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WO1999063968A1 - Preparations aqueuses contenant des medicaments faiblement solubles - Google Patents

Preparations aqueuses contenant des medicaments faiblement solubles Download PDF

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Publication number
WO1999063968A1
WO1999063968A1 PCT/JP1999/003107 JP9903107W WO9963968A1 WO 1999063968 A1 WO1999063968 A1 WO 1999063968A1 JP 9903107 W JP9903107 W JP 9903107W WO 9963968 A1 WO9963968 A1 WO 9963968A1
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WO
WIPO (PCT)
Prior art keywords
aqueous
added
preparation
present
dpy
Prior art date
Application number
PCT/JP1999/003107
Other languages
English (en)
Japanese (ja)
Inventor
Hidekazu Suzuki
Hiroyuki Ogawa
Koji Ueno
Masanobu Takeuchi
Original Assignee
Wakamoto Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wakamoto Pharmaceutical Co., Ltd. filed Critical Wakamoto Pharmaceutical Co., Ltd.
Priority to AU40615/99A priority Critical patent/AU4061599A/en
Publication of WO1999063968A1 publication Critical patent/WO1999063968A1/fr

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Classifications

    • 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
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

  • a preparation comprising a poorly soluble drug dissolved in water with polysorbate and / or polyoxyethylene hydrogenated castor oil and methylcellulose and / or hydroxypropylmethylcellulose.
  • the poorly soluble drug is at least one selected from the group consisting of an antifungal agent, a synthetic antibacterial agent, an anti-herpesvirus agent, an antiplatelet agent, an i-blocker, and a carbonic anhydrase inhibitor.
  • the poorly soluble drug is at least one selected from the group consisting of dipyridamole, acyclovir, prazosin hydrochloride, acetazolamide, metazolamide, norfloxacin, ofloxacin, lomefloxacin hydrochloride, econazol nitrate, and miconazole nitrate.
  • the pork mouth building is prepared under an aqueous solution containing polysorbate and / or polyoxyethylene castor oil and methylcellulose and / or hydroxypropylmethylcellulose and adjusted to pH 3 or less or PH 10 or more.
  • a method for preparing an aqueous formulation of acyclovir wherein the pH is adjusted to 5.5 to 8 by adding an acid or a basic component after dissolution.
  • At least one sparingly soluble drug selected from the group consisting of norfloxacin, ofloxacin, lomefloxacin hydrochloride, econazole nitrate, and miconazole nitrate is added to polysorbate and / or polyoxyethylene hydrogenated castor oil and polyethylene.
  • a method for preparing an aqueous preparation containing a poorly soluble drug by dissolving in a mixture comprising glycol and then adding water to form an aqueous preparation.
  • a solubilizer consisting of a surfactant and a water-soluble polymer for dissolving poorly soluble drugs in water.
  • the solubilizing agent according to claim 10 comprising polysorbate and / or polyoxetylene hydrogenated castor oil for dissolving a poorly soluble drug in water, and methylcellulose and / or hydroxypropylmethylcellulose.
  • the soluble according to claim 10 or 11 comprising polysorbate and / or polyoxyethylene hardened castor oil and / or methylcellulose and / or hydroxypropylmethylcellulose and polyethylene glycol for dissolving the poorly soluble drug in water.
  • Agent. Description Aqueous formulation containing poorly soluble drug
  • the present invention relates to aqueous formulations of poorly soluble drugs. More specifically, the present invention relates to a mixture of polysorbate and / or polyoxyethylene hydrogenated castor oil and methylcellulose and / or hydroxypropylmethylcellulose, more preferably polyethylene glycol (hereinafter abbreviated as PEG), and is represented by diviridamol.
  • PEG polyethylene glycol
  • the present invention relates to an aqueous preparation dissolved in water at a preferable pH region when a soluble drug is administered to a living body. Furthermore, by mixing citric acid or a pharmaceutically acceptable salt thereof with the above-mentioned composition containing PEG, a poorly soluble drug is solubilized and administered to mammals as a liquid that can flow at room temperature or lower.
  • the present invention relates to a reversible thermogelling aqueous preparation containing a hardly soluble drug, which has a property of gelling at the body temperature of a mammal, thereby increasing the bioavailability of the hardly soluble drug and maintaining the efficacy over a long period of time.
  • Dipyridamole is currently marketed internally and as an injection for the treatment of angina pectoris, myocardial infarction, ischemic heart disease and depressive heart disease. It is also known that a strong intraocular pressure-reducing effect can be obtained when an aqueous solution of dipyridamole is instilled (Japanese Patent Laid-Open No. 7-258804), and eye drops of dipyridamole are expected to be a new therapeutic agent for glaucoma. Have been.
  • the pH of eye drops is preferably 5 to 8, more preferably 6 to 8 from the viewpoint of irritation to the eyes (Japanese Patent Application Laid-Open No. Hei 7-258804 and Japan). Pharmacopoeia 13). Also, as an injection, the pH is much higher than neutral from the aspect of irritation. It is said that it is desirable not to come apart (Japanese Pharmacopoeia No. 13).
  • Acyclovir an effective drug for the treatment of infectious diseases caused by simple herpes virus, varicella and shingles virus, is also poorly soluble in water, and its solubility in water is particularly low near neutrality.
  • drug crystals precipitate in a short period of time even when used as an aqueous preparation. Therefore, it is very difficult to dissolve the ash mouth building in water near neutrality to prepare an aqueous solution formulation that can be stored for a long time.
  • Japanese Patent Application Laid-Open No. Hei 8-2686882 uses polyvinylpyrrolidone as a solubilizing agent.
  • U.S. Pat. No. 5,472,954 discloses a method for complexing with a cyclodextrin derivative.
  • the safety of cyclodextrin derivatives has not been established yet, and it has not been put to practical use.
  • aqueous pharmaceutical composition that efficiently releases a pharmaceutically active ingredient to a mammal in need of treatment
  • a number of aqueous pharmaceutical compositions that are liquid at room temperature or below and are semi-solid or gel at the body temperature of the mammal are disclosed.
  • U.S. Pat. No. 4,188,373 teaches that an aqueous composition of pull mouth nick (PLURONI C) gels by heat, and the desired sol-gel transition temperature can be obtained by adjusting the concentration of the pull mouth nick.
  • PLURONI C pull mouth nick
  • 4,474,751, 4,474,753 and 4,478,822 describe a drug release system using a thermogelled aqueous pharmaceutical composition.
  • a feature of these systems is that the sol-gel phase transition temperature and Z or gel hardness can be changed by adjusting the pH and / or ion concentration and the polymer concentration. More recently, an aqueous pharmaceutical composition that gels locally by simultaneous change of pH change and temperature rise (patent WO 91/19481) has been proposed.
  • the gelled substance used in the above aqueous composition has not yet been established for safety at all sites requiring treatment, and the concentration of the polymer in the aqueous composition is high.
  • the viscosity in the condition is high, and it is difficult to use depending on the part requiring treatment (for example, eyes).
  • An object of the present invention is to provide a formulation in which a poorly soluble drug represented by diviridamol is dissolved in water near neutrality, and a method for preparing the same.
  • Example 1 As shown in Example 1 described below, the present inventors have found that poorly soluble drugs represented by dipyridamole include polysorbate and / or polyoxetylene hardened castor oil, methylcellulose and / or hydroxypropylmethyl. The present inventors have discovered that the addition of cellulose can provide a synergistic solubilizing effect that cannot be obtained by adding each alone, and completed the present invention.
  • the present invention is a preparation prepared by dissolving a poorly soluble drug in water using polysorbate and / or polyoxyethylene hydrogenated castor oil and methylcellulose and / or hydroxypropylmethylcellulose.
  • the aqueous preparation of the present invention has excellent storage stability, and is prepared in a pH range that is preferable for administration to a living body, and therefore has low irritation during administration.
  • the poorly soluble drug is dissolved in water, so there is no foreign body sensation at the time of administration, variation in the dosage, deposition of the suspension in the container, etc., which are problems with the suspension formulation .
  • it is a liquid that can flow at or below room temperature and, when administered to mammals, gels at the body temperature of the mammal, thereby increasing the bioavailability of poorly soluble drugs and extending it over time. The medicinal effect lasts.
  • the present invention further provides dipyridamole in an aqueous solution containing polysorbate and / or polyoxetylene castor oil, methylcellulose and / or hydroxypropylmethylcellulose, and adjusted to pH 4 or less. After dissolution, a basic component is added to adjust the pH to 5 to 8 to prepare an aqueous preparation of dipyridamole; polysorbate and / or polyoxyethylene hydrogenated castor oil and methylcellulose and / or hydroxypropylmethylcellulose are added.
  • a method for preparing an aqueous preparation of Bil comprising norfloxacin, ofloxacin, lomefloxacin hydrochloride, econazole nitrate and miconazole nitrate At least one poorly soluble drug selected from the group is dissolved in a mixture of polysorbate and / or polyoxetylene hardened castor oil and polyethylene glycol, and then water is added thereto to form an aqueous formulation; It is intended to provide a method for preparing a water-containing preparation.
  • the present invention further provides a surfactant and a water-soluble polymer for dissolving a poorly soluble drug in water.
  • the poorly soluble drug used in the present invention refers to a drug which is expected to have usefulness in efficacy, but has a limited use because it is hardly soluble in water at around neutrality.
  • drugs include, for example, antifungal agents, for example, fluconazole, clotrimazole, isoconazole nitrate, econazole nitrate, miconazole nitrate, bifonazole, etc., synthetic antibacterial agents, for example, ofloxacin, sivroff hydrochloride Loxacin, tosfloxacin tosylate, norfloxacin, lomefloxacin hydrochloride, pazfloxacin, etc., anti-herpes virus agents such as acyclovir, ganciclovir, idoxperidine, vidarabine, etc., antiplatelet agents such as dipyridamole, syrosylzol H-blockers, for example, brazosin hydrochloride, bunazo
  • polysorbates 40, 60, 65, and 80 also known as Tweens 40, 60, 65, and 80. Available at Its outline, standards, uses, amounts used, and trade names are described in detail in the Pharmaceutical Excipients Dictionary (edited by the Japan Pharmaceutical Excipients Association, published by Pharmaceutical Daily).
  • polyoxyethylene hydrogenated castor oil used in the present invention examples include, for example, polyoxyethylene hydrogenated castor oils 10, 40, 50, and 60 (also known as polyoxyethylene glycerin trioxystearic acid 10, 50, 50). And 60) are readily available. Its outline, standards, uses, amounts used, and trade names are described in detail in the Pharmaceutical Excipients Dictionary (edited by the Japan Pharmaceutical Excipients Association, published by Yakuji Nippo).
  • polysorbate or polyoxyethylene castor oil are used alone or as a mixture thereof.
  • Methyl cellulose (hereinafter abbreviated as MC) used in the present invention may be any MC alone or as a mixture as long as the viscosity of the 2% aqueous solution at 20 ° C. is in the range of 13 to 12000 mPa ⁇ s. Can be used.
  • the content of the methoxyl group is preferably in the range of 26 to 33% from the viewpoint of solubility in water.
  • MC is distinguished by the viscosity of its aqueous solution.For example, commercially available varieties have the indicated viscosities of 15, 25, 100, 400, 1500, and 8000 (the figures are millipascals at 20 ° C viscosity of a 2% aqueous solution). Seconds) and are readily available. Its outline, standards, uses, amounts used, and trade names are described in detail in the Pharmaceutical Excipients Dictionary (edited by the Japan Pharmaceutical Excipients Association, published by Yakuji Nippo).
  • HPMC Hydroxypropyl methylcellulose
  • the HPMC used in the present invention preferably has a display viscosity of 10,000 or less from the viewpoint of handling.
  • the outline, standards, uses, amounts used, and trade names of HPMC are described in detail in the Pharmaceutical Excipients Dictionary (edited by the Japan Pharmaceutical Excipients Association, published by Yakuji Nippo).
  • the PEG used in the present invention includes PEG-200, PEG-300, PEG-600, PEG-1000, PEG-1540, PEG-2000, PEG-14000, PEG-6000, PEG-20000, PEG-50000, P EG-500,000, PEG-2000000 and PEG-400000
  • the weight average molecular weight of PEG used in the present invention is preferably from 300 to 50,000, particularly preferably from 1,000 to 20,000.
  • the weight average molecular weight is 300 or more, gelation due to body temperature occurs, and when the weight average molecular weight is 50,000 or less, the viscosity in a liquid state is not excessively high, and thus it is preferable. It is also possible to adjust the weight average molecular weight within the above-mentioned optimum range by mixing two or more kinds of PEG.
  • the pharmaceutically acceptable salts of citric acid used in the present invention include sodium salts and potassium salts.
  • the aqueous preparation containing a poorly soluble drug of the present invention contains a poorly soluble drug, polysorbate and Z or polyoxyethylene hydrogenated castor oil, MC and / or HPMC, preferably further contains PEG, more preferably PEG and quinone. Contains acids or salts thereof.
  • the use concentration of polysorbate and / or polyoxyethylene hydrogenated castor oil is preferably 0.01 to 2 W / V%.
  • a concentration of 2 W / V% or less is preferable because it has few side effects such as eye irritation and corneal damage, and a concentration of 0.01 W / V% is necessary for dissolving the amount of a poorly soluble drug necessary for obtaining a medicinal effect. It is preferable that this is the case.
  • the working concentration of MC and / or HPMC is preferably 0.01 to 4 W / V%.
  • a concentration of 4 W / V% or less is preferable because the viscosity of the aqueous preparation can be adjusted to a range that is easy to handle, and a concentration of 0.01 W is necessary for dissolving the amount of poorly soluble drug necessary for obtaining the efficacy. It is preferably at least / V%.
  • the concentration of MC used in an aqueous preparation is preferably 0.2 to 2 W / V%.
  • a concentration of MC of 2 W / V% or less is preferable because the viscosity can be adjusted to an easily manageable range, and a concentration of MC of 0.2 W / V% or more is preferable because gelation due to body temperature is likely to occur. .
  • the working concentration of PEG is preferably 0.1 to 13 W / V%.
  • concentration of PEG is 13 W / V% or less, it is preferable because the viscosity of the aqueous preparation is in a manageable range, and if it is 0.1 W / V% or more, it depends on body temperature. This is preferable because gelation is likely to occur.
  • the use concentration of citric acid or a salt thereof in the reversible thermogelling aqueous preparation is preferably 0.1 to 2.3 W / V%, more preferably 1 to 2.3 W / V%.
  • concentration of citric acid or a salt thereof is 2.3 W / V% or less, it is preferable because the eye irritation is small especially when administered to the eye as an eye drop, and when it is 0.1 WZV% or more, gelation due to body temperature may occur. It is preferable because it easily occurs.
  • the concentration of the poorly soluble drug is not particularly limited as long as the desired drug effect can be obtained and it can be prepared as an aqueous preparation.
  • the concentration of diviridamol is preferably from 0.001 to 0.05 W / V%, more preferably from 0.005 to 0.05 W / V%.
  • a DPY concentration of 0.05 W / V% or less is preferred because DPY is completely dissolved in water, and when administered as an eye drop to the eye, side effects such as conjunctival hyperemia are small. Is preferably 0.001 W / V% or more because sufficient drug efficacy can be expected.
  • the concentration of a synthetic antibacterial agent such as norfloxacin, ofloxacin, or lomefloxacin hydrochloride is preferably 0.01 to: LW / V%.
  • a concentration of 1 W / V% or less is preferable because the drug is completely dissolved in water, and a concentration of 0.01 W / V% or more is preferable because sufficient drug efficacy can be expected.
  • the concentration of antifungal agents such as econazole nitrate, miconazole nitrate is preferably
  • a concentration of 0.2 W / V% or less is preferable because the drug is completely dissolved in water, and a concentration of 0.01 W / V% or more is preferable because sufficient drug efficacy can be expected.
  • the gelation temperature of the reversible thermogelling aqueous preparation containing a poorly soluble drug should be about 20 to about 40 ° C because it is liquid at room temperature or below and it is desirable to gel at the body temperature of mammals. Is preferred.
  • the aqueous preparation of the present invention is preferably adjusted to have a pH of 5 to 8 in terms of irritation.
  • the pH is preferably 5 to 7 and more preferably 5 to 6 in the case of an aqueous preparation from the viewpoint of the stability of the DPY solution. From the viewpoint of gelling due to sex and body temperature, pH 5 to 8 is preferable, and pH 6 to 7.5 is more preferable.
  • the pH is preferably 5.5 to 8.
  • Various pH modifiers are used to adjust the pH of the aqueous formulations of the present invention.
  • the acids include organic acids such as ascorbic acid, gluconic acid, acetic acid, lactic acid, and citric acid, and inorganic acids such as hydrochloric acid, boric acid, phosphoric acid, and sulfuric acid.
  • the bases include potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, monoethanolamine, diethanolamine, triethanolamine, and the like.
  • Other pH adjusters include glycine, histidine, amino acids such as epsilon aminocaproic acid, and the like.
  • aqueous preparation of the present invention In preparing the aqueous preparation of the present invention, pharmaceutically acceptable isotonic agents, preservatives, preservatives, and the like are added to the aqueous preparation of the present invention as needed, as long as the effects of the present invention are not impaired. can do.
  • tonicity agent examples include saccharides such as xylitol, mannitol and budou sugar, propylene glycol, glycerin, sodium chloride, potassium salt and the like.
  • reversible stones such as penzalconium chloride, benzethonium chloride and chlorhexidine gluconate, parabens such as methyl parahydroxybenzoate, propyl parahydroxybenzoate and butyl parahydroxybenzoate, and Alcohols such as ethanol, phenylethyl alcohol and benzyl alcohol, organic acids such as sodium dehydroacetate, sorbic acid and sorbic acid potassium and their salts can be used.
  • thickeners such as hydroxyethyl cellulose, polyvinyl virolidone, polyvinyl alcohol, propylene glycol, diethylene glycol or sodium polyacrylate, EDTA (ethylenediaminetetraacetic acid) and pharmaceutically acceptable salts thereof.
  • EDTA ethylenediaminetetraacetic acid
  • tolerable salts tocopherol and derivatives thereof, and sodium sulphite.
  • the aqueous preparation of the present invention can be sterilized by filtration sterilization using a membrane filter, intermittent sterilization, or the like.
  • the aqueous preparation of the present invention can be filled in a plastic eye dropper and used as an eye drop. To preserve this for a long time, it may be packaged in a polyethylene film and aluminum foil laminated bag together with an oxygen scavenger (eg, Ageless®, Mitsubishi Gas Chemical Co., Ltd.).
  • an oxygen scavenger eg, Ageless®, Mitsubishi Gas Chemical Co., Ltd.
  • the aqueous preparation of the present invention can be filled in a plastic drop bottle and used as an eardrop. In order to preserve this for a long period of time, it may be packaged together with a deoxidizer (eg, Ageless®, Mitsubishi Gas Chemical Co., Ltd.) in a laminated bag of polyethylene film and aluminum foil.
  • a deoxidizer eg, Ageless®, Mitsubishi Gas Chemical Co., Ltd.
  • the aqueous preparation of the present invention can be filled as a nasal spray and used as a nasal drop. In order to preserve this for a long period of time, it may be packaged in a polyethylene film and aluminum foil laminated bag together with an oxygen scavenger (eg, Ageless®, Mitsubishi Gas Chemical Co., Ltd.).
  • an oxygen scavenger eg, Ageless®, Mitsubishi Gas Chemical Co., Ltd.
  • the aqueous formulation of the present invention is filled into an ampoule and sealed, and then injected (intravenous injection, intraarterial injection, subcutaneous injection, intradermal injection, intramuscular injection, intrathecal injection, intraperitoneal injection, intraocular injection, etc.). Etc.), oral liquid, inhalant and spray. Depending on the usage, it is used by filling it into a plastic drug bottle for internal liquids, an electric nebulizer for inhalants, and an atomizer for sprays.
  • a method for producing the aqueous preparation of the present invention will be described.
  • DPY as an aqueous preparation
  • acyclovir in order to prepare acyclovir as an aqueous preparation, it is preferable to dissolve acyclovir in an aqueous solution having a pH of 3 or less or 10 or more, and then adjust the pH to a predetermined value by adding a basic component or an acidic component.
  • D P Y D P Y
  • polysorbate and / or polyoxyethylene hydrogenated castor oil are added to sterile purified water and dispersed.
  • An acid is added to the solution to adjust the pH to 3 or less, and all the added components are dissolved.
  • the pH is adjusted to a predetermined value by adding a base, and the volume is adjusted to a predetermined volume with sterilized purified water.
  • various additives such as buffers, tonicity agents, preservatives, and stabilizers can be added.
  • DPY is added to a mixture of polysorbate and / or polyoxyethylene hydrogenated castor oil and PEG, and after mixing, sterile purified water is added. Mix well. Add MC to sterile purified water
  • these prepared aqueous DPY eye drops can be filled into a plastic eye drop bottle after heat sterilization such as filtration sterilization or low-temperature intermittent sterilization.
  • polysorbate 80 Reodol (registered trademark) TW-0120, Kao Corporation, hereinafter abbreviated as Tween-80
  • 3 OmL of sterilized purified water or polyoxyethylene cured in 3 OmL Castor oil 60 Nakkor (registered
  • a comparative DP Y aqueous preparation (Formulation Nos. 7 to 10) containing either SM-15 or 60 SH50 and without adding Tween-80 or HC ⁇ -60 was prepared by the same method. did. Furthermore, a comparative DP Y aqueous preparation containing either Tween-80 or HCO-60 and not adding either SM-15 or 60 SH 50 to the aqueous DP Y preparation of the present invention (formulations Ntxl 1 to 14 ) was prepared in a similar manner. In addition, two kinds of DPY aqueous preparations for comparison were prepared with a DPY concentration of 0.01 and 0.025 W / V%.
  • Table 1 shows the results of observation of the appearance of the prepared DPY aqueous formulation up to 24 hours (storage at 25 ° C) after preparation.
  • the DPY aqueous preparation (formulation # ⁇ 1-4) of the present invention which contains polysorbate or polyoxyethylene-hardened castor oil and MC or HPMC, is prepared using either polysorbate or polyoxyethylene hardened castor oil, or MC or HPMC.
  • the solubility of DPY in water is higher than that of the comparative D-II preparation containing either one of them, even though the DPY concentration is more than 2 times higher than that of the aqueous preparation (Formulation ⁇ 7, 9, 11, 13). ,It is shown that. This indicates that the combination of polysorbate and / or polyoxyethylene hydrogenated castor oil with MC and / or HPMC synergistically improves the solubility of poorly soluble drugs in water.
  • polyethylene glycol 400 (PEG400, manufactured by Wako Pure Chemical Industries, Ltd.) and polyvinyl alcohol were used for the aqueous DPY preparation of the present invention.
  • Table 1 shows the results of observation of the appearance of the prepared aqueous DP-II formulation up to 24 hours after storage (storage at 25 ° C).
  • the DPY7JC-based preparation of the present invention can be prepared as an aqueous preparation regardless of the type and grade of MC or HPMC.
  • a DP aqueous preparation of the present invention was adjusted to pH 7.5 or 8.0 with 10 W / V% monoethanolamine to prepare a comparative DPY aqueous preparation (Formulation No. 30, 31). Further, comparative DPY aqueous preparations (Formulation # ⁇ 32 to 34) to which neither Tween-80 nor SM-15 was added were prepared by the same method. In this case, the pH was adjusted to 4.0 to 5.5 with 1 OW / V% of monoethanolamine.
  • Table 3 shows the results of observation of the appearance of the prepared DP Y aqueous preparation for up to 24 hours (stored at 25 ° C) after preparation.
  • the aqueous DPY preparation of the present invention was an aqueous solution in which DPY was dissolved in the pH range of 5.0 to 7.0. However, DPY precipitated within 24 hours after preparation even when dissolved when the pH was 7.5 or more. When neither Tween-80 nor SM-15 was added, DPY did not dissolve when the pH became 5.0 or more.
  • Table 1 3 shows the results of observation of the appearance of the prepared DP Y aqueous preparation for up to 24 hours (stored at 25 ° C) after preparation.
  • the aqueous DPY preparation of the present invention was an aqueous solution in which DPY was dissolved in the pH range of 5.0 to 7.0. However, DPY precipitated within 24 hours after preparation even when dissolved when the pH was 7.5 or more. When neither Tween-80 nor SM-15 was
  • the present invention 26 0.01 5.0 0.5 SM15 0.3 aqueous solution
  • Table 4 shows the results of observing the appearance of the DPY aqueous preparation containing various concentrations of DPY, Tween_80 and SMI5 up to 24 hours (storage at 25 ° C) after preparation.
  • 0% was 0.06 W / V% or more, or when the concentration of SM15 became 0.005 WZV% or less, the dissolved DPY precipitated out within 2 hours after preparation.
  • Table 1 4 shows the results of observing the appearance of the DPY aqueous preparation containing various concentrations of DPY, Tween_80 and SMI5 up to 24 hours (storage at 25 ° C) after preparation.
  • Table 1 shows that the DPY ophthalmic solution of the present invention containing various concentrations of DPY, Tween-80 or HCO-60 and SM15 was stored at 7, 25 or 40 ° C for 3 months. The results of observing the change in the appearance of are shown. In any of the formulations (formulations Nos. 43 to 48), the DPY ophthalmic solution of the present invention showed no change in appearance such as crystal precipitation of DPY during storage, indicating that it was stable.
  • acyclovir 0.35 or 0.2 g of acyclovir, 0.5 g of Tween-80, 2 g of glycerol, 0.005 g of EDTA2Na, and 0.007 g of BZK were added to 3 OmL of sterile purified water. . While stirring the solution, 1N NaOH was added until the pH reached 10, to dissolve acyclovir. To this was added 0.5 ⁇ 31 ⁇ 15 dissolved in 4 OmL of sterile purified water. The pH was adjusted to 8.0 with 1N HCl, and sterile purified water was added to make up to 10 OmL. Further prepared acyclovir
  • Table 6 shows the results obtained by storing the acyclovir ophthalmic solution of the present invention at 25 ° C. for 2 weeks to 1 year and observing changes in appearance after storage.
  • the acyclovir ophthalmic solution of the present invention was stable after storage for 2 weeks or longer, with no crystal precipitation of acyclovir observed in any of the formulations (formulations ⁇ 49 to 51).
  • Table 1 6 shows the results obtained by storing the acyclovir ophthalmic solution of the present invention at 25 ° C. for 2 weeks to 1 year and observing changes in appearance after storage.
  • the acyclovir ophthalmic solution of the present invention was stable after storage for 2 weeks or longer, with no crystal precipitation of acyclovir observed in any of the formulations (formulations ⁇ 49 to 51).
  • PE G400 Macrogol 400, manufactured by NOF Corporation
  • DPY 0.2 g
  • Tween -80 50 mL
  • aqueous preparations of the present invention (formulation N (x52, 57) were replaced with 8 g of PEG4000 and Tween-80 was not added.
  • aqueous formulation of the present invention (formulation No. ⁇ 52, 57) was replaced with SM15 by adding 2 OmL, and PEG4000 and Tween-80 were not added.
  • the prepared aqueous preparation of the present invention or the comparative preparation (excluding prescriptions ⁇ 56 and 61) was filtered through a 0.45 ⁇ m membrane filter, filled in a glass bottle with a lid, and stored at 25 ° C. The time required for DPY crystals to precipitate was observed.
  • the DP ⁇ deposition delay was defined as the degree to which the DP ⁇ deposition time of each formulation was delayed with respect to the D ⁇ deposition time of the comparative example (prescription 54, 59) using Tween-80 and SM 15 alone. And the results are shown in Table 17 below.
  • the aqueous preparation of the present invention (formulation Not 52, 57) using polysorbate and PEG together is a comparative aqueous preparation (formulation No. ⁇ 54, 59) containing polysorbate alone or a comparison aqueous preparation containing PEG alone. This shows that the time required for crystal precipitation is longer than that of the preparations (Formulation Nos. 53 and 58), despite the fact that the amount added is half. This indicates that polysorbate and PEG have a synergistic solubilizing effect on poorly soluble drugs such as DPY.
  • aqueous formulation of the present invention (formulation # ⁇ 52, 57) using polysorbate, PEG and MC in combination was compared with the comparative aqueous formulation (formulation # ⁇ 55, 60) using only polysorbate and PEG alone or MC alone. This shows that the time required for crystallization is longer than that of aqueous preparations (formulation No. ⁇ 56, 61), although the amount of each additive is half. This indicates that polysorbate, PEG, and methylcellulose have a synergistic solubilizing effect on poorly soluble drugs such as DP III.
  • Table 9 shows the results of observation of the appearance of the aqueous preparations of the present invention containing various poorly soluble drugs prepared up to 24 hours (stored at 25 ° C) after preparation, and 25 mL of the aqueous preparations of the present invention and artificial tears. (0. 67W / V% NaCl, 0. 2W / V% NaHC0 3, 0. 00 8 W / V% CaC 1 2) showed 3. results of measurement of the gelation temperature of the aqueous solution mixed with 5 mL. The appearance after storage at 25 ° C was observed after cooling the sample on ice.
  • the aqueous preparation of the present invention can be prepared as an aqueous preparation in which a drug is dissolved in water, and has been shown to gel at a temperature near body temperature even when mixed with a body fluid such as tear fluid.
  • a comparative DPY aqueous preparation was prepared in the same manner as the aqueous preparation of the present invention.
  • Table 10 shows the results of observation of the appearance of the prepared DP Y aqueous preparation for up to 24 hours (stored at 25 ° C) after preparation, and the mixing of 25 mL of the aqueous preparation of the present invention with 3.5 mL of artificial tears. The results of measuring the gelation temperature of the aqueous solution are shown. The appearance after storage at 25 ° C is
  • the sample was observed after ice cooling.
  • the aqueous DPY formulation of the present invention can be prepared as an aqueous formulation with a DPY concentration in the range of 0.001 to 0.05 W / V%. It was shown to gel at temperature.
  • a comparative DPY aqueous preparation was prepared in the same manner as the aqueous preparation of the present invention, except that the MC was replaced with 0.1 g SM100.
  • Table 11 shows the results of observation of the appearance of the prepared DP Y aqueous formulation for up to 24 hours (stored at 25 ° C) after preparation and the mixing of 25 mL of the aqueous formulation of the present invention with 3.5 mL of artificial tears The results of measuring the gelation temperature of the aqueous solution are shown. The appearance after storage at 25 ° C was observed after cooling the sample on ice.
  • the DPY7JC preparation of the present invention can be prepared as an aqueous preparation with an MC in the range of 0.2 to 2 W / V%, and gels at a temperature near body temperature even when mixed with a body fluid such as tear fluid. It has been shown.
  • a comparative DPHY aqueous preparation was prepared in the same manner as the aqueous preparation of the present invention, except that the above citric anhydride was replaced with 0.05 g.
  • Table 12 shows the results of observation of the appearance of the prepared DP Y aqueous formulation for up to 24 hours (stored at 25 ° C) after preparation, and the aqueous solution obtained by mixing 25 mL of the aqueous formulation of the present invention with 3.5 mL of artificial tears. The results of measurement of the gelation temperature of the sample were shown. The appearance after storage at 25 ° C was observed after cooling the sample on ice.
  • the aqueous DPY formulation of the present invention can be prepared as an aqueous formulation at a citrate concentration of 0.1 W / V% or more, and shows that even when mixed with a body fluid such as tear fluid, it gels at a temperature near body temperature. Was done. Table 1 1 2
  • 29 OmL was added and mixed well.
  • a solution prepared by dissolving 3 ⁇ 15 of 1.5 and 0.5 g of SM400 in 4 OmL of sterilized purified water was added, and mixed well under ice-cooling. Further, 2.3 g of citric anhydride was added and mixed by stirring until all the added components were dissolved. Next, 5N NaOH was added to adjust the pH to 6.5, and sterile purified water was added to make up to 10 OmL, thereby obtaining an aqueous preparation of the present invention.
  • a comparative DPHY aqueous preparation was prepared in the same manner as the aqueous preparation of the present invention, except that the above PEG was replaced with 0.05 g of PEG1000.
  • Table 13 shows the results of observation of the appearance of the prepared DP Y aqueous formulation for up to 24 hours (stored at 25 ° C) after preparation, and the mixing of 25 mL of the aqueous formulation of the present invention with 3.5 mL of artificial tears The results of measuring the gelation temperature of the aqueous solution are shown. The appearance after storage at 25 ° C was observed after cooling the sample on ice.
  • the aqueous DPY preparation of the present invention can be prepared as an aqueous preparation at a PEG concentration of 0.1 to: L3W / V%, and gels at a temperature near body temperature even when mixed with a body fluid such as tear fluid. It was shown that.
  • a formulation was prepared without the addition of Tween-80 or HC0-60, and a comparative DPHY aqueous preparation was prepared in the same manner as the aqueous preparation of the present invention.
  • Table 14 shows the results of observation of the appearance of the prepared DP Y aqueous formulation up to 24 hours after storage (stored at 25 ° C), and the aqueous solution obtained by mixing 25 mL of the aqueous formulation of the present invention with 3.5 mL of artificial tears. The results of measurement of the gelation temperature of the sample were shown. The appearance after storage at 25 ° C was observed after cooling the sample on ice.
  • the aqueous DPY formulation of the present invention can be prepared as an aqueous formulation at a polysorbate or polyoxyethylene hydrogenated castor oil concentration of 0.01 to 2 W / V%, and is near body temperature even when mixed with body fluids such as tear fluid. It was shown that gelation occurred at this temperature.
  • Table 15 shows the results of observation of the appearance of the prepared DP Y aqueous preparation for up to 24 hours (stored at 25 ° C) after preparation, and mixing of 25 mL of the aqueous preparation of the present invention with 3.5 mL of artificial tears The results of measuring the gelation temperature of the aqueous solution thus obtained are shown. The appearance after storage at 25 ° C was observed after cooling the sample on ice.
  • the aqueous DP Y formulation of the present invention is aqueous-based at pH 5.0 to 8.0.
  • the results of measuring the gelation temperature of the aqueous solution thus obtained are shown.
  • the appearance after storage at 25 ° C was observed after cooling the sample on ice.
  • Table 18 shows the results of examining the change in appearance of the prepared aqueous preparation (Noil 15, 120, 121, 124 or 126) after storage at 7 ° C for 6 months.
  • the aqueous preparation containing a synthetic antibacterial agent of the present invention can be prepared as an aqueous solution of the synthetic antibacterial agent, and it was shown that even when stored in a cold place, there was no crystal precipitation of the drug and the drug was stable for a long period of time. It was also shown that even when mixed with bodily fluids such as tears, gelation occurred at a temperature near body temperature.
  • an aqueous preparation containing a comparative antifungal agent was prepared in the same manner as in the present invention except that the aqueous preparation (formulation # ⁇ 128) of the present invention was not added with HC 0-60.
  • Table 19 shows the results of an examination of the appearance change of the prepared antifungal agent-containing aqueous formulation after storage at 7 ° C for 2 months, and the mixing of 25 mL of the aqueous formulation of the present invention with 3.5 mL of artificial tears The results of measuring the gelation temperature of the aqueous solution are shown.
  • the antifungal agent-containing aqueous preparation of the present invention can be prepared as an aqueous solution of the antifungal agent, and was shown to be stable for a long time without crystal precipitation of the drug even when stored in a cold place.
  • the aqueous formulation containing the antifungal agent for comparison, to which HCO-60 or Tween-80 was not added was unable to dissolve econazole nitrate crystals from the time of preparation, and was prepared as an aqueous formulation in which the drug was dissolved in water. I could't.
  • the antifungal agent-containing aqueous preparation of the present invention gelled at a temperature near body temperature even when mixed with a body fluid such as tear fluid.
  • the poorly soluble drug-containing aqueous preparation of the present invention has a poorly soluble drug dissolved in water near neutrality, and has excellent storage stability without generation of crystals or foreign substances. Furthermore, the reversible thermogelling aqueous preparation containing a poorly soluble drug of the present invention is excellent in gelling properties and storage stability.

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Abstract

Cette invention concerne des préparations aqueuses qui contiennent un médicament faiblement soluble, de l'huile de ricin solidifiée par polysorbate et/ou polyoxyéthylène, ainsi que de la cellulose de méthyle et/ou de la cellulose d'hydroxypropyle avec, de préférence, du glycol de polyéthylène. Cette invention concerne également des préparations aqueuses qui se gélifient de manière réversible à la chaleur et qui contiennent de l'acide citrique, ou son sel, en sus de la composition susmentionnée. Ces préparations aqueuses n'irritent que faiblement les corps auxquels elles sont administrées. Les préparations aqueuses qui se gélifient de manière réversible à la chaleur possèdent d'excellentes propriétés de gélification et se gélifient à la température du corps d'un mammifère. La biodisponibilité du médicament faiblement soluble peut ainsi accrue, tandis que l'effet du médicament peut être maintenu sur une période prolongée.
PCT/JP1999/003107 1998-06-10 1999-06-10 Preparations aqueuses contenant des medicaments faiblement solubles WO1999063968A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001278788A (ja) * 2000-03-30 2001-10-10 Zeria Pharmaceut Co Ltd アラントインを配合した安定な液剤
JP2004359548A (ja) * 2003-06-02 2004-12-24 Toa Eiyo Ltd アシクロビル含有水溶液製剤
WO2005082335A1 (fr) * 2004-02-26 2005-09-09 Kowa Company., Ltd. Préparation ophtalmique
WO2007039936A1 (fr) * 2005-09-30 2007-04-12 Kobayashi Pharmaceutical Co., Ltd. Compositions à appliquer sur la muqueuse
US7612115B2 (en) * 2000-08-08 2009-11-03 Wakamoto Pharmaceutical Co., Ltd. Aqueous pharmaceutical compositions
WO2010137888A3 (fr) * 2009-05-27 2011-04-21 주식회사 삼양사 Microsphères à biodisponibilité améliorée contenant des médicaments faiblement solubles dans l'eau et leur procédé de préparation
JP2012017308A (ja) * 2010-07-09 2012-01-26 Nipro Corp ゲムシタビン水溶液製剤
JP2012214506A (ja) * 2012-08-08 2012-11-08 Kobayashi Pharmaceutical Co Ltd 粘膜適用組成物
JP2016530215A (ja) * 2013-09-25 2016-09-29 ダウ グローバル テクノロジーズ エルエルシー セルロースエーテルを含む粘膜に適用するための組成物
JP2017503805A (ja) * 2014-01-24 2017-02-02 センティス ファーマ プライベート リミテッド ブリンゾラミドを含む医薬組成物
CN109260152A (zh) * 2018-11-13 2019-01-25 禹州市中医院 一种盐酸洛美沙星滴耳液
JP2019532095A (ja) * 2016-08-24 2019-11-07 バイオツール エルエルシー アゾール系化合物の眼用製剤
WO2021001806A1 (fr) * 2019-07-04 2021-01-07 Ocular Discovery Ltd. Formulations de dipyridamole stables avec des impuretés réduites
WO2021001805A1 (fr) * 2019-07-04 2021-01-07 Ocular Discovery Ltd. Formulations de dipyridamole stables et leurs procédés de préparation

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03279324A (ja) * 1990-03-29 1991-12-10 Otsuka Pharmaceut Co Ltd 脂溶性ビタミン注射液
JPH07149624A (ja) * 1993-09-30 1995-06-13 American Home Prod Corp 静脈注射用のラパマイシン製剤

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH03279324A (ja) * 1990-03-29 1991-12-10 Otsuka Pharmaceut Co Ltd 脂溶性ビタミン注射液
JPH07149624A (ja) * 1993-09-30 1995-06-13 American Home Prod Corp 静脈注射用のラパマイシン製剤

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001278788A (ja) * 2000-03-30 2001-10-10 Zeria Pharmaceut Co Ltd アラントインを配合した安定な液剤
US7612115B2 (en) * 2000-08-08 2009-11-03 Wakamoto Pharmaceutical Co., Ltd. Aqueous pharmaceutical compositions
JP2004359548A (ja) * 2003-06-02 2004-12-24 Toa Eiyo Ltd アシクロビル含有水溶液製剤
WO2005082335A1 (fr) * 2004-02-26 2005-09-09 Kowa Company., Ltd. Préparation ophtalmique
WO2007039936A1 (fr) * 2005-09-30 2007-04-12 Kobayashi Pharmaceutical Co., Ltd. Compositions à appliquer sur la muqueuse
JP2007099647A (ja) * 2005-09-30 2007-04-19 Kobayashi Pharmaceut Co Ltd 粘膜適用組成物
US9511026B2 (en) 2009-05-27 2016-12-06 Samyang Biopharmaceuticals Corporation Poorly soluble drug containing microspheres with improved bioavailability and method of preparing the same
WO2010137888A3 (fr) * 2009-05-27 2011-04-21 주식회사 삼양사 Microsphères à biodisponibilité améliorée contenant des médicaments faiblement solubles dans l'eau et leur procédé de préparation
JP2012017308A (ja) * 2010-07-09 2012-01-26 Nipro Corp ゲムシタビン水溶液製剤
JP2012214506A (ja) * 2012-08-08 2012-11-08 Kobayashi Pharmaceutical Co Ltd 粘膜適用組成物
JP2016530215A (ja) * 2013-09-25 2016-09-29 ダウ グローバル テクノロジーズ エルエルシー セルロースエーテルを含む粘膜に適用するための組成物
KR101756095B1 (ko) 2013-09-25 2017-07-10 다우 글로벌 테크놀로지스 엘엘씨 셀룰로스 에테르를 포함하는, 점막에 적용하기 위한 조성물
JP2017503805A (ja) * 2014-01-24 2017-02-02 センティス ファーマ プライベート リミテッド ブリンゾラミドを含む医薬組成物
JP2019532095A (ja) * 2016-08-24 2019-11-07 バイオツール エルエルシー アゾール系化合物の眼用製剤
CN109260152A (zh) * 2018-11-13 2019-01-25 禹州市中医院 一种盐酸洛美沙星滴耳液
WO2021001806A1 (fr) * 2019-07-04 2021-01-07 Ocular Discovery Ltd. Formulations de dipyridamole stables avec des impuretés réduites
WO2021001805A1 (fr) * 2019-07-04 2021-01-07 Ocular Discovery Ltd. Formulations de dipyridamole stables et leurs procédés de préparation

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