LIPOSOME FORMULATIONS

Abstract: Liposome formulations containing pest growth regulators, pest repellants and pesticides are described. Specifically, ivermectin-liposome formulations are described for the treatment of parasitic infestations.

Description: LIPOSOME FORMULATIONS Background Of The Invention Technical Field 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. Background The class of compounds to which 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). At present, 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. In addition, 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. 5,733,572, describes gas-filled microspheres such as liposomes to topically deliver a variety of agents such as insect repeilants. Natural oils useful as lice repelling agents are formulated in emulsions and microcapsules in Magdassi, et al., U.S. Patent No. 5,518,736. 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. However, in spite of these various formulations, there is a continuing need for improved means for delivery of active agents such as ivermectin, in particular for a topical dosage form that will be effective at a minimal dose of active agent. More generally there is a need for improved methods and formulations for the delivery of pest growth regulators, pest repeilants and pesticides, and more specifically those active agents directed at arthropods. 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. 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, Mezei "Liposomes in the Topical Application of Drugs: a Review" in Liposomes As Drug Carriers, ed. G. Gregoriadis, John Wiley & Sons Ltd., New York, pages 663- 677 (1988). Accordingly, 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. Summary Of The Invention The present invention relates to 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. In a second aspect, the invention relates to 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. In another aspect, the invention 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 tolδ.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. In yet another aspect, 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. In another aspect of the invention the parasitic infestation is a lice infestation and administration is by topical application to the skin or hair. In another aspect of the invention 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. Description Of The Invention Pharmaceutical formulations 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. In particular, 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. It is expected that the use of 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). As used herein, the term "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. As used herein, the term "pest 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. Sometimes referred to as juvenile hormones, arthropod growth regulators include, by way of illustration and not limitation, agents such as methoprene, pyriproxyfen, lufenuron and cyromazine. As used herein, the term "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. As used herein, 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. In general, the term "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. These 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. In addition, the term "pest" is intended to include those pests of agricultural plants such as plant mites, aphids and locusts. As noted above, adult pests may be eradicated by use of pesticides, while the eggs or juvenile stage pests can be treated with a pest growth regulator to prevent development. In a preferred aspect of the invention, 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. Materials and procedures for forming liposomes and encapsulating an active agent therein, are well-known to those skilled in the art and will only be briefly described herein. Upon dispersion in an appropriate medium, a wide variety of phospholipids swell, hydrate and form multilamellar concentric bilayer vesicles with layers of aqueous media separating the lipid bilayers. These systems are referred to as multilamellar liposomes or multilamellar lipid vesicles ("MLNs") and have diameters within the range of 50 nm to 50μm. These MLNs were first described by Bangham, et al., J. Mol Biol. 13:238-252 (1965). In general, lipids or lipophilic substances are dissolved in an organic solvent. When 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. When smaller MLNs are desired, the larger vesicles are subjected to sonication or sequential filtration through filters with decreasing pore size. There are also techniques by which MLNs can be reduced both in size and in number of lamellae, for example, by 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 ("ULNs") 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. There are several well known techniques for making unilamellar vesicles. In Papahadjopoulos, et al., Biochim et Biophys Acta 135:624-238 (1968), sonication of an aqueous dispersion of phospholipids produces small ULNs having a lipid bilayer surrounding an aqueous solution. Schneider, U.S. Patent 4,089,801 describes the formation of liposome precursors by ultrasonication, followed by the addition of an aqueous medium containing amphiphilic compounds and centrifugation to form a biomolecular lipid layer system. 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. In addition to the MLNs and ULNs, liposomes can also be multivesicular. Described in Kim, et al., Biochim et Biophys Acta 728:339-348 (1983), 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. These and the aforementioned references describing various lipid vesicles suitable for use in the invention, are incorporated herein by reference. In general, 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. As recognized by those skilled in the art, while certain materials and procedures may give better results, the use of particular materials and procedures are not critical to the invention and optimum conditions can readily be determined using routine testing. In addition, the invention also contemplates the inclusion of additional materials in the formulations to facilitate active agent delivery, formulation stability, and so forth. For example, some liposome formulations may acquire a gel- like consistency upon cooling to room temperature in the absence of any adjuvants. However, modifying agents such as conventional thickeners and gelling agents can also be added to provide a formulation having the desired consistency for topical application. Additionally, 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. More specifically, 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. For example, 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. Similarly, 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. In addition, 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. In one embodiment of the invention, 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. In another embodiment, 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. Particularly useful are the phospholipids and hydrogenated phospholipids, with natural phospholipids being preferred. 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. Preferably a combination of these two phospholipids are used. However, either of these two phospholipids may be used without the other. In addition, 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. Numerous 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 (Cι- 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. Numerous suitable antioxidants are well known in the art. The preferred antioxidant is tocopherol or a tocopherol derivative, more preferably Vitamin E (α-tocopherol acetate). α-Lipoic (Opti-pure, Los Angeles, CA) is also well suited for use as an antioxidant. In addition, 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. Such 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. Typically, 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. As noted, 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. This range refers to the total amount of all active agents present in 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 2000™ 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. However, in a preferred embodiment of the invention there is no organic solvent in the aqueous phase. It is understood that the term "about" as used herein in describing the amounts of individual ingredients present in the formulation is intended to include slight deviations from the amounts set forth below, as such deviations are intended to be encompassed by the invention in as much as they are not expected to change the utility or efficacy of the formulations described herein. Table I summarizes some of exemplary preferred formulations of the invention: Table I Liposome Formulations A Preferred WT % A More Preferred WT % Of Lipid Of Aqueous Of Lipid Of Aqueous Generic Component Phase Phase Phase Phase Phospholipid 10.0-70.0 25.0-45.0 Active Agent 0.005-50.0 0.005-25.0 Modifying Agent 0-12.0 0.01-4.0 Antioxidant 0-20.0 5.0-15.0 Carrier 0-70.0 40.0-60.0 Active Agent 0-5.0 0.001-5.0 Excipient 0-2.0 0.10-0.20 Aqueous solution 93.0-100.0 93.0-99.90 The formulations of the invention may also contain other ingredients such as are well know in the formulations art. However, 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). Similarly, 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 Bι 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. 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. 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. Other formulations of the instant invention can be made in a similar manner. Table II Exemplary 0.1 wt% Tonical Liposome Formulation WT % GENERIC EXEMPLARY Of Lipid Of Aqueous WT % COMPONENT COMPONENT Phase Phase Of Total Phospholipid PH 90H 35 3.3 Hydrogenated Soy Phosphatidylcholine Active Agent Ivermectin 1 0.1 Modifying Agent Cholesterol 1 0.1 Antioxidant Vitamin E acetate 11 1.0 Carrier Ethanol 53 5.0 Excipient Benzethonium 0.1 0.15 chloride Aqueous solution Water (sterile) 99.9 90.35 In a preferred embodiment of the invention, the active agent-liposome formulation for treatment of the above conditions, is designed for topical or transdermal administration. For example, for treatment of lice infestation, an ivermectin-liposome formulation of the invention would be applied topically to the hair and scalp of the infested animal. In another embodiment, the formulation also includes 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. For example, 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. for example, tablets, pills, capsules, powders, liquids, lotions, solutions, emulsion, injectables, suspensions, suppositories, aerosols or the like. The formulation of the invention can also be administered in sustained or controlled release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for the prolonged administration of the active agent at a predetermined rate, preferably in unit dosage forms suitable for single administration of precise dosages. Depending upon the desired dosage form, the 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. Other 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 (Cι- 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 (α-tocopherol) and tocopherol derivatives, butylated hydroxyanisole, butylated hydroxytoluene, and so forth. Other suitable pharmaceutical carriers and their formulations are described in "Remington's Pharmaceutical Sciences" by E. W. Martin. If desired, 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. As stated above, 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. For such oral administration, 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. Also as indicated above, 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. 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. If desired, 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. For oral administration to infants, a liquid formulation (such as a syrup or suspension) is preferred. For a solid dosage form containing liquid, the solution or suspension, in for example propylene carbonate, vegetable oils or triglycerides, is preferably encapsulated in a gelatin capsule. For a liquid dosage form, the solution, e.g. in a polyethylene glycol, may be diluted with a sufficient quantity of a pharmaceutically acceptable liquid carrier, e.g. water, to be easily measured for administration. Alternatively, 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. In addition, if desired, 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. For parenteral administration there are especially 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, optionally together with excipients, 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. Typically, 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. There are three types of pharmaceutical inhalation devices, nebulizer inhalers, metered-dose inhalers and dry powder inhalers. 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. In order to achieve a free flowing powder, the active agent is formulated with 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. For systemic administration via suppository, traditional binders and carriers include, for example, polyethylene glycols or triglycerides, for example PEG 1000 (96%) and 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 liposome II formulation to be applied to the patient in this manner can vary within wide limits depending upon the particular site of application and the desired duration of effect. Generally, 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. In addition, 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. In a preferred embodiment of the invention, parasitic infestations are treated by administering a therapeutically effective amount of ivermectin encapsulated within lipid vesicles in a liposome formulation. Preferably, the ivermectin is present therein in an amount of between about 0.001 to 10.0 wt% of said composition. For example, by means of illustration and not limitation, 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. In particular, 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. However, the formulation may also include a pest growth regulator such as pyriproxyfen which specifically targets the juvenile stage. Therefore, 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. Accordingly, 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. In addition, the term "treatment" as used herein 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. More specifically, 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. Typically, 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. Preferably, 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. Similarly, 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. As mentioned above, efficacy is also monitored by the avoidance of adverse effects upon the animal being treated. Accordingly, 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. Generally, 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. Thus, for administration to a 70 kg person, 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. Typically, 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. In one embodiment, the pesticide is ivermectin. The composition may contain one or more additional active agents. Examples The following examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof. It should be understood that all of the parts, percentages, and proportions referred to herein and in the appended claims are by weight unless otherwise indicated. Example 1 The following trials were conducted to establish the dosage, efficacy and safety of ivermectin in a liposome suspension as a treatment for ear mites (Otodectes cynotis) in cats. Four formulations were evaluated: Control (saline), 0.001%, 0.01% and 0.1 wt% ivermectin liposome formulations. The formulation compositions are described in Table III: Table III 0.001, 0.01 and 0.1 wt% Ivermectin-Liposome Formulations FORMULATION WT % (of total formulation) COMPONENT 0.001 t% 0.01 wt% 0.1 wt% PH 90H Hydrogenated 3.3 3.3 3.3 Soy Phosphatidylcholine Ivermectin 0.001 0.01 0.1 Cholesterol 0.1 0.1 0.1 Vitamin E acetate 1.099 1.09 1.0 Ethanol 5.0 5.0 5.0 Benzethonium chloride 0.15 0.15 0.15 Water (sterile) 90.35 90.35 90.35 Dose Titration / Confirmation Studv Forty-eight cats harboring natural ear mite infections were selected for inclusion into one of four treatment groups each containing twelve individual cats. Cats were examined for the presence of live ear mites on Day 0. A single 0.5 ml application of either Control (saline), 0.001 wt%, 0.01 wt% or 0.1 wt% ivermectin- liposome formulation was administered topically into each ear canal. The subjects' ?? ears were not cleaned prior to treatment. The cats were observed hourly for the first four hours post dosing and daily thereafter. Cats were examined again at day 7 for the presence of live ear mites. No significant adverse reactions were noted during the study. Due to the very favorable treatment outcome the statistical procedure outlined in the protocol was not performed. The cure rates for the Control, 0.001 wt%, 0.01 wt%, and 0.1 wt% groups were 17%, 100%, 92%, and 100% respectively. The results were as follows: Table IV Number Of Cats Positive/Total Number Of Cats DAY O DAY 7 % Improved Control 12/12 10/12 17 0.001 wt% 12/12 0/12 100 0.01 wt% 12/12 1/12 92 0.1 wt% 12/12 0/12 100 Based on the proven efficacy of the three dosage levels tested, 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 μg. This dose is much smaller that the approved dose of ivermectin ( Heartguard for cats) which delivers 55μg or 65 μg of ivermectin when given orally. Also, after the passage of the Animal Drug Availability Act of 1996, the goal of dose determination is no longer to find the effective dose, but rather to find a safe and effective dose. Thus the use of the 0.01 wt% ivermectin-liposome formulation was deemed to meet this goal, as it was 92% efficacious when compared to the Control group. Target Animal Safety Study Twenty-four kittens, approximately four weeks old, were assigned to four treatment groups. One group served as an untreated Control group while the other groups received IX, 3X, and 5X treatment levels for a total of three consecutive days. A single application of 0.5 ml of 0.01 wt% ivermectin-liposome formulation was administered accordingly to the IX, 3X and 5X groups. For example, the 3X group received the dosage three times per day for three days. The ears of the subject animals were examined daily for signs of irritation. On day 10 a biopsy sample was taken from the anthelix of both the right and left ears of each animal for histopathology. The study concluded that the 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. Controlled Clinical Trial This study consisted of two visits to the veterinary clinic. At the initial visit the study requirements were reviewed and a complete physical exam was performed by the attending veterinarian on each candidate animal, paying particular attention to clinical signs of ear mite infestation (erythema, pruritis and ear wax accumulation). 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. At the second visit (7-10 days post treatment), 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. A total of 160 cats infested with ear mites were enrolled in the study. Of these 160 subjects, a total of 21 cats were excluded from the final analysis, due to deviation from the protocol. The final results were as follows: Table V Number Cats Positive/Total Number Of Cats DAY O DAY 7 % Improved Control 71/71 56/71 21.13 Treatment 68/68 4/68 94.12 This study demonstrated that 0.5 ml of 0.01 wt% ivermectin liposome formulation was 94% efficacious in the treatment of ear mites (Otodectes cynotis ) in cats when compared to the Control group. 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. Six formulations were evaluated for efficacy against lice: NIX ® , a 1.0 wt% permethrin formulation commercially available from Warner Lambert; RID ® , a_0.3 wt% pyrethrin formulation commercially available from Pfizer; and Control, 0.001 wt%, 0.01 wt% and 0.1 wt% ivermectin liposome formulations, as described in Table VI: Table VI Control. 0.001. 0.01 and 0.1 wt% Ivermectin-Liposome Formulations FORMULATION WT % (of total formulation) COMPONENT Control 0.001 wt% 0.01 wt% 0.1 wt% PH 90H 3.3 3.3 3.3 3.3 Hydrogenated Soy Phosphatidylcholine Ivermectin — 0.001 0.01 0.1 Cholesterol 0.1 0.1 0.1 0.1 Vitamin E acetate 1.10 1.099 1.09 1.0 Ethanol 5.0 5.0 5.0 5.0 Benzethonium 0.15 0.15 0.15 0.15 chloride Water (sterile) 90.35 90.35 90.35 90.35 Test methods were conducted as described in ASTM E938-83 for the "Standard Test Method For Effectiveness of Liquid, gel or Cream Insecticides Against Adult Human Lice", the disclosure of which is incorporated herein by reference. Lice were hatched, allowed to feed on the shaved abdomen of rabbit hosts (New Zealand white rabbits) and then evaluated at 17±1 days of age. 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 With Wash plus Rinse Without Wash plus Rinse FORMULA + 1 Hour + 24 Hour + 1 Hour + 24 Hour Untreated 0 8.6 0 6.9 NIX ® 100 100 N/A N/A RID ® 100 94.7 N/A N/A Control 0 11.1 12.3 5.8 0.001 wt% 9.3 11.8 0 17.5 0.01 wt% 4.2 38.1 0.3 100 0.1 wt% 34.3 100 N/A N/A When the formulations were washed off and rinsed after the 10 minutes immersion, 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. Table VIII Material Amount Active agent 2.0 g Soy phosphatidylcholine 9.0 g Tocopherol acetate 0.24 g Hydroxypropylmethylcellulose 1.5 g Aqueous solution of sodium chloride (0.45 wt%) and sodium bicarbonate (0.65 1 wt%) 87.26 g 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. Table IX Material Amount Active agent 1.0 g Soy phosphatidylcholine 8.0 g Tocopherol acetate 1.0 g Hydroxypropylmethylcellulose 1.0 g Tween ® 80 1.0 g CaCl 2 solution 0.8 mM 89.0 g The method of preparation was substantially the same as that described above for Example 3. Tween 80 was added last to the liposome product. While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims: Claims What is claimed is: 1. 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, said composition comprising about 2.0 tol 8.0 wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase. 2. The composition of Claim 1 wherein said lipid phase comprises about 0.005 to 50.0 wt% active agent, about 10.0 to 70.0 wt% phospholipids, about 0 to 70.0 wt% pharmaceutical carrier, about 0 to 20.0 wt% antioxidant, and about 0 to 12.0 wt% modifying agents . 3. The composition of Claim 2 wherein said lipid phase comprises about 0.005 to 25.0 wt% active agent, about 25.0 to 45.0 wt% phospholipids, about 40.0 to 60.0 wt% pharmaceutical carrier, about 1.0 to 15.0 wt% antioxidant, and about 0.01 to 4.0 wt% modifying agents. 4. The composition of Claim 1 wherein said aqueous phase comprises about 0 to 2.0 wt% excipients, about 0 to 5.0 wt% active agents and about 93.0 to 100.0 wt% aqueous solution. 5. The composition of Claim 2 wherein said antioxidant is tocopherol or a tocopherol derivative. 6. The composition of Claim 2 wherein said pharmaceutical carrier is selected from the group consisting of glycols and low molecular weight alcohols. 7. The composition of Claim 1 wherein said pest growth regulator is an arthropod growth regulator selected from the group consisting of methoprene, pyriproxyfen, lufenuron and cyromazine. 8. The composition of Claim 1 wherein said pest repellant is selected from the group consisting of citronella, dimethyl phthalate, dimethyl carbate, ethohexadiol, diethyltoluamide, indalone, benzyl benzoate, 2-ethyI-l,3- hexanediol and coumarin. 9. The composition of Claim 1 wherein said pesticide is selected from the group consisting of insecticides, parasiticides, ectoparasiticides, acaricides, miticides and anthelmintics. 10. The composition of Claim 9 wherein said pesticide is selected from the group consisting of ivermectin, benzyl benzoate, chlorophenothane, crotamiton, lindane, precipitated sulfur, pyrethrum, rotenone and allethrin. 11. The composition of Claim 10 wherein said pesticide is ivermectin. 12. The composition of Claim 10 which further comprises a pest growth regulator. 13. The composition of Claim 1 wherein said lipid phase consists essentially of 0.005 to 50.0 wt% active agents, 10.0 to 70.0 t% phospholipids, 0 to 70.0 wt% pharmaceutical carrier, 0 to 20.0 wt% antioxidant, and 0 to 12.0 wt% modifying agents; and said aqueous phase consists essentially of 0 to 2.0 wt% excipients, 0 to 5.0 wt% active agents and 93.0 to 100.0 wt% aqueous solution. 14. 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; said active agent being selected from the group consisting of pest growth regulators, pest repeilants and pesticides. 15. The composition of Claim 14 which comprises about 2.0 tolδ.O wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase. 16. The composition of Claim 15 wherein said lipid phase comprises about 0.005 to 50.0 wt% active agent, about 10.0 to 70.0 wt% phospholipids, about 0 to 70.0 wt% pharmaceutical carrier, about 0 to 20.0 wt% of an antioxidant and about 0 to 12.0 wt% modifying agents. 17. The composition of Claim 15 wherein said aqueous phase further comprises about 0 to 2.0 wt% excipients and about 0 to 5.0 wt% of one or more active agents. 18. The composition of Claim 16 wherein said antioxidant is tocopherol or a tocopherol derivative. 19. The composition of Claim 14 wherein said pest growth regulator is an arthropod growth regulator selected from the group consisting of methoprene, pyriproxyfen, lufenuron and cyromazine. 20. The composition of Claim 14 wherein said pest repellant is selected from the group consisting of citronella, dimethyl phthalate, dimethyl carbate, ethohexadiol, diethyltoluamide, indalone. benzyl benzoate, 2-ethyl-l,3- hexanediol and coumarin. 21. The composition of Claim 14 wherein said pesticide is selected from the group ■ consisting of insecticides, parasiticides, ectoparasiticides, acaricides, miticides and anthelmintics. 22. The composition of Claim 21 wherein said pesticide is ivermectin. 23. The composition of Claim 21 which further comprises a pest growth regulator. 24. A composition comprising lipid vesicles having ivermectin encapsulated therein in an amount of between about 0.001 to 10.0 wt% of said composition. 25. The composition of Claim 24 having ivermectin in an amount of between about 0.001 to 0.1 wt% of said composition 26. The composition of Claim 24 which comprises about 2.0 to 18.0 wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase. 27. The composition of Claim 26 wherein said lipid phase comprises about 0.005 to 50.0 wt% ivermectin, about 10.0 to 70.0 wt% phospholipids, about 0 to 70.0 wt% pharmaceutical carrier, about 0 to 20.0 wt% antioxidant, and about 0 to 12.0 wt% modifying agents. 28. The composition of Claim 27 wherein said lipid phase comprises about 0.01 to 5.0 wt% ivermectin. 29. The composition of Claim 27 wherein said lipid phase comprises about 25.0 to 45.0 wt% phospholipids. 30. The composition of Claim 29 wherein said phospholipids comprises a soybean oil based phospholipid or a hydrogenated phosphatidylcholine. 31. The composition of Claim 27 wherein said lipid phase comprises about 40.0 to 60.0 wt% pharmaceutical carrier. 32. The composition of Claim 31 wherein said pharmaceutical carrier is selected from the group consisting of glycols and low molecular weight alcohols. 33. The composition of Claim 27 wherein said lipid phase comprises about 1.0 to 15.0 wt% antioxidant. 34. The composition of Claim 33 wherein said antioxidant is selected from the group consisting of tocopherol, a tocopherol derivative and α-lipoic. 35. The composition of Claim 27 wherein said lipid phase comprises about 0.01 to 4.0 wt% modifying agent. 36. The composition of Claim 35 wherein said modifying agent is cholesterol. 37. The composition of Claim 26 wherein said aqueous phase comprises about 0 to 2.0 wt% excipients, about 0 to 5.0 wt% active agents and about 93.0 to 100.0 wt% aqueous solution. 38. The composition of Claim 37 wherein said aqueous solution is sterile water or a buffered aqueous solution. 39. The composition of Claim 38 wherein said excipient is l-(cis-3-chloroallyl)- 3,5,7-triaza-l-azoniaadamantane chloride or benzethonium chloride. 40. The composition of Claim 24 which comprises phospholipids, ethanol, tocopherol or a tocopherol derivative, cholesterol, water and benzethonium chloride. 41. The composition of Claim 24 wherein said lipid phase consists essentially of 0.005 to 50.0 wt% active agents, 10.0 to 70.0 t% phospholipids, 0 to 70.0 wt% pharmaceutical carrier, 0 to 20.0 wt% antioxidant, and 0 to 12.0 wt% modifying agents; and said aqueous phase consists essentially of 0 to 2.0 wt% excipients, 0 to 5.0 wt% active agents, and 93.0 to 100.0 wt% aqueous solution. 42. The composition of Claim 24 which further comprises one or more active agents selected from the groups consisting of pest growth regulators, pest repeilants and pesticides. 43. 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 tol8.0 wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase. 44. The method of Claim 43 wherein said lipid phase comprises about 0.005 to 50.0 wt% pesticide, about 10.0 to 70.0 wt% phospholipids, about 0 to 70.0 wt% pharmaceutical carrier, about 0 to 20.0 wt% antioxidant, and about 0 to 12.0 wt% modifying agent; and said aqueous phase comprises about 0 to 2.0 wt% excipients, about 0 to 5.0 wt% active agents and about 93.0 to 100.0 wt% aqueous solution. 45. The method of Claim 44 wherein said lipid phase comprises 0.005 to 25.0 wt% pesticide. 46. The method of Claim 44 wherein said pesticide is administered topically. 47. The method of Claim 44 wherein said pesticide is administered orally or rectally. 48. The method of Claim 43 wherein said pesticide is selected from the group consisting of insecticides, parasiticides, ectoparasiticides, acaricides, miticides and anthelmintics. 49. The method of Claim 48 wherein said pesticide is selected from the group consisting of ivermectin, benzyl benzoate, chlorophenothane, crotamiton, lindane, precipitated sulfur, pyrethrum, rotenone and allethrin. 50. The method of Claim 49 wherein said pesticide is ivermectin. 51. The method of Claim 50 wherein said pest infestation is a lice infestation. 52. The method of Claim 51 which further comprises administering a pest growth regulator which is contained within said liposome formulation. 53. The method of Claim 50 wherein said pest infestation is a mite infestation. 54. The method of Claim 43 wherein said pest infestation is vibrio vulnifica. 55. 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 which comprises about 2.0 tolδ.O wt% lipid phase and about 82.0 to 98.0 wτ% aqueous phase. 56. The method of Claim 55 wherein said lipid phase comprises about 0.005 to 50.0 wt% pest growth regulator, about 10.0 to 70.0 wt% phospholipids, about 0 to 70.0 wt% pharmaceutical carrier, about 0 to 20.0 wt% antioxidant, and about 0 to 12.0 wt% modifying agents; and said aqueous phase comprises about 0 to 2.0 wt% excipients, about 0 to 5.0 wt% active agents and about 93.0 to 100.0 wt% aqueous solution. 57. The method of Claim 56 wherein said lipid phase comprises 0.005 to 25.0 wt% pest growth regulator. 58. The method of Claim 55 wherein said pest growth regulator is administered topically. 59. The method of Claim 55 wherein said pest growth regulator is administered orally or rectally. 60. The method of Claim 56 wherein said pest growth regulator is an arthropod growth regulator selected from the group consisting of methoprene, pyriproxyfen, lufenuron and cyromazine. 61. A method for repelling pests which comprises administering a therapeutically effective amount of a pest repellant 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. 62. The method of Claim 61 wherein said lipid phase comprises about 0.005 to 50.0 wt% pest repellant, about 10.0 to 70.0 wt% phospholipids, about 0 to 70.0 wt% pharmaceutical carrier, about 0 to 20.0 wt% antioxidant, and about 0 to 12.0 wt% modifying agent; and said aqueous phase comprises about 0 to 2.0 wt% excipients, about 0 to 5.0 wt% active agents and about 93.0 to 100.0 wt% aqueous solution. 63. The method of Claim 62 wherein said lipid phase comprises 0.005 to 50.0 wt% pest repellant. 64. The method of Claim 61 wherein said pest repellant is administered topically. 65. The method of Claim 61 wherein said pest repellant is administered orally or rectally. 66. The method of Claim 62 wherein said pest repellant is selected from the group consisting of citronella, dimethyl phthalate, dimethyl carbate, ethohexadiol, diethyltoluamide, indalone, benzyl benzoate, 2-ethyl-l,3-hexanediol and coumarin. 67. The method of Claim 61 wherein said pests are chiggers, fleas, mosquitoes, biting gnats or flies. 68. A method for treating parasitic infections 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. 69. The method of Claim 68 wherein said liposome formulation comprises about 2.0 tolδ.O wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase. 70. The method of Claim 69 wherein said lipid phase comprises about 0.005 to 50.0 wt% ivermectin, about 10.0 to 70.0 wt% phospholipids, about 0 to 70.0 wt% pharmaceutical carrier, about 0 to 20.0 wt% antioxidant, and about 0 to 12.0 wt% modifying agent; and said aqueous phase comprises about 0 to 2.0 wt% excipients, about 0 to 5.0 wt% active agents and about 93.0 to 100.0 wt% aqueous solution. 71. The method of Claim 68 wherein said ivermectin is administered topically. 72. The method of Claim 68 wherein said ivermectin is administered orally or rectally. 73. The method of Claim 71 wherein said parasitic infection is caused by the presence of lice, mites or scabies. 74. The method of Claim 71 wherein said composition further comprises a pest growth regulator. 75. The method of Claim 71 wherein said ivermectin is present in an amount within the range of 0.001 to 0.1 wt% of said composition. 76. A method of treating a lice or mite infestation on an animal comprising the step of topically applying an ivermectin-containing liposome formulation to the skin or hair of the animal, said application being about 0.005 to 0.5 grams of formulation per square centimeter of skin. 77. The method of Claim 76 wherein said liposome formulation comprises about 2.0 tol 8.0 wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase. 78. The method of Claim 77 wherein said lipid phase comprises about 0.005 to 50.0 wt% ivermectin. 79. The method of Claim 78 wherein said lipid phase comprises about 0.005 to 25.0 wt% ivermectin, about 25.0 to 45.0 wτ% phospholipids, about 40.0 to 60.0 wt% pharmaceutical carrier, about 1.0 to 15.0 wt% antioxidant, and about 0.01 to 4.0 wt% modifying agents. 80. The method of Claim 77 wherein said aqueous phase comprises about 0 to 2.0 wt% excipients, about 0 to 5.0 wt% active agents and about 93.0 to 100.0 wt% aqueous solution. 81. The method of Claim 76 wherein said application is about 0.01 to 0.05 grams of formulation per square centimeter of skin. 82. The method of Claim 76 wherein said ivermectin is present in an amount within the range of 0.001 to 0.1 wt% of said formulation. 83. The method of Claim 76 wherein a lice infestation is being treated and said formulation further comprises a pest growth regulator. 84. 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 and holding a composition comprising lipid vesicles having at least one pest growth regulator, pest repellant or pesticide encapsulated therein, said composition comprising about 2.0 tol 8.0 wt% lipid phase and about 82.0 to 98.0 wt% aqueous phase. 85. The article of manufacture of Claim 84 wherein said pest growth regulator, pest repellant or pesticide is present in an amount of about 0.001 to 10.0 wt% of said composition. 86. The article of manufacture of Claim 85 wherein said pesticide is ivermectin.

Inventors: BAKER MARTIN T, HEPLER DOUGLAS, KINZELL JOHN, BAKER, MARTIN, T., HEPLER, DOUGLAS, KINZELL, JOHN
Applicants: BLUE RIDGE PHARMACEUTICALS INC, OPTIME THERAPEUTICS INC, BLUE RIDGE PHARMACEUTICALS, INC., OPTIME THERAPEUTICS, INC.
Application year: 2000
Main classification: A61K9
IPC codes: A01N25, A01N29, A01N31, A01N35, A01N37, A01N43, A01N47, A01N53, A01N61, A01N65, A61K8, A61K9, A61K31, A61K33, A61K36, A61K47, A61P17, A61P33, A61Q17