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WO1999027940A1 - Preparation pour traitement local des infections de la peau - Google Patents

Preparation pour traitement local des infections de la peau Download PDF

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Publication number
WO1999027940A1
WO1999027940A1 PCT/IL1998/000582 IL9800582W WO9927940A1 WO 1999027940 A1 WO1999027940 A1 WO 1999027940A1 IL 9800582 W IL9800582 W IL 9800582W WO 9927940 A1 WO9927940 A1 WO 9927940A1
Authority
WO
WIPO (PCT)
Prior art keywords
amphotericin
composition
infection
lipid
drug
Prior art date
Application number
PCT/IL1998/000582
Other languages
English (en)
Inventor
Shoshana Frankenburg
Yechezkel Barenholz
Dvora Glick
Sidney N. Klaus
Original Assignee
Yissum Research Development Company Of The Hebrew University Of Jerusalem
Hadasit Medical Research Services And Development Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yissum Research Development Company Of The Hebrew University Of Jerusalem, Hadasit Medical Research Services And Development Ltd. filed Critical Yissum Research Development Company Of The Hebrew University Of Jerusalem
Priority to IL13634298A priority Critical patent/IL136342A0/xx
Priority to AU13500/99A priority patent/AU1350099A/en
Publication of WO1999027940A1 publication Critical patent/WO1999027940A1/fr

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Classifications

    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to topical formulations of antimicrobial agents.
  • the invention is directed to the use of topical formulations of amphotericin B against parasites and infectious organisms, and to the topical use of synergistic combinations of amphotericin B with other antifiingal agents.
  • Amphotericin B a polyene antibiotic
  • Amphotericin B is a potent antifiingal and antiparasitic agent having a broad spectrum of activity, against organisms having ergosterol in their membranes. It is commonly used as a systemic agent, administered intravenously, against such infections as aspergillosis, systemic candidiasis, cryptococcosis, North American blastomycosis, coccidioido- mycosis, histoplasmosis, zygomycosis, and sporotrichosis. It has also shown high activity against leishmania infection. However, because amphotericin B can be highly toxic, particularly nephrotoxic, when given systemically, it is thus generally used only after other treatments have failed (e.g. Giri, 1993).
  • Toxic side effects are typically greatly reduced when a drug is administered topically, since much lower doses can generally be used, and a very small amount of the drug is absorbed systemically.
  • topical amphotericin B preparations on mucous membrane surfaces such as those of the eye, mouth and respiratory and digestive passages, often in combination with other agents, has been described (e.g. Lotery et al, 1994; Pleyer et al, 1992; Aerdts et al, 1991; Bent et al, 1996).
  • the skin is a very effective barrier for substances with a molecular weight higher than a few hundred daltons.
  • CL Cutaneous leishmaniasis
  • paromomycin an aminoglycoside antibiotic
  • the currently available topical treatment for CL is a formulation of paromomycin and memylbenzethonium chloride. This preparation also has the disadvantages of significant initial irritation and high cost.
  • the present invention includes, in one aspect, a composition and method for topical treatment of a fungal or protozoal infection of the skin or nails.
  • the composition includes a therapeutic amount of a lipid formulation of amphotericin B, dispersed in an aqueous carrier containing about 2% to about 35% by volume ethanol relative to water.
  • a therapeutic amount of such a composition is administered topically to the site of infection in a subject in need of such treatment.
  • the aqueous carrier is about 5% to 25% by volume ethanol relative to water; more preferably, the formulation is glucose-free.
  • the lipid-based formulation is preferably a stable complex of amphotericin B witfi at least one amphipamic lipid molecule. It may also be a liposomal formulation, comprising amphotericin B encapsulated in liposomes composed of vesicle-forming lipids.
  • the lipids are preferably phospholipids, glycolipids, sterols, or sterol derivatives, or a combination thereof, having a high affinity for amphotericin B.
  • Particularly preferred lipids are selected from dimyristoyl phosphatidyl choline (DMPC), dimyristoyl phosphatidyl glycerol (DMPG), and distearoyl phosphatidyl glycerol (DSPG), soy phosphatidyl choline, egg phosphatidyl choline, cholesterol, and cholesteryl esters, such as cholesteryl sulfate. Cholesteryl sulfate is particularly preferred.
  • the fungal or protozoal infection being treated is present in a human subject.
  • the topical infection may be, for example, cutaneous leishmaniasis, cutaneous candidiasis, Candida paronychia or Candida onychomycosis infection.
  • the infection being treated is cutaneous leishmaniasis.
  • the composition further includes a second drug with anti-dermatophyte activity
  • the method of die invention further comprises administering such a second drug with the above-described lipid formulation of amphotericin B.
  • the dermatophyte infection being treated is preferably a tinea or onychomycosis infection.
  • the second drug is preferably griseofulvin, allicin, a polyoxin, a nikkomycin, or fluorocytosine, and is most preferably griseofulvin or allicin.
  • the combined composition has potentiated anti-dermatophyte activity relative to the combined activity of compositions containing either amphotericin B or the second drug alone.
  • compositions and methods for topical treatment of a fungal or protozoal infection of the skin or nails where the composition includes a therapeutic amount of allicin dispersed in an aqueous carrier containing about 2% to about 35% by volume ethanol relative to water.
  • a therapeutic amount of such a composition is administered topically to the site of infection in a subject in need of such treatment.
  • the aqueous carrier is about 5% to 25% by volume ethanol relative to water.
  • Figure 1 shows the effect of formulations of amphotericin B/cholesteryl sulfate (Amphocif) in various solvents, applied topically, on the size of cutaneous leishmaniasis lesions in CBA inbred mice;
  • Figure 2 shows the effect of Amphocif in aqueous ethanol and of aqueous ethanol alone on CL lesion size, as in Figure 1 ;
  • Figure 3 shows the effect of Amphocil * in aqueous ethanol and in distilled water, and of Fungizone® in aqueous ethanol, on CL lesion size, as in Figures 1-2;
  • Figures 4 and 5 are graphic representations of selected data from Tables 5 and 6, respectively, showing levels of AmB measured in the skin and internal organs after topical administration of AmB/lipid complexes in aqueous ethanol.
  • amphipathic lipid molecule refers to a molecule of a lipid, that is, any of a group of hydrophobic substances found in nature and having aliphatic hydrocarbon chains, e.g. fatty acids, sterols, phospholipids, and various derivatives diereof, having a hydrophobic region and a polar, hydrophilic region.
  • Vesicle-forming lipids which can form bilayer vesicles in water, or which can be stably incorporated into a lipid bilayer, with the hydrophobic moiety in contact with the interior, hydrophobic region of the bilayer membrane, and the polar head group moiety oriented toward the exterior, polar surface of the membrane.
  • Vesicle-forming lipids of this type typically include one or two hydrophobic acyl hydrocarbon chains or a steroid group and may contain a chemically reactive group, such as an amine, acid, ester, aldehyde or alcohol, at die polar head group.
  • phospholipids such as phosphatidyl choline (PC), phosphatidyl glycerol (PG), phosphatidyl ethanolamine (PE), phosphatidic acid (PA), phosphatidyl inositol (PI), and sphingomyelin (SM), where the two hydrocarbon chains are typically between about 14-22 carbon atoms in length, and have varying degrees of unsaturation.
  • PC phosphatidyl choline
  • PG phosphatidyl glycerol
  • PE phosphatidyl ethanolamine
  • PA phosphatidic acid
  • PI phosphatidyl inositol
  • SM sphingomyelin
  • DMPC dimyristoyl phosphatidyl choline
  • DMPG dimyristoyl phosphatidyl glycerol
  • DSPG distearoyl phosphatidyl glycerol
  • a "stable complex" of amphotericin B with at least one amphipathic lipid molecule is a complex in which the lipid molecule has a high binding affinity for amphotericin B.
  • the affinity is at least comparable to that of cholesteryl sulfate. Binding, or lack thereof, of AmB to a lipid or mixture of lipids may be evaluated by spectroscopic or other methods, as discussed in Section HA below. ⁇ . Topical Amphotericin B Formulations and Effect on Cutaneous Leishmaniasis Lesions
  • amphipathic phospholipids as described above, as well as sterols and sterol derivatives, may be used in die current compositions.
  • polar cholesteryl esters such as cholesteryl sulfate
  • compounds having a high affinity for AmB are most effective in the topical formulations described herein.
  • Amphocil® as discussed below, d e lipid component, cholesteryl stearate, has a much higher AmB association constant than sodium deoxycholate, used in Fungizone® (Cohen et al., 1996).
  • the binding affinity of a lipid for AmB may be measured by various me iods reported in d e literature, many of which are based on changes in the absorption spectra of AmB upon complexation. See, for example, Janoff et al, 1991; Readio et al. (1982) and references therein. Circular dichroism spectroscopy (Jullien et al, 1988; Milhaud et al, 1994) has been reported to be more accurate in systems widi higher concentrations of AmB.
  • the interaction of AmB with lipid vesicles may also be evaluated by observing leakage of marker substances from such vesicles (e.g. carboxyfluorescein, as reported by Milhaud et al, 1994).
  • amphotericin B formulations used to produce die results shown in Figs. 1-3 were prepared using Amphocil' * , a complex of amphotericin B and cholesteryl sulfate, available as a colloidal dispersion from Sequus Pharmaceuticals.
  • This preparation normally administered by injection, contains small (approximately 100 ran) diskoid particles (see e.g. Barenholz and Cohen, 1995) composed of 1: 1 (molar ratio) amphotericin B and cholesteryl sulfate.
  • the commercial preparation also contains glucose (5%), as do most drug formulations intended for i.v. injection.
  • Dispersions of Amphocil * were prepared in the following media:
  • Amphotericin B itself is insoluble in water or ethanol; however, Amphocil * disperses easily in aqueous solutions of 5% glucose or 5% ethanol. To obtain a dispersion in propylene glycol or glycerol, strong vortexing and ultrasonic irradiation were necessary. The amount of amphotericin B was quantified using HPLC followed by absorbance at 408 ran, and brought to a concentration of 5 mg/ml for particle size measurement.
  • a glucose-free preparation used in d e clinical trial described in Section D, was prepared by diluting Amphocil * widi water and dialyzing the solution (cellophane dialysis tubing, molecular weight cutoff 12-14,000 daltons) against double distilled water for 24 hours, before addition of ethanol.
  • Formulations C, D and E which dispersed widi difficulty, formed particles which were too large to be measured by photon correlation spectroscopy: These preparations were measured widi a Coulter multisizer, which measures particle size from 0.8-30 ⁇ m.
  • mice CBA inbred mice, which develop self healing lesions, were used for the in vivo experiments.
  • Each mouse was injected in the base of the tail with 5 x 10 6 promastigotes from a stationary (infective) growth culture. These parasites were found to be sensitive to aqueous formulations in vitro (see below).
  • the mice were divided into groups of at least 8 mice each, with one group as an untreated control.
  • the topical preparations used were dispersions of Amphocil * in glycerol, propylene glycol, 10% EtOH in DDW, and 5% glucose in DDW, as described above.
  • Lesion size was measured weekly. To determine the diameter, the average was taken between the longest distance across the lesion and the lengtii of the line bisecting this distance at a 90° angle. Results are shown in Fig. 1.
  • the Figure shows that topical administration of Amphocil® in 10% ethanol caused a marked reduction in lesion size. The effect was statistically significant from week 3 onwards. The group receiving Amphocil® in 5% glucose had statistically smaller lesions than the controls at only one timepoint (week 4), and the other groups showed little or no effect.
  • Each patient was given two vials, one containing Amphocil® dispersed in a 5% edianol solution and die odier containing 5 % ethanol in water.
  • the location of the lesions was designated on respective bottles (e.g. bottle #1: right leg and arm; bottle #2: left shin and knee).
  • the patient was instructed to apply 2-5 drops from the designated bottles onto each lesion three times daily.
  • the first 5 patients were treated with a glucose (5%)-containing AmB preparation, and the next 6 patients were treated with a glucose-free preparation.
  • Each treated lesion received 1.5-3.75 mg amphotericin B per day. Patients were followed up every 1-2 weeks in the course of the treatment.
  • Amphocil® as described above, was dissolved in 5% edianol : 95% distilled water to a concentration of 5 mg/ml AmB. This preparation contained 5% glucose.
  • water was added to Amphocil®, and die solution was dialyzed (cellophane dialysis tubing, molecular weight cut off 12-14000 daltons) against double distilled water for 24 hours, before addition of edianol. Size distribution and mean particle size of the dispersion were compared before and after dialysis by photon correlation spectroscopy using Coulter submicron particle analysis (Coulter N4SD submicron particle analyzer, Coulter Electronics Ltd, Luton, England).
  • Size distribution was unimodal before and after dialysis, although mean size increased slightly, frcm 104 ⁇ 23 nm before dialysis to 129 ⁇ 29 ran after dialysis. After dialysis, particle size remained stable for at least 5 weeks when stored at 4 °C.
  • Lesion diameters were measured every 7-14 days in the course of die treatment. Lesion area (mm 2 ) was determined, and die difference before and after treatment ( ⁇ mm 2 ) was calculated. The nonparametric Wilcoxon Matched-Pairs Signed-Ranks Test was used for statistical analysis. The SPSS program was used to run the analysis.
  • ⁇ mm 2 lesion size after treatment - lesion size before treatment; i: % increase in lesion size.
  • Omer lipid formulations of amphotericin B may also be used, preferably complexes of amphotericin B with amphipadiic lipid molecules having a high affinity for the drug, as well as dispersions of liposomes in which die drug has been encapsulated, according to well known mediods.
  • ABPLC amphotericin B phospholipid complex, described in Engelhard et al., 1993
  • ABPLC is a 1 :3 molar complex of AmB with a 7:3 molar mixture of DMPC and DMPG. This complex tends to form large (approx. 2.75 ⁇ m) aggregate particles (Barenholz and Cohen, 1995).
  • a topical formulation of ABPLC in 0.9% NaCl/5% ethanol was found to be at least as effective as die AmB/cholesteryl sulfate formulations in reducing lesion size, in spite of the large particle size in this formulation.
  • different types of AmB/lipid assemblies have been found to be effective.
  • the commercial AmB preparation Fungizone * (Bristol Myers Squibb) contains sodium deoxycholate, which has relatively low affinity for the drug (see e.g. Brajtburg and Bolard, 1996; Janoff et al., 1991). Accordingly, ethanolic formulations containing Fungizone * were much less effective topically than diose described above (Fig. 3), although diey were highly effective in vitro (see Section 1TI below).
  • dosages of AmB administered topically result in much lower levels of the drug in internal organs than lower dosages administered systemically. Accordingly, higher dosages may be used with greatly reduced toxic side effects.
  • an effective amount of an aqueous ethanolic solution or dispersion of a lipid/AmB complex, such as described herein, is applied to the site of the infection, preferably about once daily.
  • the formulation is glucose-free.
  • a single application preferably contains about 5 to 500 ⁇ g, and more preferably about 20 to 200 ⁇ g, of amphotericin B, depending on die severity of the infection. Applications are repeated as necessary until die infection is substantially reduced or eliminated. H3. Effect of Amphotericin B Formulations on Leishmania Major Promastigotes in vitro
  • Amphotericin B/deoxycholate (Fungizone * ) in 5% edianol, although highly effective in killing parasites in vitro (see Table 4), was ineffective in vivo when applied topically (Fig. 3).
  • die deoxycholate carrier molecule has a relatively low affinity for AmB.
  • Table 5 shows the level of AmB detected in body tissues ( ⁇ g/g) after topical administration of various levels of Amphocil * in 10% EtOH, as described above. Selected data from the table are also represented graphically in Figure 4.
  • Table 7 shows the biodistribution of AmB after intravenous administration of Amphocil * , ABPLC, and Fungizone * .
  • the data show diat, even for much smaller cumulative dosages (40 to 100 ⁇ g, vs. one to several mg for topical application), comparable or sometimes greater levels of drug were detected in die internal tissues.
  • Amphocil * in particular, large amounts of the drug were found in the liver and spleen.
  • mice 1 Five i.v. injections to 20g mice of 0.4 ⁇ g g (8 ⁇ g) Fungizone ® or 1 ⁇ g/g (20 ⁇ g) Amphocil ® or ABPLC
  • Amphotericin B although a very effective antif ngal agent, is much less active against dermatophytes. Amphotericin B acts by binding to ergosterol in the cell membrane, which is also present in dermatophytes, resulting in an increase in membrane permeability and leakage of intracellular components.
  • Amphotericin B acts by binding to ergosterol in the cell membrane, which is also present in dermatophytes, resulting in an increase in membrane permeability and leakage of intracellular components.
  • One possible explanation for its decreased activity in dermatophytes is the presence of larger amounts of chitin-containing cell wall of these fungi.
  • the activity of AmB against dermatophytes may be enhanced by the addition of drugs which act against these organisms by a different mechanism.
  • griseofulvin an effective drug against dermatophytes, inhibits cell division by interfering with the structure and function of microtubules, and is also believed to affect cell wall syntiiesis. It is widely considered die drug of choice for the treatment of tinea capitis, especially Microsporum species. Polyoxins and nikkomycins are inhibitors of chitin synthetase and have been shown to be effective against certain dermatophytes, although tiieir spectrum of activity appears to be more restricted dian that of griseofulvin. Fluorocytosine is believed to act via die replacement of uracil with 5-fluorouracil in die RNA of the organism.
  • Fungizone * (a micellar formulation containing sodium deoxycholate; Bristol Myers Squibb), when used separately, affected fungal growdi only minimally (reduction in radius about 1 mm in each case). Bod drugs used in combination, however, had a significant inhibitory effect (9 mm). The combination tiius showed a significantly potentiated antifungal effect relative to the combined effects of each agent used alone.

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Abstract

L'invention porte sur des préparations et les procédés associés pour le traitement de mycoses et protozooses de la peau et des ongles. Lesdites préparations comportent une formule lipidique d'amphotéricine B dispersée dans un excipient aqueux contenant d'environ 2 % à environ 35 % en volume d'éthanol par rapport à l'eau.
PCT/IL1998/000582 1997-12-01 1998-11-30 Preparation pour traitement local des infections de la peau WO1999027940A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
IL13634298A IL136342A0 (en) 1997-12-01 1998-11-30 Formulation for topical treatment of skin infections
AU13500/99A AU1350099A (en) 1997-12-01 1998-11-30 Formulations for topical treatment of skin infections

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US6748597P 1997-12-01 1997-12-01
US60/067,485 1997-12-01
US10178398P 1998-09-25 1998-09-25
US60/101,783 1998-09-25

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WO1999027940A1 true WO1999027940A1 (fr) 1999-06-10

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IL (1) IL136342A0 (fr)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084645A3 (fr) * 2003-03-27 2005-03-24 Stone Island Holdings Ltd Utilisation d'allicine comme conservateur, desinfectant, antimicrobien ou biocide
WO2012042072A1 (fr) * 2010-09-27 2012-04-05 Universidad Complutense De Madrid Formulations topiques d'amphotéricine b et procédé d'obtention
US9326953B2 (en) 2003-04-25 2016-05-03 The Penn State Research Foundation Method and system for systemic delivery of growth arresting, lipid-derived bioactive compounds

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WO1985005030A1 (fr) * 1984-05-02 1985-11-21 The Liposome Company, Inc. Preparations de medicaments de toxicite reduite
FR2593394A1 (fr) * 1986-01-30 1987-07-31 Ire Celltarg Sa Procede de preparation de liposomes contenant une subtance active lipophile, notamment de l'amphotericine, liposomes et nouveau medicament obtenus
EP0260811A2 (fr) * 1986-08-21 1988-03-23 Vestar, Inc. Particules phospholipidiques encapsulant des antibiotiques polyéniques pour le traitement d'une infection fongique systémique
WO1990006775A1 (fr) * 1988-12-14 1990-06-28 Liposome Technology, Inc. Nouvelle composition de liposomes non phospholipidique a liberation soutenue de medicaments
EP0418153A1 (fr) * 1989-09-14 1991-03-20 The Liposome Company, Inc. Nouveau procédé de préparation de microparticules lipidiques
EP0429248A2 (fr) * 1989-11-20 1991-05-29 Shiseido Company Limited Composition émulsifiée
WO1993018749A1 (fr) * 1992-03-17 1993-09-30 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Liposomes a charge negative excedentaire
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Publication number Priority date Publication date Assignee Title
WO1985005030A1 (fr) * 1984-05-02 1985-11-21 The Liposome Company, Inc. Preparations de medicaments de toxicite reduite
FR2593394A1 (fr) * 1986-01-30 1987-07-31 Ire Celltarg Sa Procede de preparation de liposomes contenant une subtance active lipophile, notamment de l'amphotericine, liposomes et nouveau medicament obtenus
EP0260811A2 (fr) * 1986-08-21 1988-03-23 Vestar, Inc. Particules phospholipidiques encapsulant des antibiotiques polyéniques pour le traitement d'une infection fongique systémique
WO1990006775A1 (fr) * 1988-12-14 1990-06-28 Liposome Technology, Inc. Nouvelle composition de liposomes non phospholipidique a liberation soutenue de medicaments
US5277914A (en) * 1989-03-31 1994-01-11 The Regents Of The University Of California Preparation of liposome and lipid complex compositions
EP0418153A1 (fr) * 1989-09-14 1991-03-20 The Liposome Company, Inc. Nouveau procédé de préparation de microparticules lipidiques
EP0429248A2 (fr) * 1989-11-20 1991-05-29 Shiseido Company Limited Composition émulsifiée
WO1993018749A1 (fr) * 1992-03-17 1993-09-30 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Liposomes a charge negative excedentaire

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Title
CHEMICAL ABSTRACTS, vol. 125, no. 2, 8 July 1996, Columbus, Ohio, US; abstract no. 18740, XP002095239 *
J.W.HIEMENZ ET AL.: "LIPID FORMULATIONS OF AMPHOTERICIN B : RECENT PROGRESS AND FUTURE DIRECTIONS", CLIN. INFECT. DIS., vol. 22, no. 2, 1996, pages S133 - S144 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004084645A3 (fr) * 2003-03-27 2005-03-24 Stone Island Holdings Ltd Utilisation d'allicine comme conservateur, desinfectant, antimicrobien ou biocide
EA011631B1 (ru) * 2003-03-27 2009-04-28 Стоун Айлэнд Холдингз Лтд. Аллицин
US9326953B2 (en) 2003-04-25 2016-05-03 The Penn State Research Foundation Method and system for systemic delivery of growth arresting, lipid-derived bioactive compounds
WO2012042072A1 (fr) * 2010-09-27 2012-04-05 Universidad Complutense De Madrid Formulations topiques d'amphotéricine b et procédé d'obtention
ES2387440A1 (es) * 2010-09-27 2012-09-21 Universidad Complutense De Madrid Formulaciones topicas de anfotericina b y metodo de obtencion

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AU1350099A (en) 1999-06-16

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