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WO2003039435A2 - Procede de preparation de dispersions colloidales d'amphotericine b; composes a base d'amphothericine b pour l'administration par voies enterale, parenterale et topique; et utilisation de ces composes dans le traitement des mycoses systemiques et des infections parasitaires - Google Patents

Procede de preparation de dispersions colloidales d'amphotericine b; composes a base d'amphothericine b pour l'administration par voies enterale, parenterale et topique; et utilisation de ces composes dans le traitement des mycoses systemiques et des infections parasitaires Download PDF

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Publication number
WO2003039435A2
WO2003039435A2 PCT/BR2002/000157 BR0200157W WO03039435A2 WO 2003039435 A2 WO2003039435 A2 WO 2003039435A2 BR 0200157 W BR0200157 W BR 0200157W WO 03039435 A2 WO03039435 A2 WO 03039435A2
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WIPO (PCT)
Prior art keywords
amphotericin
superaggregate
items
amb
obtaining
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PCT/BR2002/000157
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English (en)
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WO2003039435A3 (fr
Inventor
José Maciel Rodrigues JUNIOR
Gisele Santos Goncalves
Original Assignee
Universidade Federal De Minas Gerais - Ufmg
Cristália Produtos Químicos E Farmaceuticos Ltda
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Priority to AU2002347229A priority Critical patent/AU2002347229A1/en
Publication of WO2003039435A2 publication Critical patent/WO2003039435A2/fr
Publication of WO2003039435A3 publication Critical patent/WO2003039435A3/fr

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    • 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
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • 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
    • A61K9/0012—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
    • A61K9/14—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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 refers to the process of obtaining pharmaceutical compounds consisting of colloidal dispersions of amphotericin B obtained by the heating of the antibiotic in the presence of biliar salts, resulting in stable pharmaceutical compounds, which could be freeze-dried (lyophilized) and enable to be reconstituted in water-based solutions usable paraentemal, or in a gel form. It refers also to its use in the treatment of infections whose etiological agents are susceptible to this antibiotic after administration intestinally, paraenteral and topically.
  • Amphotericin B is a polyene antibiotic, with a wide spectrum of antifungal action, isolated in 1953 from a culture of Streptomyces nodosus. It is understood as a macrolides that contains, on one side of the lactone ring, 7 trans conjugated double bonds and one 3-amino-3, 6-didesoxymannose (micosamine) group connected to the ring by a glycosidic bond; and on the other side an equal number of hydroxylic groups.
  • the structure of AMB is highly lipophilic and not really dissoluble in water.
  • the AMB Due to the presence of the carboxylic group on the main ring and the NH 2 group of micosamine the AMB possesses an amphote c behaviour, forming soluble salts at extreme pHs. Despite being insoluble in water the AMB is commonly administered intravenously in a formulation that contains biliar salt sodium deoxycholate (DOC) as a tensoactive (Barner et al., Antibiotics Annual 1957-1958: pp. 53-58) commercially known as Fungizon® and owned by Bristol Myers Squib.
  • DOC biliar salt sodium deoxycholate
  • AMB antifungal activity due to its affinity for the sterols of the cell wall of the susceptible fungi.
  • the link of AMB to ergosterol results in disruption of the cellular membrane, possibly by the formation of pores consisting of AMB joined with sterol. These effects cause the depolarization of the membrane and the increase in permeability to protons and monovalent cations, which permits the loss of the cytoplasmic contents bringing about the death of the cell (Brajtburg et al. Amphotericin B: Current understanding mechanisms of action. Antimicrobials Agents Chemotheraphy, 34(2): 183-88, 1990.).
  • AMB's action on fungal cells involves more than one mechanism.
  • AMB is the most powerful antifungal available, being the drug of choice for the treatment of systemic mycoses, especially in patients with a compromised immunological system.
  • Clinical studies currently in progress show the interest of this antibiotic against different manifestations of leishmaniasis. (Yardley and Croft. A comparison of the activities of three amphotericin B lipid formulations against experimental visceral and cutaneous leishmaniasis. International Journal of Antimicrobials Agents, 13(4):243-248). Nevertheless, the use of this pharmaceutical is limited by the sha ⁇ and chronic reactions following its administration.
  • Nephrotoxicity is the severest adverse chronic effect associated with AMB and could be classified as tubular and glomerular.
  • the clinical and laboratorial manifestations include lowering the rate of glomerular filtration and the flow of renal blood, hypocalaemia, hypomagnesemia, tubular acidosis and nephrocalcinosis.
  • AMB One of the mechanisms involved in the chronic toxicity of AMB is its endocitosis mediated for LDL by specific receptors, bringing the pharmaceutical to high intracellular concentrations, which results in the inhibition of endosomic and lysosomic fusion (Vertut-Doi et al. The endocytic process in CHO cells, a toxic pathway of the polyene antibiotic amphotericin B. Antimicrobials Agents and Chemotherapy. 38(10):2373-79, 1994).
  • Some research suggests that elevations in the levels of LDL are associated with the increase in renal toxicity caused by AMB (Wasan et al. Influence of lipoproteins on renal cytotoxicity and antifungal activity of amphotericin B. Antimicrobials Agents and Chemotherapy. 38(2):223-27, 1994).
  • AMB an appropriate substance to incorporate in lipidic systems, like, for example, liposomes.
  • Lipidic formulations have been widely explored as carriers of pharmaceuticals.
  • Seroka et al. Antimicrobial Agents and Chemotherapy 31 :421-429, 1987; Adler-Moor et al., US Patent 5.043,107; Lopez-Berestein et al. Treatment and prophylaxis of disseminated infection due to Candida albicans in mice with liposome-encapsulated amphotericin. Journal of Infectious Disease, 147(5):939-44, 1983; Mehta et al.
  • Liposomal associated amphotericin B is toxic to fungal cells but not to mammalian cells. Biochimica et Biophysica Acta, 770:230-34, 1984). These lipidic formulations alter AMB's pharmacokinetic properties and its pattern of distribution in tissues. Currently, three lipidic formulations containing AMB are being clinically evaluated: Amphotec (ABCD); Sequus Pharmaceuticals, Inc), Ambisome (AMB-L; Nextar Pharmaceuticals, Inc) and Abelcet (ABLC, Lipossome Co., Inc). These three products differ in the types and proportions of phospholipids: AMB, which can be an important determinant of the antifungal activity and of the toxicity.
  • the liposomes can selectively transfer AMB to the fungal cells, avoiding mammal cell membranes (Mehta et al. Liposomal associated amphotericin B is toxic to fungal cells but not to mammalian cells. Biochimica et Biophysica Acta, 770:230-34, 1984).
  • the pharmacokinetic alterations of AMB, or its distribution AMB can also contribute to reduction of the toxicity.
  • the liposomes of AMB provide a reduction of the renal concentration of AMB and elevation of the concentrations in the organs of the mononuclear phagocytic system (SFM), mainly the liver and spleen (Boswell et al.Toxicological profile and pharmaco- kinetics of a unilamellar liposomal vesicle formulation of amphotericin B in rats.
  • SFM mononuclear phagocytic system
  • AmBisome amphotericin B
  • a third possible mechanism is the selective degradation of the liposomes for phospholipases and lipases present in the fungi liberating the pharmaceutical directly into the target cells (Perkins et al. Amphotericin B- phospholipid interactions responsible for reduced mammalian cell toxicity. Biochimica et Biophysica Acta. 1107:271-82, 1992; Hutchaleelaha et a ⁇ . Comparative pharmacokinetics and interspecies scaling of amphotericin B in several mammalian species. Journal of Pharmacy and Pharmacology 49:178-83, 1997).
  • AMB exists as a mixture of different types in balance monomers soluble oligomers and insoluble aggregates. The proportion of each form depends on the concentration and the solvent of the stock solution (Legrand et al. Effects of aggregation and solvent on the toxicity of amphotericin B to human erythrocytes. Antimicrobials Agents and Chemotherapy. 36(11 ):2518-22, 1992). The activity and the selectivity of AMB demonstrate correlation to the aggregation state and size of the particles. In accordance with Glues and Dussault, the toxicity of this antibiotic administered as monomeros is decreased (Gruda & Dussault.
  • Fungizon® is marketed as a freeze-dried (lyophilized) powder that contains 50 mg of AMB, 41 mg of DOC and 20 mg of phosphate cap, as a compound AMB-DOC.
  • AMB DOC forms a colloidal dispersion with particles measuring about 0.4 ⁇ m in diameter. After its administration, this formulation is dissociated into DOC and free AMB. Seeking to improve the therapeutic index of AMB and to reduce the incidence of adverse reactions related to its administration, new derivations and formulations of AMB have been proposed.
  • Proposals include patents US 4.522.803; US 4.963.297 and US 5.616.334, which describe the obtaining of amphotericin B compositions consisting of liposomes or complex lipidics for paraenteral administration.
  • the lipidic compositions present a variety of inconveniences, from the complexity of their preparations to the high cost involved.
  • the patent US 5.776.904 describes a process of obtaining amphotericin
  • compositions found in the development and or marketing of AMB combines the properties of effectiveness, low cost and technical ease in their production.
  • these formulations containing AMB have been proven to be well tolerated by the patients, reducing the incidence of sharp adverse reactions and of nephrotoxicity, the process of obtaining these presents high cost and difficulties.
  • none of these products should be considered as standard therapy for systemic mycoses and much less for tropical diseases such as leishmaniasis; its usage being presently limited to patients who demonstrate little tolerance for, or who don't respond to the conventional treatment with AMB-DOC.
  • compositions of AMB in the superagreggate form present the capacity to reduce the toxicity of the amphotericine B while maintaining its activity.
  • the technique involved in the obtaining of these superaggregates is ineffective from the point of view of stability of the formulations; since after the reconstituting and heating, the preparations must be used quickly. It is also a homegrown technique, involving the preparation of the compositions at the moment of their use, a fact which impedes its application in a simple and widespread way by medical professionals, due to the impossibility of analytical control of these compositions when being prepared.
  • One of the objectives of the present invention is the process of obtaining compositions containing amphotericin B in its superaggregate form, without the use of equipments that require high energy consumption, capable of treating infections caused by fungi, parasites and other agents affected by that antibiotic.
  • the obtaining of the formulations for parenteral and topical use containing amphotericin B in its superaggregate form, following the procedure of the invention herein, can be achieved using the following protocols: Protocol A:
  • Protocol B (lyophi ⁇ ze)it.
  • a gelling agent in the aqueous phase selected from among the derivatives of carboxymethylcellulose in concentrations varying from 1 % to 6% in weight or hydroethylcellulose in concentrations varying between
  • compositions prepared following Protocolo B can contain stabilizing agents so that they present a longer period of time before expiring.
  • the metasulfites of sodium or potassium in the concentrations of 0.05% to 0.2% are preferable, or chelating agents, such as tartaric acid or citric acid in concentrations from 0.01 % to 1 % in weight in the final composition.
  • amphotericin B used for the preparation of the superaggregates formulations can be used in its common crystalline usual form and/or in its amorphous form, this last one obtained by differentiated crystallization procedures as described by (Bartner et al., Studies on a new solubilized preparation of amphotericin B. Antibiotics Annual, 1957- 1958: 53-58), where the amorphous form is prepared through the dissolution of the crystalline amphotericin B in dimethylsulfoxide, when the solution formed is added to a room temperature solution sodium chloride (0.4%) causing the amorphous precipitation of the amphotericin B.
  • basic inorganic salts can be used, such as the hydroxides of the alkaline metals, those of sodium and potassium, the salts of the alkaline earth metals, such as those of magnesium, calcium and barium, the carbonates or bicarbonates of the alkaline metals, such as those of sodium, potassium or of the alkaline earth metals, such as those of magnesium, calcium and barium.
  • the alkalinizing agents listed could be used in their solid forms or in stock solutions in pre-defined concentrations, in a way that facilitates the adjustment of the pH of the prepared solutions.
  • the neutralization of the alkaline solutions can be made by the addition of appropriate inorganic acids such as hydrochloric, sulfuric or phosphoric acids, used in their concentrated forms or diluted, or by the addition of salts, such as the sodium or potassium phosphate, among others.
  • the prepared solutions according to the Protocol are processed in such a way that they will be obtained as sterile formulations, appropriate for injectable use.
  • the sterilization process preferably adopted is of filtration through a sterilizing membrane of 0.22 ⁇ m.
  • the non-sterilization of the product limits its use to parenteral or ophthalmic methods.
  • the sterilization stage is not necessary, and conservative formulations could instead be added, preferentially esters of p-hydroxybenzoic acid (0.02% to 0.2%).
  • a second objective of the invention herein is to demonstrate the effectiveness of the prepared compositions in the gel form for topical use, whether containing stabilizers or not, in the treatment of infections caused by Leishmania amazonensis.
  • Leishmaniasis is an endemic disease in several areas of Brazil. Because of the fact of being a deforming affliction whose treatment is still extremely limited in terms of effective medicines capable reversing the unbridled damage, this disease is a very great reason for concern among the population subject to it as much as among the health professionals in search of an effective treatment.
  • a third objective of the invention herein is to facilitate the maintenance of activity of injectable compositions against Candida albicans, expandable to other fungal manifestations affected by the drug, and the maintenance of activity after heating under the described conditions, as well as reduction of the toxicity after intravenous administration.
  • the injectable compositions prepared in agreement with the present invention present a less toxic pattern than those prepared conventionally, including all those currently available on the market, such as, for instance, Fungizon® being appropriate for intravenous administration for the treatment of varied infections, particularly the infections caused by fungi and parasites.
  • compositions described in the present invention can be used in the treatment of various infections caused by fungi, parasites and/or other agents, being appropriate for use in humans and also in animals, and used in the fields of human and veterinary medicine.
  • the formulation obtained in the present invention possesses the advantage of not having in the composition lipids in the liposomal form or complexities that would result in higher costs in the production process and a decrease in the stability of the formulations.
  • a great advantage of the present invention consists in the reduction of the toxicity of the amphotericin B, since a differentiated bio-distribuition is observed among the two forms, resulting in the reduction of the toxicity when administered in the heated form.
  • Example 1 Process for obtaining the superaggregate form of amphotericin B 1) Dissolve 12.4 grams of sodium deoxycholate in 1320 ml of water for injectable form; 2) Add to this solution 15 grams of crystalline amphotericin B and let it agitate vigorously for one hour;
  • Example 2 Process for obtaining the superaggregate form of amphotericin B starting with the amphotericin in its amorphous form
  • the formulation obtained in this way has the appearance of a freeze- dried (lyophilized) yellow powder.
  • Total sterility of the formulation can be obtained by including in the process described above a step using a sterilizing filter.
  • the final formulation should be kept under refrigeration (at temperatures between 2 and 8°C).
  • Example 3 Process of obtaining the formulation of amphotericin B for topical use in its superaggregate form as a gel: 1) Dissolve 12.4 grams of sodium deoxycholate in 1320 ml of water for injectable use; 2) Add to this solution 15 grams of crystalline amphotericin B and let agitate vigorously for one hour;
  • Example 4 Evaluation of the leishmanicidic activity of formulations containing AMB in its aggregate and conventional forms created for the topical treatment of cutaneous leishmaniasis in mice C57B16.
  • mice C57B1/6 were infected with a sample of Leishmania amazonensis at the base of the tail. In general, this type produces, in humans, simple and limited lesions, containing numerous parasites at the edges of the lesions. Treatment was begun two months after the infection process showed the emergence of the nodules.
  • mice were treated topically with the gel formulations of conventional AMB and the heated form containing urea as a promoter of absorption.
  • the treatment consisted of two daily applications at the site of the infection over a period of 30 days.
  • the animals were organized into 3 groups of 11 mice each: 1 ) a control group not treated; 2) a group treated with heated AMB containing 10% urea topically applied; 3) a group treated with conventional AMB containing 10% urea, topically applied.
  • All the animals were found to be in the nodule stage that is characterized by intact epidermis, strongly infiltrated by microphages and numerous parasites.
  • mice were separated into groups (randomly) and treated according to the protocol described above.
  • the dilution test was used on the amphotericin B in the conventional and heated forms in serial concentrations of half n° 3 containing a culture of Candida albicans ATCC 2915.
  • the smallest concentration of amphotericin B capable of inhibiting microbial growth after 18 hours of incubation (CIM - minimum inhibitory concentration) has been determined.
  • the 50% (DL50) lethal dose of conventional and heated amphotericin B was determined in Swiss mice, using the intravenous administration. It was determined by the number of dead animals over a period of 15 days after administration of a single intravenous dose. Mice, weighing between 20-25 g, were separated into groups of 10 animals. The amphotericin B was administered into the vein of the tail in different doses (2 to 10 mg/kg). The injection was administered slowly for 30 seconds. The animals were examined in the same way in search of signs of intoxication, lethargy, modification of behavior and death. The 50% lethal dose was calculated at 4.5 mg/kg for the conventional formulation of amphotericin B.

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Abstract

L'invention concerne un procédé de préparation de compositions à base d'amphotéricine B sous forme superagrégée qui sont destinées à traiter les infections provoquées par les champignons, les parasites et d'autres agents sensibles à cet antibiotique. L'invention concerne en outre la préparation stable de l'amphotéricine B dans sa forme superagrégée, en présence de désoxycholate de sodium lyophilisé et stérile, qui répond aux exigences d'une préparation injectable à administration entérale, parentérale ou topique tout en étant faiblement toxique par rapport aux formes classiques d'administration de l'amphotéricine B.
PCT/BR2002/000157 2001-11-05 2002-11-05 Procede de preparation de dispersions colloidales d'amphotericine b; composes a base d'amphothericine b pour l'administration par voies enterale, parenterale et topique; et utilisation de ces composes dans le traitement des mycoses systemiques et des infections parasitaires WO2003039435A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2002347229A AU2002347229A1 (en) 2001-11-05 2002-11-05 Process of obtaining colloidal dispersions of amphotercin b; compounds based on amphothericine b for enteral, paraenteral and topical use; use of these compounds in the treatment of systemic mycoses and parasitic infections

Applications Claiming Priority (2)

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BRPI0105500-3 2001-11-05
BR0105500-3A BR0105500A (pt) 2001-11-05 2001-11-05 Processo de obtenção de dispersões coloidais de anfotericina b; composições à base de anfotericina b de uso enteral, parenteral e tópico; uso destas composições no tratamento de micoses sistêmicas e infecções parasitárias

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WO2003039435A3 WO2003039435A3 (fr) 2004-03-18

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005065712A3 (fr) * 2004-01-07 2006-04-27 Polytherics Ltd Complexes presentant une activite d'adjuvant
CN110343650A (zh) * 2019-05-28 2019-10-18 浙江工业大学 一种高产两性霉素b的重组结节链霉菌及其应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5059591B1 (en) * 1983-05-26 2000-04-25 Liposome Co Inc Drug preparations of reduced toxicity

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005065712A3 (fr) * 2004-01-07 2006-04-27 Polytherics Ltd Complexes presentant une activite d'adjuvant
AU2005203908B2 (en) * 2004-01-07 2011-02-03 Polytherics Limited Complexes having adjuvant activity
CN110343650A (zh) * 2019-05-28 2019-10-18 浙江工业大学 一种高产两性霉素b的重组结节链霉菌及其应用

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BR0105500A (pt) 2004-06-22
WO2003039435A3 (fr) 2004-03-18

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