug content

 In (i) above, after the drug-containing OZW-type ME was completely emulsified, ethanol was appropriately added to destroy the O / W-type ME. Then, each was diluted with a mobile phase, and the drug content was measured by an absolute calibration curve method using a Waters HPLC system. HP LC conditions are as follows.

 (AG-041 R)

 · Column: YMC A— 312 C 18 (150 x 4.6 mm)

• Eluent: 60% CH ₃ CN

 • Detection wavelength: UV 245 nm

 • Flow velocity: 1 m1 / min

• Injection volume: 50 μ1 (BO-653)

Column: YMC A-203 C 8 (250 x 4.6 mm) Eluent: CH ₃ CN: Me OH: H ₂₀ = 6: 30: 5

 Detection wavelength: UV294 nm

 Flow velocity: 1.2 m 1 / min

 Flow rate 50 μI

(Te s t o s t e r o n e)

Column: YMC A- 3 12 C 18 (150 x 4.6 mm) Eluent: 43% CH ₃ CN-0 1% TFA

 Detection wavelength: UV254 nm

 Flow velocity: 1 m 1 / min

 Injection volume: 50 1

^ l o u p r o f e n)

Column: YMC A- 31 2 C 1 8 (1 50 x 6 mm.) _{Eluent: Me OH: H 2 O:} H 3 PO 4 = 700 300: 1 detection wavelength: UV225 nm

 Flow: 2ml / min

 Injection volume: 50 μ1

(Ke t o p r o f e n)

Column: YMC A- 3 12 C 18 (150 x 4.6 mm) Eluent: CH ₃ CN: MeOH: H ₂₀ = 36: 54: 10 Detection wavelength: UV26 5 nm

 Flow velocity: 1.2 m 1 / min

 Injection volume 50 μI

^ Γ a m o x l i e n)

Column: YMC A- 3 12 C 18 (150 x 4.6 mm) Eluent: CH ₃ CN: l OmM phosphate buffer (pH 2.0) = 40 60

Detection wavelength: UV243 nm Flow rate: 1.2 m1 / min

 Injection volume: 50 1

 (To b u t ami d e)

Column: YMC A-312 C 18 (150 x 4.6 mm) Elution ί Night: CH ₃ CN: 1 / 15M phosphate buffer (pH 7.0) = 2.5: 77.5 + PI C-A3m 1 / 1

 Detection wavelength: UV254 nm

 Flow velocity: 1 m 1 / m. In

 Injection volume: 50 μ1

 (D i o p y r am i d e)

Column: YMC A—312 C 18 (150 x 4.6 mm) Eluent: 50 mM CHgCOOH: 5 OmM CH ₃ COONH ₄ H ₂₀ : CH ₃ CN = 9.0: 13.5: 22.5: 55.0 Detection wavelength: UV254 nm

 Flow velocity: 2 m 1 Z min

 Injection volume: 50 1

 (Ch or amph e n i c o l)

Column: YMC A—312 C 18 (150 x 4.6 mm) Eluent: 50 mM CHgCOOH: 5 OmM CH ₃ COONH ₄

H ₂ 0: CH ₃ CN = 9.0 3.5: 22.5: 55.0 Detection wavelength: UV254nm

 Flow rate: 2ml / min

 Injection volume: 50 μ1

The results are shown in Tables 15 to 24. Table 15

AG-041R

 0 / W Composition of ME pre-composition (w / w¾) Emulsification time Gaussian particle size distribution AG-041 R content c. NASE-E00 DGMO-C HC0-40 AG-041R PBS (hr) Mean S.D. (nm) Chi-square (mg / ml)

810 in EtOH (pH6.8)

 5 0 1 9 5 80 to 1 0 Transparent 23.5 ± 8.3 2.11 16.98 ± 0.76

5 0 5 5 5 80 to 2.0 White 17.3 ± 10.3 2.05 14.90 Sat 0.27

Table 16

BO-653

 0 / ff ME 0 / W ME composition (w / w¾)

BO-653 EtOH DGMO-C HCO-40 PBS emulsification time in composition Appearance Gaussian particle size distribution NIC0MP particle size distribution BO-653 content

BO-653% (pH6.8) (hr) Mean ± S.D. (Nm) Chi-square Peak-1 (nm) Peak— 2 (nm) Peak—3 (nn) (rag / ml)

2 0.4 9.6 1 9 80 ~ 1 Transparent 12.6 ± 3.3 11.87 15.7 (100.0¾) 3.92 ± 0.04

10 2.0 8.0 1 9 80 ~ 2 transparent 16.4 ± 4.2 5.35 20.2 (100. 0¾) 21.16 Sat. 03

25 5.0 5.0 0 1 9 80 to 4 Slightly transparent 14.4 ± 8. 9 21.07 32.0 (95.4¾) 899.8 (1.0¾) 39974.3 (3.6.¾) 61. 15 ± 0.85

BO-653

 0 / W Composition of pre-ME composition (w / w%) Emulsification time Appearance Gaussian particle size distribution NIC0MP particle size distribution B0-653 content

Λ "† t-t 810 E00 DGMO-C HCO-40 BO-653 PBS (hr) Mean soil SD (nm) Chi-square Peak-1 (nm) Peak-2 (mn) Peak-3 (nm) Ong ml ) in EtOH (pH6.8)

 5 1 9 5 (low) 80 to 8 Slightly transparent 15.8 Sat 9.5 15.91 63.7 (100.0 »19.44 ± 0.11

5 ¹ 1 9 5 (low) ■ 80-8 slightly transparent 18.3 U. 5 '15.91 80.2 (100.0¾) 19.58 Sat.

18

 Testosterone

 0 / W ME pre-composition composition (w / ff «emulsification time Appearance Gaussian particle size distribution Testosterone

 E00 DGMO-C HCO-40 Testosterone PBS (hr) Mean S.D. (nm) Chi-square content (mg〉

 810 in EtOH (pH6.8)

 5 1 9 5 (low) 80 -8 White 12.2 Sat 7.3 1.88 6.18 person 0.10

 5 1 9 5 (low) 80 〜l White 20.6 person 9.2 2.16 6.15 ± 0.04 Table 19

0 / W Composition of ME pre-composition (w /) Emulsification time Appearance Gaussian particle size distribution NIC0MP particle size distribution Ibuprofen Hachi'nasate E00 DGMO-C HC0-40 Ibuprofen PBS (hr) Mean ± SD (nm) Chi 2 槩 Peak -1 m) Peak-2 (nm) Peak-3 (nm) content / ral)

810 in EtOH (pH6.8)

 5 1 9 5 (high) 80 to 6 Light white 547.7 ± 481 4 1473.22 '30.9 (79.8¾) 149.2 (1.4¾) 1528.6 (18.Z%) 20.16 ± 0.55

05 5 1 9 5 (high) 80 to 2 Transparent 11.7 Sat 6 4 60.45 39.5 (100.0¾) 21.40 ± 0.23

 5 1 9 5 (low) 80 to 8 pale white .5 ± 12.1 331.49 26.6 (97.7¾) 511.2 (2.3¾) 7.06 ± 0.15

5 1 9 5 (low) 80 ~ l Transparent U.5 soil 7.2 43.31 50.5 (100.0%) 7.19 soil 0.07

Table 20

0 / W ME pre-composition composition (w / w¾) Emulsification time Appearance Gaussian particle size distribution NI COM? Particle size distribution etoprofen

 n'ft--E00 DGMO-C HCO-40 Ketoprofe.n PBS (hr) Mean soil S. D. (ran) Chi-square Peak-1 (nm) Content (mg / ml)

 810 in EtOH (pH6.8)

 5 1 9 5 (high) 80 ~ 2 Transparent 19.4 ± 6.7 2.37 15.44 Sat 0.13

 5 1 9 5 (low) 80 to 4 Opacity 11.8 ± 9.2 113.19 26.2 (98.9¾) 6.20 ± 0.04

5 1 9 5 (low) 80 ~ 2 Transparent 21.3 ± 8.5 2.26 6.39 ± 0.06

Table 2

Table 22

0 / W ME pre-composition composition (M emulsification time Appearance Gaussian particle size distribution To 1 but amide

 A't -l * E00 DGMO-C HCO-40 Tolbutamide PBS (hr) Mean soil S.D. (nm) Chi-square content (Kg / ml)

 810 in EtOH (pH6.8)

 5 1 9 5 (low) 80 to 8 pale white 22. is 8.8 '1.94 5.47 soil 0.14

Table 23

0 / W ME pre-composition composition (w / wS emulsification time Appearance Gaussian particle size distribution Hidden MP particle size distribution Disopyramide

ナ Naseth Ε00 DGM0-C HCO-40 Disopyramide PBS (hr) Mean soil S.D. (nm) i square Peak-1 (nm) Peak— 2 (nm) Peak-3 (nm) Content Ong inl)

Table 24

 Chloramphenicol

 Composition of pre-composition (ff /) Emulsification time Gaussian particle size distribution NICOMP particle size distribution Chloramphenicol

Λ'ϋ-Eto E00 DGMO-C HCO-40 Chloramphenicol PBS (hr) Mean S. (AE) Chi-square Peak-1 (nsj) Peak-2 (nm) Peak-3 (Bin) Content (nig ml)

810 in EtOH (pH6.8)

 5 1 9 5 (high) 80-24 Transparent 15.2 Sat 7, 3 17.68 41.7 (100.Q%) 9.84 Sat 0.12

00 5 5 5 5 (high) 80 to 8 White 41.3 ± 29.7 90.7 48.8 (90.4¾) 41.2 (9.6¾) 10, 01 Sat 0.15

 5 1 9 5 (high) 80 to 2 Transparent 19.2 Sat 8.6 18.84 46.I (100.ϋ%) 10.63 ± 0.35

5 I 9 5 (low) 80 to 4 Transparent 14.9 ± 7.6 21.28 46.1 (100.0¾) 4.01 Sat 0.Π

5 5 5 5 (low) 80 to 8 White 36.9 ± 27.3 53.27 47.8 (91.3¾) 263.3 (0.4¾) 400.5 (8.3¾) 4.04 Sat 0.08

5 I 9 5 (low) 80 to 2 Transparent 18.3 Soil 10.3 14.72 33.9 (99.3%) 399.1 (0.7¾) 3, 9 is 0.11

(3) Results · In most of the formulation examples, the OZW-type ME pre-composition was completely oxidized within 8 hours. In most of the formulation examples, 90% or more of small particles having a particle size of 60 nm or less were found, indicating that a good microemulsion was formed.

 The drug content was almost the same as the charge.

 When BO-655 itself was used as an oil in the O / W-type ME pre-composition, the emulsification rate decreased as the B-655 content increased. Within this range, the smaller the BO-653 content, the smaller the particle size. (Example 5)

 Eight of the nine drugs used in Example 4 were used to study the absorption of the microemulsion (ME) pre-composition from the rat digestive tract.

 1. Experimental materials and reagents

 AG—041R, Ibuprofen, Ketoprofen, ChloramphaneNicol oTolbumutamid, Tamoxifen, Disopyramid ^ BO—653 used in Example 4 were used.

 Other laboratory equipment, chemicals, etc. were used in Example 1 unless otherwise specified.

The same ones as in ~ 4 were used.

 2. Laboratory animals

 Seven-week-old male SD rats were obtained from Japan SLC and were at a temperature of 24 ± 2. C, Humidity 55 ± 10%, Ventilation rate 10-30 times Z, Lighting time 5-5-19 hours Constant temperature / humidity Animal breeding room, free water supply (tap water, feed CE-2 (Clea Japan) )) The animals were preliminarily reared for 1 week to reach the age of 8 weeks (body weight: 236.7 g to 270.3 g), and then used for experiments.

 3. Experimental method

 (1) Preparation of dosing solution

 (i) Preparation of ZW-type ME pre-composition containing each drug

HCO-40, DGMO_C, Panacet 810 and the ethanol solution of each drug (BO-653: 30 Omg / Drugs other than m1, BO-653: Add 6 Omg / m1), stir with a stirrer at room temperature for 2 hours, and add 50mg / 0.6ml (BO-653) and 10mg / 0 6 ml (except for BO-653), an OZW-type ME pre-composition having the following formulation was prepared. The following formulation was selected because, in Example 4, the O / W-type ME pre-composition in this treatment became AZW-type ME.

 -Prescription

 Panacet 8 10 5% 60 Omg

D GMO 1% 1 2 Omg

HCO-40 9% 1 08 Omg Drug ethanol solution 5% 60 Omg

(60 or 300mg / m1)

 (ii) Preparation of O / W ME containing each drug

 9.6 ml of PBS (pH 6.8) was added to each of the above OZW-type ME-containing compositions containing each drug, and the mixture was stirred at room temperature for 2 hours with a stirrer to obtain 10 mg / 3 ml (BO-653). ) And 50 mg / 3m 1 (BO-653), and OW-type MEs containing each drug were prepared as shown below.

 • prescription

 Panassate 8 10 5% 60 Omg

DGMO 1% 1 2 Omg HCO-40 9% 1 08 Omg Ethanol solution of drug 5% 60 Omg

(60 or 30 Omg / m 1)

 PB S (pH 6.8) 80% 9.6 ml

(iii) Preparation of aqueous solution of each drug, add 765 ml of PEG200: EtOH: DW = 6: 1: 1.5 (v / v) aqueous solution to Tamoxifen (30 mg) and sonicate. And dissolved to give an aqueous solution of 1 Omg / 2.55 ml of Tamoxixifen. Soybean oil was added to BO-653 (15 Omg) to a final volume of 9 ml and mixed to give a 50 mg / 3 ml 1 BO-653 aqueous solution. For drugs other than Tamo xifen and BO—65 3, are drugs 301118? £ G200: EtOH: DW = 6: 1: 3 (v / v) An aqueous solution (9 ml) was added and dissolved by sonication to prepare a 10 mgZ3 ml aqueous solution of each drug.

 (iv) Preparation of suspension of each drug

 Add 0.5% CMC_Na aqueous solution to BO-653 (15 Omg) so that the final volume becomes 9 ml, and suspend uniformly using a homogenizer to obtain 50 mg / A 3 ml suspension was prepared.

 For drugs other than BO-653, the drug is ground in an agate mortar, sieved (45-75 5α), and then in agate mortar, 0.5% CMC—Na for 30 mg of the drug. 9 ml of an aqueous solution was added and suspended so as to be uniform, thereby preparing a suspension of 1 OmgZSm1.

 (2) Evaluation of gastrointestinal absorption of OZW-ME pre-composition of each drug in rats (i) Animal treatment

 All day and night fast · Heparin lock (approximately 50 U / m 1-saline) treated PE-50 tube was introduced into the femoral artery of rats fed water freely under ether anesthesia to prepare for blood collection. Was. After the operation, they were fixed in a ballman cage and left for 2 hours to awaken.

 (ii) administration

 Approximately 2 hours after the end of surgery, the OZW-ME pre-composition, OZW-ME, suspension, and aqueous solution of each drug will have a drug dose of 1 OmgZkg (50 mgZkg for BO-653). As described above. For the O / W type ME pre-composition, 4-fold volume of PBS (pH 6.8) was continuously administered.

 (iii) Plasma drug concentration measurement

 Immediately before drug administration, 500 μl of blood was collected from each of the force neurons inserted into the femoral artery.

Further, at 5, 15, 30, 30 minutes, 1, 2, 4, 6, 8, and 24 hours after the administration, blood was collected at about 500 μI each, and the blood was collected at 4 ° C'l OOOO pm. Plasma was obtained by centrifugation for 3 minutes. Plasma (200 μl) was deproteinized, extracted with an organic solvent, redissolved in mobile phase ', and the drug concentration in plasma was measured using RP-HPLC (HP LC column). The case is the same as in Example 3).

 (i V) Data analysis

 The AUC was calculated by the trapezoidal method, and the ratio of each AUC to the AUC in the suspension (relative bioavailability (Re1ative BA)) was calculated from the obtained changes in the concentration of each drug in the plasma. Was. The results are shown in Table 25. Table 25

In Table 25 above, each data is represented by the average soil SD of four cases.

The relative bioavailability of the aqueous solution, OZW ME and O / W ME pre-compositions for the suspension is 12% soil 15% and 279 ± 251% for AG-041 R, respectively.ぴ 210 ± 60%, Ibuprofen 926 ± 208%, 871 ± 119% and 798 ± 105%, Ketoprofen 216 ± 20%, 156 ± 28% and 146 ± 24%, Ch 358 ± 46%, 203 ± 26% and 1 for 1 or amp henicol, respectively 56 employees and 47%. In the case of Tolbut amide, 375 ± 54%, 282 ± 42% and 279 ± 15%, respectively, in Tamo xifen, 227 ± 29%, 285 ± 107% and 224 ± 117%, and in disopyramide, respectively The values were 87 ± 18%, 208 ± 40% and 152 ± 27%, and those of BO-653 were 10990 ± 5859%, 6367 ± 1 355% and 7845 ± 2380%, respectively.

 The gastrointestinal absorption when administered as a pre-O / W ME composition was not significantly different from the gastrointestinal absorption when OZW ME was administered for any of the drugs studied, and was almost the same. Was showing sex.

 The absorbability of the O / W ME before the OZW ME pre-composition was superior to that of the suspension in both cases.

 In addition, an improvement effect of the OZW-type ME pre-composition on AUC variation was observed with five kinds of drugs. In other words, in To lbut ami de and BO-653, administration of the 〇ZW-type ME pre-composition reduced paracki to 2 to 4 times that of suspensions and solutions, and Ke toprofen, Chlor amp henicol And Disopyramide decrease the suspension to 40-80% of the suspension, and can improve the variation in gastrointestinal absorption of poorly water-soluble drugs when administered in combination with O / W-type ME It was speculated that there was a possibility. (Example 6)

 OZW type microemulsions of the present invention were prepared using various oils, hydrophilic surfactants and lipophilic surfactants, and their physical properties were examined.

 1. Experimental materials and reagents

 The following four types of oils, eight types of lipophilic surfactants and 18 types of hydrophilic surfactants were used.

 (i) Oil

• No. ⁰ Nassate 810

 '' Echinole Oleoleate (EOO)

• Olive oil: (Nikko Chemicals) • Triacetin: (Wako Pure Chemical Industries)

(ii) Lipophilic surfactant

 • DGMO—C (HLB value: 5.5)

 • DGMI S (HLB value: 5.5)

 -SO-10 (trade name) (Sorbitan monooleate (HLB value: 4.

3)): (Nikko Chemicals)

 • SO-15 (trade name) (Sorbitan sesquioleate (HLB value: 3.7)): (Nikko Chemicals)

 -SO-3 OR (trade name) (Sorbitan trioleate (HLB value ··· 4.0)): (Nikko Chemicals)

 • SI-10R (trade name) (sorbitan monoisostearate (HLB value: 5.0)): (Nikko Chemicals)

 • HCO-5 (polyoxyethylene (5) hydrogenated castor oil (HLB value: 6.0)):

 · NP-2 (trade name) (Polyoxyethylene (2) nonylphenyl ether (HLB value: 4.5)): (Nikko Chemicals)

(iiii) hydrophilic surfactant

 • T L 10 (trade name) (Monoxy palm oil fatty acid polyoxyethylene (20) sorbitan (HLB value: 16.9)): (Nikko Chemicals)

 · TP-10 (brand name) (polyoxyethylene monopalmitate (20) sorbitan (HLB value: 15.6)): (Nikko Chemicals)

 • TO-10M (trade name) (Polyoxyethylene monooleate (20) Sorbitan (HLB value: 15.0)): (Nikko Chemical Cane)

 • GL-1 (trade name) (polyoxyethylene monolaurate (6) sorbit (HLB value: 15.5)): (Nikko Chemicals)

 • GO-4 30N (trade name) (Polyoxyethylene tetraoleate (30) Sorbit (HLB value: 11.5)): (Nikko Chemicals)

 • GO—440 (HLB value: 12.5)

• GO—460 (trade name) (Polyoxyethylene tetraoleate (6 0) Sorbit (HLB value: 14.0)): (Nikko Chemicals)

 • HCO—40 (HLB value: 12.5)

 • HCO-50 (trade name) (Polyoxyethylene (50) hydrogenated castor oil (HLB value: 13.5)): (Nikko Chemicals)

 · HCO-60 (trade name) (Polyoxyethylene (60) hydrogenated castor oil

(HLB value: 14.0)): (Nikko Chemicals)

 • MYL—10 (polyethylene glycol monolaurate (10 EO) (HLB value: 12.5))

 • BL—4.2 (brand name) (polyoxyethylene (4.2) lauryl ether (HLB value: 11.5)): (Nikko Chemicals)

 • BL-9EX (brand name) (Polyoxyethylene (9) lauryl ether (HLB value: 14.5)): (Nikko Chemicals)

 • NP—7.5 (brand name) (polyoxyethylene (7.5) nonylphenyl ether (HLB value: 14.0)): (Nikko Chemicals)

 · ΝΡ—10 (brand name) (Polyoxyethylene (10) nonylphenyl ether (HLB value: 16.5)): (Nikko Chemicals)

 • Hexaglynl-L (trade name) (Hexaglyceryl monolaurate)

(HLB value: 14.5)): (Nikko Chemicals)

 • Decaglynl-L (trade name) (Decaglyceryl monolaurate (HLB value: 15.5)): (Nikko Chemicals)

 • Decaglynl—OV (brand name) (Decaglyceryl monooleate (HLB value: 12.0)): (Nikko Chemicals)

 Unless otherwise stated, the same experimental instruments and chemicals as those used in the above Examples were used.

 2. Experimental method

 (1) Preparation of OZW type ME

As shown in Tables 26 to 29, OZW ME was prepared by combining various oils, lipophilic surfactants, and hydrophilic surfactants. The mixing ratio of various oils, lipophilic surfactants, and hydrophilic surfactants is as follows: When an outside oil was used, the formulation-2 was followed. These formulations were determined as follows. Since the total amount of surfactant required to emulsify a 5% w / w oil was 10% w / w, the oil concentration was fixed at 5% w / w and the lipophilic surfactant: hydrophilic Microemulsion forming ability was examined by changing the surfactant ratio to 1: 9, 2: 8, 5: 5, 8: 2, 9: lw / w. Since the microemulsion forming ability was the best when the ratio of lipophilic surfactant: hydrophilic surfactant was 1: 9, this blending ratio was adopted. When olive oil is used, if the oil concentration is 5% w / w and the total amount of surfactants is 10% w / w, no surfactant can be used to emulsify the oil. Since no oil was formed, a formulation was used in which the oil concentration was reduced to 1%.

 In Formula 1 1, 30 mg of oil, 30 mg of lipophilic surfactant, 270 mg of hydrophilic surfactant and 150 mg of ethanol were added to a 5 mL transparent glass pail, and the mixture was stirred with a stirrer at room temperature for 10 minutes. .8) 2520 mg was added, and the mixture was further stirred with a stirrer at room temperature for 2 hours. In addition, in Formula 2, 150 mg of oil, 30 mg of lipophilic surfactant, 270 mg of hydrophilic surfactant, and 150 mg of ethanol were added to a 5 mL transparent glass vial, and the mixture was stirred for 10 minutes at room temperature with a stirrer. (pH 6.8) 2400 mg, and the mixture was further stirred at room temperature with a stirrer for 2 hours.

 [Prescription 1 1]

 Oil 7o W / W 30mg Lipophilic surfactant 0 7/0 W / W 30mg Hydrophilic surfactant 9% w / w 270mg Ethanol mono o% w / w 150mg PBS (pH 6.8) 8 4% w / w 2520mg

 [Prescription 1 2]

Oil 5% w / w 150mg Lipophilic surfactant 1% w / w 30mg Hydrophilic surfactant 9% w / w 270mg Ethanore / 5% w / w 150mg PBS (pH 6.8) 80% w / w 2400mg

Table 26 Physical properties of O / W type microemulsion when Panassate 810 is used as oil Composition Appearance

 Oil Lipophilic surfactant Presence of hydrophilic surfactant Peak-1 (nm) Peak-2 (nm) Peak-3 (nm) Panacet 810 DGMO-C GO-440 Transparent + 42.8 (100.010)

Panacet 810 DGMO-C HCO-40 Transparent + 31.7 (100.0%)

Panassate 810 DGMO-C HCO-50 Light white 118.0 (100.0%)

Panacet 810 DGMO-C HCO-60 pale white 139.6 (100.0 »)

Panassate 810 DGMIS GO— 440 Transparent + 27.8 (100.0 »)

Panacet 810 DG IS HCO-40 Transparent + 74.9 (100.0%)

Panaceto 810 SO-10 GO-440 Transparent + 14.6 + 6.6

Panacet 810 SO-10 HCO-40 Transparent + 20.3 ± 10.2

Panacet 810 SO-10 HCO-50 Light white 85.6 (100.0%)

Panacet 810 SO-15 GO-440 Transparent + 91.0 (100.0 »)

Panacet 810 SO-15 HCO-40 Transparent + 64.2 (100.050

Panacet 810 SO-15 HCO-60 5 # color 134.2 (100.0%)

Panacet 810 SO-30R HCO-40 Transparent + 128.8 (100.0%)

Panassate 810 SI-10R GO-440 Transparent + 13.8 ± 6.1

Panassate 810 HCO-5 GO-430N Transparent + 37.4 (100.0 »)

Panaceto 810 HCO-5 GO-440 Transparent + 69.6 (100.0¾)

Panassate 810 HCO-5 HCO-40 Transparent + 80.3 (100.050

Panacet 810 HCO-5 HCO-50 Light white 134.2 (100.0¾)

Panassate 810 HCO-5 NP-7.5 Transparent + 20.3 (100.0W

Panacet 810 NP-2 GO-440 Transparent + 13.6 ± 5.2

Panassate 810 NP-2 HCO-50 pale white 139.6 (100.0¾)

Table 27 Physical properties of O / W type microemulsion when EOO is used as oil

Table 28 Physical properties of O / W type microemulsion using olive oil as oil

 Appearance Tyndall light

 Oil Lipophilic surfactant Presence or absence of hydrophilic surfactant Peak-1 (nm) Peak-2 (nm) Peak-3 (nm) Olly force DG O-C HCO-40 Transparent + 36.9 (100.0¾)

 DGMO-C HCO-50 Transparent + 63.1 (100.0X)

Olive oil DGMO-C HCO-60 clear + 58.7 (100.0K)

Olive oil DGMIS HCO-40 clear + 71.8 (100.0%)

Olive oil DG IS HCO-50 Transparent + 65.3 (100.0¾)

Olive oil DG IS HCO-60 clear + 58.7 (100.0¾)

Olive oil SO-10 HCO-40 Transparent + 76.2 (100.0%)

Olive oil SO-10 HCO-50 + .Ό ϋϋ.ϋ%

Olive oil SO-10 HCO-60 clear + 144.3 (100.0%)

Olive oil SO-15 HCO-40 clear + 65.3 (100.0¾)

Olive oil SO-15 HCO-50 Transparent + 70.7 (100.0Χ)

Olive oil SO-15 HCO-60 transparent + 54.4 (100.0%)

Olive oil SO-30R HCO-40 transparent + 16.6 ± 6.3

Olive oil SO-30R HCO-50 White 119.9 (100.0%)

Olive oil SI-10R HCO-40 transparent + 15.3 ± 4.5

Olive oil SI-10R HCO-50 Transparent + 15,4 ± 5.2

Olive oil SI-10R HCO-60 clear + 15.2 ± 7.8

Aged leave oil HCO-5 GO-440 Transparent + 14.5 (100.0%)

Olive oil HCO-5 HCO-40 Transparent + 51.9 (100.0%)

Olive oil HCO-5 HGO-50 clear + 28.5 (99.6%) 141.4 (0.4¾) year old leave oil HCO-5 HCO-60 clear + 57.5 (100.0¾)

Olive oil NP-2 HCO-40 transparent + 14.9 ± 3.5

Olive oil NP-2 HCO-50 transparent 44.1 (90.6%) 130.4 (9.4%) Olive oil NP-2 HCO-60 transparent + 47.9 (100.0%)

Table 29 Physical properties of OW type microemulsion using triacetin as oil

(2) Physical property evaluation

 (i) Particle size measurement

 Each OZW-type ME sample was appropriately diluted with PBS (pH 6.8), and the particle size distribution was measured using a dynamic light scattering particle size distribution analyzer NI COMP C370. The results are shown in Tables 26-29.

 (ii) Appearance: Observation of emulsified state

 Appearance · The emulsified state was visually observed.

 Further, each O / W-type ME sample was irradiated with light using Technolite KHL-100 (Kenko Ichigo Co., Ltd.) to visually confirm the presence or absence of Tyndall light. The Tyndall phenomenon is a phenomenon in which, when light is applied to a liquid in which fine particles are dispersed or suspended, the light path appears to be bluish milky white. Since this phenomenon is caused by the scattering of light by the dispersed colloid particles, the presence or absence of tindal light is an indicator of whether microemulsions are formed.

 The results are shown in Tables 26-29.

 (3) Result

 As is clear from Tables 26 to 29, the average particle diameter of the obtained OZW-type ME was 150 nm or less in any combination.

When Panacet 810 was used as the oil, the average particle size was less than 100 nm in about 71% of the combination and less than 50 nm in about 43% of the combination. Combination of OZW-type MEs with an average particle size of 50 nm or less when using Panacet 810 was GO-440 as a hydrophilic surfactant when DGMO-C was used as a lipophilic surfactant. The combination of HCO-40; When DGMIS is used as the lipophilic surfactant, The combination with GO-440 is used as the hydrophilic surfactant; When SO-10 is used as the lipophilic surfactant Is a combination of GO-440 or HCO-40 as a hydrophilic surfactant; a combination of GO-440 as a hydrophilic surfactant when SI-10R is used as a lipophilic surfactant; When HCO-5 is used as a surfactant, a combination of GO-430N or NP-7.5 is used as a hydrophilic surfactant; when NP-2 is used Was a combination of GO-440 as a hydrophilic surfactant.

 When 1 / ヽ of EOO was used as the oil, the average particle size was less than 100 nm in about 77% of the combination, and less than 50 nm in about 46%. The O / W-type ME with an average particle size of 50 nm or less was obtained when EOO was used, because when DGMO-C was used as the lipophilic surfactant, TO_10M and GO-460 were used as hydrophilic surfactants. Or a combination of HCO-60; a combination of TO-10M as a hydrophilic surfactant when DGMIS is used; a combination of TO-10M as a hydrophilic surfactant when SO-10 is used. Combination of GO-460 or HCO-50; When SO-15 was used, use of TO-10M, combination of GO-460 or HCO-50 as hydrophilic surfactant; SO-30R In some cases, a combination of HCO-40 as a hydrophilic surfactant; In the case of using SI-10R, a combination of TO-10M, GO-460 or HCO-40 as a hydrophilic surfactant When NP-2 was used, it was a combination of hydrophilic † biosurfactant '[· GA-440 or NP-10 as a bioactive agent

 When olive oil was used as the oil, the average particle size was less than 100 nm in about 92% of the combination, and less than 50 nm in about 42%. OZW-type ME with an average particle size of 50 nm or less was obtained when olive oil was used, because when DGMO-1C was used as the lipophilic surfactant, HC 0-40 was used as the hydrophilic surfactant. When using SO-30R, a combination of HC O-40 as a hydrophilic surfactant; When using SI-10R, HCO-40, as a hydrophilic surfactant Combination of HCO-50 or HCO-60; Combination of GO-440 or HCO-50 as hydrophilic surfactant when using HCO-5; Hydrophilic 'I "when using NP-2 It was a combination of HCO-40 or HCO-60 as the raw surfactant.

When triacetin was used as the oil, the average particle size was less than 100 nm in about 95% of the combination and less than 50 nm in about 83% of the combination. The O / W-type ME with an average particle size of 50 nm or less was obtained when using triacetin because DG-MO was used as the hydrophilic surfactant when DGMO_C was used as the lipophilic surfactant. 10, TP-1 10, TO-10M, GO-440, GO-460, HCO-40, HCO- Combination of 50, HCO-60, BL-9EX or NP-10; When DGMI S is used, TL-10, TP-10, HCO-40, HCO-50, HCO- Combination of 60, MY L-10 or BL-9 EX; When SO-10 is used, TP-10, TO-10M, GO-460, HCO_40, HCO-50, Combination of NP-7.5 or NP-10; When SO-15 is used, TP-10, TO-10M, GO-460, HCO-40, HCO-50, HCO-50 as hydrophilic surfactant Combination of —60 or NP—7.5; When SO—3 OR is used, use a combination of HCO-40, HCO-50, or HCO-60 as a hydrophilic surfactant; use SI-10 R If you use TP-10, TO-10M, GO-460, HCO-40, HCO-50, MYL-10 or NP-10 as a hydrophilic surfactant, use HCO-5 , As a hydrophilic surfactant Combination of GO-440, HCO-40, HCO-50 or HC O-60; When NP-2 is used, TL-10, TP-10, TO-10M or GO as hydrophilic surfactant — 460 threads. Industrial applicability

 As described above, the pre-oZw-type microemulsion composition and the o / w-type mic-mouth emulsion formulation of the present invention exhibit excellent absorbability even in a living body and are useful for improving the bioavailability of poorly soluble drugs. Expected.

Claims

The scope of the claims

 1. (1) poorly water-soluble drugs,

 (2) oil,

 (3) a hydrophilic surfactant, and

 (4) a lipophilic surfactant whose H and B values are 4.0 to 9.0,

 An O / W type microphone mouth emulsion pre-composition comprising:

2. The composition according to claim 1, wherein the weight ratio of the hydrophilic surfactant to the lipophilic surfactant is 9 ::! To 5: 5.

3. The composition according to claim 1, wherein the lipophilic surfactant is a lipophilic surfactant having an HLB value of 4.0 to 6.0.

4. The composition according to any one of claims 1 to 3, wherein the hydrophilic surfactant 'I "raw material is a hydrophilic surfactant having an HLB value of 11.5 to 17.5.

5. The composition according to claim 4, wherein the hydrophilic surfactant is a hydrophilic surfactant having an HLB value of 11.5 to 15.6.

6. The composition according to any one of claims 1 to 5, further comprising a solubilizer for a poorly water-soluble drug.

7. The composition according to claim 6, wherein the dissolution aid is ethanol.

8. The composition according to any one of claims 1 to 7, wherein the lipophilic surfactant is diglyceryl monooleate.

9. The hydrophilic surfactant is polyoxyethylene hard castor oil. 9. The composition according to any one of claims 8 to 8.

10. Lipophilic surfactants are diglyceryl monooleate, diglyceryl monoisostearate, sorbitan monooleate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monoisostearate, polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene ( 2) Claims selected from the group consisting of nonylphenol ethers! The composition according to any one of claims 9 to 9.

1 10. The composition according to any one of claims 1 to 9, wherein the lipophilic surfactant is selected from the group consisting of diglycerinole monooleate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate.

12. The hydrophilic surfactants are monococonut oil fatty acid polyoxyethylene (20) sorbitan, polyoxyethylene monopalmitate (20) sorbitan, polyoxyethylene monooleate (20) sorbitan, polyoxyethylene monolaurate (6) sorbit , Polyoxyethylene tetraoleate (30) sorbit, Polyoxyethylene tetraoleate (40) sorbit, Polyoxyethylene tetraoleate (60) sorbite, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) ) Hardened castor oil, polyoxyethylene (60) Hardened castor oil, polyethylene glycol monolaurate (10EO), polyoxyethylene (4.2) lauryl ether, polyoxyethylene (9) lauryl ether, polyoxyethylene (7.5) ) Noyulphenyl A Le, Poriokishechi Ren (10) Bruno - Ruff enyl ether, Kisaguriseriru to monolaurate, claims selected from the group consisting of mono-Orein decaglyceryl:! The composition according to any one of claims 1 to 11.

13. Hydrophilic surfactant is polyoxyethylene monopalmitate (20) sorbitan, polyoxyethylene monooleate (20) sonorebitan, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, Polyethylene (60) Hard castor oil, Polyoxyethylene (4.2) Laurinole The composition according to any one of claims 1 to 11, wherein the composition is selected from the group consisting of ether, polyoxyethylene (9) laurinooleate, hexaglyceryl monolaurate, and deglyceryl monooleate.

14. (1) poorly water-soluble drugs,

 (2) oil,

 (3) hydrophilic surfactant,

 (4) a lipophilic surfactant having an HLB value of 4.0 to 9.0, and

(5) Water

 An o / w type microphone mouth emulsion formulation comprising:

15. The microphone mouth emulsion preparation according to claim 14, wherein the weight ratio of the hydrophilic surfactant to the lipophilic surfactant is from 9: 1 to 5: 5.

16. The microphone-mouth emulsion according to claim 14 or 15, wherein the lipophilic surfactant is a lipophilic surfactant having an HLB value of 4.0 to 6.0.

17. The microphone mouth emulsion preparation according to any one of claims 14 to 16, wherein the hydrophilic surfactant is a hydrophilic surfactant having an HLB value of 11.5 to 17.5.

18. The microphone mouth emulsion preparation according to claim 17, wherein the hydrophilic surfactant is a hydrophilic surfactant having an HLB value of 11.5 to 15.6.

19. The microemulsion preparation according to any one of claims 14 to 18, further comprising a solubilizer for a poorly water-soluble drug.

20. The emulsifier according to claim 19, wherein the solubilizing agent is ethanol.

, Preparations.

21. The microemulsion according to any one of claims 14 to 20, wherein the lipophilic surfactant is diglyceryl monooleate.

22. The microphone mouth emulsion preparation according to any one of claims 14 to 21, wherein the hydrophilic surfactant is polyoxyethylene hard castor oil.

23. The lipophilic surfactants are diglyceryl monooleate, diglycerinole monoisostearate, sonorebitan monooleate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monoisostearate, polyoxyethylene (5) hydrogenated castor oil, polyoxyethylene (2) The microemulsion preparation according to any one of claims 14 to 22, which is selected from the group consisting of nonylphenyl ether.

24. The microemulsion according to any one of claims 14 to 22, wherein the lipophilic surfactant is selected from the group consisting of diglyceryl monooleate, sorbitan monooleate, sorbitan sesquioleate, and sorbitan trioleate. .

25. The hydrophilic surfactant is mono-coconut oil fatty acid polyoxyethylene (20) sorbitan, polyoxyethylene monopalmitate (20) sorbitan, polyoxyethylene monooleate (20) sorbitan, polyoxyethylene monolaurate (6) sorbit , Polyoxyethylene tetraoleate (30) sonorebit, polyoxyethylene tetraoleate (40) sorbite, polyoxyethylene tetraoleate (60) sonorebit, polyoxyethylene (40) castor oil, polyoxyethylene (50) Hardened castor oil, polyoxyethylene (60) Hardened castor oil, polyethylene glycol monolaurate (10EO), polyoxyethylene (4.2) lauryl ether, polyoxyethylene (9) lauryl ether, polyoxyethylene (7.5) Noninorefeni Reetenore, Poriokishechi Len (1 0) Noninorefe two Noreeteru, Kisaguriseriru to monolaurate, claim 14 to 24 selected from the group consisting of mono-Orein decaglyceryl 2. The microphone mouth emulsion preparation according to item 1.

26. The hydrophilic surfactant is polyoxyethylene monopalmitate (20) sorbitan, polyoxyethylene monooleate (20) sorbitan, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, 25. The method according to claim 14, wherein the polyoxyethylene (60) is hydrogenated castor oil, polyoxyethylene (4.2) laurinole ether, polyoxyethylene (9) lauryl ether, hexaglyceryl monolaurate, or decaglyceryl monooleate. The microphone mouth emulsion preparation according to any one of the above.