COMPOSITIONS AND METHODS FOR TOPICAL DELIVERY OF OLIGONUCLEOTIDES

Abstract: The present invention relates to compositions and methods which enhance the delivery of oligonucleotides and other nucleosidic moieties via topical routes of administration. Preferred compositions include liposomes or penetration enhancers for the delivery of such moieties to dermal and/or epidermal tissue in an animal for investigative, therapeutic or prophylactic purposes.

Description: COMPOSITIONS AND METHODS FOR TOPICAL DELIVERY OF OLIGONUCLEOTIDES CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of U.S. patent application serial no. 09/082,336 filed on May 21, 1998, the disclosure of which is incorporated herein by reference in its entirety. FIELD OF THE INVENTION The present invention relates to new compositions and methods for the topical delivery of nucleic acids to the epidermis, the dermis, and strata therein, of animals. More particularly, the present invention is directed to the use of liposomes and penetration enhancers to effect transport of oligonucleotides and other nucleic acids into the epidermis and dermis. More specific objectives and advantages of the invention will hereinafter be made clear or become apparent to those skilled in the art during the course of explanation of preferred embodiments of the invention. BACKGROUND OF THE INVENTION Due to recent advances in biotechnology, particularly in the field of molecular biology, there has been significant progress in the treatment of diseases previously intractable, including cancers, genetic diseases, autoimmune disorders and AIDS . Many of these advances are achieved through the administration of nucleic acid molecules to a subject, often human. Often the administered nucleic acids are oligonucleotides. The present invention is particularly drawn to compositions and methods for modulating the production of selected proteins or other biological effectors in an animal, which involves the administration of nucleic acids, including oligonucleotides such as, for example, antisense oligonucleotides, to the dermis and epidermis of an animal. Various modes of administration of oligonucleotides to subjects have been shown to be effective for delivery of oligonucleotides to particular tissues or organs for the treatment of several diseases and/or disorders. For example, U.S. Patent No. 5,595,978, issued January 21, 1997, to Draper et al . , discloses intravitreal injection as a means for the direct delivery of antisense oligonucleotides to the vitreous humor of the mammalian eye for the purpose of treating viral infections thereof. To date, however, attempts to effectively deliver oligonucleotides to the dermis and epidermis have not been realized. The topical administration of oligonucleotides offers the promise of simpler, easier, and more effective delivery of nucleic acids to the epidermis and dermis without the need for sterile procedures and their concomitant expenses (e.g., hospitalization, physician fees, etc.) . Thus, there is a need to provide compositions and methods for the topical delivery of oligonucleotides to the epidermis and dermis, and to selected strata therein, of an animal. It is desirable that such novel compositions and methods provide for the simple, efficient and convenient delivery of therapeutic nucleic acids, especially oligonucleotides . SUMMARY OF THE INVENTION In accordance with the present invention, compositions and methods are provided for topical delivery of nucleic acids in an animal. In particular, the present invention provides compositions and methods for modulating the production of selected proteins or other biological effectors in an animal, which involves the administration of an oligonucleotide, especially an antisense oligonucleotide, via topical means to an animal, thereby circumventing the complications and expense which may be associated with intravenous and other parenteral modes of in vivo administration . "Topical administration" refers to the delivery of a nucleic acid to an animal by contacting, directly or otherwise, a formulation comprising the oligonucleotide to all or a portion of the skin (epidermis) of an animal. The term encompasses several routes of administration including, but not limited to, topical and transdermal . A common requirement for these modes of administration is penetration of the skin's permeability barrier and efficient delivery to the target tissue or stratum. In one aspect, topical administration is used as a means to penetrate the epidermis and dermis and ultimately achieve systemic delivery of oligonucleotides. In another aspect, topical administration is used as a means to selectively deliver oligonucleotides to the epidermis or dermis of an animal, or to specific strata thereof. Compositions of the present invention may be a mixture of components or phases as are present in emulsions (including microemulsions and creams) , and related formulations comprising two or more phases. In one aspect, the pharmaceutical compositions of the invention comprise a plurality of at least one type of nucleic acid and a plurality of at least one type of liposome. In certain embodiments, the nucleic acid is encapsulated, i.e., contained within the liposomes, while in others the nucleic acid is mixed with preformed liposomes to achieve an uncharacterized, presumably external, configuration with the liposomes; certain compositions of the invention comprise both types of [liposome :nucleic acid] configurations. As detailed infra, the nucleic acid formulated in the pharmaceutical compositions of the invention can be, for example, an antisense oligonucleotide, a ribozyme, a peptide nucleic acid (PNA) , an external guide sequence (EGS) , a molecular decoy or an aptamer. The liposome portion of the pharmaceutical compositions of the invention can be a neutral liposome, an anionic liposome, or a anionic fusogenic liposome . Preferred liposomes are formed from one or more phospholipids, such as dimyristoyi phosphatidylcholine, dipalmitoyl phosphatidylcholine, dimyristoyi phosphatidylglycerol, or dioleoyl phosphatidylethanolamine . Particularly preferred liposomes are formed from a phospholipid, phosphatidylcholine derived from some natural source or a synthetic phosphatidylcholine molecule (hereinafter referred to in general as "phosphatidylcholine"), and a sterol such as, e. g. , cholesterol. In general, the liposome is present in an amount which is effective to deliver the nucleosidic moiety to dermal or epidermal tissue in an animal . In another aspect, the pharmaceutical compositions of the invention comprise at least one nucleosidic moiety and at least one penetration enhancer for enhancing penetration of the nucleosidic moiety into dermal or epidermal tissue in an animal. Representative penetration enhancers include fatty acids (such as isopropyl myristate) , bile salts, chelating agents, surfactants, and non- surfactants ; such as unsaturated cyclic ureas, 1-alkyl- alkanones, 1-alkenylazacyclo-alakanones , and steroidal anti- inflammatory agents), glycols, pyrrols, 1- acylazacycloheptan-2-ones ("azones"), and terpenes. Also provided are methods for delivering nucleosidic moieties to dermal or epidermal tissue in an animal comprising one of the applying a pharmaceutical composition of the invention to epidermal tissue. In certain methods, the nucleosidic moiety is delivered preferentially to cells of the dermal tissue, while in other methods the nucleosidic moiety is delivered preferentially to cells of the epidermal tissue. Because of the advantages of topical delivery of drugs of the antisense class, the compositions and methods of the invention can be used in therapeutic methods as explained in more detail herein. The compositions and methods herein provided may also be used ;o examine the function of various proteins and genes ir. vitro in cultured or preserved dermal tissues and in animals. The invention can be thus applied to examine the function of any gene, including, in animal other than a human, those essential to animal development . The methods of the invention can also be used therapeutically or prophylactically, for example, for the treatment of animals that are known or suspected to suffer from diseases such as psoriasis, lichen planus, toxic epidermal necrolysis, ertythema multifor e, basal cell carcinoma, squamous cell carcinoma, malignant melanoma, Paget ' s disease, Kaposi's sarcoma, pulmonary fibrosiε, Lyme disease and viral, fungal and bacterial infections of the skin. BRIEF DESCRIPTION OF THE FIGURES The numerous objects and advantages of the present invention can be better understood by those skilled in the art by reference to the accompanying figures, in which: Figures 1 and 2 show in tabular form results of epidermal and dermal delivery of oligonucleotides with various vehicle enhancers. DETAILED DESCRIPTION OF THE INVENTION I . Overview The invention is drawn to the topical administration of a nucleic acid, such as an oligonucleotide, having biological activity in an animal. By "having biological activity, " it is meant that the nucleic acid functions to modulate the expression of one or more genes in an animal as reflected in either absolute function of the gene (such as ribozyme activity) or by production of proteins coded by such genes . In the context of this invention, "to modulate" means to either effect an increase (stimulate) or a decrease (inhibit) in the expression of a gene. Such modulation can be achieved by, for example, an antisense oligonucleotide by a variety of mechanisms known in the art, including but not limited to transcriptional arrest; effects on RNA processing (capping, polyadenylation and splicing) and transportation; enhancement or reduction of cellular degradation of the target nucleic acid; and translational arrest (Crooke et al . , Exp . Opin . Ther . Patents , 1996, 6 : 1 ) . The present invention provides methods and compositions for delivery of nucleic acids, particularly oligonucleotides, to the epidermis and/or dermis of an animal to increase the bioavailability of the nucleic acid therein. As used herein, the term "bioavailability" refers to the amount of the administered drug therapy (in this case the oligonucleotide) that reaches and acts upon its target. The term is used for drugs whose efficacy is measured relative to the concentration in the blood even though the ultimate site of action of the drug might be outside the blood, e.g., intracellular (see van Berge-Henegouwen et al . , Gastroenterology, 1977, 73 , 300) . The compositions and methods of the invention may be used to provide prophylactic, palliative or therapeutic relief from a disease or disorder that is treatable in whole or in part with one or more nucleic acids . In a preferred embodiment, such a disease or disorder is treatable in whole or in part via topical administration of an antisense oligonucleotide to an animal having such a disease or disorder. As used in the present invention, unless specified otherwise, the term "animal" refers to mammals including but not limited to humans and primates; avians including chickens and turkeys; domestic household, sport or farm animals including dogs, cats, sheep, goats, cows, horses and pigs; lab animals including rats, mice, rabbits and guinea pigs; fish; reptiles; and zoo animals. The term "skin," as used herein, refers to the epidermis and/or dermis of an animal. Mammalian skin consists of two major, distinct layers. The outer layer of the skin is called the epidermis . The epidermis is comprised of the stratum corneum, the stratum granulosum, the stratum spinosum, and the stratum basale, with the stratum corneum being at the surface of the skin and the stratum basale being the deepest portion of the epidermis. The epidermis is between 50 μm and 0.2 mm thick, depending on its location on the body. Beneath the epidermis is the dermis, which is significantly thicker than the epidermis. The dermis is primarily composed of collagen in the form of fibrous bundles. The collagenous bundles provide support for, inter alia , blood vessels, lymph capillaries, glands, nerve endings and immunologically active cells . One of the major functions of the skin as an organ is to regulate the entry of substances into the body. The principal permeability barrier of the skin is provided by the stratum corneum, which is formed from many layers of cells in various states of differentiation. The spaces between cells in the stratum corneum is filled with different lipids arranged in lattice-like formations which provide seals to further enhance the skin's permeability barrier. The permeability barrier provided by the skin is such that it is largely impermeable to molecules having molecular weight greater than about 750 Da. For larger molecules to cross the skin's permeability barrier, mechanisms other than normal osmosis must be used. Consequently, there is a need for compositions and methods to facilitate the transport of nucleic acids through the skin's permeability barrier to the epidermis and the dermis. Several factors determine the permeability of the skin to administered agents . These factors include the characteristics of the treated skin, the characteristics of the delivery agent, interactions between both the drug and delivery agent and the drug and skin, the dosage of the drug applied, the form of treatment, and the post treatment regimen. To selectively target the epidermis and dermis, it is sometimes possible to formulate a composition that comprises one or more penetration enhancers that will enable penetration of the drug to a preselected stratum. A preferred method for the delivery of biologically active substances to the skin is topical administration. Topical administration can be used as the route of administration when local delivery of a drug is desired at, or immediately adjacent to, the point of application of the drug composition or formulation. Three general types of topical routes of administration include administration of a drug composition to mucous membranes, skin or eyes . Transdermal drug delivery is a valuable route for the administration of lipid soluble therapeutics . The dermis is more permeable than the epidermis and therefore absorption is much more rapid through abraded, burned or denuded skin. Inflammation and other physiologic conditions that increase blood flow to the skin also enhance transdermal adsorption. Absorption via this route may be enhanced by the use of an oily vehicle (inunction) or through the use of one or more penetration enhancers . Other effective ways to deliver drugs via the transdermal route include hydration of the skin and the use of controlled release topical patches . The transdermal route provides a potentially effective means to deliver a drug for systemic and/or local therapy. In addition, iontophoresis (transfer of ionic solutes through biological membranes under the influence of an electric field) (Lee et al . , Cri tical Reviews in Therapeutic Drug Carrier Systems , 1991, p. 163), phonophoresis or sonophoresis (use of ultrasound to enhance the absorption of various therapeutic agents across biological membranes, notably the skin and the cornea) (Lee et al . , Cri tical Reviews in Therapeutic Drug Carrier Systems , 1991, p. 166), and optimization of vehicle characteristics relative to dose deposition and retention at the site of administration (Lee et al . , Critical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 168) may be useful methods for enhancing the transport of drugs across mucosal sites in accordance with compositions and methods of the present invention. II. Pharmaceutical Compositions Pharmaceutical compositions of the present invention include, but are not limited to, solutions, emulsions, and liposome-containing formulations. These compositions may be generated from a variety of components that include, but are not limited to, preformed liquids, self-emulsifying solids and self-emulsifying semisolids . The pharmaceutical formulations of the present invention, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier (s) or excipient(s) . In general the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product . The compositions of the present invention may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers. In one embodiment of the present invention the pharmaceutical compositions may be formulated and used as foams. Pharmaceutical foams include formulations such as, but not limited to, emulsions, microemulsions , creams, jellies and liposomes. While basically similar in nature these formulations vary in the components and the consistency of the final product. The know-how on the preparation of such compositions and formulations is generally known to those skilled in the pharmaceutical and formulation arts and may be applied to the formulation of the compositions of the present invention. A. Emulsions The compositions of the present invention may be prepared and formulated as emulsions. Emulsions are typically heterogenous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 urn in diameter. (Idson, in " Pharmaceuti cal Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 199; Rosoff, in " Pharmaceutical Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 245; Block in " Pharmaceuti cal Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 2, p. 335; Higuchi et al . , in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 1985, p. 301). Emulsions are often biphasic systems comprising of two immiscible liquid phases intimately mixed and dispersed with each other. In general, emulsions may be either water in oil (w/o) or of the oil in water (o/w) variety. When an aqueous phase is finely divided into and dispersed as minute droplets into a bulk oily phase the resulting composition is called a water in oil (w/o) emulsion. Alternatively, when an oily phase is finely divided into and dispersed as minute droplets into a bulk aqueous phase the resulting composition is called an oil in water (o/w) emulsion. Emulsions may contain additional components in addition to the dispersed phases and the active drug which may be present as a solution in either the aqueous phase, oily phase or itself as a separate phase. Pharmaceutical excipients such as emulsifiers, stabilizers, dyes, and anti-oxidants may also be present in emulsions as needed. Pharmaceutical emulsions may also be multiple emulsions that are comprised of more than two phases such as, for example, in the case of oil in water in oil (o/w/o) and water in oil in water (w/o/w) emulsions. Such complex formulations often provide certain advantages that simple binary emulsions do not. Multiple emulsions in which individual oil droplets of an o/w emulsion enclose small water droplets constitute a w/o/w emulsion. Likewise a system of oil droplets enclosed in globules of water stabilized in an oily continuous provides an o/w/o emulsion. Emulsions are characterized by little or no thermodynamic stability. Often, the dispersed or discontinuous phase of the emulsion is well dispersed into the external or continuous phase and maintained in this form through the means of emulsifiers or the viscosity of the formulation. Either of the phases of the emulsion may be a semisolid or a solid, as is the case of emulsion- style ointment bases and creams. Other means of stabilizing emulsions entail the use of emulsifiers that may be incorporated into either phase of the emulsion. Emulsifiers may broadly be classified into four categories: synthetic surfactants, naturally occurring emulsifiers, absorption bases, and finely dispersed solids (Idson, in " Pharmaceutical Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 199). Synthetic surfactants, also known as surface active agents, have found wide applicability in the formulation of emulsions and have been reviewed in the literature (Rieger, in " Pharmaceutical Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 285; Idson, in "Pharmaceu ical Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 199" . Surfactants are typically amphiphilic and comprise a hydrophilic and a hydrophobic portion. The ratio of the hydrophilic to the hydrophobic nature of the surfactant has been termed the hydrophile/lipophile balance (HLB) and is a valuable tool in categorizing and selecting surfactants in the preparation of formulations. Surfactants may be classified into different classes based on the nature of the hydrophilic group into: nonionic, anionic, cationic and amphoteric (Rieger, in " Pharmaceuti cal Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 285). Naturally occurring emulsifiers used in emulsion formulations include lanolin, beeswax, phosphatides, lecithin and acacia. Absorption bases possess hydrophilic properties such that they can soak up water to form w/o emulsions yet retain their semisolid consistencies, such as anhydrous lanolin and hydrophilic petrolatum. Finely divided solids have also been used as good emulsifiers especially in combination with surfactants and in viscous preparations. These include polar inorganic solids, such as heavy metal hydroxides, nonswelling clays such as bentonite, attapulgite, hectorite, kaolin, montmorillonite, colloidal aluminum silicate and colloidal magnesium aluminum silicate, pigments and nonpolar solids such as carbon or glyceryl tristearate . A large variety of non-emulsifying materials are also included in emulsion formulations and contribute to the properties of emulsions. These include fats, oils, waxes, fatty acids, fatty alcohols, fatty esters, humectants, hydrophilic colloids, preservatives and antioxidants (Block, in " Pharmaceutical Dosage Forms, " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 335; Idson, in "Pharmaceutical Dosage Forms, " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 199). Hydrophilic colloids or hydrocclloids include naturally occurring gums and synthetic polymers such as polysaccharides (for example, acacia, agar, alginic acid, carrageenan, guar gum, karaya gum, and tragacanth) , cellulose derivatives (for example, carboxymethylc cellulose and carboxypropyl cellulose) , and synthetic polymers (for example, carbomers, cellulose ethers, and carboxyvinyl polymers) . These disperse or swell in water to form colloidal solutions that stabilize emulsions by forming strong interfacial films around the dispersed-phase droplets and by increasing the viscosity of the external phase. Since emulsions often contain a number of ingredients such as carbohydrates, proteins, sterols and phosphatides that may readily support the growth of microbes, these formulations often incorporate preservatives. Commonly used preservatives included in emulsion formulations include methylparaben, propylparaben, quaternary ammonium salts, benzalkonium chloride, esters of p-hydroxybenzoic acid, boric acid and phenoxyethanol . Antioxidants are also commonly added to emulsion formulations to prevent deterioration of the formulation. Antioxidants used may be free radical scavengers such as tocopherols, alkyl gallates, butylated hydroxyanisole, butylated hydroxytoluene, or reducing agents such as ascorbic acid and sodium metabisulfite, and antioxidant synergists such as citric acid, tartaric acid, and lecithin . Preservatives used in any oligonucleotide formulation will preferably have a broad spectrum of antimicrobial activity and be compatible with highly negatively charged oligonucleotides at neutral pH. To determine preferred preservatives, oligonucleotides were incubated with various preservatives in the presence and absence of selected organisms [Staphylococcus aureus (ATCC No. 6538), Escherichia coli (ATCC No. 8739), Candida albicans (ATCC No. 10231) and Aspergillus niger (ATCC No. 16404) ] according to USP 23 Antimicrobial Effectiveness Test (AET) procedures. According to results of these studies it has been discovered that preferred preservatives for oligonucleotide formulations include a combination of methylparaben, propylparaben and phenoxyethanol. The total amount of the preservative combination will depend on the dosage form used but will in general be from about 0.1% to 20% by weight. In topical emulsion compositions of the invention, the preservative combination will be present in an amount from about 0.1% to 10%, preferably 0.5% to 8% and more preferably 1% to 5%. In a preferred embodiment, methylparaben and propylparaben will each be present in an amount from about 0.1% to 1% and phenoxyethanol in an amount from about 1 to 5%. In a particularly preferred embodiment methylparaben, propylparaben and phenoxyethanol will be present in a ratio of about 1: 1:5 respectively. The application of emulsion formulations via dermatological, oral and parenteral routes and methods for their manufacture have been reviewed in the literature (Idson, in " Pharmaceutical Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 199). Emulsion formulations for oral delivery have been very widely used because of reasons of ease of formulation, efficacy from an absorption and bioavailability standpoint. (Rosoff, in " Pharmaceutical Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 245; Idson, in " Pharmaceutical Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 199) . Mineral-oil base laxatives, oil-soluble vitamins and high fat nutritive preparations are among the materials that have commonly been administered orally as o/w emulsions . In one embodiment of the present invention, the compositions of oligonucleotides and nucleic acids are formulated as microemulsions . A microemulsion may be defined as a system of water, oil and amphiphile which is a single optically isotropic and thermodynamically stable liquid solution (Rosoff, in "Pharmaceutical Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 245) . Typically microemulsions are systems that are prepared by first dispersing an oil in an aqueous surfactant solution and then adding a sufficient amount of a fourth component, generally an intermediate chain- length alcohol to form a transparent system. Therefore, microemulsions have also been described as thermodynamically stable, isotropically clear dispersions of two immiscible liquids that are stabilized by interfacial films of surface-active molecules (Leung and Shah, in : Controlled Release of Drugs : Polymers and Aggregate Sys tems , Rosoff, M., Ed., 1989, VCH Publishers, New York, pages 185-215) . Microemulsions commonly are prepared via a combination of three to five components that include oil, water, surfactant, cosurfactant and electrolyte. Whether the microemulsion is of the water- in-oil (w/o) or an oil-in-water (o/w) type is dependent on the properties of the oil and surfactant used and on the structure and geometric packing of the polar heads and hydrocarbon tails of the surfactant molecules (Schott, in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 1985, p. 271). The phenomenological approach utilizing phase diagrams has been extensively studied and has yielded a comprehensive knowledge, to one skilled in the art, of how to formulate microemulsions (Rosoff, in " Pharmaceutical Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 245; Block, in " Pharmaceuti cal Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 335). Compared to conventional emulsions, microemulsions offer the advantage of solubilizing water- insoluble drugs in a formulation of thermodynamically stable droplets that are formed spontaneously. Surfactants used in the preparation of microemulsions include, but are not limited to, ionic surfactants, non- ionic surfactants, Brij 96, polyoxyethylene oleyl ethers, polyglycerol fatty acid esters, tetraglycerol monolaurate (ML310) , tetraglycerol monooieate (MO310) , hexaglycerol monooieate (PO310) , hexaglycerol pentaoleate (PO500) , decaglycerol monocaprate (MCA750) , decaglycerol monooieate (MO750) , decaglycerol sequioleate (SO750) , decaglycerol decaoleate (DAO750) , alone or in combination with cosurfactantε . The cosurfactant, usually a short-chain alcohol such as ethanol, 1-propanol, and 1-butanol, serves to increase the interfacial fluidity by penetrating into the surfactant film and consequently creating a disordered film because of the void space generated among surfactant molecules. Microemulsions may, however, be prepared without the use of cosurfactants and alcohol-free self-emulsifying microemulsion systems are known in the art. The aqueous phase may typically be, but is not limited to, water, an aqueouε εolution of the drug, glycerol, PEG300, PEG400, polyglycerols , propylene glycols, and derivatives of ethylene glycol. The oil phase may include, but is not limited to, materials such as Captex 300, Captex 355, Capmul MCM, fatty acid esters, medium chain (C8-C12) mono, di, and tri-glycerides, polyoxyethylated glyceryl fatty acid esters, fatty alcohols, polyglycolized glycerides , saturated polyglycolized C8-C10 glycerides, vegetable oils and silicone oil. Microemulεionε are particularly of intereεt from the standpoint of drug solubilization and the enhanced absorption of drugs. Lipid based microemulsions (both o/w and w/o) have been proposed to enhance the oral bioavailability of drugs, including peptides (Constantinides et al . , Pharmaceutical Research, 1994, 11 , 1385; Ritschel, et . Find . Exp . Clin . Pharmacol . , 1993, 13 , 205). Microemulsions afford advantages of improved drug solubilization, protection of drug from enzymatic hydrolysis, possible enhancement of drug absorption due to surfactant-induced alterations in membrane fluidity and permeability, ease of preparation, ease of oral administration over solid dosage forms, improved clinical potency, and decreased toxicity (Constantinides et al . , Pharmaceutical Research, 1994, 11 , 1385; Ho et al . , J. Pharm . Sci . , 1996, 85, 138). Often microemulsions may form spontaneously when their components are brought together at ambient temperature. This may be particularly advantageous when formulating thermolabile drugs, peptides or oligonucleotides . Microemulsions have also been effective in the transdermal delivery of active components in both cosmetic and pharmaceutical applications. It is expected that the microemulεion compoεitions and formulations of the present invention will facilitate the increased systemic absorption of oligonucleotides and nucleic acids from the gaεtrointestinal tract, as well as improve the local cellular uptake of oligonucleotides and nucleic acids within the gastrointestinal tract, vagina, buccal cavity and other areas of administration. Microemulsions of the present invention may also contain additional components and additives such as sorbitan monostearate (Grill 3), Labrasol, and penetration enhancers to improve the properties of the formulation and to enhance the absorption of the oligonucleotides and nucleic acids of the present invention. Penetration enhancers used in the microemulsions of the present invention may be classified as belonging to one of five broad categories - surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants (Lee et al . , Cri tical Reviews in Therapeutic Drug Carrier Systems, 1991, p. 92). Each of these classeε has been discussed above. In a particularly preferred embodiment, emulsion compositions comprise isopropyl myristate (IPM) as an emollient. IPM emulsions of the invention may be in cream form and incorporate PM in an amount from about 1 % to 50% by weight, more preferably 5% to 20% and most preferably about 10%. In preferred cream emulsions, glycerol monostearate serves as the oil phase emulsifier while polyoxyl 40 stearate serves as the water phase emulsifier, each present in an amount from about 1% to 30% and more preferably 5% to 20%. In a particularly preferred embodiment, glycerol monostearate is present in an amount of about 10% by weight and polyoxyl 40 stearate in an amount of about 15%. Preferred cream emulsions may further comprise viscosity-increasing agents such as hydroxypropyl methylcellulose. In a particularly preferred embodiment, hydroxypropyl methylcellulose is present in an amount from about 0.01% to about 5%, more preferably from 0.1% to 2% and most preferably about 0.5%. B . Liposomes There are many organized surfactant structures besides microemulsions that have been studied and used for the formulation of drugs. These include monolayers, micelles, bilayers and vesicles. Vesicles, such as liposomes, have attracted great interest because of their specificity and the duration of action they offer from the standpoint of drug delivery. As used in the present invention, the term "liposome" means a vesicle composed of amphiphilic lipids arranged in a spherical bilayer or bilayerε . Liposomes are unilamellar or multilamellar vesicles which have a membrane formed from a lipophilic material and an aqueous interior. The aqueous portion contains the composition to be delivered. Cationic liposomes possess the advantage of being able to fuse to the cell wall. Non-cationic liposomes, although not able to fuse as efficiently with the cell wall, are taken up by macrophages in vivo. In order to cross intact mammalian skin, lipid vesicles must pass through a series of fine pores, each with a diameter less than 50 nm, under the influence of a suitable transdermal gradient. Therefore, it is desirable to use a liposome which is highly transformable and able to pass through such fine pores. Further advantages of liposomes include; liposomes obtained from natural phospholipids are biocompatible and biodegradable; liposomes can incorporate a wide range of water and lipid soluble drugs; liposomes can protect encapsulated drugs in their internal compartments from metabolism and degradation (Rosoff, in " Pharmaceutical Dosage Forms , " Lieberman, Rieger and Banker (Eds.), 1988, volume 1, p. 245) . Important considerations in the preparation of liposome formulations are the lipid surface charge, vesicle size and the aqueous volume of the liposomes . Liposomes are useful for the transfer and delivery of active ingredients to the site of action. Because the liposomal membrane is structurally similar to biological membranes, when liposomes are applied to a tissue, the liposomes start to merge with the cellular membranes . As the merging of the liposome and cell progresses, the liposomal contents are emptied into the cell where the active agent may act. Liposomal formulations have been the focus of extensive investigation as the mode of delivery for many drugs . There is growing evidence that for topical administration, liposomes present several advantages over other formulations. Such advantages include reduced side- effects related to high systemic absorption of the administered drug, increased accumulation of the administered drug at the desired target, and the ability to administer a wide variety of drugs, both hydrophilic and hydrophobic, into the skin. Several reports have detailed the ability of liposomes to deliver agents including high-molecular weight DNA into the skin. Compounds including analgesics, antibodies, hormones and high-molecular weight DNAs have been administered to the skin. The majority of applications resulted in the targeting of the upper epidermis. Liposomeε fall into two broad classes. Cationic liposomes are positively charged liposomes which interact with the negatively charged DNA molecules to form a stable complex. The positively charged DNA/liposome complex binds to the negatively charged cell surface and is internalized in an endosome. Due to the acidic pH within the endosome, the liposomes are ruptured, releasing their contentε into the cell's cytoplasm (Wang et al . , Biochem . Biophys . Res . Commun . , 147 (1987) 980-985). Liposomes which are pH-sensitive or negatively-charged, entrap DNA rather than complex with it. Since both the DNA and the lipid are similarly charged, repulsion rather than complex formation occurs. Nevertheless, some DNA is entrapped within the aqueous interior of these liposomeε . pH-εenεitive liposomes have been used to deliver DNA encoding the thymidine kinase gene to cell monolayers in culture. Expression of the exogenous gene was detected in the target cells (Zhou et al . , Journal of Controlled Release, 19, (1992) 269-274) . One major type of liposomal composition includes phospholipids other than naturally-derived phosphatidylcholine. Neutral liposome compositions, for example, can be formed from dimyristoyi phosphatidylcholine (DMPC) or dipalmitoyl phosphatidylcholine (DPPC) . Anionic liposome compositions generally are formed from dimyristoyi phosphatidylglycerol, while anionic fuεogenic lipoεomes are formed primarily from dioleoyl phosphatidylethanolamine (DOPE) . Another type of lipoεomal compoεition iε formed from phosphatidylcholine (PC) such as, for example, εoybean PC, and egg PC. Another type iε formed from mixtures of phospholipid and/or phosphatidylcholine and/or cholesterol. Several studies have assessed the topical delivery of liposomal drug formulations to the skin. Application of liposomes containing interferon to guinea pig skin resulted in a reduction of skin herpes εoreε while delivery of interferon via other eanε (e.g. aε a solution or as an emulsion) were ineffective (Weiner et al . , Journal of Drug Targeting, 1992, Vol.2 , 405-410) . Further, an additional study tested the efficacy of interferon administered as part of a liposomal formulation to the administration of interferon using an aqueous system, and concluded that the liposomal formulation was superior to aqueous administration (du Plessis et al . , Antiviral Research, 18, 1992, 259-265). Non-ionic lipoεomal εystems have also been examined to determine their utility in the delivery of drugs to the skin, in particular systemε comprising non-ionic surfactant and cholesterol. Non-ionic lipoεomal formulations comprising Novasome" I (glyceryl dilaurate/cholesterol/polyoxyethylene-10-3tearyl ether) and Novaεome" II (glyceryl diεtearate/ choleεterol/polyoxyethylene-10-stearyl ether) were used to deliver cyclosporin-A into the dermis of mouse skin. Resultε indicated that εuch non- ionic liposomal systems were effective in facilitating the deposition of cyclosporin-A into different layers of the skin. Transferεomes are yet another type of liposomes, and are highly deformable lipid aggregateε which are attractive candidates for drug delivery vehicles . Transfersomeε may be deεcribed as lipid droplets which are so highly deformable that they are easily able to penetrate through pores which are smaller than the droplet . Tranεferεomes are adaptable to the environment in which they are used, e.g. they are self-optimizing ^adaptive to the shape of pores in the skin) , self-repairing, frequently reach their targets without fragmenting, and often self- loading. To make transferεomes it is possible to add surface edge-activators, usually surfactantε, to a εtandard liposomal composition. Transfersomes have been used to deliver serum albumin to the skin. The transferεome- mediated delivery of serum albumin has been shown to be as effective as subcutaneous injection of a solution containing serum albumin. Surfactants find wide application in formulations εuch aε emulεionε (including microemulεions) and liposomes. The most common way of classifying and ranking the properties of the many different types of surfactantε, both natural and synthetic, is by the use of the hydrophile/lipophile balance (HLB) . The nature of the hydrophilic group (also known as the ^ head' ) provides the most useful meanε for categorizing the different surfactantε used in formulations (Rieger, in "Pharmaceutical Dosage Forms," Marcel Dekker, Inc., New York, NY, 1988, p. 285). If the surfactant molecule is not ionized, it iε classified as a nonionic surfactant. Nonionic εurfactantε find wide application in pharmaceutical and coεmetic productε and are usable over a wide range of pH values . In general their HLB values range from 2 to about 18 depending on their structure. Nonionic surfactants include nonionic esters such as ethylene glycol esters, propylene glycol esters, glyceryl esters, polyglyceryl esters, sorbitan esters, sucrose esters, and ethoxylated esterε. Nonionic alkanolamides and ethers such as fatty alcohol ethoxylates, propoxylated alcohols, and ethoxylated/ propoxylated block polymers are also included in this class . The polyoxyethylene surfactants are the most popular members of the nonionic εurfactant class . If the surfactant molecule carries a negative charge when it is disεolved or dispersed in water, the surfactant is classified as anionic. Anionic surfactantε include carboxylateε such as soaps, acyl lactylates, acyl amides of amino acids, esters of sulfuric acid such as alkyl sulfates and ethoxylated alkyl sulfates, sulfonates such aε alkyl benzene εulfonateε, acyl iεethionateε, acyl taurates and εulfoεuccinateε, and phosphates. The most important memberε of the anionic surfactant class are the alkyl sulfates and the soaps. If the surfactant molecule carries a positive charge when it is dissolved or dispersed in water, the surfactant is classified as cationic. Cationic surfactants include quaternary ammonium saltε and ethoxylated amines . The quaternary ammonium saltε are the most used memberε of thiε class. If the surfactant molecule has the ability to carry either a positive or negative charge, the surfactant is classified as amphoteric. Amphoteric surfactantε include acrylic acid derivativeε, substituted alkylamides, N- alkylbetaineε and phoεphatideε . The use of surfactants in drug products, formulations and in emulsions has been reviewed (Rieger, in "Pharmaceutical Dosage Forms," Marcel Dekker, Inc., New York, NY, 1988, p. 285) . C. Penetration Enhancers In one embodiment, the present invention employs various penetration enhancers to effect the efficient delivery of nucleic acids, particularly oligonucleotides, to the skin of animals . Most drugs are present in solution in both ionized and nonionized forms. However, usually only lipid soluble or lipophilic drugs readily cross cell membranes. It has been discovered that even non-lipophilic drugε may cross cell membranes if the membrane to be crosεed iε treated with a penetration enhancer. In addition to aiding the diffusion of non-lipophilic drugs across cell membranes, penetration enhancers alεo enhance the permeability of lipophilic drugε. Penetration enhancerε may be classified aε belonging to one of five broad categories, i.e., surfactantε, fatty acidε, bile εaltε, chelating agents, and non-chelating non-surfactants (Lee et al . , Crit . Rev. Ther . Drug Carrier Systemε, 1991, p.92) . Each of the above mentioned classes of penetration enhancers are described below in greater detail . Surfactants: In connection wit the present invention, surfactants (or "surface-active agents") are chemical entities which, when dissolved in an aqueous εolution, reduce the εurface tenεion of the solution or the interfacial tension between the aqueouε solution and another liquid, with the reεult that absorption of oligonucleotides through the mucosa is enhanced. In addition to bile salts and fatty acids, these penetration enhancers include, for example, sodium lauryl sulfate, polyoxyethylene-9-lauryl ether and polyoxyethylene-20-cetyl ether, (Lee et al . , Crit. Rev. Ther. Drug Carrier Systems, 1991, p.92); and perfluorhemical emulsionε, such as FC-43 Takahashi et al . , J. Pharm . Pharmacol . , 1988, 40:252). Fatty acids: Variouε fatty acidε and their derivatives which act as penetration enhancers include, for example, oleic acid, lauric acid, capric acid (n-decanoic acid) , myristic acid, palmitic acid, stearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein (1- monooleoyl-rac-glycerol) , dilaurin, caprylic acid, arachidonic acid, glycerol 1-monocaprate, 1- dodecylazacycloheptan-2-one, acylcarnitines, acylcholines, C;,_ 10 alkyl esterε thereof (e.g., methyl, isopropyl and t- butyl), and mono- and di-glycerides thereof (i.e., oleate, laurate, caprate, myristate, palmitate, stearate, linoleate, etc.) (Lee et al . , Crit. Rev. Ther. Drug Carrier Systems, 1991, p.92; Muranishi, Crit. Rev. Ther. Drug Carrier Syεtems, 1990, 7:1; El Hariri et al . , J. Pharm. Pharmacol., 1992, 44:651) . Bile salts: The physiological role of bile includes the facilitation of dispersion and absorption of lipids and fat-soluble vitaminε (Brunton, Chapter 38 in: Goodmank Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al . Ed . , McGraw-Hill, New York, 1996, pageε 934-935) . Various natural bile salts, and their synthetic derivatives, act aε penetration enhancers. Thus the term "bile salts" includes any of the naturally occurring components of bile aε well aε any of their synthetic derivatives. The bile saltε of the invention include, for example, cholic acid (or its pharmaceutically acceptable sodium εalt, εodium cholate), dehydrocholic acid (εodium dehydrocholate) , deoxycholic acid (sodium deoxycholate) , glucholic acid (sodium glucholate) , glycholic acid (sodium glycocholate) , glycodeoxycholic acid (sodium glycodeoxycholate) , taurocholic acid (sodium taurocholate) , taurodeoxycholic acid (εodium taurodeoxycholate) , chenodeoxycholic acid (εodium chenodeoxycholate) , urεodeoxycholic acid (UDCA) , sodium tauro-24 , 25-dihydro- fusidate (STDHF) , sodium glycodihydrofusidate and polyoxyethylene-9-lauryl ether (POE) (Lee et al . , Cri tical Reviews in Therapeutic Drug Carrier Systems , 1991, page 92; Swinyard, Chapter 39 In : Remington ' s Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Eaεton, PA, 1990, pages 782-783; Muranishi, Cri tical Reviews in Therapeutic Drug Carrier Systems , 1990, 7:1; Yamamoto et al . , J. Pharm . Exp . Ther. , 1992, 263 : 25 ; Yamashita et al . , J. Pharm . Sci . , 1990, 79:579). Chelating Agents: Chelating agents, as used in connection with the present invention, can be defined as compounds that remove metallic ions from solution by forming complexes therewith, with the result that absorption of oligonucleotides through the mucosa is enhanced. With regards to their use as penetration enhancers in the present invention, chelating agents have the added advantage of also serving as DNase inhibitorε, aε most characterized DNA nucleaseε require a divalent metal ion for catalyεis and are thus inhibited by chelating agents (Jarrett, J. Chromatogr . , 1993, 618 , 315) . Chelating agents of the invention include but are not limited to disodium ethylenediaminetetraacetate (EDTA), citric acid, salicylates (e.g., sodium salicylate, 5-methoxysalicylate and homovanilate) , N-acyl derivativeε of collagen, laureth-9 and N-amino acyl derivativeε of beta- diketones (enamines) (Lee et al . , Critical Reviews in Therapeutic Drug Carrier Systems, 1991, page 92; Muranishi, Cri tical Reviews in Therapeutic Drug Carrier Systems , 1990, 7:1; Buur et al . , J. Control Rel . , 1990, 14:43). Non-chelating non-surfactants : As used herein, non-chelating non-surfactant penetration enhancing compounds can be defined as compounds that demonstrate insignificant activity as chelating agents or as surfactants but that nonetheless enhance absorption of oligonucleotides through the alimentary mucosa (Muranishi, Cri tical Reviews in Therapeutic Drug Carrier Systems, 1990, 7:1) . Thiε class of penetration enhancers include, for example, unsaturated cyclic ureaε, 1-alkyl- and 1-alkenylazacyclo-alkanone derivativeε (Lee et al . , Critical Reviews in Therapeutic Drug Carrier Systems , 1991, page 92) ; and non-steroidal anti- inflammatory agents such as diclofenac sodium, indomethacin and phenylbutazone (Yamashita et al . , J. Pharm . Pharmacol . , 1987, 39:621). Agents that enhance uptake of oligonucleotides at the cellular level may also be added to the pharmaceutical and other compositions of the present invention. For example, cationic lipids, such as lipofectin (Junichi et al , U.S. Patent No. 5,705,188), cationic glycerol derivatives, and polycationic molecules, such as polylysine (Lollo et al . , PCT Application WO 97/30731), are also known to enhance the cellular uptake of oligonucleotides . Other agents may be utilized to enhance the penetration of the administered nucleic acids, including glycols such as ethylene glycol and propylene glycol, pyrrols such as 2-pyrrol, azones, and terpenes such as limonene and menthone . D. Carriers Certain compositions of the present invention also incorporate carrier compounds in the formulation. As used herein, "carrier compound" or "carrier" can refer to a nucleic acid, or analog thereof, which is inert (i.e., does not posseεε biological activity per se) but is recognized as a nucleic acid by in vivo proceεεeε that reduce the bioavailability of a nucleic acid having biological activity by, for example, degrading the biologically active nucleic acid or promoting its removal from circulation. The coadministration of a nucleic acid and a carrier compound, typically with an excess of the latter substance, can result in a subεtantial reduction of the amount of nucleic acid recovered in the liver, kidney or other extracirculatory reεervoirε, presumably due to competition between the carrier compound and the nucleic acid for a common receptor. For example, the recovery of a partially phosphorothioate oligonucleotide in hepatic tissue can be reduced when it is coadministered with polyinosinic acid, dextran sulfate, polycytidic acid or 4-acetamido-4 ' isothiocyano-εtilbene- 2 , 2 ' -diεulfonic acid (Miyao et al . , Antisense Res . Dev. , 1995, 5, 115; Takakura et al . , Antisense & Nucl . Acid Drug Dev. , 1996, 6, 111 ) . E. Excipients In contrast to a carrier compound, a "pharmaceutical carrier" or "excipient" is a pharmaceutically acceptable solvent, suspending agent or any other pharmacologically inert vehicle for delivering one or more nucleic acids to an animal. The excipient may be liquid or solid and is selected, with the planned manner of administration in mind, εo aε to provide for the desired bulk, consistency, etc. , when combined with a nucleic acid and the other components of a given pharmaceutical composition. Typical pharmaceutical carriers include, but are not limited to, binding agents (e.g., pregelatiniεed maize εtarch, polyvinylpyrrolidone or hydroxypropyl methylcelluloεe, etc.); fillerε (e.g., lactoεe and other sugars, microcrystalline cellulose, pectin, gelatin, calcium sulfate, ethyl cellulose, polyacrylates or calcium hydrogen phosphate, etc.); lubricants (e.g., magnesium stearate, talc, silica, colloidal silicon dioxide, εtearic acid, metallic stearates, hydrogenated vegetable oils, corn εtarch, polyethylene glycols, sodium benzoate, sodium acetate, etc.); disintegrants (e.g., starch, sodium starch glycolate, etc.); and wetting agents (e.g., εodium lauryl sulphate, etc. ) . Pharmaceutically acceptable organic or inorganic excipient suitable for non-parenteral administration which do not deleteriously react with nucleic acidε can also be used to formulate the compositionε of the present invention. Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt εolutionε, alcoholε, polyethylene glycolε, gelatin, lactose, amyloεe, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like. Formulations for topical administration of nucleic acids may include sterile and non- sterile aqueous solutions, non-aqueous solutionε in common εolventε such aε alcoholε, or εolutionε of the nucleic acids in liquid or solid oil baseε . The εolutionε may also contain buffers, diluents and other suitable additiveε . Pharmaceutically acceptable organic or inorganic excipientε suitable for non-parenteral administration which do not deleteriously react with nucleic acids can be used. Suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycolε, gelatin, lactoεe, amyloεe, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose, polyvinylpyrrolidone and the like. F. Other Components The compositionε of the present invention may additionally contain other adjunct components conventionally found in pharmaceutical compositionε, at their art-established usage levels. Thus, for example, the compositions may contain additional, compatible, pharmaceutically-active materials such as, for example, antipruritics, astringents, local anesthetics or anti- inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the composition of present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizerε . However, εuch materials, when added, should not unduly interfere with the biological activities of the components of the compositionε of the preεent invention. The formulationε can be εterilized and, if deεired, mixed with auxiliary agents, e.g., lubricants, preservativeε, εtabilizers, wetting agents, emulsifierε, εaltε for influencing oεmotic pressure, buffers, colorings flavorings and/or aromatic substances and the like which do not deleteriously interact with the nucleic acid(ε) of the formulation. Aqueous suεpensions may contain substances which increase the viscoεity of the suspenεion including, for example, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, εorbitol and/or dextran. The suspension may also contain stabilizerε. III. Oligonucleotides The present invention employs pharmaceutical compoεitionε comprising biologically active oligonucleotides useful for prophylactic, palliative or therapeutic purpoεes and, in isolated tisεueε or organs or in an animal other than a human, for investigative use. Typically, the formulations of the invention will comprise an oligonucleotide in an amount of from about 0.005 ng/mL to about 400 mg/mL, preferably from about 0.01 ng/mL to about 200 mg/mL, most preferably from about 0.1 ng/mL to about 100 mg/mL, where "about" indicates + . 5% of the indicated concentration . In the context of this invention, the term "oligonucleotide" refers to an oligomer cr polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimeticε thereof. Thiε term includeε oligonucleotideε composed of naturally-occurring nucleobases, sugars and covalent intersugar (backbone) linkages as well as oligonucleotides having non-naturally-occurring portions which function similarly. Such modified or εubstituted oligonucleotides are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for nucleic acid target and increaεed εtability in the presence of nucleases . A discuεεion of antisense oligonucleotides and some desirable modifications can be found in De Mesmaeker et al . (Ace. Chem. Res . , 1995, 28, 366). Generally, oligonucleotideε formulated in the compositions of the invention may be from about 8 to about 100 nucleotides in length, more preferably from about 10 to about 50 nucleotides in length, and most preferably from about 10 about 25 nucleotides in length. Oligonucleotides that are formulated in the compositions of the invention include (1) antisense compounds and (2) other bioactive oligonucleotideε. These compounds are described in more detail, infra . A. Antisense Compounds: Aε used herein, the term "antisenεe compound" encompasses, inter alia, antisense oligonucleotides, antisenεe peptide nucleic acids (PNAs), ribozymes and EGSs (deεcribed infra) . In antiεenεe modulation of messenger RNA (mRNA) , hybridization of an antisense compound with its mRNA target interferes with the normal role of mRNA and causes a modulation of its function in cells . The functions of mRNA to be interfered with include all vital functions such as translocation of the RNA to the site for protein translation, actual translation of protein from the RNA, splicing of the RNA to yield one or more mRNA specieε, turnover or degradation of the mRNA and poεεibly even independent catalytic activity which may be engaged in by the RNA. The overall effect of εuch interference with mRNA function iε modulation of the expression of a protein, wherein "modulation" means either an increase .stimulation) or a decrease inhibition) in the expresεion of the protein. In the context of the preεent invention, inhibition iε the preferred form of modulation of gene expression. Antisenεe compoundε can exert their effect by a variety of means. One such meanε iε the antisense-mediated direction of an endogenous nucleaεe, such as RNase H in eukaryotes or RNase P in prokaryotes, to the target nucleic acid (Chiang et al . , J. Biol . Chem. , 1991, 266, 18162; Forεter et al . , Science, 1990, 249, 783). The sequences that recruit RNase P are known as External Guide Sequences, hence the abbreviation "EGS" (Guerrier-Takada et al . , Proc . Natl . Acad . Sci . USA, 1997, 94 , 8468). Another means involves covalently linking a synthetic moiety having nucleaεe activity to an oligonucleotide having an antisense sequence, rather than relying upon recruitment of an endogenous nuclease. Synthetic moieties having nuclease activity include, but are not limited to, enzymatic RNAs, lanthanide ion complexeε, and the like (Haseloff et al . , Nature, 1988, 334 , 585; Baker et al . , J. Am . Chem . Soc , 1997 , 119, 8749) . As used herein, the term "antisense compound" also includes ribozymes, synthetic RNA molecules and derivatives thereof that catalyze highly specific endoribonucleaεe reactionε (εee, generally, U.S. Patent 5,543,508 to Haseloff et al . and U.S. Patent 5,545,729 to Goodchild et al . ) . The cleavage reactions are catalyzed by the RNA molecules themselves. In naturally occurring RNA molecules, the siteε of εelf-catalyzed cleavage are located within highly conserved regions of RNA secondary structure (Buzayan et al . , Proc . Na tl . Acad . Sci . USA, 1986, 83 , 8859; Forεter et al . , Cell , 1987, 50 , 9). Naturally occurring autocatalytic RNA molecules have been modified to generate ribozymes which can be targeted to a particular cellular or pathogenic RNA molecule with a high degree of specificity. Thus, ribozymes serve the εame general purpose as antiεenεe oligonucleotideε (i.e., modulation of expreεsion of a specific gene) and, like oligonucleotideε, are nucleic acidε possessing significant portions of single- εtrandedness . That iε, ribozy eε have εubεtantial chemical and functional identity with other bioactive compounds and may thus be formulated for pharmaceutical delivery using the liposomes of the present invention. The antisense compounds formulated in the compoεitions of the invention (1) may be from about 8 to about 100 nucleotideε in length, more preferably from about 10 to about 30 nucleotideε in length, (2) are targeted to a nucleic acid sequence required for the expression of a gene from a mammal, including a human, and (3), when contacted with cells expressing the target gene, modulate its expression. Due to the biological activity of the gene product encoded by the target gene, modulation of its expression has the desirable reεult of providing εpecific prophylactic, palliative and/or therapeutic effectε. B. Other Bioactive Oligonucleotides: The term "Other Bioactive Oligonucleotide" encompasses, inter alia, aptamers and molecular decoys (described infra) . Aε used herein, the term is meant to refer to any oligonucleotide (including a PNA) that (1) provides a prophylactic, palliative or therapeutic effect to an animal in need thereof and (2) acts by a non-antiεenεe mechanism, i . e . , by some means other than by hybridizing to a nucleic acid. The name aptamer has been coined by Ellington et al . {Nature, 1990, 346, 818) to refer to nucleic acid molecules that fit and therefore bind with significant specificity to non-nucleic acid ligands such as peptides, proteins and small molecules such as drugs and dyes . Because of theεe εpecific ligand binding properties, nucleic acids and oligonucleotides that may be classified as aptamers may be readily purified or isolated via affinity chromatography using columns that bear immobilized ligand. Aptamerε may be nucleic acids that are relatively short to those that are as large as a few hundred nucleotides . For example, RNA aptamers that are 155 nucleotideε long and that bind dyes such as Cibacron Blue and Reactive Blue 4 with good selectivity have been reported (Ellington et al . , Nature, 1990, 346, 818) . While RNA molecules were first referred to as aptamers, the term as used in the present invention referε to any nucleic acid or oligonucleotide that exhibitε specific binding to small molecule ligands including, but not limited to, DNA, RNA, DNA derivativeε and conjugateε, RNA derivativeε and conjugates, modified oligonucleotides, chimeric oligonucleotides, and gapmerε (see, e.g., U.S. Patent 5,523,389, to Ecker et al . , issued June 4, 1996 and incorporated herein by reference) . Molecular decoys are short double-stranded nucleic acids (including single-stranded nucleic acids designed to "fold back" on themselveε) that mimic a site on a nucleic acid to which a factor, such as a protein, binds. Such decoys are expected to competitively inhibit the factor; that is, because the factor molecules are bound to an excesε of the decoy, the concentration of factor bound to the cellular site corresponding to the decoy decreases, with resulting therapeutic, palliative or prophylactic effects. Methods of identifying and constructing decoy molecules are described in, e.g., U.S. Patent 5,716,780 to Edwards et al . Another type of bioactive oligonucleotide is an RNA-DNA hybrid molecule that can direct gene converεion of an endogenous nucleic acid (Cole-Strauss et al . , Science, 1996, 273 , 1386) . Any of the preceding bioactive oligonucleotides may be formulated in the lipoεomes of the invention and used for prophylactic or therapeutic purpoεeε . C. Oligonucleotide Modifications An oligonucleotide iε a polymer of a repeating unit generically known as a nucleotide. An unmodified (naturally occurring) nucleotide haε three components: (1) a nitrogen-containing heterocyclic base linked by one of its nitrogen atoms to (2) a 5-pentofuranosyl sugar and (3) a phosphate esterified to one of the 5 ' or 3 ' carbon atoms of the sugar. When incorporated into an oligonucleotide chain, the phosphate of a first nucleotide is also esterified to an adjacent sugar of a second, adjacent nucleotide via a 3 '-5' phosphate linkage . As is known in the art, a nucleoside is a base- εugar combination. The base portion of the nucleoside is normally a heterocyclic base. The two most common clasεeε of εuch heterocyclic baεeε are the purines and the pyrimidines. Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to either the 2 ' , 3 ' or 5 ' hydroxyl moiety of the sugar. In forming oligonucleotides, the phosphate groups covalently link adjacent nucleosides to one another to form a linear polymeric compound. The respective ends of this linear polymeric structure can be further joined to form a circular structure, however, within the context of the invention, open linear structures are generally preferred. Within the oligonucleotide structure, the phosphate groups are commonly referred to as forming the intersugar "backbone" of the oligonucleotide. The normal linkage or backbone of RNA and DNA is a 3 ' to 5 ' phosphodiester linkage. The backbone of an oligonucleotide (or other antisense compound) positionε a εeries of bases in a specific order; the written repreεentation of thiε ordered εeries of bases, usually written in 5 ' to 3 ' order unless otherwise indicated, is known as a nucleotide or nucleobase sequence . Oligonucleotides may comprise nucleotide sequences sufficient in identity and number to effect specific hybridization with a particular nucleic acid. Such oligonucleotides which specifically hybridize to a portion of the sense strand of a gene are commonly described as "antisense." In the context of the invention, "hybridization" means hydrogen bonding, which may be Watson- Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleotideε. For example, adenine and thymine are complementary nucleobases which pair through the formation of hydrogen bondε . "Complementary," aε used herein, refers to the capacity for precise pairing between two nucleotides. For example, if a nucleotide at a certain position of an oligonucleotide is capable of hydrogen bonding with a nucleotide at the same position of a DNA or RNA molecule, then the oligonucleotide and the DNA or RNA are considered to be complementary to each other at that position. The oligonucleotide and the DNA or RNA are complementary to each other when a sufficient number of corresponding poεitionε in each molecule are occupied by nucleotideε which can hydrogen bond with each other. "Specifically hybridizable" and "complementary" are thus terms which are used to indicate a εufficient degree of complementarity or precise pairing such that stable and εpecific binding occurs between the oligonucleotide and the DNA or RNA target. An oligonucleotide is specifically hybridizable to its target sequence due to the formation of base pairε between εpecific partner nucleobaεeε in the interior of a nucleic acid duplex. Among the naturally occurring nucleobaseε, guanine (G) bindε to cytosine (C) , and adenine (A) binds to thymine (T) or uracil (U) . In addition to the equivalency of U (RNA) and T )DNA) as partners for A, other naturally occurring nucleobase equivalents are known, including 5- methylcytoεine and 5-hydroxymethylcytoεine (HMC) (C equivalentε) , and 5-hydroxymethyluracil 'U equivalent) . Furthermore, synthetic nucleobases which retain partner specificity are known in the art and include, for example, 7 -deaza-Guanine, which retains partner specificity for C. Thus, an oligonucleotide ' s capacity to specifically hybridize with its target sequence will not be altered by a chemical modification to a nucleobase in the nucleotide sequence of the oligonucleotide which does not impact its specificity for a partner nucleobase in the target nucleic acid. It is understood in the art that the nucleobase sequence of an oligonucleotide or other antisense compound need not be 100% complementary to its target nucleic acid sequence to be specifically hybridizable. An antisense compound is specifically hybridizable to its target nucleic acid when there is a sufficient degree of complementarity to avoid non-specific binding of the oligonucleotide to non- target εequences under conditions in which specific binding iε desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatment, or, in the case of in vi tro assays, under assay conditions. Antisense oligonucleotideε are commonly used as reεearch reagents, diagnostic aids, and therapeutic agentε. For example, antisense oligonucleotideε, which are able to inhibit gene expreεεion with exquiεite εpecificity, are often uεed by those of ordinary skill to elucidate the function of particular genes, for example to diεtinguish between the functions of various members of a biological pathway. This specific inhibitory effect has, therefore, been harnesεed by those skilled in the art for research uses. The specificity and senεitivity of oligonucleotides is also harnesεed by those of skill in the art for therapeutic uεeε . Specific exampleε of preferred antiεense compounds useful in this invention include oligonucleotides containing modified backbones or non-natural intersugar linkages. As defined in this specification, oligonucleotides having modified backbones include those that retain a phoεphoruε atom in the backbone and thoεe that do not have a phoεphorus atom in the backbone . For the purposeε of this specification, and as sometimes referenced in the art, modified oligonucleotideε that do not have a phoεphorus atom in their intersugar backbone can also be conεidered to be oligonucleoεideε . Specific oligonucleotide chemical modifications are described in the following subεections . It iε not necessary for all positionε in a given compound to be uniformly modified, and in fact more than one of the following modificationε may be incorporated in a εingle antisenεe compound or even in a εingle reεidue thereof, for example, at a single nucleoside within an oligonucleotide. Modified Linkages: Preferred modified oligonucleotide backbones include, for example, phoεphorothioateε, chiral phoεphorothioateε, phoεphoro- dithioateε, phoεphotrieεters, aminoalkylphosphotriesterε , methyl and other alkyl phosphonates including 3 ' -alkylene phosphonates and chiral phosphonates, phosphinates, phoεphoramidateε including 3 ' -amino phosphoramidate and aminoalkylphosphoramidates, thionophoεphcramidateε , thiono- alkylphoεphonates, thionoalklyphosphotriesters, and borano- phoεphateε having normal 3 '-5' linkages, 2 '-5' linked analogε of these, and those having inverted polarity wherein the adjacent pairε of nucleoεide units are linked 3 '-5' to 5 '-3' or 2 '-5' to 5'-2'. Various saltε, mixed salts and free acid forms are also included. Repreεentative United Stateε Patents that teach the preparation of the above phosphorus atom containing linkages include, but are not limited to, U.S. Patents Nos. 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196, 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717, 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306, 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,625,050; and 5,697,248, certain of which are commonly owned with this application, and each of which iε herein incorporated by reference . Preferred modified oligonucleotide backbones that do not include a phosphorus atom therein i.e., oligonucleoεides) have backbones that are formed by short chain alkyl or cycloalkyl intersugar linkages, mixed heteroatom and alkyl or cycloalkyl intersugar linkageε, or one or more εhort chain heteroatomic or heterocyclic interεugar linkageε . Theεe include thoεe having morpholino linkageε (formed in part from the εugar portion of a nucleoside) ; siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and εulfonamide backbones; amide backbones; and otherε having mixed N, 0, S and CH 2 component partε . Repreεentative United States patents that teach the preparation of the above oligonucleosideε include, but are not limited to, U.S. Patentε Noε . 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240, 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704, 5,623,070; 5,663,312; 5,633,360; 5,677,437; and 5 , 677 , 439 , certain of which are commonly owned with thiε application, and each of which iε herein incorporated by reference. In other preferred oligonucleotide mimeticε, both the εugar and the interεugar linkage, i.e., the backbone, of the nucleotide units are replaced with novel groups. The base unitε are maintained for hybridization with an appropriate nucleic acid target compound. One such oligomeric compound, an oligonucleotide mimetic that has been shown to have excellent hybridization propertieε, iε referred to aε a peptide nucleic acid (PNA) . In PNA compoundε, the sugar-backbone of an oligonucleotide iε replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative United Stateε patentε that teach the preparation of PNA compounds include, but are not limited to, U.S. Patents Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found in Nielsen et al . ' Science, 1991, 254 , 1497) . Most preferred embodimentε of the invention are oligonucleotideε with phoεphorothioate backboneε and oligonucleosides with heteroatom backbones, and in particular -CH 2 -NH-0-CH 2 - , -CH 2 -N(CH 3 ) -0-CH : - [known as a methylene (methylimino) or MMI backbone], -CH 2 -0-N (CH 3 ) -CH 2 - ,- CH 2 -N(CH : .) -N(CH 3 ) -CH 2 - and -0-N(CH 3 ) -CH_-CH 2 - [wherein the native phosphodiester backbone is represented aε -0-P-0-CH 2 -] of the above referenced U.S. Patent 5,489,677, and the amide backbones of the above referenced U.S. Patent No. 5,602,240. Also preferred are oligonucleotides having morpholino backbone structures of the above-referenced U.S. Patent No. 5,034,506. Modified Nucleobases: The compounds of the invention may additionally or alternatively comprise nucleobase (often referred to in the art simply as "base") modifications or substitutions. As used herein, "unmodified" or "natural" nucleobases include the purine bases adenine (A) and guanine (G) , and the pyrimidine baseε thymine (T) , cytoεine (C) and uracil (U) . Modified nucleobaεes include other synthetic and natural nucleobaseε εuch aε 5-methylcytoεine (5-me-C) , 5-hydroxymethyl cytoεine, xanthine, hypoxanthine , 2-aminoadenine, 6 -methyl and other alkyl derivativeε of adenine and guanine, 2-propyl and other alkyl derivativeε of adenine and guanine, 2-thiouracil, 2- thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil) , 4-thiouracil, 8-halo, 8- amino, 8-thiol, 8-thioalkyl, 8 -hydroxyl and other 8- εubεtituted adenines and guanineε, 5-halo particularly 5- bromo, 5-trifluoromethyl and other 5-εubstituted uracils and cytoεineε, 7-methylguanine and 7-methyladenine, 8-azaguanine and 8 -azaadenine, 7-deazaguanine and 7-deazaadenine and 3- deazaguanine and 3-deazaadenine. Further nucleobases include those disclosed in United States Patent No. 3,687,808, those disclosed in the Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J.I., ed. John Wiley & Sons, 1990, those disclosed by Englisch et al . , Angewandte Chemie, International Edi tion, 1991, 30 , 613, and those disclosed by Sanghvi, Y.S., Chapter 15, Antisense Research and Applications, pages 289-302, Crooke, S.T. and Lebleu, B., ed., CRC Presε, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the oligomeric compoundε of the invention. Theεe include 5-substituted pyrimidines, 6- azapyrimidineε and N-2, N-6 and 0-6 substituted purines , including 2-aminopropyladenine, 5-propynyluracil and 5- propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex εtability by 0.6-1.2°C ( Id . , pages 276-278) and are presently preferred base substitutions, even more particularly when combined with 2'- methoxyethyl sugar modificationε . Representative United Stateε patents that teach the preparation of certain of the above noted modified nucleobaεes as well as other modified nucleobaεes include, but are not limited to, the above noted U.S. Patent 3,687,808, as well aε U.S. Patents 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; and 5 , 681 , 941, certain of which are commonly owned, and each of which is herein incorporated by reference, and commonly owned United States patent application 08/762,488, filed on December 10, 1996, also herein incorporated by reference. Sugar Modifications: The antisense compounds of the invention may additionally or alternatively compriεe one or more εubεtituted sugar moietieε. Preferred oligonucleotideε compriεe one of the following at the 2 ' poεition: OH; F; 0-, S-, or N-alkyl, 0- , S-, or N-alkenyl, or 0, S- or N-alkynyl, wherein the alkyl, alkenyl and alkynyl may be εubεtituted or unεubstituted C ± to C 10 alkyl or C 2 to C 1C alkenyl and alkynyl. Particularly preferred are 0[ (CH,) n 0] m CH = , 0(CH 2 ) n 0CH 3 , 0(CH 2 ) n NH 2/ 0 (CH ; ) n CH 3, 0 (CH 2 ) r 0NH =r and 0(CH 2 ) n ON[ (CH) n CH 3 ) ] 2 , where n and m are from 1 to about 10. Other preferred oligonucleotides comprise one of the following at the 2' position: C x to C 10 lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or 0- aralkyl, SH, SCH 3 , OCN, Cl, Br, CN, CF 3 , OCF 3 , SOCH 3 , S0 2 CH 3/ 0N0 2; N0 2/ N 3/ NH 2ι heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic propertieε of an oligonucleotide, and other εubεtituentε having εimilar propertieε. A preferred modification includes 2 ' -methoxyethoxy [2 ' -0-CH 2 CH 2 OCH 3 , also known as 2 ' -0- (2-methoxyethyl) or 2 ' -MOE] Martin et al . , Helv. Chim . Acta , 1995, 78, 486), i.e., an alkoxyalkoxy group. A further preferred modification includes 2'- dimethylaminooxyethoxy, i.e., a 0 (CH 2 ) 2 0N 'CH 3 ) 2 group, also known aε 2'-DMA0E, as described in co-owned United States patent application Serial Number 09/016,520, filed on January 30, 1998, the contentε of which are herein incorporated by reference. Other preferred modifications include 2 ' -methoxy (2'-0-CH 3 ), 2' -aminopropoxy (2 ' -OCH 2 CH 2 CH_NH 2 ) and 2'-fluoro (2'-F) . Similar modifications may alεo be made at other positionε on the oligonucleotide, particularly the 3' position of the sugar on the 3 ' terminal nucleotide or in 2' -5' linked oligonucleotides and the 5' position of 5' terminal nucleotide. Oligonucleotides may also have sugar mimeticε εuch as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative United States patents that teach the preparation of such modified sugars structures include, but are not limited to, U.S. Patents Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,0531 5,639,873; 5,646,265; 5,658,873; 5,670,633; and 5 , 700 , 920 , certain of which are commonly owned, and each of which is herein incorporated by reference, and commonly owned United States patent application 08/468,037, filed on June 5, 1995, alεo herein incorporated by reference. Other Modifications: Additional modifications may also be made at other poεitions on the oligonucleotide, particularly the 3 ' position of the sugar on the 3 ' terminal nucleotide and the 5' position of 5' terminal nucleotide. For example, one additional modification of the oligonucleotides of the invention involves chemically linking to the oligonucleotide one or more moietieε or conjugates which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. Such moieties include but are not limited to lipid moieties such as a choleεterol moiety (Letεinger et al . , Proc. Natl. Acad. Sci. USA, 1989, 86, 6553), cholic acid (Manoharan et al., Bioorg . Med. Chem. Lett., 1994, 4, 1053), a thioether, e.g., hexyl- S-tritylthiol (Manoharan et al . , Ann. N.Y. Acad. Sci., 1992, 660, 306; Manoharan et al . , Bioorg. Med. Chem. Let., 1993, 3, 2765), a thiocholeεterol (Oberhauεer et al . , Nucl. Acids Res., 1992, 20, 533), an aliphatic chain, e.g., dodecandiol or undecyl reεidues (Saiεon-Behmoaraε et al., EMBO J., 1991, 10, 111; Kabanov et al . , FEBS Lett., 1990, 259, 327; Svinarchuk et al., Biochimie, 1993, 75, 49), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethylammonium 1,2-di- O-hexadecyl-rac-glycero-3-H-phosphonate [Manoharan et al., Tetrahedron Lett., 1995, 36, 3651; Shea et al., Nucl. Acids Res., 1990, 18, 3777), a polyamine or a polyethylene glycol chain (Manoharan et al . , Nucleosides & Nucleotides, 1995, 14, 969), or adamantane acetic acid (Manoharan et al . , Tetrahedron Lett., 1995, 36, 3651), a pai ityl moiety (Mishra et al . , Biochim. Biophys . Acta, 1995, 1264, 229), or an octadecylamine or hexylamino-carbonyl-oxycholeεterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923) . Repreεentative United States patents that teach the preparation of such oligonucleotide conjugateε include, but are not limited to, U.S. Patents Noε . 4,828,979; 4, 948,882 5,218,105; 5,525,465; 5,541,313; 5,545,730 5,552,538 5,578,717, 5,580,731; 5,580,731; 5,591,584 5,109,124 5,118,802; 5,138,045; 5,414,077; 5,486,603 5,512,439 5,578,718; 5,608,046; 4,587,044; 4,605,735 4,667,025 4,762,779; 4,789,737; 4,824,941; 4,835,263 4,876,335; 4,904,582; 4,958,013, 5,082,830; 5,112,963 5,214,136; 5,082,830; 5,112,963, 5,214,136; 5,245,022 5,254,469; 5,258,506; 5,262,536, 5,272,250; 5,292,873 5,317,098; 5,371,241, 5,391,723 5,416,203, 5,451,463 5,510,475; 5,512,667; 5,514,785, 5,565,552; 5,567,810 5,574,142; 5,585,481; 5,587,371, 5,595,726; 5,597,696 5,599,923; 5,599,928 and 5,688,941, certain of which are commonly owned, and each of which is herein incorporated by reference. Chimeric Oligonucleotides: The present invention also includes antisense compounds which are chimeric compounds. "Chimeric" antisenεe compounds or "chimeras," in the context of this invention, are antisense compounds, particularly oligonucleotideε, which contain two or more chemically diεtinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotide compound. These oligonucleotides typically contain at least one region wherein the oligonucleotide is modified εo aε to confer upon the oligonucleotide increaεed reεiεtance to nuclease degradation, increased cellular uptake, and/or increased binding affinity for the target nucleic acid. An additional region of the oligonucleotide may serve as a substrate for enzymeε capable of cleaving RNA: DNA or RNA: RNA hybridε . By way of example, RNaεe H iε a cellular endonucleaεe which cleaveε the RNA εtrand of an RNA: DNA duplex. Activation of RNase H, therefore, reεultε in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide inhibition of gene expresεion. Consequently, comparable resultε can often be obtained with εhorter oligonucleotideε when chimeric oligonucleotides are used, compared to phosphorothioate oligodeoxynucleotideε hybridizing to the same target region. Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if neceεεary, aεsociated nucleic acid hybridization techniques known in the art. RNase H-mediated target cleavage is distinct from the use of ribozymeε to cleave nucleic acids, and ribozymes are not comprehended by the present invention. By way of example, such "chimeras" may be "gapmers," i.e., oligonucleotides in which a central portion (the "gap") of the oligonucleotide serves as a subεtrate for, e.g., RNase H, and the 5' and 3' portions (the "wings") are modified in such a fashion so as to have greater affinity for, or stability when duplexed with, the target RNA molecule but are unable to support nuclease activity (e.g., 2'-fluoro- or 2 ' -methoxyethoxy- εubεtituted). Other chimeras include "hemimerε," that iε, oligonucleotideε in which the 5 ' portion of the oligonucleotide serves as a εubεtrate for, e.g., RNaεe H, whereas the 3' portion is modified in such a fashion so as to have greater affinity for, or stability when duplexed with, the target RNA molecule but is unable to support nucleaεe activity (e.g., 2'-fluoro- or 2 ' -methoxyethoxy- substituted), or vice-versa. A number of chemical modifications to oligonucleotides that confer greater oligonucleotide : RNA duplex stability have been described by Freier et al . (Nucl . Acids Res . , 1997, 25 , 4429). Such modifications are preferred for the RNase H-refractory portions of chimeric oligonucleotides and may generally be used to enhance the affinity of an antisense compound for a target RNA. Chimeric antisenεe compoundε of the invention may be formed aε compoεite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleoεideε and/or oligonucleotide mimeticε as described above. Such compounds have also been referred to in the art as hybrids or gapmers. Representative United States patents that teach the preparation of such hybrid structureε include, but are not limited to, U.S. Patentε Nos. 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; and 5,700,922, certain of which are commonly owned, and each of which is herein incorporated by reference, and commonly owned and allowed United States patent application serial number 08/465,880, filed on June 6, 1995, also herein incorporated by reference. A further preferred modification includes 2 ' - dimethylamino oxyethoxy, i.e., a 0 (CH 2 ) 2 ON(CH 3 ) 2 group, alεo known aε 2'-DMAOE, aε deεcribed in co-owned United States patent application Serial Number 09/016,520, filed on January 30, 1998, the contents of which are herein incorporated by reference. Other preferred modifications include 2 ' -methoxy (2'-0-CH 3 ), 2 ' -aminopropoxy (2'- OCH 2 CH 2 CH 2 NH : ) and 2'-fluoro (2'-F). Similar modifications may also be made at other positionε on the sugar group, particularly the 3 ' poεition of the εugar on the 3 ' terminal nucleotide or in 2 '-5' linked oligonucleotideε and the 5' position of 5' terminal nucleotide. The nucleosides of the oligonucleotideε may also have sugar mimetics εuch aε cyclobutyl moieties in place of the pentofuranosyl εugar. Unsubstituted and εubεtituted phosphodiester oligonucleotideε are alternately εynthesized on an automated DNA synthesizer Applied Biosystems model 380B) uεing εtandard phoεphoramidite chemiεtry with oxidation by iodine. Phosphorothioates are synthesized as per the phosphodiester oligonucleotides except the standard oxidation bottle was replaced by 0.2 M εolution of 3H-1,2- benzodithiole-3-one 1,1-dioxide in acetonitrile for the stepwise thiation of the phosphite linkages. The thiation wait step was increased to 68 sec and was followed by the capping step. After cleavage from the CPG column and deblocking in concentrated ammonium hydroxide at 55°C (18 hr) , the oligonucleotides were purified by precipitating twice with 2.5 volumes of ethanol from a 0.5 M NaCl εolution. Phosphinate oligonucleotides are prepared as described in U.S. Patent 5,508,270, herein incorporated by reference. Alkyl phoεphonate oligonucleotides are prepared as described in U.S. Patent 4,469,863, herein incorporated by reference . 3 ' -Deoxy-3 ' -methylene phoεphonate oligonucleotides are prepared as deεcribed in U.S. Patentε 5,610,289 or 5,625,050, herein incorporated by reference. Phosphoramidite oligonucleotides are prepared as described in U.S. Patent, 5,256,775 or U.S. Patent 5,366,878, hereby incorporated by reference. Alkylphoεphonothioate oligonucleotides are prepared as described in published PCT applications PCT/US94/00902 and PCT/US93/06976 (publiεhed as WO 94/17093 and WO 94/02499, respectively) . 3 ' -Deoxy-3 ' -amino phosphoramidate cligonucleotideε are prepared as described in U.S. Patent 5,476,925, herein incorporated by reference. Phosphotriester oligonucleotides are prepared as described in U.S. Patent 5,023,243, herein incorporated by reference. Boranophosphate oligonucleotideε are prepared as described in U.S. Patents 5,130,302 and 5,177,198, both herein incorporated by reference. Methylenemethylimino linked oligonucleosideε, also identified as MMI linked oligonucleosides, methylenedi- methylhydrazo linked oligonucleosideε, also identified as MDH linked oligonucleosides, and methylenecarbonylamino linked oligonucleosides, also identified as amide-3 linked oligonucleosides, and methyleneaminocarbcnyl linked oligonucleosides, also identified as amide-4 linked oligonucleosides, as well as mixed backbone compounds having, for instance, alternating MMI and PO or PS linkageε are prepared aε deεcribed in U.S. Patentε 5,378,825; 5,386,023; 5,489,677; 5,602,240 and 5,610,289, all of which are herein incorporated by reference. Formacetal and thioformacetal linked oligonucleosides are prepared as described in U.S. Patents 5,264,562 and 5,264,564, herein incorporated by reference. Ethylene oxide linked oligonucleosides are prepared aε deεcribed in U.S. Patent 5,223,618, herein incorporated by reference . Peptide nucleic acids (PNAε) are prepared in accordance with any of the variouε procedures referred to in Peptide Nucleic Acids (PNA): Synthesis, Properties and Potential Applications, Bioorganic & Medicinal Chemistry, 1996, 4, 5. They may also be prepared in accordance with U.S. Patentε 5,539,082; 5,700,922, and 5 , 719, 262 , herein incorporated by reference. Examples of specific oligonucleotides and the target genes which they inhibit, that may be employed in formulations of the preεent invention include: ISIS-2302 GCCCA AGCTG GCATC CGTCA SEQ ID NO : 1 ICAM-1 IΞIS-15839 GCCCA AGCTG GCATC CGTCA SEQ ID NO:l) ICAM-1 ISIS-1939 CCCCC ACCAC TTCCC CTCTC SEQ ID NO:2) ICAM-1 ISIS-2503 TCCGT CATCG CTCCT CAGGG SEQ ID NO:4) Ha-raε ISIS-2922 GCGTT TGCTC TTCTT CTTGC G SEQ ID NO : 5 ) HCMV ISIS-13312 GCGTT TGCTC TTCTT CTTGC G SEQ ID NO : 5 ) HCMV ISIS-3521 GTTCT CGCTG GTGAG TTTCA 'SEQ ID NO: 6) PKCα ISIS-9605 GTTCT CGCTG GTGAG TTTCA [SEQ ID NO: 6) PKCα ISIS-9606 GTTCT CGCTG GTGAG TTTCA )SEQ ID NO: 6) PKCα ISIS-14859 AACTT GTGCT TGCTC SEQ ID NO: 7) PKCα ISIS-5132 TCCCG CCTGT GACAT GCATT SEQ ID NO : 8 ) c-raf ISIS-14803 GTGCT CATGG TGCAC GGTCT SEQ ID NO: 9) HCV ISIS-28089 GTGTG CCAGA CACCC TATCT SEQ ID NO: 10) TNFα ISIS-104838 GCTGA TTAGA GAGAG GTCCC ' SEQ ID NO: 11) TNFα ISIS-2105 TTGCT TCCAT CTTCC TCGTC [SEQ ID NO: 12) HPV wherein (i) each oligo backbone linkage iε a phoεphorothioate linkage (except ISIS-9605) and (ii) each εugar iε 2 ' -deoxy unless represented in bold font in which case it incorporates a 2 ' -O-methoxyethyl group and iii) underlined cytoεine nucleoεideε incorporate a 5 -methyl substituent on their nucleobaεe. ISIS-9605 incorporates natural phosphodiester bonds at the first five and last five linkageε with the remainder being phoεphorothioate linkages . D. Synthesis of Oligonucleotides: The oligonucleotides used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase syntheεiε. Equipment for such synthesis is sold by εeveral vendorε including, for example, Applied Bioεystems (Foster City, CA) . Any other means for such synthesis known in the art may additionally or alternatively be employed. It is also known to use εimilar techniques to prepare other oligonucleotides εuch as the phoεphorothioateε and alkylated derivative . Teachings regarding the synthesis of particular modified oligonucleotides may be found in the following U.S. patentε or pending patent applications, each of which is commonly asεigned with thiε application: U.S. Patents Nos. 5,138,045 and 5,218,105, drawn to polyamine conjugated oligonucleotides; U.S. Patent No. 5,212,295, drawn to monomers for the preparation of oligonucleotides having chiral phosphoruε linkages; U.S. Patents Nos. 5,378,825 and 5,541,307, drawn to oligonucleotides having modified backbones; U.S. Patent No. 5,386,023, drawn to backbone modified oligonucleotideε and the preparation thereof through reductive coupling; U.S. Patent No. 5,457,191, drawn to modified nucleobases based on the 3-deazapurine ring system and methods of synthesis thereof; U.S. Patent No. 5,459,255, drawn to modified nucleobases based on N-2 subεtituted purineε; U.S. Patent No. 5,521,302, drawn to proceεses for preparing oligonucleotideε having chiral phoεphorus linkages; U.S. Patent No. 5,539,082, drawn to peptide nucleic acids; U.S. Patent No. 5,554,746, drawn to oligonucleotideε having β-lactam backbones; U.S. Patent No. 5,571,902, drawn to methods and materials for the synthesiε of oligonucleotides; U.S. Patent No. 5,578,718, drawn to nucleosides having alkylthio groups, wherein such groups may be used as linkers to other moieties attached at any of a variety of positionε of the nucleoside; U.S. Patents Nos. 5,587,361 and 5,599,797, drawn to oligonucleotideε having phoεphorothioate linkageε of high chiral purity; U.S. Patent No. 5,506,351, drawn to processes for the preparation of 2 ' - 0-alkyl guanosine and related compoundε , including 2,6- diaminopurine compounds; U.S. Patent No. 5,587,469, drawn to oligonucleotides having N-2 εubstituted purines; U.S. Patent No. 5,587,470, drawn to oligonucleotides having 3- deazapurineε; U.S. Patentε Noε . 5,223,168, iεεued June 29, 1993, and 5,608,046, both drawn to conjugated 4 ' -deεmethyl nucleoside analogs; U.S. Patent Nos. 5,602,240, and 5,610,289, drawn to backbone modified oligonucleotide analogs; and U.S. patent application Serial No. 08/383,666, filed February 3, 1995, and U.S. Patent No. 5,459,255, drawn to, inter alia, methods of syntheεizing 2'-fluoro- oligonucleotideε . E. Bioeguivalents : In addition to oligonucleotide drugε per se, the pharmaceutical compoεitions of the present invention can be used to formulate any pharmaceutically acceptable saltε, esters, or salts of such eεterε, or any other compound which, upon administration to an animal including a human, iε capable of providing (directly or indirectly) a biologically active oligonucleotide or residue thereof. Accordingly, for example, the disclosure is alεo drawn to "prodrugs" and "pharmaceutically acceptable saltε" of the oligonucleotides of the invention, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents . Oligonucleotide Prodrugs: The oligonucleotide and nucleic acid compounds employed in the compositions of the present invention may additionally or alternatively be prepared to be delivered in a "prodrug" form. The term "prodrug" indicates a therapeutic agent that iε prepared in an inactive form that is converted to an active form (i.e., drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals and/or conditions. In particular, prodrug versions of the antiεenεe compoundε may be prepared as SATE [ (S-acetyl-2-thioethyl) phosphate] derivativeε according to the methods disclosed in WO 93/24510 (Gosselin et al . , publiεhed December 9, 1993). Pharmaceutically Acceptable Salts: The term "pharmaceutically acceptable εaltε" refers to phyεiologically and pharmaceutically acceptable εaltε of the oligonucleotide and nucleic acid compoundε employed in the compoεitionε of the preεent invention (i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effectε thereto) . Pharmaceutically acceptable base addition εalts are formed with metals or amines, such aε alkali and alkaline earth metals or organic amines. Exampleε of metals used as cations are sodium, potasεium, magneεium, calcium, ammonium, polyamineε εuch as spermine and spermidine, and the like. Examples of suitable amineε are chloroprocaine, choline, N,N' -dibenzylethylenediamine, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge et al . , "Pharmaceutical Salts," J. of Pharma Sci . , 1977, 66 : 1 ) . The baεe addition εalts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner. The free acid form may be regenerated by contacting the salt form with an acid and isolating the free acid in the conventional mann r. The free acid forms differ from their reεpective εalt forms somewhat in certain physical propertieε εuch as solubility in polar solvents, but otherwise the εaltε are equivalent to their respective free acid for purposes of the present invention. n-1 Derivatives: During the process of oligonucleotide synthesiε, nucleoεide monomerε are attached to the chain one at a time in a repeated series of chemical reactions such as nucleoside monomer coupling, oxidation, capping and detritylation. The stepwise yield for each nucleoεide addition iε above 99%. That meanε that less than 1% of the sequence chain failed to be generated from the nucleoside monomer addition in each step as the total results of the incomplete coupling followed by the incomplete capping, detritylation and oxidation (Smith, Anal . Chem . , 1988, 60, 381A) . All the shorter oligonucleotides, ranging from (n-1), (n-2), etc., to 1-merε (nucleotideε; , are preεent as impurities in the n-mer olignucleotide product. Among the impurities, [n-2)-mer and εhorter oligonucleotide impurities are present in very small amounts and can be easily removed by chromatographic purification (Warren et al . , Chapter 9 In : Methods in Molecular Biology, Vol . 26 : Protocols for Oligonucleotide Conjugates , Agrawal, S., Ed., 1994, Humana Preεε Inc., Totowa, NJ, pages 233-264) . However, due to the lack of chromatographic selectivity and product yield, some (n-1) -mer impurities are still present in the full-length (i.e., n-mer oligonucleotide product after the purification process . The (n-1) portion consists of the mixture of all possible single base deletion sequences relative to the n- mer parent oligonucleotide. Such (n-1) impurities can be clasεified as terminal deletion or internal deletion sequenceε, depending upon the poεition of the miεεing baεe (i.e., either at the 5' or 3 ' terminuε or internally) . When an oligonucleotide containing εingle baεe deletion εequence impurities is used as a drug (Crooke, He atologic Pathology, 1995, 9, 59) , the terminal deletion εequence impurities will bind to the same target mRNA as the full length sequence but with a slightly lower affinity. Thus, to some extent, such impurities can be considered aε part of the active drug component, and are thuε conεidered to be bioequivalentε for purposeε of the preεent invention. IV. Therapeutic Indications and Other Uses Psoriasis: One therapeutic indication of particular intereεt for topical delivery of oligonucleotides and other nucleic acids is psoriasis. Psoriasiε iε a common chronic and recurrent disease characterized by dry, well- circumscribed, silvery, scaling papuleε and plaqueε of variouε sizeε . The disease varies in severity from a few leεions to widespread dermatosis with diεabling arthritiε or exfoliation. The ultimate cause of pεoriaεiε iε not known, but the thick εcaling that occurε iε probably due to increaεed epidermal cell proliferation ( The Merck Manual of Diagnosis and Therapy, 15th Ed., pp. 2283-2285, Berkow et al . , ed . , Rahway, N.J., 1987). Inhibitcrε of Protein Kinaεe C (PKC; , ICAM-1 and tumour necroεis factor (TNFα) have been shown to have both antiproliferative and anti- inflammatory effects in vi tro . Some antipεoriasiε drugε, such aε cycloεporin A and anthralin, have been shown to inhibit PKC, and inhibition of PKC haε been suggested as a therapeutic approach to the treatment of psoriasiε (Hegemann, L. and G. Mahrle, Pharmacology of the Skin, H. Mukhtar, ed., pp. 357-368, CRC Preεε, Boca Raton, FL, 1992). Antiεense compounds targeted to Protein Kinase C (PKC) proteins are described in U.S. Patents Nos. 5,620,963 to Cook et al . and 5,681,747 to Boggε et al . Inflammation: Another type of therapeutic indication of particular interest for topical modes of delivery includes inflammatory disorders of the skin. These occur in a variety of forms including, for example, lichen planus, toxic epidermal necrolyis (TEN), ertythema multiforme and the like ( The Merck Manual of Diagnosis and Therapy, 15th Ed., pp. 2286-2292, Berkow et al . , edε., Rahway, N.J., 1987). Expreεsion of ICAM-1 haε been associated with a variety of inflammatory skin disorderε such aε allergic contact dermatitiε, fixed drug eruption, lichen planus and psoriaεiε (Ho et al., J. Am. Acad. Dermatol . , 1990, 22 , 64; Griffithε et al . , Am. J. Pathology, 1989, 135 , 1045; Liεby et al . , Br . J. Dermatol . , 1989, 120 , 479; Shiohara et al . , Arch . Dermatol . , 1989, 125, 1371; Regezi et al . , Oral Surg . Oral Med . Oral Pathol . , 1996, 81 , 682) . Moreover, intraperitoneal administration of a monoclonal antibody to ICAM-1 decreaεeε ovalbumin- induced eosinophil infiltration into skin in mice (Hakugawa et al . , J. Dermatol . , 1997, 24 , 73). Antiεenεe compoundε targeted to ICAM-1 are deεcribed in U.S. Patents Nos. 5,514,788 and 5,591,623, and co-pending U.S. patent applications Serial Nos. 09/009,490 and 09/062,416, January 20, 1998 and April 17, 1998, reεpectively, all to Bennett et al . Other antiεenεe targets for εkin inflammatory diεorderε are VCAM-1 and PECAM-1. Intraperitoneal administration of a monoclonal antibody to VCAM-1 decreases ovalbumin- induced eosinophil infiltration into the skin of mice (Hakugawa et al . , J. Dermatol . , 1997, 24 , 73). Antisense compounds targeted to VCAM-1 are described in U.S. Patents Nos. 5,514,788 and 5,591,623. PECAM-1 proteins are glycoproteins which are expreεsed on the surfaces of a variety of cell types (for reviews, see Newman, J. Clin . Inves t . , 1997, 99 , 3 and DeLisser et al . , Immunol . Today, 1994, 15, 490) . In addition to directly participating in cell-cell interactionε, PECAM-1 apparently also regulates the activity and/or expreεεion of other molecules involved in cellular interactions (Litwin et al . , J. Cell Biol . , 1991 , 139, 219) and is thus a key mediator of εeveral cell: cell interactions. Antisense compounds targeted to PECAM-1 are described in co-pending U.S. patent application Serial No. 09/044,506, filed March 19, 1998, by Bennett et al . Skin Cancers: Another type of therapeutic indication of intereεt for topical delivery of oligonucleotideε encompasseε a variety of cancers of the skin. Representative skin cancers include benign tumors (warts, moles and the like) and malignant tumors εuch aε, for example, baεal cell carcinoma, εquamous cell carcinoma, malignant melanoma, Paget ' s disease, Kaposi's sarcoma and the like ( The Merci Manual of Diagnosis and Therapy, 15th Ed., pp. 2301-2310, Berkow et al . , edε . , Rahay, N.J., 1987), A number of molecular targetε involved in tumorigeneεis, maintenance of the hyperproliferative state and metastaεiε are targeted to prevent or inhibit εkin cancerε, or to prevent their εpread to other tissueε. The ras oncogeneε are guanine-binding proteinε that have been implicated in cancer by, e.g., the fact that activated ras oncogenes have been found in about 30% of human tumors generally; this figure approached 100% in carcinomas of the exocrine pancreas (for a review, see Downward, Trends in Biol . Sci . , 1990, 15 , 469). Antiεense compounds targeted to H-ras and K-ras are described in U.S. Patent No. 5,582,972 to Lima et al . , 5,582,986 to Monia et al . and 5,661,134 to Cook et al . , and in published PCT application WO 94/08003. Protein Kinase C (PKC) proteinε have alεo been implicated in tumorigenesi . Antisense compounds targeted to Protein Kinase C (PKC) proteins are deεcribed in U.S. Patents Nos. 5,620,963 to Cook et al . and 5,681,747 to Boggs et al . Also of interest are AP-1 εubunits and JNK proteins, particularly in regard to their roles in tumorigenesis and metastasis. The process of metastaεiε involveε a εequence of events wherein (1 a cancer cell detaches from its extracellular matrices, (2) the detached cancer cell migrates to another portion of an animal's body, often via the circulatory syεtem, and (3 attaches to a distal and inappropriate extracellular matrix, thereby created a focus from which a secondary tumor can arise. Normal cells do not possess the ability to invade or metaεtaεize and/or undergo apoptosiε (programmed cell death) if such events occur (Ruoslahti, Sci . Amer. , 1996, 275 , 72). However, many human tumorε have elevated levelε of activity of one or more matrix metalloproteinases [MMPs) (Stetler- Stevenson et al . , Annu . Rev. Cell Biol . , 1993, 9, 541; Bernhard et al . , Proc . Natl . Acad . Sci . (U. S .A . ) , 1994, 91 , 4293. The MMPs are a family of enzymes which have the ability to degrade components of the extracellular matrix (Birkedal-Hansen, Current Op . Biol . , 1995, 7, 728). In particular, one member of thiε family, matrix metalloproteinase-9 (MMP-9), is often found to be expreεsed only in tumors and other diεeaεed tiεεueε (Himelstein et al . , Invasion & Metastasis , 1994, 14 , 246 . Several studieε have εhown that regulation of the MMP-9 gene may be controlled by the AP-1 transcription factor (Kerr et al . , Science, 1988, 242 , 1242; Kerr et al . , Cell , 1990, 61 , 267; Gum et al . , J. Biol . Chem . , 1996, 271, 10672; Hua et al . , Cancer Res . , 1996, 56 , 5279). Inhibition of AP-1 function has been shown to attenuate MMP-9 expresεion (U.S. patent application Serial No. 08/837,201). AP-1 iε a heterodimeric protein having two subunitε, the gene products of fos and jun . Antiεense compoundε targeted to c-fos and c-jun are described in co-pending U.S. patent application Serial No. 08/837,201, filed March 14, 1997, by Dean et al . Furthermore, AP-1 is itεelf activated in certain circumstances by phosphorylation of the Jun subunit at an amino-terminal position by Jun N-terminal kinaseε (JNKs) . Thuε, inhibition of one or more JNKε iε expected to reεult in decreaεed AP-1 activity and, conεequentially, reduced MMP expreεsion. Antisense compounds targeted to JNKs are described in co-pending U.S. patent application Serial No. 08/910,629, filed August 13, 1997, by Dean et al . Infectious Diseases of the Skin: Also of interest for topical formulations of oligonucleotideε are infectious diεeaεes of the skin. Such infections are caused by viral, bacterial or fungal agentε. In the case of Lyme disease, the tick borne causative agent thereof, the spirochete Borrelia burgdorferi , up-regulates the expression of ICAM-1, VCAM-1 and ELAM-1 on endothelial cells in vitro (Boggemeyer et al . , Cell Adhes . Comm. , 1994, 2, 145) . Furthermore, it has been propoεed that the mediation of the diεeaεe by the anti- inflammatory agent predniεolone iε due in part to mediation of thiε up-regulation of adhesion molecules (Hurtenbach et al . , Int . J. Immunopharmac . , 1996, 18 , 281) . Thuε, potential targetε for therapeutic mediation (or prevention) of Lyme diεeaεe include ICAM-1, VCAM-1 and ELAM-1 ( supra) . Other infectiouε diεeaεe of the skin which are tractable to treatment using the compoεitionε and methodε of the invention include disorders resulting from infection by bacterial, viral or fungal agentε ( The Merck Manual of Diagnosis and Therapy, 15th Ed., pp. 2263-2277, Berkow et al . , eds . , Rahay, N.J., 1987). With regards to infections of the skin cauεed by fungal agentε, U.S. Patent 5,691,461 provideε antiεenεe compounds for inhibiting the growth of Candida alhicans . With regards to infections of the skin caused by viral agentε, U.S. Patent 5,166,195, 5,523,389 and 5,591,600 provide oligonucleotide inhibitors of Human Immunodeficiency Virus (HIV). U.S. Patent 5,004,810 provides oligomers capable of hybridizing to herpeε εimplex virus Vmw65 mRNA and inhibiting its replication. U.S. Patent 5,194,428 and 5,580,767 provide antiεenεe compounds having antiviral activity againεt influenzavirus . U.S. Patent 4,806,463 provides antisense compounds and methodε uεing them to inhibit HTLV-III replication. U.S. Patentε 4,689,320, 5,442,049, 5,591,720 and 5,607,923 are directed to antiεense compounds as antiviral agents specific to cytomegalovirus (CMV) . U.S. Patent 5,242,906 provideε antiεense compoundε uεeful in the treatment of latent Epεtein-Barr viruε (EBV) infectionε. U.S. Patentε 5,248,670, 5,514,577 and 5,658,891 provide antiεenεe compoundε uεeful in the treatment of herpeεvirus infectionε. U.S. Patentε 5,457,189 and 5,681,944 provide antiεenεe compoundε useful in the treatment of papillomavirus infectionε. The antiεense compounds disclosed in these patents, which are herein incorporated by reference, may be used with the compositions of the invention to effect prophylactic, palliative or therapeutic relief from diseases caused cr exacerbated by the indicated pathogenic agents . Investigative Uses: Antiεense oligonucleotides employed in the compositions of the preεent invention may also be used to determine the nature, function and potential relationship of various genetic components of the body to diεeaεe or body states in animals. Heretofore, the function of a gene haε been chiefly examined by the construction of loεε-of-function mutationε in the gene (i.e., "knock-out" mutationε) in an animal (e.g., a tranεgenic mouεe) . Such taεkε are difficult, time-conεuming and cannot be accomplished for genes essential to animal development since the "knock-out" mutation would produce a lethal phenotype . Moreover, the loεε-of-function phenotype cannot be tranεiently introduced during a particular part of the animal ' ε life cycle or diεease state; the "knock-out" mutation iε always present. "Antisenεe knockouts," that is, the selective modulation of expreεεion of a gene by antiεenεe oligonucleotideε, rather than by direct genetic manipulation, overcomeε theεe limitations (εee, for example, Albert et al . , Trends in Pharmacological Sciences, 1994, 15, 250) . In addition, some genes produce a variety of mRNA transcriptε as a reεult of proceεses εuch aε alternative splicing; a "knock-out" mutation typically removes all for ε of mRNA tranεcriptε produced from εuch geneε and thuε cannot be uεed to examine the biological role of a particular mRNA tranεcript. Antiεenεe oligonucleotideε have been εystemically administered to rats in order to study the role of the N-methyl-D-aspartate receptor in neuronal death, to mice in order to investigate the biological role of protein kinase C-a, and to rats in order to examine the role of the neuropeptide Yl receptor in anxiety (Wahlestedt et al . , Nature, 1993, 363 :260 ; Dean et al . , Proc . Natl . Acad . Sci . U. S. A . , 1994, 91:11762; and Wahlestedt et al . , Science, 1993, 259:528, respectively). In instances where complex families of related proteins are being investigated, "antisense knockouts" (i.e., inhibition of a gene by systemic administration of antisenεe oligonucleotides) may represent the most accurate means for examining a specific member of the family (see, generally, Albert et al . , Trends Pharmacol . Sci . , 1994, 15:250). By providing compositions and methods for the simple non-parenteral delivery of oligonucleotideε and other nucleic acidε, the preεent invention overcomeε theεe and other shortcomings. V. Treatment Regimens The administration of therapeutic or pharmaceutical compoεitionε comprising the lipoεomes of the invention is believed to be within the skill of those in the art. In general, a patient in need of therapy or prophylaxis is adminiεtered a compoεition comprising a liposomally formulated bioactive agentε in accordance with the invention, commonly in a pharmaceutically acceptable carrier, in doεes ranging from 0.01 ug to 100 g per kg of body weight depending on the age of the patient and the severity of the disorder or disease state being treated. Dosing iε dependent on εeverity and responsiveness of the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution or prevention of the disease εtate iε achieved. Optimal dosing εcheduleε can be calculated from meaεurements of drug accumulation in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages may vary depending on the relative potency of individual antisenεe compounds, and can generally be estimated based on EC 50 ε found to be effective in in vi tro and in vivo animal models. In the context of the invention, the term "treatment regimen" is meant to encompass therapeutic, palliative and prophylactic modalitieε of adminiεtration of one or more lipoεomal compoεitions of the invention. A particular treatment regimen may last for a period of time which will vary depending upon the nature of the particular disease or disorder, its εeverity and the overall condition of the patient, and may extend from once daily to once every 20 yearε . Following treatment, the patient iε monitored for changeε in hiε/her condition and for alleviation of the εymptomε of the diεorder or disease state. The dosage of the lipoεomal compoεition may either be increaεed in the event the patient does not respond significantly to current dosage levels, or the dose may be decreased if an alleviation of the symptomε of the diεorder or diεease state is observed, or if the disorder or diεeaεe εtate has been ablated. An optimal dosing εchedule iε used to deliver a therapeutically effective amount of the bioactive agent encapsulated within the liposomes of the invention being administered via a particular mode of administration. The term "therapeutically effective amount, '' for the purpoεes of the invention, refers to the amount of oligonucleotide- containing pharmaceutical compoεition which iε effective to achieve an intended purpoεe without undesirable εide effectε (such as toxicity, irritation or allergic responεe) . Although individual needε may vary, determination of optimal rangeε for effective amountε of pharmaceutical compoεitionε is within the skill of the art. Human doseε can be extrapolated from animal εtudieε (Katocε et al . , Chapter 27 In : Remington ' s Pharmaceutical Sciences , 18th Ed., Gennaro, ed., Mack Publiεhing Co., Eaεton, PA, 1990). Generally, the dosage required to provide an effective amount of a pharmaceutical composition, which can be adjusted by one εkilled in the art, will vary depending on the age, health, physical condition, weight, type and extent of the disease or disorder of the recipient, frequency of treatment, the nature of concurrent therapy (if any) and the nature and scope of the deεired effect(s) (Nieε et al . , Chapter 3 In : Goodman & Gilman ' s The Pharmacological Basis of Therapeutics , 9th Ed., Hardman et al . , edε . , McGraw-Hill, New York, NY, 1996) . Following εucceεεful treatment, it may be deεirable to have the patient undergo maintenance therapy to prevent the recurrence of the diεeaεe state, wherein the bioactive agent is administered in maintenance doses, ranging from 0.01 ug to 100 g per kg of body weight, once or more daily, to once every 20 years. For example, in the case of in individual known or suspected of being prone to an autoimmune or inflammatory condition, prophylactic effects may be achieved by administration of preventative doses, ranging from 0.01 ug to 100 g per kg of body weight, once or more daily, to once every 20 years. In like fashion, an individual may be made leεε suεceptible to an inflammatory condition that is expected to occur as a reεult of εome medical treatment, e.g., graft versus host diseaεe resulting from the transplantation of cells, tisεue or an organ into the individual . Prophylactic modalities for high risk individuals are alεo encompaεsed by the invention. As used herein, the term "high risk individual" iε meant to refer to an individual for whom it haε been determined, via, e.g., individual or family hiεtory or genetic testing, that there is a significantly higher than normal probability of being susceptible to the onset or recurrence of a diεease or disorder. For example, a εubject animal could have a personal and/or family medical history that includes frequent occurrences of a particular disease or disorder. Aε another example, a εubject animal could have had such a suεceptibility determined by genetic εcreening according to techniques known in the art (see, e.g., U.S. Congreεs, Office of Technology Asεeεsment, Chapter 5 In : Genetic Moni toring and Screening in the Workplace, OTA-BA-455, U.S. Government Printing Office, Washington, D.C., 1990, pages 75-99) . As part of a treatment regimen for a high risk individual, the individual can be prophylactically treated to prevent the onset or recurrence of the diseaεe or disorder. The term "prophylactically effective amount" is meant to refer to an amount of a pharmaceutical compoεition which produces an effect observed aε the prevention of the onset or recurrence of a disease or disorder. Prophylactically effective amounts of a pharmaceutical composition are typically determined by the effect they have compared to the effect observed when a second pharmaceutical composition lacking the active agent iε administered to a similarly situated individual. From in vivo animal studies wherein oligonucleotides have been administered topically or mtradermally it has been shown that oligonucleotides become widely distrubuted from the site of administration For example oligonucleotide ISIS- 2302 was topicalK applied on the back of mini pigs and rats Samples of dermal and epidermal tissue analyzed by capillary gel electrophoresis and lmmunohistochemical staining detected significant levels of the oligonucleotide not only at the administration site (back) but also on stomach, neck and hmd leg Accordingly there is provided a method for delivering an oligonucleotide to a first dermal or epidermal tissue site m an animal compnsing applying said oligonucleotide to a second dermal or epidermal tissue site m said animal wherein said first site is removed from said second site In preferred embodiments, the oligonucleotide is administered topically in a pharmaceutical composition of the invention, in particular in an emulsion as described herein The method is particularly useful for ensunng delivery of oligonucleotide evenly to dermal or epidermal tissue and/or over a great area or to sites that would otherwise be difficult to apply or would be sensitive to direct administration EXAMPLES The following examples illustrate the invention and are not intended to limit the same. Thoεe skilled in the art will recognize, or be able to ascertain through routine experimentation, numerous equivalents to the specific εuDstances and procedures described herein. Such equivalents are conεidered to be within the εcope of the present invention. Example 1: Oligonucleotides A. General Synthetic Techniques: Oligonucleotideε were syntheεized on an automated DNA synthesizer using standard phosphoramidite chemistry with oxidation using iodine. Beta-cyanoethyldiisopropyl phoεphoramidites were purchased from Applied Biosyεtemε (Foster City, CA) . For phosphorothioate oligonucleotideε, the εtandard oxidation bottle was replaced by a 0.2 M solution cf 3H-1,2- benzodithiole-3-one-l, 1-dioxide in acetonitrile for the εtepwise thiation of the phosphite linkages . B. Oligonucleotide Purification: After cleavage from the controlled pore glass (CPG) column (Applied Biosystems) and deblocking in concentrated ammonium hydroxide, at 55°C for 18 hours, the oligonucleotideε were purified by precipitation 2x from 0.5 M NaCl with 2.5 volumeε of ethanol followed by further purification by reverse phase high liquid presεure chromatography (HPLC) . Analytical gel electrophoreεiε waε accomplished in 20% acrylarnide, 8 M urea and 45 mM Tris-borate buffer (pH 7) . C. Oligonucleotide Labeling: In order to follow the distribution of oligonucleotides in si tu were radiolabelled to high εpecific activity by εynthetic incorporation of 35 S uεing hydrogen phoεphonate chemistry essentially as described by Stein et al . ' Anal . Biochem . , 1990, 188 , 11) . D. Oligonucleotide Structure: The oligonucleotides used in the studies described herein have the following structures and biological activities. ISIS 2302 iε a 2 ' -deoxyoligonucleotide having a phoεphorothioate backbone and the εequence 5 ' -GCC-CAA-GCT- GGC-ATC-CGT-CA-3' (SEQ ID N0:1). ISIS 2302 iε targeted to the 3 ' -untranslated region (3'-UTR) of the human ICAM-1 gene. ISIS 2302 is deεcribed in U.S. Patentε 5,514,788 and 5,591,623, hereby incorporated by reference. ISIS 1939 is a 2 ' -deoxyoligonucleotide having a phosphorothioate backbone and the sequence 5 ' -CCC-CCA-CCA- CTT-CCC-CTC-TC-3' (SEQ ID NO:2). ISIS 1939 is targeted to the 3 ' -untranslated region (3'-UTR) of the human ICAM-1 gene. ISIS 1939 is described in U.S. Patents 5,514,788 and 5,591,623, hereby incorporated by reference. ISIS 15839 is a phosphorothioate isosequence "hemimer" derivative of ISIS 2302 having the structure 5'- GCC-CAA-GCT-GGC-ATC-CGT-CA-3' (SEQ ID NO:l), wherein emboldened "C" reεidues have 5-methylcytcsine (m5c) bases and wherein the emboldened, double-underlined residues further comprise a 2 ' -methoxyethoxy modification (other residues are 2 ' -deoxy) . ISIS 15839 is deεcribed in co- pending U.S. Patent application Serial No. 09/062,416, filed April 17, 1998, hereby incorporated by reference. ISIS 3082 iε a 2 ' -deoxyoligonucleotide having a phoεphorothioate backbone and the sequence 5 ' -TGC-ATC-CCC- CAG-GCC-ACC-AT-3 ' (SEQ ID NO : 3 ) . ISIS 3G82 iε targeted to the 3 ' -untranεlated region (3 ' -UTR) of the murine ICAM-1 gene. ISIS 3082 is described in Stepkowεki et al . [J. Immunol., 1994, 153 , 5336). ISIS 2503 iε a 2 ' -deoxyoligonucleotide having a phoεphorothioate backbone and the εequence 5 ' -TCC-GTC-ATC- GCT-CCT-CAG-GG-3 ' (SEQ ID NO:4). ISIS 2503 is targeted to the translation initiation codon of the human oncogene, Haras. ISIS 2503 is described in U.S. Patent 5,576,208, hereby incorporated by reference. ISIS 1939 (SEQ ID NO: 2), a phosphorothioate oligonucleotide targeted to a sequence in the 3 -untranεlated region of ICAM-1 mRNA has been found to exhibit significant biological activity. ISIS 2302 (SEQ ID NO: 1), which hybridizes to the ICAM-1 mRNA at a position 143 bases 3' to the ISIS 1939 target εite waε alεo found to be of similar activity in biological assays. Examination of the predicted RNA secondary εtructure of the human ICAM-1 mRNA 3'- untranεlated region (Zuker, Science, 1989, 244 , 48) surprisingly suggested that both ISIS 1939 and ISIS 2302 hybridize to sequences predicted to be in a stable stem- loop εtructure of the mRNA. Current dogma εuggeεtε that when designing antisense oligonucleotides regions of RNA secondary εtructure εhould be avoided. Thus, ISIS 1939 and ISIS 2302 would not have been predicted to inhibit ICAM-1 expreεsion. ISIS 2302 has been found to inhibit ICAM-1 expreεsion in human umbilical vein cells, human lung carcinoma cells (A549) , human epidermal carcinoma cells (A431) , and human keratinocytes . ISIS 2302 has also demonstrated εpecificity for itε target ICAM-1 over other potential nucleic acid targets εuch aε HLA-α and HLA-β. Both ISIS 2302 (SEQ ID NO:l) and ISIS 1939 (SEQ ID NO:2) markedly reduced ICAM-1 expression, as detected by northern blot analyεiε to determine mRNA levelε, in C8161 human melanoma cells. In an experimental metastasis asεay, ISIS 2302 decreased the metastatic potential of C8161 cellε, and eliminated the enhanced metaεtatic ability of C8161 cells reεulting from TNF-α treatment. ISIS 2302 haε alεo εhown significant biological activity in animal models of inflammatory diseaεe. The data from animal testing has revealed strong anti-inflammatory effects of ISIS 2302 in a number of inflammatory diseases including Crohn's disease, rheumatoid arthritis, psoriaεis, ulcerative colitis, and kidney transplant rejection. When tested on humanε, ISIS 2302 haε εhown good εafety and activity againεt Crohn's disease. Further ISIS 2302 has demonεtrated a εtatiεtically significant steroid-sparing effect on treated subjects εuch that even after five monthε post-treatment subjects have remained weaned from steroids and in disease remission. This is a surpriεing and significant finding regarding ISIS 2302 's theraDeutic effects. Example 2 : Sources of Compounds In general, the compounds used in the studieε deεcribed herein are available from a variety of commercial εourceε, or can be synthesized from available reagents by those skilled in the- art using methods known in the art. For sake of convenience, some specific commercial suppliers of the more significant compounds uεed in, or identified by, the εtudieε deεcribed herein are provided in the following list. Choi (choleεterol) is purchased from Avanti Polar Lipids, Inc. ,Alabaster, AL) or from Sigma Chemical Corp. (St. Louis, MO) . l-Dodecyl-2-pyrrolidinone is purchased from Aldrich Chemical Co. (Milwaukee, WI) . DOPE (dioleoylphosphatidylethanolamine) iε purchased from Avanti. DMPC (dimyristoylphoεphatidylcholine) is purchased from Avanti or Sigma. DPPC (dipalmitoylphosphatidylcholine) iε purchased from Sigma, Avanti or Genzyme Corp. (Cambridge, MA) . DMPG (dimyristoylphosphatidylglycol) iε purchaεed from Avanti or Sigma. DMSO (dimethyl εulfoxide) is purchased from Sigma or Aldrich. IPM (iεopropyl myristate, a.k.a. myristic acid isopropyl eεter) iε purchaεed from Sigma or Aldrich. Menthone iε purchased from Aldrich. l-Methyl-2-pyrrolidinone is purchased from Sigma. Oleic acid is purchased from Sigma. PG (propylene glycol, a.k.a. 1, 2-propanediol) is purchased from Sigma or Aldrich. T een 40 [polyoxyethylene (2)εorbitan monopalmitate] is purchased from Sigma or Aldrich. Azone (dodecyl azone, a.k.a. laurocapram) is purchased from Shanghai Daniel Chem Technologies Co., Ltd., Shanghai, People's Republic of China. Limonene (d-limonene) is purchased from Sigma. MIGLY0L T1' 818 is purchased from Hhls AG, Marl, Germany . Example 3: In Vi tro Skin Testing Male and female hairleεs SKH1 rr.ice 6-8 weeks old were obtained from Charles River Laboratories (Wilmington, MA) and were euthanized using carbon dioxide asphyxiation. Fresh and frozen skinε were mounted on a vertical Franz diffuεion cell (Permegear, New Jersey) with each εkin having a diffusional area of 0.636 cm 2 . Receptor chambers having a volume of 5.1 ml were filled with isotonic phoεphate buffer (pH 7.2) containing 0.1% (v/v) of 36% aqueouε formaldehyde as preservative . Receptor temperatureε were maintained at 37 ± 0.5°C and stirred continuously at 600 rpm. The skins were allowed to hydrate for 1 hour prior to starting an experiment. Experiments generally were performed at 24 hours . Penetration enhancers/vehicles were added into the donor compartment for 1 hour and then washed off with 500 μl of methanol. The total amount of enhancer/vehicle that waε added to each donor compartment waε 10 μl (unleεε otherwiεe noted) . After methanol wash, the skin was lightly wiped and blown dry to remove any visible moisture. In an experiment studying the effect of methanol on penetration enhancement, no wash was performed. Also, in experiments studying the effectε of pretreatment time, the amount of time the enhancer was allowed to stay on the skin was varied (i.e., 30 minutes or 1, 2 or 3 hours) . Oligonucleotide [i.e., ISIS 2302 (SEQ ID NO:l)] was added on top of the enhancer solution. ISIS 2302 was added to each donor compartment as a 200 ..1 normal saline solution containing both 1 mg of unlabeled oligonucleotide and approximately 300,000 decays per minute ("DPM") of radiolabeled oligonucleotide. Epidermal, dermal and receptor penetration values are expressed aε the ratio of the countε penetrated verεus the control counts. The following chemicals were used as enhancers/vehicles: propylene glycol (PC , dimethyl εulfoxide (DMSO) , isopropyl myristate (IPM), Azone, MIGLYOL™ 818, oleic acid, d-limonene, limonene, l-dodecyl-2- pyrrolidinone (ldodecyl2pyrrol) , l-methyl-2-pyrrolidinone (lMethyl2pyrrol) , menthone, ethanol and T EEN 40. Statistical analyseε were performed on Excel using Students t-test (two- sample aεεuming equal varianceε) along with averageε, standard deviations, and standard errors. Female hairless mice were preferentially used as the studies progressed due to an uncharacterized but recurring follicular infection that appeared to preferentially target male mice. As shown in Figure 1, the beεt epidermal penetration enhancerε for the delivery of Iεiε 2302 are iεopropyl myriεtate ("IPM"; 1.67%, 2.14% and 3.11% , menthone (2.93%), ethylene glycol (2.41%), l-methyl-2-pyrroiidinone ("lMethyl2pyrrol" ; 2.41%), d-limonene (1.55%), MIGLYOL 818 ® (1.62%) and dimethyl εulfoxide (DMSO; 1.56%). In contraεt, for dermal penetration, the best penetration enhancerε are Tween 40 (1.42%), oleic acid (~1.0%), d-limonene (0.72%), 1- dodecyl-2-pyrrolidinone ( "ldodecyl2pyrrol" ; 0.67%), DMSO (0.38%) and 1-methyl-2-pyrrolidinone ( "lMethyl2pyrrol" ; 0.25%) . There iε no little or no correlation between epidermal penetration enhancement and dermal penetration enhancement, an effect which may be due to different mechanisms of action of delivery to the two layers, rates of penetration, the duration of the experiments, the duration of enhancer pretreatments, or a combination of εuch f ctorε . "Receptor penetration" in the tables referε to the percentage dose that migrates through the isolated skin and thuε deposits in a receptacle at the end of the experimental set-up. A high value in this column indicates the formulation has potential as a systemic delivery vehicle. Experiments with Azone were carried out to examine how much of a factor methanol is in the delivery of Isis 2302; theεe reεults are alεo shown in Figure 1. Azone pretreatment with a methanol wash resulted in epidermal and dermal penetration values of 1.31% and 0.16%, respectively, whereas the values for experiments without methanol values were 0.72% and 0.13% for epidermal and dermal penetration, respectively. Ethanol had little effect on the penetration of ISIS 2302 when limonene was uεed as an enhancer. Higher volumes of limonene and isopropyl myriεtate did not result in an increase in the penetration. Example 4: Cream Formulations and Effects of Oligonucleotide Chemistries Studies were carried out to optimize the formulation containing isopropyl myristate, and the results are shown in Figure 2. Duration of pretreatment ranging from 30 minutes to 3 hours had little effect on the penetration of ISIS 2302. Lower concentration of isopropyl myristate in the range of 10 to 35% v/v in water reduced the penetration significantly; however, the coarse mixture of isopropyl myristate and water applied in very small quantities (10-30 μL) may have resulted in spotty coverage of the skin. Lower amounts of ISIS 2302 resulted in an increase in the percent of applied dose penetrated. In order to formulate a cream from isopropyl myristate, its viscosity was increaεed uεing oil soluble agents and surfactants such as glyceryl monosterate, stearic acid and bees wax. Oligonucleotide was diεεolved in a water phaεe consisting of aqueous εurfactantε and viεcoεity imparting agentε such as polyoxyl-40 stearate and polyethylene glycol derivatives. Cream formulations consisting of Water (36-45% w/w) , Isopropyl Myristate (30-48% w/w) , Glyceryl monostearate [10-16% w/w) , Polyoxyl-40 Stearate (0-15% w/w) and antimicrobial preservativeε (benzyl alcohol, methylparaben, propylparaben) were studied in vi tro for penetration. Oligonucleotide was thoroughly mixed with the cream formulations to give a final concentration of 1 mg oligonucleotide for each 149 mg cream. Appropriate controls were uεed to determine the radioactivity per mg of cream. The cream formulation with 30% iεopropyl myriεtate resulted in an epidermal penetration of 1.66% and a dermal penetration of 1.57% for ISIS 2302 (Figure 2) . Similar penetration values were seen with cream formulation containing 48% isopropyl myriεtate. A cream formulation of ISIS 15839, a 5-methylcytosine- compriεing 2 ' -methoxyethoxy iεosequence hemimer derivative of ISIS 2302, with 30% isopropyl myristate showed a very high dermal penetration, i.e., 11% of the applied dose. The results presented in Figure 2 thus demonstrate that oligonucleotideε of different chemical compoεitionε penetrate the εkin when formulated in iεopropyl myristate cream formulations. Example 5: In Vivo Testing of ICAM-1 Suppression The oligonucleotide ISIS 3082 (SEQ ID NO:3), which is targeted to the murine ICAM-1 gene, waε mixed with empty ("f") lipoεomes or encapsulated into ("e") lipoεomes as set forth below to determine the degree of ICAM-1 suppression effected thereby: 1. DOPE-f Liposomeε (DOPE :DPPC : Choi; 20:60:20 %w/w) mixed with ISIS 3082 to obtain 10 mg/mL ISIS 3082; 2. ISIS 3082 εolution at 10 mg/mL; 3. DOPE-f Liposomes (DOPE :DPPC: Choi; 20:60:20 %w/w) mixed with ISIS 3082 to obtain 10 mg/mL ISIS 3082; 4. DOPE-e Lipoεomeε (DOPE :DPPC: Choi; 20:60:20 %w/w) with ISIS 3082 encapεulated in the liposomes, not purified, to obtain 10 mg/mL ISIS 3082; 5. DMPG-f Liposomes (DMPG:DPPC :Chθl; 20:60:20 %w/w) mixed with ISIS 3082 to obtain 10 mg/mL ISIS 3082; 6. DMPG-e Liposomes (DMPG:DPPC :Chθl ; 20:60:20 %w/w) with ISIS 3082 encapsulated in the liposomeε, not purified, to obtain 10 mg/mL ISIS 3082; 7. DMPC-f Lipoεomeε (DMPC:DPPC :Choi; 20:60:20 %w/w) mixed with ISIS 3082 to obtain 10 mg/mL ISIS 3082; 8. DMPC-e Lipoεomeε (DMPC :DPPC :Chcl ; 20:60:20 %w/w) with ISIS 3082 encapεulated in the DMPC lipoεomes, not purified, to obtain 10 mg/mL ISIS 3082; 12. No treatment, phorbol myristate acetate ("PMA") positive control; and 13. No treatment, no PMA control ("basal"). Liposome Preparation: The liposomes were prepared by hydrating a dry film of lipids in a glaεε container with either phoεphate buffered saline at pH 7.4 or a 10 mg/mL solution of ISIS 3082 in PBS. The hydrated lipids were then extruded 21 times through a 50 nm membrane to form small liposomeε with final lipid concentration of ~ 100 mg/mL, drug concentration of ~10 mg/mL and particle size of ~100 nm. Animal Studies: Liposome formulations were applied to the back of hairless mice using a Hilltop" " chamber (Hilltop Research, Cincinnati, OH) that keeps the formulation in place. Three mice were tested in each group. Forty-eight hours after the formulation application, the treated part of the skin waε challenged with PMA to induce ICAM-1. Mice were εacrificed 4 hours after PMA application and skin collected for Northern analyses of the mRNA levels, which were performed esεentially according to the protocol detailed in Exampleε 3 and 7 of co- pending U.S. Patent application Serial No. 09/062,416, filed April 17, 1998, hereby incorporated by reference. The results with ISIS 3082 mixed with empty lipoεomeε are aε follows: The DOPE and DMPG liposomeε εhow about 30% to about 40% reduction in PMA-induced ICAM-1 expression, whereas the phoεphate buffered εaline solution formulation and DPPC liposomeε εhow much lower reduction. The reεultε prove that ISIS 3082 penetrates the skin when mixed with liposomeε and that the penetration of drug thuε achieved iε εufficient to cause a biological effect. The results with ISIS 3082 encapsulated in the liposomes are as follows: DMPG-e 58.54 + 12.40 The liposome formulations comprising DOPE, DPPC or DMPG and encapsulating ISIS 3082 all εhow a 30-50% reduction in ICAM-1 mRNA, showing that ISIS 3082 penetrates the εkin when encapεulated in lipoεomeε and that the penetration of drug thuε achieved iε εufficient to cauεe a biological effect. Example 6: Comparison of Topical and Systemic Administration of Oligonucleotides In order to develop a formulation for the local delivery of oligonucleotideε via topical adminiεtration, the following experiments were carried out. Formulations: A cream formulation of 2% ISIS 2503 (SEQ ID N0:4), intended for topical application, was compared to 20 mg/mL formulations in saline administered via intravenous, subcutaneouε or intradermal meanε . The cream formulation waε prepared by heating the oil phaεe [containing isopropyl myristate (30% w/w) and glyceryl monostearate 10% w/w) ] and the aqueous phase [containing water (45% w/w) and polyoxyl-40-stearate (15% w/w)] to 70°C followed by homogenization at 7,000 rpm using a Siiverεon L4RT mixer (Silverεon Machineε, East Long Meadows, MA , after which the mixture was allowed to cool to room temperature. The particle size of the oil phase droplet in the cream had a mean diameter of 1.0 urn. ISIS 2503 was mixed with the cream by trituration. Animal Studies: SCID mice (Taconic Farms, Inc., Germantown, NY ~6 weeks old, were transplanted with human skin and allowed to establish the xenograft for 6 weeks. 200 mg cream or 20 mg/kg solution were administered at 48, 24 and 4 hours prior to TNF-a administration. TNF-D was injected in to the xenograft to induce inflammation. Mice were sacrificed and εkin iεolated for immunohiεtochemiεtry. Stained tiεsue samples show a pronounced accumulation of the oligonucleotideε in the nuclei of the cellε in the viable epidermiε upon treatment with the cream formulations. Accumulation is also seen in the dermis but no nuclear accumulation is visible. The cream formulation thus provides for the selective delivery of oligonucleotides to cells of the dermis . In contrast, photomicrographs of skin treated intravenously with the solution formulation show accumulation of oligonucleotide in the dermis but no nuclear accumulation is visible. There waε no accumulation in the epidermis. Similarly, photomicrographs of skin treated intradermally with the solution formulation show a large amount of oligonucleotide in the proximity of the needle tract in the dermis and some in the epidermis. Again, however, there is no nuclear accumulation. Taken together, the preceding reεultε εhow that oligonucleotide delivered to the dermiε by systemic or direct injection route does not accumulate in the cells of viable epidermis whereas topical delivery with the cream formulation can target the viable epidermis. The cream formulation can thus be used to prepare pharmaceutical and other formulationε compriεing any of a variety of oligonucleotideε, including but not limited to thoεe deεcribed herein, intended for dermal delivery. The invention thuε provideε methodε for preventing or treating a variety of dermal diεeaεe and diεorderε, such methods comprising contacting the skin of an animal with a pharmaceutical composition comprising an oligonucleotide according to the present discloεure. Example 7 : IPM cream formulations An oil phaεe waε prepared by diεsolving methylparaben (3mg) , propylparaben (4.8mg), phenoxyethanol (lOmg) and glycerol monostearate (lOOmg) in heated iεopropyl myriεtate IPM (lOOmg) . The aqueouε phase was prepared by dissolving monobasic sodium phoεphate monohydrate (3mg) and dibasic sodium phosphate heptahydrate (9 mg) in a target weight of water for a lg total formulation. The pH of the aqueous εolution waε adjusted to 7 ± 0.2 with IN monobasic sodium phosphate and IN sodium hydroxide. The solution was heated and methylparaben (2mg) , propylparaben (0.2mg), phenoxyethanol (15mg) and polyoxyl 40 stearate (150mg) were then added followed by hydroxypropyl methylcellulose (5mg) and oligonucleotide ISIS- 2302 (O.lmg, lmg, 5mg and 20mg) . The oil phase waε then added to the water phaεe while homogenizing to form the emulsion which was then cooled to room temperature. Those skilled in the art will appreciate that numerous changes and modifications may be made to the preferred embodiments of the invention and that such changes and modifications may be made without departing from the spirit of the invention. It is therefore intended that the appended claims cover all such equivalent variations as fall within the true spirit and scope of the invention. It is intended that each of the patents, applications, printed publications, and other published documents mentioned or referred to in this εpecification be herein incorporated by reference in their entirety.

Claims: What is claimed is: 1. A pharmaceutical composition comprising an oligonucleotide admixed with a topical delivery agent. 2. The pharmaceutical compoεition of claim 1 wherein εaid topical delivery agent, when present at an effective concentration, iε effective to deliver εaia oligonucleotide to epidermal tiεsue in an animal. 3. The pharmaceutical compoεition of claim 1 wherein εaid topical delivery agent, when present at an effective concentration, is effective to deliver said oligonucleotide to dermal tisεue in an animal. 4. The pharmaceutical compoεition of claim 1 wherein said topical delivery agent is a plurality of microscopic veεicleε. 5. The pharmaceutical compoεition of claim 4 wherein εaid microscopic vesicleε are liposomes. 6. The pharmaceutical composition of claim 4 wherein the major proportion of said oligonucleotide in said pharmaceutical composition is encapεulated within εaid microscopic vesicleε. 7. The pharmaceutical composition of claim 4 wherein the major proportion of said oligonucleotide in εaid pharmaceutical composition is not encapsulated within said microscopic vesicleε. 8. The pharmaceutical composition of claim 5 wherein said liposomes are selected from the group consisting of neutral liposomeε, anionic liposomes and anionic fusogenic liposomeε . 9. The pharmaceutical composition of claim 4 wherein said microscopic vesicles comprise dimyristoyi phosphatidylcholine . 10. The pharmaceutical composition of claim 4 wherein εaid microεcopic veεicles comprise dipalmitoyl phosphatidylcholine . 11. The pharmaceutical composition of claim 4 wherein said microscopic veεicleε compriεe dimyriεtoyl phoεphatidylglycerol . 12. The pharmaceutical compoεition of claim 4 wherein said microεcopic veεicles comprise dioleoyl phosphatidylethanolamine . 13. The pharmaceutical composition of claim 4 wherein said microscopic vesicleε compriεe phospholipid, phosphatidylcholine and cholesterol. 14. The pharmaceutical composition of claim 13 wherein said phospholipid, said phosphatidylcholine and εaid choleεterol are present in about a 20:60:20 mol% ratio. 15. The pharmaceutical composition of claim 4 wherein said microscopic vesicleε compriεe phoεphatidylcholine . 16. The pharmaceutical composition of claim 15 wherein said phosphatidylcholine iε derived from soybeans or eggs . 17. The pharmaceutical composition of claim 4 wherein said microscopic veεicles compriεe non-ionic εurfactant and cholesterol. 18. The pharmaceutical compoεition of claim 4 wherein said microscopic vesicleε comprise a εurfactant. 19. The pharmaceutical compoεition of claim 4 wherein εaid microεcopic vesicles are formulated to effect dermal delivery of said oligonucleotide in an animal. 20. The pharmaceutical composition of claim 4 wherein said microscopic vesicles are formulated to effect epidermal delivery of εaid oligonucleotide in an animal. 21. The pharmaceutical compoεition of claim 1 wherein said oligonucleotide is an antisenεe compound. 22. The pharmaceutical compoεition of claim 21 wherein εaid antiεenεe compound iε a ribozyme, an external guide εequence, an antiεense oligonucleotide or an antisense peptide nucleic acid. 23. The pharmaceutical composition of claim 1 wherein εaid oligonucleotide is an aptamer or a molecular decoy . 24. The pharmaceutical composition of claim 1 wherein at leaεt one of εaid covalent linkages of εaid oligonucleotide is a modified covalent linkage. 25. The pharmaceutical composition of claim 24 wherein said modified covalent linkage is selected from the group consiεting of a phoεphorothioate linkage, a phoεphotrieεter linkage, a methyl phosphonate linkage, a methylene (methylimino) linkage, a morpholino linkage, an amide linkage, a polyamide linkage, a short chain alkyl intersugar linkage, a cycloalkyl intersugar linkage, a short chain heteroatomic intersugar linkage and a heterocyclic intersugar linkage . 26. The pharmaceutical compoεition of claim 1 wherein at leaεt one of the nucleotides of said oligonucleotide has a modified εugar moiety. 27. The pharmaceutical compoεition of claim 26 wherein εaid modified εugar moiety has a substitution or addition at the 2' poεition of a moiety εelected from the group conεiεting of -OH, -SH, -SCH 3 , -F, -OCN, -0CH 3 OCH 3 , - OCH 3 0(CH 2 ) n OL, -0(CH 2 ) n NH 2 or -0(CH 2 ) n CH 3 where n iε from 1 to about 10, a C-_ to C 10 lower alkyl group, an alkoxyalkoxy group, a εubεtituted lower alkyl group, a εubεtituted alkaryl group, a substituted aralkyl group, -Cl, -Br, -CN, -CF 3 , -OCF 3 , an -0- alkyl group, an -S-alkyl group, an N-alkyl group, an 0-alkenyl group, an S-alkenyl group, an N-alkenyl group, -SOCH,, -S0 2 CH 3 , -0N0 2 , -N0 2 , -N 3 , -NH 2 , a heterocycloalkyl group, a heterocycloalkaryl group, an aminoalkylamino group, a polyalkylamino group, a subεtituted εilyl group, an RNA cleaving group, a reporter group, a DNA intercalating group, a group for improving the pharmacokinetic properties of an oligonucleotide, a group for improving the pharmacodynamic propertieε of an oligonucleotide, a methoxyethoxy group and a methoxy group . 28. The pharmaceutical compoεition of claim 1 wherein at least one of the nucleotides of said oligonucleotide has a modified nucleobase. 29. The pharmaceutical composition of claim 1 wherein εaid oligonucleotide iε a chimeric oligonucleotide. 30. The pharmaceutical compoεition of claim 30 wherein εaid chimeric oligonucleotide iε a hemimer . 31. The pharmaceutical composition of claim 1 wherein said oligonucleotide modulates expression of a cellular adhesion protein or modulates a rate of cellular proliferation. 32. A pharmaceutical composition comprising an oligonucleotide admixed with a topical penetration enhancer. 33. The pharmaceutical composition of claim 32 wherein said topical penetration enhancer is a fatty acid. 34. The pharmaceutical composition of claim 33 wherein said fatty acid iε εelected from a group consisting of arachidonic acid, oleic acid, lauric acid, caprylic acid, capric acid, myristic acid, palmitic acid, εtearic acid, linoleic acid, linolenic acid, dicaprate, tricaprate, monoolein, dilaurin, glyceryl 1-monocaprate, 1- dodecylazacycloheptan-2-one, an acylcarnitine, an acylcholine, or a C 1 . 10 alkyl ester, monoglyceride, diglyceride or pharmaceutically acceptable εalt thereof. 35. The pharmaceutical composition of claim 34 wherein said fatty acid iε isopropyl myristate. 36. The pharmaceutical composition of claim 32 wherein said topical penetration enhancer is a bile salt. 37. The pharmaceutical compoεition of claim 36 wherein said bile salt is selected from a group conεiεting of cholic acid, dehydrocholic acid, deoxychoiic acid, glucholic acid, glycholic acid, glycodeoxycholic acid, taurocholic acid, taurodeoxycholic acid, chenodeoxycholic acid, ursodeoxycholic acid, εodium tauro-24, 25-dihydro-fuεidate, sodium glycodihydrofusidate, polyoxyethylene-9-lauryl ether or a pharmaceutically acceptable εalt thereof. 38. The pharmaceutical compoεition of claim 32 wherein εaid topical penetration enhancer iε a chelating agent. 39. The pharmaceutical composition of claim 38 wherein said chelating agent is selected from a group consisting of EDTA, citric acid, a salicyciate, a jW-acyl derivative of collagen, laureth-9, an N-amino acyl derivative of a beta-diketone or a mixture thereof. 40. The pharmaceutical composition of claim 32 wherein εaid topical penetration enhancer is a surfactant. 41. The pharmaceutical composition of claim 40 wherein said surfactant is εelected from a group consisting of sodium lauryl sulfate, polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether, a perfluorchemical emulsion or a mixture thereof . 42. The pharmaceutical compoεition of claim 32 wherein εaid topical penetration enhancer iε εelected from a group conεiεting of unεaturated cyclic ureaε, 1-alkyl- aikanoneε, 1-alkenylazacyclo-alakanones, steroidal anti- inflammatory agents and mixtures thereof. 43. The pharmaceutical composition of claim 32 wherein said topical penetration enhancer is a glycol, a pyrrol, an azone, or a terpenes . 44. A method of modulating the expression of a gene in an animal comprising administering to εaid animal the pharmaceutical composition of claim 32. 45. The pharmaceutical composition of claim 32 wherein said oligonucleotide and said topical penetration enhancer form an emulsion. 46. The pharmaceutical composition of claim 45 wherein said emulsion is a cream. 47. The pharmaceutical compoεition of claim 46 wherein εaid topical penetration enhancer is isopropyl myristate . 48. The pharmaceutical compoεition of claim 46 wherein said isopropyl myristate is present in an amount from about 1% to 50% by weight. 49. The pharmaceutical composition of claim 47 wherein εaid iεopropyl myristate iε preεent in an amount from about 5% to 20% by weight. 50. The pharmaceutical compoεition of claim 47 further comprising methylparaben. 51. The pharmaceutical composition of claim 47 further comprising propylparaben. 52. The pharmaceutical composition of claim 47 further comprising phenoxyethanol. 53. The pharmaceutical composition of claim 47 further comprising a preservative combination comprising methylparaben, propylparaben and phenoxyethanol in an amount from about 0.5% to 10% by weight. 54. The pharmaceutical composition of claim 53 wherein said preservative combination is present in an amount from about 1% to 5% by weight. 55. The pharmaceutical composition of claim 47 wherein the oil phase emulsifier is glycerol monostearate and the water phase emulsifier iε polyoxyl 40 stearate. 56. The pharmaceutical composition of claim 47 further comprising a viscosity increasing agent. 57. The pharmaceutical composition of claim 56 wherein said viscosity increasing agent is hydroxypropyl methylcellulose . 58. The pharmaceutical composition of claim 47 wherein the pH of εaid composition is about 7. 59. The pharmaceutical composition of claim 47 wherein said oligonucleotide iε complementary to a portion of an mRNA εequence coding for an ICAM. 60. The pharmaceutical compoεition of claim 59 wherein said oligonucleotide is ISIS-2302. 61. The pharmaceutical composition of claim 60 wherein said oligonucleotide iε ISIS-15839. 62. The pharmaceutical compoεition of claim 47 wherein εaid oligonucleotide is complementary to a portion of an mRNA sequence coding for tumor necroεis factor. 63. The pharmaceutical composition of claim 62 wherein said oligonucleotide is ISIS-104838. 63. A method for delivering an oligonucleotide to dermal or epidermal tissue in an animal comprising applying to said epidermal tissue a pharmaceutical composition according to claim 1. 64. A method for delivering an oligonucleotide to dermal or epidermal tissue in an animal comprising applying to said epidermal tissue a pharmaceutical composition according to claim 47. 65. A method of treating psoriasis comprising administering to dermal or epidermal tissue in an animal in need of treatment therefor a pharmaceutical composition according to claim 60. 66. A method for delivering an oligonucleotide to a first dermal or epidermal tissue site in an animal comprising applying said oligonucleotide to a second dermal or epidermal tissue site in said animal wherein said first site iε removed from εaid second site. 67. The method of claim 66 wherein said oligonucleotide is in a pharmaceutical composition according to claim 1. 68. The method of claim 66 wherein said oligonucleotide is in a pharmaceutical composition according to claim 47. 69. The method of claim 66 wherein said oligonucleotide is applied topically to epidermal tisεue of said εecond site.

Inventors: COOK PHILLIP D, ECKER DAVID J, HARDEE GREGORY E, MEHTA RAHUL, TEMPLIN MICHAEL V, TSAI YALI JENNIFER, COOK, PHILLIP, D., ECKER, DAVID, J., HARDEE, GREGORY, E., MEHTA, RAHUL, TEMPLIN, MICHAEL, V., TSAI, YALI, JENNIFER
Applicants: COOK PHILLIP D, ECKER DAVID J, HARDEE GREGORY E, ISIS PHARMACEUTICALS INC, MEHTA RAHUL, TEMPLIN MICHAEL V, TSAI YALI JENNIFER, COOK, PHILLIP, D., ECKER, DAVID, J., HARDEE, GREGORY, E., ISIS PHARMACEUTICALS, INC., MEHTA, RAHUL, TEMPLIN, MICHAEL, V., TSAI, YALI, JENNIFER
Application year: 1999
Main classification: C12Q1
IPC codes: A61K9, A61K31, A61K47, A61K48, C07H21, C12N15, C12Q1