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WO2014007239A1 - Composition contenant de l'amphotéricine b - Google Patents

Composition contenant de l'amphotéricine 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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WIPO (PCT)
Prior art keywords
amphotericin
polyethylene glycol
water
fatty acid
lower alcohol
Prior art date
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Ceased
Application number
PCT/JP2013/068117
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English (en)
Japanese (ja)
Inventor
肇 伊吹
光明 桑野
健太 吉井
貴司 坪井
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Santen Pharmaceutical Co Ltd
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Santen Pharmaceutical Co Ltd
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Filing date
Publication date
Application filed by Santen Pharmaceutical Co Ltd filed Critical Santen Pharmaceutical Co Ltd
Publication of WO2014007239A1 publication Critical patent/WO2014007239A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
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  • Animal Behavior & Ethology (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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PCT/JP2013/068117 2012-07-03 2013-07-02 Composition contenant de l'amphotéricine b Ceased WO2014007239A1 (fr)

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JP2012-149273 2012-07-03

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CA3053566A1 (fr) * 2017-02-21 2018-08-30 Ico Therapeutics Inc. Formulations orales solides d'amphotericine b

Non-Patent Citations (5)

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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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