EP1220657A1 - Compositions de sels d'argent encapsulees dans un liposome - Google Patents

Compositions de sels d'argent encapsulees dans un liposome

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Publication number
EP1220657A1
EP1220657A1 EP00967484A EP00967484A EP1220657A1 EP 1220657 A1 EP1220657 A1 EP 1220657A1 EP 00967484 A EP00967484 A EP 00967484A EP 00967484 A EP00967484 A EP 00967484A EP 1220657 A1 EP1220657 A1 EP 1220657A1
Authority
EP
European Patent Office
Prior art keywords
silver
composition
liposomes
encapsulated
group
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP00967484A
Other languages
German (de)
English (en)
Inventor
Frank Dicosmo
Lori Burrows
Valerio Ditizio
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Covalon Technologies Ltd
Original Assignee
1170535 ONTARIO Inc
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 1170535 ONTARIO Inc filed Critical 1170535 ONTARIO Inc
Publication of EP1220657A1 publication Critical patent/EP1220657A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/24—Heavy metals; Compounds thereof
    • A61K33/38—Silver; Compounds thereof
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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
    • A61P31/12—Antivirals
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • 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
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
    • 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 encapsulated silver salt compositions for the treatment of bacterial and fungal infections in mammals. More specifically, the present invention provides liposome encapsulated silver salt compositions for treating bacterial and fungal infections in man and other mammals.
  • Silver is known to have general antimicrobial properties directed against a wide range of bacteria and as such, has been used to treat infections. Silver has been used for several years in clinical settings during which time its efficacy and safety have been well-established. Clinically, silver has been used to coat the surface of polymer sheets used as wound dressings to prevent the infection of burns (Tredgett, et al., 1998).
  • U.S. Patent No. 1,761,590 discloses the use of silver sulfadiazine in ointments for the treatment of burns.
  • U.S. Patent No. 4,404,197 discloses the use of ointments for burns containing both silver and antibiotics, specifically norfloxacin, in which the antibiotic produces a synergistic increase in the biocidal activity of the silver.
  • U.S. Patent No. 5,374,432 (the disclosure of which is incorporated herein by reference) discloses the use of both silver salts and antibiotics selected from aminoglycosides and quinolones, in combination, for the treatment of burns, ocular and other infections.
  • Burkholderia (formerly Pseudomonas) cepacia, a common soil- and water-borne Gram negative bacterium, is known to infect patients with the genetic diseases chronic granulomatous disease (CGD) and cystic fibrosis (CF) (Govan and Deretic. 1996).
  • CCD chronic granulomatous disease
  • CF cystic fibrosis
  • B. cepacia is highly resistant to killing by cationic antimicrobials such as aminoglycosides, polymyxin B, and defensins due to the low levels of negatively-charged phosphate residues in the core region of its outer membrane.
  • CF patients have mutations in the gene encoding the cystic fibrosis transmembrane regulator (CFTR), a chloride channel required for proper transmembrane sodium balance (Zielenski and Tsui, 1995).
  • CFTR cystic fibrosis transmembrane regulator
  • the symptoms of CF include production of extremely dehydrated and viscous mucous in the pancreatic and bile ducts leading to digestive disorders, disorders of the reproductive tract ducts which often leads to infertility, and in the lungs which leads to breathing disorders, infection and finally death.
  • the viscosity of CF pulmonary mucous impairs normal mucociliary clearance of potential pathogens, permitting some species of bacteria to establish chronic infections.
  • the bacterial species most likely to establish chronic pulmonary infections are P. aeruginosa (up to 80% of CF patients) and B. cepacia (10-40%, depending on the CF center). Once patients become colonized with the bacteria, they undergo repeated cycles of acute infection which lead to pulmonary damage and eventual loss of lung function. Twenty percent of patients infected with B. cepacia are also in danger of succumbing to "cepacia syndrome", a fulminant pneumonia and bacteremia that is rapidly fatal, often in less than 48 hours (Govan and Deretic, 1996). In addition in its resistance to cationic antibiotics, B. cepacia is also highly resistant to most other antibiotics (Govan et al, 1996).
  • the present invention provides encapsulated silver compositions for use in the treatment of infection in humans and in other mammals.
  • encapsulated silver salt compositions According to the present invention there is provided in one aspect, encapsulated silver salt compositions.
  • a bactericidal composition comprising;
  • an anti-fungal composition comprising; - an encapsulated silver component; and
  • a bactericidal composition comprising an encapsulated silver component and a pharmaceutically acceptable carrier, wherein said encapsulated silver component has a modification allowing for the targeting of such composition to specific cells and/or tissues.
  • encapsulated silver compositions for the treatment of infection in humans and in other mammals.
  • the type of encapsulation may be selected from liposomes, microspheres, nanospheres and other lipid, polymer or protein material which may be further modified to target specific tissues and/or organs.
  • compositions of the present invention may be applied topically, by injection, by inhalation or by systemic application to burn wounds, full thickness wounds, ocular infections and other infected and infection-prone areas, including internal infections of organs such as the lungs, prostate, bladder, etc.
  • compositions of the present invention have use in treating a variety of bacterial infections caused by Burkholderia cepacia or any gram negative and gram positive bacteria in general as well as a variety of yeast infections caused by aspergillus , fusarium, Candida, phy corny ces and allscheria.
  • an infection in a mammal comprising the steps of administering an effective amount of an encapsulated silver salt composition in a mixture with a pharmaceutically acceptable diluent or carrier to said mammal at the site of infection.
  • a further aspect of the present invention is a method for treating
  • Burkholderia cepacia infections in patients having chronic granulomatous disease or cystic fibrosis comprising administering an effective amount of a composition comprising an encapsulated silver salt and a pharmaceutically acceptable diluent or carrier to such patients.
  • a composition comprising an encapsulated silver salt and a pharmaceutically acceptable diluent or carrier to such patients.
  • a liposome composition comprising a silver salt that is stable in vivo and in vitro.
  • a liposome composition having an encapsulated silver salt composition that has a long blood circulation life time.
  • the invention has particular use as an aerosol bactericidal liposome encapsulated silver lactate composition for use in combating Burkholderia cepacia infection in the lungs in cystic fibrosis patients.
  • Figure 1 shows silver liposome effux from liposome formulations prepared containing silver lactate and/or vitamin E.
  • compositions of the invention comprise at least one silver component provided as a solution or emulsion contained within phospholipid vesicles called liposomes.
  • the liposomes may be unilamellar or multilamellar and are formed of constituents selected from phosphatidylcholine, dipalmitoylphosphatidylcholine, sphingomyelin, cholesterol, phosphatidylethanolamine, phosphatidylserine, phosphatidylinosital, demyristoylphosphatidylcholine and combinations thereof.
  • the invention includes the use of liposomes having a bilayer membrane formed of a cationic vesicle-forming lipid and a neutral vesicle- forming lipid.
  • the liposomes have a control core with an inner surface and entrapped in the core and localized predominantly on the inner surface is the silver component.
  • the cationic lipid may include for example but are not limited to 1,2- dioleoxyloxy-3-(trimethylamino) propane, N-[l-(2,3,-ditetradecyloxy)propyl]-N,N- dimethyl-N-hydroxyethylammonium bromide and dimethyldioctadecylammonium.
  • the neutral vesicle- forming lipid is in one embodiment, a phospholipid.
  • the neutral lipid is derivitized with a hydrophilic polymer such as polyethylene glycol.
  • the multilamellar liposomes comprise multilamellar vesicles of similar composition to unilamellar vesicles, but are prepared so as to result in a plurality of compartments in which the silver component in solution or emulsion is entrapped.
  • other adjuvants and modifiers may be included in the liposomal formulation such as polyethyleneglycol, or other materials such as vitamin E and other antioxidants known to those skilled in the art which may act to stabilize the silver component incorporated therein.
  • liposomes include dipalmitoyl- phosphatidylcholine: cholesterol (1 :1) it is understood by those skilled in the art that any number of liposome bilayer compositions can be used in the composition of the present invention.
  • Liposomes may be prepared by a variety of known methods such as those disclosed in U.S. Patent No. 4,235,871 (the contents of which is incorporated herein by reference) and in RRC, Liposomes: A Practical Approach. IRL Press, Oxford, 1990, pages 33-101.
  • the liposomes containing the silver component may have modifications such as having non-polymer molecules, ligands or moieties bound to the exterior of the liposome such as haptens, enzymes, antibodies or antibody fragments, cytokines and hormones and other small proteins, carbohydrates, lectins, magnetic particles (eg. aqueous-based ferro fluid EMB807), polypeptides or non-protein molecules which confer a desired enzymatic or surface recognition feature to the liposome.
  • Surface molecules which preferentially target the liposome to specific organs tissue regions or cell types may include for example antibodies which target the liposomes to cells bearing specific antigens. Techniques for coupling such molecules are well known to those skilled in the art (see for example U.S.
  • Patent 4,762,915 the disclosure of which is incorporated herein by reference).
  • any number of lipids bearing a positive or negative net charge may be used to alter the surface charge or surface charge density of the liposome membrane.
  • the liposomes can also incorporate thermal sensitive or pH sensitive lipids as a component of the lipid bilayer to provide controlled degradation of the lipid vesicle membrane.
  • sterically stabilized liposomes are produced to contain polyethylene glycol as an essential component of their surface and the method of making such liposomes is well known to those skilled in the art.
  • hydrophilic polymers such as polylactic acid, polyglycolic acid, polyvinyl- pyrrolidone, polymethyloxazoline, polyethyloxazoline, polyhydroxyl propyl methacrylamide, polymethacrylamide and derivatized celluloses, such as hydroxy methycellulose or hydroxyethycellulose may also be used to surface coat the liposomes to effectively extend the blood circulation time of the liposomes.
  • the size of the liposomes can be prepared based on the intended target and route of administration. Liposomes of less than about 300 nm and preferably between about 50 nm to 300 nm may be suitable. Furthermore, the composition of the present invention may include liposomes of different sizes.
  • liposomes are the preferred encapsulant for use in the composition of the present invention it is understood by those skilled in the art that other types of encapsulants may also be used to encapsulate the silver component.
  • Microspheres including but not limited to those composed of ion-exchange resins, crystalline ceramics, biocompatible glass, latex and dispersed particles are suitable for use in the present invention.
  • nanospheres and other lipid, polymer or protein materials can also be used.
  • the silver component of the invention may be elemental silver or a silver salt.
  • Suitable silver salts include silver acetate, silver benzoate, silver chloride, silver carbonate, silver iodate, silver iodide, silver lactate, silver laurate, silver nitrate, silver oxide, silver palmitate, silver protein, silver sulfadiazine and mixtures thereof.
  • the preferred silver component for use in the composition of the present invention is silver lactate.
  • the silver component will in general be incorporated in the liposome in amounts of 1-200 mM, most preferably 25-100 mM.
  • the liposomes containing a silver salt may additionally contain other suitable emulsifiers and/or buffers as required. It is also understood that the liposomes may additionally comprise further active agents together with the silver salt which may help to benefit the patient.
  • Other active agents may include but are not limited to therapeutic drugs and pharmacologically active agents such as antineoplastics, antitumor agents, antibiotics, antifungals, antivirals, antiparasitic compounds, anesthetics, cytokines and antiinflammatory compounds.
  • Suitable carriers for use in the present invention include but are not limited to sterile distilled water, physiological phosphate buffered saline, physiological saline, and other carriers generally regarded by current medical practice.
  • compositions of the present invention provide desirable properties that make them particularly suitable for the treatment of bacterial and fungal infections that are either localized and/or systemic and of open full-thickness wounds, burns wounds, ocular infections and infections of internal organs, such as the lungs, bladder, prostate, etc.
  • the infection-prone sites are envisaged to be any area exposed to bacteria and fungi such as full thickness wounds of the skin, scrapes, cuts, punctures and burns of the skin, as well as wounds created during surgery, the sites of penetration into the body of in-dwelling devices such as catheters, drains, sutures, pins, and the like, but are not limited to these. Infections of internal organs caused by bacteria and fungi are likewise considered to be accessible to the liposome encapsulated silver salt compositions of the present invention.
  • compositions of the invention provide a wide antimicrobial spectrum, as is generally known to those skilled in the art, but also exhibit enhanced efficacy such that lower doses of the active agent (i.e. silver component) can be employed. This is especially beneficial since lower doses of silver reduce the risk of side-effects in the patient. Furthermore, the use of liposomes minimizes any adverse effects of the agents that they encapsulate, increase the residency of the active agent at the desired site, and increase the stability of the active agent at the desired site.
  • the active agent i.e. silver component
  • a pharmaceutical composition for administration to subjects in a biologically compatible form suitable for administration in vivo for treating various bacterial and fungal infections comprises a safe and effective amount of the encapsulated silver salt composition alone, or in combination with other agents and pharmaceutical carriers.
  • the composition may be administered to any living organism including humans and animals.
  • safe and effective as used herein is meant providing sufficient potency in order to decrease, prevent, ameliorate or treat a bacterial or fungal infection affecting a subject while avoiding serious side effects.
  • a safe and effective amount will vary depending on the age of the subject, the physical condition of the subject being treated, the severity of the infection, the duration of treatment and the nature of any concurrent therapy.
  • Administration of a therapeutically active amount of the liposome encapsulated silver salt composition of the present invention is defined as an amount effective, at dosages and for periods of time necessary to achieve the desired result. This may also vary according to factors such as the disease state, age, sex, and weight of the subject, and the ability of the encapsulated silver salt composition to elicit a desired response in the subject. Dosage procedures may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
  • pharmaceutically acceptable carrier as used herein is meant one or more compatible solid or liquid delivery systems.
  • pharmaceutically acceptable carriers are sugars, starches, cellulose and its derivatives, powdered tragacanth, malt, gelatin, collagen, talc, stearic acids, magnesium stearate, calcium sulfate, vegetable oils, polyols, agar, alginic acids, pyrogen-free water, isotonic saline, phosphate buffer, and other suitable non-toxic substances used in pharmaceutical formulations.
  • Other excipients such as wetting agents and lubricants, tableting agents, stabilizers, anti-oxidants and preservatives are also contemplated.
  • compositions described herein can be prepared by known methods for the preparation of pharmaceutically acceptable compositions which can be administered to subjects, such that an effective quantity of the active substance is combined in a mixture with a pharmaceutically acceptable carrier.
  • Suitable carriers are described for example in Remington's Pharmaceutical Sciences (Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., USA 1985).
  • the compositions include, albeit not exclusively, solutions of the substance in association with one or more pharmaceutically acceptable vehicles or diluents, and contained in buffered solutions with a suitable pH and iso-osmotic with the physiological fluids.
  • the liposome encapsulated silver salt composition can also be administered parenterally or intraperitoneally.
  • Suspensions of the active compound (the encapsulated silver salt) as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the composition may be administered in a convenient manner such as by injection (subcutaneous, intravenous etc.), oral administration, inhalation, transdermal application, or rectal administration. Depending on the route of administration, the active substance may be coated in a material to protect the compound of the composition from any conditions which may inactivate the compound.
  • the liposomal encapsulated silver salt compositions can be delivered in the form of tablets, capsules, cachets, gelcaps, solutions, suspensions and the like.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersion and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that easy syringability exists.
  • the liposome encapsulated silver salt composition of the present invention may be administered to a mammal alone or in combination with pharmaceutically acceptable carriers, as noted above, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice.
  • the silver salt liposomes of the present invention are reliably produced and effectively allow the efflux of the silver salt component contained therein ( Figure 1). Furthermore, as also seen in Figure 1 , the addition of antioxidants such as vitamin E for example, may act to help the encapsulation of additional silver salt within the liposomes such that more is present for efflux and thus local or systemic treatment of various infection and fungal infection.
  • the liposome encapsulated silver salt composition of the present invention effectively inhibits the growth and spread of various species of bacteria and yeast as is shown in the following examples and therefore have use in the treatment of mammalian localized and systemic infection.
  • lipid-to-other constituents ratio may be used to effectively achieve the embodiments of this invention.
  • the lipids were dissolved in chloroform (4 mL) and the solvent was removed in vacuo.
  • the resulting lipid film was dried in vacuo for two hours and rehydrated with 1 mL of 1-200 mM silver lactate solutions, preferably 100 mM aqueous silver lactate solution at 45° C. Liposomes were then frozen in liquid nitrogen and thawed in a 45° C water bath, 5 times, followed by high pressure extrusion through two 100 nm -pore diameter membranes, 10 times.
  • Example 2 In Vitro Anti-bacterial Activity against Burkholderia cepacia using liposomes of Example 1 A broth microdilution assay (National Committee for Clinical Laboratory
  • MIC minimum inhibitory concentration
  • Bacteria were grown overnight in Mueller Hintoni broth (Difco) and diluted in the same medium to match the 0.5 MacFarland turbidity standard. Empty liposomes, liposomal silver lactate (50 mM) and silver lactate (50 mM) were used undiluted and at serial doubling dilutions in Mueller-Hinton broth.
  • One hundred ⁇ l of each compound or diluted compound was mixed with 100 ⁇ l of standardized bacterial suspension in individual wells of a polystyrene 96-well microtitre plate. The plate was incubated in the dark in a humidified container at 37°C for 18 hr. The highest dilution that prevented growth of the bacteria (as determined by visible turbidity) was designated the MIC.
  • the lipid mixture was extruded three times through a 100 nm membrane filter to yield the liposomes containing silver lactate.
  • Silver Lactate-loaded Liposome Characteristics The silver lactate-loaded liposomes are a cream or yellowish cream suspension, soluble in a mixture of chloroform/methanol/water (2.8/5.7/2) called the single phase and have a density of 1.0042.
  • Silver Ion Concentration Assay Approximately 60 ⁇ l of the silver liposome suspension (LS-Ag) was taken to which 2 drops of concentrated nitric acid and 1 ml of 2 M sulfuric acid were added.
  • the liposome formulations containing Vitamin E (Ag-lpVe RT and Ag-lpVe 37) encapsulate approximately 3.2 mg Silver lactate/ml of liposome suspension while the liposome formulations without Vitamin E (Ag-lipo 37 and Ag- IpRT) hold 2.6 mg Silver lactate/ml of liposome suspension.
  • Vitamin E containing liposomes show that approximately 1.2 mg silver lactate/ml of liposome suspension is retained after 24 hours and at room temperature, the liposomes retain 2.2 mg Silver lactate/ml of liposome suspension.
  • the most stable liposome formulation in terms of silver lactate retention was that containing Vitamin E (Ag-lp Ve).
  • Vitamin E serves to stabilize the liposome system from apparent oxidation and is therefore beneficial for the formulation. While it is recommended that thel silver lactate containing liposome formulations of the present invention incorporate Vitamin E or other suitable antioxidant it is not required.
  • Example 4 Minimal inhibitory concentration values for liposomal silver lactate Bacteria were grown from glycerol stocks overnight at 37°C in Mueller
  • Hinton broth Cells were harvested by centrifugation and washed three times in sterile phosphate buffered saline, pH 7.0. The culture densities were adjusted to match a MacFarland standard of 0.5 (approximately 10 7 colony forming units per ml). Liposomes loaded with silver lactate (4.0 mg/ml) were diluted in Mueller-Hinton broth to 50 ⁇ g/ml silver lactate. Doubling dilutions of 100 ⁇ l were set up across the columns of 2 polystyrene 96-well microtitre plates.
  • Each species was tested across a single row (10 ⁇ l added per well), with Mueller Hinton alone inoculated as a positive control for growth and uninoculated Mueller Hinton as a negative control. The plates were incubated overnight at 37°C in a humidified chamber. The MIC was scored as the highest dilution preventing growth of the organism.

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Abstract

L'invention concerne des compositions encapsulées de sels d'argent destinées au traitement d'infections de surface et de plaies profondes et d'autres régions sujettes aux infections bactériennes et fongiques. Les compositions renferment un lactate d'argent encapsulé dans un liposome ou d'autres sels d'argent adéquats dans un excipient pharmaceutiquement acceptable.
EP00967484A 1999-10-14 2000-10-13 Compositions de sels d'argent encapsulees dans un liposome Withdrawn EP1220657A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US15942799P 1999-10-14 1999-10-14
US159427P 1999-10-14
PCT/CA2000/001199 WO2001026627A1 (fr) 1999-10-14 2000-10-13 Compositions de sels d'argent encapsulees dans un liposome

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EP1220657A1 true EP1220657A1 (fr) 2002-07-10

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EP (1) EP1220657A1 (fr)
JP (1) JP2003511404A (fr)
AU (1) AU7767200A (fr)
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FR2853548B1 (fr) * 2003-04-11 2008-09-05 Mayoly Spindler Lab Nouvelles utilisations du proteinate d'argent dans la prevention du syndrome respiratoire aigu severe(sras)
WO2004112805A1 (fr) * 2003-06-20 2004-12-29 Johnson & Johnson Medical Limited Antimicrobien a l'argent
JP2005104924A (ja) * 2003-09-30 2005-04-21 Kobayashi Pharmaceut Co Ltd 外用医薬組成物
WO2009085651A1 (fr) 2007-12-20 2009-07-09 Nucryst Pharmaceuticals Corp. Particules de carbonate de métal et leurs méthodes d'obtention
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GB201200490D0 (en) 2012-01-12 2012-02-22 Univ Bath Wound dressing
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CA2387145A1 (fr) 2001-04-19

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