WO1993023015A1 - Compositions comprenant des aminoglycosides dans des liposomes et procede de preparation - Google Patents

Compositions comprenant des aminoglycosides dans des liposomes et procede de preparation Download PDF

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Publication number
WO1993023015A1
WO1993023015A1 PCT/PT1993/000001 PT9300001W WO9323015A1 WO 1993023015 A1 WO1993023015 A1 WO 1993023015A1 PT 9300001 W PT9300001 W PT 9300001W WO 9323015 A1 WO9323015 A1 WO 9323015A1
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Prior art keywords
aminoglycoside
liposomal
phosphatidylinositol
process according
lipid
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PCT/PT1993/000001
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English (en)
Inventor
Maria Eugénia MEIRINHOS DA CRUZ
Isabel Maria Costa Mimoso ATAÍDE DE CARVALHOSA NUNES DIAS
Ana Paula Gameiro Francisco
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Instituto Nacional De Engenharia E Tecnologia Industrial/Departamento De Tecnologia De Indústrias Químicas
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Publication of WO1993023015A1 publication Critical patent/WO1993023015A1/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
    • 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—Liposomes
    • 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—Liposomes
    • A61K9/1277—Processes for preparing; Proliposomes
    • 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

  • This invention relates to liposomal preparations containing relatively high levels of charged molecules, such as phosphatidylinositol, resulting in increased entrapment efficiency of aminoglycoside drugs and increased therapeutic effectiveness and lower toxicity.
  • the aminoglycosides are a family of bactericidal antibiotics which contain amino sugars in glycosidic linkages. They are polycations and their polarity is primarily responsible for the phar acokinetic properties shared by the group.
  • the aminoglycosides inhibit protein synthesis in a variety of microorganisms, and are useful therapeutically and prophylactically in the treatment of serious, often life-threatening bacterial infections. They are particularly useful in the treatment of infections (e.g., septice ia, peritonitis, pneumonia, urinary tract infections) due to organisms which are resistant to other antibiotics, such as species of Pseudomonas, E.
  • aminoglycosides are often limited by potentially serious adverse toxicities. Among these are ototoxicity, nephrotoxicity and a potentially fatal neuromuscular paralysis.
  • the ototoxicity effects can involve both cochlear (auditory) and vestibular toxicity.
  • the nephrotoxicity effects include abnormalities of tubular resorption and renal morphology.
  • the muscular paralysis and difficulty in respiration may be due to blockage of the neuromuscular junction due to the aminoglycosides by inhibiting acetylcholine release.
  • the order of increasing ability of the aminoglycosides to effect acute toxic reactions often correlates with the ability to effect nephrotoxicit .
  • the mechanism underlying the toxicities of the aminoglycosides may be associated with the ability of the aminoglycosides to bind to polyphosphoinositides found in inner ear and Kidney tissues. It has been postulated that phosphatidylinositol diphosphate serves as a receptor for the drugs and renders these tissues more sensitive than others to this family of drugs. Lodhi et al., Biochem. Pharmacol. 29:597-601 (1980). Thus, considerable effort has focused on these putative a inoglycoside receptors as a means to ameliorate the associated toxicities.
  • aminoglycosides could be complexed with phosphatidylinositolphosphates prior to administration to reduce interactions between the drug and the endogenous toxicity receptor. See Janoff et al., U.S. Patent No. 4,897,384. Although Janoff et al. also discuss the possibility of administering these drug-lipid complexes as liposomes, the difficulty remains in formulating stable liposomes with charged lipids such as phosphatidylinositol in the presence of water, as would be necessary for most aminoglycosides. Further, in Janoff the drug portion of the drug-lipid conjugate is exposed to the patient and may become separated from the conjugate in the patient.
  • Liposomal formulations of aminoglycosides have been suggested as a way to achieve higher potency pharmaceutical preparations with smaller volume and thus causing less tissue injury upon administration. Liposomes have shown evidence of protection against the toxicity effects. (Guargon et al. , Antimicrob. Agents Chemother. 34:235-240 (1990); Micier et al., Antimicrob. Agents Chemother. 34:343-348 (1990); and Bally et al., WO 88/04573 (1987)). However, these liposome-aminoglycoside formulations are obtained with high drug/lipid ratios and have low encapsulation efficiencies.
  • the present invention relates to liposomal formulations containing an antibiotic, characterized by having drug/lipid ratios up to 10 mg/100 mg lipid, the size of liposomes ranging from 5 ⁇ m to 0.01 ⁇ m and the encapsulation efficiencies typically being greater than 60%.
  • the liposomal antibiotics when administered to animals, increase the half-life circulation time in plasma, efficiently reduce the acute toxicity and increase the antimicrobial activities, compared to the free drugs.
  • the process for the preparation of liposomal formulations is characterized by forming multilamellar liposomes containing the antibiotic and subjecting the liposomes to lyophilization, rehydration and optionally extrusion under pressure.
  • the processes of the present invention provide liposomal formulations of aminoglycosides with high incorporation efficiency, low toxicity and high pharmacological activity.
  • the present invention comprises a process of dehydration and rehydration, followed by an optional extrusion process through a porous membrane or other liposome sizing procedure.
  • This process comprises the following main steps: a) multilamellar liposomes (MLV) are prepared which contain intra and extra-liposomal drug; b) using dextrose or other physiologic osmolarity medium in the rehydration step; c) avoiding a freeze-thaw step before lyophilization; d) using a high dilution volume of liposomes before optional filtration; e) using as starting material for extrusion liposomes which have not been previously separated from extraliposomal drug.
  • MLV multilamellar liposomes
  • a chloroform lipid mixture (ranging from about 10 mg lipid/ml chloroform up to 100 mg/ml or more) is dried under nitrogen stream.
  • the resulting lipid concentration ranges from about 30 mM up to about 120 mM, preferably about 45 to 75 mM, and in certain preferred embodiments described in the Examples below range from 49 mM up to about 61 mM.
  • the lipid mix is preferably negatively charged, and most preferably containing a relatively high concentration of phosphatidylinositol, hydrogenated phosphatidylinositol, phosphatidylinositol mono and biphosphate and the like.
  • the liposomal preparations are typically mixtures of at least two components and more usually three or more: a glycerophospholipid (e.g., phosphatidylcholine, dimirystoylphosphatidycholine, dipalmitoylphosphatidylcholine) ; cholesterol (optionally present); and a negatively charged molecule (lipidic or not) such as phosphatidylinositol, dicetylphosphate, with each component of the liposomal preparation (when present) in molar ratios of 40-70%, 10-30%, and 20-50%, respectively.
  • a glycerophospholipid e.g., phosphatidylcholine, dimirystoylphosphatidycholine, dipalmitoylphosphatidylcholine
  • cholesterol optionally present
  • a negatively charged molecule lipidic or not
  • each component of the liposomal preparation when present in molar ratios of 40-70%, 10-30%, and
  • a preferred combination is phosphatidylcholine: cholesterol: phosphatidylinositol at 5:1:4, with total lipid concentration ranging from 49 to about 64 mM.
  • the components of the lipid mixture are chosen so at least one component, e.g., phosphatidylinositol, is capable of binding the aminoglycoside antibiotic and is present in the lipid mixture at a concentration of at least about 20-60%, preferably at least about 25% to 40% concentration of total lipid components.
  • the resultant negatively charged lipid starting mix produces higher antibiotic encapsulation efficiencies and stable liposomes while minimizing drug-associated toxicities and maximizing antibiotic effectiveness.
  • the lipidic film is hydrated with an aqueous solution of antibiotic, such as an aminoglycoside.
  • concentration of the drug solution can vary considerably, from as low as about 0.05 mg/ml up to as much as 100 mg/ml or more, but more typically 1 mg/ml up to 10 mg/ml, e.g., 4.6 mg/ml as described in an Example below.
  • concentration of lipid for hydration ranges up to 50 mg/ml to as high as 100 mg/ml or more. It is desirable to produce liposomes with high drug/lipid ratio, without exceding saturation of lipidic membrane of liposomes. Going beyond saturation the encapsulation efficiency will be reduce without increasing intraliposomal drug. Thus, it is important that the encapsulation efficiency of the process to be as high as possible to produce liposomes containing adequate amounts of therapeutic drug, even for small initial amount of drug.
  • the antibiotic is preferably an aminoglycoside, such as neomycin, Kanamycin, amikacin, tobramycin, genta icin (including gentaraicin C 1# c ⁇ a a n C 2 ), sisomicin, netilmicin, streptomycin, paromomycin and other members of the aminoglycoside family as described in, e.g., Drug Evaluations, Chpt. 6, Amer. Med. Assn. 1990, but other antibiotics (e.g., polyene antibiotics and non-antibiotic drugs may also benefit from the processes of the present invention. In Examples described below a particularly preferred aminoglycoside is netilmicin.
  • the concentration of the aminoglycoside in the aqueous solution used to hydrate the lipid film and thus in the final liposome can vary considerably, depending on the particular drug chosen, the components of the lipidic mixture, the ionic strength, osmolarity, pH, temperature and incorporation method used.
  • the antibiotic or derivatives in the resulting liposome/antibiotic formulation can be contained primarily in the aqueous phase, in the lipid phase, or in the aqueous and lipid phase.
  • the multilmellar liposomes so formed are then subjected to freezing either in liquid nitrogen (-170°C) or for one hour in a deep freezer (-70°C) followed by lyophilization on a freeze dryer (lyophilizer) at 25 mtorr for overnight.
  • the resulting powder is rehydrated in two successive steps: first with a sugar solution at a portion (e.g. 1/10) of the initial volume of physiologic osmolarity, e.g., a 5% solution of dextrose, galactose, mannose, sucrose, etc. that does not interfere with drug activity with vigorous vortexing followed by a stabilizing rest period at room temperature of about 30 min.
  • saline solution e.g., NaCl 154 mM
  • the resulting liposome/drug mixture is then diluted 5- to 10-fold with saline solution and, optionally, is sized.
  • the sized or non-sized mixture is ultracentrifuged at 250,000 g during 30 min. and the pellet resuspended in saline solution.
  • sizing liposomes to a desired size.
  • One sizing method is homogenization, which relies on shearing energy to fragment large liposomes into smaller ones.
  • multilamellar vesicles are recirculated through a standard emulsion homogenizer until selected liposome sizes, typically between about 0,1 and 0,5 microns, are observed.
  • Extrusion of liposome through a small-pore polycarbonate membrane ou an asymmetric ceramic membrane under pressure is also an effective method for reducing liposome sizes to a relatively well-defined size distribution.
  • the suspension is cycled through the membrane one or more times until the desired liposomes size distribution is achieved.
  • the liposomes may be extruded through successively smaller-pore membranes (e.g., from 3.0 ⁇ m down to 0.01 ⁇ , as desired) to achieve a gradual reduction in liposome size.
  • the particle size distribution can be monitored by conventional laser-beam particle size discrimination.
  • a particularly preferred embodiment of the invention produces liposome/aminoglycoside formulations with high encapsulation efficiency at a low initial drug:lipid ratio.
  • the lipid mixture is phosphatidylcholine: cholesterol: phosphatidylinositol at 5:1:4, with relative lipid concentration of 49-64 mM. Hydration takes place with, e.g., 2.3 to 4.6 mg/ml netilmicin, followed by freezing at -170 ⁇ C or -70°C and lyophilization.
  • Rehydration to a final osmolarity of 300 mOSM is accomplished by the addition of 5% dextrose in one- tenth the volume of antibiotic used, followed by filling to the initial volume with 154 mM NaCl.
  • the final liposomal/aminoglycoside formulation has a diameter of about 0.900 ⁇ m ⁇ 0.095 ⁇ m, but can be smaller if extruded, and possessed an encapsulation efficiency of 66 ⁇ 1%, a drug:lipid ratio of 1:30 to 1:40 and a drug: phosphatidylinositol ratio of 1:12-1:15.
  • the drug is secluded from the external medium (in contrast to typical drug-lipid conjugates) and cannot be displaced from the liposome by a stronger ligand as might occur in other preparations.
  • the improved therapeutic and pharmacokinetic effects that result are not necessarily related to the final amount of drug in the liposome/drug mixture, but the fact that the drug is in a liposomal form having the characteristics described herein.
  • the present process for aminoglycoside encapsulation is a significant improvement over earlier protocols, e.g., as decribed in Bally et al., WO 88/04573 (1987), for a number of reasons which include, among others: (1) the present process starts from multilamellar liposomes containing drug and not from empty liposomes to which drug is later added; (2) the process does not use the combination of freeze-thaw steps before lyophilization; (3) the process produces liposomes having a physiological osmolarity, using dextrose or the like in rehydration step, which is preferred for pharmaceutical administration; (4) the problem of forming stable aminoglycoside:liposome formulations using a relatively high concentration of a negatively charged lipid such as phosphatidylinositol is solved; and (5) low starting concentrations of aminoglycoside still permit high encapsulation efficiencies.
  • the liposomal/aminoglycoside formulations prepared according to the processes of the present invention exhibit encapsulation efficiencies greater then 60% without alteration of in vitro biological activity. Moreover, when injected in animals (mice) a liposomal/aminoglycoside formulation prepared as described herein demonstrated a circulating time 12-18 fold longer when compared to the free (non liposomal) aminoglycoside (netilmicin). The present formulations also evidenced a reduced toxicity compared to free drug, wich is particularly significant in view of the toxicities typically associated with aminoglycosides and the fact that their use is severely limited by those toxicities.
  • liposomal formulations of aminoglycosides produced according to the present invention may be administered at higher concentrations, and hence enhanced efficacy, without fear of increased toxicity to a patient.
  • liposomal/aminoglycoside formulations of the invention are also highly effective as therapeutic agents.
  • the formulations prepared by the present process demonstrated a higher therapeutic activity when compared to free aminoglycoside.
  • the larger size liposomes those which are not extruded and range in size from 0.8-1 ⁇ m, may be more efficacious when used therapeutically than the smaller, extruded liposomes (0.1- 0.2 ⁇ m) which have longer residence times in the circulation and thus are particularly useful when administered prophylactically.
  • the liposomal/antibiotic formulations of the invention may contain additional substances which serve to target the liposome and hence antibiotic to a particular tissue or cell, such as a bacterial, as well as increase the half-life of the composition.
  • the antibiotic is incorporated as part of a liposome as described herein, alone or in conjunction with a targeting molecule which binds to, e.g., a receptor prevalent among the suspected infecting bacterial cells, such as monoclonal antibodies or the binding fragments thereof which bind to the lipid A, core or lipopolysaccharide side chains of gram-negative bacteria, or with other therapeutic or compositions.
  • a pharmaceutical composition of a liposo e/antibiotic suspension prepared according to the present invention can be administered intravenously, locally, topically, etc. in a dose which varies according to, interalia, the manner of administration, the drug being delivered, and the stage of the infection or other condition being treated.
  • compositions may be in the form of liquid or semi-solid dosage forms, such, for example, as liquids, suspensions, pastes, creams, etc., and may be in unit-dosage forms suitable for administration of relatively precise dosages.
  • the liposomal/antibiotic compositions may include a conventional pharmaceutical carrier or excipient and, in addition, may include other medicinal agents, antibiotics, growth factors, etc.
  • compositions of the invention can be provided separately or may be compounded with conventional nontoxic carriers.
  • Such compositions may contain about 5-100% active ingredient (liposome/antibiotic complexes), more preferably about 5-25%.
  • the concentration of the complexes in these formulations can vary widely, and will be selected primarily by intended use, viscosities, etc., in accordance with the particular mode of administration selected and the infection being treated. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington 's Pharmaceutical Science , 17th ed., Mack Publishing Company, Easton, PA (1985), which is incorporated herein by reference.
  • the composition or formulation to be administered will, in any event, contain a quantity of the liposome/antibiotic complexes sufficient to achieve the desired therapeutic or prophilactic effect in the subject being treated.
  • the pharmaceutical compositions are administered parenterally, e.g. , intravenously or intramuscularly.
  • the invention provides pharmaceutical compositions for parenteral administration which comprise a liposomal/antibiotic complex at a physiological osmolarity, suspended in an acceptable carrier as desired, preferably an aqueous carrier.
  • an acceptable carrier preferably an aqueous carrier.
  • aqueous carriers may be used, e.g., 0.4% saline, 0.3% glycine, and the like.
  • These compositions may be sterilized by conventional, well known sterilization techniques, or may be sterile filtered.
  • compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.
  • auxiliary substances such as pH adjusting and buffering agents, tonicity adjusting agents, wetting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, sorbitan monolaurate, triethanolamine oleate, etc.
  • compositions of the invention are administered to a warm-blooded animal, such as humans, already suffering from an infection in an amount sufficient to terminate or significantly inhibit the progression of the infection. Amounts adequate to accomplish these effects are defined as a "therapeutically effective doses". Amounts effective for this use will depend on the severity of the infection and its site, and the general susceptibility of the bacterium to the antibiotic being used, e.g., netilmicin, and the general state of health of the patient being treated. The amounts wil generally be less than those typically employed with free drug under similar circunstances.
  • the amount of drug administered via the liposomal/drug formulations of the invention can also be increased above those typically used for free drug due to the minimization of toxicity to the patient and the overall increased therapeutic effectiveness of the preparations compared to free drug, as illustrated hereinbelow, as might be necessary in the case of severe, life-threatening infections. Maintenance dosages over a prolonged period of time may be adjusted as necessary. For veterinary uses in animals other than humans higher levels may also be administered as necessary. Determining actual amounts of the liposomal/drug complexes necessary to treat a particular condition as described above will be through standard empirical methods well known in the art.
  • compositions containing the liposomal/drug complexes of the invention are administered to a host susceptible to or otherwise at risk of infection.
  • a host susceptible to or otherwise at risk of infection is defined to be a "prophylactically effective dose".
  • dosages may be less than those typically employed with free drug, particularly in view of the extended half-lives provided by the present formulations.
  • liposomes of smaller size i.e., less than 0.2 ⁇ m
  • compositions of the invention may be administered alone or as adjunct therapy or prophylaxis.
  • the compositions can be used in combination with other drugs, including antibiotics, found to improve treatment responses. In this manner, a synergistic effect may be attained that yields a clinical efficacy greater than that realized with any single factor.
  • liposome aminoglycoside formulations prepared as described above where the aminoglycoside was netilmicin, the lipid mixture was phosphatidylcholine:cholesterol:phosphatidyli-nositol at 5:1:4, with relative lipid concentration of 49-64 mM. Hydration took place with 2.3 to 2.5 mg/ml netilmicin, followed by freezing at -170°C or -70°C and lyophilization. Rehydration to a final osmolarity of 300 mOSM was accomplished by adding 5% dextrose in one-tenth the volume of antibiotic used, followed by filling to the initial volume with 154 mM NaCl.
  • the final liposomal/aminoglycoside formulation had a diameter of about 0.20 ⁇ m ⁇ 0.01 ⁇ m.
  • Table 1 shows encapsulation parameters which characterize the liposomal antibiotic formulations of this invention.
  • Encapsulation efficiency means the ratio of the final drug/lipid and the initial drug/lipid, in percentage. The percent recovery indicates the percentage of final to initial drug concentration. For conversion to moles of lipid, the average molecular weight of lipid is treated as 700 g/mol.
  • formulations prepared by the present process showed a substantial reduction of acute toxicity, since with the maximum possible injected dose 100% of animals survived without any sign of anaphylactic shock.
  • an animal model of peritonitis was perfomed using Swiss (Charles River) mice.
  • the infection was obtained by inoculating with a netilmicin sensitive bacterial suspension of E ⁇ _ coli (approximately 1x10 8 bacteria/ml).
  • Groups of six mice were used and two types of treatment assayed: prophylactically (given 24 hours before infection) or immediately post-infection (0 hours) (therapeutically).
  • the control group was injected with 154 mM NaCl.
  • the therapeutic dose was 10 fold lower than dose used prophylactically (2 mg/Kg).
  • the percent survival was calculated after 24 days (Table 4).

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  • Pharmacology & Pharmacy (AREA)
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Abstract

L'invention concerne des formulations de liposomes comprenant un antibiotique et un rapport médicament/lipides allant jusqu'à 10 mg/100mg de lipides. La dimension des liposomes varie de 5 à 0,01 νm et leur efficacité d'enrobage dépasse couramment 60 %. Ces antibiotiques contenus dans des liposomes, administrés à des animaux, accroissent la demi-vie du temps de circulation dans le plasma, réduisent efficacement la toxicité aigue et augmentent l'activité antimicrobienne par rapport aux médicaments libres. L'invention porte aussi sur un procédé permettant de préparer ces formulations de liposomes et consistant à former des liposomes multilamellaires qui contiennent l'antibiotique et à soumettre ces liposomes à une lyophilisation, à une réhydratation et, éventuellement, à une extrusion sous pression.
PCT/PT1993/000001 1992-05-14 1993-05-14 Compositions comprenant des aminoglycosides dans des liposomes et procede de preparation WO1993023015A1 (fr)

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PT100486 1992-05-14
PT100486A PT100486B (pt) 1992-05-14 1992-05-14 Aminoglucosidos lipossomais com altas eficacia de encapsulacao e actividade terapeutica, nomeadamente a netilmicina, e processo para a sua preparcao

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0678295A2 (fr) * 1994-04-22 1995-10-25 Ugo Citernesi Procédé de préparation de complexes d'un phospholipide avec une substance active utilisables pour la fabrication de liposomes
WO1996019972A1 (fr) * 1994-12-23 1996-07-04 Universite De Montreal Composition antibacterienne aux liposomes, a faible rigidite
US5756121A (en) * 1992-12-02 1998-05-26 Nexstar Pharmaceuticals, Inc. Antibiotic formulation and use for drug resistant infections
US5756120A (en) * 1993-06-23 1998-05-26 Nexstar Pharmaceuticals, Inc. Antibiotic formulation and use for drug resistant infections
US5958449A (en) * 1992-12-02 1999-09-28 Nexstar Pharmaceuticals, Inc. Antibiotic formulation and use for bacterial infections
US6613352B2 (en) 1999-04-13 2003-09-02 Universite De Montreal Low-rigidity liposomal formulation

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US4952405A (en) * 1988-10-20 1990-08-28 Liposome Technology, Inc. Method of treating M. avium infection
EP0485143A1 (fr) * 1990-11-06 1992-05-13 Instituto Nacional De Engenharia E Tecnologia Industrial Compositions liposomales et leurs procédés de préparation

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WO1985005030A1 (fr) * 1984-05-02 1985-11-21 The Liposome Company, Inc. Preparations de medicaments de toxicite reduite
WO1988004573A1 (fr) * 1986-12-23 1988-06-30 The Liposome Company, Inc. Preparation antibiotique a base de liposomes
US4952405A (en) * 1988-10-20 1990-08-28 Liposome Technology, Inc. Method of treating M. avium infection
EP0485143A1 (fr) * 1990-11-06 1992-05-13 Instituto Nacional De Engenharia E Tecnologia Industrial Compositions liposomales et leurs procédés de préparation

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CAJAL Y., ET AL.: "GENTAMICIN ENCAPSULATION IN LIPOSOMES: FACTORS AFFECTING THE EFFICIENCY.", JOURNAL OF LIPOSOME RESEARCH., TAYLOR & FRANCIS, PHILADELPHIA, PA., US, vol. 02., no. 01., 1 January 1992 (1992-01-01), US, pages 11 - 22., XP000246007, ISSN: 0898-2104 *
CHEMICAL ABSTRACTS, vol. 107, no. 13, 28 September 1987, Columbus, Ohio, US; abstract no. 108910p, S. AU ET AL 'aminoglycoside antibiotics preferentially increase permeability in phosphoinositide-containing membranes: a study with carboxyfluorescein in liposomes' page 25 ;column 1 ; *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5756121A (en) * 1992-12-02 1998-05-26 Nexstar Pharmaceuticals, Inc. Antibiotic formulation and use for drug resistant infections
US5958449A (en) * 1992-12-02 1999-09-28 Nexstar Pharmaceuticals, Inc. Antibiotic formulation and use for bacterial infections
US6221388B1 (en) 1992-12-02 2001-04-24 Gilead Sciences, Inc. Antibiotic formulation and use for bacterial infections
US5759571A (en) * 1993-05-11 1998-06-02 Nexstar Pharmaceuticals, Inc. Antibiotic formulation and use for drug resistant infections
US5756120A (en) * 1993-06-23 1998-05-26 Nexstar Pharmaceuticals, Inc. Antibiotic formulation and use for drug resistant infections
EP0678295A2 (fr) * 1994-04-22 1995-10-25 Ugo Citernesi Procédé de préparation de complexes d'un phospholipide avec une substance active utilisables pour la fabrication de liposomes
EP0678295A3 (fr) * 1994-04-22 1995-12-20 Ugo Citernesi Procédé de préparation de complexes d'un phospholipide avec une substance active utilisables pour la fabrication de liposomes.
WO1996019972A1 (fr) * 1994-12-23 1996-07-04 Universite De Montreal Composition antibacterienne aux liposomes, a faible rigidite
US5662929A (en) * 1994-12-23 1997-09-02 Universite De Montreal Therapeutic liposomal formulation
AU702463B2 (en) * 1994-12-23 1999-02-25 Universite De Montreal Low rigidity liposomal antibacterial composition
US6613352B2 (en) 1999-04-13 2003-09-02 Universite De Montreal Low-rigidity liposomal formulation

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