WO2000002534A1 - Kit a preparer avant usage avec preparation contenant un medicament et solvant destine a cette fin - Google Patents

Kit a preparer avant usage avec preparation contenant un medicament et solvant destine a cette fin Download PDF

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Publication number
WO2000002534A1
WO2000002534A1 PCT/JP1999/003742 JP9903742W WO0002534A1 WO 2000002534 A1 WO2000002534 A1 WO 2000002534A1 JP 9903742 W JP9903742 W JP 9903742W WO 0002534 A1 WO0002534 A1 WO 0002534A1
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WO
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Prior art keywords
drug
preparation
kit
fat emulsion
drugs
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PCT/JP1999/003742
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English (en)
Japanese (ja)
Inventor
Takae Inoue
Hideto Kodaira
Koji Munechika
Takashi Imagawa
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Welfide Corporation
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Filing date
Publication date
Application filed by Welfide Corporation filed Critical Welfide Corporation
Priority to AU46508/99A priority Critical patent/AU4650899A/en
Publication of WO2000002534A1 publication Critical patent/WO2000002534A1/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

Definitions

  • the present invention relates to a kit for preparation of a drug-containing preparation having a drug and a fine particle preparation as constituents, and a dissolving agent thereof.
  • the kit for preparation of a drug-containing preparation at the time of use is in the form of an injection containing a combination of a drug and its dissolving agent.
  • Advantages include prevention of microbial contamination during preparation, prevention of errors (mixing mistakes) during co-injection preparation, quick response in emergency situations, and improved quality of treatment.
  • kits for use at the time of use As a dissolving agent for such a kit for use at the time of use, water for injection or physiological saline has already been put into practical use, but recently, as a dissolving agent for drugs, particularly poorly soluble drugs, fat is used. There are reports on kits for use at the time of use using emulsions.
  • WO Publication No. 89/022625 relates to a kit for the preparation of a drug-containing fat emulsion at the point of use.
  • the average particle size of fat particles in a fat emulsion is only described as 1 ⁇ m or less, and there is no description about visually confirming the presence or absence of insoluble foreign matter. No suggestion is given.
  • Doi Publication No. 412 5255 relates to a twin ampoule of prostaglandin and liposomal Z fat emulsion.
  • the specific disclosure is only liposomes, and there is no specific disclosure about fat emulsion.
  • it is difficult to visually recognize the insoluble foreign matter.
  • the acidic drug and / or the basic drug are stored separately from the fat emulsion, ribosome, etc., and by mixing them at the time of use, precipitation of the drug in the liquid can be suppressed. Kits for preparation before use have been reported.
  • the preparation obtained from the conventional kit for use at the time of use can suppress the generation of insoluble foreign substances or solve the problem of not generating them, but it is easy to confirm insoluble foreign substances.
  • the above-mentioned prior art does not suggest reducing the particle size of each dissolving agent used in order to visually check insoluble foreign matter. Confirmation of the presence or absence of insoluble foreign matter is necessary, especially when administering the drug as an injection.However, no kit has been developed so far to allow the insoluble foreign matter to be easily visually recognized. Powerful.
  • the dissolving agent is a fine particle preparation, insoluble foreign matter is not generated, and the presence or absence of insoluble foreign matter can be visually recognized. An attempt was made to develop a kit for preparation before use.
  • the present inventors have further studied in view of the above circumstances, and have attempted to develop a safe-to-use kit for use in which the dissolving agent is a fat emulsion and which is excellent in safety.
  • the present inventors have conducted intensive studies, and as a result, using a fine particle preparation having an average particle diameter of 100 nm or less as a dissolving agent, no insoluble foreign matter was generated, and the presence or absence of insoluble foreign matter was determined.
  • the present inventors have conducted intensive studies and, as a result, have developed an excellent kit for use at the time of use using a fat emulsion having an average particle diameter of 100 nm or less as a dissolving agent. .
  • the present invention relates to a kit which can be prepared at the time of use of a drug-containing preparation, which has a fine particle preparation having an average particle size of 100 nm or less as a drug and particles as a component.
  • the present invention relates to a drug dissolving agent comprising a fine particle preparation having an average particle diameter of 100 nm or less.
  • the present invention relates to a kit capable of preparing a drug-containing preparation at the time of use, which has a fat emulsion having an average particle diameter of a drug and fat particles of 1 O Onm or less as a component.
  • the present invention relates to a drug dissolving agent comprising a fat emulsion having an average particle diameter of fat particles of 100 nm or less.
  • the “fine particle preparation” in the present invention is a suspension in which fine particles are dispersed in water, and includes, for example, a fat emulsion and a liposomal preparation.
  • a ribosome preparation is a suspension in which ribosomes are dispersed in water.
  • the drug used in the present invention is not particularly limited as long as it has hydrophobicity, lipophilicity or lipophilicity, or has both of these properties and water solubility.
  • a wide range of drugs can be used.
  • prostaglandin E had E 2, F!
  • steroids antiinflammatory drugs diamethasone, palmitic Sande Kisamesazon, Hydrocortisone, prednisolone, betamethasone, triamcinolone, methylprednisolone, etc.
  • non-steroidal anti-inflammatory drugs indomethacin, acemetacin, flurbiprofen, aspirin, ibupu oral phen, flufenamic acid, ke Toprofen, piroxicam, phenylbutazone, etc.
  • anti-cancer drugs 5—fluorouracil, adriamycin, benzoylperrea compounds, daunomycin, bleomycin, mitomycin, etc.), vitamins (A, K, E, D, CoQi) ., etc.), radioactive isotopes (9 9 m T c, etc.), antibiotics (Sepharose Rosupori S, penicillin class, quino
  • Additives can be further added to the drug used in the present invention, if necessary.
  • Additives include those commonly used as drug additives, such as water, phospholipids, oils, surfactants, cyclodextrin, albumin, inorganic salts, and organic acids. Salts and the like are exemplified.
  • the form of the drug of the present invention is not particularly limited, and examples thereof include a powder and a liquid.
  • solubilizer in the present invention examples include a fine particle preparation having an average particle diameter of 100 nm or less, and the fine particle preparation is preferably a fat emulsion or a liposomal (lipid complex) preparation. Is mentioned.
  • the fat emulsion of the present invention contains an oil component, an emulsifier and an appropriate amount of water.
  • Examples of the oil component used in the present invention generally include vegetable oil, fish oil, and chemically synthesized triglycerides.
  • vegetable oils include soybean oil, olive oil, safflower oil, corn oil, sesame oil, cottonseed oil, peanut oil, castor oil, perilla oil, perilla oil, and the like.
  • soybean oil is used.
  • the soybean oil is preferably refined soybean oil, and more preferably, for example, refined soybean oil is high-purity refined soybean oil obtained by further refining by steam distillation (purity is exemplified by at least 99% as triglyceride. It is).
  • Examples of chemically synthesized triglycerides include medium-chain fatty acid triglyceride (MCT), structured triglyceride, long-chain fatty acid triglyceride (tripalmitin, trimyristin, etc.), and hard fat. It is.
  • the addition amount of the oil component is preferably 1 to 50% (wZv), more preferably 3 to 30% (wV) in the fat emulsion.
  • the emulsifier used in the present invention is not particularly limited as long as it can be added to pharmaceuticals, and includes known phospholipids, such as egg yolk phospholipid, soybean phospholipid, and hydrogenated products thereof. Purified phospholipids are used.
  • the purified phospholipid is mainly composed of phosphatidylcholine and phosphatidylethanolamine, and contains other phospholipids such as phosphatidylinositol, phosphatidylserine, sphingomyelin and the like.
  • purified phosphatidylethanolamine may be used from purified natural phospholipids.
  • Phospholipids such as egg yolk and soybean may be used.
  • purification is performed using an inorganic adsorbent such as silica gel or alumina.
  • the phospholipid thus obtained is mainly composed of phosphatidylcholine (Japanese Patent Application Laid-Open No. Sho 60-149524, which is disclosed in US Pat. No. 4,684,633 and EP-1507732-). Corresponding to A).
  • These phospholipids may be used alone or in combination of two or more.
  • the constituent fatty acids of the phospholipids may be either saturated or unsaturated.
  • the addition amount of the above phospholipid is 1 to 500 parts by weight, preferably 10 to 100 parts by weight, based on 100 parts by weight of the oil component.
  • it is preferably 1 to: I 0% (w / V).
  • a nonionic surfactant can be used in addition to the above phospholipid.
  • the nonionic surfactant include polyalkylene glycols (for example, polyethylene glycol having an average molecular weight of 1,000 to 10,000: preferably 10,000 to 6,000). Cole), polyoxyanolylene copolymer (for example, polyxylene-polyethylene having an average molecular weight of 1,000 to 200,000, preferably 2,000 to 10,000,000).
  • Oxypropylene copolymer hydrogenated castor oil polyoxyalkylene derivative [eg, hydrogenated castor oil polyoxyethylene mono (20) -ether, identical (40) -ether, identical (100)- Castor oil polyoxyalkylene derivative [eg, castor oil polyoxyethylene mono (20) -ether, same (40) -ether, same (100) -ether] and the like.
  • the amount of the nonionic surfactant added in the fat emulsion is preferably 5% (w / V) or less, more preferably 1% (w / V) or less. In addition, it is preferable that the above-mentioned nonionic surfactant is added in an amount of 0.1% (w / V) or more.
  • the phospholipid and the nonionic surfactant can each be used alone as an emulsifier in the fat emulsion of the present invention.
  • phospholipids are used. It is also possible to use both together,
  • a known emulsifying aid in this field can be added to the fat emulsion.
  • examples thereof include linear or branched aliphatic amines having 2 to 22 carbon atoms, such as primary amines and secondary amines, and pharmacologically acceptable salts thereof.
  • preferred examples include ethanolamine, propylamine, octylamine, stearylamine, oleylamine, linoleamine, and the like.
  • Examples of these pharmacologically acceptable salts include mineral salts (hydrochloride, hydrobromide, sulfate, sulfite, nitrate, phosphate, etc.), organic acid salts (acetate) , Lactate, succinate, maleate, fumarate, malate, tartrate, citrate, methanesulfonate, etc.).
  • the amount of the aliphatic amine is preferably not more than 1.0% (wZV), more preferably not more than 0.5% (w / V) in the fat emulsion.
  • fatty acid may be added as a pharmacologically acceptable salt such as emulsifying adjuvant pharmaceuticals
  • a pharmacologically acceptable salt such as emulsifying adjuvant pharmaceuticals
  • it may be linear or branched.
  • these salts include pharmacologically acceptable salts such as alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (potassium salts, magnesium salts, etc.).
  • the addition amount of these emulsifiers is preferably not more than 1.0% (w / V), more preferably not more than 0.5% (w / V) in the fat emulsion.
  • a stabilizer if necessary, a stabilizer, a polymer substance, a tonicity agent and the like can be added to the fat emulsion.
  • stabilizers examples include cholesterols, glycerin and fatty acid monomers thereof.
  • Monoesters eg, monopalmitin, monostearin, monoolein, monolinolein, etc.
  • saccharides such as monosaccharides (eg, glucose, fructose, etc.), disaccharides (eg, maltose, sucrose, etc.), sugar alcohols (eg, Sorbitol, xylitol, etc.), antioxidants (eg, tocopherols) and the like.
  • These stabilizers are not particularly limited as long as they can be used as pharmaceuticals.
  • the addition amount of these stabilizers is preferably 5% (w / V) or less, more preferably 1% (w / v) or less, in the fat emulsion.
  • polymer substance examples include albumin, a vinyl polymer (for example, polyvinyl pyrrolidone, polyvinyl alcohol, etc.), a nonionic surfactant, gelatin, and hydroxyxetyl starch.
  • albumin human-derived albumin is preferable due to the problem of antigenicity.
  • the amount of these high molecular substances to be added is preferably 5% (w / V) or less, more preferably 1% (wZV) or less, in the fat emulsion.
  • the tonicity agent examples include glycerin, monosaccharides (eg, glucose, fructose, etc.), disaccharides (eg, maltose, sucrose, etc.), sugar alcohols (eg, sorbitol, xylitol, etc.) , An electrolyte (eg, sodium chloride, etc.) and the like, and it is only necessary that the minimum amount required for isotonicity be added. Further, if necessary, a pH adjuster may be added to the fat emulsion.
  • monosaccharides eg, glucose, fructose, etc.
  • disaccharides eg, maltose, sucrose, etc.
  • sugar alcohols eg, sorbitol, xylitol, etc.
  • An electrolyte eg, sodium chloride, etc.
  • a pH adjuster may be added to the fat emulsion.
  • pH adjusters include sodium hydroxide, hydrochloric acid, various organic acids (eg, acetic acid, citric acid, phosphoric acid, lactic acid, etc.), various amines (eg, Tris, histidine, etc.), various buffers Liquids (eg, acetic acid-based, phosphate-based buffers, etc.) are exemplified.
  • the fat emulsion according to the present invention is produced by a known production method, for example, the following method. That is, a predetermined amount of an oil component (for example, soybean oil), phospholipids, and other additives described above are mixed as necessary, and the mixture is heated as necessary to obtain a conventional homogenizer (for example, a high-pressure injection homogenizer, A water-in-oil dispersion is prepared by homogenization using an ultrasonic homogenizer, etc.
  • a conventional homogenizer for example, a high-pressure injection homogenizer, A water-in-oil dispersion is prepared by homogenization using an ultrasonic homogenizer, etc.
  • the fat emulsion obtained above can be further refined.
  • Methods for making the particles in a fat emulsion finer are known. Specifically, a method of increasing the amount of an emulsifier (for example, a phospholipid) (WO Publication No. 91/07733, etc.), a method of emulsifying under high pressure (Japanese Patent Application Laid-Open No. JP-A-10-31017), etc., etc., and a particle preparation having an average particle diameter of 100 nm or less can be obtained by a method according to these methods.
  • an emulsifier for example, a phospholipid
  • Japanese Patent Application Laid-Open No. JP-A-10-31017 Japanese Patent Application Laid-Open No. JP-A-10-31017
  • a particle preparation having an average particle diameter of 100 nm or less can be obtained by a method according to these methods.
  • Examples of the ribosome (lipid complex) in the present invention include the following embodiments.
  • the lipids that are components of the ribosome include phospholipids, glycolipids, cholesterol, fatty acids, and derivatives thereof.
  • As the lipid for forming the ribosome any nontoxic lipid that is physiologically acceptable and can be metabolized can be used in the present invention.
  • phospholipids examples include phosphatidylcholine (PC), phosphatidylserine, phosphatidic acid, phosphatidylglycerol, phosphatidylinositol, sphingomyelin, dicetylphosphate, cardiolipin and lysophosphatidylcholine.
  • PC phosphatidylcholine
  • phosphatidylserine phosphatidic acid
  • phosphatidylglycerol phosphatidylinositol
  • sphingomyelin dicetylphosphate
  • cardiolipin cardiolipin
  • lysophosphatidylcholine can be extracted from natural materials such as soybean oil or egg yolk.
  • Purified or hydrogenated hydrogenated fatty acids to make up the constituent fatty acids hydroogenated phospholipids.
  • the constituent fatty acids may be replaced with specific fatty acids, for example, palmitic acid or myristic acid (diacylphosphatidy
  • Egg yolk lecithin, hydrogenated and purified soy lecithin, egg yolk-derived phosphatidylcholine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, distearylphosphatidylcholine, and dimyristylphosphatidylcholine are exemplified.
  • glycolipids examples include ceramide, celeb mouth side, sphingosine, salfatide, gangliosides, and dariceroglycolipids.
  • Fatty acids include, for example, oleic acid, lauric acid, myristic acid, palmitic acid and stearic acid.
  • the lipid derivative examples include phosphatidylethanolamine and a polyoxyethylene derivative of a fatty acid, and a polysaccharide derivative of a fatty acid and cholesterol.
  • lipids are used in the ribosome preparation in an amount of 1 to 30% (w / V), preferably 2 to 20% (w / V).
  • Ribosomes can be prepared, for example, by detergent removal, hydration, ultrasound, reversed-phase distillation, freeze-thaw, ethanol injection, extrusion (eXtrusion), and high-pressure emulsification. it can.
  • Gel filtration, dialysis, ultrafiltration and the like are generally used as surfactant removal methods.
  • an organic solvent for example, chloroform and ethanol
  • the organic solvent is removed to prepare a lipid thin film.
  • a liposome can be formed by adding a suitable aqueous solvent and shaking or stirring to the well-known method. The obtained liposomes can be further miniaturized.
  • the obtained ribosome is then washed, if necessary, with a physiologically acceptable aqueous solution, sterilized by filtration, and dispensed to prepare a liquid preparation, a pellet form and a suspension form.
  • Formulation is in accordance with known methods in the production of pharmaceuticals.
  • the above preparation is also provided as a lyophilized preparation by freezing a liquid preparation and then drying it under a reduced pressure.
  • monosaccharides eg, glucose, etc.
  • disaccharides eg, sucrose, etc.
  • At least one polymer selected from albumin, dextran, bur polymer, gelatin and hydroxyethyl starch may be blended as a stabilizer.
  • the stabilizing agent may be incorporated into the liposome together with the drug in the void, or may be added to the ribosome preparation containing the drug (that is, added to the liposome outside of the liposome). good record, even if the combined distribution to, c, of course, also the inside and outside of the ribosome.
  • the amount of the stabilizer to be added is 0.5 to 10 parts by weight, preferably 1 to 5 parts by weight, per 1 part by weight of lipid.
  • a pH adjuster and a tonicity adjusting agent may be added to the above-mentioned preparation, and the same as the pH adjuster and the tonicity adjusting agent may be added to the fat emulsion. Things.
  • the particles in the fine particle preparation of the present invention prepared as described above are extremely fine.
  • the average particle size of the particles in the microparticle formulation is less than 100 nm, and the smaller the average particle size, the lower the turbidity of the drug-containing formulation.From the viewpoint of ease of manufacture or cost, the average particle size is less than 10 nm. Preferably it is. It is preferable that 90% or more of the particles contained in the drug product have a particle size of 100 nm or less. If the average particle size exceeds 100 nm, the presence or absence of insoluble foreign substances in the drug-containing drug product is visually confirmed. It becomes difficult.
  • the particle size can be measured using an Autosizer-1c (trade name, manufactured by Malvern).
  • the fine particle preparation of the present invention can be adjusted to a physiologically acceptable pH using the above-mentioned pH adjusting agent, which is preferable since pain at an injection site can be reduced. For this reason, the solubility is reduced at physiological pH, and by applying the dissolving agent of the present invention to a drug that may generate a precipitate, the pH can be adjusted to the physiological pH without generating a precipitate. .
  • the drug and the fine particle preparation of the kit for use at the time of preparation of the present invention be housed in another chamber of a container having a plurality of chambers.
  • a container that removes the isolation means that isolates each of the chambers.
  • Specific examples of the container include a multi-chamber bag made of synthetic resin, a multi-chamber syringe, a drug vial integrated with a solution-filled bag, and the like.
  • the kit for use at the time of preparation according to the present invention has a form in which, when the microparticle preparation is a ribosome preparation, the drug, water, and lyophilized ribosome are stored in separate chambers of the above-described container having a plurality of chambers. May be used. In this case, first use
  • a synthetic resin double-chamber bag has at least a chamber for filling a particulate preparation and a chamber for filling a drug, and each chamber has a partition wall. It is a bag that can be removed when used and destroyed.
  • the synthetic resin include polyolefin, and in particular, polyethylene and polypropylene.
  • the multi-chamber syringe is disclosed in, for example, “Development of Pharmaceuticals, Vol. 9, Pharmaceutical Packaging and Containers (II), 378-389, 410-402, Published by Hirokawa Shoten”.
  • the integrated drug vial and solution-filled bag are described in, for example, “Continuing Drug Development, Volume 9, Pharmaceutical Packaging and Containers (II), 387-389, 411-1402. , Published by Hirokawa Shoten Co., Ltd., and has at least a bag for filling a fine particle preparation and a vial for filling a drug, each of which has a partition wall, and the partition wall is used.
  • remove by destruction, etc.Z Exclude, connect both chambers, transfer the fine particle formulation to the drug vial through the connector by bombing, dissolve the drug, and then return it to the bag as the drug solution by bombing again It is a container that can be used.
  • the compounding ratio of the drug and the solubilizer contained in the kit for use at the time of use in the present invention differs depending on the type of the drug and the type of the emulsifier. For example, with respect to 1 volume of the microparticle preparation prepared by the above method, if the drug is a steroid having anti-inflammatory activity, 0.01 to 10% by weight, and if the drug is a prostaglandin,
  • the drug and the fine particle preparation are simply mixed. That is, the drug may or may not be incorporated in the particulate formulation.
  • the drug-containing formulation can be prepared by shaking the drug and the microparticle formulation by hand for up to 30 seconds, or by using a vortex shaker for up to 10 seconds.
  • the drug-containing preparation according to the present invention is administered orally or parenterally.
  • parenteral administration it is preferable to administer intravenously, intraarterially, subcutaneously, intradermally, intramuscularly, topically, etc. by injection, continuous infusion and the like.
  • the dissolving agent of the present invention can be applied to various drugs that may cause insoluble foreign substances when prepared into a desired form, such as a poorly soluble drug or a drug whose solubility is reduced by physiological pH.
  • a drug-containing preparation can be prepared without generating insoluble foreign matter, and the presence or absence of insoluble foreign matter in the preparation can be visually recognized.
  • a 100 ml total amount of a fat emulsion was prepared by a conventional method, and the pH was adjusted to 6.5 to Adjusted to 8.5. Further, the particle size distribution was 10 to: 100 nm, and the average particle size was 60 nm.
  • Example 1 As a drug, 10 ⁇ g of prostaglandin E and 2 ml of the fat emulsion obtained in Example 1 were separately stored to obtain a kit for preparation before use. At the time of use, the two were mixed and shaken by hand for a maximum of 30 seconds to obtain a drug-containing preparation.
  • Example 1 50 mg of flurbiprofen axetil as a drug and 5 ml of the fat emulsion obtained in Example 1 were separately stored to obtain a kit for preparation at the time of use. At the time of use, both were mixed and shaken by hand for a maximum of 30 seconds to obtain a drug-containing preparation.
  • Example 1 In the kit for fresh preparation obtained in Example 1, the drug and the fat emulsion were mixed and shaken by hand for a maximum of 30 seconds to obtain a drug-containing preparation.
  • the pH of this formulation was 6.5 to 8.5, and macroscopic observation showed no precipitation of the drug. Further, when observed with the naked eye two hours later, no insoluble foreign matter was found.
  • the mixture was heated and dissolved, and stirred with a homomixer to obtain a coarse emulsion. Furthermore, after emulsifying under high pressure using a manton-gaurin homogenizer, the pH of the resulting solution was adjusted to 6.5 to 8.5 to prepare a total of 100 ml of fat emulsion. did.
  • the particle size of the fat emulsion was measured with an automatic sizer 2c (trade name, manufactured by Malvern). As a result, the particle size distribution was 10 to 100 nm, and the average particle size was 60 nm. .
  • Dexamethasone palmitate 4 mg as a drug and fat emulsion l ml after pH adjustment can be peeled off using a multilayered polyethylene sheet
  • Mr. Replacement (Rule 26) They were stored in separate chambers of a plastic container consisting of two chambers separated by a suitable adhesive, and a kit for preparation of a drug-containing preparation at the time of use was obtained. At the time of use, the adhesive part separating the two chambers was peeled off and shaken by hand for a maximum of 30 seconds to obtain a drug-containing preparation.
  • Example 5
  • a drug-containing preparation was obtained in the same manner as in Example 4, except that the drug was 10 ⁇ g of prostaglandin and 2 ml of the fat emulsion was blended.
  • a drug-containing preparation was obtained in the same manner as in Example 4, except that the drug was flurbiprofen axetil 5 O mg and the fat emulsion was mixed with 5 m 1.
  • Example 4 As a result of visually observing the drug-containing preparation obtained in Example 4, no precipitation of the drug was observed. After the preparation was prepared, it was allowed to stand at room temperature for 3 hours, and was visually observed again. As a result, no insoluble foreign matter was found. This confirmed that the stability of the preparation prepared with the kit of the present invention was high.
  • the absorbance of the fat emulsion immediately after preparation was measured at a wavelength of 62 nm, and was found to be 0.332.
  • the particle size of the fat emulsion was measured using an Autosizer-1c (trade name, manufactured by Malvern). The particle size distribution was 10 to 100 nm, and the average particle size was about
  • the drugs in each Example are as shown in Table 1, and the drugs and fat emulsions of the compounding amounts shown in Table 1 were separately prepared from the kit having the same form as the kit used in Example 4. By storing in the room, a kit for preparation of a drug-containing preparation was obtained.
  • the drugs in Table 1 were formulated in the following solution form.
  • Furosemide solution (trade name: Lasix Injection, Hextomaryon Roussel, 100 mg / 1 Oml solution)
  • Thiamyl sodium solution (trade name: Isozol, manufactured by Yoshitomi Pharmaceutical, 0.5 g dissolved in 20 ml of water for injection)
  • Amrinone solution (trade name: Cartonic injection, manufactured by Yamanouchi Pharmaceutical, 100 mg 20 ml solution)
  • the adhesive part separating the two chambers of each kit obtained in Examples 7 to 9 was peeled off and shaken by hand for a maximum of 30 seconds to obtain a drug-containing preparation. After the preparations were prepared, they were left at room temperature for 3 hours and visually observed. As a result, no precipitate was found to be formed in any of the preparations. Further, the absorbance at a wavelength of 62 nm before and after passing through a filter having a pore size of 0.22 // m was measured for the preparation after standing. Table 2 shows the measured results. From the results obtained, no difference was observed in the absorbance before and after passing through the filter.
  • the absorbance of the formulation immediately after preparation was measured at a wavelength of 62 nm, and was found to be 0.059.
  • the particle size of the ribosome preparation was measured using an Autosizer-1c (trade name, manufactured by Malvern). As a result, the particle size distribution was 10 to 100 nm, and the average particle size was about 40 nm. .
  • the drugs in each example are as shown in Table 3, and the drugs and liposomal preparations having the compounding amounts shown in Table 3 were prepared in the same form as the kit used in Example 4. Thus, a kit for preparation of a drug-containing preparation at the time of use was obtained by storing in a separate room.
  • the drugs in Table 3 were formulated in the following solution form.
  • Potassium potassium canrenoate aqueous solution for injection (trade name: Soldactone Injection, manufactured by SAL Pharmaceuticals, 100 mg dissolved in 10 ml of water for injection)
  • Aqueous solution of thiamir sodium for injection (trade name: Isosol, manufactured by Yoshitomi Pharmaceutical, 0.5 g dissolved in 20 ml of water for injection)
  • Dipyridamole solution (trade name: Persantin, manufactured by Nippon Behringer Ingelheim, 10 mg Z 2 ml solution)
  • the adhesive part serving as two chambers of each kit obtained in Examples 10 to 14 was peeled off, and the mixture was shaken by hand for a maximum of 30 seconds to obtain a drug-containing preparation. After the preparations were prepared, they were left at room temperature for 3 hours and visually observed. As a result, no precipitate was found to be formed in any of the preparations. Further, the absorbance at a wavelength of 62 nm before and after passing through a filter having a pore size of 0.22 ⁇ m was measured for the preparation after standing. Table 4 shows the measurement results. From the results obtained, no difference was observed in the absorbance before and after passing through the filter.
  • the drug-containing preparation prepared from the kit of the present invention does not generate insoluble foreign substances, and thus can be administered more safely by injection or the like. Furthermore, the drug-containing preparation of the present invention has low turbidity and excellent visibility, and the presence or absence of insoluble foreign matter can be easily confirmed. Therefore, the present invention can provide a drug-containing preparation with excellent safety.
  • the preparation using the dissolving agent of the present invention is stable, does not generate insoluble foreign matter in the preparation, has low turbidity, and has excellent visibility, and thus has excellent safety.
  • the kit of the present invention stores the drug and the fine particle preparation (eg, fat emulsion, ribosome, etc.) in isolation until preparation before use, it is difficult to formulate a drug or a fine particle preparation having low stability with the conventional fine particle preparation. It is also applicable to drugs.
  • the drug can be administered at a physiological pH by adjusting the fine particle preparation to a physiological pH. This can reduce pain at the injection site.
  • the use of the lysing agent of the present invention adjusted to physiological pH allows the solubility to be adjusted at physiological pH.
  • this product can be easily prepared in a short time when needed, and can be used in combination with a container that can be dispensed immediately after preparation, making it extremely easy to use.
  • This application is based on Japanese Patent Application No. 195404 filed in Japan, the contents of which are incorporated in full herein.

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  • Medicinal Preparation (AREA)

Abstract

L'invention concerne un kit à préparer avant usage avec une préparation contenant un médicament. Il est constitué d'un médicament et d'une préparation finement granulaire possédant une granularité moyenne inférieure ou égale à 100 nm. A l'intérieur du kit préparé avant utilisation il ne se forme pas de corps étrangers insolubles, la présence de tout corps étranger insoluble pouvant être détectée à l'oeil nu. Cela permet d'atteindre un niveau de sécurité élevé grâce à un solvant pour médicaments comprenant une préparation finement granulaire possédant une granularité moyenne inférieure ou égale à 100 nm. La préparation contenant des médicaments et préparée au moyen du kit ci-décrit peut être appliquée de manière sure aux injections et similaires car aucun corps étranger ne se forme dans cette préparation. En outre, la préparation contenant des médicaments possède une faible turbidité, la présence de tout corps étranger insoluble pouvant être détectée à l'oeil nu, ce qui permet une meilleure stabilité. Le solvant et le kit sont applicables aux médicaments qui ne manifestent qu'une faible stabilité au stockage dans des préparations finement granulaires et à ceux qui ne peuvent être que difficilement transformés en préparations finement granulaires. En outre, ces médicaments peuvent être administrés à leur valeur pH physiologique.
PCT/JP1999/003742 1998-07-10 1999-07-09 Kit a preparer avant usage avec preparation contenant un medicament et solvant destine a cette fin WO2000002534A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU46508/99A AU4650899A (en) 1998-07-10 1999-07-09 Kit of drug-containing preparation to be prepared before using and resolvent therefor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP19540498 1998-07-10
JP10/195404 1998-07-10

Publications (1)

Publication Number Publication Date
WO2000002534A1 true WO2000002534A1 (fr) 2000-01-20

Family

ID=16340557

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/003742 WO2000002534A1 (fr) 1998-07-10 1999-07-09 Kit a preparer avant usage avec preparation contenant un medicament et solvant destine a cette fin

Country Status (2)

Country Link
AU (1) AU4650899A (fr)
WO (1) WO2000002534A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002532535A (ja) * 1998-12-22 2002-10-02 アメリカ合衆国 水不溶性薬剤送達システム
JP2010013461A (ja) * 2001-03-27 2010-01-21 Phares Pharmaceutical Research Nv 低い水溶性を有する生物学的に活性な化合物を可溶化するための方法および組成物
JP2010270023A (ja) * 2009-05-20 2010-12-02 Techno Guard Kk 薬物を保持した脂肪粒子を含む非水系組成物およびその製造方法
JP2013544367A (ja) * 2010-12-06 2013-12-12 ラモット アット テル−アビブ ユニバーシティー リミテッド 薬物検出のための方法およびキット

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01249716A (ja) * 1988-03-29 1989-10-05 Taisho Pharmaceut Co Ltd 微粒子脂肪乳剤

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH01249716A (ja) * 1988-03-29 1989-10-05 Taisho Pharmaceut Co Ltd 微粒子脂肪乳剤

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002532535A (ja) * 1998-12-22 2002-10-02 アメリカ合衆国 水不溶性薬剤送達システム
JP2010013461A (ja) * 2001-03-27 2010-01-21 Phares Pharmaceutical Research Nv 低い水溶性を有する生物学的に活性な化合物を可溶化するための方法および組成物
JP2010270023A (ja) * 2009-05-20 2010-12-02 Techno Guard Kk 薬物を保持した脂肪粒子を含む非水系組成物およびその製造方法
JP2013544367A (ja) * 2010-12-06 2013-12-12 ラモット アット テル−アビブ ユニバーシティー リミテッド 薬物検出のための方法およびキット

Also Published As

Publication number Publication date
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