WO2003002095A1 - Preparation d'une micro-emulsion de type huile-eau - Google Patents

Preparation d'une micro-emulsion de type huile-eau Download PDF

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Publication number
WO2003002095A1
WO2003002095A1 PCT/JP2002/006568 JP0206568W WO03002095A1 WO 2003002095 A1 WO2003002095 A1 WO 2003002095A1 JP 0206568 W JP0206568 W JP 0206568W WO 03002095 A1 WO03002095 A1 WO 03002095A1
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WIPO (PCT)
Prior art keywords
polyoxyethylene
sorbitan
surfactant
monooleate
castor oil
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PCT/JP2002/006568
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English (en)
Japanese (ja)
Inventor
Hiroshi Araya
Takayuki Yoshimori
Original Assignee
Chugai Seiyaku Kabushiki Kaisha
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Publication of WO2003002095A1 publication Critical patent/WO2003002095A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers

Definitions

  • 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.
  • the microemulsion is an oil-Z water system stabilized by the surface phase of a surfactant.
  • 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.
  • 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.
  • 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.
  • the weight ratio of the hydrophilic surfactant to the lipophilic surfactant may be 9: 1 to 5: 5. preferable.
  • the HLB value of the lipophilic surfactant is preferably 4.0 to 6.0.
  • the lipophilic surfactant is diglyceryl monooleate.
  • 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.
  • the hydrophilic surfactant preferably has an HLB value of 11.5 to: 17.5, and 11. More preferably, it is 5 to 15.6.
  • the hydrophilic surfactant freshener is a polyoxyethylene hydrogenated castor oil.
  • 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 pheny
  • 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 ⁇ / w-type microemulsion preparation of the present invention may further contain a solubilizer for poorly water-soluble drugs.
  • a solubilizer for poorly water-soluble drugs Ethanol is preferred as a solubilizer.
  • Consisting of means that other components and components may be included.
  • 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.
  • the largest dimension (eg, diameter) of a particle or droplet is about 1
  • 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).
  • solubilizers such as ethanol, anhydrous ethanol, propylene glycol, macrogol, and glycerin.
  • a drug having a LogD (water-octanol partition coefficient) of 2 or more can be used.
  • 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 .
  • vegetable oils 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.
  • 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.
  • 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
  • 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.
  • 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.
  • mono-coconut oil polyoxyethylene (20) sorbitan, polyoxyxylene (monopalmitate) (20) sorbitan, polyoxyethylene (monooleate) (20) sonorevitan, polyoxyethylene monolaurate (6) sorbit, tetraoleic acid Polyoxyethylene
  • the HLB Hydrophilicity and lipophilicity of a surfactant molecule.
  • the HLB of the nonionic surfactant is calculated by the following equation:
  • 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)
  • diglyceryl monoisostearate eg, DGMIS (trade name), Nikko Chemicals
  • diglyceryl monoisostearate eg, DGMIS (trade name), Nikko Chemicals
  • diglyceryl monooleate, diglyceryl monoisostearate, sorbitan monooleate, sonorebitan sesquioleate, sorbitan trioleate, recbitan 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.
  • the drug concentration 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
  • 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.
  • 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%.
  • 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.
  • a thickener, a diluent, an antioxidant, a stabilizer, a buffer, a seasoning, a fragrance and the like can be mentioned.
  • a thickener may be used, and known pharmaceutically acceptable polymer materials, inorganic thickeners and the like can be used.
  • 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-abi-abino, fruit flavor, heart water, menthol, and the like. All are known compounds that are pharmaceutically acceptable.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • CP-060 S fumarate (Lot No. V617A30) was manufactured by Chugai Pharmaceutical Co., Ltd. by the method described in JP-A-10-287672.
  • Triester F810 (trade name), (force prillic acid. Capric triglyceride): Nikko Chemicals
  • the other reagents were of a special grade.
  • 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.
  • Ethanol was added to CP-0600S fumarate, and sonication was performed to dissolve it to a concentration of 300 mg / m1.
  • HCO-40 270 ⁇ 1
  • DGMO-C 301
  • oil 150 ⁇ l of either ⁇ or Panacetate 8 or Triester F810
  • 300 mg / 1 CP-600S fumarate in ethanol (1 50 ⁇ 1) was added, and the mixture was similarly stirred for 10 minutes.
  • 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.
  • Table 2 en Solvent g Surfactant content (3 ⁇ 4) CP-060S charge measurement CP-060S particle size distribution.
  • 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.
  • 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.
  • 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. .
  • 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.
  • 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.
  • Plasma was added to IN Na ⁇ (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.
  • AUC area under the plasma concentration curve
  • MRT absorption rate constant and average residence time
  • the time to reach the maximum plasma concentration of CP-060S 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 reached 508.1 ⁇ 188.7-594.5 ⁇ 174. lng / ml.
  • 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).
  • aqueous solution Formulation 5
  • oil-free formulation Formulation 1
  • 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.
  • PEG200 brand name: Pure chemistry
  • Perex OT-P (trade name), di (2-ethylhexyl) sodium sulfosuccinate: Kao
  • 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.
  • 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.
  • Meaner SD (m_g / ml) 650nm
  • Mean soil SD (nra) _Chi square Peak- l (nm) _Peak-2 (nm) Peak-3 (nm)
  • ER-1039 could be dissolved up to a concentration of about 6 mgZml.
  • the surfactant is DGMO-C and HCO-40 and Tributyrin
  • Panassate 810 or olive oil is used as the oil (preparation_1, 2, 5)
  • 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.
  • 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.
  • ER_1039 ER-1039-containing ⁇ ZW-type ME aqueous solutions and suspensions were each administered into the stomach using a rat probe for intragastric use.
  • the amount of the administered solution was set to 20 mgZkg based on the actually measured ER_1039 content obtained in 3. (1) above.
  • 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.
  • 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%.
  • 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.
  • the Cmax X AUC relative bioavailability
  • 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.
  • CP-060S fumarate (Lot No. V6 17 A30) was produced by Chugai Pharmaceutical Co., Ltd. by the method described in JP-A-10-287672.
  • 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.
  • 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.
  • 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 ⁇ s.
  • the formulation of the administration solution is the same as the formulation used in 3. (1) above.
  • 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.
  • 4 times volume of PBS (pH 6.8) was continuously administered.
  • 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 ⁇ l), and the Waters HP LC CP_600S was quantified using the system.
  • 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.
  • Mean S. D Mean S.D. Mean S.D.
  • Relative B.A. (3 ⁇ 4) 100 .39.94 115.40 31.79 115.45 28.31
  • 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.
  • ka 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.
  • 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.
  • Chloram feniconole Chloramphinicol, molecular weight 323.1, Lot No. 106H0971, Sigma
  • Disoviramide (Disopyramide, molecular weight 339.5, Lot No. 47H1400, Sigma)
  • Ketoprofen (Ketoprofen, molecular weight 254.3, LotNo. 126H1330, Sigma)
  • Tamoxifen (Tamo x ifen, molecular weight 371.5, Lot No. 28H 1033, Sigma)
  • Testosterone Teestostelone, molecular weight 288.4, Lot No. GE 01, Tokyo Chemical Industry
  • 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).
  • 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
  • BO-653 is an oily substance
  • 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.
  • 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)
  • PBS pH 6.8, 2.4 m1
  • O / W-type ME pre-composition containing drug 60 Omg
  • milk Rate the time required for the uniformity to be visually observed was measured and defined as the emulsification time.
  • n'ft--E00 DGMO-C HCO-40 Ketoprofe.n PBS (hr) Mean soil S. D. (ran) Chi-square Peak-1 (nm) Content (mg / ml)
  • composition of pre-composition (ff /) Emulsification time Gaussian particle size distribution NICOMP particle size distribution Chloramphenicol
  • the drug content was almost the same as the charge.
  • Example 4 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.
  • ME microemulsion
  • Example 1 Example 1
  • Other laboratory equipment, chemicals, etc. were used in Example 1 unless otherwise specified.
  • 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.
  • the drug is ground in an agate mortar, sieved (45-75 5 ⁇ ), 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.
  • 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).
  • a drug dose 1 OmgZkg (50 mgZkg for BO-653).
  • 4-fold volume of PBS (pH 6.8) was continuously administered.
  • Plasma was obtained by centrifugation for 3 minutes. Plasma (200 ⁇ l) 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).
  • 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
  • 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. ⁇ 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%.
  • OZW type microemulsions of the present invention were prepared using various oils, hydrophilic surfactants and lipophilic surfactants, and their physical properties were examined.
  • oils The following four types of oils, eight types of lipophilic surfactants and 18 types of hydrophilic surfactants were used.
  • HCO-5 polyoxyethylene (5) hydrogenated castor oil (HLB value: 6.0):
  • 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)
  • HCO-50 trade name (Polyoxyethylene (50) hydrogenated castor oil (HLB value: 13.5)): (Nikko Chemicals)
  • 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.
  • 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.
  • 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 average particle diameter of the obtained OZW-type ME was 150 nm or less in any combination.
  • 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 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.
  • 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.
  • 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.
  • 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.

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Abstract

L'invention concerne la préparation d'une micro-émulsion permettant à un médicament d'être plus efficacement utilisé d'un point de vue biologique. La préparation d'une micro-émulsion de type huile-eau comprend (1) un médicament peu soluble dans l'eau, (2) une huile, (3) un agent de surface hydrophile, (4) un agent de surface oléophile à HLB de 4,0 à 9,0, et (5) de l'eau.
PCT/JP2002/006568 2001-06-28 2002-06-28 Preparation d'une micro-emulsion de type huile-eau WO2003002095A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111034861A (zh) * 2020-02-10 2020-04-21 中国科学院兰州化学物理研究所盱眙凹土应用技术研发中心 一种利用月桂酸单甘油酯制备水包油乳液包被植物精油的方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63150221A (ja) * 1986-12-15 1988-06-22 Shiseido Co Ltd 結晶性薬物含有乳化組成物
WO1995024893A1 (fr) * 1994-03-16 1995-09-21 R.P. Scherer Limited Systemes d'administration s'appliquant a des medicaments hydrophobes
WO1997040823A1 (fr) * 1996-04-26 1997-11-06 R.P. Scherer Limited Preparation pharmaceutique orale contenant des hormones sexuelles
WO1999044584A1 (fr) * 1998-03-06 1999-09-10 Novartis Ag Preconcentres d'emulsion a base de cyclosporine ou d'un macrolide

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63150221A (ja) * 1986-12-15 1988-06-22 Shiseido Co Ltd 結晶性薬物含有乳化組成物
WO1995024893A1 (fr) * 1994-03-16 1995-09-21 R.P. Scherer Limited Systemes d'administration s'appliquant a des medicaments hydrophobes
WO1997040823A1 (fr) * 1996-04-26 1997-11-06 R.P. Scherer Limited Preparation pharmaceutique orale contenant des hormones sexuelles
WO1999044584A1 (fr) * 1998-03-06 1999-09-10 Novartis Ag Preconcentres d'emulsion a base de cyclosporine ou d'un macrolide

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111034861A (zh) * 2020-02-10 2020-04-21 中国科学院兰州化学物理研究所盱眙凹土应用技术研发中心 一种利用月桂酸单甘油酯制备水包油乳液包被植物精油的方法

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