WO2014007239A1 - Composition containing amphotericin b - Google Patents

Composition containing amphotericin b Download PDF

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Publication number
WO2014007239A1
WO2014007239A1 PCT/JP2013/068117 JP2013068117W WO2014007239A1 WO 2014007239 A1 WO2014007239 A1 WO 2014007239A1 JP 2013068117 W JP2013068117 W JP 2013068117W WO 2014007239 A1 WO2014007239 A1 WO 2014007239A1
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Prior art keywords
amphotericin
polyethylene glycol
water
fatty acid
lower alcohol
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PCT/JP2013/068117
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French (fr)
Japanese (ja)
Inventor
肇 伊吹
光明 桑野
健太 吉井
貴司 坪井
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参天製薬株式会社
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Publication of WO2014007239A1 publication Critical patent/WO2014007239A1/en

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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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to a water-soluble solid composition and an aqueous composition containing amphotericin B and fatty acid polyethylene glycol, and methods for producing them.
  • Amphotericin B is one of the polyene antibiotics and is extremely poorly soluble in water and has the disadvantage that it is very poorly absorbed into the body even when taken. It is used as an injection with high therapeutic value for fungal infection, and as a tablet and syrup for the abnormal growth of Candida in the digestive tract (in the gastrointestinal tract) due to its low absorbability to the living body.
  • Fatty acid polyethylene glycol is a surfactant, and there are many compounds with different degrees of polymerization of the polyethylene glycol moiety.
  • an injectable preparation containing amphotericin B as an active ingredient for example, “Fungisone (registered trademark) 50 mg for injection” and “Ambisome (registered trademark) intravenous infusion 50 mg” are known. Since mixing changes when mixed, certain restrictions are imposed on its use (Non-Patent Documents 1 and 2). In addition, when these injections are mixed with other injections in hospital preparations, etc., it is usually sterilized by filtration using a filter with a pore size of 0.22 ⁇ m for the purpose of reducing the risk of infection. It cannot be sterilized by filtration using a 0.22 ⁇ m filter, and 50 mg for ambisome intravenous infusion cannot be sterilized by filtration using a filter having a pore diameter of 0.22 ⁇ m.
  • Patent Document 1 describes an invention relating to a method for producing a fine particle dispersion characterized in that a sparingly soluble drug such as amphotericin B is micronized to a nano-order size using a high-pressure homogenizer. However, amphotericin B is not dissolved.
  • the present invention relates to a water-soluble solid and aqueous composition containing amphotericin B, and eye drops, ear drops, inhalants, internal preparations, dermatological agents or dental oral cavity containing these compositions. It is an object of the present invention to provide pharmaceutical preparations and methods for producing them.
  • a solid composition containing amphotericin B and fatty acid polyethylene glycol is found to dissolve in water to form a clear aqueous solution
  • the aqueous composition containing amphotericin B, fatty acid polyethylene glycol and water is clear and stable even when mixed with physiological saline, and is clear and stable.
  • the present invention has been completed by finding out what can be done.
  • the amphotericin B-containing aqueous composition of the present invention was found to have good permeability of a 0.22 ⁇ m pore size filter for filtration sterilization and is more convenient than existing amphotericin B-containing injectable preparations. .
  • the present invention relates to the following.
  • a water-soluble solid composition containing amphotericin B and fatty acid polyethylene glycol (2) The solid composition according to the above (1), which is produced through a step of distilling off the lower alcohol after dissolving amphotericin B in the lower alcohol.
  • An aqueous composition containing amphotericin B, fatty acid polyethylene glycol and water (4)
  • the aqueous composition according to the above (4) which is produced through a step of distilling off the lower alcohol after dissolving amphotericin B in the lower alcohol.
  • the above (4) or (5) wherein the concentration of amphotericin B is 0.01 to 20% (w / w) and the concentration of fatty acid polyethylene glycol is 0.01 to 40% (w / w) Aqueous composition.
  • the fatty acid polyethylene glycol is at least one selected from the group consisting of polyethylene glycol monostearate 55, polyethylene glycol monostearate 40, and polyethylene glycol monostearate 25, as described in (1) to (6) above Solid composition or aqueous composition.
  • the present invention relates to the following.
  • (10) A water-soluble solid composition containing amphotericin B and fatty acid polyethylene glycol obtained by the following step 1 or 2.
  • Step 1 Dissolve amphotericin B in lower alcohol, then distill off lower alcohol, and then add fatty acid polyethylene glycol
  • Step 2 Dissolve amphotericin B and fatty acid polyethylene glycol in lower alcohol, and then distill off lower alcohol
  • Step 1 Dissolve amphotericin B in lower alcohol, then distill off lower alcohol, and then add fatty acid polyethylene glycol and water
  • Step 2 Dissolve amphotericin B and fatty acid polyethylene glycol in lower alcohol, then distill off lower alcohol And then adding water. (12) Possible in water containing 1 to 50% (w / w) amphotericin B and 50 to 99% (w / w) fatty acid polyethylene glycol obtained by step 1 or 2 below. A soluble solid composition.
  • Step 1 Dissolve amphotericin B in lower alcohol, then distill off lower alcohol, and then add fatty acid polyethylene glycol
  • Step 2 Dissolve amphotericin B and fatty acid polyethylene glycol in lower alcohol, and then distill off lower alcohol (13)
  • An aqueous composition comprising 0.01 to 20% (w / w) amphotericin B, 0.01 to 40% (w / w) fatty acid polyethylene glycol and water obtained by the following step 1 or 2.
  • Step 1 Dissolve amphotericin B in lower alcohol, then distill off lower alcohol, and then add fatty acid polyethylene glycol and water
  • Step 2 Dissolve amphotericin B and fatty acid polyethylene glycol in lower alcohol, then distill off lower alcohol
  • the fatty acid polyethylene glycol is at least one selected from the group consisting of polyethylene glycol monostearate 55, polyethylene glycol monostearate 40 and polyethylene glycol monostearate 25 (10) ) To (13).
  • a water-soluble solid composition and an aqueous composition containing amphotericin B and fatty acid polyethylene glycol, and eye drops, ear drops, inhalants, internal preparations containing these compositions It is possible to obtain a dermatological agent or a dental and oral preparation and a method for producing them.
  • the solid composition containing amphotericin B and fatty acid polyethylene glycol of the present invention is a solid soluble in water, and if this dissolves in water, a clear aqueous solution containing amphotericin B is obtained.
  • the amphotericin B-containing solid composition of the present invention can be used for tablets, capsules, granules, powders, and the like.
  • the aqueous composition containing amphotericin B, fatty acid polyethylene glycol and water of the present invention is a clear aqueous solution in which amphotericin B is dissolved in water, and can be sterilized by filtration as necessary.
  • the amphotericin B-containing aqueous composition of the present invention is a stable aqueous solution, and does not cause a change in formulation even when mixed with physiological saline (electrolyte solution). It is suitable for in vivo administration and can be sterilized by filtration using a 0.22 ⁇ m pore size filter, which is more convenient than existing preparations.
  • FIG. 2 is a diagram showing the appearance of the compositions obtained in Examples 1 to 4 and Comparative Examples 1 and 2.
  • FIG. 3 is a view showing the appearance of a solution obtained by mixing the composition obtained in Examples 1 to 4 or Comparative Example 3 with physiological saline.
  • soluble in water means that it is dissolved in water to form a clear solution.
  • solid means solid (including wax), not liquid or gaseous.
  • aqueous means dissolved in an aqueous solvent in a clear state.
  • “Amphhotericin B” used in the present invention is an excellent antifungal agent, and there are those having differences in purity, properties, etc., but are not particularly limited as long as they are commercially available or obtained by a known production method. .
  • the “fatty acid polyethylene glycol” used in the present invention is not particularly limited as long as it is commercially available or can be obtained by a known production method, and usually includes those having a polyethylene glycol moiety having a polymerization degree of 2 to 150, preferably Is 25-55.
  • “Fatty acid polyethylene glycol” used in the present invention is polyethylene glycol monostearate, polyethylene glycol monoisostearate, polyethylene glycol distearate, polyethylene glycol monolaurate, polyethylene glycol monopalmitate, etc.
  • the numerical value described together with PEG indicates the degree of polymerization of the polyethylene glycol moiety.
  • the “lower alcohol” used in the present invention is an alcohol having 1 to 5 carbon atoms capable of dissolving amphotericin B, preferably methanol or ethanol, more preferably methanol.
  • amphotericin B can be easily distilled off at low temperatures after dissolving amphotericin B, so that amphotericin B is not thermally decomposed.
  • the “water” used in the present invention is not particularly limited as long as it is water, and examples thereof include water for injection, distilled water, purified water, sterilized water, and sterilized purified water.
  • the fatty acid polyethylene glycol is usually used in an amount of 1 to 100 parts by weight, preferably 2 to 70 parts by weight, more preferably 2 to 50 parts by weight with respect to 1 part by weight of amphotericin B.
  • a lower alcohol of 50 L or less is usually used for 1 g of amphotericin B.
  • methanol is preferably used in an amount of 20 L or less, more preferably 5 L or less based on 1 g of amphotericin B.
  • amphotericin B, or amphotericin B and fatty acid polyethylene glycol are dissolved in the lower alcohol and then the lower alcohol is distilled off. Therefore, it is desirable that the amount of the lower alcohol used is as small as possible.
  • the lower alcohol is distilled off to allow pharmaceutically acceptable in the aqueous composition. It is desirable not to leave more than the amount that is produced.
  • amphotericin B or amphotericin B and fatty acid polyethylene glycol are usually dissolved in lower alcohol at 4 ° C. to room temperature.
  • a lower alcohol solution containing amphotericin B or amphotericin B and fatty acid polyethylene glycol B is used. Although it can be heated, it is preferable to heat to 40 ° C. or less as much as possible.
  • the method for distilling off the lower alcohol is not particularly limited, but in order to avoid the thermal decomposition of amphotericin B, for example, if an evaporator is used, the lower alcohol is distilled off under reduced pressure at a low temperature (for example, 40 ° C. or lower). Can do. Moreover, a solid substance can also be obtained at a relatively low temperature by a spray drying technique.
  • the mixing ratio of amphotericin B in the water-soluble solid composition containing amphotericin B of the present invention is 1 to 50% (w / w), preferably 2 to 40% (w / w), more preferably 3 to 35% (w / w).
  • the blending ratio of amphotericin B in the aqueous composition containing amphotericin B of the present invention is insufficient amphotericin B, the efficacy is insufficient, and if it is excessive, clarity or stability may be impaired. 0.01 to 20% (w / w), preferably 0.01 to 15% (w / w), more preferably 0.02 to 10% (w / w).
  • the blending ratio of the fatty acid polyethylene glycol in the water-soluble solid composition containing amphotericin B of the present invention is 50 to 99% (w / w), preferably 60 to 98% (w / w), more preferably Is 65 to 97% (w / w).
  • the blending ratio of the fatty acid polyethylene glycol in the aqueous composition containing amphotericin B of the present invention is 0.01 to 30% (w / w), preferably 0.01 to 20% (w / w). Preferably, it is 0.01 to 10% (w / w).
  • amphotericin B / fatty acid polyethylene glycol in the amphotericin B-containing composition of the present invention is not particularly limited, but is 1/100 to 1/1 (mass ratio), preferably 1/70 to It is 1/2, more preferably 1/50 to 1/2.
  • the amphotericin B-containing composition of the present invention can be applied, for example, as a medicine, veterinary medicine, or agricultural chemical. In the case of pharmaceuticals and animal drugs, they can be administered either orally or parenterally. Examples of the dosage form include injections, eye drops, ear drops, suction agents, internal preparations (tablets, capsules, granules, powders), dermatological agents, dental and oral preparations, etc. It can be formulated using known techniques. Moreover, since the amphotericin B-containing composition of the present invention is soluble in water or physiological saline, it can be dissolved at the time of use and used as a liquid preparation such as an injection. The content of amphotericin B contained in the water-soluble solid composition and aqueous composition containing amphotericin B of the present invention can be appropriately adjusted depending on symptoms, age, dosage form and the like.
  • amphotericin B-containing composition of the present invention is an oral preparation such as a tablet, capsule, granule, powder, etc., lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, calcium hydrogen phosphate Excipients such as, stearic acid, magnesium stearate, lubricants such as talc, binders such as starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, low substituted hydroxypropylcellulose, calcium citrate Disintegrants such as hydroxypropylmethylcellulose, macrogol, silicone resin coatings, stabilizers such as ethyl paraoxybenzoate and benzyl alcohol, sweeteners, acidulants, flavoring agents such as fragrances, etc. It can be prepared by blending in accordance with the requirements.
  • the amphotericin B-containing aqueous composition of the present invention includes, for example, parenteral preparations such as injections and eye drops, isotonic agents such as sodium chloride and concentrated glycerin, sodium phosphate, sodium acetate, and ⁇ -aminocaproic acid. And the like, stabilizers such as sodium citrate and sodium edetate, and preservatives such as benzalkonium chloride and paraben can be blended as necessary.
  • amphotericin B-containing aqueous composition of the present invention is a stable aqueous solution, and does not change its composition even when mixed with physiological saline (electrolyte solution), and further sterilized by filtration using a 0.22 ⁇ m pore size filter. Therefore, it is more convenient than existing preparations.
  • Example B A water-soluble solid composition containing amphotericin B was obtained in the same manner as in Example A, except that 50 mg of MYS-40 was used instead of 25 mg of MYS-40 in Example A.
  • Example C A water-soluble solid composition containing amphotericin B was obtained in the same manner as in Example A except that 100 mg of MYS-40 was used instead of 25 mg of MYS-40 in Example A.
  • Example D A water-soluble solid composition containing amphotericin B was obtained in the same manner as in Example A, except that 150 mg of MYS-40 was used instead of 25 mg of MYS-40 in Example A.
  • Example E A water-soluble solid composition containing amphotericin B was obtained in the same manner as in Example A, except that 10 mg of MYS-40 was used instead of 25 mg of MYS-40 in Example A.
  • Example F The amphotericin B is contained in the same manner as in Example A except that 25 mg of MYS-40 of Example A is used and 25 mg of polyoxyl stearate (hereinafter referred to as “MYS-55”) manufactured by Nikko Chemicals is used. A water-soluble solid composition was obtained.
  • MYS-55 polyoxyl stearate
  • Example G A water-soluble solid composition containing amphotericin B was obtained in the same manner as in Example A, except that 100 mg of MYS-55 was used instead of 25 mg of MYS-40 in Example A.
  • Example H In place of 25 mg of MYS-40 of Example A, amphotericin B is contained in the same manner as in Example A, except that 100 mg of polyoxyl 25 stearate (hereinafter referred to as “MYS-25”) manufactured by Nikko Chemicals is used. A water-soluble solid composition was obtained.
  • MYS-25 polyoxyl 25 stearate
  • Example I After dissolving 300 mg of AMPH-B in 1200 mL of methanol, methanol was distilled off at about 35 ° C. under reduced pressure to obtain a solid residue. 100 mg of this residue was mixed with 2 g of MYS-40 heated to about 40 ° C. to obtain a water-soluble solid composition containing amphotericin B.
  • Example J A water-soluble solid composition containing amphotericin B was obtained by performing the same operation as in Example A, except that 500 mL of ethanol was used instead of 20 mL of methanol in Example A.
  • Table 1 shows the composition of Examples A to J.
  • Comparative Example 1 100 mg of MYS-40 was dissolved in 5 mL of water for injection. To this aqueous solution, 5 mg of AMPH-B was added and stirred at about 4 to 10 ° C. in the dark to obtain a turbid composition containing amphotericin B.
  • Comparative Example 2 5 mg of AMPH-B was dissolved in 20 mL of methanol. 100 mg of polysorbate 80 as a surfactant was added to this solution and dissolved, and then methanol was distilled off at about 35 ° C. under reduced pressure to obtain a composition containing amphotericin B. After adding 5 mL of water for injection to this amphotericin B-containing composition, the composition containing amphotericin B was obtained by stirring at about 4 to 10 ° C. under light shielding.
  • Comparative Example 3 “50 mg for fungizone injection” was added to 10 mL of water for injection and dissolved.
  • a clear aqueous solution can be obtained only by dissolving in alcohol and then distilling off the lower alcohol and then adding water to form an aqueous composition.
  • Amphotericin B concentration in an aqueous composition containing amphotericin B (Preparation of standard solution for measurement) 2.5 mg of AMPH-B was dissolved in 5 mL of DMSO, and DMSO was further added to make 10 mL (AMPH-B-DMSO solution). 920, 960, and 980 ⁇ L of DMSO were weighed into the microtubes, respectively, and 80, 40, and 20 ⁇ L of AMPH-B-DMSO solution were added to obtain standard solutions for measurement.
  • the AMPH-B concentration in each sample solution was measured at a wavelength of 390 nm with an absorption plate reader (SpectraMax Plus 384 , Molecular Devices), and calculated by comparing with the absorbance of the standard solution for measurement.
  • Table 2 shows the concentration of AMPH-B in each sample solution.
  • the supernatant obtained after centrifuging the compositions obtained in Examples 1 to 4 was used.
  • the composition obtained in Comparative Example 3 was dissolved by adding 10 mL of water for injection to 50 mg of fungizone for injection according to the preparation method described in the package insert.
  • the mixture with physiological saline was mixed at a volume ratio of 1: 1 as described above, and the appearance was observed at room temperature.
  • the aqueous composition containing amphotericin B of the present invention is stable without causing a change in composition even when mixed with physiological saline (electrolyte solution), whereas Comparative Example 3 ( A commercially available amphotericin B-containing preparation for injection) is turbid due to a change in formulation. Therefore, the aqueous composition containing amphotericin B of the present invention is stable without causing any change in composition even when mixed with an electrolyte solution such as physiological saline.
  • compositions obtained in Examples 1 and 2 had almost no resistance and good filter permeability, but the compositions obtained in Comparative Examples 2 and 3 had high resistance and could pass through the filter completely. could not.
  • aqueous composition containing amphotericin B of the present invention diluted with physiological saline can be sterilized by filtration using a 0.22 ⁇ m pore size filter.
  • Example 3 Tablet (1 tablet) 0.3 g of water-soluble solid composition of Example A Lactose 66.4mg Corn starch 20mg Carboxymethylcellulose calcium 6mg Hydroxypropylcellulose 4mg Magnesium stearate 0.6mg
  • a coating agent for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.
  • a desired tablet can be obtained by changing suitably the kind and quantity of the water-soluble solid composition and additive of Example A.

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Abstract

The present invention relates to: a water-soluble solid composition and an aqueous composition, each of which contains amphotericin B and a fatty acid polyethylene glycol; and methods for producing the compositions.

Description

アムホテリシンＢ含有組成物Amphotericin B-containing composition
　本発明は、アムホテリシンＢと脂肪酸ポリエチレングリコールとを含有する水に可溶な固形組成物および水性組成物、並びにそれらの製造方法に関する。 The present invention relates to a water-soluble solid composition and an aqueous composition containing amphotericin B and fatty acid polyethylene glycol, and methods for producing them.
　アムホテリシンＢは、ポリエン系抗生物質のひとつであって水に極めて難溶性であり、服用しても生体内への吸収性が極めて低いなどの短所を有するが、その優れた薬効のため深在性真菌感染症に対する治療価値の高い注射剤として、また、その生体への低い吸収性を利用して消化管内（胃腸内）におけるカンジダの異常増殖に対する錠剤およびシロップ剤として用いられている。 Amphotericin B is one of the polyene antibiotics and is extremely poorly soluble in water and has the disadvantage that it is very poorly absorbed into the body even when taken. It is used as an injection with high therapeutic value for fungal infection, and as a tablet and syrup for the abnormal growth of Candida in the digestive tract (in the gastrointestinal tract) due to its low absorbability to the living body.
　脂肪酸ポリエチレングリコールは、界面活性剤であり、それにはポリエチレングリコール部分の重合度が異なる多数の化合物が存在する。 Fatty acid polyethylene glycol is a surfactant, and there are many compounds with different degrees of polymerization of the polyethylene glycol moiety.
　アムホテリシンＢを有効成分とする注射用製剤として、例えば「ファンギゾン（登録商標）注射用５０ｍｇ」、「アムビゾーム（登録商標）点滴静注用５０ｍｇ」が知られているが、いずれも他の注射剤と混合すると配合変化するため、その使用には一定の制約が設けられている(非特許文献１、２)。また、院内調剤などにおいてこれらの注射剤を他の注射剤と混合する場合、通常、感染リスク低減の目的で孔径０．２２μｍのフィルターを用いて濾過滅菌を行うが、ファンギゾン注射用５０ｍｇについては孔径０．２２μｍのフィルターを用いて濾過滅菌することはできず、また、アムビゾーム点滴静注用５０ｍｇについても孔径０．２２μｍのフィルターを用いて濾過滅菌することはできない。 As an injectable preparation containing amphotericin B as an active ingredient, for example, “Fungisone (registered trademark) 50 mg for injection” and “Ambisome (registered trademark) intravenous infusion 50 mg” are known. Since mixing changes when mixed, certain restrictions are imposed on its use (Non-Patent Documents 1 and 2). In addition, when these injections are mixed with other injections in hospital preparations, etc., it is usually sterilized by filtration using a filter with a pore size of 0.22 μm for the purpose of reducing the risk of infection. It cannot be sterilized by filtration using a 0.22 μm filter, and 50 mg for ambisome intravenous infusion cannot be sterilized by filtration using a filter having a pore diameter of 0.22 μm.
　また、ファンギゾン注射用には可溶化剤としてデオキシコール酸が含まれているため、これを使用する場合にはその強力な界面活性作用に起因する強い粘膜刺激性や溶血性などが問題となっている（非特許文献３）。
　特許文献１には、アムホテリシンＢなどの難溶性薬物を高圧ホモジナイザーを用いてナノオーダーサイズに微粒子化することを特徴とする微粒子分散液の製造方法に関する発明が記載されているが、この微粒子分散液においてアムホテリシンＢが溶解しているわけではない。 In addition, since deoxycholic acid is included as a solubilizer for fungizone injection, strong mucosal irritation and hemolysis due to its strong surface-active action become a problem when it is used. (Non-patent Document 3).
Patent Document 1 describes an invention relating to a method for producing a fine particle dispersion characterized in that a sparingly soluble drug such as amphotericin B is micronized to a nano-order size using a high-pressure homogenizer. However, amphotericin B is not dissolved.
国際公開２００５／０９４７８８号International Publication No. 2005/094788
　アムホテリシンＢを含有する点眼液等の外用剤、注射液、内服剤などを提供するために、生理食塩水などの電解質溶液と混合しても配合変化せず澄明・安定であり、さらに投与による生体への負荷を軽減することができるアムホテリシンＢを含有する組成物を開発することが求められている。
　本発明は、アムホテリシンＢを含有する水に可溶な固形組成物および水性組成物、および、それらの組成物を含む点眼剤、点耳剤、吸引剤、内服剤、皮膚科用剤または歯科口腔用製剤、並びに、それらの製造方法を提供することを課題とする。 In order to provide external preparations such as ophthalmic solutions containing amphotericin B, injection solutions, oral preparations, etc., even if mixed with an electrolyte solution such as physiological saline, the composition is not changed and is stable and stable. There is a need to develop a composition containing amphotericin B that can reduce the burden on the body.
The present invention relates to a water-soluble solid and aqueous composition containing amphotericin B, and eye drops, ear drops, inhalants, internal preparations, dermatological agents or dental oral cavity containing these compositions. It is an object of the present invention to provide pharmaceutical preparations and methods for producing them.
　本発明者は、上記課題を解決するために鋭意研究を行った結果、
（１）アムホテリシンＢと脂肪酸ポリエチレングリコールとを含有する固形組成物が、水に溶解して澄明な水溶液となることを見出し、そして、
（２）アムホテリシンＢ、脂肪酸ポリエチレングリコールおよび水を含有する水性組成物が、生理食塩水と混合しても配合変化せず澄明・安定であり、結果として投与による生体への負荷を軽減することができることを見出し、本発明を完成させた。
　さらに、本発明のアムホテリシンＢ含有水性組成物は、濾過滅菌用の孔径０．２２μｍフィルターの透過性も良好であり、既存のアムホテリシンＢ含有注射用製剤よりも利便性に優れていることを見出した。 The inventor has conducted extensive research to solve the above problems,
(1) A solid composition containing amphotericin B and fatty acid polyethylene glycol is found to dissolve in water to form a clear aqueous solution, and
(2) The aqueous composition containing amphotericin B, fatty acid polyethylene glycol and water is clear and stable even when mixed with physiological saline, and is clear and stable. As a result, the burden on the living body due to administration may be reduced. The present invention has been completed by finding out what can be done.
Furthermore, the amphotericin B-containing aqueous composition of the present invention was found to have good permeability of a 0.22 μm pore size filter for filtration sterilization and is more convenient than existing amphotericin B-containing injectable preparations. .
　すなわち、本発明は、以下に関する。
（１）アムホテリシンＢと脂肪酸ポリエチレングリコールとを含有する水に可溶な固形組成物。
（２）アムホテリシンＢを低級アルコールに溶解後、低級アルコールを留去する工程を経て製造される上記（１）記載の固形組成物。
（３）アムホテリシンＢの濃度が１～５０％（ｗ／ｗ）であり、脂肪酸ポリエチレングリコールの濃度が５０～９９％（ｗ／ｗ）である上記（１)又は（２）記載の固形組成物。
（４）アムホテリシンＢ、脂肪酸ポリエチレングリコールおよび水を含有する水性組成物。
（５）アムホテリシンＢを低級アルコールに溶解後、低級アルコールを留去する工程を経て製造される上記（４）記載の水性組成物。
（６）アムホテリシンＢの濃度が０．０１～２０％（ｗ／ｗ）であり、脂肪酸ポリエチレングリコールの濃度が０．０１～４０％（ｗ／ｗ）である上記（４）または（５）記載の水性組成物。
（７）脂肪酸ポリエチレングリコールが、モノステアリン酸ポリエチレングリコール５５、モノステアリン酸ポリエチレングリコール４０およびモノステアリン酸ポリエチレングリコール２５からなる群から選択される少なくとも１種である上記（１）～（６）記載の固形組成物または水性組成物。
（８）低級アルコールが、メタノールまたはエタノールである上記（１）～（６）記載の固形組成物または水性組成物。
（９）上記（１）～（８）記載の固形組成物または水性組成物を含む注射剤、点眼剤、点耳剤、吸引剤、内服剤、皮膚科用剤または歯科口腔用製剤。 That is, the present invention relates to the following.
(1) A water-soluble solid composition containing amphotericin B and fatty acid polyethylene glycol.
(2) The solid composition according to the above (1), which is produced through a step of distilling off the lower alcohol after dissolving amphotericin B in the lower alcohol.
(3) The solid composition according to the above (1) or (2), wherein the concentration of amphotericin B is 1 to 50% (w / w) and the concentration of fatty acid polyethylene glycol is 50 to 99% (w / w) .
(4) An aqueous composition containing amphotericin B, fatty acid polyethylene glycol and water.
(5) The aqueous composition according to the above (4), which is produced through a step of distilling off the lower alcohol after dissolving amphotericin B in the lower alcohol.
(6) The above (4) or (5), wherein the concentration of amphotericin B is 0.01 to 20% (w / w) and the concentration of fatty acid polyethylene glycol is 0.01 to 40% (w / w) Aqueous composition.
(7) The fatty acid polyethylene glycol is at least one selected from the group consisting of polyethylene glycol monostearate 55, polyethylene glycol monostearate 40, and polyethylene glycol monostearate 25, as described in (1) to (6) above Solid composition or aqueous composition.
(8) The solid composition or aqueous composition according to the above (1) to (6), wherein the lower alcohol is methanol or ethanol.
(9) An injection, an eye drop, an ear drop, an inhalant, an internal preparation, a dermatological agent or a dental oral preparation comprising the solid composition or the aqueous composition according to the above (1) to (8).
　更に、本発明は、以下に関する。
（１０）下記工程１または２によって得られるアムホテリシンＢおよび脂肪酸ポリエチレングリコールを含有する水に可溶な固形組成物。
工程１：アムホテリシンＢを低級アルコールに溶解後、低級アルコールを留去してから、脂肪酸ポリエチレングリコールを加える工程
工程２：アムホテリシンＢおよび脂肪酸ポリエチレングリコールを低級アルコールに溶解後、低級アルコールを留去する工程
（１１）下記工程１または２によって得られるアムホテリシンＢ、脂肪酸ポリエチレングリコールおよび水を含有する水性組成物。
工程１：アムホテリシンＢを低級アルコールに溶解後、低級アルコールを留去してから、脂肪酸ポリエチレングリコールおよび水を加える工程
工程２：アムホテリシンＢおよび脂肪酸ポリエチレングリコールを低級アルコールに溶解後、低級アルコールを留去してから水を加える工程
（１２）下記工程１または２によって得られる１～５０％（ｗ／ｗ）のアムホテリシンＢおよび５０～９９％（ｗ／ｗ）の脂肪酸ポリエチレングリコールを含有する水に可溶な固形組成物。
工程１：アムホテリシンＢを低級アルコールに溶解後、低級アルコールを留去してから、脂肪酸ポリエチレングリコールを加える工程
工程２：アムホテリシンＢおよび脂肪酸ポリエチレングリコールを低級アルコールに溶解後、低級アルコールを留去する工程
（１３）下記工程１または２によって得られる０．０１～２０％（ｗ／ｗ）のアムホテリシンＢ、０．０１～４０％（ｗ／ｗ）の脂肪酸ポリエチレングリコールおよび水を含有する水性組成物。
工程１：アムホテリシンＢを低級アルコールに溶解後、低級アルコールを留去してから、脂肪酸ポリエチレングリコールおよび水を加える工程
工程２：アムホテリシンＢおよび脂肪酸ポリエチレングリコールを低級アルコールに溶解後、低級アルコールを留去してから水を加える工程
（１４）脂肪酸ポリエチレングリコールが、モノステアリン酸ポリエチレングリコール５５、モノステアリン酸ポリエチレングリコール４０およびモノステアリン酸ポリエチレングリコール２５からなる群から選択される少なくとも１種である上記（１０）～（１３）記載の固形組成物または水性組成物。
（１５）低級アルコールが、メタノールまたはエタノールである上記（１０）～（１３）記載の固形組成物または水性組成物。
（１６）上記（１０）～（１５）記載の固形組成物または水性組成物を含む注射剤、点眼剤、点耳剤、吸引剤、内服剤、皮膚科用剤または歯科口腔用製剤。
（１７）アムホテリシンＢを低級アルコールに溶解後、低級アルコールを留去し、ついで脂肪酸ポリエチレングリコールを加える、アムホテリシンＢを含有する水に可溶な固形組成物の製造方法。
（１８）アムホテリシンＢおよび脂肪酸ポリエチレングリコールを低級アルコールに溶解後、低級アルコールを留去する、アムホテリシンＢを含有する水に可溶な固形組成物の製造方法。
（１９）アムホテリシンＢを低級アルコールに溶解後、低級アルコールを留去し、ついで脂肪酸ポリエチレングリコールおよび水を加える、アムホテリシンＢを含有する水性組成物の製造方法。
（２０）アムホテリシンＢおよび脂肪酸ポリエチレングリコールを低級アルコールに溶解後、低級アルコールを留去し、ついで水を加える、アムホテリシンＢを含有する水性組成物の製造方法。 Furthermore, the present invention relates to the following.
(10) A water-soluble solid composition containing amphotericin B and fatty acid polyethylene glycol obtained by the following step 1 or 2.
Step 1: Dissolve amphotericin B in lower alcohol, then distill off lower alcohol, and then add fatty acid polyethylene glycol Step 2: Dissolve amphotericin B and fatty acid polyethylene glycol in lower alcohol, and then distill off lower alcohol (11) An aqueous composition containing amphotericin B obtained by the following step 1 or 2, fatty acid polyethylene glycol, and water.
Step 1: Dissolve amphotericin B in lower alcohol, then distill off lower alcohol, and then add fatty acid polyethylene glycol and water Step 2: Dissolve amphotericin B and fatty acid polyethylene glycol in lower alcohol, then distill off lower alcohol And then adding water. (12) Possible in water containing 1 to 50% (w / w) amphotericin B and 50 to 99% (w / w) fatty acid polyethylene glycol obtained by step 1 or 2 below. A soluble solid composition.
Step 1: Dissolve amphotericin B in lower alcohol, then distill off lower alcohol, and then add fatty acid polyethylene glycol Step 2: Dissolve amphotericin B and fatty acid polyethylene glycol in lower alcohol, and then distill off lower alcohol (13) An aqueous composition comprising 0.01 to 20% (w / w) amphotericin B, 0.01 to 40% (w / w) fatty acid polyethylene glycol and water obtained by the following step 1 or 2.
Step 1: Dissolve amphotericin B in lower alcohol, then distill off lower alcohol, and then add fatty acid polyethylene glycol and water Step 2: Dissolve amphotericin B and fatty acid polyethylene glycol in lower alcohol, then distill off lower alcohol (14) The fatty acid polyethylene glycol is at least one selected from the group consisting of polyethylene glycol monostearate 55, polyethylene glycol monostearate 40 and polyethylene glycol monostearate 25 (10) ) To (13).
(15) The solid or aqueous composition according to the above (10) to (13), wherein the lower alcohol is methanol or ethanol.
(16) An injection, an eye drop, an ear drop, an inhalant, an internal preparation, a dermatological preparation or a dental oral preparation comprising the solid composition or the aqueous composition according to the above (10) to (15).
(17) A method for producing a solid composition soluble in water containing amphotericin B, wherein amphotericin B is dissolved in lower alcohol, then the lower alcohol is distilled off, and then fatty acid polyethylene glycol is added.
(18) A method for producing a water-soluble solid composition containing amphotericin B, wherein amphotericin B and fatty acid polyethylene glycol are dissolved in lower alcohol and then the lower alcohol is distilled off.
(19) A method for producing an aqueous composition containing amphotericin B, wherein amphotericin B is dissolved in lower alcohol, then the lower alcohol is distilled off, and then fatty acid polyethylene glycol and water are added.
(20) A method for producing an aqueous composition containing amphotericin B, wherein amphotericin B and fatty acid polyethylene glycol are dissolved in a lower alcohol, then the lower alcohol is distilled off and then water is added.
　本発明によれば、アムホテリシンＢと脂肪酸ポリエチレングリコールとを含有する水に可溶な固形組成物および水性組成物、および、それらの組成物を含む点眼剤、点耳剤、吸引剤、内服剤、皮膚科用剤または歯科口腔用製剤、並びに、それらの製造方法を得ることができる。
　本発明のアムホテリシンＢと脂肪酸ポリエチレングリコールとを含有する固形組成物は、水に可溶な固形物であり、これが水に溶解すればアムホテリシンＢを含有する澄明な水溶液となる。本発明のアムホテリシンＢ含有固形組成物は、例えば錠剤、カプセル剤、顆粒剤、散剤などに利用できる。
　また、本発明のアムホテリシンＢ、脂肪酸ポリエチレングリコールおよび水を含有する水性組成物は、アムホテリシンＢが水に溶解した澄明な水溶液であり、必要に応じて濾過滅菌することも可能である。
　また、本明細書に記載した各種の試験結果より、本発明のアムホテリシンＢ含有水性組成物は、安定な水溶液であり、また、生理食塩水（電解質溶液）と混合しても配合変化を起こさず生体内投与に適し、さらに、孔径０．２２μｍフィルターを用いて濾過滅菌することが可能であるので、既存の製剤よりも利便性に優れている。 According to the present invention, a water-soluble solid composition and an aqueous composition containing amphotericin B and fatty acid polyethylene glycol, and eye drops, ear drops, inhalants, internal preparations containing these compositions, It is possible to obtain a dermatological agent or a dental and oral preparation and a method for producing them.
The solid composition containing amphotericin B and fatty acid polyethylene glycol of the present invention is a solid soluble in water, and if this dissolves in water, a clear aqueous solution containing amphotericin B is obtained. The amphotericin B-containing solid composition of the present invention can be used for tablets, capsules, granules, powders, and the like.
The aqueous composition containing amphotericin B, fatty acid polyethylene glycol and water of the present invention is a clear aqueous solution in which amphotericin B is dissolved in water, and can be sterilized by filtration as necessary.
Moreover, from the various test results described in the present specification, the amphotericin B-containing aqueous composition of the present invention is a stable aqueous solution, and does not cause a change in formulation even when mixed with physiological saline (electrolyte solution). It is suitable for in vivo administration and can be sterilized by filtration using a 0.22 μm pore size filter, which is more convenient than existing preparations.
実施例１～４および比較例１～２で得られた組成物の外観を示す図である。FIG. 2 is a diagram showing the appearance of the compositions obtained in Examples 1 to 4 and Comparative Examples 1 and 2. 実施例１～４または比較例３で得られた組成物を生理食塩水と混合して得られた溶液の外観を示す図である。FIG. 3 is a view showing the appearance of a solution obtained by mixing the composition obtained in Examples 1 to 4 or Comparative Example 3 with physiological saline.
　以下に、本発明について詳細に説明する。 Hereinafter, the present invention will be described in detail.
　本明細書において、「水に可溶な」とは、水に溶解して、澄明な溶液となることを意味する。 In this specification, “soluble in water” means that it is dissolved in water to form a clear solution.
　本明細書において、「固形」とは、液体状や気体状ではなく、固体状（蝋状を含む）であることを意味する。 In this specification, “solid” means solid (including wax), not liquid or gaseous.
　本明細書において、「水性」とは、水性溶媒に澄明な状態で溶解していることを意味する。 In this specification, “aqueous” means dissolved in an aqueous solvent in a clear state.
〔本発明の組成物〕 [Composition of the present invention]
（１）アムホテリシンＢ (1) Amphotericin B
　本発明で用いられる「アムホテリシンＢ」は、優れた抗真菌剤であり、純度、性状などに違いのあるものが存在するが、市販または公知の製造方法により得られるものであれば、特に制限されない。 “Amphhotericin B” used in the present invention is an excellent antifungal agent, and there are those having differences in purity, properties, etc., but are not particularly limited as long as they are commercially available or obtained by a known production method. .
（２）脂肪酸ポリエチレングリコール (2) Fatty acid polyethylene glycol
　本発明で用いられる「脂肪酸ポリエチレングリコール」は、市販または公知の製造方法により得られるものであれば特に限定されないが、通常ポリエチレングリコール部分の重合度が、２～１５０であるものが挙げられ、好ましくは２５～５５である。 The “fatty acid polyethylene glycol” used in the present invention is not particularly limited as long as it is commercially available or can be obtained by a known production method, and usually includes those having a polyethylene glycol moiety having a polymerization degree of 2 to 150, preferably Is 25-55.
　本発明で用いられる「脂肪酸ポリエチレングリコール」は、モノステアリン酸ポリエチレングリコール、モノイソステアリン酸ポリエチレングリコール、ジステアリン酸ポリエチレングリコール、モノラウリン酸ポリエチレングリコール、モノパルミチン酸ポリエチレングリコール等であり、モノステアリン酸ポリエチレングリコールとしては、例えばモノステアリン酸ポリエチレングリコール２０（ＰＥＧ－２０）、モノステアリン酸ポリエチレングリコール２５（ＰＥＧ－２５）、モノステアリン酸ポリエチレングリコール４０（ＰＥＧ－４０）、モノステアリン酸ポリエチレングリコール５５（ＰＥＧ－５５）、モノステアリン酸ポリエチレングリコール１００（ＰＥＧ－１００）、モノステアリン酸ポリエチレングリコール１５０（ＰＥＧ－１５０）であり、より好ましくはモノステアリン酸ポリエチレングリコール２５（ＰＥＧ－２５）、モノステアリン酸ポリエチレングリコール４０（ＰＥＧ－４０）、モノステアリン酸ポリエチレングリコール５５（ＰＥＧ－５５）などが挙げられる。ＰＥＧと共に記載される数値は、ポリエチレングリコール部分の重合度を示す。 “Fatty acid polyethylene glycol” used in the present invention is polyethylene glycol monostearate, polyethylene glycol monoisostearate, polyethylene glycol distearate, polyethylene glycol monolaurate, polyethylene glycol monopalmitate, etc. For example, polyethylene glycol monostearate 20 (PEG-20), polyethylene glycol monostearate 25 (PEG-25), polyethylene glycol monostearate 40 (PEG-40), polyethylene glycol monostearate 55 (PEG-55), Polyethylene glycol monostearate 100 (PEG-100), polyethylene glycol monostearate 150 A PEG-0.99), more preferably polyethylene glycol monostearate 25 (PEG-25), polyethylene glycol monostearate 40 (PEG-40), polyethylene glycol 55 (PEG-55 monostearate), and the like. The numerical value described together with PEG indicates the degree of polymerization of the polyethylene glycol moiety.
（３）低級アルコール (3) Lower alcohol
　本発明で用いられる「低級アルコール」は、アムホテリシンＢを溶解させることができる炭素数１～５のアルコールであって、好ましくはメタノール、エタノールであり、より好ましくは、メタノールである。とりわけメタノールまたはエタノールを用いれば、アムホテリシンＢを溶解させた後、低温でも容易にこれらを留去することができるため、アムホテリシンＢを熱分解させないという長所を有する。 The “lower alcohol” used in the present invention is an alcohol having 1 to 5 carbon atoms capable of dissolving amphotericin B, preferably methanol or ethanol, more preferably methanol. In particular, if methanol or ethanol is used, amphotericin B can be easily distilled off at low temperatures after dissolving amphotericin B, so that amphotericin B is not thermally decomposed.
（４）水 (4) Water
　本発明で用いられる「水」は、水であれば特に制限されないが、例えば、注射用水、蒸留水、精製水、滅菌水、滅菌精製水などが挙げられる。 The “water” used in the present invention is not particularly limited as long as it is water, and examples thereof include water for injection, distilled water, purified water, sterilized water, and sterilized purified water.
（５）製造条件 (5) Manufacturing conditions
　本発明においては、アムホテリシンＢ１質量部に対して、脂肪酸ポリエチレングリコールを、通常１～１００質量部、好ましくは２～７０質量部、より好ましくは２～５０質量部を用いる。 In the present invention, the fatty acid polyethylene glycol is usually used in an amount of 1 to 100 parts by weight, preferably 2 to 70 parts by weight, more preferably 2 to 50 parts by weight with respect to 1 part by weight of amphotericin B.
　本発明においては、アムホテリシンＢ１ｇに対して、通常５０Ｌ以下の低級アルコールを用いる。低級アルコールとして、例えばメタノールを用いる場合は、アムホテリシンＢ１ｇに対して、メタノールを、好ましくは２０Ｌ以下、より好ましくは５Ｌ以下で用いる。 In the present invention, a lower alcohol of 50 L or less is usually used for 1 g of amphotericin B. For example, when methanol is used as the lower alcohol, methanol is preferably used in an amount of 20 L or less, more preferably 5 L or less based on 1 g of amphotericin B.
　本発明においては、アムホテリシンＢ、またはアムホテリシンＢおよび脂肪酸ポリエチレングリコールを低級アルコールに溶解させた後、低級アルコールを留去するので、低級アルコールの使用量はなるべく少ない方が望ましい。 In the present invention, amphotericin B, or amphotericin B and fatty acid polyethylene glycol are dissolved in the lower alcohol and then the lower alcohol is distilled off. Therefore, it is desirable that the amount of the lower alcohol used is as small as possible.
　本発明においては、本発明のアムホテリシンＢを含有する水に可溶な固形組成物または水性組成物を生体に投与する場合には、低級アルコールを留去して該水性組成物中に医薬として許容される量以上に残存させないことが望ましい。 In the present invention, when a water-soluble solid composition or aqueous composition containing amphotericin B of the present invention is administered to a living body, the lower alcohol is distilled off to allow pharmaceutically acceptable in the aqueous composition. It is desirable not to leave more than the amount that is produced.
　本発明においては、低級アルコールに、アムホテリシンＢ、または、アムホテリシンＢおよび脂肪酸ポリエチレングリコールを、通常、４℃～室温で溶解する。アムホテリシンＢ、または、アムホテリシンＢおよび脂肪酸ポリエチレングリコールの溶解性を向上させ、また、低級アルコールの使用量を減少させるために、アムホテリシンＢ、または、アムホテリシンＢおよび脂肪酸ポリエチレングリコールＢを含有する低級アルコール溶液を加温することもできるが、なるべく４０℃以下に加温することが好ましい。 In the present invention, amphotericin B or amphotericin B and fatty acid polyethylene glycol are usually dissolved in lower alcohol at 4 ° C. to room temperature. In order to improve the solubility of amphotericin B or amphotericin B and fatty acid polyethylene glycol, and to reduce the amount of lower alcohol used, a lower alcohol solution containing amphotericin B or amphotericin B and fatty acid polyethylene glycol B is used. Although it can be heated, it is preferable to heat to 40 ° C. or less as much as possible.
　本発明において、低級アルコールを留去する方法は特に限定されないが、アムホテリシンＢが熱分解することを避けるために、例えばエバポレーターを用いれば低温（例えば４０℃以下）で低級アルコールを減圧留去することができる。また、スプレードライ技術により、比較的低温で固形物を得ることもできる。 In the present invention, the method for distilling off the lower alcohol is not particularly limited, but in order to avoid the thermal decomposition of amphotericin B, for example, if an evaporator is used, the lower alcohol is distilled off under reduced pressure at a low temperature (for example, 40 ° C. or lower). Can do. Moreover, a solid substance can also be obtained at a relatively low temperature by a spray drying technique.
　本発明のアムホテリシンＢを含有する水に可溶な固形組成物中のアムホテリシンＢの配合割合は、１～５０％（ｗ／ｗ）、好ましくは２～４０％（ｗ／ｗ）、より好ましくは３～３５％（ｗ／ｗ）である。 The mixing ratio of amphotericin B in the water-soluble solid composition containing amphotericin B of the present invention is 1 to 50% (w / w), preferably 2 to 40% (w / w), more preferably 3 to 35% (w / w).
　また、本発明のアムホテリシンＢを含有する水性組成物中のアムホテリシンＢの配合割合は、アムホテリシンＢが過少になると薬効が不十分となり、過大になると澄明性又は安定性が損なわれることがあるため、０．０１～２０％（ｗ／ｗ）、好ましくは０．０１～１５％（ｗ／ｗ）、より好ましくは０．０２～１０％（ｗ／ｗ）である。 Moreover, since the blending ratio of amphotericin B in the aqueous composition containing amphotericin B of the present invention is insufficient amphotericin B, the efficacy is insufficient, and if it is excessive, clarity or stability may be impaired. 0.01 to 20% (w / w), preferably 0.01 to 15% (w / w), more preferably 0.02 to 10% (w / w).
　本発明のアムホテリシンＢを含有する水に可溶な固形組成物中の脂肪酸ポリエチレングリコールの配合割合は、５０～９９％（ｗ／ｗ）、好ましくは６０～９８％（ｗ／ｗ）、より好ましくは６５～９７％（ｗ／ｗ）である。 The blending ratio of the fatty acid polyethylene glycol in the water-soluble solid composition containing amphotericin B of the present invention is 50 to 99% (w / w), preferably 60 to 98% (w / w), more preferably Is 65 to 97% (w / w).
　また、本発明のアムホテリシンＢを含有する水性組成物中の脂肪酸ポリエチレングリコールの配合割合は、０．０１～３０％（ｗ／ｗ）、好ましくは０．０１～２０％（ｗ／ｗ）、より好ましくは０．０１～１０％（ｗ／ｗ）である。 The blending ratio of the fatty acid polyethylene glycol in the aqueous composition containing amphotericin B of the present invention is 0.01 to 30% (w / w), preferably 0.01 to 20% (w / w). Preferably, it is 0.01 to 10% (w / w).
　本発明のアムホテリシンＢ含有組成物におけるアムホテリシンＢと脂肪酸ポリエチレングリコールの配合割合（アムホテリシンＢ／脂肪酸ポリエチレングリコール）は、特に限定されないが１／１００～１／１（質量比）、好ましくは１／７０～１／２、より好ましくは１／５０～１／２である。 The blending ratio of amphotericin B and fatty acid polyethylene glycol (amphotericin B / fatty acid polyethylene glycol) in the amphotericin B-containing composition of the present invention is not particularly limited, but is 1/100 to 1/1 (mass ratio), preferably 1/70 to It is 1/2, more preferably 1/50 to 1/2.
　本発明のアムホテリシンＢ含有組成物は、例えば医薬、動物薬、農薬として適用することができる。医薬や動物薬の場合には、経口でも、非経口でも投与することができる。投与剤型としては、注射剤、点眼剤、点耳剤、吸引剤、内服剤（錠剤、カプセル剤、顆粒剤、散剤）、皮膚科用剤、歯科口腔用製剤などが挙げられ、それらは汎用されている技術を用いて製剤化することができる。また、本発明のアムホテリシンＢ含有組成物は、水または生理食塩水に可溶であるので、用時溶解させて注射剤などの液剤として使用することもできる。なお、本発明のアムホテリシンＢを含有する水に可溶な固形組成物および水性組成物に含まれるアムホテリシンＢの含有量は、症状、年齢、剤形などにより適宜調整することができる。 The amphotericin B-containing composition of the present invention can be applied, for example, as a medicine, veterinary medicine, or agricultural chemical. In the case of pharmaceuticals and animal drugs, they can be administered either orally or parenterally. Examples of the dosage form include injections, eye drops, ear drops, suction agents, internal preparations (tablets, capsules, granules, powders), dermatological agents, dental and oral preparations, etc. It can be formulated using known techniques. Moreover, since the amphotericin B-containing composition of the present invention is soluble in water or physiological saline, it can be dissolved at the time of use and used as a liquid preparation such as an injection. The content of amphotericin B contained in the water-soluble solid composition and aqueous composition containing amphotericin B of the present invention can be appropriately adjusted depending on symptoms, age, dosage form and the like.
　本発明のアムホテリシンＢ含有組成物は、例えば、錠剤、カプセル剤、顆粒剤、散剤などの経口剤であれば、乳糖、マンニトール、デンプン、結晶セルロース、軽質無水ケイ酸、炭酸カルシウム、リン酸水素カルシウムなどの賦形剤、ステアリン酸、ステアリン酸マグネシウム、タルクなどの滑沢剤、デンプン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドンなどの結合剤、カルボキシメチルセルロース、低置換度ヒドロキシプロピルセルロース、クエン酸カルシウムなどの崩壊剤、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコン樹脂などのコーティング剤、パラオキシ安息香酸エチル、ベンジルアルコールなどの安定化剤、甘味料、酸味料、香料などの矯味矯臭剤などを必要に応じて配合して調製することができる。 If the amphotericin B-containing composition of the present invention is an oral preparation such as a tablet, capsule, granule, powder, etc., lactose, mannitol, starch, crystalline cellulose, light anhydrous silicic acid, calcium carbonate, calcium hydrogen phosphate Excipients such as, stearic acid, magnesium stearate, lubricants such as talc, binders such as starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, carboxymethylcellulose, low substituted hydroxypropylcellulose, calcium citrate Disintegrants such as hydroxypropylmethylcellulose, macrogol, silicone resin coatings, stabilizers such as ethyl paraoxybenzoate and benzyl alcohol, sweeteners, acidulants, flavoring agents such as fragrances, etc. It can be prepared by blending in accordance with the requirements.
　本発明のアムホテリシンＢ含有水性組成物は、例えば、注射剤、点眼剤などの非経口剤であれば、塩化ナトリウム、濃グリセリンなどの等張化剤、リン酸ナトリウム、酢酸ナトリウム、ε－アミノカプロン酸などの緩衝化剤、クエン酸ナトリウム、エデト酸ナトリウムなどの安定化剤、塩化ベンザルコニウム、パラベンなどの防腐剤などを必要に応じて配合して調製することができる。 The amphotericin B-containing aqueous composition of the present invention includes, for example, parenteral preparations such as injections and eye drops, isotonic agents such as sodium chloride and concentrated glycerin, sodium phosphate, sodium acetate, and ε-aminocaproic acid. And the like, stabilizers such as sodium citrate and sodium edetate, and preservatives such as benzalkonium chloride and paraben can be blended as necessary.
　本発明のアムホテリシンＢ含有水性組成物は、安定な水溶液であり、また、生理食塩水（電解質溶液）と混合しても配合変化を起こさず、さらに、孔径０．２２μｍフィルターを用いて濾過滅菌することが可能であるので、既存の製剤よりも利便性に優れている。 The amphotericin B-containing aqueous composition of the present invention is a stable aqueous solution, and does not change its composition even when mixed with physiological saline (electrolyte solution), and further sterilized by filtration using a 0.22 μm pore size filter. Therefore, it is more convenient than existing preparations.
　以下に、各種の実施例および試験結果を示すが、これらの例は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。 Various examples and test results are shown below, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.
１．アムホテリシンＢと脂肪酸ポリエチレングリコールとを含有する水に可溶な固形組成物の調製
実施例Ａ
　ナカライテスク社製のアムホテリシンＢ（以下「ＡＭＰＨ－Ｂ」とする） ５ｍｇを、約４～１０℃で、メタノール ２０ｍＬに溶解した。この溶液に界面活性剤である日光ケミカルズ社製のステアリン酸ポリオキシル４０（以下「ＭＹＳ－４０」とする） ２５ｍｇを、約４～１０℃で加えて溶解し、減圧下約３５℃でエバポレーターを用いてメタノールを留去することにより、アムホテリシンＢを含有する水に可溶な固形組成物を得た。 1. Preparation of water-soluble solid composition containing amphotericin B and fatty acid polyethylene glycol Example A
5 mg of amphotericin B (hereinafter referred to as “AMPH-B”) manufactured by Nacalai Tesque was dissolved in 20 mL of methanol at about 4 to 10 ° C. In this solution, 25 mg of polyoxyl stearate 40 (hereinafter referred to as “MYS-40”) manufactured by Nikko Chemicals as a surfactant is added and dissolved at about 4 to 10 ° C., and an evaporator is used at about 35 ° C. under reduced pressure. Then, methanol was distilled off to obtain a water-soluble solid composition containing amphotericin B.
実施例Ｂ
　実施例ＡのＭＹＳ－４０ ２５ｍｇに代えてＭＹＳ－４０ ５０ｍｇを用いる以外は実施例Ａと同様の操作を行ってアムホテリシンＢを含有する水に可溶な固形組成物を得た。 Example B
A water-soluble solid composition containing amphotericin B was obtained in the same manner as in Example A, except that 50 mg of MYS-40 was used instead of 25 mg of MYS-40 in Example A.
実施例Ｃ
　実施例ＡのＭＹＳ－４０ ２５ｍｇに代えてＭＹＳ－４０ １００ｍｇを用いる以外は実施例Ａと同様の操作を行ってアムホテリシンＢを含有する水に可溶な固形組成物を得た。 Example C
A water-soluble solid composition containing amphotericin B was obtained in the same manner as in Example A except that 100 mg of MYS-40 was used instead of 25 mg of MYS-40 in Example A.
実施例Ｄ
　実施例ＡのＭＹＳ－４０ ２５ｍｇに代えてＭＹＳ－４０ １５０ｍｇを用いる以外は実施例Ａと同様の操作を行ってアムホテリシンＢを含有する水に可溶な固形組成物を得た。 Example D
A water-soluble solid composition containing amphotericin B was obtained in the same manner as in Example A, except that 150 mg of MYS-40 was used instead of 25 mg of MYS-40 in Example A.
実施例Ｅ
　実施例ＡのＭＹＳ－４０ ２５ｍｇに代えてＭＹＳ－４０ １０ｍｇを用いる以外は実施例Ａと同様の操作を行ってアムホテリシンＢを含有する水に可溶な固形組成物を得た。 Example E
A water-soluble solid composition containing amphotericin B was obtained in the same manner as in Example A, except that 10 mg of MYS-40 was used instead of 25 mg of MYS-40 in Example A.
実施例Ｆ
　実施例ＡのＭＹＳ－４０ ２５ｍｇに代えて日光ケミカルズ社製のステアリン酸ポリオキシル５５（以下「ＭＹＳ－５５」とする）２５ｍｇを用いる以外は実施例Ａと同様の操作を行ってアムホテリシンＢを含有する水に可溶な固形組成物を得た。 Example F
The amphotericin B is contained in the same manner as in Example A except that 25 mg of MYS-40 of Example A is used and 25 mg of polyoxyl stearate (hereinafter referred to as “MYS-55”) manufactured by Nikko Chemicals is used. A water-soluble solid composition was obtained.
実施例Ｇ
　実施例ＡのＭＹＳ－４０ ２５ｍｇに代えてＭＹＳ－５５ １００ｍｇを用いる以外は実施例Ａと同様の操作を行ってアムホテリシンＢを含有する水に可溶な固形組成物を得た。 Example G
A water-soluble solid composition containing amphotericin B was obtained in the same manner as in Example A, except that 100 mg of MYS-55 was used instead of 25 mg of MYS-40 in Example A.
実施例Ｈ
　実施例ＡのＭＹＳ－４０ ２５ｍｇに代えて日光ケミカルズ社製のステアリン酸ポリオキシル２５（以下「ＭＹＳ－２５」とする） １００ｍｇを用いる以外は実施例Ａと同様の操作を行ってアムホテリシンＢを含有する水に可溶な固形組成物を得た。 Example H
In place of 25 mg of MYS-40 of Example A, amphotericin B is contained in the same manner as in Example A, except that 100 mg of polyoxyl 25 stearate (hereinafter referred to as “MYS-25”) manufactured by Nikko Chemicals is used. A water-soluble solid composition was obtained.
実施例Ｉ
　ＡＭＰＨ－Ｂ ３００ｍｇをメタノール １２００ｍＬで溶解後、減圧下約３５℃でメタノールを留去して固体の残留物を得た。この残留物１００ｍｇを約４０℃に加温したＭＹＳ－４０ ２ｇに混和することによりアムホテリシンＢを含有する水に可溶な固形組成物を得た。 Example I
After dissolving 300 mg of AMPH-B in 1200 mL of methanol, methanol was distilled off at about 35 ° C. under reduced pressure to obtain a solid residue. 100 mg of this residue was mixed with 2 g of MYS-40 heated to about 40 ° C. to obtain a water-soluble solid composition containing amphotericin B.
実施例Ｊ
　実施例Ａのメタノール ２０ｍＬに代えてエタノール ５００ｍＬを用いる以外は実施例Ａと同様の操作を行ってアムホテリシンＢを含有する水に可溶な固形組成物を得た。 Example J
A water-soluble solid composition containing amphotericin B was obtained by performing the same operation as in Example A, except that 500 mL of ethanol was used instead of 20 mL of methanol in Example A.
　実施例Ａ～Ｊの配合組成を表１に示す。 Table 1 shows the composition of Examples A to J.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
２．アムホテリシンＢ、脂肪酸ポリエチレングリコールおよび水を含有する水性組成物の調製
実施例１～１０
　実施例Ａ～Ｊで得られた各アムホテリシンＢを含有する水に可溶な固形組成物に、水性組成物中のアムホテリシンＢの濃度が０．１％となるように注射用水を加えた後、遮光下、約４～１０℃で攪拌して澄明なアムホテリシンＢを含有する水性組成物［実施例１～１０］を得た。 2. Preparation of aqueous compositions containing amphotericin B, fatty acid polyethylene glycol and water Examples 1-10
After water for injection was added to the water-soluble solid composition containing each amphotericin B obtained in Examples A to J so that the concentration of amphotericin B in the aqueous composition was 0.1%, The mixture was stirred at about 4 to 10 ° C. in the dark to obtain an aqueous composition [Examples 1 to 10] containing clear amphotericin B.
比較例１
　ＭＹＳ－４０ １００ｍｇを注射用水５ｍＬに溶解した。この水溶液にＡＭＰＨ－Ｂ ５ｍｇを添加して、遮光下、約４～１０℃で攪拌して混濁したアムホテリシンＢを含有する組成物を得た。 Comparative Example 1
100 mg of MYS-40 was dissolved in 5 mL of water for injection. To this aqueous solution, 5 mg of AMPH-B was added and stirred at about 4 to 10 ° C. in the dark to obtain a turbid composition containing amphotericin B.
比較例２
　ＡＭＰＨ－Ｂ ５ｍｇをメタノール ２０ｍＬで溶解した。この溶液に界面活性剤であるポリソルベート８０ １００ｍｇを加えて溶解後、減圧下約３５℃でメタノールを留去することによりアムホテリシンＢを含有する組成物を得た。このアムホテリシンＢ含有組成物に、注射用水 ５ｍＬを加えた後、遮光下、約４～１０℃で攪拌して混濁したアムホテリシンＢを含有する組成物を得た。 Comparative Example 2
5 mg of AMPH-B was dissolved in 20 mL of methanol. 100 mg of polysorbate 80 as a surfactant was added to this solution and dissolved, and then methanol was distilled off at about 35 ° C. under reduced pressure to obtain a composition containing amphotericin B. After adding 5 mL of water for injection to this amphotericin B-containing composition, the composition containing amphotericin B was obtained by stirring at about 4 to 10 ° C. under light shielding.
比較例３
　「ファンギゾン注射用５０ｍｇ」を注射用水 １０ｍＬに加えて溶解させた。 Comparative Example 3
“50 mg for fungizone injection” was added to 10 mL of water for injection and dissolved.
（結果）
　実施例１～４および比較例１～２で得られた各組成物の外観を図１に示す。 (result)
The appearance of each composition obtained in Examples 1-4 and Comparative Examples 1-2 is shown in FIG.
（考察）
　実施例１～１０、比較例１～２および図１から明らかなように、市販のＡＭＰＨ－Ｂをメタノールで処理［溶解・留去］することなくそのまま用いても澄明な水溶液とはならず、また、脂肪酸ポリエチレングリコール（ＭＹＳ－５５、ＭＹＳ－４０、ＭＹＳ－２５）に代えてポリオキシエチレンソルビタンオレイン酸エステル（ポリソルベート８０）を用いても澄明な水溶液は得られない。したがって、（１）アムホテリシンＢを低級アルコールに溶解後、低級アルコールを留去して得られたものに脂肪酸ポリエチレングリコールと水を加えた水性組成物、または（２）アムホテリシンＢおよび脂肪酸ポリエチレングリコールを低級アルコールに溶解後、低級アルコールを留去してから水を加えた水性組成物とすることによってはじめて澄明な水溶液が得られる。 (Discussion)
As is clear from Examples 1 to 10, Comparative Examples 1 and 2 and FIG. 1, even if commercially available AMPH-B is used as it is without being treated (dissolved and distilled off) with methanol, it does not become a clear aqueous solution, Also, a clear aqueous solution cannot be obtained by using polyoxyethylene sorbitan oleate (polysorbate 80) instead of fatty acid polyethylene glycol (MYS-55, MYS-40, MYS-25). Therefore, (1) an aqueous composition in which fatty acid polyethylene glycol and water are added to a product obtained by dissolving amphotericin B in lower alcohol and then distilling off lower alcohol, or (2) lowering amphotericin B and fatty acid polyethylene glycol to lower A clear aqueous solution can be obtained only by dissolving in alcohol and then distilling off the lower alcohol and then adding water to form an aqueous composition.
３．アムホテリシンＢを含有する水性組成物中のアムホテリシンＢ濃度
　（測定用標準液の調製）
　ＡＭＰＨ－Ｂ ２．５ｍｇをＤＭＳＯ ５ｍＬに溶解し、さらにＤＭＳＯを加えて１０ｍＬとした（ＡＭＰＨ－Ｂ-ＤＭＳＯ溶液）。マイクロチューブにＤＭＳＯをそれぞれ９２０、９６０、９８０μＬ量り取り、ＡＭＰＨ－Ｂ-ＤＭＳＯ溶液 ８０、４０、２０μＬをそれぞれ添加して測定用標準液とした。 3. Amphotericin B concentration in an aqueous composition containing amphotericin B (Preparation of standard solution for measurement)
2.5 mg of AMPH-B was dissolved in 5 mL of DMSO, and DMSO was further added to make 10 mL (AMPH-B-DMSO solution). 920, 960, and 980 μL of DMSO were weighed into the microtubes, respectively, and 80, 40, and 20 μL of AMPH-B-DMSO solution were added to obtain standard solutions for measurement.
　（試料溶液の調製）
　実施例１～４および比較例１～２で得られた組成物を１３、０００ｒｐｍ １０分間遠心分離し、その上清を得た（上清液）。マイクロチューブにＤＭＳＯ ９９０μＬを量り取り、上清液 １０μＬを添加して各試料溶液とした。 (Preparation of sample solution)
The compositions obtained in Examples 1 to 4 and Comparative Examples 1 to 2 were centrifuged at 13,000 rpm for 10 minutes to obtain the supernatant (supernatant liquid). 990 μL of DMSO was weighed into a microtube, and 10 μL of supernatant was added to prepare each sample solution.
　各試料溶液中のＡＭＰＨ－Ｂ濃度は吸光プレートリーダー（ＳｐｅｃｔｒａＭａｘ Ｐｌｕｓ３８４、Ｍｏｌｅｃｕｌａｒ Ｄｅｖｉｃｅｓ社）にて波長３９０ｎｍで測定し、測定用標準液の吸光度と比較して算出した。 The AMPH-B concentration in each sample solution was measured at a wavelength of 390 nm with an absorption plate reader (SpectraMax Plus 384 , Molecular Devices), and calculated by comparing with the absorbance of the standard solution for measurement.
　（結果）
　各試料溶液中のＡＭＰＨ－Ｂ濃度を表２に示す。 (result)
Table 2 shows the concentration of AMPH-B in each sample solution.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　（考察）
　表２より、実施例１～４で得られた組成物中のＡＭＰＨ－Ｂの濃度は理論濃度と一致しているので、本発明のアムホテリシンＢを含有する水性組成物は水への溶解性に優れていることが明らかとなった。 (Discussion)
From Table 2, since the concentration of AMPH-B in the compositions obtained in Examples 1 to 4 is in agreement with the theoretical concentration, the aqueous composition containing amphotericin B of the present invention is soluble in water. It became clear that it was excellent.
　４．生理食塩水による配合変化
　実施例１～４および比較例３で得られた組成物を生理食塩水と混合して配合変化の有無を検討した。 4). Changes in formulation due to physiological saline The compositions obtained in Examples 1 to 4 and Comparative Example 3 were mixed with physiological saline to examine the presence or absence of changes in the formulation.
　（試験材料および方法）
　実施例１～４で得られた組成物を遠心分離処理した後の上清液を用いた。生理食塩水と各上清液は、生理食塩水：上清液＝１：１（容量比）で混合し、室温にて外観を観察した。
　比較例３で得られた組成物は添付文書に記載の調製法に従ってファンギゾン注射用５０ｍｇに注射用水１０ｍＬを添加して溶解した。生理食塩水との混合は上記と同様に容量比１：１で混合し、室温にて外観を観察した。 (Test materials and methods)
The supernatant obtained after centrifuging the compositions obtained in Examples 1 to 4 was used. The physiological saline and each supernatant liquid were mixed with physiological saline: supernatant liquid = 1: 1 (volume ratio), and the appearance was observed at room temperature.
The composition obtained in Comparative Example 3 was dissolved by adding 10 mL of water for injection to 50 mg of fungizone for injection according to the preparation method described in the package insert. The mixture with physiological saline was mixed at a volume ratio of 1: 1 as described above, and the appearance was observed at room temperature.
　（結果）
　実施例１～４または比較例３で得られた組成物を、生理食塩水と混合後して得られる溶液の外観を図２に示す。 (result)
The appearance of the solution obtained by mixing the composition obtained in Examples 1 to 4 or Comparative Example 3 with physiological saline is shown in FIG.
　（考察）
　図２から明らかなように、本発明のアムホテリシンＢを含有する水性組成物は、生理食塩水（電解質溶液）と混合しても配合変化を起こさず安定であるのに対して、比較例３（市販のアムホテリシンＢ含有注射用製剤）は配合変化を起こして混濁している。したがって、本発明のアムホテリシンＢを含有する水性組成物は、生理食塩水などの電解質溶液と混合しも配合変化を起こさず安定である。 (Discussion)
As is clear from FIG. 2, the aqueous composition containing amphotericin B of the present invention is stable without causing a change in composition even when mixed with physiological saline (electrolyte solution), whereas Comparative Example 3 ( A commercially available amphotericin B-containing preparation for injection) is turbid due to a change in formulation. Therefore, the aqueous composition containing amphotericin B of the present invention is stable without causing any change in composition even when mixed with an electrolyte solution such as physiological saline.
　５．フィルター通過性
　実施例１～２および比較例２～３で得られた組成物を用いて、孔径０．２２μｍフィルターの通過性を検討した。 5. Filter passability Using the compositions obtained in Examples 1-2 and Comparative Examples 2-3, the passability of filters having a pore size of 0.22 μm was examined.
　(試験材料および方法)
　実施例１～２および比較例２～３と生理食塩液を１：１（容量比）の割合で混合した各混合液をシリンジに取り、ついで、ミリポア社の直径３３ｍｍ、孔径０．２２μｍフィルター（型番：Millex(登録商標)-GV）に装着してプランジャーを指で押して抵抗の有無を確認した。 (Test materials and methods)
Each mixed solution obtained by mixing Examples 1-2 and Comparative Examples 2-3 and physiological saline at a ratio of 1: 1 (volume ratio) was taken in a syringe, and then a filter having a diameter of 33 mm and a pore diameter of 0.22 μm (available from Millipore) (Model number: Millex (registered trademark) -GV) and the plunger was pressed with a finger to check for resistance.
　（結果）
　実施例１～２で得られた組成物では、抵抗はほとんどなくフィルター通過性が良好であったが、比較例２～３で得られた組成物では抵抗が大きくフィルターを完全に通過させることができなかった。 (result)
The compositions obtained in Examples 1 and 2 had almost no resistance and good filter permeability, but the compositions obtained in Comparative Examples 2 and 3 had high resistance and could pass through the filter completely. could not.
　（考察）
　本発明のアムホテリシンＢを含有する水性組成物を生理食塩水（電解質液）で希釈したものは、孔径０．２２μｍフィルターを用いて濾過滅菌することが可能となる。 (Discussion)
The aqueous composition containing amphotericin B of the present invention diluted with physiological saline (electrolyte solution) can be sterilized by filtration using a 0.22 μm pore size filter.
　６．製剤例（実施例）
本発明のアムホテリシンＢを含有する水に可溶な固形組成物または水性組成物を用いた代表的な製剤例を以下に示す。 6). Formulation Example (Example)
A typical formulation example using a water-soluble solid composition or aqueous composition containing amphotericin B of the present invention is shown below.
１）注射剤（１０ｍＬ中）
実施例Ａの水に可溶な固形組成物　　　　　　　　　　　　　　０．３ｇ
塩化ナトリウム　　　　　　　　　　　　　　　　　　　　　　９０ｍｇ
水酸化ナトリウム　　　　　　　　　　　　　　　　　　　　　　　適量
塩酸　　　　　　　　　　　　　　　　　　　　　　　　　　　　　適量
滅菌精製水　　　　　　　　　　　　　　　　　　　　　　　　　　適量
　実施例Ａの水に可溶な固形組成物および添加物の混合比を適宜変更することにより、所望の注射剤を得ることができる。また、凍結乾燥して用時溶解用注射剤とすることもできる。 1) Injection (in 10 mL)
0.3 g of water-soluble solid composition of Example A
Sodium chloride 90mg
Sodium hydroxide Appropriate amount Appropriate hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount By appropriately changing the mixing ratio of the solid composition soluble in water and the additive of Example A, a desired injection can be obtained. It can also be lyophilized to give an injection for dissolution at the time of use.
２）点眼剤（１００ｍＬ中）
実施例１の水性組成物　　　　　　　　　　　　　　　　　　　　　３ｇ
塩化ナトリウム　　　　　　　　　　　　　　　　　　　　　９００ｍｇ
塩化ベンザルコニウム　　　　　　　　　　　　　　　　　　　１０ｍｇ
水酸化ナトリウム　　　　　　　　　　　　　　　　　　　　　　　適量
塩酸　　　　　　　　　　　　　　　　　　　　　　　　　　　　　適量
滅菌精製水　　　　　　　　　　　　　　　　　　　　　　　　　　適量
　実施例１の水性組成物および添加物の種類および量を適宜変更することにより、所望の点眼剤を得ることができる。 2) Eye drops (in 100 mL)
3 g of the aqueous composition of Example 1
Sodium chloride 900mg
Benzalkonium chloride 10mg
Sodium hydroxide Appropriate amount Appropriate hydrochloric acid Appropriate amount Sterilized purified water Appropriate amount By appropriately changing the type and amount of the aqueous composition and additive of Example 1, a desired eye drop can be obtained.
３）錠剤（１錠）
実施例Ａの水に可溶な固形組成物　　　　　　　　　　　　　　０．３ｇ
乳糖　　　　　　　　　　　　　　　　　　　　　　　　　６６．４ｍｇ
トウモロコシデンプン　　　　　　　　　　　　　　　　　　　２０ｍｇ
カルボキシメチルセルロースカルシウム　　　　　　　　　　　　６ｍｇ
ヒドロキシプロピルセルロース　　　　　　　　　　　　　　　　４ｍｇ
ステアリン酸マグネシウム　　　　　　　　　　　　　　　　０．６ｍｇ
　上記処方の錠剤に、コーティング剤（たとえば、ヒドロキシプロピルメチルセルロース、マクロゴール、シリコーン樹脂などの通常のコーティング剤）２ｍｇを用いてコーティングを施し、目的とするコーティング錠を得る。また、実施例Ａの水に可溶な固形組成物および添加物の種類および量を適宜変更することにより、所望の錠剤を得ることができる。 3) Tablet (1 tablet)
0.3 g of water-soluble solid composition of Example A
Lactose 66.4mg
Corn starch 20mg
Carboxymethylcellulose calcium 6mg
Hydroxypropylcellulose 4mg
Magnesium stearate 0.6mg
The tablet with the above formulation is coated with 2 mg of a coating agent (for example, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin, etc.) to obtain the desired coated tablet. Moreover, a desired tablet can be obtained by changing suitably the kind and quantity of the water-soluble solid composition and additive of Example A.
４）カプセル剤（１カプセル中）
実施例Ａの水に可溶な固形組成物　　　　　　　　　　　　　　０．３ｇ
乳糖　　　　　　　　　　　　　　　　　　　　　　　　　　１００ｍｇ
トウモロコシデンプン　　　　　　　　　　　　　　　　　　　３０ｍｇ
ポビドン　　　　　　　　　　　　　　　　　　　　　　　　　１５ｍｇ
タルク　　　　　　　　　　　　　　　　　　　　　　　　　　　５ｍｇ
　実施例Ａの水に可溶な固形組成物と乳糖の混合比を適宜変更することにより、所望のカプセル剤を得ることができる。 4) Capsule (in 1 capsule)
0.3 g of water-soluble solid composition of Example A
Lactose 100mg
Corn starch 30mg
Povidone 15mg
Talc 5mg
A desired capsule can be obtained by appropriately changing the mixing ratio of the water-soluble solid composition of Example A and lactose.

Claims (9)

  1. 　アムホテリシンＢと脂肪酸ポリエチレングリコールとを含有する水に可溶な固形組成物。 A water-soluble solid composition containing amphotericin B and fatty acid polyethylene glycol.
  2. 　アムホテリシンＢを低級アルコールに溶解後、低級アルコールを留去する工程を経て製造される請求項１記載の固形組成物。 The solid composition according to claim 1, which is produced through a step of distilling off the lower alcohol after dissolving amphotericin B in the lower alcohol.
  3. 　アムホテリシンＢの濃度が１～５０％（ｗ／ｗ）であり、脂肪酸ポリエチレングリコールの濃度が５０～９９％（ｗ／ｗ）である請求項１または２記載の固形組成物。 3. The solid composition according to claim 1, wherein the concentration of amphotericin B is 1 to 50% (w / w) and the concentration of fatty acid polyethylene glycol is 50 to 99% (w / w).
  4. 　アムホテリシンＢ、脂肪酸ポリエチレングリコールおよび水を含有する水性組成物。 An aqueous composition containing amphotericin B, fatty acid polyethylene glycol and water.
  5. 　アムホテリシンＢを低級アルコールに溶解後、低級アルコールを留去する工程を経て製造される請求項４記載の水性組成物。 The aqueous composition according to claim 4, which is produced through a step of distilling off the lower alcohol after dissolving amphotericin B in the lower alcohol.
  6. 　アムホテリシンＢの濃度が０．０１～２０％（ｗ／ｗ）あり、脂肪酸ポリエチレングリコールの濃度が０．０１～４０％（ｗ／ｗ）である請求項４または５記載の水性組成物。 6. The aqueous composition according to claim 4, wherein the concentration of amphotericin B is 0.01 to 20% (w / w) and the concentration of fatty acid polyethylene glycol is 0.01 to 40% (w / w).
  7. 　脂肪酸ポリエチレングリコールが、モノステアリン酸ポリエチレングリコール５５、モノステアリン酸ポリエチレングリコール４０およびモノステアリン酸ポリエチレングリコール２５からなる群から選択される少なくとも１種である請求項１～６記載の固形組成物または水性組成物。 7. The solid composition or aqueous composition according to claim 1, wherein the fatty acid polyethylene glycol is at least one selected from the group consisting of polyethylene glycol monostearate 55, polyethylene glycol monostearate 40, and polyethylene glycol monostearate 25. object.
  8. 　低級アルコールが、メタノールまたはエタノールである請求項１～６記載の固形組成物または水性組成物。 The solid composition or aqueous composition according to claims 1 to 6, wherein the lower alcohol is methanol or ethanol.
  9. 　請求項１～８記載の固形組成物または水性組成物を含む注射剤、点眼剤、点耳剤、吸引剤、内服剤、皮膚科用剤または歯科口腔用製剤。 9. An injection, an eye drop, an ear drop, an inhalant, an internal preparation, a dermatological preparation or a dental oral preparation containing the solid composition or the aqueous composition according to claim 1.
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Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
DAROLE, PRADNYA S. ET AL.: "Formulation and evaluation of microemulsion based delivery system for amphotericin B", AAPS PHARMSCITECH, vol. 9, no. 1, 2008, pages 122 - 128 *
KAUR, RABINDER ET AL.: "Comparison of polyethylene glycol and polyoxyethylene stearate as excipients for solid dispersion systems of griseofulvin and tolbutamide. I: Phase equilibriums", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 69, no. LL, 1980, pages 1317 - 1321 *
KAUR, RABINDER ET AL.: "Comparison of polyethylene glycol and polyoxyethylene stearate as excipients for solid dispersion systems of griseofulvin and tolbutamide. II: Dissolution and solubility studies", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 69, no. LL, 1980, pages 1321 - 1326 *
TASSET, C. ET AL.: "The influence of Myrj 59 on the solubility, toxicity and activity of amphotericin B", JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 43, no. 5, 1991, pages 297 - 302 *
TASSET, CHANTAL ET AL.: "Comparison of nephrotoxicities of different polyoxyethylene formulations of amphotericin B in rats", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 36, no. 7, 1992, pages 1525 - 1531 *

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