WO2020247851A1 - Transdermal vaccine delivery - Google Patents

Abstract

Petrolatum-based topical transdermal vaccine compositions and methods of vaccination and treatment using the same. The petrolatum-based compositions may include petrolatum, a liquid comprising at least one antigen, wherein the liquid is suspended in the petrolatum.

Description

TRANSDERMAL VACCINE DELIVERY

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001 ] This application claims the benefit of priority to U.S . Provisional Application Ser. No. 62/857,752, filed June 5, 2019, and U.S. Provisional Application Ser. No. 62/861,947, filed June 14, 2019, the entire contents of which are hereby incorporated by reference, for all purposes, in their entirety.

FIELD

[0002] The present disclosure is broadly concerned with topical therapeutic delivery systems and topical vaccine compositions and methods of treatment or vaccination using such compositions. The disclosure is also concerned with monovalent or polyvalent petrolatum-based topical transdermal vaccine delivery compositions comprising live attenuated vaccine (LAV), inactivated (killed antigen), subunit (purified antigen), and/or toxoid (inactivated toxins), as well as methods of treatment or vaccination using such compositions.

BRIEF DESCRIPTION OF THE FIGURES

[0003] The application file contains at least one photograph executed in color. Copies of this patent application publication with color photographs will be provided by the Office upon request and payment of the necessary fee.

[0004] FIG. 1 depicts an electron microscope micrograph showing the structure of typical skin, according to an exemplary embodiment of the present disclosure.

[0005] FIG. 2 is a diagrammatic view depicting penetration of the presently disclosed petrolatum-based topical transdermal vaccine delivery compositions through the skin to deliver antigens ( e.g ., vaccine) to blood vessels and tissues below the skin, according to an exemplary embodiment of the present disclosure.

DETAILED DESCRIPTION

[0006] Various embodiments of the disclosure are discussed in detail below. While specific implementations are discussed, it should be understood that this is done for illustration purposes only. A person skilled in the relevant art will recognize that other components and configurations may be used without parting from the spirit and scope of the disclosure. [0007] The present disclosure provides petrolatum-based transdermal vaccine delivery systems and topical vaccine compositions and methods of treatment or vaccination using such compositions. It has been unexpectedly discovered that the presently disclosed petrolatum-based transdermal vaccine delivery compositions are capable of penetrating the skin of a subject to deliver a pharmaceutically effective amount of an antigen or vaccine to the tissues and blood vessels below the skin. FIG. 1 depicts an electron micrograph of skin comprising corneocytes interspaced by intercellular lipid bilayers. As shown in FIG. 2, water-based topical formulations cannot penetrate the corneocytes nor pass through the intercellular lipids interspersed between the corneocytes. However, the presently disclosed petrolatum-based compositions are capable of delivering one or more antigens through the intercellular lipid channels to penetrate the epidermal layer and enable deep delivery of vaccines and/or antigens to the tissues and blood vessels below the skin. Accordingly, the presently disclosed compositions may provide for topical transdermal vaccination options using a petrolatum-based transdermal delivery system.

[0008] According to at least one aspect of the present disclosure, a petrolatum-based transdermal vaccine composition is disclosed. The petrolatum-based transdermal vaccine composition may include petrolatum and a liquid comprising at least one antigen. The liquid is suspended in the petrolatum. In some instances, the liquid may be a polar solvent such as water. The at least one antigen may be dissolved in the liquid. The composition may be a monovalent vaccine composition comprising a single strain of a single antigen or may be a polyvalent vaccine composition comprising two or more strains or serotypes of the same antigen.

[0009] The at least one antigen may be selected from the group consisting of a live attenuated vaccine (LAV), an inactivated (killed antigen) vaccine, a subunit (purified antigen) vaccine, a toxoid (inactivated toxin) vaccine, and any combination thereof. In some cases, the at least one antigen is a live attenuated vaccine selected from the group consisting of turberculosis (BCG), oral polio vaccine (OPV), measles, rotavirus, yellow fever, and any combination thereof. In other cases, the at least one antigen is an inactivated antigen selected from the group consisting of whole-cell pertussis (wP), inactivated polio virus (IPV), and any combination thereof. In yet other instances, the at least one antigen is a subunit or purified antigen selected from the group consisting of acellular pertussis (aP), Haemophilus influenzae type B (Hib), pneumococcal (PCV- 7, PCV-10, PCV-13), hepatitis B (HepB), and any combination thereof. In still other instances, the at least one antigen is a toxoid or an inactivated toxin antigen selected from tetanus toxoid (TT), diphtheria toxoid, and any combination thereof.

[0010] In some cases, the petrolatum-based composition may include greater than about 80% by weight petrolatum, or greater than about 85% by weight petrolatum, or greater than about 90% by weight petrolatum, or greater than about 95% by weight petrolatum. In some instances, the petrolatum-based composition may include a cationic biocide. For instance, the petrolatum- based composition may include a cationic biocide selected from the group consisting of benzalkonium chloride, cetrimide, chlorhexidine, polihexanide biguanide, and any combination thereof.

[0011] Importantly, it has surprisingly been discovered that the liquid comprising the at least one antigen may be dispersed or suspended in the petrolatum without an added emulsifier, even if the liquid is water. According to at least one aspect of the present disclosure, the liquid comprising the at least one antigen is dispersed in the petrolatum in the form of nanodroplets.

[0012] In at least some instances, the polar solvent may be water. In some cases, the polar solvent is a saline solution comprising water and sodium chloride. In other cases, the polar solvent comprises dissolved sodium chloride.

[0013] According to one aspect of the present disclosure, the petrolatum-based transdermal vaccine composition may include one or more cationic biocides. The one or more cationic biocides may serve as a penetration enhancing agent, a preservative, and/or as a mixing agent capable of enhancing the dispersion of liquid comprising antigen in the petrolatum carrier. The cationic biocide may be benzalkonium chloride, cetrimide, chlorhexidine, polihexanide biguanide, or any combination thereof. In some cases, the cationic biocide is a mixture of benzalkonium chloride and polihexanide biguanide.

[0014] In at least some instances, the composition excludes an added emulsifier. As used herein, the term“added emulsifier,” refers to a composition component or formulation ingredient added to the composition or formulation beyond those components or ingredients recited or disclosed herein. In general, an“added emulsifier” would be an excipient added to the composition or formulation in order to enhance the mixing or emulsification of polar composition or formulation components, such as a polar solvent or water comprising the at least one antigen, in the hydrophobic or non-polar petrolatum. In some cases, the presently disclosed compositions contain no emulsifiers. [0015] According to one aspect of the present disclosure, the polar solvent and at least one antigen are dispersed in the petrolatum in the form of nanodroplets. As used herein, the term “nanodroplets,” in all of its forms, refers to a nanosized droplet comprising a liquid, and any dissolved or colloidal constituents, having a diameter ranging from 10 nm to 5000 nm. In at least some instances, the nanodroplets may have a diameter ranging from 100 nm to 5000 nm, or from 500 nm to 1500 nm, or from 500 nm to 2000 nm, or from 1000 nm to 5000 nm, or from 500 nm to 5000 nm, or from 500 nm to 2500 nm, or from 10 nm to 200 nm, or from 10 nm to 500 nm, or from 1000 nm to 2500 nm. In cases in which the composition includes one or more cationic biocides, the liquid or polar solvent, antigen, and cationic biocide may be dispersed in the petrolatum in the form of nanodroplets. In all cases, the antigen solution may be dispersed in the petrolatum to form a stable suspension such that the antigen solution does not separate from the petrolatum for at least six months.

[0016] According to one aspect of the present disclosure, a method of vaccinating a subject is provided. The method includes applying the presently disclosed petrolatum-based transdermal vaccine compositions to an area of the skin of a subject in need of vaccination.

I. PETROLATUM-BASED COMPOSITIONS

[0017] According to one aspect, the present disclosure provides for compositions that are petrolatum-based. A petrolatum-based composition is made up primarily of petrolatum. The characteristics of a petrolatum-based composition differ from a composition containing only a small amount of petrolatum. In some embodiments, the petrolatum-based composition is greater than about 80% petrolatum. In other embodiments, the petrolatum-based composition is greater than about 81% petrolatum, greater than about 82% petrolatum, greater than about 83% petrolatum, greater than about 84% petrolatum, greater than about 85% petrolatum, greater than about 86% petrolatum, greater than about 87% petrolatum, greater than about 88% petrolatum, greater than about 89% petrolatum, greater than about 90% petrolatum, greater than about 91% petrolatum, greater than about 92% petrolatum, greater than about 93% petrolatum, greater than about 94% petrolatum, greater than about 95% petrolatum, greater than about 96% petrolatum, greater than about 97% petrolatum, greater than about 98% petrolatum, or greater than about 99% petrolatum. The petrolatum is preferably medical grade petrolatum. [0018] The presently disclosed composition may include less than 1% by weight antigen. In at least some instances, the petrolatum-based composition may be formulated to transdermally deliver pharmaceutically acceptable amount of one or more antigens such that a pharmaceutically acceptable vaccination response is induced in the subject.

[0019] In addition to the presently disclosed antigens, the compositions may also include one or more cationic biocides, such as quaternary ammonium compounds, bisbiguanides, and polymeric biguanides. In particular, the cationic biocides that may be included in the compositions may include, but are not limited to, benzalkonium chloride, cetrimide, chlorhexidine, polihexanide biguanide (polihexanide, polyhexamethylene guanide, poly(iminoimidocarbonyl- iminoimidocarbonyl-iminohexamethylene), poly(hexamethylenebiguanide), polyaminopropyl biguanide) and salts or combinations thereof. In one embodiment, the composition contains a mixture of polihexanide biguanide (PMHB) and benzalkonium chloride (BZK) preservative. The total amount of cationic biocide in the composition generally constitutes less than about 1% by weight of the total composition. In preferred embodiments, the cationic biocide constitutes from about 0.1% to about 0.5% by weight, or more preferably, from about 0.1% to about 0.3% by weight to the total composition.

[0020] The remaining weight of the composition, typically from about 0.1% to about 6% by weight of the petrolatum-based composition, is liquid. In a preferred embodiment, the composition contains about 5% water.

[0021] The antigen, cationic biocides, and liquid that may be used do not react with the petrolatum. Instead, the antigen, cationic biocides, and liquid that may be included in the compositions are dispersed in the petrolatum as nanodroplets, and the petrolatum serves as a suspension matrix for the liquid comprising the antigen. The nanodroplets are an aggregation of antigen, liquid, and any dissolved constituents in the liquid, such as preservatives and/or cationic biocides, in the petrolatum base. The nanodroplets typically contain a small amount of water in addition to the antigen. The nanodroplets may also contain dissolved salts or other constituents, such as sodium chloride, that may be present to stabilize the one or more antigens. The nanodroplets may also include one or more cationic biocides. The nanodroplets may vary in size but generally the longest dimension of the nanodroplets measures from about 100 nm to about 5000 nm, or from about 500 nm to about 1500 nm, or from about 500 nm to about 2000 nm, or from about 1000 nm to about 5000 nm, or from about 500 nm to about 5000 nm, or from about 500 nm to about 2500 nm, or from about 10 nm to about 200 nm, or from about 10 nm to about 500 nm, or from about 1000 nm to about 2500 nm, or from about 10 nm to about 5000 nm. In various embodiments, the nanodroplets range from about 100 nm to about 5000 nm, or from about 500 nm to about 1500 nm, or from about 500 nm to about 2000 nm, or from about 1000 nm to about 5000 nm, or from about 500 nm to about 5000 nm, or from about 500 nm to about 2500 nm, from about 10 nm to about 100 nm, from about 100 nm to about 1000 nm, from about 20 nm to about 200 nm, from about 30 nm to about 300 nm, from about 40 nm to about 400 nm, from about 50 nm to about 500 nm, from about 60 nm to about 600 nm, from about 70 nm to about 700 nm, from about 80 nm to about 800 nm, from about 90 nm to about 900 nm, from about 900 nm to about 1000 nm. In at least some instances, the nanodroplets are dispersed throughout the petrolatum homogeneously.

[0022] Surprisingly, embodiments of the present invention do not require an emulsifier. An emulsifier, as used herein, is an added formulation ingredient used to reduce the tension between hydrophilic and hydrophobic surface ingredients, thereby facilitating the mixture hydrophilic and hydrophobic ingredients. Prior to the present invention, those skilled in the art expected that an emulsifier would be needed to disperse polar ingredients, such as a polar solvent or liquid, such as water, and associated polar solvent and dissolved salts and/or cationic biocides, in a non-polar petrolatum suspension matrix. Where an emulsifier is used, it has a hydrophilic- lipophilic balance (HLB) of less than 10.

[0023] The compositions described herein are stable. In one aspect, stability refers to the integrity of the composition as a whole, and in particular, the stability of the nanodroplets in the petrolatum. Under ambient conditions, the petrolatum and the liquid comprising the antigen will not separate for greater than two years, meaning that the composition is shelf stable for at least two years. Even under accelerated conditions, such as reduced pressure, the petrolatum and the antigen solution do not separate, but rather the antigen solution remains suspended as nanodroplets in the petrolatum. In addition to the stability of the nanodroplets within the composition, the compositions described herein also show exceptional chemical stability for the antigen and other components of the antigen solution. The chemical stability stems primarily from the low- temperature manufacturing process described below. The absence of excessive heat conditions in the manufacturing of the compositions improves the efficacy and chemical stability (resistance to degradation) of the antigens. [0024] In some embodiments, the petrolatum-based compositions described herein consist essentially of petrolatum, at least one antigen, and water. In one preferred embodiment, the petrolatum-based compositions consist essentially of petrolatum, at least one antigen, benzalkonium chloride, polihexanide biguanide, and water. In alternative embodiments, the petrolatum-based compositions described herein consist of petrolatum, at least one antigen, a cationic biocide, and water or consist of petrolatum, at least one antigen, benzalkonium chloride, polihexanide biguanide, and water.

[0025] In other embodiments, the petrolatum-based compositions described herein may further comprise a dermatologically acceptable carrier. A“dermatologically-acceptable carrier,” as used herein, is a component or components suitable for use in contact with human keratinous tissue without undue toxicity, incompatibility, instability, allergic response, and the like. Where employed, the carrier is inert in the sense of not bringing about a deactivation of the active ingredients, and in the sense of not bringing about any adverse effect on the skin areas to which it is applied. Common dermatological additives are also envisioned for some embodiments.

[0026] Additionally, the compositions may be incorporated in predetermined therapeutically effective amounts into disposables such as wipes, gauze, patches, wraps, bandages, adhesive strips, sponge, cotton swab, glove, sock, wrist bands, fabric, fibers, sutures, medication pad, underwear, tissue, pain-relief gel pack or bed liner and the like. For instance, the composition may be applied to the surface of, or impregnated into disposables or applicators.

II. PROCESS FOR MAKING PETROLATUM-BASED COMPOSITIONS

[0027] The process for preparing the presently disclosed compositions may comprise: (a) dissolving one or more antigens in a solvent to give a antigen solution; (b) heating the petrolatum to a temperature sufficient to give a melted petrolatum, and heating the antigen solution to a temperature higher than the temperature of the petrolatum to give a heated antigen solution;

(c) mixing the melted petrolatum and the heated antigen solution to give a melted mixture; and,

(d) cooling the melted mixture to give the petrolatum-based composition. As would be appreciated by one of skill in the art, steps (a) - (d) are conducted sequentially.

[0028] The antigen is first dissolved in a solvent to give a antigen solution. Acceptable solvents for the antigen solution include water or other solvents. Generally polar solvents, such as water, are used. If cationic biocides are included in the composition, they are typically dissolved in the polar solvent at a concentration ranging from about 0.05% to about 5%. Typically, the amount of solvent used is from about 1: 10 to about 1:30 the amount of petrolatum and more preferably is about 1:20 to the amount of petrolatum by volume. The amount of antigen and cationic biocides, if used, can be calculated by one skilled in the art to provide the desired weight percentage for the final composition.

[0029] Both the antigen solution and the petrolatum are heated. The heating of these two ingredients can be conducted at the same time or sequentially so long as the melted petrolatum and the heated antigen solution are at the appropriate temperatures during the mixing step. Petrolatum is a solid that melts at approximately 37°C. As such, petrolatum may be heated to any temperature at or above 37°C. For instance, the petrolatum may be heated to a temperature ranging from about 37°C to about 45°C, from about 40°C to about 50°C, from about 45°C to about 55°C, or from about 50°C to about 60°C. Higher temperatures may also be envisioned for antigens that do not denature or degrade at higher temperatures. Preferably, the petrolatum is heated to a temperature ranging from about 37°C to about 55°C, more preferably to a temperature ranging from about 37°C to about 50°C. Heat may be provided to the petrolatum by any method known in the art, but a water bath or low temperature hot plate are preferred.

[0030] The antigen solution is heated to a temperature above the temperature of the melted petrolatum. Any temperature above the temperature of the melted petrolatum may be used in a method of the present disclosure, provided that the heat does not cause excessive degradation of the antigen, or excessive evaporation of the active ingredient or polar solvent. For instance, the antigen solution may be heated to a temperature that is about 1°C to about 10°C, about 5°C to about 15°C, about 10°C to about 20°C, about 15°C to about 25°C, about 20°C to about 30°C higher than the temperature of the melted petrolatum. Higher temperatures may also be envisioned for antigens that do not denature or degrade at higher temperatures. Preferably, the antigen solution is heated to a temperature that is about 1°C to about 10°C higher than the temperature of the melted petrolatum. In another embodiment, the antigen solution is heated to a temperature that is about 1°C to about 5°C higher than the melted petrolatum. In still other embodiments, the antigen solution is heated to a temperature that is about 1°C, 2°C, 3°C, 4°C, or 5°C above the temperature of the melted petrolatum. Again, the heating can be provided by any means known in the art but is preferably provided by a water bath or low temperature hot plate. [0031] Once both the petrolatum and the antigen solution are heated as described above, the melted petrolatum and the heated antigen solution are mixed to give a melted mixture containing petrolatum and the heated antigen solution. The mixing can be accomplished by a variety of methods including homogenization, acoustic mixing, and high RPM mixing. Depending on the batch size, the size of the mixer, and the type of mixing, the mixing may be conducted for several minutes or more. When mixed in accordance with the parameters disclosed above, the melted petrolatum and the heated antigen solution fuse in the melted mixture.

[0032] After the melted petrolatum and the heated antigen solution have fused they are allowed to cool and solidify into the composition. Cooling may be achieved by reducing the amount of heat provided to the melted mixture, or cooling may be achieved passively under conditions where no heating is added. In some embodiments, cooling is controlled so that the temperature of the melting mixture is gradually lowered to ambient temperatures. The product is preferably packaged a few degrees above its solidification point so that the packaging can be filled by pouring the melted mixture. The composition preferably solidifies to the final composition in the package. The package is sealed after this solidification.

[0033] The process may be conducted with two or more antigens. The antigens may be dissolved in solvent separately or may be dissolved in the same solvent. Addition of additional antigens does not change the process steps above.

III. METHODS OF USE OF PETROLATUM-BASED COMPOSITIONS

[0034] According to an aspect of the present disclosure, the presently disclosed petrolatum-based topical transdermal vaccine compositions may be used to vaccinate or treat a subject in need of vaccination. The presently disclosed compositions, advantageously deliver one or more antigens transdermally to the shallow tissues and blood vessels below the skin of a subject providing both local and systemic vaccination and immune response. In general, the presently disclosed methods of treatment include applying the petrolatum-based topical transdermal vaccine compositions to an area of the skin of a subject in need of vaccination.

[0035] The compositions may be applied topically to a subject in need of vaccination. The subject is preferably human but the composition may also be useful in animals, particularly mammals, for example domestic animals, livestock, or other types of animals. Typically, the composition is applied to the skin of the subject. As used herein, the terms“applied to the skin” or“applying to the skin,” in all their forms, as used throughout this disclosure in reference to applying the presently disclosed compositions to the skin of a subject, refers to all modes of administration of the compositions to the skin of a patient including topical administration of the compositions directly to the skin of a subject or causing contact between the compositions and the skin of a patient through, for instance, a wrap, gauze, bandage, or other delivery system impregnated or containing the presently disclosed compositions.

[0036] The amount of composition applied in the methods described herein can and will vary depending on the condition being treated and the severity of that condition. Generally, the amount used is sufficient to cover the affected skin area with a thin layer of the composition. The composition is applied directly to the skin. In some embodiments, the composition is spread so that it forms a thin layer over the treatment area. In other embodiments, the composition is spread by a melting action that occurs as the warmth of the patient’s skin melts the petrolatum or pharmaceutically acceptable carrier. The composition may be covered with a bandage after application. The compositions may also be impregnated into a bandage or other material that is applied to the treatment area.

[0037] The composition when applied to the skin is non- irritant and no n-cyto toxic. These properties allow the composition to be used on sensitive areas of the skin. These characteristics also allow for use to treat or prevent the subject’s condition over a long period, such as for example 2 weeks, 4 weeks, 6 weeks, 8 weeks, or longer without irritation to the treated area. It will be recognized however, that the compositions may be used for shorter periods of time if necessary.

[0038] The compositions are also capable of extended release of the antigen to the area of application.“Extended release” as used herein means that the compositions release one or more antigens to the application site over a period of time extending past twelve hours. The time over which the extended release is provided is variable depending on the amount of the composition that is applied, but in general, the release of antigen is extended beyond the initial application and antigen has been shown to be released for up to 1 week.

[0039] The compositions of the present disclosure also offer kinetic release when applied to the skin. Kinetic release means that antigen is released to the treatment area more rapidly when the treatment area is hotter. IV. TOPICAL COMPOSITIONS

[0040] According to one aspect, the present disclosure provides for a topical therapeutic composition. The composition comprises a topical delivery carrier and a liquid comprising at least one therapeutic agent. The liquid is suspended in the carrier. The at least one agent can be dissolved in the liquid.

[0041] The topical therapeutic composition can comprise greater than about 80% by weight carrier, greater than about 85% by weight carrier, greater than about 90% by weight carrier, or greater than about 95% by weight carrier. The liquid can be dispersed in the carrier in the form of nanodroplets. The composition can comprise less than aboutl% by weight of the at least one agent.

[0042] The composition can exclude an added emulsifier, contain no emulsifier, or contain no added emulsifier. The composition can further comprise a preservative. For instance, the carrier, the liquid, or combination thereof can comprise a preservative.

[0043] The composition can be capable of transdermally delivering the at least one agent to a subject in need thereof. The composition can also be capable of delivering the at least one agent through the nail to a subject in need thereof. The composition can be capable of topically delivering the at least one antigen to a subject in need thereof sufficiently to vaccinate the subject. The composition can be capable of topically delivering the at least one antigen to a subject in need thereof sufficiently to cause a vaccination response in the subject.

[0044] The delivery carrier can be a volatile or semi-volatile oil. The carrier can be selected from animal oil, vegetable oil, natural oil, synthetic oil, hydrocarbon oils, silicone oils, and semi- synthetic derivatives thereof. The carrier can also be selected from the group consisting of mineral oil, squalene oil, flavor oils, silicon oil, essential oils, water insoluble vitamins, Isopropyl stearate, Butyl stearate, Octyl palmitate, Cetyl palmitate, Tridecyl behenate, Diisopropyl adipate, Dioctyl sebacate, Menthyl anthranhilate, Cetyl octanoate, Octyl salicylate, Isopropyl myristate, neopentyl glycol dicarpate cetols, Ceraphyls®, Decyl oleate, diisopropyl adipate, 02- 15 alkyl lactates, Cetyl lactate, Lauryl lactate, Isostearyl neopentanoate, Myristyl lactate, Isocetyl stearoyl stearate, Octyldodecyl stearoyl stearate, Hydrocarbon oils, Isoparaffin, Fluid paraffins, Isododecane, Petrolatum, Argan oil, Canola oil, Chile oil, Coconut oil, corn oil, Cottonseed oil, Flaxseed oil, Grape seed oil, Mustard oil, Olive oil, Palm oil, Palm kernel oil, Peanut oil, Pine seed oil, Poppy seed oil, Pumpkin seed oil, Rice bran oil, Safflower oil, Tea oil, Truffle oil, Vegetable oil, Apricot (kernel) oil, Jojoba oil (simmondsia chinensis seed oil), Grapeseed oil, Macadamia oil, Wheat germ oil, Almond oil, Rapeseed oil, Gourd oil, Soybean oil, Sesame oil, Hazelnut oil, Maize oil, Sunflower oil, Hemp oil, Bois oil, Kuki nut oil, Avocado oil, Walnut oil, Fish oil, berry oil, allspice oil, juniper oil, seed oil, almond seed oil, anise seed oil, celery seed oil, cumin seed oil, nutmeg seed oil, leaf oil, basil leaf oil, bay leaf oil, cinnamon leaf oil, common sage leaf oil, eucalyptus leaf oil, lemon grass leaf oil, melaleuca leaf oil, oregano leaf oil, patchouli leaf oil, peppermint leaf oil, pine needle oil, rosemary leaf oil, spearmint leaf oil, tea tree leaf oil, thyme leaf oil, wintergreen leaf oil, flower oil, chamomile oil, clary sage oil, clove oil, geranium flower oil, hyssop flower oil, jasmine flower oil, lavender flower oil, manuka flower oil, Marhoram flower oil, orange flower oil, rose flower oil, ylang-ylang flower oil, Bark oil, cassia Bark oil, cinnamon bark oil, sassafras Bark oil, Wood oil, camphor wood oil, cedar wood oil, rosewood oil, sandalwood oil, rhizome (ginger) wood oil, resin oil, frankincense oil, myrrh oil, peel oil, bergamot peel oil, grapefruit peel oil, lemon peel oil, lime peel oil, orange peel oil, tangerine peel oil, root oil, valerian oil, Oleic acid, Linoleic acid, Oleyl alcohol, Isostearyl alcohol, semi- synthetic derivatives thereof, and combinations thereof. In one aspect, the carrier is petrolatum. In another aspect, the carrier is coconut oil.

[0045] The liquid can be a polar solvent or a non-polar solvent. In some aspects, the liquid is a polar solvent. The polar solvent can be selected from methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, s-butanol, t-butanol, formic acid, acetic acid, water, and combinations thereof. In one aspect, the polar solvent is water. In another aspect, the polar solvent is saline solution.

[0046] In some aspects, the at least one therapeutic agent can be water soluble. As used herein, a“water soluble” or“highly water soluble” therapeutic agent refers to an agent in its free base, free acid or salt form having solubility in water in excess of about 10 mg/ml at room temperature (20-25°C). In certain embodiments, the API may have a water solubility of greater than about 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, or 250 mg/mL at room temperature.

[0047] The therapeutic agent may be selected from the group consisting of a vaccine, and antimicrobial, abortifacients, ACE inhibitors, adrenocorticotropic hormones, a-adrenergic agonists, a-adrenergic blockers, a-glucosidase inhibitors, anabolic steroids, narcotic analgesics, non-narcotic analgesics, anorexics, antohelmintics, antiallergics, antialopecials, antiamoebics, antianginals, antiarrhythmics, antiarthritics, antiasthmatics, antibiotics, anticholinergics, anticonvulsants, antidepressants, antidiabetics, antidiarrheals, antidotes, antidyskinetics, antiemetics, antiestrogens, antifungals, antiglaucoma agents, antigout agents, antihistaminics, antihypertensives, nonsteroidal antiinflamatories, antimalarials, antimigraines, antimuscarinics, antinauseants, antineoplastics, antiparkinsonians, antipheochromocytoma agents, antipneumocystis, antiprostatic hyperplasia agent, antiprotozoals, antipruritics, antipsoriatics, antipsychotics, antipyretics, antirickettsials, antispasmodics, antithrombocythemics, antithrombotics, antithyroid agents, antituberculosis agents, antitussives, antiulceratives, antivirals, anxiolytics, aromatase inhibitors, autonomic drugs, barbiturates, benzodiazepine antagonists, b-adrenergic antagonists, b-adrenergic blockers, bradycardic agents, bronchodilators, calcium channel blockers, carbonic anhydrase inhibitors, cardiac drugs, cardiotonics, choleretics, cholinergics, cholinesterase inhibitors, cholinesterase reactivators, CNS stimulants, cytoprotectants, decongestants, diuretics, dopamine receptor agonists, dopamine receptor antagonists, ectoparasiticides, emetics, expectorants, fibrinogen receptor antagonists, gastric secretion inhibitors, gastrointestinal drugs, gastroprokinetics, genitourinary smooth muscle relaxants, heavy metal antagonists, hemostatics, histamine H2 receptor antagonists, hypnotics, immunomodulators, immunosuppressants, iron preparations, keratolytics, MAO inhibitors, mucolytics, muscle relaxants, mydriatics, narcotic antagonists, nootropics, opiate agonists, oxytocics, potassium channel activators, respiratory stimulants, sedatives, serenics, serotonin receptor agonists, serotonin receptor antagonists, serotonin uptake inhibitors, stimulants, sympatholytic agents, sympathomimetics, thrombolytics, tocolytics, tranquilizers, vasodilators, vasoprotectants, and vitamins.

[0048] Non-limiting examples of water soluble therapeutic agents include abacavir sulfate, acebutolol, acetaminophen, acyclovir, albendazole, alendronate sodium, allopurinol, amoxicilline, amantadine HC1, aminobenzoate potassium, aminocaproic acid, aminoarone HC1, amitriptyline hydrochloride, amphetamine, aspirin, atenolol, atorvastatin calcium, atropine sulfate, azithromycin, balsalazide, benzepril hydrochloride, bepridil HC1, betaine HC1, bisoprolol fumarate, buformin, bupropion HC1, calacyclovir, capecitabine, captopril, carisoprodol, cefadroxil, cefdnir, cefixime, cefpodoxime proxetil, cefprozil, cefuroxime axetil, celecoxib, cetrizine hydrochloride, chondroitin, chlorathiazide, chlorpheniramine maleate, chlorpromazine HC1, chlorzoxazone, choline magnesium trisalicylate, cimetidine, ciprofloxacin, clavulanate potassium, clindamycin, clomipramine hydrochloride, clonidine hydrochloride, clopidogrel bisulfate, cloxacillin sodium, codeine phosphate, colchicines, colsevelam HC1, creatine, cyclophosphamide, cyproheptadine, delavirdine mesylate, demeclocycline HC1, diclofenac, didanosine, diethylcarbamazine citrate, diltiazem HC1, DL-methionine, doxepine HC1, doxycycline, efavirenz, eprosartan mesylate, entacapone, ethembutol hydrochloride, eprosartan, erythromycin, ethosuximide, etidronate disodium, etodolac, ferrous sulfate, flecainide acetate, felbamate, fexofenadine HC1, firocoxib, fluconazole, fluoxetine hydrochloride, fluriprofen, fluvastatin, fosonopril sodium, fumarate, gabapentine, gatifloxacin, ganciclovir, guaifenesine, hydralazine hydrochloride, hydrocodone bitartrate, hydroxychloroquine sulfate, hydroxyurea, hydroxyzine hydrochloride, ibuprofen, indinavir sulfate, irbesartan, isoflavone, isoniazid, isosorbide mononitrate, ketoprofen, lactobionate, lamivudine, levamisole hydrochloride, levofloxacin, lisinopril, lithium carbonate, losartan potassium, mebendazole, mefenamic acid, meperidine HC1, mesalamine, metaprolol tartrate, metaxalone, metformin HC1, methenamine mandelate, methdopa, methocarbamol, methylphenidate, methylphenidate hydrochloride, metyrosine, minocycline hydrochloride, modafinil, montelukast sodium, morphine sulfate, moxifloxacin HC1, mycophenolate mefetil, nabumetone, naproxen sodium, nefazodone HC1, nelfinavir meslyate, neostigmine bromide, niacin, nicotinamide, nitrofurantoin, nifurtimox, nizatidine, norfloxacin, nortriptyline hydrochloride, ofloxacin, olanzepine, orlistat, oxybytynin chloride, pancreatin, pantothenic acid, penicillamine, penicillin V potassium, pentosan polysulfate sodium, phenformin, phenylbutazone, phenytoin sodium, phytoestrogen, potassium chloride, pramipexole, pravastatin sodium, praziquantel, primaquine phosphate, proanthocyanidin, procainamide, promethazine, promethazine hydrochloride, propafenone HC1, propanolol HC1, propoxyphene hydrochloride, propoxyphene napsylate, prazosin, pseudophedrine hydrochloride, pseudoephedrine sulfate, psyllium, pycnogenol, pyrazinamide, pyridostigmine bromide, pyridoxine hydrochloride, pyruvate, quetiapine carafate, quinidine sulfate, quinapril hydrochloride, ramipril, ranitidine hydrochloride, reboxetine, rifabutin, rifampin, risedronate sodium, rofecoxib, rosiglitazone maleate, salbutamol sulfate, saquinavir mesylate, sertraline HC1, sevelamer HC1, sildenafil, simethicone, sodium valproate, sotalol HC1, stavudine, succimer, sumanirole, sumatriptan succinate, suntheanine, terazosin hydrochloride, terbinafine HC1, tetracycline HC1, theophylline, thiobendazole, ticlopidine HC1, timolol meleate, tocainide HC1, tolcapne, tolmetin sodium, tramadol HC1, trovafloxacin mesylate, valacyclovir HC1, valganciclovir HC1, valsartan, vancomycin, venlafaxine hydrochloride, verapamil HC1, warfarin sodium, xylamine, zidovudine, and combinations thereof.

[0049] In some aspects, the at least one therapeutic agent can be a vaccine, an antimicrobial, or a combination thereof. In some aspects, the at least one therapeutic agent is a vaccine and an antimicrobial. The vaccine can be a monovalent vaccine comprising a single strain of a single antigen. The vaccine can also be a polyvalent vaccine comprising two or more strains or serotypes of the same antigen. The vaccine can be selected from the group consisting of a live attenuated vaccine (LAV), an inactivated (killed antigen) vaccine, a subunit (purified antigen) vaccine, a toxoid (inactivated toxin) vaccine, and any combination thereof. The vaccine can also be a live attenuated vaccine selected from the group consisting of turberculosis (BCG), oral polio vaccine (OPV), measles, rotavirus, yellow fever, and any combination thereof. The vaccine can comprise an inactivated antigen selected from the group consisting of whole-cell pertussis (wP), inactivated polio virus (IPV), and any combination thereof. The vaccine can also comprise a subunit or purified antigen selected from the group consisting of acellular pertussis (aP), Haemophilus influenzae type B (Hib), pneumococcal (PCV-7, PCV-10, PCV-13), hepatitis B (HepB), and any combination thereof. In some aspects, the vaccine comprises a toxoid or an inactivated toxin antigen selected from tetanus toxoid (TT), diphtheria toxoid, and any combination thereof.

[0050] In some aspects, the therapeutic agent is a cationic biocide. The cationic biocide can be selected from the group consisting of benzalkonium chloride, cetrimide, chlorhexidine, polihexanide biguanide, and any combination thereof. In one aspect, the cationic biocide is a mixture of benzalkonium chloride and polihexanide biguanide.

[0051] The topical therapeutic composition can be prepared by a process comprising the steps of: a) dissolving the at least one therapeutic agent in the liquid to provide a therapeutic solution; b) heating the carrier; c) heating the therapeutic solution to a second temperature higher than the temperature of the carrier to provide a heated therapeutic solution; d) mixing the heated carrier and the heated therapeutic solution to give a heated mixture; and e) cooling the melted mixture to provide the therapeutic composition. The second temperature is higher than the first temperature. If the carrier is a solid, the first temperature is sufficient to melt the carrier. The first temperature can be about 1°C to about 5°C higher than the second temperature. V. METHODS OF USING TOPICAL COMPOSITIONS

[0052] According to another aspect, the present disclosure provides for a method of vaccinating a subject. The method comprises topically applying a therapeutic composition to an area of the skin of a subject in need of vaccination. According to other aspects, the present disclosure provides for a method of topically applying a therapeutic composition to a subject in need of treatment. In another aspect, the present disclosure provides for a method of causing an immune response in a subject, the method comprising topically applying a therapeutic composition to a subject in need of treatment. In other aspects, the present disclosure provides a method of vaccinating a subject in need thereof using a topical therapeutic composition. The method comprises applying the therapeutic composition to a subject in need of vaccination. The composition can be as described in Section IV above.

VI. METHODS OF PREPARING TOPICAL COMPOSITIONS

[0053] According to another aspect, the present disclosure provides for a process for preparing a topical therapeutic composition. The process comprises the steps of: a) dissolving at least one therapeutic agent in a liquid to provide an therapeutic solution; b) heating a topical delivery carrier; c) heating the therapeutic solution to a second temperature; d) mixing the heated carrier and the heated therapeutic solution to give a heated mixture; and e) cooling the melted mixture to provide the therapeutic composition. The second temperature is higher than the first temperature. The first temperature is sufficient to melt the carrier if the carrier is solid.

[0054] In some aspects, the first temperature is about 1°C to about 5°C higher than the second temperature. In some aspects, an emulsifier is not used. The liquid can be a polar solvent. In one aspect, the liquid is water. The composition can comprise greater than about 80% by weight carrier, greater than about 85% by weight of the therapeutic agent, greater than about 90% by weight agent, or greater than about 95% by weight agent.

VII. STATEMENTS OF THE PRESENT DISCLOSURE

[0055] Numerous examples are provided herein to enhance understanding of the present disclosure. A specific set of statements are provided as follows. [0056] Statement 1: A petrolatum-based transdermal vaccine composition comprising: petrolatum; and a liquid comprising at least one antigen; wherein the liquid is suspended in the petrolatum.

[0057] Statement 2: The petrolatum-based composition according to Statement 1, wherein the at least one antigen is dissolved in the liquid.

[0058] Statement 3: The petrolatum-based composition according to Statement 1 or Statement 2, wherein the liquid is a polar solvent.

[0059] Statement 4: The petrolatum-based composition according to any one of the preceding Statements 1-3, wherein the vaccine composition is a monovalent vaccine composition comprising a single strain of a single antigen.

[0060] Statement 5: The petrolatum-based composition according to any one of the preceding Statements 1-4, wherein the vaccine composition is a polyvalent vaccine composition comprising two or more strains or serotypes of the same antigen.

[0061] Statement 6: The petrolatum-based composition according to any one of the preceding Statements 1-5, wherein the at least one antigen is selected from the group consisting of a live attenuated vaccine (LAV), an inactivated (killed antigen) vaccine, a subunit (purified antigen) vaccine, a toxoid (inactivated toxin) vaccine, and any combination thereof.

[0062] Statement 7: The petrolatum-based composition according to any one of the preceding Statement 1-6, wherein the at least one antigen is a live attenuated vaccine selected from the group consisting of turberculosis (BCG), oral polio vaccine (OPV), measles, rotavirus, yellow fever, and any combination thereof.

[0063] Statement 8: The petrolatum-based composition according to any one of the preceding Statements 1-6, wherein the at least one antigen is an inactivated antigen selected from the group consisting of whole-cell pertussis (wP), inactivated polio virus (IPV), and any combination thereof.

[0064] Statement 9: The petrolatum-based composition according to any one of the preceding Statements 1-6, wherein the at least one antigen is a subunit or purified antigen selected from the group consisting of acellular pertussis (aP), Haemophilus influenzae type B (Hib), pneumococcal (PCV-7, PCV-10, PCV-13), hepatitis B (HepB), and any combination thereof. [0065] Statement 10: The petrolatum-based composition according to any one of the preceding Statements 1-6, wherein the at least one antigen is a toxoid or an inactivated toxin antigen selected from tetanus toxoid (TT), diphtheria toxoid, and any combination thereof.

[0066] Statement 11: The petrolatum-based composition according to any one of the preceding Statements 1-10, wherein the liquid is water.

[0067] Statement 12: The petrolatum-based composition according to any one of the preceding Statements 1-11, wherein the composition comprises greater than about 80% by weight petrolatum.

[0068] Statement 13: The petrolatum-based composition according to any one of the preceding Statements 1-12, wherein the composition comprises greater than about 85% by weight petrolatum.

[0069] Statement 14: The petrolatum-based composition according to any one of the preceding Statements 1-13, wherein the composition comprises greater than about 90% by weight petrolatum.

[0070] Statement 15: The petrolatum-based composition according to any one of the preceding Statements 1-14, wherein the composition comprises greater than about 95% by weight petrolatum.

[0071] Statement 16: The petrolatum-based composition according to any one of the preceding Statements 1-15, further comprising a cationic biocide.

[0072] Statement 17: The petrolatum-based composition according to Statement 16, wherein the cationic biocide is selected from the group consisting of benzalkonium chloride, cetrimide, chlorhexidine, polihexanide biguanide, and any combination thereof.

[0073] Statement 18: The petrolatum-based composition according to Statement 16, wherein the cationic biocide is a mixture of benzalkonium chloride and polihexanide biguanide.

[0074] Statement 19: The petrolatum-based composition according to any one of the preceding Statements 1-18, wherein the liquid comprising the at least one antigen is dispersed in the petrolatum in the form of nanodroplets.

[0075] Statement 20: The petrolatum-based composition according to any one of Statements 16-18, wherein the liquid, at least one antigen, and cationic biocide are dispersed in the petrolatum in the form of nanodroplets. [0076] Statement 21: The petrolatum-based composition according to any one of the preceding Statements 1-20, wherein the composition excludes an added emulsifier.

[0077] Statement 22: The petrolatum-based composition according to any one of the preceding Statements 1-20, wherein the composition contains no emulsifier.

[0078] Statement 23: The petrolatum-based composition according to any one of the preceding Statements 1-20, wherein the composition contains no added emulsifier.

[0079] Statement 24: The petrolatum-based composition according to any one of the preceding Statements 1-23, wherein the liquid is a saline solution comprising water and sodium chloride.

[0080] Statement 25: The petrolatum-based composition according to any one of the preceding Statements 1-24, wherein the polar solvent further comprises a preservative.

[0081] Statement 26: The petrolatum-based composition according to any one of the preceding Statements 1-25, wherein the petrolatum-based composition comprises less than 1% by weight of the at least one antigen.

[0082] Statement 27: The petrolatum-based composition according to any one of the preceding Statements 1-26, wherein the petrolatum-based composition is capable of transdermally delivering the at least one antigen to a subject in need thereof.

[0083] Statement 28: The petrolatum-based composition according to any one of the preceding Statements 1-26, wherein the petrolatum-based composition is capable of transdermally delivering the at least one antigen to a subject in need thereof sufficiently to vaccinate the subject.

[0084] Statement 29: The petrolatum-based composition according to any one of the preceding Statements 1-26, wherein the petrolatum-based composition is capable of transdermally delivering the at least one antigen to a subject in need thereof sufficiently to cause a vaccination response in the subject.

[0085] Statement 30: The petrolatum-based composition according to any one of the preceding Statements 1-29, wherein the petrolatum-based composition is prepared by a process comprising: a) dissolving the at least one antigen in the liquid to provide an antigen solution; b) heating the petrolatum to a temperature sufficient to cause the petrolatum to melt to give a melted petrolatum and heating the antigen solution to a temperature higher than the temperature of the melted petrolatum to provide a heated antigen solution; c) mixing the melted petrolatum and the heated antigen solution to give a melted mixture; and d) cooling the melted mixture to provide the petrolatum-based composition.

[0086] Statement 31: The petrolatum-based composition according to Statement 30, wherein the heated antigen solution has a temperature that is about 1°C to about 5°C higher than the temperature of the melted petrolatum.

[0087] Statement 32: The petrolatum-based composition according to Statement 30 or Statement 31, wherein an emulsifier is not used.

[0088] Statement 33: The petrolatum-based composition according to any one of the preceding Statements 1-32, wherein the liquid comprising the at least one antigen is substantially suspended in the petrolatum.

[0089] Statement 34: The petrolatum-based composition according to any one of the preceding Statements 1-32, wherein the liquid comprising the at least one antigen is substantially suspended in the petrolatum such that no liquid is observed to separate from the petrolatum-based composition for at least 3 months.

[0090] Statement 35: The petrolatum-based composition according to any one of the preceding Statements 1-32, wherein the liquid comprising the at least one antigen is substantially suspended in the petrolatum such that no liquid is observed to separate from the petrolatum-based composition for at least 6 months.

[0091] Statement 36: The petrolatum-based composition according to any one of the preceding Statements 1-32, wherein the liquid comprising the at least one antigen is permanently suspended in the petrolatum.

[0092] Statement 37: The petrolatum-based composition according to any one of the preceding Statements 1-36, wherein the at least one antigen maintains efficacy for at least 3 months when stored at 40°C ± 2°C and 75% ± 5% relative humidity.

[0093] Statement 38: A method of vaccinating a subject, the method comprising applying the petrolatum-based composition according to any one of the preceding Statements 1-37 to an area of the skin of a subject in need of vaccination.

[0094] Statement 39: A method of treating a subject, the method comprising applying the petrolatum-based composition according to any one of the preceding Statements 1-37 to an area of the skin of a subject in need of treatment. [0095] Statement 40: A method of causing an immune response in a subject, the method comprising applying the petrolatum-based composition according to any one of the preceding Statements 1-37 to an area of the skin of a subject in need of treatment.

[0096] Statement 41: A method of vaccinating a subject in need thereof using a topical transdermal delivery system, the method comprising applying the petrolatum-based composition according to any one of the preceding Statements 1-37 to an area of the skin of a subject in need of vaccination.

[0097] Statement 42: A process for preparing a petrolatum-based transdermal vaccine composition, the process comprising: a) dissolving at least one antigen in a liquid to provide an antigen solution; b) heating petrolatum to a temperature sufficient to cause the petrolatum to melt to give a melted petrolatum and heating the antigen solution to a temperature higher than the temperature of the melted petrolatum to provide a heated antigen solution; c) mixing the melted petrolatum and the heated antigen solution to give a melted mixture; and d) cooling the melted mixture to provide the petrolatum-based transdermal vaccine composition.

[0098] Statement 43: The process according to Statement 42, wherein the heated antigen solution has a temperature that is about 1°C to about 5°C higher than the temperature of the melted petrolatum.

[0099] Statement 44: The process according to Statement 42 or Statement 43, wherein an emulsifier is not used.

[00100] Statement 45: The process according to any one of the preceding Statements 42- 44, wherein the liquid is a polar solvent.

[00101] Statement 46: The process according to any one of the preceding Statements 42- 44, wherein the liquid is water.

[00102] Statement 47: The process according to any one of the preceding Statements 42- 46, wherein the composition comprises greater than about 80% by weight petrolatum.

[00103] Statement 48: The process according to any one of the preceding Statements 42- 46, wherein the composition comprises greater than about 85% by weight petrolatum.

[00104] Statement 49: The process according to any one of the preceding Statements 42- 46, wherein the composition comprises greater than about 90% by weight petrolatum.

[00105] Statement 50: The process according to any one of the preceding Statements 42- 46, wherein the composition comprises greater than about 95% by weight petrolatum. [00106] Statement 51: A topical therapeutic composition comprising: a topical delivery carrier; and a liquid comprising at least one therapeutic agent; wherein the liquid is suspended in the carrier.

[00107] Statement 52: The topical therapeutic composition of Statement 51, wherein the delivery carrier is a volatile or semi- volatile oil.

[00108] Statement 53: The topical therapeutic composition in any one of the preceding Statements 51-52, wherein the carrier is selected from animal oil, vegetable oil, natural oil, synthetic oil, hydrocarbon oils, silicone oils, and semi- synthetic derivatives thereof.

[00109] Statement 54: The topical therapeutic composition in any one of the preceding Statements 51-53, wherein the carrier is selected from the group consisting of mineral oil, squalene oil, flavor oils, silicon oil, essential oils, water insoluble vitamins, Isopropyl stearate, Butyl stearate, Octyl palmitate, Cetyl palmitate, Tridecyl behenate, Diisopropyl adipate, Dioctyl sebacate, Menthyl anthranhilate, Cetyl octanoate, Octyl salicylate, Isopropyl myristate, neopentyl glycol dicarpate cetols, Ceraphyls®, Decyl oleate, diisopropyl adipate, 02-15 alkyl lactates, Cetyl lactate, Lauryl lactate, Isostearyl neopentanoate, Myristyl lactate, Isocetyl stearoyl stearate, Octyldodecyl stearoyl stearate, Hydrocarbon oils, Isoparaffin, Fluid paraffins, Isododecane, Petrolatum, Argan oil, Canola oil, Chile oil, Coconut oil, corn oil, Cottonseed oil, Flaxseed oil, Grape seed oil, Mustard oil, Olive oil, Palm oil, Palm kernel oil, Peanut oil, Pine seed oil, Poppy seed oil, Pumpkin seed oil, Rice bran oil, Safflower oil, Tea oil, Truffle oil, Vegetable oil, Apricot (kernel) oil, Jojoba oil (simmondsia chinensis seed oil), Grapeseed oil, Macadamia oil, Wheat germ oil, Almond oil, Rapeseed oil, Gourd oil, Soybean oil, Sesame oil, Hazelnut oil, Maize oil, Sunflower oil, Hemp oil, Bois oil, Kuki nut oil, Avocado oil, Walnut oil, Fish oil, berry oil, allspice oil, juniper oil, seed oil, almond seed oil, anise seed oil, celery seed oil, cumin seed oil, nutmeg seed oil, leaf oil, basil leaf oil, bay leaf oil, cinnamon leaf oil, common sage leaf oil, eucalyptus leaf oil, lemon grass leaf oil, melaleuca leaf oil, oregano leaf oil, patchouli leaf oil, peppermint leaf oil, pine needle oil, rosemary leaf oil, spearmint leaf oil, tea tree leaf oil, thyme leaf oil, wintergreen leaf oil, flower oil, chamomile oil, clary sage oil, clove oil, geranium flower oil, hyssop flower oil, jasmine flower oil, lavender flower oil, manuka flower oil, Marhoram flower oil, orange flower oil, rose flower oil, ylang-ylang flower oil, Bark oil, cassia Bark oil, cinnamon bark oil, sassafras Bark oil, Wood oil, camphor wood oil, cedar wood oil, rosewood oil, sandalwood oil), rhizome (ginger) wood oil, resin oil, frankincense oil, myrrh oil, peel oil, bergamot peel oil, grapefruit peel oil, lemon peel oil, lime peel oil, orange peel oil, tangerine peel oil, root oil, valerian oil, Oleic acid, Linoleic acid, Oleyl alcohol, Isostearyl alcohol, semi- synthetic derivatives thereof, and combinations thereof.

[00110] Statement 55: The topical therapeutic composition in any one of the preceding Statements 51-54, wherein the carrier is coconut oil.

[00111] Statement 56: The topical therapeutic composition in any one of the preceding Statements 51-55, wherein the liquid is a polar solvent or a non-polar solvent.

[00112] Statement 57: The topical therapeutic composition in any one of the preceding Statements 51-56, wherein the liquid is a polar solvent.

[00113] Statement 58: The topical therapeutic composition of Statement 57, wherein the polar solvent is selected from methanol, ethanol, isopropanol, n-propanol, isobutanol, n-butanol, s-butanol, t-butanol, formic acid, acetic acid, water, and combinations thereof.

[00114] Statement 59: The topical therapeutic composition in any one of the preceding Statements 51-58, wherein the liquid is water.

[00115] Statement 60: The topical therapeutic composition in any one of the preceding Statements 51-59, wherein the liquid is a saline solution.

[00116] Statement 61: The topical therapeutic composition in any one of the preceding Statements 51-60, wherein the at least one agent is dissolved in the liquid.

[00117] Statement 62: The topical therapeutic composition in any one of the preceding Statements 51-61, wherein the at least one therapeutic agent is a vaccine, an antimicrobial, or a combination thereof.

[00118] Statement 63: The topical therapeutic composition in any one of the preceding Statements 51-62, wherein the at least one therapeutic agent is a vaccine and an antimicrobial.

[00119] Statement 64: The topical therapeutic composition in any one of the preceding Statements 51-63, wherein the at least one therapeutic agent is a monovalent vaccine comprising a single strain of a single antigen.

[00120] Statement 65: The topical therapeutic composition in any one of the preceding Statements 51-64, wherein the therapeutic agent is a polyvalent vaccine comprising two or more strains or serotypes of the same antigen.

[00121] Statement 66: The topical therapeutic composition in any one of the preceding Statements 51-65, wherein the at least one agent is selected from the group consisting of a live attenuated vaccine (LAV), an inactivated (killed antigen) vaccine, a subunit (purified antigen) vaccine, a toxoid (inactivated toxin) vaccine, and any combination thereof.

[00122] Statement 67: The topical therapeutic composition in any one of the preceding Statements 51-66, wherein the at least one agent is a live attenuated vaccine selected from the group consisting of turberculosis (BCG), oral polio vaccine (OPV), measles, rotavirus, yellow fever, and any combination thereof.

[00123] Statement 68: The topical therapeutic composition in any one of the preceding Statements 51-67, wherein the at least one agent is a vaccine comprising an inactivated antigen selected from the group consisting of whole-cell pertussis (wP), inactivated polio virus (IPV), and any combination thereof.

[00124] Statement 69: The topical therapeutic composition in any one of the preceding Statements 51-68, wherein the at least one agent is a vaccine comprising a subunit or purified antigen selected from the group consisting of acellular pertussis (aP), Haemophilus influenzae type B (Hib), pneumococcal (PCV-7, PCV-10, PCV-13), hepatitis B (HepB), and any combination thereof.

[00125] Statement 70: The topical therapeutic composition in any one of the preceding Statements 51-69, wherein the at least one agent is a vaccine comprising a toxoid or an inactivated toxin antigen selected from tetanus toxoid (TT), diphtheria toxoid, and any combination thereof.

[00126] Statement 71: The topical therapeutic composition in any one of the preceding Statements 51-70, wherein the at least one therapeutic agent is a cationic biocide.

[00127] Statement 72: The topical therapeutic composition of Statement 71, wherein the cationic biocide is selected from the group consisting of benzalkonium chloride, cetrimide, chlorhexidine, polihexanide biguanide, and any combination thereof.

[00128] Statement 73: The topical therapeutic composition of Statement 71, wherein the cationic biocide is a mixture of benzalkonium chloride and polihexanide biguanide.

[00129] Statement 74: The topical therapeutic composition in any one of the preceding Statements 51-73, wherein the composition comprises greater than about 80% by weight carrier.

[00130] Statement 75: The topical therapeutic composition in any one of the preceding Statements 51-74, wherein the composition comprises greater than about 85% by weight carrier.

[00131] Statement 76: The topical therapeutic composition in any one of the preceding Statements 51-75, wherein the composition comprises greater than about 90% by weight carrier. [00132] Statement 77: The topical therapeutic composition in any one of the preceding Statements 51-76, wherein the composition comprises greater than about 95% by weight carrier.

[00133] Statement 78: The topical therapeutic composition in any one of the preceding Statements 51-77, wherein the liquid is dispersed in the carrier in the form of nanodroplets.

[00134] Statement 79: The topical therapeutic composition in any one of the preceding Statements 51-78, wherein the composition excludes an added emulsifier.

[00135] Statement 80: The topical therapeutic composition in any one of the preceding Statements 51-79, wherein the composition contains no emulsifier.

[00136] Statement 81: The topical therapeutic composition in any one of the preceding Statements 51-80, wherein the composition contains no added emulsifier.

[00137] Statements 82: The topical therapeutic composition in any one of the preceding Statements 51-81, wherein the composition further comprises a preservative.

[00138] Statement 83: The topical therapeutic composition in any one of the preceding Statements 51-82, wherein the carrier, the liquid, or combination thereof comprises a preservative.

[00139] Statement 84: The topical therapeutic composition in any one of the preceding Statements 51-83, wherein the composition comprises less than aboutl% by weight of the at least one agent.

[00140] Statement 85: The topical therapeutic composition in any one of the preceding Statements 51-84, wherein the composition is capable of transdermally delivering the at least one agent to a subject in need thereof.

[00141] Statement 86: The topical therapeutic composition in any one of the preceding Statements 51-85, wherein the composition is capable of delivering the at least one agent through the nail to a subject in need thereof.

[00142] Statement 87: The topical therapeutic composition in any one of the preceding Statements 51-86, wherein the composition is capable of topically delivering the at least one antigen to a subject in need thereof sufficiently to vaccinate the subject.

[00143] Statement 88: The topical therapeutic composition in any one of the preceding Statements 51-87, wherein the composition is capable of topically delivering the at least one antigen to a subject in need thereof sufficiently to cause a vaccination response in the subject.

[00144] Statement 89: The topical therapeutic composition in any one of the preceding claims, wherein the composition is prepared by a process comprising: a) dissolving the at least one therapeutic agent in the liquid to provide a therapeutic solution; b) heating the carrier; c) heating the therapeutic solution to a second temperature higher than the temperature of the carrier to provide a heated therapeutic solution; d) mixing the heated carrier and the heated therapeutic solution to give a heated mixture; and e) cooling the melted mixture to provide the therapeutic composition; wherein the second temperature is higher than the first temperature.

[00145] Statement 90: The topical therapeutic composition of Statement 89, wherein the first temperature is sufficient to melt the carrier.

[00146] Statement 91: The topical therapeutic composition in any one of Statements 89- 90, wherein the first temperature is about 1°C to about 5°C higher than the second temperature.

[00147] Statement 92: A method of vaccinating a subject, the method comprising topically applying the therapeutic composition according to any one of the preceding Statements 51-88 to an area of the skin of a subject in need of vaccination.

[00148] Statement 93: A method of vaccinating a subject, the method comprising topically applying the therapeutic composition according to any one of the preceding Statements 51-88 to a subject in need of treatment.

[00149] Statement 94: A method of causing an immune response in a subject, the method comprising topically applying the therapeutic composition according to any one of the preceding Statements 51-88 to a subject in need of treatment.

[00150] Statement 95: A method of vaccinating a subject in need thereof using a topical therapeutic composition, the method comprising applying the therapeutic composition according to any one of the preceding claims to a subject in need of vaccination.

[00151] Statement 96: A process for preparing a topical therapeutic composition, the process comprising: a) dissolving at least one therapeutic agent in a liquid to provide an therapeutic solution; b) heating a topical delivery carrier; c) heating the therapeutic solution to a second temperature; d) mixing the heated carrier and the heated therapeutic solution to give a heated mixture; and e) cooling the melted mixture to provide the therapeutic composition; wherein the second temperature is higher than the first temperature.

[00152] Statement 97: The process of Statement 96, wherein the first temperature is sufficient to melt the carrier.

[00153] Statement 98: The process of any one of the preceding Statements 96-97, wherein the first temperature is about 1°C to about 5°C higher than the second temperature. [00154] Statement 99: The process of any one of the preceding Statements 96-98, wherein an emulsifier is not used.

[00155] Statement 100: The process of any one of the preceding Statements 96-99, wherein the liquid is a polar solvent.

[00156] Statement 101: The process of any one of the preceding Statements 96-100, wherein the liquid is water.

[00157] Statement 102: The process of any one of the preceding Statements 96-101, wherein the composition comprises greater than about 80% by weight carrier.

[00158] Statement 103: The process of any one of the preceding Statements 96-102, wherein the composition comprises greater than about 85% by weight of the therapeutic agent.

[00159] Statement 104: The process of any one of the preceding Statements 96-103, wherein the composition comprises greater than about 90% by weight agent.

[00160] Statement 105: The process of any one of the preceding Statements 96-104, wherein the composition comprises greater than about 95% by weight agent.

Claims

CLAIMS What is claimed is:

1. A petrolatum-based transdermal vaccine composition comprising:

petrolatum; and

a liquid comprising at least one antigen;

wherein the liquid is suspended in the petrolatum.

2. The petrolatum-based composition according to claim 1, wherein the at least one antigen is dissolved in the liquid.

3. The petrolatum-based composition according to claim 1 or claim 2, wherein the liquid is a polar solvent.

4. The petrolatum-based composition according to any one of claims 1-3, wherein the vaccine composition is a monovalent vaccine composition comprising a single strain of a single antigen.

5. The petrolatum-based composition according to any one of claims 1-3, wherein the vaccine composition is a polyvalent vaccine composition comprising two or more strains or serotypes of the same antigen.

6. The petrolatum-based composition according to any one of claims 1-5, wherein the at least one antigen is selected from the group consisting of a live attenuated vaccine (LAV), an inactivated (killed antigen) vaccine, a subunit (purified antigen) vaccine, a toxoid (inactivated toxin) vaccine, and any combination thereof.

7. The petrolatum-based composition according to any one of claims 1-6, wherein the at least one antigen is a live attenuated vaccine selected from the group consisting of turberculosis (BCG), oral polio vaccine (OPV), measles, rotavirus, yellow fever, and any combination thereof.

8. The petrolatum-based composition according to any one of claims 1-6, wherein the at least one antigen is an inactivated antigen selected from the group consisting of whole-cell pertussis (wP), inactivated polio virus (IPV), and any combination thereof.

9. The petrolatum-based composition according to any one of claims 1-6, wherein the at least one antigen is a subunit or purified antigen selected from the group consisting of acellular pertussis (aP), Haemophilus influenzae type B (Hib), pneumococcal (PCV-7, PCV-10, PCV-13), hepatitis B (HepB), and any combination thereof.

10. The petrolatum-based composition according to any one of claims 1-6, wherein the at least one antigen is a toxoid or an inactivated toxin antigen selected from tetanus toxoid (TT), diphtheria toxoid, and any combination thereof.

11. The petrolatum-based composition according to any one of the preceding claims 1-10, wherein the liquid is water.

12. The petrolatum-based composition according to any one of the preceding claims 1-11, wherein the composition comprises greater than about 80% by weight petrolatum.

13. The petrolatum-based composition according to any one of the preceding claims 1-12, wherein the composition comprises greater than about 85% by weight petrolatum.

14. The petrolatum-based composition according to any one of the preceding claims 1-13, wherein the composition comprises greater than about 90% by weight petrolatum.

15. The petrolatum-based composition according to any one of the preceding claims 1-14, wherein the composition comprises greater than about 95% by weight petrolatum.

16. The petrolatum-based composition according to any one of the preceding claims 1-15, further comprising a cationic biocide.

17. The petrolatum-based composition according to claim 16, wherein the cationic biocide is selected from the group consisting of benzalkonium chloride, cetrimide, chlorhexidine, polihexanide biguanide, and any combination thereof.

18. The petrolatum-based composition according to claim 16, wherein the cationic biocide is a mixture of benzalkonium chloride and polihexanide biguanide.

19. The petrolatum-based composition according to any one of the preceding claims 1-18, wherein the liquid comprising the at least one antigen is dispersed in the petrolatum in the form of nanodroplets.

20. The petrolatum-based composition according to any one of claims 16-18, wherein the liquid, at least one antigen, and cationic biocide are dispersed in the petrolatum in the form of nanodroplets.

21. The petrolatum-based composition according to any one of the preceding claims 1-20, wherein the composition excludes an added emulsifier.

22. The petrolatum-based composition according to any one of the preceding claims 1-20, wherein the composition contains no emulsifier.

23. The petrolatum-based composition according to any one of the preceding claims 1-20, wherein the composition contains no added emulsifier.

24. The petrolatum-based composition according to any one of the preceding claims 1-23, wherein the liquid is a saline solution comprising water and sodium chloride.

25. The petrolatum-based composition according to any one of the preceding claims 1-24, wherein the polar solvent further comprises a preservative.

26. The petrolatum-based composition according to any one of the preceding claims 1-25, wherein the petrolatum-based composition comprises less than 1% by weight of the at least one antigen.

27. The petrolatum-based composition according to any one of the preceding claims 1-26, wherein the petrolatum-based composition is capable of transdermally delivering the at least one antigen to a subject in need thereof.

28. The petrolatum-based composition according to any one of the preceding claims 1-26, wherein the petrolatum-based composition is capable of transdermally delivering the at least one antigen to a subject in need thereof sufficiently to vaccinate the subject.

29. The petrolatum-based composition according to any one of the preceding claims 1-26, wherein the petrolatum-based composition is capable of transdermally delivering the at least one antigen to a subject in need thereof sufficiently to cause a vaccination response in the subject.

30. The petrolatum-based composition according to any one of the preceding claims 1-29, wherein the petrolatum-based composition is prepared by a process comprising: a) dissolving the at least one antigen in the liquid to provide an antigen solution; b) heating the petrolatum to a temperature sufficient to cause the petrolatum to melt to give a melted petrolatum and heating the antigen solution to a temperature higher than the temperature of the melted petrolatum to provide a heated antigen solution; c) mixing the melted petrolatum and the heated antigen solution to give a melted mixture; and d) cooling the melted mixture to provide the petrolatum-based composition.

31. The petrolatum-based composition according to claim 30, wherein the heated antigen solution has a temperature that is about 1°C to about 5°C higher than the temperature of the melted petrolatum.

32. The petrolatum-based composition according to claim 30 or claim 31, wherein an emulsifier is not used.

33. The petrolatum-based composition according to any one of claims 1-32, wherein the liquid comprising the at least one antigen is substantially suspended in the petrolatum.

34. The petrolatum-based composition according to any one of claims 1-32, wherein the liquid comprising the at least one antigen is substantially suspended in the petrolatum such that no liquid is observed to separate from the petrolatum-based composition for at least 3 months.

35. The petrolatum-based composition according to any one of claims 1-32, wherein the liquid comprising the at least one antigen is substantially suspended in the petrolatum such that no liquid is observed to separate from the petrolatum-based composition for at least 6 months.

36. The petrolatum-based composition according to any one of claims 1-32, wherein the liquid comprising the at least one antigen is permanently suspended in the petrolatum.

37. The petrolatum-based composition according to any one of the preceding claims 1-36, wherein the at least one antigen maintains efficacy for at least 3 months when stored at 40°C ± 2°C and 75% ± 5% relative humidity.

38. A method of vaccinating a subject, the method comprising applying the petrolatum-based composition according to any one of the preceding claims 1-37 to an area of the skin of a subject in need of vaccination.

39. A method of treating a subject, the method comprising applying the petrolatum-based composition according to any one of the preceding claims 1-37 to an area of the skin of a subject in need of treatment.

40. A method of causing an immune response in a subject, the method comprising applying the petrolatum-based composition according to any one of the preceding claims 1-37 to an area of the skin of a subject in need of treatment.

41. A method of vaccinating a subject in need thereof using a topical transdermal delivery system, the method comprising applying the petrolatum-based composition according to any one of the preceding claims 1-37 to an area of the skin of a subject in need of vaccination.

42. A process for preparing a petrolatum-based transdermal vaccine composition, the process comprising:

a) dissolving at least one antigen in a liquid to provide an antigen solution; b) heating petrolatum to a temperature sufficient to cause the petrolatum to melt to give a melted petrolatum and heating the antigen solution to a temperature higher than the temperature of the melted petrolatum to provide a heated antigen solution; c) mixing the melted petrolatum and the heated antigen solution to give a melted mixture; and d) cooling the melted mixture to provide the petrolatum-based transdermal vaccine composition.

43. The process according to claim 42, wherein the heated antigen solution has a temperature that is about 1°C to about 5°C higher than the temperature of the melted petrolatum.

44. The process according to claim 42 or claim 43, wherein an emulsifier is not used.

45. The process according to any one of the preceding claims 42-44, wherein the liquid is a polar solvent.

46. The process according to any one of the preceding claims 42-44, wherein the liquid is water.

47. The process according to any one of the preceding claims 42-46, wherein the composition comprises greater than about 80% by weight petrolatum.

48. The process according to any one of the preceding claims 42-46, wherein the composition comprises greater than about 85% by weight petrolatum.

49. The process according to any one of the preceding claims 42-46, wherein the composition comprises greater than about 90% by weight petrolatum.

50. The process according to any one of the preceding claims 42-46, wherein the composition comprises greater than about 95% by weight petrolatum.