[go: up one dir, main page]

WO2000042990A1 - Formulations de liposomes - Google Patents

Formulations de liposomes Download PDF

Info

Publication number
WO2000042990A1
WO2000042990A1 PCT/US2000/001743 US0001743W WO0042990A1 WO 2000042990 A1 WO2000042990 A1 WO 2000042990A1 US 0001743 W US0001743 W US 0001743W WO 0042990 A1 WO0042990 A1 WO 0042990A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
pest
ivermectin
lipid
lipid phase
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.)
Ceased
Application number
PCT/US2000/001743
Other languages
English (en)
Inventor
John Kinzell
Martin T. Baker
Douglas Hepler
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.)
OPTIME Therapeutics Inc
Idexx Pharmaceuticals Inc
Original Assignee
Blue Ridge Pharmaceuticals Inc
OPTIME Therapeutics 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 Blue Ridge Pharmaceuticals Inc, OPTIME Therapeutics Inc filed Critical Blue Ridge Pharmaceuticals Inc
Priority to MXPA01007486A priority Critical patent/MXPA01007486A/es
Priority to AU26272/00A priority patent/AU781703B2/en
Priority to JP2000594447A priority patent/JP2002535268A/ja
Priority to EP00904531A priority patent/EP1154755A4/fr
Priority to IL14456100A priority patent/IL144561A0/xx
Publication of WO2000042990A1 publication Critical patent/WO2000042990A1/fr
Priority to IL144561A priority patent/IL144561A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/02—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing liquids as carriers, diluents or solvents
    • A01N25/04—Dispersions, emulsions, suspoemulsions, suspension concentrates or gels
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/14—Ectoparasiticides, e.g. scabicides

Definitions

  • the present invention relates to a formulation for the delivery of pest growth regulators, pest repeilants and pesticides using liposomes. More specifically, the invention relates to liposome formulations containing ivermectin.
  • ivermectin belongs is described in Chabala, et al., U.S. Patent No. 4,199,569. These compounds have parasiticidal activity as anthelmintics, insecticides, ectoparasiticides and acaracides and have been found to be useful in the treatment of parasitic infestations affecting animals, including humans. More specifically, ivermectin is classified as a veterinary therapeutic for use as an anthelmintic, insecticide and acaricide, while the human therapeutic classification is as an anthelmintic, more specifically for the treatment of human onchocerciasis (river blindness).
  • ivermectin a commercially available ivermectin formulation is Stromectol (Merck & Co.), which is available in a solid dosage form.
  • a formulation using surface modified microcapsules that contain active agents such as ivermectin is described by Speaker, et al, U.S Patent No. 5,686,113.
  • the following disclosures describe several other means for delivery of insect repeilants. Lau, et al., U.S. Patent No. 5,173,303 describes a liposome formulation for the delivery of the insecticide N, N diethyl-m-toluamide (DEET). Unger, et al., U.S. Patent No.
  • Therapeutic agents are also shown to be administered in a liposome formulation having a relatively high (20-40 wt%) alcohol content (Touitou, U.S. Patent No. 5,716,638).
  • Wallach, et al., U.S. Patent No. 5,019,392 describes one formulation that minimizes the use of organic solvents by use of non-phospholipid vesicles.
  • Liposomes are vesicles made of membrane-like lipid bilayers separated by aqueous layers. Liposomes have been widely used to encapsulate biologically active agents for use as drug carriers since water- or lipid-soluble substances may be entrapped within the aqueous layers or within the bilayers themselves. There are numerous variables that can be adjusted to optimize this drug delivery system. These include, the number of lipid layers, size, surface charge, lipid composition and the methods of preparation.
  • liposomes Most pharmaceutical applications of liposomes have focused on their use in injectable formulations. However, use of liposomes in topical formulations has been shown to provide for better drug delivery than conventional vehicles, both from the standpoint of enhanced penetration and enhanced localization. See for example,
  • the present invention provides for an improved means and method for delivery of pest growth regulators, pest repeilants and pesticides using a liposome-based formulation.
  • the present invention relates to a liposome composition
  • a liposome composition comprising 0.001 to 10.0 wt% of at least one active agent selected from the group consisting of pest growth regulators, pest repeilants and pesticides, where the composition comprises about 2.0 to 18.0 wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase.
  • the present invention also relates to a composition comprising lipid vesicles having ivermectin encapsulated therein in an amount of between about 0.001 to 10.0 wt% of the composition.
  • the invention in a second aspect, relates to a liposomal pharmaceutical composition
  • a liposomal pharmaceutical composition comprising: (a) a lipid phase comprising phospholipids and at least one active agent; and (b) an aqueous phase comprising an aqueous solution; the active agents being selected from the group consisting of pest growth regulators, pest repeilants and pesticides.
  • the aqueous phase may further comprise one or more excipients and one or more active agents.
  • the lipid phase may further comprise a pharmaceutical carrier, an antioxidant and modifying agents.
  • Still another aspect of the invention pertains to a method for treating a pest infestation which comprises administering a therapeutically effective amount of a pesticide encapsulated within lipid vesicles in a liposome formulation which comprises about 2.0 to 18.0 wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase.
  • the pesticide typically comprises 0.005 to 50.0 wt% of the lipid phase.
  • the invention in another aspect, relates to a method for controlling a pest population which comprises administering a therapeutically effective amount of a pest growth regulator encapsulated within lipid vesicles in a liposome formulation about 2.0 tol8.0 wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase.
  • the pest growth regulator typically comprises 0.005 to 50.0 wt% of the lipid phase.
  • Another aspect of the invention pertains to a method for repelling pests which comprises administering a therapeutically effective amount of a pest repellant encapsulated within lipid vesicles in a liposome formulation about 2.0 tol ⁇ .O wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase.
  • the pest repellant typically comprises 0.005 to 50.0 wt% of the lipid phase.
  • the invention pertains to a method for treating parasitic infestations, which comprises administering a composition comprising lipid vesicles having ivermectin encapsulated therein in an amount of between about 0.001 to 10.0 wt% of said composition.
  • the parasitic infestation is a lice infestation and administration is by topical application to the skin or hair.
  • the parasitic infestation is a mite infestation and administration is by topical application to the ears.
  • Another aspect of the invention relates to a method of treating a lice or mite infestation on an animal by topically administering ivermectin, which comprises the step of topically applying an ivermectin-containing liposome formulation to the skin or hair of an animal, said application being about 0.005 to 0.5 grams of formulation per square centimeter of skin.
  • the invention also pertains to an article of manufacture comprising a container in association with instructions and/or a label indicating that the subject composition can be used to control pests, i.e., used as a pest growth regulator, pest repellant or pesticide and holding a composition comprising lipid vesicles having at least one pest growth regulator, pest repellant or pesticide encapsulated therein, where the composition comprises about 2.0 tol 8.0 wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase.
  • compositions based on liposomes are particularly suitable for use with pest growth regulators, pest repeilants and pesticides.
  • the benefits of liposomes are believed to be related to favorable changes in tissue distribution and pharmacokinetic parameters that result from liposome entrapment of active agents, and may be applied to pest growth regulators, pest repeilants and pesticides.
  • the formulations of the instant invention provide for improved active agent delivery such that a minimal amount of active agent is needed to obtain the desired effect. Controlled release liposome liquid pharmaceutical formulations for injection, oral or rectal administration can also be used.
  • liposomes in the methods and formulations described herein will have broad utility in the improved delivery of pest growth regulators, pest repeilants and pesticides to an animal or agricultural plants.
  • Animals to be treated include humans, companion animals (e.g., feline and canine), and agriculturally bred animals such as horses and including those raised for human consumption, such as bovine, porcine and poultry (e.g. avian).
  • active agent is intended to mean any compound or composition that, when present in a therapeutically effective amount, produces an effect on pests, more specifically a negative effect such as one that eradicates pests, or hinders growth and development, or acts as a deterrent, and so forth. More specifically, the term active agent is used to collectively refer to pest growth regulators, pest repeilants and pesticides. The term “active agent” is also intended to include use of a single active agent or use of several active agents in combination.
  • At least one active agent will be encapsulated within the liposomes, while any additional active agents may be encapsulated in the same liposomes as the first active agent, may be encapsulated within separate liposomes or may be included within the aqueous phase.
  • arthropod growth regulators is used to mean an active agent used to regulate pest growth, and insect growth in particular, or to prevent re- infestation by attacking the newly hatched or juvenile stage pests.
  • arthropod growth regulators include, by way of illustration and not limitation, agents such as methoprene, pyriproxyfen, lufenuron and cyromazine.
  • Pest repeilants is used to mean an active agent that repels or deters pests from animals or agricultural plants which have been treated with the agent and includes, by way of illustration and not limitation, agents such as citronella, dimethyl phthalate, dimethyl carbate, ethohexadiol, diethyltoluamide, indalone, benzyl benzoate, 2-ethyl-l,3-hexanediol and coumarin. Pest repeilants also include agents that prevent pests from being attracted to a treated animal or plant, for example by masking, altering or neutralizing any scent or chemical on the animal or plant that attracts pests.
  • the term "pesticides” is used to mean an active agent used to attack and eradicate those pests or parasites that are know to infest and/or harm animals or agricultural plants, in particular those that infest the skin and/or hair of an animal.
  • the term “pesticide” includes, by way of illustration and not limitation, parasiticides, ectoparasiticides, acaricides, miticides and anthelmintics, along with specific agents such as ivermectin, benzyl benzoate, chlorophenothane, crotamiton, lindane, precipitated sulfur, pyrethrum, rotenone and allethrin.
  • Pesticides such as ivermectin are particularly suited for combination with a pest growth regulator and/or pest repellant, such that one an infestation of adult pests has been eradicated, re- infestation is prevented either by hindering egg or juvenile stage development or by repelling adult pests.
  • pest refers to organisms and microorganisms, including pathogens, that negatively affect animals and plants by colonizing, attacking or infecting them, and includes those organisms that spread disease and/or damage the animal and/or compete for host nutrients.
  • pest organisms include, by way of illustration, and not limitation arthropods, bacteria, and parasitic worms such as nematodes.
  • Arthropods include insects such as fleas, mosquitoes, lice (including those that infest humans such as Pediculus humanus capitis, head louse, Pediculus humanus corporis, body or clothes louse, and Phthirus pubis, crab louse), biting gnats, flies, scabies (more accurately, Sarcoptes scabiei, the parasite that causes scabies) and vibrio vulnifwa; and arachnids such as spiders, ticks and mites such as chiggers.
  • the term "pest” is intended to include those pests of agricultural plants such as plant mites, aphids and locusts.
  • a liposome formulation is used for the topical application of ivermectin to treat diseases caused by lice, scabies and mites and for the oral administration to treat diseases caused by parasites such as those belonging to the Ascaridae family, in particular Ascaridae Galli and Ascaridae canus, which attack the fatty tissues of chickens, pigs, dogs and cats.
  • Ivermectin can be used in combination with a pest growth regulator such as pyriproxyfen, which may be encapsulated with the ivermectin, encapsulated in separate liposomes which are then mixed with the ivermectin-containing liposomes, or added to the aqueous phase.
  • a pest growth regulator such as pyriproxyfen
  • lipids or lipophilic substances are dissolved in an organic solvent.
  • the solvent is removed, such as under vacuum by rotary evaporation, the lipid residue forms a film on the wall of the container.
  • An aqueous solution that typically contains electrolytes or hydrophilic biologically active materials are then added to the film.
  • Large MLNs are produced upon agitation.
  • the larger vesicles are subjected to sonication or sequential filtration through filters with decreasing pore size.
  • pressurized extrusion Barenholz, et al., FEBS Lett. 99:210-214 (1979)).
  • Liposomes can also take the form of unilamellar vesicles, which are prepared by more extensive sonication of MLVs, and consist of a single spherical lipid bilayer surrounding an aqueous solution.
  • Unilamellar vesicles can be small, having diameters within the range of 200-500 A, while larger ULNs can have diameters within the range of 1000-10,000 A.
  • UPNs Unilamellar vesicles
  • Small ULNs can also be prepared by the ethanol injection technique described by Batzri, et al., Biochim et Biophys Acta 298:1015-1019 (1973) and the ether injection technique of Deamer, et al. Biochim et Biophys Acta 443:629-634 (1976). These methods involves the rapid injection of an organic solution of lipids into a buffer solution, which results in the rapid formation of unilamellar liposomes.
  • Another technique for making ULNs is taught by Weder, et al. in "Liposome Technology", ed. G. Gregoriadis, CRC Press Inc., Boca Raton. Florida, Nol. I, Chapter 7, pg. 79-107 (1984).
  • This detergent removal method involves solubilizing the lipids and additives with detergents by agitation or sonication to produce the desired vesicles.
  • Papahadjopoulos, et al., U.S. Patent 4,235,871 describes the preparation of large ULNs by a reverse phase evaporation technique that involves the formation of a water-in-oil emulsion of lipids in an organic solvent and the material to be encapsulated in an aqueous buffer solution. The organic solvent is removed under pressure to yield a mixture which, upon agitation or dispersion in an aqueous media , is converted to large ULNs.
  • Suzuki et al., U.S. Patent No. 4,016,100 describes another method of encapsulating agents in unilamellar vesicles by freezing an aqueous phospholipid dispersion of the agent and lipids.
  • liposomes can also be multivesicular.
  • these multivesicular liposomes are spherical and contain internal granular structures.
  • the outer membrane is a lipid bilayer and the internal region contains small compartments separated by bilayer septrum.
  • a comprehensive review of all the aforementioned lipid vesicles and methods for their preparation are described in "Liposome Technology", ed. G. Gregoriadis, CRC Press Inc., Boca Raton, Florida, Nol. I, II, & III (1984).
  • Mezei, et al., U.S. Patents No. 4,485,054 and Mezei, U.S. Patents No. 4,761,288 also describe methods of preparing lipid vesicles.
  • one or more active agents are dissolved or dispersed in a lipid- containing organic solvent.
  • the solvent is then evaporated, usually under reduced pressure, to yield a thin lipid film containing the active agent(s).
  • the lipid film is then hydrated, with agitation, using a aqueous phase containing any desired electrolytes and lipid vesicles containing the active agent(s) are produced.
  • the invention also contemplates the inclusion of additional materials in the formulations to facilitate active agent delivery, formulation stability, and so forth.
  • additional materials such as conventional thickeners and gelling agents can also be added to provide a formulation having the desired consistency for topical application.
  • a modifying agent such as a preservative, an antioxidant or excipients will often be added to the formulation.
  • the amount of active agent to be included in the liposome formulation can vary within wide limits depending upon the intended application and the lipid used. Further, while one active agent will be encapsulated within the liposomes, any additional active agents may be encapsulated within the same or different liposomes or may be added to the aqueous phase.
  • the level of the active agent in the liposome formulation of the invention can vary within the full range employed by those skilled in the art, e.g., from about 0.001 weight percent (wt%) to about 99.99 wt% of the active agent based on the total formulation, with the balance (about 0.01-99.99 wt%) being the lipid and aqueous phase substituents. However, the formulations of the invention contemplate some preferred ranges of active agent, which are set forth in detail below.
  • the active agent is administered at a therapeutically effective amount, e.g., a dosage sufficient to provide treatment for the disease state being treated, for example a parasitic infestation.
  • Administration of the active agent- liposome formulation can be via any of the accepted modes of administration for agents that serve similar utilities.
  • This invention is intended to be utilized for any disease state treated by the active agents in their current commercially available forms.
  • one embodiment for the invention pertains to a method for treating a pest infestation which comprises administering a therapeutically effective amount of a pesticide encapsulated within lipid vesicles in a liposome formulation.
  • a pest population can be controlled by administering a therapeutically effective amount of a pest growth regulator encapsulated within lipid vesicles in a liposome formulation, and pests can be repelled by administering a therapeutically effective amount of a pest repellant encapsulated within lipid vesicles in a liposome formulation.
  • any of the aforementioned methods can also include one or more other active agents that function the same as or different from the first active agent, for example, a method for treating a pest infestation can involve administering a pesticide alone, or in combination with one or more other pesticides, pest growth regulators and/or pest repeilants.
  • a liposome composition comprises 0.001 to 10.0 wt% of at least one active agent selected from the group consisting of pest growth regulators, pest repeilants and pesticides, where the composition comprises about 2.0 to 18.0 wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase.
  • a liposomal pharmaceutical composition comprises: (a) a lipid phase comprising phospholipids and at least one active agent; and (b) an aqueous phase comprising an aqueous solution and optionally further comprising one or more active agents; the active agents being selected from the group consisting of pest growth regulators, pest repeilants and pesticides.
  • a preferred active agent-liposome formulation or composition has a lipid and aqueous phase, and will contain active agents in an amount of about 0.001 to 10.0 wt% of the total formulation. However, more typically, the total amount of active agents will be about 0.001 to 0.5 wt% of the total formulation, with a preferred range being about 0.001 to 0.2 wt% of the total formulation.
  • the formulations of the invention comprise about 2.0 to 18.0 wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase.
  • An exemplary formulation is comprised of about 9.5 wt% lipid phase and about 90.5 wt% aqueous phase, and contains about 0.001 to 0.1 wt% of active agent(s).
  • the lipid phase contains at least one active agent and phospholipids.
  • the lipid phase may optionally contain one or more pharmaceutical carriers (as described above), an antioxidant and other modifying agents.
  • the lipid phase contains about 0.005 to 50.0 wt% active agent, typically about 0.005 to 25.0 ⁇ vt% active agent, and preferably about 0.005 to 7.0 wt%. These ranges refer to the total amount of active agents present in the lipid phase.
  • the lipid phase may comprise about 2.0 to 75.0 wt% phospholipids, typically about 25.0 to 45.0 wt% phospholipids.
  • Numerous lipids are useful in the manufacture of the lipid phase of the formulation of the invention, and include by way of illustration and not limitation, phospholipids such as phosphatidyl chlolines, lysophosphatidyl chlolines, phosphatidyl serines, phosphatidyl ethanolamines, phosphatidyl inositols, cardiolipin, and sphingomyelin; natural phospholipids such as egg yolk lecithin, soybean lecithin, and soybean oil based phospholipids; glycolipids, dialkyl-type synthetic surfactants; polar lipids and neutral lipids; fatty acids; and the like.
  • phospholipids and hydrogenated phospholipids are particularly useful.
  • Soybean oil based phospholipids are well suited for use in the invention, for example the hydrogenated phosphatidylcholine, Phospholipon ® 90H ("PH-90H”) and the hydrogenated phosphatidylcholine, Phospholipon ® 80H (“PH-80H”), manufactured by American Lecithin Company, Oxford, Connecticut.
  • PH-90H hydrogenated phosphatidylcholine
  • Phospholipon ® 80H Phospholipon ® 80H
  • the lipid phase may optionally contain one or more pharmaceutically acceptable carriers, comprising from about 0 to 70.0 wt% of the lipid phase, and typically from about 40.0 to 60.0 wt% of the lipid phase.
  • pharmaceutically acceptable carriers are suitable for use in the invention, as are described herein, and may be used alone or in combination.
  • Preferred carriers include glycols such as propylene glycol, polyethylene glycol, polypropylene glycol and glycol ethers, and low molecular weight alcohols (C ⁇ - 6 ) such as 200 proof ethanol, along with a combination of a glycol and low molecular weight alcohol. Such combinations are typically within the range of about 50 to 100 wt% alcohol and 0 to 50 wt% glycol.
  • the lipid phase may optionally also contain about 0 to 20.0 wt% of an antioxidant, more typically about 1.0 to 15.0 wt% antioxidant.
  • an antioxidant typically about 1.0 to 15.0 wt% antioxidant.
  • suitable antioxidants are well known in the art.
  • the preferred antioxidant is tocopherol or a tocopherol derivative, more preferably Vitamin E ( ⁇ -tocopherol acetate).
  • ⁇ -Lipoic Opti-pure, Los Angeles, CA is also well suited for use as an antioxidant.
  • the lipid phase may optionally contain one or more suitable modifying agents such as are well known in the art and include materials such as conventional thickeners, gelling agents, preservatives, stabilizers, emulsifiers, and so forth.
  • suitable modifying agents include, by way of illustration and not limitation, stearylamine, phosphatidic acid, dicetyl phosphate, sterols, cholesterol and cholesterol stearate, lanolin extracts, hydroxypropylmethylcellulose, carboxymethylcellulose, sorbitol, and the like.
  • the amount of modifying agents will range from about 0 to 12.0 wt% of the lipid phase, typically about 0.01 to 4.0 wt% of the lipid phase.
  • the aqueous phase comprises an aqueous solution and may optionally comprise one or more excipients and/or active agents.
  • the aqueous phase comprises about 0 to 2.0 wt% of one or more excipients, about 0 to 5.0 wt% of one or more active agents, with the balance of the aqueous phase comprising about 93.0 to 100.0 wt% aqueous solution.
  • An exemplary aqueous phase is comprised of about 99.90 wt% aqueous solution and about 0.10 wt% excipients.
  • the aqueous phase may optionally contain one or more active agents which, when present, will preferably comprise about 0.001 to 5.0 wt% of the aqueous phase.
  • the aqueous solution is preferably sterile water such as distilled water, but use of other aqueous solutions are also contemplated by the invention. These include, by way of example, a physiological saline solution, a buffer solution such as an aqueous solution of NaCl and sodium bicarbonate, a CaCl 2 solution, an aqueous carbohydrate solution, detuerated water, or other isotopic forms of H 2 0, buffered solutions of organic acids and bases, and the like, or any combination thereof.
  • Excipients when present, will preferably comprise about 0.10 to 2.0 wt%, preferably 0.10 to 0.20 wt% of the aqueous phase.
  • Suitable excipients for inclusion in the aqueous phase include, for example, preservatives and detergents.
  • Dowicil 2000TM brand l-(cis-3-chloroallyl)-3,5,7-triaza-l-azoniaadamantane chloride, manufactured by Dow Chemical has been found to be a particularly suitable preservative.
  • Another suitable preservative which may in some formulations be preferable, is benzethonium chloride.
  • Typical pharmaceutically acceptable detergents include Tween 80.
  • the aqueous phase may also contain a water soluble organic solvent such as, by way of illustration and not limitation, polyhydric alcohols including glycerin, propylene glycol, polypropylene glycol, triethylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, etc.; alcohols such as benzyl alcohols, etc.; ethers; ketones; esters and glycerin esters such as monoacetin, diacetin, glycerophosphoric acid, etc.; and various aromatic and aliphatic hydrocarbons including fluorocarbons.
  • a water soluble organic solvent such as, by way of illustration and not limitation, polyhydric alcohols including glycerin, propylene glycol, polypropylene glycol, triethylene glycol, polyethylene glycol, diethylene glycol monoethyl ether, etc.; alcohols such as benzyl alcohols, etc.; ethers; ketones; esters and glycerin esters such as mono
  • a Preferred WT % A More Preferred WT % Of Lipid Of Aqueous Of Lipid Of Aqueous
  • the formulations of the invention may also contain other ingredients such as are well know in the formulations art.
  • the invention also encompasses a formulation wherein the lipid phase consists essentially of 0.005 to 50.0 wt% active agent, 10.0 to 70.0 wt% phospholipids, 0 to 70.0 wt% pharmaceutical carrier, 0 to 20.0 wt% antioxidant. and 0 to 12.0 wt% of one or more modifying agents; more preferably consisting essentially of 0.005 to 7.0 wt% active agent. 25.0 to 45.0 wt% phospholipids, 40.0 to 60.0 wt% pharmaceutical carrier, 1.0 to 15.0 wt% antioxidant, and 0.01 to 4.0 wt% modifying agent(s).
  • the aqueous phase may consist essentially of 93.0 to 100.0 wt% aqueous solution, 0 to 2.0 wt% excipients and 0 to 5.0 wt% active agents; more preferably consisting essentially of 93.0 to 99.90 wt% aqueous solution and 0.10 to 0.20 wt% excipients.
  • a particularly useful formulation for use in the methods of the invention is a composition comprising lipid vesicles having ivermectin encapsulated therein in an amount of between about 0.001 to 10.0 wt% of the total composition.
  • Particularly preferred compositions are formed as suspensions and contain ivermectin as the active agent in an amount within the range of about 0.001 to 0.1 wt% of the total formulation.
  • Such formulations preferably contain ivermectin as the active agent in an amount within the range of about 0.01 to 1.0 wt% of the lipid phase, with 0.1 to 1.0 wt% of the lipid phase being preferred.
  • Ivermectin (pharmacopeial grade) is typically at least 80 wt% 22,23- dihydroavermectin B ⁇ a and not more than 20 wt% 22,23-dihydroavermectin Bi b , i-e., 80-100 wt% of the former and 0-20 wt% of the latter.
  • Table II One preferred formulation is described in Table II, where the components of the formulations are described, both as a weight percent of their respective phase (lipid or aqueous) and as a weight percent of the total formulation. This formulation can be made by methods such as are well known in the art.
  • Example 1 The method used to make the formulations used in Example 1 involved adding ivermectin (pharmacopeial grade), soy phosphatidylcholine (PH-90H and PH-80H), cholesterol (Sigma Chem. Co.) and Vitamin E acetate (Spectrum Chemical Co.) to ethanol.
  • This lipid phase was heated at 55-65°C, and gently stirred until a clear solution resulted, and was maintained at the prescribed temperature.
  • Benzethonium chloride (Spectrum Chemical Co.) was added to the sterile water (Baxter) and the resulting aqueous phase was heated to 50-65°C and maintained at the desired temperature.
  • the lipid phase was then injected into the aqueous phase, while the aqueous phase was simultaneously being agitated.
  • Table II Exemplary 0.1 wt% Tonical Liposome Formulation
  • Aqueous solution Water (sterile) 99.9 90.35
  • the active agent-liposome formulation for treatment of the above conditions is designed for topical or transdermal administration.
  • an ivermectin-liposome formulation of the invention would be applied topically to the hair and scalp of the infested animal.
  • the formulation also includes a pest growth regulator such as pyriproxyfen.
  • a pest growth regulator such as pyriproxyfen.
  • Another example is the topical application of ivermectin to the ears of an animal suffering from a mite infestation. It is understood however, that any pharmaceutically acceptable mode of administration can be used.
  • administration can be via any accepted systemic or local route, for example, via parenteral, oral (particularly for infant formulations), intravenous, nasal, bronchial inhalation (i.e., aerosol formulation), and so forth.
  • Rectal administration in the form of a suppository is particularly well suited for delivery of active agents that are directed against intestinal parasites.
  • Oral administration to non-human animals is preferably by the addition of the active agent- liposome formulation to feed or drinking water.
  • Administration to plants can be by spraying the formulation on the infested areas, for example.
  • the active agent-liposome formulation can be in the form of solid, semi-solid or liquid or aerosol dosage forms, such as.
  • composition of the invention may include additional conventional pharmaceutical carriers, excipients, other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.
  • Carriers can be selected from the various oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil, sesame oil, and the like. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical carriers include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, glycols such as propylene glycol, polyethylene glycol, glycol ethers, polyglycols and similar compounds, water, low molecular weight alcohols (C ⁇ - 6 ) such as ethanol, cetyl alcohol, stearyl alcohol and other similar compounds, and the like.
  • the formulation of the invention also preferably contains an antioxidant such as, by means of illustration and not limitation, tocopherol, more specifically Vitamin E ( ⁇ -tocopherol) and tocopherol derivatives, butylated hydroxyanisole, butylated hydroxytoluene, and so forth.
  • an antioxidant such as, by means of illustration and not limitation, tocopherol, more specifically Vitamin E ( ⁇ -tocopherol) and tocopherol derivatives, butylated hydroxyanisole, butylated hydroxytoluene, and so forth.
  • suitable pharmaceutical carriers and their formulations are described in "Remington's Pharmaceutical Sciences” by E. W. Martin.
  • the liposome formulation to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
  • non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, etc.
  • oral administration can be used to deliver the active agent- liposome formulation using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
  • a pharmaceutically acceptable, non-toxic composition is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, povidone, magnesium stearate, sodium saccharine, talcum, cellulose, croscarmellose sodium, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • Such compositions take the form of solutions, suspensions, dispersible tablets, pills, capsules, powders, sustained release formulations and the like.
  • the liposome formulations may take the form of a capsule, liquid suspension, pill or tablet and thus the formulation will contain, along with the active agent, a diluent such as lactose, sucrose, dicalcium phosphate, water, and the like; a disintegrant such as croscarmellose sodium, starch or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as a starch, polyvinylpyrrolidone, gum acacia, gelatin, cellulose and derivatives thereof, and the like, and may or may not contain a preservative such as benzethonium chloride and the like.
  • a diluent such as lactose, sucrose, dicalcium phosphate, water, and the like
  • a disintegrant such as croscarmellose sodium, starch or derivatives thereof
  • a lubricant such as magnesium stearate and the like
  • a binder such as a starch
  • Liquid pharmaceutically administrable liposome formulations can, for example, be prepared by dissolving, dispersing, etc. the active agent (for example, about 0.5 to 20.0 wt%) and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension.
  • a carrier such as, for example, water, saline, aqueous dextrose, glycerol, glycols, ethanol, and the like, to thereby form a solution or suspension.
  • the liposome formulation to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, suspending agents, emulsifying agents, or solubilizing agents or solubility enhancers, pH buffering agents and the like, for example, sodium acetate, sodium citrate, cyclodextrins and cyclodextrine derivatives, polyoxyethylene, sorbitan monolaurate or stearate, triethanolamine oleate, etc. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art.
  • the formulation to be administered will, in any event, contain a quantity of the active agent in an amount effective to alleviate the symptoms of the subject being treated.
  • a liquid formulation such as a syrup or suspension
  • a liquid formulation such as a syrup or suspension
  • the solution or suspension in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule.
  • the solution e.g. in a polyethylene glycol
  • a pharmaceutically acceptable liquid carrier e.g. water
  • liquid or semi-solid oral formulations may be prepared by dissolving or dispersing the active agent(s) in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g. propylene carbonate) and the like, and encapsulating these solutions or suspensions in hard or soft gelatin capsule shells.
  • Parenteral administration of the liposome formulations of the invention is generally characterized by injection, either subcutaneously, intramuscularly or intravenously, and can include intradermal or intraperitoneal injections as well as intrasternal injection or infusion techniques.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like.
  • the liposome formulations to be administered may also contain minor amounts of non-toxic auxiliary substances as described herein.
  • the active agent can be administered parenterally, for example, by incorporating the active agent in a liposome formulation followed by dispersal into an acceptable infusion fluid.
  • a typical daily dose of the active agent can be administered by one infusion, or by a series of infusions spaced over periodic intervals.
  • suitable aqueous solutions of an active agent in water-soluble form for example in the form of a water-soluble salt, or aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilizers.
  • the active agent can also be in the form of a lyophilisate and can be made into a solution prior to parenteral administration by the addition of suitable solvents.
  • the composition will comprise 0.02-8.0 wt% of the active agent in solution.
  • a more recently devised approach for parenteral administration employs the implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained. See, e.g., U.S. Patent No. 3,710,795, which is hereby incorporated by reference.
  • Aerosol administration is an effective means for delivering a liposome formulation directly to the respiratory tract and has the following advantages: it circumvents the effects of enzymatic degradation, poor absorption from the gastrointestinal tract, or loss of the active agent due to the hepatic first-pass effect; it administers active agents which would otherwise fail to reach their target sites in the respiratory tract due to their molecular size, charge or affinity to extra-pulmonary sites; it provides for fast absorption into the body via the alveoli of the lungs; and it avoids exposing other organ systems to the active agent, which is important where exposure might cause undesirable side effects.
  • Nebulizer devices produce a stream of air that causes the active agent-liposome formulation to suspend as a mist which is carried into the patient's respiratory tract by inhalation.
  • Metered-dose inhalers typically have the active agent-liposome formulation packaged with a compressed gas and, upon actuation, discharge a measured amount of the active agent by compressed gas, thus affording a reliable method of administering a set amount of active agent(s).
  • Dry powder inhalers administer the active agent in the form of a free flowing powder that can be dispersed in the patient's air-stream during breathing by the device.
  • the active agent is formulated with an excipient, such as lactose.
  • an excipient such as lactose.
  • a measured amount of the active agent is stored in a capsule form and is dispensed to the patient with each actuation. All of the above methods can be used for administering the present invention.
  • binders and carriers include, for example, polyethylene glycols or triglycerides, for example PEG 1000 (96%) and PEG 4000 (4%).
  • PEG 1000 polyethylene glycols or triglycerides
  • PEG 4000 4%
  • Such suppositories may be formed from mixtures containing the active agent in the range of from about 0.5-10 wt%; preferably from about 1-2 wt%.
  • the liposome formulation of the invention can also be administered transdermally, which term is used to mean delivery of therapeutic agents through body surfaces and membranes, including by means of illustration and not limitation, buccal and mucosal membranes, body tissues, and skin (epithelium and stratum corneum), and will preferably include an effective amount of a permeation enhancer.
  • Transdermal delivery can be accomplished by numerous means, for example, by topical application of a formulation such as a lotion, or by means of a transdermal or electrotransport active agent delivery system.
  • a preferred method of administration of the liposomal formulation of the invention is topically, and without any permeation of the active agent into or through the skin (e.g., scalp, ears, etc) or other body surface (e.g., mucosal, buccal, etc.), i.e., the active agent is effective on the skin or other body surface.
  • the active agent is effective on the skin or other body surface.
  • a method of topically administering an active agent in the formulation of the invention involves the step of applying an active agent-containing liposome formulation to the skin or hair of an animal, said application being about 0.005 to 0.5 grams of liposome formulation per square centimeter of surface should be sufficient, with an amount of between 0.01 to 0.05 g/cm 2 being useful in many cases.
  • the liposome formulations of the present invention may also be applied topically under occlusion to obtain enhanced effect.
  • the compositions described herein have a wide variety of utilities in dealing with pests and the problems associated therewith.
  • One embodiment of the invention pertains to a method for treating a pest infestation which comprises administering a therapeutically effective amount of a pesticide encapsulated within lipid vesicles in a liposome formulation which comprises about 2.0 to 18.0 wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase.
  • the formulation can be administered by applying the formulation in the vicinity of the pest infestations such as a topical application on infected skin, for example, on the scalp or within the ears.
  • the formulation can also be administered orally or rectally in an appropriate dosage form to treat internal pest infestations.
  • This invention is also intended to be utilized to deliver a pesticide for the treatment of insect infestations such as vibrio vulnifica.
  • a similar formulation having a pest growth regulator encapsulated within lipid vesicles can be used in a method for controlling a pest population.
  • a similar formulation having a pest repellant encapsulated within lipid vesicles can be used in a method for repelling pests. This method finds particular utility in repelling pests such as chiggers, fleas, mosquitoes, biting gnats and flies, by delivering a suitable pest repellant.
  • parasitic infestations are treated by administering a therapeutically effective amount of ivermectin encapsulated within lipid vesicles in a liposome formulation.
  • the ivermectin is present therein in an amount of between about 0.001 to 10.0 wt% of said composition.
  • this invention is intended to be utilized to deliver ivermectin for the treatment of diseases such as parasitic infestations, for example, lice, including those that infest humans such as Pediculus humanus capitis, Pediculus humanus corporis and Phthirus pubis (crab louse); mites; and Sarcoptes scabiei.
  • ivermectin is particularly useful in the treatment of lice infestations as ivermectin is believed to kill not only the adult lice, but also to affect the viability of the eggs.
  • the formulation may also include a pest growth regulator such as pyriproxyfen which specifically targets the juvenile stage.
  • the infestation can be eradicated in one application of the ivermectin- liposome formulation of the invention.
  • Current therapies are only effective at killing the adult lice, thus requiring subsequent treatments to kill each hatched generation.
  • the term "therapeutically effective amount” refers to that amount of the active agent which, when administered to an animal in need thereof, is sufficient to effect treatment (as defined above) as a pest growth regulator, pest repellant or insecticide such as an anthelmintic, insecticide or acaricide.
  • the amount that constitutes a “therapeutically effective amount” will vary depending on the condition or disease and its severity, and the animal to be treated, its weight, age, etc., but may be determined routinely by one of ordinary skill in the art with regard to contemporary knowledge and to this disclosure.
  • treatment covers any treatment of a disease in an animal, particularly a human, and includes: (i) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e. arresting its development; or (iii) relieving the disease, i.e. causing regression of the disease.
  • the term "therapeutically effective amount” includes an effective pest growth regulating amount, an effective pesticidal amount and an effective pest-repelling amount, depending upon the particular application for which the formulation is being used.
  • the efficacy of the formulation will be determined by the effect upon the pests, for example mortality, and the avoidance of adverse effects upon the animal being treated.
  • an effective pest growth regulating amount is an amount of the liposome formulation, more specifically the active agent, where 90% or greater pest-growth regulation is achieved.
  • an effective pesticidal amount is an amount of the liposome formulation, more specifically the active agent, where 90% or greater mortality against pests is achieved.
  • An effective pest-repelling amount is an amount of the liposome formulation, more specifically the active agent, where 90% or greater of the pests are repelled from the animal being treated.
  • the amount of liposome formulation or active agent used in the methods of the invention meets the growth regulation, mortality, or repelling criteria above, and preferably exhibits no adverse effects on the animal being treated.
  • a daily dose is from about 0.01-100.0 mg/kg of body weight, preferably about 0.1-64.3 mg/kg of body weight, more typically about 0.3-43.0 mg/kg of body weight.
  • the dosage range would be about 0.7 mg to 7 g per day, preferably about 7.0 mg to 4.5 g per day, and most preferably about 21 mg to 3.0 g per day.
  • the amount of the active agent administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician. Such use optimization is well within the knowledge of those of ordinary skill in the art.
  • An example of a suitable dosage is exemplified by a method of topically administering ivermectin comprising the step of applying an ivermectin-containing liposome formulation to the skin or hair of an animal, where the application is about 0.005 to 0.5 grams of formulation per square centimeter of skin, preferably about 0.01 to 0.05 grams of formulation per square centimeter of skin.
  • Another embodiment of the invention pertains to an article of manufacture comprising a container in association with instructions and/or a label indicating that the subject composition can be used to control pests, i.e., used as a pest growth regulator, pest repellant or pesticide and holding a composition comprising lipid vesicles having at least one pest growth regulator, pest repellant or pesticide encapsulated therein, where the composition comprises about 2.0 to 18.0 wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase.
  • the instructions and/or label would provide information about methods of administering the composition, the dosage form, any contraindications, information regarding proper storage of the article, and so forth.
  • the pest growth regulator, pest repellant or pesticide is present in an amount of between about 0.001 to 10.0 wt% of the composition.
  • the pesticide is ivermectin.
  • the composition may contain one or more additional active agents.
  • Vitamin E acetate 1.099 1.09 1.0
  • the dose of 0.01 % was chosen as the effective dose for the Target Animal Safety Study and the Clinical Field Trial. This decision was based on several factors, which are outlined as follows: Safety is not an issue because the dose of ivermectin delivered to the cat with the use of the liposome suspension (assuming 100 % absorption) was 100 ⁇ g.
  • test substance (0.01 wt% ivermectin-liposome formulation) did not produce any adverse effects when administered to the ears of four week old kittens for three consecutive days at a dose rate of up to 5X the normal treatment level.
  • the ear swabs were evaluated for the presence or absence of ear mites.
  • Treatment with 0.5 ml of 0.01 wt% ivermectin-liposome formulation was administered if ear mites were found to be present.
  • an examination of the ears was performed for clinical signs of ear mite infestation and ear swabs were evaluated for the presence or absence of ear mites.
  • Example 2 The following trials were conducted to establish the dosage, efficacy and safety of ivermectin in a liposome suspension as a treatment for adult body lice (Pediculus humanus) in humans.
  • Vitamin E acetate 1.10 1.099 1.09 1.0
  • the lice were then placed in a test container, which was dipped into the insecticide formulation being evaluated (NIX ® and RID ® products, Control, 0.001 wt%, 0.01 wt% or 0.1 wt% ivermectin liposome formulation).
  • the lice were kept under the pesticide for 1, 4 or 10 minutes, after which the container was placed in distilled water and agitated. The container was removed and the lice rinsed in water. The lice were transferred to an incubator, and mortality is evaluated at one hour and at 24 hours after treatment.
  • Table VII Corrected Mean Percent Mortality
  • NIX and the 0.1 wt% ivermectin liposome formulation provided 100% mortality 24 hours after immersion and water rinsing.
  • the RID ® product while statistically inferior to the NIX ® product and the 0.1 wt% formulation, still provided a satisfactory 94.7% mortality.
  • the 0.01 wt% ivermectin liposome formulation also provided 100% mortality 24 hours after immersion when the formulation was allowed to remain on the adult lice, without washing or rinsing. This formulation was less effective (only 38.1% mortality at +24 hours) when it was washed and rinsed off the lice.
  • the 0.01 wt% ivermectin liposome formulation was the least effective as it provided only 17.5% mortality, even in the absence of a wash and rinse.
  • Example 3 This example illustrates the preparation of a representative liposome formulation for administration of an active agent of the invention.
  • the active agent, soy phosphatidylcholine and tocopherol acetate were dissolved in a chloroform:methanol (2: 1 v/v) solvent solution in a pear-shaped flask containing 100 g of small glass beads.
  • the solvent was evaporated in a rotary evaporator at 30°C under reduced pressure until a thin, smooth film of the lipid and ivermectin was obtained on the surface of the glass beads and the wall of the flask.
  • the resulting lipid film was hydrated at 55°C using the aqueous sodium chloride and sodium bicarbonate solution in an environment shaker for 30 minutes.
  • the hydroxypropylmethylcellulose was added to the formulation within 5 seconds after the lipid film and aqueous solution were mixed.
  • Example 4 This example illustrates the preparation of a representative liposome formulation for administration of an active agent of the invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Pest Control & Pesticides (AREA)
  • Wood Science & Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Agronomy & Crop Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Plant Pathology (AREA)
  • Environmental Sciences (AREA)
  • Zoology (AREA)
  • Dentistry (AREA)
  • Organic Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Toxicology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Epidemiology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Plant Substances (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Cosmetics (AREA)

Abstract

On décrit des formulations de liposomes contenant des régulateurs de croissance des parasites, des répulsifs contre les parasites et des pesticides. On décrit plus spécifiquement des formulations de liposomes contenant de l'ivermectine avec lesquelles on traite les infestations parasitaires.
PCT/US2000/001743 1999-01-25 2000-01-24 Formulations de liposomes Ceased WO2000042990A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
MXPA01007486A MXPA01007486A (es) 1999-01-25 2000-01-24 Formulaciones de liposomas.
AU26272/00A AU781703B2 (en) 1999-01-25 2000-01-24 Liposome formulations
JP2000594447A JP2002535268A (ja) 1999-01-25 2000-01-24 リポソーム処方物
EP00904531A EP1154755A4 (fr) 1999-01-25 2000-01-24 Formulations de liposomes
IL14456100A IL144561A0 (en) 1999-01-25 2000-01-24 Liposome compositions and methods for treating pests utilizing the same
IL144561A IL144561A (en) 1999-01-25 2001-07-25 Liposome compositions and methods for combating pests utilizing the same

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US11709499P 1999-01-25 1999-01-25
US60/117,094 1999-01-25

Publications (1)

Publication Number Publication Date
WO2000042990A1 true WO2000042990A1 (fr) 2000-07-27

Family

ID=22370960

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2000/001743 Ceased WO2000042990A1 (fr) 1999-01-25 2000-01-24 Formulations de liposomes

Country Status (6)

Country Link
EP (1) EP1154755A4 (fr)
JP (1) JP2002535268A (fr)
AU (1) AU781703B2 (fr)
IL (2) IL144561A0 (fr)
MX (1) MXPA01007486A (fr)
WO (1) WO2000042990A1 (fr)

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001089500A3 (fr) * 2000-05-24 2002-04-25 Jordan Loyal Holtzman Agents et methodes d'augmentation des niveaux de chaperonines cerebrales
JP2003342171A (ja) * 2002-05-23 2003-12-03 Usv Ltd ディスラノール投与のための組成物
FR2900052A1 (fr) * 2006-04-19 2007-10-26 Galderma Sa Composition comprenant au moins une phase aqueuse et au moins une phase grasse comprenant de l'ivermectine
WO2007053760A3 (fr) * 2005-11-01 2008-01-10 Dow Agrosciences Llc Compositions pesticides presentant une activite amelioree
EP1476121A4 (fr) * 2002-02-08 2010-10-27 Merck Sharp & Dohme Composition topique d'ivermectine
KR101085157B1 (ko) * 2007-08-31 2011-11-18 한국화학연구원 1,3,5-트리아진-2,4,6-트리아민 화합물 또는 그의 약학적으로 허용 가능한 염, 및 이를 포함하는 약학적 조성물
CN103070951A (zh) * 2013-02-01 2013-05-01 吉林农业大学 一种治疗牛螨病的外用药物组合物及其制备方法
EP2653160A1 (fr) * 2006-10-12 2013-10-23 Topaz Pharmaceuticals Inc. Formulations topiques dýavermectines et procédés d'élimination et prophylaxie de souches des morpions
US8765697B2 (en) 2009-04-30 2014-07-01 Dow Agrosciences, Llc. Pesticide compositions exhibiting enhanced activity
US8785379B2 (en) 2009-04-30 2014-07-22 Dow Agrosciences, Llc. Pesticide compositions exhibiting enhanced activity
US8796476B2 (en) 2009-04-30 2014-08-05 Dow Agrosciences, Llc Pesticide compositions exhibiting enhanced activity and methods for preparing same
WO2015073439A1 (fr) * 2013-11-12 2015-05-21 Lipotec Laboratories Llc Formulations de liposomes-substances attractives
CN105338816A (zh) * 2014-06-05 2016-02-17 南斯泰克有限公司 利用液状硫磺的环保型农药、肥料用组合物的制备方法
US9445975B2 (en) 2008-10-03 2016-09-20 Access Business Group International, Llc Composition and method for preparing stable unilamellar liposomal suspension
US20160278373A1 (en) * 2004-06-01 2016-09-29 Agscitech Inc. Biosurfactant compositions and methods for providing plant nutrients
EP2348832B1 (fr) 2008-10-29 2019-01-16 Arbor Pharmaceuticals, LLC Système de conservation pour formulations topiques thérapeutiques à base d'émulsion
CN110393187A (zh) * 2019-09-05 2019-11-01 湖南宇山玉月农业科技有限公司 一种红脂大小蠹杀虫剂
EP3794028A4 (fr) * 2018-05-15 2022-05-11 Flagship Pioneering Innovations VI, LLC Compositions de lutte contre les agents pathogènes et leurs utilisations
US12163142B2 (en) 2018-08-24 2024-12-10 Flagship Pioneering Innovations Vi, Llc Methods for manufacturing plant messenger packs
CN119286599A (zh) * 2024-09-26 2025-01-10 广州增城潮徽生物技术有限公司 一种驱虫、抑菌、除螨脂质体制剂及其制备方法与应用

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5711867B2 (ja) * 2003-04-24 2015-05-07 ガルデルマ・ソシエテ・アノニム 皮膚科学的疾患の治療のためのアイバメクチンの使用
FR2867684B1 (fr) * 2004-03-18 2006-05-05 Galderma Sa Gel creme contenant de l'ivermectine
MX2020012146A (es) * 2018-05-15 2021-02-26 Flagship Pioneering Innovations Vi Llc Composiciones para el control de plagas y usos de las mismas.
EP3861857A1 (fr) * 2020-02-07 2021-08-11 Novaliq GmbH Composition antiparasitaire

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5173303A (en) * 1989-05-25 1992-12-22 Technology Unlimited, Inc. Cutaneous delivery of organic materials
US5766627A (en) * 1993-11-16 1998-06-16 Depotech Multivescular liposomes with controlled release of encapsulated biologically active substances

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4199569A (en) * 1977-10-03 1980-04-22 Merck & Co., Inc. Selective hydrogenation products of C-076 compounds and derivatives thereof
OA06863A (fr) * 1980-08-04 1983-02-28 Merck & Co Inc Solubilisation de l'invermectine dans l'eau.
US5019392A (en) * 1988-03-03 1991-05-28 Micro-Pak, Inc. Encapsulation of parasiticides
FR2655542B1 (fr) * 1989-12-13 1994-02-11 Oreal Composition cosmetique pour application topique contenant des huiles essentielles.
NZ276305A (en) * 1993-11-16 1997-10-24 Depotech Corp Controlled release vesicle compositions
GB2303791B (en) * 1994-05-24 1999-02-10 Agri Tek Inc Method of preparing a predetermined active agent stock solution for liposomal microencapsulation of active agents for agricultural uses
FR2761912B1 (fr) * 1997-04-14 1999-07-02 Capsulis Procede destine a faire adherer un produit sur une surface
US5952372A (en) * 1998-09-17 1999-09-14 Mcdaniel; William Robert Method for treating rosacea using oral or topical ivermectin
EP1146959B1 (fr) * 1998-11-13 2008-06-04 William A. Heriot Dispositif de production de liposomes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5173303A (en) * 1989-05-25 1992-12-22 Technology Unlimited, Inc. Cutaneous delivery of organic materials
US5766627A (en) * 1993-11-16 1998-06-16 Depotech Multivescular liposomes with controlled release of encapsulated biologically active substances

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1154755A4 *

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001089500A3 (fr) * 2000-05-24 2002-04-25 Jordan Loyal Holtzman Agents et methodes d'augmentation des niveaux de chaperonines cerebrales
EP1476121A4 (fr) * 2002-02-08 2010-10-27 Merck Sharp & Dohme Composition topique d'ivermectine
JP2003342171A (ja) * 2002-05-23 2003-12-03 Usv Ltd ディスラノール投与のための組成物
US20160278373A1 (en) * 2004-06-01 2016-09-29 Agscitech Inc. Biosurfactant compositions and methods for providing plant nutrients
WO2007053760A3 (fr) * 2005-11-01 2008-01-10 Dow Agrosciences Llc Compositions pesticides presentant une activite amelioree
US9592249B2 (en) 2006-04-19 2017-03-14 Galderma S.A. Compositions comprising at least one aqueous phase and at least one fatty phase which comprises avermectin compounds
EP2374449A3 (fr) * 2006-04-19 2012-02-29 Galderma S.A. Composition comprenant au moins une phase aqueuse et au moins une phase grasse comprenant de l'ivermectine
US8362069B2 (en) 2006-04-19 2013-01-29 Galderma S.A. Compositions comprising at least one aqueous phase and at least one fatty phase which comprises avermectin compounds
FR2900052A1 (fr) * 2006-04-19 2007-10-26 Galderma Sa Composition comprenant au moins une phase aqueuse et au moins une phase grasse comprenant de l'ivermectine
WO2007119028A3 (fr) * 2006-04-19 2008-04-03 Galderma Sa Composition comprenant au moins une phase aqueuse et au moins une phase grasse comprenant de l'ivermectine
EP2653160A1 (fr) * 2006-10-12 2013-10-23 Topaz Pharmaceuticals Inc. Formulations topiques dýavermectines et procédés d'élimination et prophylaxie de souches des morpions
US11229207B2 (en) 2006-10-12 2022-01-25 Arbor Pharmaceuticals, Llc Topical avermectin formulations and methods for elimination and prophylaxis of susceptible and treatment resistant strains of head lice
US8791153B2 (en) 2006-10-12 2014-07-29 Sanofi-Topaz, Inc. Topical avermectin formulations and methods for elimination and prophylaxis of susceptible and treatment-resistant strains of head lice
US8927595B2 (en) 2006-10-12 2015-01-06 Sanofi-Topaz, Inc. Topical avermectin formulations and methods for elimination and prophylaxis of susceptible and treatment resistant strains of head lice
KR101085157B1 (ko) * 2007-08-31 2011-11-18 한국화학연구원 1,3,5-트리아진-2,4,6-트리아민 화합물 또는 그의 약학적으로 허용 가능한 염, 및 이를 포함하는 약학적 조성물
US9445975B2 (en) 2008-10-03 2016-09-20 Access Business Group International, Llc Composition and method for preparing stable unilamellar liposomal suspension
EP2348832B2 (fr) † 2008-10-29 2024-12-25 Arbor Pharmaceuticals, LLC Système de conservation pour formulations topiques thérapeutiques à base d'émulsion
EP2348832B1 (fr) 2008-10-29 2019-01-16 Arbor Pharmaceuticals, LLC Système de conservation pour formulations topiques thérapeutiques à base d'émulsion
US8785379B2 (en) 2009-04-30 2014-07-22 Dow Agrosciences, Llc. Pesticide compositions exhibiting enhanced activity
US8796476B2 (en) 2009-04-30 2014-08-05 Dow Agrosciences, Llc Pesticide compositions exhibiting enhanced activity and methods for preparing same
US8765697B2 (en) 2009-04-30 2014-07-01 Dow Agrosciences, Llc. Pesticide compositions exhibiting enhanced activity
US9374997B2 (en) 2009-04-30 2016-06-28 Dow Agrosciences Llc Pesticide compositions exhibiting enhanced activity
US9247730B2 (en) 2009-04-30 2016-02-02 Dow Agrosciences Llc Pesticide compositions exhibiting enhanced activity and methods for preparing same
US9480256B2 (en) 2009-04-30 2016-11-01 Dow Agrosciences Llc Pesticide compositions exhibiting enhanced activity
CN103070951A (zh) * 2013-02-01 2013-05-01 吉林农业大学 一种治疗牛螨病的外用药物组合物及其制备方法
WO2015073439A1 (fr) * 2013-11-12 2015-05-21 Lipotec Laboratories Llc Formulations de liposomes-substances attractives
US20160270400A1 (en) * 2013-11-12 2016-09-22 Lipotec Laboratories Llc Liposome-Attractant Formulations
CN105338816A (zh) * 2014-06-05 2016-02-17 南斯泰克有限公司 利用液状硫磺的环保型农药、肥料用组合物的制备方法
EP3794028A4 (fr) * 2018-05-15 2022-05-11 Flagship Pioneering Innovations VI, LLC Compositions de lutte contre les agents pathogènes et leurs utilisations
US12163142B2 (en) 2018-08-24 2024-12-10 Flagship Pioneering Innovations Vi, Llc Methods for manufacturing plant messenger packs
CN110393187A (zh) * 2019-09-05 2019-11-01 湖南宇山玉月农业科技有限公司 一种红脂大小蠹杀虫剂
CN119286599A (zh) * 2024-09-26 2025-01-10 广州增城潮徽生物技术有限公司 一种驱虫、抑菌、除螨脂质体制剂及其制备方法与应用

Also Published As

Publication number Publication date
IL144561A0 (en) 2002-05-23
AU781703B2 (en) 2005-06-09
AU2627200A (en) 2000-08-07
JP2002535268A (ja) 2002-10-22
MXPA01007486A (es) 2003-06-24
EP1154755A1 (fr) 2001-11-21
EP1154755A4 (fr) 2003-08-13
IL144561A (en) 2007-07-04

Similar Documents

Publication Publication Date Title
AU781703B2 (en) Liposome formulations
KR960005137B1 (ko) 물질 전달용 리포스피어
US5221535A (en) Sustained release formulations of insect repellent
CN1655673B (zh) 用于治疗体外寄生虫感染的方法和组合物
CN1915016B (zh) 农药制剂
IE904098A1 (en) Lipospheres for controlled delivery of substances
US8791153B2 (en) Topical avermectin formulations and methods for elimination and prophylaxis of susceptible and treatment-resistant strains of head lice
JPH10500687A (ja) 抗菌性水中油エマルジョン
US20030040504A1 (en) Ectoparasiticidal compositions and methods of their use
US20180116209A1 (en) Liposome Formulations
US20160270400A1 (en) Liposome-Attractant Formulations
EA002756B1 (ru) Пестицидная композиция в форме растворимых в воде гранул
WO2024201283A1 (fr) Compositions insecticides et arachnicides et utilisations associées

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AU CA CR DM GD HR IL IN JP MA MX TZ YU ZA

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
ENP Entry into the national phase

Ref document number: 2000 594447

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PA/a/2001/007486

Country of ref document: MX

Ref document number: 144561

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2000904531

Country of ref document: EP

Ref document number: 26272/00

Country of ref document: AU

WWP Wipo information: published in national office

Ref document number: 2000904531

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 26272/00

Country of ref document: AU