Compositions and penetration enhancing delivery systems for topical and transdermal administration of pharmaceuticals and cosmetics, and methods of using same

Abstract

The present invention provides a penetration enhancer delivery system, whereby an active agent is delivered at the intracellular and organelle level. The system includes a therapeutically effective amount of at least one active agent, and at least one dermal penetration enhancer, wherein a dermal penetration enhancer comprises CoR. The invention also includes methods of treatment, including increasing bone density, rejuvenating skin and regrowing hair.

Description

[0001] COMPOSITIONS AND PENETRATION ENHANCING DELIVERY SYSTEMS FOR TOPICAL AND TRANSDERMAL ADMINISTRATION OF PHARMACEUTICALS AND COSMETICS, AND METHODS OF USING SAME

[0002] Field of the Present Invention

[0003] The present invention relates to penetration-enhancing delivery systems (penetrating at the intracellular and organelle levels), for example, topical and transdermal drug and cosmetic compositions and delivery thereof. More specifically, the invention relates to topical and transdermal penetration enhancing compositions for use in the local or systemic delivery of physiologically active agents, or cosmetic agents, to an animal, including a human.

[0004] Background of the Present Invention

[0005] The skin, being the largest organ in humans, offers a pathway for drug delivery, bypassing several drawbacks of oral and parenteral routes. Drug delivery through the skin involves transferring the drug from a topical product to a locally targeted area with dermal circulation throughout the body and deeper tissues. However, the skin's barrier function presents a challenge for delivery. Conventional formulations with micronized active components, such as lotions, gels, ointments and creams, often result in poor penetration when delivering drugs to the skin.

[0006] Deficiencies in the state of the art of active agent delivery relate to lack of efficacy of drugs and cosmetics that are applied topically or transdermally because of the low drug flux across the skin; examples of such drugs include testosterone, amlodipine, fentanyl, and buprenorphine. Other drugs (e.g., glyceryl trinitrate) are difficult to deliver due to the inability to adequately control the rate of drug delivery or require a very large application area. For example, polar drugs tend to penetrate the skin too slowly due to the protective banders of the skin. Since most drugs are of a polar nature this limitation is significant.

[0007] The rate of drug delivery across a dermal surface can be increased by dermal penetration enhancers. However, a problem with known dermal penetration enhancers is that they are often toxic, irritating or allergenic. These enhancers tend to be proton accepting solvents such as dimethylsulfoxide (DMSO) and dimethyacetamide. Dimethyl sulfoxide and dimethyl acetamide are not clinically acceptable for such reasons. Although N,N-diethyl-m-toluamide (Deet) and 1- dodecal-azacycloheptane-2-one (Azone®) have lower reported toxicities, their toxicities are still such that they are not widely used. The present invention overcomes the disadvantages of the prior art by providing drug delivery systems that simplify current methods, improve efficacy and ensure safety without toxicity. The systems include compositions which are designed to directly target intracellular communication and organelle level delivery through the mitochondrial pathway. The compositions function as both a carrier and therapeutic agent while minimizing off-target accumulation. The compositions also function as transdermal penetration enhancers which are effective while not being irritating or toxic.

[0008] Summary of the Present Invention

[0009] In one aspect, the present invention provides a penetration enhancer delivery system, whereby an active agent is delivered at the intracellular and organelle level. The system comprises: a therapeutically effective amount of at least one active agent and at least one dermal penetration enhancer, wherein a dermal penetration enhancer comprises CoR. The active agent is a pharmaceutical drug, or prodrug thereof, or a cosmetically functional composition. In some embodiments, the delivery system further comprises a co-solvent, surfactant, emulsifier, antioxidant, preservative, stabilizer, diluent or a mixture of two or more of said components. In some embodiments, the delivery system is applied by an aerosol or spray, or by transdennal patch, or by lotion, cream or ointment. In some embodiments, CoR is present in the amount of about 0.01 to about 50 wt % of the system.

[0010] In one aspect, the present invention provides a method of treating a disease or condition in a subject in need thereof. The method comprises applying an effective amount of an active agent, in the form of the penetration enhancer delivery system, to a dermal surface or mucosal membrane of said subject, hi one embodiment, the active agent comprises male hormone replacement, female hormone replacement, androgen replacement, male contraception or female contraception. In one embodiment, the disease or condition is soft tissue injury, narcotic withdrawal, severe post-operative pain, motion sickness, oestrogen dependent breast cancer, prostatic enlargement and / or prostatic cancer, alopecia and acne, anxiety disorders, male impotence, Raynauds syndrome and varicose veins, sleep disorders, jetlag, herpes virus infections, deep vein thrombosis, migraine, high blood pressure, malaria, diagnosis of cystic fibrosis, asthma, nocturnal asthma, a diminished left ventricular ejection fraction, heart disease or bone mineral density loss. In one embodiment, the condition is a cosmetic condition, e.g., wrinkled skin, dry skin, age-related thing of the skin, dark spots, alopecia and enlarged pores, and acne scars.

[0011] In one aspect, the invention provides a method to increase or stabilize bone mineral density. The method comprises administering about 250mg to about 700mg of CoR to a subject in need thereof, one to four times a day. In one embodiment, the method comprises administering about 500mg capsule of CoR to a subject in need thereof three times a day.

[0012] In one aspect, the invention provides a method to increase left ventricular ejection fraction (LVEF). The method comprises administering about 250mg to about 700mg of CoR to a subject in need thereof, one to four times a day. In one embodiment, the method comprises administering about 500mg capsule of CoR to a subject in need thereof three times a day.

[0013] In one aspect, the invention provides a method of rejuvenating facial skin and / or increasing dermal thickness. The method comprises topically administering a therapeutic facial cream, wherein the cream comprises a CoR enhancer and at least one active agent, wherein the active agent is an antioxidant, a vitamin, collagen, a hormone, a mineral or combinations thereof, wherein the facial cream comprises about 20wt% to about 60wt% of the active agents with the balance being CoR in a cream carrier. In one embodiment, the facial cream comprises about 50wt% of the active agents with the balance being CoR in a cream earner. Examples of active agents include coenzyme Q10, vitamin E, retinol, vitamin D3, vitamin K2, B complex, biotin, copper, zinc, selenium, magnesium, calcium and potassium.

[0014] In one aspect, the invention provides a method of regrowing hair. The method comprising topically administering a hair regrowth cream, wherein the cream comprises a CoR enhancer and at least one active agent, wherein the active agent is an antioxidant, a vitamin, collagen, a hormone, a mineral or combinations thereof, wherein the hair regrowth cream comprises about 20wt% to about 60wt% of the active agents with the balance being CoR in a cream carrier. In one embodiment, the hair regrowth cream comprises about 50wt% of the active agents with the balance being CoR in a cream carrier.

[0015] Brief Description of the Drawings

[0016] FIG. 1 show's a 3D facial reconstruction of a subject before and after a facial cream therapy comprising CoR.

[0017] FIG. 2 shows photographs of subject before and after a hair growth therapy comprising CoR. Detailed Description of the Present Invention

[0018] The present invention includes compositions which function as delivery systems (e.g., carriers) and penetration enhancers when used along with active agent(s), and as therapeutic agents per se. The composition comprises CoR (Cofactor Raphanin). The invention also includes methods of delivery and methods of treatment. The compositions, systems and methods of the present invention are suitable for use for all animals, including, for example, humans.

[0019] CoR (Cofactor Raphanin) is a natural polar molecule classified as a sulfoxide, typically represented by the structural formula R-S(=O)-R', where R and R' denote organic groups. The bond between the sulfur and oxygen atoms exhibits characteristics of both a dative bond and a polarized double bond. The double-bond resonance form suggests that there are 10 electrons surrounding sulfur.

[0020] CoR is also known as "sulforaphene" or "raphanin," with the molecular formula C6H9NOS2. CoR is designated by several aliases, including sulforaphen, sulphoraphen, 4- isothiocyanato-1-(methylsulfinyl)-1-butene, and 4-methylsulfmyl-3-butenyl isothiocyanate, with an approximate molecular weight of 175.26 g / mol. and the following structure:

[0021] CoR is a naturally occurring compound found, for example, in the seeds of radishes (Raphani semen). CoR, derived from its precursor glucoraphanin (a type of glucosinolate), exhibits stability through hydrolysis facilitated by the enzyme myrosinase or gut bacteria. Therefore, in certain embodiments, sulforaphene can be isolated from certain root vegetables, such as radish. Isolated naturally occurring sulforaphene can also be purified for use in the present methods. The term “isolated,” when used in reference to a compound such as sulforaphene means that the compound has been removed from its naturally occurring environment or the environment from which it was formed and is substantially free of other molecules material. By “substantially free”, it is meant that isolated compound accounts for at least 60%, 70%, 80%, 90%, or 95% (by dry weight or volume) of a composition or preparation. For example, an isolated sulforaphene composition can be substantially free from other compounds (proteins, lipids, collagen) or materials of the plant from which it was obtained, i.e., sulforaphene represents more than about 80% of the volume of the preparation, more than about 90% of the volume of the preparation or more than about 95% of the volume of the preparation. The level of purification can be based on the intended use. Methods for isolating and purifying sulforaphene from radish seeds are known by those of ordinary skill the art, and any such method can be used here. For example, radish seeds may be defatted prior to forming an aqueous extract using known defatting procedures such as those set forth in West, L. et al., JAgric. Food Chem. (2004) 52, pp. 916-926 the entire contents of which is hereby incorporated by reference. Here, the plant or a portion thereof may be ground, pulverized or blended prior to addition of aqueous extract or simultaneously with the addition of an aqueous extract. Extraction of sulforaphene may be conducted with water or water containing an organic solvent, such as ethyl alcohol. Specifically, in some instances, an aqueous extract of crucifer plants is formed by contacting crucifer seeds with water having a temperature of 60 to 110° C for at least 5 minutes. The aqueous extract can then be contacted with an adsorbent that preferentially adsorbs to sulforaphene instead of other compounds in the extract, such as activated carbon, silica, chemically-modified silica, bleaching clay and the like as well as and mixtures thereof. Once the desired compound is adsorbed it can be isolated from highly molecular weight proteins or compounds. In other embodiments, the sulforaphene can be synthetically produced such as, for example, clink chemistry, combinatory chemistry, cycloaddition reactions or solid-phase synthesis. Additionally, other known methods for forming synthetic sulforaphene will be readily known by those of skill in the art.

[0022] Compositions and Delivery Systems

[0023] The present invention relates to CoR topical and transdermal drug and cosmetic composition delivery, and vehicles thereof. More specifically, the invention relates to topical and transdermal penetration enhancing agents for use in the local or systemic delivery of physiologically active agents, or cosmetic agents, to an animal, including a human. The invention also relates to systems and vehicles for the delivery of physiologically active agents across the skin layers, a dermal surface or mucosal membrane of an animal.

[0024] The present delivery systems and methods of delivery include local, systemic, topical and transdermal delivery of active agent(s). The present delivery systems / methods outperform current systems / methods by enhancing therapeutic efficacy while ensuring safety and minimizing toxicity. In some embodiments, the present delivery systems and methods are specifically designed for intracellular and organelle-targeted delivery though the mitochondrial pathway.

[0025] The CoR transdermal penetration enhancers optimize local delivery methods. The delivery systems containing the active agent(s) can be administered topically to the skin or to the mucosa. The delivery systems increase drug efficacy, reduce systemic side effects, and provide therapeutic concentrations necessary for preventing infections from entering the bloodstream. In some embodiments, the delivery systems enable targeted effects directly on the tracheal mucosa while facilitating the systemic delivery of active pharmaceutical agents and cosmetic compounds.

[0026] In one aspect, the present invention provides compositions and systems to enhance the delivery of at least one physiologically, or cosmetically, functional, active agent. These compositions and systems comprise CoR, i.e., a CoR component. In one embodiment, these compositions / systems are administered topically or on mucosal membranes to enhance the activity and / or penetration of an active agent. In one embodiment, these compositions / systems are administered to enhance the transdermal delivery of at least one active agent.

[0027] The “active agent” can be a natural ingredient, nutraceutical, pharmaceutical drug, or prodrug, or a cosmetic composition. A “prodrug” of a physiologically active agent is a structurally related compound, or derivative of an active agent, which is converted to the desired physiologically active compound in the body of the animal. The CoR component improves the rate of transport of an active agent across skin layers or mucous membranes, whether it be for local application (i.e., minimal penetration) or systemic delivery or delivery into skin cells (i.e., transdermal delivery). A list of active agents are provided herein below.

[0028] The CoR component itself has therapeutic activity. In some embodiments, the compositions and systems of the present invention simultaneously function as both a carrier and a therapeutic agent. This dual functionality results in a delivery system that markedly reduces off-target effects while enhancing the precision of targeted delivery. In contrast, state of the art delivery systems (e.g., nanocarriers) solely serve as transport vehicles and lack the capability to determine the accumulation of carrier materials post-delivery.

[0029] The compositions / systems are formulated according to their desired end use. That is, depending on the specific active agent and end use, the relative amount of the CoR component in a composition is varied. For example, in some embodiments, the CoR component is present so that the active agent only penetrates one or more skin layers; in other embodiments, the CoR component is present so that the active agent penetrates more deeply to yield a systemic effect or penetrate the skin intracellularly to affect the mitochondria of the skin cells in all layers of skin.

[0030] For example, the topically-applied compositions / systems of the present invention can target sites in one or more different skin layers (i.e. epidermis, dermis and hypodermis), the skin appendages (e.g. hair follicles with associated sebaceous glands, sweat glands and nails), and underlying tissues. The stratum corneum is the outer layer of the skin (part of the epidermis), composed of (approximately 15) layers of terminally differentiated keratinocytes made primarily of the proteinaceous material keratin arranged in a “brick and mortar” fashion with the mortar being comprised of a lipid matrix made primarily from cholesterol, ceramides and long chain fatty acids. Surprisingly, the compositions and systems of the invention exhibit appreciable penetration of active agents into the stratum corneum which has previously presented a formidable barrier to drug absorption.

[0031] In some embodiments, the active agents of the topically-applied compositions / systems penetrate more deeply for transdermal delivery. The term “transdermal” refers to being able to pass through unbroken skin. More specifically, the transdermal systems are designed to penetrate through one or all skin layers to exert their effects on deeper or more distant tissues, or even elicit a systemic effect. Transdermal penetration can be: appendageal (intercellular) penetration and transcellular (intracellular) permeation. Appendageal penetration involves the passage of active agents through the hair follicle, sebaceous glands, or sweat glands. In this embodiment, the CoR component functions as a transdermal penetration enhancer by facilitating the local and systemic delivery of active drugs and cosmetic agents by crossing the stratum corneum to penetrate deeper into epidermal layers, dermis, and mucosal membranes in humans and animals.

[0032] An example of a transdermal systemic active agent delivery is a transdermal patch device. These patch devices are like bandages which are attached to the surface of intact skin for prolonged periods of time to allow a desired systemic delivery of an active agent. These transdermal patch devices occlude the skin and trap the active agent, together with volatiles and vehicle excipients, between the skin and an outer impermeable backing membrane. The membrane prevents the evaporation or diffusion of vehicle excipients, volatiles and active agent into an environment other than the target skin site. The prolonged length of time required for transfer of the active agent and excipients from the patch into the skin using the penetration enhancer of the present invention does not result in local skin irritation.

[0033] In some embodiments, the CoR penetration enhancer serve as topical enhancers specifically crafted for targeted delivery to the mitochondria, optimizing local administration techniques. Transcellular permeation occurs through the comeocytes (specialized skin cells in the stratum comeum) and the intracellular lipid matrix in the mitochondrial. The CoR component facilitates a direct pathway through the skin layers of the epidermis, dermis, and finally the hypodermis, since mitochondria exists inside all skin layers.

[0034] In another aspect, the present invention provides methods for administering at least one systemic- or locally-acting physiologically, or cosmetically functional, active agent, to an animal which comprises applying an effective amount of the active agent in the form of a composition or delivery system according to the present invention. Although it is preferred that the active agent and the CoR penetration enhancer be delivered by simultaneous administration, the penetration enhancer may be applied before or after the application of the physiologically active agent, if desired.

[0035] Penetration Enhancing Formulations

[0036] The delivery compositions and systems preferably comprise an active agent intimately mixed with the CoR dermal penetration enhancer. The relative amounts of a specific active agent and CoR is dependent upon numerous factors, including, for example, the desired depth of skin penetration (e.g., dermal or transdermal), whether the active agent is to have a systemic or localized activity, whether there are additional penetration ingredients in a particular formulation, the size of the application area, the desired rate of absorption, the particular type of delivery system (e.g., occlusive or non-occlusive), etc.

[0037] The concentration / amount of an active agent used in the delivery system will depend on its properties and may be equivalent to that normally utilized for the particular agent in conventional formulations. Both the amount of active agent and the amount of CoR penetration enhancer will be influenced by the type of effect desired. For example, if a more localized effect is required in treating a superficial infection with an antibacterial agent, lower amounts of physiologically active agents and lower concentrations of enhancer may be appropriate. As another example of where lower concentrations of CoR enhancer may be appropriate is for cosmetic agents for moisturizing, rejuvenation or lightening of skin. Where deeper penetration is desired, as in the case of local anesthesia, a higher concentration of CoR enhancer may be appropriate. Where it is desired to achieve systemic concentration of an active agent, proportionately higher concentrations of the enhancer of the invention may be required in the transdermal drug delivery system, and the amount of active agent included in the composition should be sufficient to provide the blood level desired. However, it should be noted, because of the effect of the penetration enhancer of the invention, the dosage of an active agent may often be less than that conventionally used. Typically, a dosage near the lower end of the useful range of the particular agent may be employed initially and increased as indicated from the observed response if necessary.

[0038] Surprisingly, CoR exhibits appreciable penetration into and substantivity for the outer layers of the skin, namely the stratum corneum which has previously presented a formidable barrier to drug absorption. “Substantivity” is the extended association between the delivery system of the present invention and the skin. The stratum corneum creates the rate-limiting bander for diffusion of the active agent across the skin. CoR surprisingly enhances the absorption of active agents, and prodrugs thereof, through the skin and mucous membranes to yield systemic effects while avoiding the significant pharmacological disadvantages and toxicities of prior art enhancers.

[0039] Without being bound to a specific mechanism of action, it is believed that upon application to the skin, the delivery system facilitates the redox reaction entry of the active agent and CoR into the skin layers and into the skin cells. Once inside the skin, the CoR may serve as a carrier entering the lipid matrix of mitochondria and / or act as a solubilizer, enhancing the penetration rate of the active agent through the skin layers and into the subject being treated. This process occurs as mitochondria (an organelle inside a skin cell) are present in all skin layers, allowing enhanced transdermal penetration delivery into skin cells. Thus, the redox reaction of CoR occurs in mitochondria.

[0040] It is believed that the CoR transdermal penetration enhancer is readily absorbed into the stratum corneum in sufficient quantities to form a reservoir or depot of the dermal penetration enhancer within the stratum corneum. As the dermal penetration enhancer crosses through the skin to form the skin-depot, the active agent contained therein is transported through the skin and contained within the depot. “Skin-depot” refers to a reservoir or deposit of active agent and dermal penetration enhancer within the stratum corneum, whether it be intra-cellular (within keratinocytes) or inter-cellular. These depots are believed to form within the lipid matrix of the stratum corneum wherein the lipid matrix creates a rate-limiting barrier for diffusion of the active agent across the skin and allows the dennally administered active agent to be systemically released over a period of time, usually up to 24 hours or more.

[0041] The amount of the CoR penetration enhancer present may, for example, be in the range from about 0.01 to about 50 wt % of a composition or delivery system, more typically, from about 1.0 to about 25 wt % of a composition or delivery system, and more typically, from about 2.0 to about 10 wt % of a composition or delivery system, with the balance substantially comprising active agent(s). Additionally, the amount of the CoR penetration enhancer will vary depending on the species of animal, its age, weight and the condition to be treated, as would be known to a skilled artisan.

[0042] A large range of systemic active agents can be delivered to a subject in need thereof by the compositions, systems and methods of the present invention. For example, the delivery system delivers a physiologically active agent to an animal without the need for an occlusive patch device. For example, the drug delivery system of the present invention may be applied to the skin by means of an aerosol, spray, pump-pack, brush, swab, or other applicator.

[0043] In addition to the active agent and the CoR penetration enhancer of the present invention, further additives can be included in the compositions and systems of the present invention. Examples of additives are earners, stabilizers, anti-oxidants, colorants, diluents and excipients that do not alter the performance of sulforaphene to such an extent that treatment is ineffective. Exemplar)' carriers include, but are not limited to, physiological saline, Ringer's, phosphate solution or buffer, buffered saline, and other carriers known in the art. The carrier can be a solid or a liquid, or both, and can contain from about 0.1% to 100%, 0.1% to 90%, 0.1% to 80%, 0.1% to 70%, 0.1% to 60%, 0.1% to 50%, 0.1% to 40%, 0.1% to 30%, 0.1% to 20% or 0.1% to 10% by weight of sulforaphene. For example, the compositions of the present invention can be in the form of ointments, creams, shampoos, conditions, bar soap or liquid soaps, lotions, pastes, gels, powders, jellies, solutions, suspensions, aerosols, oils, emulsions, liposomes, vesicles, suppositories, mousses, sprays (e.g., nasal sprays), aerosols, buccal and sub lingual tablets, gingival and buccal patches or any one of a variety of transdermal devices. Carriers may include petroleum jelly (e.g., Vaseline®), lanolin, polyethylene glycols, alcohols, and combinations thereof. In some embodiments, the drug delivery compositions / systems according to the present invention can include co-solvents, surfactants, emulsifiers, antioxidants, preservatives, stabilizers, diluent or combinations thereof. The amount and type of components used should be compatible with the dermal penetration enhancers of this invention as well as with the active ingredient. A co-solvent or other standard adjuvant, such as a surfactant, may be required to maintain the agent in solution or suspension at the desired concentration. These are preferably used in the range 1 to 50%. Examples of surfactants include ethoxylated fatty alcohols, glycerol mono stearate, phosphate esters. Emulsifiers and surfactants can be included in the range of 0.1 to 10%, as may be preservatives such as hydroxybenzoate esters for preservation of the compound preferably in amounts of 0.01 % to 0.5 %. Typical co-solvents and adjuvants may be ethyl alcohol, isopropyl alcohol, acetone, dimethyl ether and glycol ethers such as diethylene glycol mono ethyl ether. These may be used in amounts of 1 to 50%.

[0044] Methods of Treatment (Topical Administration)

[0045] In another aspect, the present invention provides a method of treatment or prophylaxis of a condition or a disorder in an animal which comprises administering the CoR composition without an additional active agent. A therapeutically effective amount of CoR by itself, typically in a carrier (e.g., earner cream), is applied to a dermal surface or mucosal membrane of an animal, in need of such treatment.

[0046] In another aspect, the present invention provides a method for the treatment or prophylaxis of a disease or condition in an animal which comprises topical or transdermal administration to a dermal surface or mucosal membrane of an animal, in need of such treatment, of a therapeutically effective amount of a delivery system according to the present invention, along with an active agent.

[0047] In another aspect, the present invention provides a method for the treatment or prophylaxis of a cosmetic condition in an animal which comprises transdermal administration to a dermal surface or mucosal membrane of said animal, in need of such treatment, of a therapeutically effective amount of a cosmetic agent in delivery system according to the present invention. For example, the cosmetic agent can affect the appearance of skin (e.g., rejuvenate sagging or thinning skin, increase dermal thickness, lighten or brighten the skin, reduce wrinkles or dark spots, and moisturize the skin). While administering the delivery systems of the invention with cosmetic agents, additional devices may be employed, such as, for example, microneedling devices, micro-coring or laser devices.

[0048] In one embodiment of the invention, a therapeutic facial cream is provided. Preferably, along with the CoR enhancer, active ingredients are added, as described herein. Some examples of active ingredients include: antioxidants (e.g., coenzyme Q10), vitamins (e.g., vitamin E, retinol (vitamin A), vitamin D3+K2, B complex, biotin), collagen, hormones (e.g., testosterone, progesterone, estrogen), minerals (e.g., copper, zinc, selenium, magnesium, calcium, potassium) and silica. Further active ingredients may include peptides, such as, for example, palmitoyl pentapeptide-4. Typically, a facial cream is about 20wt% to about 60wt% of the active ingredients with the balance being CoR in a cream earner; more typically, the facial cream contains about 50wt% of the active agent ingredients and about 50wt% of the CoR cream carrier. Typically, the active ingredients are in about equal quantities to one another.

[0049] In one embodiment of the invention, a hair regrowth cream is provided. Preferably, along with the CoR enhancer, active ingredients are added, as described herein. Some examples of active ingredients include: antioxidants (e.g., coenzyme Q10), vitamins (e.g., vitamin E, retinol (vitamin A), vitamin D3+K2, B complex, biotin), collagen, and hormones (e.g., testosterone, progesterone, estrogen). Typically, a hair regrowth cream is about 20wt% to about 60wt% of the active ingredients with the balance being a CoR in a cream carrier; more typically, the hair regrowth cream contains about 50wt% of the active agent ingredients and about 50wt% of the CoR cream carrier. Typically, the active ingredients are in about equal quantities to one another.

[0050] Oral Dietary Supplement Compounds Containing CoR

[0051] In one aspect of the present invention, oral dietary supplement compounds comprising CoR are provided. For example, the compounds can be administered in the form of tablets, capsules, pills, troches, elixirs, suspensions, syrups, wafers, chewing gum and the like. The supplements can be administered to treat any of the diseases or conditions listed herein. Typically, the dosage of CoR to treat such diseases and conditions is about 250mg to about 700mg of CoR, for example, about 500mg, about one to four times a day, for example three times a day.

[0052] In one embodiment, the present invention provides a method to increase or stabilize bone mineral density. The method comprises administering about 250mg to about 700mg of CoR to a subject in need thereof, for example, about 500mg, about one to four times a day, for example three times a day. A subject in need thereof would be a person who would benefit from inhibiting or reversing bone mineral density loss, or increasing bone mineral density. In an embodiment, a subject in need thereof is administered a capsule consisting essentially of about 500 mg of CoR, optionally, along with an excipient / carrier.

[0053] In one embodiment, the present invention provides a method to increase left ventricular ejection fraction (LVEF). The method comprises administering about 250mg to about 700mg of CoR to a subject in need thereof, for example, about 500mg, about one to four times a day, for example three times a day. A subject in need thereof would be a person who would benefit from increasing their LVEF due to a heart disease or disorder. In an embodiment, a subject in need thereof is administered a capsule consisting essentially of about 500 mg of CoR, optionally, along with an excipient / carrier.

[0054] In some embodiments, the supplement compound can further comprise an active ingredient as provided herein.

[0055] Typically, the supplement compounds of the invention can be formulated with a suitable pharmaceutical carrier (vehicle) or excipient, as understood by practitioners in the art. These preparations can be made according to conventional chemical methods. In the case of tablets for oral use, carriers commonly used include lactose and corn starch, and lubricating agents such as magnesium stearate are commonly added. For oral administration in capsule form, useful carriers include lactose and com starch. Further examples of carriers and excipients include milk, sugar, certain types of clay, gelatin, stearic acid or salts thereof, calcium stearate, talc, vegetable fats or oils, gums, glycols, emulsifying and / or suspending agents, sweetening and / or flavoring agents.

[0056] Vaccines

[0057] Current vaccine delivery systems predominantly elicit systemic immune responses, which, while valuable, are insufficient for providing robust protection at mucosal surfaces, key entry points for viral pathogens. These mucosal regions, such as the nasal cavity and throat, play a crucial role in the initial stages of viral infection. Consequently, traditional systemic vaccines, which are administered via intramuscular routes, may struggle to activate and sustain local immune defenses at these crucial sites. As a result, these vaccines frequently do not prevent viral infections in the upper airway, impeding their overall effectiveness. This inadequacy is particularly concerning in the context of respiratory viruses, where the upper airway is often the primary site of invasion. Furthermore, the inability of systemic vaccines to adequately mitigate viral transmission dynamics can leave vulnerable populations, including the elderly and immunocompromised individuals, at heightened risk. To improve vaccine efficacy, it is essential to develop delivery systems that target mucosal immunity more effectively. Potential strategies may include the use of intranasal or oral vaccines, which can stimulate localized immune responses. These alternative delivery methods can harness the mucosal immune system’s unique properties, such as the production of secretory IgA antibodies and the recruitment of local immune cells, ultimately enhancing protective mechanisms at the site of entry. Additionally, novel formulations might consider adjuvants specifically designed to promote mucosal immunity, and microsphere or nanoparticle technologies could facilitate targeted delivery and sustained release of the vaccine components.

[0058] Nasal vaccines induce both systemic and mucosal immune responses, offering dual protection. This targeting of mucosal surfaces, the primary entry' points for viruses, boosts local immunity and decreases the risk of initial viral invasion. However, the use of cCHP nanocarriers for nasal vaccine delivery raises concerns regarding potential unintended consequences.

[0059] In one embodiment of the present invention, the CoR compositions are used as carriers for vaccines (i.e., CoR carriers), for example, nasal vaccines. These CoR carriers offer significant advantages to nasal vaccine delivery systems utilizing the mitochondrial pathway. In one embodiment, the present invention provides methods to boost cellular innate immunity by placing CoR composition into a vaccine, or into an adjuvant of a vaccine. This method enables direct delivery of vaccines to intracellular and organelles levels, effectively boosting cellular innate immunity against pathogens. Examples of vaccine types include DNA and RNA vaccines.

[0060] The messenger RNA (mRNA) therapeutic platform is particularly promising for addressing infectious diseases, cancer, and genetic disorders. While lipid nanoparticle-mRNA or polymer systems have been developed for targeted mRNA delivery, challenges related to safety, toxicity, and delivery materials remain.

[0061] In contrast, in the CoR carrier-mRNA system of the present invention, the CoR composition activates FAD nearly three times more efficiently, significantly enhancing mRNA delivery' efficacy due to FAD's involvement in 89% of the human genotype. This system effectively overcomes many issues associated with current nanoparticle applications. The inventor found that using additional materials, like modified viruses for mRNA delivery, may result in side effects associated with other genes within that modified mRNA family,

[0062] In one embodiment, the delivery systems and methods are nasal vaccines. As compared with current nasal vaccine delivery methods, the present nasal vaccines significantly enhance efficacy and reduce systemic side effects. The present methods achieve therapeutic concentrations needed to effectively prevent pathogens from entering the bloodstream. Additionally, the present vaccines allow for precise targeting of therapeutic effects directly on the tracheal mucosa, while improving the systemic bioavailability of active pharmaceutical agents through advanced delivery mechanisms.

[0063] Examples of RNA (e.g., mRNA) vaccines include polynucleotide encoding a Middle East respiratory syndrome coronavirus (MERS-CoV) antigen and / or Bat SARS-like coronavirus WIV1, (SL-CoV-WIVl).

[0064] In one embodiment, the present delivery systems comprise delivery of cellular and gene therapies. These systems enable precise intracellular and organelle-targeted delivery, since CoR is a polar molecule capable of penetrating cellular membranes and directly reach the mitochondria. The ability to target arid deliver therapeutic agents directly to mitochondria benefits regenerative medicine and addresses complex disorders.

[0065] Example Diseases and Conditions to be Treated and / or Prevented

[0066] Examples of diseases or conditions that may be treated and / or prevented by using the drug delivery systems / compositions and methods of the present invention include, but are not limited to, male hormone replacement in testosterone deficient hypogonadal men, female hormone replacement therapy for postmenopausal women, androgen replacement therapy for females lacking libido, male contraception, female contraception, soft tissue injury, bone loss, mineral loss, osteoporosis, narcotic withdrawal, severe post-operative pain, motion sickness, oestrogen dependent breast cancer, prostatic enlargement and / or prostatic cancer, alopecia and acne, anxiety disorders, male impotence, Raynauds syndrome and varicose veins, sleep disorders such as jetlag, herpes virus infections, deep vein thrombosis, migraine, high blood pressure, malaria, diagnosis of cystic fibrosis and asthma, particularly nocturnal asthma, smoking cessation, psychotic disorders, severe postnatal depression, virilization and obesity.

[0067] Examples of cosmetic conditions include sagging skin due to loss of the deeper subcutaneous tissue of muscle, fat and connective tissue; irregular connective tissue; loss of connective tissue, hair follicles, blood vessels, lymphatic vessels, sweat glands, thin skin; wrinkled skin; dry skin; dark spots; alopecia; enlarged pores; acne; and acne scars.

[0068] Cosmetic treatments include rejuvenating the skin, lightening or brightening the skin, reducing wrinkles or dark spots or acne, moisturizing the skin, treating / reversing alopecia (hair loss), pore and acne scar reduction. Additionally, cosmetic effects include reversing conditions due to skin loss of nutrition (ATP-bioenergy) and mitochondrial dysfunction since mitochondria exists in all skin layers.

[0069] Examples of Specific Active Agents;

[0070] Physiologically active agents that may be used in the topical or transdermal drug delivery systems of the present invention include any locally or systemically active agents which are compatible with the sulforaphene dermal penetration enhancer of the present invention and which can be delivered through the skin with the assistance of the dermal penetration enhancer to achieve a desired effect. Both pharmaceutical and cosmetic active agents can be delivered by the systems and methods of the present invention.

[0071] Preferred active agents include steroids and other hormone derivatives, more preferably testosterone, oestradiol, ethinyloestradiol, progesterone, norethisterone acetate and gestodene; and non-steroidal anti-inflammatory drugs, preferably ibuprofen, ketoprofen, flurbiprofen, naproxen and diclofenac; and opioid analgesics, preferably fentanyl and buprenorphine; and antinauseants, preferably prochlorperazine, metochlopramide, ondansetron and scopolamine; and antioestrogens, preferably tamoxifen and epitiostanol and the aromatase inhibitors, preferably exemestane and 4-hydroxy-androstenedione and its derivatives; and 5-alpha reductase inhibitors, preferably finasteride, turosteride, LY191704 and MK-306; and anxiolytics, preferably alprazolam; and prostaglandins, preferably alprostadil and prostacylcin and their derivatives; and melatonin; and anti-virals, preferably n-docosanol, tromantadine and lipophilic pro-drugs of acyclovir; and low molecular weight heparin, preferably enoxaparin; and anti-migraine compounds, preferably sumatriptan; and antihypertensives, preferably clonidine, amlodipine and nitrendipine; and anti-malarials, preferably primaquine; and minoxidil and minoxidil pro-drugs; and pilocarpine; and bronchodilators, preferably salbutamol, terbutaline, salmeterol; and anti- depressants, preferably ibogaine, bupropion and rolipram; and anti- Alzheimer's agents, preferably fluphenazine and haloperidol; and anti-parkinson agents, preferably N-0923; and antiandrogens, preferably cyproterone acetate; and anorectic agents, preferably mazindol. Further examples of active agents (grouped by therapeutic class) include:

[0072] Alimentary System

[0073] Antidiarrhoeals such as diphenoxylate, loperamide and hyoscyamine.

[0074] Cardiovascular System

[0075] Antihypertensives such as hydralazine, minoxidil, captopril, enalapril, clonidine, prazosin, debrisoquine, diazoxide, guanethidne, methyldopa, reserpine, trimetaphan.

[0076] Calcium channel blockers such as diltiazem, felodopine, amlodipine, nitrendipine, nifedipine and verapamil.

[0077] Antiarrhyrthmics such as amiodarone, flecainide, disopyramide, procainamide, mexiletene and quinidine.

[0078] Antiangina agents such as glyceryl trinitrate, erythritol tetranitrate, pentaerythritol tetranitrate, mannitol hexanitrate, perhexilene, isosorbide dinitrate and nicorandil.

[0079] Beta-adrenergic blocking agents such as alprenolol, atenolol, bupranolol, carteolol, labetalol, metoprolol, nadolol, nadoxolol, oxprenolol, pindolol, propranolol, sotalol, timolol and timolol maleate.

[0080] Cardiotonic glycosides such as digoxin and other cardiac glycosides and theophylline derivatives.

[0081] Adrenergic stimulants such as adrenaline, ephedrine, fenoterol, isoprenaline, orciprenaline, rimeterol, salbutamol, salmeterol, terbutaline, dobutamine, phenylephrine, phenylpropanolamine, pseudoephedrine and dopamine.

[0082] Vasodilators such as cyclandelate, isoxsuprine, papaverine, dipyrimadole, isosorbide dinitrate, phentolamine, nicotinyl alcohol, co-dergocrine, nicotinic acid, glyceryl trinitrate, pentaerythritol tetranitrate and xanthinol.

[0083] Antimigraine preparations such as ergotamine, dihydroergotamine, methysergide, pizotifen and sumatriptan.

[0084] Drugs Affecting Blood and Haemopoietic Tissues

[0085] Anticoagulants and thrombolytic agents such as warfarin, dicoumarol, low molecular weight heparins such as enoxaparin; streptokinase and its active derivatives. Haemostatic agents such as aprotinin, tranexamic acid and protamine. Central Nervous System

[0086] Analgesics, antipyretics including the opiod analgesics such as buprenorphine, dextromoramide, dextropropoxyphene, fentanyl, alfentanil, sufentanil, hydromorphone, methadone, morphine, oxycodone, papaveretum, pentazocine, pethidine, phenoperidine, codeine and dihydrocodeine. Others include acetylsalicylic acid (aspirin), paracetamol, and phenazone.

[0087] Hypnotics and sedatives such as the barbiturates, amylobarbitone, butobarbitone and pentobarbitone and other hypnotics and sedatives such as choral hydrate, chlormethiazole, hydroxyzine and meprobamate.

[0088] Antianxiety agents such as the benzodiazepines, alprazolam, bromazepam, chlordiazepoxide, clobazam, chlorazepate, diazepam, flunitrazepam, flurazepam, lorazepam, nitrazepam, oxazepam, temazepam and triazolam.

[0089] Neuroleptic and antipsychotic drugs such as the phenothiazines, chlorpromazine, fluphenazine, pericyazine, perphenazine, promazine, thiopropazate, thioridazine and trifluoperazine and the butyrophenones, droperidol and haloperidol and the other antipsychotic drugs such as pimozide, thiothixene and lithium.

[0090] Antidepressants such as the tricyclic antidepressants amitryptyline, clomipramine, desipramine, dothiepin, doxepin, imipramine, nortriptyline, opipramol, protriptyline and trimipramine and the tetracyclic antidepressants such as mianserin and the monoamine oxidase inhibitors such as isocarboxazid, phenelizine, tranylcypromine and moclobemide and selective serotonin re-uptake inhibitors such as fluoxetine, paroxetine, citalopram, fluvoxamine and sertraline.

[0091] CNS stimulants such as caffeine.

[0092] Anti-alzheimer’s agents such as tacrine.

[0093] Antiparkinson agents such as amantadine, benserazide, carbidopa, levodopa, benztropine, biperiden, benzhexol, procyclidine and dopamine-2 agonists such as S(-)-2-(N-propyl-N-2- thienylethylamino)-5-hydroxytetralin (N-0923).

[0094] Anticonvulsants such as phenytoin, valproic acid, primidone, phenobarbitone, methylphenobarbitone and carbamazepine, ethosuximide, methsuximide, phensuximide, sulthiame and clonazepam.

[0095] Antiemetics, antinauseants such as the phenothiazines, prochloperazine, thiethylperazine and 5HT-3 receptor antagonists such as ondansetron and granisetron and others such as dimenhydrinate, diphenhydramine, metoclopramide, domperidone, hyoscine, hyoscine hydrobromide, hyoscine hydrochloride, clebopride and brompride.

[0096] Musculoskeletal System

[0097] Non-steroidal anti-inflammatory agents including their racemic mixtures or individual enantiomers where applicable, such as ibuprofen, flurbiprofen, ketoprofen, aclofenac, diclofenac, aloxiprin, aproxen, aspirin, diflunisal, fenoprofen, indomethacin, mefenamic acid, naproxen, phenylbutazone, piroxicam, salicylamide, salicylic acid, sulindac, desoxysulindac, tenoxicam, tramadol and ketoralac.

[0098] Additional non-steroidal antiinflammatory agents which can be formulated in combination with the dermal penetration enhancers include salicylamide, salicylic acid, flufenisal, salsalate, triethanolamine salicylate, aminopyrine, antipyrine, oxyphenbutazone, apazone, cintazone, flufenamic acid, clonixeril, clonixin, meclofenamic acid, flunixin, coichicine, demecolcine, allopurinol, oxypurinol, benzydamine hydrochloride, dimefadane, indoxole, intrazole, mimbane hydrochloride, paranylene hydrochloride, tetrydamine, benzindopyrine hydrochloide, fluprofen, ibufenac, naproxol, fenbufen, cinchophen, diflumidone sodium, fenamole, flutiazin, metazamide, letimide hydrochloride, nexeridine hydrochloride, octazamide, molinazole, neocinchophen, nimazole, proxazole citrate, tesicam, tesimide, tolmetin, and triflumidate.

[0099] Antirheumatoid agents such as penicillamine, aurothioglucose, sodium aurothiomalate, methotrexate and auranofm.

[0100] Muscle relaxants such as baclofen, diazepam, cyclobenzaprine hydrochloride, dantrolene, methocarbamol, orphenadrine and quinine.

[0101] Agents used in gout and hyperuricaemia such as allopurinol, colchicine, probenecid and sulphinpyrazone.

[0102] Hormones and Steroids

[0103] Oestrogens such as oestradiol, oestriol, oestrone, ethinyloestradiol, mestranol, stilboesirol, dienoestrol, epioestriol, estropipate and zeranol.

[0104] Progesterone and other progestagens such as allyloestrenol, dydrgesterone, lynoestrenol, norgestrel, norethyndrel, norethisterone, norethisterone acetate, gestodene, levonorgestrel, medroxyprogesterone and megestrol.

[0105] Antiandrogens such as cyproterone acetate and danazol. Antioestrogens such as tamoxifen and epitiostanol and the aromatase inhibitors, exemestane and

[0106] 4-hydroxy-androstenedione and its derivatives. Androgens and anabolic agents such as testosterone, methyltestosterone, clostebol acetate, drostanolone, forazabol, nandrolone oxandrolone, stanozolol, trenbolone acetate, dihydro-testosterone, 17-a-methyl-19- nortestosterone and fluoxymesterone.

[0107] 5-alpha reductase inhibitors such as finasteride, turosteride, LY-191704 and MK-306. Corticosteroids such as betamethasone, betamethasone valerate, cortisone, dexamethasone, dexamethasone 21 -phosphate, fludrocortisone, flumethasone, fluocinonide, fluocinonide desonide, fluocinolone, fluocinolone acetonide, fluocortolone, halcinonide, halopredone, hydrocortisone, hydrocortisone 17-valerate, hydrocortisone 17-butyrate, hydrocortisone 21- acetate methylprednisolone, prednisolone, prednisolone 21 -phosphate, prednisone, triamcinolone, triamcinolone acetonide.

[0108] Further examples of steroidal antiinflammatory agents for use in the instant compositions include include cortodoxone, fluoracetonide, fludrocortisone, difluorsone diacetate, flurandrenolone acetonide, medrysone, amcinafel, amcinafide, betamethasone and its other esters, chloroprednisone, clorcortelone, descinolone, desonide, dichlorisone, difluprednate, flucloronide, flumethasone, flunisolide, flucortolone, fluoromethalone, fluperolone, fluprednisolone, meprednisone, methylmeprednisolone, paramethasone, cortisone acetate, hydrocortisone cyclopentylpropionate, cortodoxone, flucetonide, fludrocortisone acetate, flurandrenolone acetonide, medrysone, amcinafal, amcinafide, betamethasone, betamethasone benzoate, chloroprednisone acetate, clocortolone acetate, descinolone acetonide, desoximetasone, dichlorisone acetate, difluprednate, flucloronide, flumethasone pivalate, flunisolide acetate, fluperolone acetate, fluprednisolone valerate, paramethasone acetate, prednisolamate, prednival, triamcinolone hexacetonide, cortivazol, formocortal and nivazol.

[0109] Pituitary hormones and their active derivatives or analogs such as corticotrophin, thyrotropin, follicle stimulating hormone (FSH), luteinising hormone (LH) and gonadotrophin releasing hormone (GnRH).

[0110] Hypoglycaemic agents such as insulin, chlorpropamide, glibenclamide, gliclazide, glipizide, tolazamide, tolbutamide and metformin.

[0111] Thyroid hormones such as calcitonin, thyroxine and liothyronine and antithyroid agents such as carbimazole and propylthiouracil. Other miscelaneous hormone agents such as octreotide.

[0112] Pituitary inhibitors such as bromocriptine.

[0113] Ovulation inducers such as clomiphene.

[0114] Genitourinary System

[0115] Diuretics such as the thiazides, related diuretics and loop diuretics, bendrofluazide, chlorothiazide, chlorthalidone, dopamine, cyclopenthiazide, hydrochlorothiazide, indapamide, mefruside, methycholthiazide, metolazone, quinethazone, bumetanide, elhacrynic acid and frusemide and pottasium sparing diuretics, spironolactone, amiloride and triamterene. Antidiuretics such as desmopressin, lypressin and vasopressin including their active derivatives or analogs.

[0116] Obstetric drugs including agents acting on the uterus such as ergometrine, oxytocin and gemeprost.

[0117] Prostaglandins such as alprostadil (PGE1), prostacyclin (PGI2), dinoprost (prostaglandin F2- alpha) and misoprostol.

[0118] Antimicrobials

[0119] Antimicrobials including the cephalosporins such as cephalexin, cefoxytin and cephalothin. Penicillins such as amoxycillin, amoxycillin with clavulanic acid, ampicillin, bacampicillin, benzathine penicillin, benzylpenicillin, carbenicillin, cloxacillin, methicillin, phenethicillin, phenoxymethylpenicillin, flucloxacillin, mezlocillin, piperacillin, ticarcillin and azlocillin. Tetracyclines such as minocycline, chlortetracycline, tetracycline, demeclocycline, doxycycline, methacycline and oxy tetracycline and other tetracycline-type antibiotics.

[0120] Aminoglycosides such as amikacin, gentamicin, kanamycin, neomycin, netilmicin and tobramycin. Antifungals such as amorolfine, isoconazole, clotrimazole, econazole, miconazole, nystatin, terbinafine, bifonazole, amphotericin, griseofulvin, ketoconazole, fluconazole and flucytosine, salicylic acid, fezatione, ticlatone, tolnaftate, triacetin, zinc, pyrithione and sodium pyrithione.

[0121] Quinolones such as nalidixic acid, cinoxacin, ciprofloxacin, enoxacin and norfloxacin. Sulphonamides such as phthalylsulphthiazole, sulfadoxine, sulphadiazine, sulphamethizole and su Iphamethoxazo le .

[0122] Sulphones such as dapsone. Other miscellaneous antibiotics such as chloramphenicol, clindamycin, erythromycin, erythromycin ethyl carbonate, erythromycin estolate, erythromycin glucepate, erythromycin ethylsuccinate, erythromycin lactobionate, roxithromycin, lincomycin, natamycin, nitrofurantoin, spectinomycin, vancomycin, aztreonam, colistin IV, metronidazole, tinidazole, fusidic acid and trimethoprim; 2 -thiopyridine N-oxide; halogen compounds, particularly iodine and iodine compounds such as iodine-PVP complex and diiodohydroxyquin; hexachlorophene; chlorhexidine; chloroamine compounds; benzoylperoxide.

[0123] Antituberculosis drugs such as ethambutol, isoniazid, pyrazinamide, rifampicin and clofazimine. Antimalarials such as primaquine, pyrimethamine, chloroquine, hydroxychloroquine, quinine, mefloquine and halofantrine.

[0124] Antiviral agents such as acyclovir and acyclovir prodrugs, famciclovir, zidovudine, didanosine, stavudine, lamivudine, zalcitabine, saquinavir, indinavir, ritonavir, n-docosanol, tromantadine and idoxuridine.

[0125] Anthelmintics such as mebendazole, thiabendazole, niclosamide, praziquantel, pyrantel embonate and diethylcarbamazine.

[0126] Cytotoxic agents such as plicamycin, cyclophosphamide, dacarbazine, fluorouracil and its prodrugs, methotrexate, procarbazine, 6-mercaptopurine and mucophenolic acid.

[0127] Metabolism

[0128] Anorectic and weight reducing agents including dexfenfluramine, fenfluramine, diethylpropion, mazindol and phentermine.

[0129] Agents used in hypercalcaemia such as calcitriol, dihydrotachysterol and their active derivatives or analogs.

[0130] Respiratory System

[0131] Antitussives such as ethylmorphine, dextromethorphan and pholcodine.

[0132] Expectorants such as acetylcysteine, bromhexine, emetine, guaiphenesin, ipecacuanha ans saponins.

[0133] Decongestants such as phenylephrine, phenylpropanolamine ans pseudoephedrine. Bronchospasm relaxants such as ephedrine, fenoterol, orciprenaline, rimiterol, salbutamol, sodium cromoglycate, cromoglycic acid and its prodrugs, terbutaline, ipratropium bromide, salmeterol and theophylline and theophylline derivatives. Allergy and Immune System

[0134] Antihistamines such as meclozine, cyclizine, chlorcyclizine, hydroxyzine, brompheniramine, chlorpheniramine, clemastine, cyproheptadine, dexchlorpheniramine, diphenhydramine, diphenylamine, doxylamine, mebhydrolin, pheniramine, tripolidine, azatadine, diphenylpyraline, methdilazine, terfenadine, astemizole, loratidine and cetirizine.

[0135] Local anaesthetics such as bupivacaine, amethocaine, lignocaine, cinchocaine, dibucaine, mepivacaine, prilocaine and etidocaine.

[0136] Stratum comeum lipids, such as ceramides, cholesterol and free fatty acids, for improved skin barrier repair.

[0137] Neuromuscular blocking agents such as suxamethonium, alcuronium, pancuronium, atracurium, gallamine, tubocurarine and vecuronium.

[0138] Smoking cessation agents such as nicotine, bupropion and ibogaine.

[0139] Insecticides and other pesticides which are suitable for local or systemic application. Dermatological agents, such as vitamins A and E, vitamin E acetate and vitamin E sorbate. Allergens for desensitisation such as house dust mite allergen.

[0140] Nutritional agents, such as vitamins, essential amino acids and essential fats.

[0141] Keratolytics such as the alpha-hydroxy acids, glycollic acid and salicylic acid.

[0142] Psychicenergisers, such as 3 -(2-aminopropyl) indole, 3-(2-aminobutyl)indole, and the like. Anti-acne agents such as containing isotretinoin, tretinoin and benzoyl peroxide.

[0143] Anti-psoriasis agents such as containing etretinate, cyclosporin and calcipotriol.

[0144] Anti-itch agents such as capsaicin and its derivatives such as nonivamide.

[0145] Anticholinergic agents, which are effective for the inhibition of axillary sweating and for the control of prickly heat. The antiperspirrant activity of agents such as methatropine nitrate, propantheline bromide, scopolamine, methscopolamine bromide, and the new class of soft antiperspirants, quaternary acyloxymethyl ammonium salts.

[0146] Dental or orthodontic systems:

[0147] Dental drugs use of antiseptic drugs involves utilizing topical antibiotic gels to reduce bacteria and plaque, preventing, or treating gingivitis and periodontal disease. These gels are essential for maintaining oral health after dental procedures, aiding in the prevention and treatment of inflamed gums and periodontitis. The application of this ointment with a brush is crucial for its effectiveness in preventing gingival swelling, infections, and controlling bad breath when massaged into the gums with a toothbrush. Additionally, Topical Ever, an anesthetic used in orthodontics, serves as an alternative to local infiltration for various procedures like soft-tissue laser surgery, temporary anchorage device placement, and transmucosal alveolar micro- osteoperforation. It effectively combats gum diseases by addressing inflammation.

[0148] Natural Products

[0149] Active peptides and proteins, e.g., vasopressin and human growth hormone.

[0150] Borneol, lilac, pepper, white mustard, ginger onion, garlic, leek, ).

[0151] Analgesic and anti -inflammation: capsaicin, aconitine, turpentine, strychnine, triptolide (TPL), sinomenine, colchicine, curcumin, berberine, lycopene, glycyrrhetic acid, catechin, geniposide, resveratrol, andrographolide, paeonol, mangiferin.

[0152] Skin repair: camptothecin derivatives, atragaloside IV, asiaticoside.

[0153] Antitumor: bufalin, podophyllotoxin, paclitaxel, ligustilide.

[0154] Psoriasis and Antifungal: psoralen, harmaline, baicalin, hesperidin.

[0155] Reduce UVB damage, Repair DNA injury, Anti-oxidative activity and skin whitening: ferulic acid, cinnamic acid, usnic acid, menthol, pomegranate.

[0156] Stem Cells.

[0157] Protein Rich Plasma Therapy.

[0158] Nutraceuticals: vitamins, herbal products (e.g., garlic (allicin), ginger, echinacea, ginseng, liquorice, onion, senna, turmeric (curcumin), dietary enzymes (e.g., bromelain and papain), phytonutrients (e.g., resveratrol), carotenoids (e.g., lycopene), prebiotics and probiotics. Cosmetically Functional Active Agents

[0159] Protein Rich Plasma Therapy (PRP), Platelet Rich Fibrin (PRF) Therapy, Moisturizers, RetinA, Exosomes, Hyaluronic Acid, Ascorbic Acid, Vitamins A, D, E, Omega 3 Fatty Acids, Skin Tighteners (e.g., hydroquinone), Azelaic Acid, Witch Hazel, Salicylic acid, Glycols, palmitoyl pentapepiide-4.

[0160] And further including all other ingredients or active agents for use in supporting, assisting, sustaining, raising, enhancing, and aiding of the cosmetics effects.

[0161] Vaccines and Gene Therapy

[0162] Nucleotides to be used in RNA and DNA vaccines and gene therapy. Further Features and Potential Mechanisms of Action of CoR

[0163] Investigations into CoR's (Cofactor Raphanin) unique negative charges with its polarity have established it as the first cofactor known to directly traverse cell membranes and lipid layers, facilitating its reach to mitochondria. This capability enhances ATP production and activates the primary cofactor FAD in mitochondria, marking a significant advancement nearly 200 years after the discovery of mitochondria in 1819. Additionally, it further has revealed its capability to activate FAD, the major redox factor in the electron transport chain (ETC).

[0164] The proposed mechanisms of action for CoR suggest that it functions as a polar solvent characterized by its distinctive negative charge properties, particularly in the context of the electron transport chain (ETC). The negative charges associated with the phosphate groups in adenosine triphosphate (ATP) are critical for its structure and function. Each of the three phosphate groups within ATP carries a negative charge due to the nature of the phosphate bonds, contributing to the molecule’s high-energy potential. This negative charge creates repulsive forces between the phosphate groups, which, when released during hydrolysis, drives cellular processes. Disruption in ATP production may occur due to alterations in the electron transport chain or the availability of this polar solvent negative charges, ultimately impacting cellular energy metabolism.

[0165] Redox signaling at the crossroads of human health and disease. Redox biology is at the core of life sciences, accompanied by the close correlation of redox processes with biological activities. Redox homeostasis is a prerequisite for human health, in which the physiological levels of nonradical reactive oxygen species (ROS) function as the primary second messengers to modulate physiological redox signaling by orchestrating multiple redox sensors. However, excessive ROS accumulation, termed oxidative stress (OS), leads to biomolecule damage and subsequent occurrence of various diseases such as type 2 diabetes, atherosclerosis, and cancer. Herein, starting with the evolution of redox biology, ROS as a double-edged sword in disease progression suggest two different therapeutic strategies to treat redox-relevant diseases, in which targeting ROS sources and redox-related effectors to manipulate redox homeostasis will largely promote precision medicine. The pathological conditions will facilitate the development of redox medicine and benefit patients with redox-relevant diseases.

[0166] Redox imbalance accounts for many diseases including neurological disorders, immune system disorders, cardiovascular diseases, and skeletal diseases. Electron flow is one of the most fundamental and common perspectives in understanding biology. The electron transfer process, which refers to the transformation of energy from an excited state, is fundamental.

[0167] The delivery of electrons from the donor molecules to the terminal acceptor molecules triggers oxidative processes, defined as redox reactions. Redox reactions are the sources of intracellular energy, harvested from electron flow during the transfer from one reductant (oxidation) to another oxidant (reduction). High-energy electrons must move to a new resting acceptor, for humans, intracellular enzymes reduce oxygen, which enters the cell and captures energy to accelerate ATP production. CoQ10 is a cofactor that plays several roles within the inner mitochondrial membranes. However, there is currently no evidence to support that oral intake of CoQ10 effectively reaches the mitochondria. CoR, as a delivery vehicle, enhances the transfer of Coenzyme Q10 to the mitochondrial respiratory chain.

[0168] CoR is a novel polar solvent with unique negative charges with its polarity and chirality, enhancing its ability to penetrate cellular organelles, especially mitochondria. Unlike DMSO, CoR is non-toxic and effectively reaches mitochondria. This positions CoR as a superior alternative to DMSO, improving drug delivery and cryopreservation efficacy while ensuring safety in intracellular communications.

[0169] The CoR novel penetration enhancer delivery system presents strategies, enabling efficient delivery of drugs through the three layers of skin, and overcoming the limitations of current penetrates, making it an ideal option for drug delivery via the topical route. Enhancing ATP bioenergy and preserving a localized effect using nanocarriers can lead to an effective treatment for various infections and skin disorders by achieving cellular self-healing and repair.

[0170] Declining mitochondrial function is a critical determinant of cellular aging, significantly impacting the bioenergetic landscape of cells. As mitochondrial function wanes, there is a concomitant reduction in adenosine triphosphate (ATP) synthesis, which is essential for energy metabolism and cellular homeostasis. This decrease in ATP production not only hampers cellular activities but also precipitates increased apoptotic and necrotic cell death, thus accelerating the aging process at the organismal level.

[0171] CoR's innovative approach focuses on rejuvenating ATP levels within living cells, targeting the restoration of mitochondrial bioenergetics. By employing advanced regenerative techniques, this methodology seeks to enhance mitochondrial function and optimize cellular energy production. The implications of such interventions are profound, holding significant promise for promoting healthy longevity and preserving overall vitality throughout the lifespan. This strategy not only aims to mitigate the effects of aging but also strives to sustain optimum physiological function, contributing positively to the quality of life.

[0172] In one significant aspect, CoR acts as a penetration enhancer for mitochondria, enabling the activation of Flavin Adenine Dinucleotide (FAD) at nearly three times the level observed in control samples. FAD is the primary cofactor responsible for facilitating the electron transport chain (ETC) processes critical to mitochondrial function. Remarkably, these processes are associated with approximately 90% of chemical reactions occurring in the body and are linked to 89% of the human genotype. This highlights the substantial contribution of CoR as a penetration enhancer in mitochondrial synthesis and overall cellular metabolism.

[0173] CoR's novel penetration enhancer activates FAD, enhancing nearly 90% of redox reactions crucial for optimal mitochondrial respiration. This innovation improves cellular energy efficiency while reducing harmful byproducts like apoptosis, protein misfolding, excessive free radicals, and calcium overload — key factors in aging and age-related diseases. By mitigating these detrimental processes, CoR promotes healthier cellular function and longevity, potentially transforming therapeutic strategies against aging and related conditions.

[0174] CoR's innovative penetration enhancer crucially activates flavin adenine dinucleotide (FAD), a coenzyme essential for cellular function in approximately 89% of the human genome. This FAD activation advances next-generation cell and gene therapies aligned with precision medicine. CoR enables targeted therapeutics using advanced genetic technologies to combat genetic disorders, cancer, and degenerative diseases.

[0175] CoR is the first documented penetration enhancer that specifically targets mitochondria, which sen e as the energy hub of cells. Their function is continuously influenced by their interactions with other essential subcellular organelles, central to eukaryotic metabolism. Mitochondria form a dynamic network with the endoplasmic reticulum (ER), lysosomes, cytoskeleton, peroxisomes, and nucleus, facilitating signal transduction, vesicle transport, and membrane interactions. These connections play a crucial role in regulating vital processes, including energy metabolism, biosynthesis, apoptosis, and cellular turnover. In cancer, metabolic reprogramming significantly alters organelle dynamics and cellular function. CoR acts as a penetration enhancer, enabling the efficient passage through cell membranes to target the mitochondria, which are organelles encapsulated by lipid layers within the cell. This underscores the importance of both functional and physical communication between organelles, especially in relation to ATP production by mitochondria, essential for the functioning of other organelles.

[0176] In one embodiment, the proposed delivery systems are a significant advancement in the realm of cellular and gene therapies. The unique physicochemical properties of CoR, particularly its distinct negative charges, empower its ability to traverse cellular membranes effectively and facilitate direct access to mitochondria. This mechanism enhances the precision of intracellular signaling pathways and enables organelle-specific delivery of therapeutic agents.

[0177] Furthermore, the ability of CoR to selectively target and deliver bioactive agents directly to the mitochondria is significantly advantageous for next-generation cell and gene therapies, including gene editing applications. This targeted delivery mechanism is essential for addressing complex disorders at the mitochondrial and organellar levels, as it enhances cellular repair processes and facilitates functional restoration. By circumventing the inherent limitations associated with conventional delivery systems, this approach not only increases therapeutic efficacy but also improves safety profiles for the treatment and prevention of challenging diseases such as cancer and Alzheimer’s disease. The precision of CoR in mitochondrial targeting is a pivotal advancement for therapeutics for combating these debilitating conditions.

[0178] EXAMPLES

[0179] Human Testing Data: Oral administration of CoR capsules Bone Density Testing Results

[0180] A "T-score" -1 or higher is considered normal bone density; a score between -1 and -2.5 indicates osteopenia (low bone mass), and a score of -2.5 or lower indicates osteoporosis. In the instant study, a 63-year-old female was administered a 500 mg capsule containing CoR, three times a day, with a meal, beginning in May 2019. This study demonstrates an increase or stabilization in bone mineral density upon administration of a 500 mg CoR capsule, rather than the typical expected decline in bone density with age.

[0181] Human Testing Data: Oral administration of CoR capsules Bone Density Testing Results

[0182] This in vivo study involves a female who began CoR supplementation in January 2022 at the age of 54 with a 500 mg capsule containing CoR, three times a day, with a meal. A comparative analysis of bone mineral density (BMD) measurements before and after CoR supplementation reveals significant biological and physiological alterations. The findings suggest that an earlier initiation of CoR treatment correlates with improved outcomes, as supported by data sets from two distinct age groups. The findings demonstrate a substantial increase in bone mineral density upon CoR supplementation. Human Testing Data: Oral administration of CoR capsules in a female. Ejection Fraction

[0183] A reduced ejection fraction (EF) is a key contributor to heart failure, a condition where the heart muscle weakens and stiffens, impairing its ability to pump blood effectively. The EF frequently worsens with age. In the instant study, a 69-year-old female was administered a 500 mg capsule containing CoR three times a day, with a meal, beginning in May 2019. This study demonstrates an improvement in left ventricular ejection fraction (LVEF) upon CoR supplementation.

[0184] Human Testing Data: Oral administration of CoR capsules in a male.

[0185] Ejection Fraction

[0186] In the instant study, a 69-year-old male was administered a 500 mg capsule containing CoR three times a day, with a meal, beginning in May 2019. The male had been diagnosed with ASHD (arteriosclerotic heart disease), CHF (congestive heart failure), Abnormal EKG, Angina pectoris, Cardiomyopathy, Heart murmur, previous Heart attack, High cholesterol, and MI (myocardial infarction). This study demonstrated an improvement in left ventricular ejection fraction (LVEF), resulting in stabilization of LVEF (rather than a decline which is typical with age) with CoR supplementation. Human Testing Data: Transdermal Penetration Enhancement of Facial Cream Facial Rejuvenation

[0187] The following example demonstrates the enhancement of the efficacy of pharmaceutical and natural ingredients (i.e., active agent ingredients) when used in conjunction with CoR cream carriers for facial skin rejuvenation.

[0188] A therapeutic facial cream was produced with the following formulation; substantially equal parts of following active agent ingredients; Coenzyme Q10, Vitamin E, Biotin, Natural Collagen, Testosterone, Progesterone, Estrogen, Retinol (vitamin A), Vitamin D3+K2, B complex, Copper, Zinc, Selenium, Magnesium, Calcium, Potassium, and Silica. These active agent ingredients were formulated with CoR cream as a carrier. The final therapeutic facial cream contained about 50wt% of the active agent ingredients and about 50wt% of the CoR cream carrier.

[0189] The therapeutic cream was topically administered to facial skin of a woman (bom October 1955) for a period of two years (i.e., November 2022 to February 4, 2025) on a daily basis.

[0190] The therapeutic cream was applied daily from. This therapeutic cream was systemically alternated with CoR by itself over the course of one month to enhance the cream’s efficacy and optimize the benefits of each formulation cycle.

[0191] FIG. 1 shows the results of a 3D facial reconstruction comparison of before and after treatment. The comparison shows notable changes in both facial morphology and dermal thickness. Specifically, the visible analysis identifies distinct alterations in the contours and dimensions of key facial features, including the cheeks, chin, eyes, and lips. Additionally, variations in skin thickness across different facial regions suggest potential influences from underlying biological factors. These findings highlight the dynamic nature of facial restructuring.

[0192] The dermis, a connective tissue layer comprised of muscles and adipose tissue, accounts for 90% of its thickness. Age-related factors affecting facial shape include fat and bone loss, muscle weakness, diminished laxity, and gravitational effects. Consequently, the skin becomes increasingly loose and sagging. Additionally, the enlargement of the eye sockets leads to a downward displacement of the surrounding muscles and ligaments.

[0193] The data show's that CoR carriers, acting as transdermal penetration enhancers, effectively penetrate the stratum corneum and skin barriers to deliver active compounds into deeper dermal layers. This targets and nourishes all the skin layers, muscle tissue, adipose tissue, ligaments, tendons and bone density. The biochemical and physiological interactions promote facial volumetric restoration through enhanced cellular metabolism and tissue regeneration, significantly reducing visible signs of aging, such as sagging, and improving overall facial aesthetics.

[0194] Human Testing Data: Topical Administration of CoR Cream

[0195] Hair Loss

[0196] The following example demonstrates the enhancement of the efficacy of pharmaceutical and natural ingredients (i.e., active agent ingredients) when used in conjunction with CoR cream carriers for hair regrowth.

[0197] A hair regrowth cream was produced with the following formulation: substantially equal parts of following active agent ingredients: Coenzyme Q10, Vitamin E, Biotin, Natural Collagen, Testosterone, Progesterone, Estrogen, Retinol (vitamin A), Vitamin D3+K2, and B complex. These ingredients were formulated with CoR cream as a carrier. The final hair regrowth cream contained about 50wt% of the active agent ingredients and about 50wt% of the CoR cream carrier.

[0198] A hair regrowth cream was topically administered daily to bald scalp skin of a man (bom October 1951) for 6 months, from November 2022 to April 2023. Benefits continue to be evident. See FIG. 2. The left image, from February 6, 2025, shows significant hair growth compared to the right image from October 22, 2022. Further analysis reveals smaller, newly developed hair follicles, indicating an active regeneration process influenced by biological and physiological factors, underscoring the dynamic nature of hair follicle restoration.

[0199] Coenzyme Q10 (CoQ10), also known as ubiquinone, is vital for ATP production within the mitochondria. The intake of CoQ10 elevates plasma levels that just reflecting extracellular concentrations; however, its primary action occurs at the mitochondrial organelle level that is intracellular level. The CoR (carrier) possesses the capability to facilitate the intracellular delivery of CoQ10 to its site of action, thereby enhancing its therapeutic efficacy on hair follicals and across various clinical applications.

[0200] Additionally, vitamin E and biotin contribute to scalp health and promote hair growth, with the CoR carrier improving their penetration into deeper layers for enhanced therapeutic effectiveness. Natural collagen, testosterone, progesterone, estrogen, retinol (vitamin A), vitamin D3 + K2, and the B complex vitamins are similarly delivered by the CoR carrier to deeper layers, thereby augmenting their clinical benefits. In Vitro Toxicity Testing of CoR

[0201] In vitro data for Skin:

[0202] SK-MEL-31 (15k cells / well): A CTG cell viability assay (Promega Cat#G7571) was conducted to assess ATP production. Finding: CoR treatment significantly increases ATP levels in mitochondria compared to control.

[0203] In vitro data for Muscle

[0204] CoR treatment significantly increases ATP levels in mitochondria of A-204 muscle cells compared to control and enhances FAD levels nearly threefold.

Claims

CLAIMS1. A penetration enhancer system for delivery of an active agent at the intracellular and organelle level, the system comprises: a therapeutically effective amount of at least one active agent; and at least one dermal penetration enhancer, wherein a dermal penetration enhancer comprises CoR.

2. The penetration enhancer system according to claim 1, wherein the active agent is a pharmaceutical drug, or prodrug thereof, or a cosmetically functional composition.

3. The penetration enhancer system according to claim 1, further comprising a co-solvent, surfactant, emulsifier, antioxidant, preservative, stabilizer, diluent or a mixture of two or more of said components.

4. The penetration enhancer system according to claim 1, wherein the system is applied by an aerosol or spray.

5. The penetration enhancer system according to claim 1, wherein the system is applied by transdermal patch.

6. The penetration enhancer system according to claim 1, wherein the delivery system is applied by lotion, cream or ointment.

7. The penetration enhancer system according to claim 1, wherein CoR is present in the amount of about 0.01 to about 50 wt % of the system.

8. A method of treating a disease or condition in a subject in need thereof, the method comprising applying an effective amount of the active agent in the form of a system according to claim 1 to a dermal surface or mucosal membrane of said subject.

9. The method according to claim 8, wherein the active agent comprises male hormone replacement, female hormone replacement, androgen replacement, male contraception or female contraception.

10. A method according to claim 8, wherein the disease or condition is soft tissue injury, narcotic withdrawal, severe post-operative pain, motion sickness, oestrogen dependent breast cancer, prostatic enlargement and / or prostatic cancer, alopecia and acne, anxiety disorders, male impotence, Raynauds syndrome and varicose veins, sleep disorders, jetlag, herpes virus infections, deep vein thrombosis, migraine, high blood pressure, malaria, diagnosis of cystic fibrosis, asthma, nocturnal asthma, a diminished left ventricular ejection traction, heart disease or bone mineral density loss.

11. The method according to claim 8, wherein the condition is a cosmetic condition selected from the group consisting of wrinkled skin, dry skin, age-related thing of the skin, dark spots, alopecia and enlarged pores, and acne scars.

12. A method to increase or stabilize bone mineral density, the method comprising administering about 250mg to about 700mg of CoR to a subject in need thereof, one to four times a day.

13. The method according to claim 12, wherein the method comprises administering about 500mg of CoR to a subject in need thereof three times a day.

14. A method to increase left ventricular ejection fraction (LVEF), the method comprising administering about 250mg to about 700mg of CoR to a subject in need thereof, one to four times a day.

15. The method according to claim E1, wherein the method comprises administering about 500mg of CoR to a subject in need thereof, three times a day.

16. A method of rejuvenating facial skin, the method comprising topically administering a therapeutic facial cream, wherein the cream comprises a CoR enhancer and at least one active agent, wherein the active agent is an antioxidant, a vitamin, collagen, a hormone, a mineral or combinations thereof, wherein the facial cream comprises about 20wt% to about 60wt% of the active agents with the balance being CoR in a cream carrier.

17. The method of claim 16, wherein the facial cream comprises about 50wt% of the active agents with the balance being CoR in a cream carrier.

18. The method of claim 17, wherein the antioxidant is coenzyme Q10, the vitamin is vitamin E, retinol, vitamin D3, vitamin K2, B complex, biotin, or combinations thereof, the mineral is copper, zinc, selenium, magnesium, calcium, potassium and combinations thereof.

19. A method of increasing dermal thickness, the method comprising topically administering a therapeutic facial cream, wherein the cream comprises a CoR enhancer and at least one active agent, wherein the active agent is an antioxidant, a vitamin, collagen, a hormone, a mineral or combinations thereof, wherein the facial cream comprises about 20wt% to about 60wt% of the active agents with the balance being CoR in a cream carrier.

20. A method of regrowing hair, the method comprising topically administering a hair regrowth cream, wherein the cream comprises a CoR enhancer and at least one active agent, wherein the active agent is an antioxidant, a vitamin, collagen, a hormone, a mineral or combinations thereof, wherein the hair rcgrowth cream comprises about 20wt% to about 60wt% of the active agents with the balance being CoR in a cream carrier.

21. The method of Claim 20, wherein the hair regrowth cream comprises about 50wt% of the active agents with the balance being CoR in a cream carrier.

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