WO2019055268A2 - Drug delivery system - Google Patents

Abstract

The present invention targets the Zika virus and other disease-causing microbes including viruses, bacteria, fungi, and parasites. It does this using agents and methods with little toxicity compared to existing therapies.

Description

DRUG DELIVERY SYSTEM

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Serial Number 62/557,971 filed

September 13, 2017, the entirety of which is incorporated herein by reference.

SPECIFICATION BACKGROUND OF THE INVENTION

The emergence of the Zika virus represents a global health threat (Sikka, V. et al. "The emergence of Zika Virus as a Global Health Security Threat: A Review and Consensus Statement of the INDUSEM Joint Working Groups (JWG). Journal of Global Infectious Diseases. 8 (2016): 3-15). The present invention represents a method for prevention and treatment of the Zika virus. It provides physical, chemical, and metabolic barriers to infection by this pathogenic agent.

The Zika virus is a member of the family Flavi viridae and is an RNA containing virus. It is usually transmitted by an Aedes mosquito which inj ects it into the skin with a stinger, causing infection of three types of skin cells (epidermal keratinocytes, dermal fibroblasts, dermal macrophagesXHamel, R, et al., "Biology of Zika Virus Infection in Human Skin Cells" J. Virol. 89 (2015) : 8880-8896.) and men proceeds to a viremia. It can also be transmitted sexually. It is asymptomatic in 80% of people infected, but causes mild to moderate systemic symptoms such as arthralgia, myalgia, and rash in 20% of people. Additionally it has caused catastrophic nervous system developmental impairment and microcephaly in fetuses and newborns, and Guillan Barre paralytic syndrome in some adults. There is at this time no preventative vaccine or direct antiviral treatment. There is no way to reverse the catastrophic developmental impairment in embryos, fetuses, and newborns. For Guillan Barre syndrome, only supportive care and immunoglobulin treatment, which is only partially effective, are available.

The invention provides means for prevention and treatment of other dangerous pathogenic organisms. It is active against an unusually wide range of pathogens and has a lesser toxicity compared to many currently available antimicrobial therapies. All references cited herein are incorporated herein by reference in their entireties.

All references cited herein are incorporated herein by reference in their entireties.

BRIEF SUMMARY OF THE INVENTION

The method is comprised of two parts. These two parts can be administered together or sequentially. Part A-Methods for depletion of guanosine-containing nucleosides and nucleotides.

Part B-Methods for administering melanin and/or increasing the body content of melanin by modulation of metabolic processes.

The parts are briefly summarized below.

Part A - Method for depletion of guanosine-containing nucleosides and nucleotides.

Guanine is a purine base which is a component of nucleosides such as guanosine and nucleotides such as guanosine monophosphate, guanosine diphosphate, and guanosine triphosphate, cyclic guanosine monophosphate, etc. Guanine is required for replication of most DNA and RNA. It is also a component of the ubiquitous G protein receptors, which are involved in innumerable signaling pathways.

Most microorganisms that cause disease do so partially by replicating themselves in high numbers. This includes viruses, bacteria, fungi, and parasites. This requires replication of DNA in bacteria, fungi, and parasites, and replication of DNA or RNA in viruses. In Zika, it is the RNA which replicates.

It has been demonstrated that restriction or complete inhibition of guanine supplies prevents replication of some viruses and other pathogenic organisms such as bacteria. This can be accomplished by several chemical agents (e.g. mycophenolic acid, tiazofiirin, selenazofurin,, ribavirin, 5-ethynyl- 1 -P-D-ribofuranosylimidazole-4-carboxa^ J., and De Clercq, E.

"Mycophenolate Mofetil Strongly Potentiates the Anti-herpesvirus Activity of Acyclovir." Antiviral research 40 (1998): 53-56.). Restriction of guanine supplies is not generally not used in medical treatment of any infectious disease. It should be noted that early studies of mycophenolate showed relatively rapid emergence of bacterial resistance, and perhaps this is the reason why this strategy has not been adopted. Additionally, it is possible to significantly deplete a human's supply of guanosine by a novel selective diet restriction which is described below. Part B -Methods for administering melanin and/or increasing the body content Qf melanin by modulation of metabolic processes.

Melanin is a pigment best known for its ability in human skin to absorb ultraviolet radiation from the sun. Melanin has been clearly demonstrated to have antimicrobial properties which are active against some viruses, bacteria, fungi and parasites. Its mechanism of action seems to be unknown. The best studied melanin in the literature is derived from cuttlefish ink. Cuttlefish is a type of cephalopod. Octopus and squid are also cephalopods and also have inks, which are used as a defense mechanism against predators. The ink, contains approximately 15 to 20% melanin, about 5% protein and carbohydrates, and the rest is water. Human beings also continuously synthesize melanin in the skin and perhaps in the nervous system. Various hormones and other agents have been demonstrated to be capable of increasing melanin synthesis in humans and other mammals. One example is Melanocyte- Stimulating Hormone (MSH).

The present invention represents a fundamentally novel strategy in developing therapy against Zika virus, other microbes and parasites. Historically, and increasingly so in the recent years, researchers, pharmaceutical companies, and governments devote their efforts toward targeting single agents or small groups of specific microbes. For instance, an enormous amount of resources has appropriately been devoted to fighting the HTV virus. However, as a result, most of the therapies developed are only active against that single microbe. Similarly, many of the new antibiotics developed in the last few decades are targeted to a small group of microbes. For instance the cephalosporins were developed specifically against penicillin resistant bacteria While of course these advances are welcome, the cephalosporins are generally only active against the rather limited organisms against which the}' were developed.

The present invention represents a fundamentally different strategy from the historical strategy just described. The present invention targets the Zika virus and other disease-causing microbes including viruses, bacteria, fungi, and parasites. It does this using agents and methods with little toxicity compared to existing therapies.

The invention provides a pharmaceutical oral mucosal delivery composition comprising: a therapeutically effective amount of a first agent which is selected from the group consisting of beta-carotene, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof; a therapeutically effective amount of a third agent which is selected from the group consisting of mycophenolic acid, mycophenolate mofetil, derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; and at least one pharmaceutically acceptable excipient. The invention provides a pharmaceutical oral mucosal delivery composition wherein the composition is provided in a sublingual or buccal dosage form. The invention provides a pharmaceutical oral mucosal delivery composition, wherein the composition comprises at least one pharmaceutically acceptable excipient selected from the group consisting of buffer, preservative, isotonic agent, an antioxidant, and combinations thereof. The invention provides a pharmaceutical oral mucosal delivery' composition wherein the dosage form is selected from the group consisting of a tablet, a chewing gum, a gel, a patch, a lozenge, a troche, a pastille, a sachet, and a rapid disintegrating tablet. The invention provides a pharmaceutical oral mucosal delivery composition wherein the composition comprises the first agent in a dose from about 10 mg to about 450 mg, the second agent in a dose from about 10 mg to about 450 mg, and the third agent in a dose from about 10 mg to about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the first agent is beta- carotene and the first agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the second agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the third agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the first agent is present in an amount of from 2% to 50% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal deliver}' composition wherein the first agent is present in an amount of from 25% to 30% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein said first agent is beta-carotene and the therapeutically effective amount of beta-carotene comprises at least about 75 mg to about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein said therapeutically effective amount of beta-carotene comprises about 240 mg. The invention provides a pharmaceutical oral mucosal deliver}' composition wherein the second agent is present in an amount of from 2% to 50% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the second agent is present in an amount of from 25% to 30% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the third agent is present in an amount of from 2% to 50% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal deliver}' composition wherein the third agent is present in an amount of from 25% to 30% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the weight ratio of the first agent to the second agent is selected from the group consisting of about 10:1, about 5:1, about 3:1, about 2:1, about 1:1, about 1 :2, about 1:3, about 1:5, and about 1:10. The invention provides a pharmaceutical oral mucosal deliver}' composition wherein the weight ratio of the first agent to the second agent to the third agent is selected from the group consisting of about 1:1:1, about 0.01 : 1 : 1 , about 1:1 :0.01, about 1:0.1:1, about 0.01 :0.1 : 1 , about 1 :0.1 :0.01, about 1:0.9:1, about 0.01 :0.9: 1, and about 1 :0.9:0.01. The invention provides a pharmaceutical oral mucosal delivery composition wherein the composition further comprises at least one flavoring agent, artificial coloring, sweetener, lubricating agent, disintegration agent, permeation enhancer, lubricating agent, diluent, base, buffering agent, or combinations thereof.

The invention provides a pharmaceutical oral mucosal delivery composition comprising: a therapeutically effective amount of a first agent which is selected from the group consisting of beta-carotene, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, guanosine monophosphate, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof; a therapeutically effective amount of a third agent which is at least one mineral selected from the group consisting of calcium, chromium, copper, iodine, iron, magnesium, manganese, phosphorus, potassium, selenium, zinc, derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; And at least one pharmaceutically acceptable excipient. The invention provides a pharmaceutical oral mucosal delivery composition wherein the composition is provided in a sublingual or buccal dosage form. The invention provides a pharmaceutical oral mucosal deliver}' composition wherein the composition comprises at least one pharmaceutically acceptable excipient selected from the group consisting of buffer, preservative, isotonic agent, an antioxidant, and combinations thereof. The invention provides a pharmaceutical oral mucosal delivery composition wherein the dosage form is selected from the group consisting of a tablet, a chewing gum, a gel, a patch, a lozenge, a troche, a pastille, a sachet, and a rapid disintegrating tablet. The invention provides a pharmaceutical oral mucosal delivery composition wherein the composition comprises the first agent in a dose from about 10 mg to about 450 mg, the second agent in a dose from about 10 mg to about 450 mg, and the third agent in a dose from about 10 mg to about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the first agent is beta-carotene and the first agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the second agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the third agent is present in an amount selected from the group consisting of about 75 mg, about 1 SO mg, about 225 mg, about 300 mg, and about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the first agent is guanosine monophosphate and the first agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450. The invention provides a pharmaceutical oral mucosal delivery composition wherein the first agent is present in an amount of from 2% to 50% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the first agent is present in an amount of from 25% to 30% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein said first agent is beta-carotene and the therapeutically effective amount of beta-carotene comprises at least about 75 mg to about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein said therapeutically effective amount of beta-carotene comprises about 240 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein said therapeutically effective amount of guanosine monophosphate comprises at least about 75 mg to about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein said first agent is guanosine monophosphate and the therapeutically effective amount of guanosine monophosphate comprises about 240 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the second agent is present in an amount of from 2% to 50% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the second agent is present in an amount of from 25% to 30% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the third agent is present in an amount of from 2% to 50% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the third agent is present in an amount of from 25% to 30% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the concentration of the second agent is from about 0.01% to about 90% of the dry matter weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the weight ratio of the first agent to the second agent is selected from the group consisting of about 10:1, about 5:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:5, and about 1 : 10. The invention provides a pharmaceutical oral mucosal delivery composition wherein the weight ratio of the first agent to the second agent to the third agent is selected from the group consisting of about 1:1:1, about 0.01 : 1 : 1, about 1:1 :0.01, about 1:0.1:1, about 0.01 :0.1 :1, about 1:0.1:0.01, about 1:0.9:1, about 0.01 :0.9:1, and about 1:0.9:0.01. The invention provides a pharmaceutical oral mucosal delivery composition wherein the composition further comprises at least one flavoring agent, artificial coloring, sweetener, lubricating agent, disintegration agent, permeation enhancer, lubricating agent, diluent, base, buffering agent, or combinations thereof.

The invention provides a pharmaceutical oral mucosal delivery composition comprising: a therapeutically effective amount of a first agent which is selected from the group consisting of beta-carotene, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, guanosine monophosphate, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof; a therapeutically effective amount of at least one third agent which is selected from the group consisting of melanin, melanin precursors, melanin derivatives, melanin analogs and related substances, and combinations thereof; And at least one pharmaceutically acceptable excipient. The invention provides a pharmaceutical oral mucosal delivery composition wherein the composition is provided in a sublingual or buccal dosage form. The invention provides a pharmaceutical oral mucosal delivery composition, wherein the composition comprises at least one pharmaceutically acceptable excipient selected from the group consisting of buffer, preservative, isotonic agent, an antioxidant, and combinations thereof.

The invention provides a pharmaceutical oral mucosal delivery composition wherein the dosage form is selected from the group consisting of a tablet, a chewing gum, a gel, a patch, a lozenge, a troche, a pastille, a sachet, and a rapid disintegrating tablet. The invention provides a pharmaceutical oral mucosal delivery composition wherein the composition comprises the first agent in a dose from about 10 mg to about 450 mg, the second agent in a dose from about 10 mg to about 450 mg, and the third agent in a dose from about 10 mg to about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the first agent is beta- carotene and the first agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the second agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the third agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the first agent is guanosine monophosphate and the first agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450. The invention provides a pharmaceutical oral mucosal delivery composition wherein the first agent is present in an amount of from 2% to 50% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the first agent is present in an amount of from 25% to 30% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein said first agent is beta- carotene and the therapeutically effective amount of beta-carotene comprises at least about 75 mg to about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein said therapeutically effective amount of beta-carotene comprises about 240 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein said therapeutically effective amount of guanosine monophosphate comprises at least about 75 mg to about 450 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein said first agent is guanosine monophosphate and the therapeutically effective amount of guanosine monophosphate comprises about 240 mg. The invention provides a pharmaceutical oral mucosal delivery composition wherein the second agent is present in an amount of from 2% to 50% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the second agent is present in an amount of from 25% to 30% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal deliver}' composition wherein the third agent is present in an amount of from 2% to 50% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the third agent is present in an amount of from 25% to 30% of the total weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the concentration of the second agent is from about 0.01% to about 90% of the dry matter weight of the composition. The invention provides a pharmaceutical oral mucosal delivery composition wherein the weight ratio of the first agent to the second agent is selected from the group consisting of about 10:1, about 5:1, about 3:1, about 2:1, about 1 :1, about 1:2, about 1:3, about 1:5, and about 1:10. The invention provides a pharmaceutical oral mucosal delivery composition wherein the weight ratio of the first agent to the second agent to the third agent is selected from the group consisting of about 1:1:1, about 0.01:1:1, about 1:1:0.01, about 1:0.1:1, about 0.01:0.1:1, about 1:0.1:0.01, about 1:0.9:1, about 0.01:0.9:1, and about 1:0.9:0.01. The invention provides a pharmaceutical oral mucosal delivery composition wherein the composition further comprises at least one flavoring agent, artificial coloring, sweetener, lubricating agent, disintegration agent, permeation enhancer, lubricating agent, diluent, base, buffering agent, or combinations thereof.

The invention provides for the use of the compositions of the invention for the production of a medicament for treating the indications as set forth herein.

In accordance with a further embodiment, the present invention provides a use of the pharmaceutical compositions described above, an amount effective for use in a medicament, and most preferably for use as a medicament for treating a disease or disorder in a subject.

In accordance with yet another embodiment, the present invention provides a use of the pharmaceutical compositions described above, and at least one additional therapeutic agent, in an amount effective for use in a medicament, and most preferably for use as a medicament for treating a disease or disorder associated with disease in a subject.

DETAILED DESCRIPTION OF THE INVENTION

To the extent that the term "include," "have," or the like is used in the description or the claims, such term is intended to be inclusive in a manner similar to the term "comprise" as "comprise" is interpreted when employed as a transitional word in a claim.

The word "exemplary" is used herein to mean "serving as an example, instance, or illustration." Any embodiment described herein as "exemplary" is not necessarily to he construed as preferred or advantageous over other embodiments.

These and other embodiments of the invention are described herein below or are evident to persons of ordinary skill in the art based on the following disclosures.

The term "administration" of the pharmaceutically active compounds and the pharmaceutical compositions defined herein includes transmucosal application. Nasal, sublingual and buccal administration is particularly preferred in the present invention.

"Ameliorate" or "amelioration" means a lessening of the detrimental effect or severity of the disease in the subject receiving therapy, the severity of the response being determined by means that are well known in the art.

By "compatible" herein is meant that the components of the compositions which comprise the present invention are capable of being commingled without interacting in a manner which would substantially decrease the efficacy of the pharmaceutically active compound under ordinary use conditions. The terms "effective amount" or "pharmaceutically effective amount" refer to a relatively nontoxic but sufficient amount of the agent to provide the desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, such as acute radiation syndrome, or any other desired alteration of a biological system. Such amounts are described below. An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

As used herein, the term "excipient" means the substances used to formulate active pharmaceutical ingredients (API) into pharmaceutical formulations; in a preferred embodiment, an excipient does not lower or interfere with the primary therapeutic effect of the API. Preferably, an excipient is therapeutically inert. The term "excipient" encompasses carriers, diluents, vehicles, solubilizers, stabilizers, bulking agents, acidic or basic pH-adjusting agents and binders. Excipients can also be those substances present in a pharmaceutical formulation as an indirect or unintended result of the manufacturing process. Preferably, excipients are approved for or considered to be safe for human and animal administration, i.e., GRAS substances (generally regarded as safe). GRAS substances are listed by the Food and Drug administration in the Code of Federal Regulations (CFR) at 21 CFR 182 and 21 CFR 184, incorporated herein by reference.

As used herein, the terms "formulate" refers to the preparation of a pharmaceutical composition in a form suitable for administration to a mammalian patient, preferably a human. Thus, "formulation" can include the addition of pharmaceutically acceptable excipients, diluents, or carriers and pH adjusting agents.

"Oral mucosal deliver}'" refers to application of an active agent (such as a pharmaceutical composition) to one or more mucosal membranes of the oral cavity, including buccal (cheek), sublingual (under tongue), lips, gums, palates, and tongue, and passage of the active agent through the membranes covering these places and its entry into the bloodstream.

"Oral mucosal delivery vehicle" refers to a drug delivery system capable of oral mucosal delivery of at least one active agent.

The term "permeation enhancer" or "penetration enhancer" as used herein refers to an agent that improves the rate of transport of a pharmacologically active agent (e.g. , beta-carotene) across the mucosal surface. Typically a penetration enhancer increases the permeability of mucosal tissue to a pharmacologically active agent. Penetration enhancers, for example, increase the rate at which the pharmacologically active agent permeates through membranes and enters the bloodstream. Enhanced permeation effected through the use of penetration enhancers can be observed, for example, by measuring the flux of the pharmacologically active agent across animal or human membranes as described in the Examples herein below. An "effective" amount of a permeation enhancer as used herein means an amount that will provide a desired increase in mucosal membranes permeability to provide, for example, the desired depth of penetration of a selected compound, rate of administration of the compound, and amount of compound delivered.

By "pharmaceutically acceptable" or "pharmacologically acceptable" is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, a "pharmaceutically acceptable carrier" is a material mat is relatively nontoxic and generally inert and does not affect the functionality of the active ingredients adversely. Examples of pharmaceutically acceptable carriers are well known and they are sometimes referred to as diluents, vehicles or excipients. The carriers may be organic or inorganic in nature. In addition, the formulation may contain additives such as flavoring agents, coloring agents, thickening or gelling agents, emulsifiers, wetting agents, buffers, stabilizers, and preservatives such as antioxidants.

The term "pharmaceutical composition" as used herein means a composition that is made under conditions such that it is suitable for administration to, for example, humans, e.g., it is made under GMP conditions and contains pharmaceutically acceptable excipients, e.g., without limitation, stabilizers, pH adjusting agents, bulking agents, buffers, carriers, diluents, vehicles, solubilizers, and binders.

A liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol such as glycerol, propylene glycol, or liquid polyethylene glycols and the like, vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The prevention of the growth of microorganisms can be accomplished by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

As used herein, the term "subj ect" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalia class: humans, non- human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non- mammals include, but are not limited to, birds, fish and the like. The term does not denote a particular age or sex.

As used herein, the terms "treating" or "treatment" of a disease include preventing the disease, i.e. preventing clinical symptoms of the disease in a subject that may be exposed to, or predisposed to, the disease, but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e., arresting the development of the disease or its clinical symptoms, such as by suppressing or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

As used herein, the term "minerals" refers to inorganic substances, metals, and the like required in the human diet and is understood to include, inter alia, boron, calcium, chromium, copper, iodine, iron, magnesium, manganese, molybdenum, nickel, phosphorus, potassium, selenium, silicon, tin, vanadium, zinc, and the like, and combinations or mixtures thereof.

The term "about" and the use of ranges in general, whether or not qualified by the term about, means that the number comprehended is not limited to the exact number set forth herein, and is intended to refer to ranges substantially within the quoted range while not departing from the scope of the invention. As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term.

The present invention relates to compositions comprising for example, beta-carotene, and pharmaceutically acceptable derivatives thereof and/or guanosine monophosphate and pharmaceutically acceptable salts and derivatives thereof; with cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof for transmucosal delivery. The compositions are suitable for sublingual, nasal, and buccal administration use, and provide for absorption of the drug across the oral and nasal mucosa

The invention is also directed to methods of treatment comprising administering the inventive compositions by transmucosal delivery. The inventive methods may improve bioavailability relative to oral dosage forms, especially in those patients with abnormally slow gastric emptying. Such methods can involve administration of the novel compositions described herein. The methods may provide treatment for a variety of conditions amenable to amelioration by for example, beta-carotene, and pharmaceutically acceptable derivatives thereof; with cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof for transmucosal administration, without the occurrence of possible side effects associated with oral ingestion. The present invention provides a pharmaceutical composition comprising for example, a first agent which is selected from the group consisting of beta-carotene, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, guanosine monophosphate, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipientfor transmucosal delivery, wherein the pharmaceutically acceptable composition is provided in a form suitable for transmucosal delivery through nasal, sublingual, or buccal administration.

When the composition of the invention is put into the mouth, rapid delivery of the treatment occurs by the following three routes: sublingual, enhanced absorption through the buccal mucosa, and enhanced absorption through the gastrointestinal tract.

The sublingual route is well-documented to absorb almost as quickly as intravenous inj ection, and avoids first pass metabolism. The mixture greatly enhances the absorption of the buccal mucosa, permitting its substantial surface area in the mouth to absorb almost as quickly as the sublingual route and also to avoid first pass metabolism. The mixture enhances the absorption within the gastrointestinal tract to 5 to 10 times what it would be with beta-carotene alone.

In my experience, a simple mixture of beta-carotene and/or guanosine monophosphate with sodium cholate may not remain stable over a few months. The invention involves formulations which stabilize the mixture, and also devices for the simultaneous administration of the two substances when not premixed.

Placing of a substance in the mouth results in absorption by three major routes. (1) Swallowing through the esophagus initiates digestion by the gastrointestinal tract. (2) Sublingual absorption results in rapid and substantial blood levels of the substance, approaching the effect of intravenous injection. For instance sublingual nitroglycerin provides relief within minutes from angina (cardiac pain). (3) Absorption through the buccal mucosa is the third route.

Each of these routes of absorption has its advantages and relative disadvantages. (1) Swallowing through the esophagus permits complete digestion of anything placed in the mouth, and substances in very large quantity, but it is often slower than other routes, and results in "first pass metabolism" through the liver, which may be a disadvantage. (2) Sublingual absorption is remarkably rapid and effective, and has the benefit of avoiding first pass metabolism, but there is a small surface area under the tongue for sublingual absorption to occur. (3) Buccal mucosal absorption provides a much larger surface area than does sublingual absorption, but the degree of absorption is substantially less than that of sublingual.

These and other embodiments of the invention are described herein below or are evident to persons of ordinary skill in the art based on the following disclosures.

The term "administration" of the pharmaceutically active compounds and the pharmaceutical compositions defined herein includes transmucosal application. Nasal, sublingual and buccal administration is particularly preferred in the present invention.

"Ameliorate" or "amelioration" means a lessening of the detrimental effect or severity of the disease in the subject receiving therapy, the severity of the response being determined by means mat are well known in the art.

By "compatible" herein is meant that the components of the compositions which comprise the present invention are capable of being commingled without interacting in a manner which would substantially decrease the efficacy of the pharmaceutically active compound under ordinary use conditions.

The terms "effective amount" or "pharmaceutically effective amount" refer to a relatively nontoxic but sufficient amount of the agent to provide the desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, such as acute radiation syndrome, or any other desired alteration of a biological system. Such amounts are described below. An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.

As used herein, the term "excipient" means the substances used to formulate active pharmaceutical ingredients (API) into pharmaceutical formulations; in a preferred embodiment, an excipient does not lower or interfere with the primary' therapeutic effect of the API. Preferably, an excipient is therapeutically inert. The term "excipient" encompasses carriers, diluents, vehicles, solubilizers, stabilizers, bulking agents, acidic or basic pH-adj listing agents and binders. Excipients can also be those substances present in a pharmaceutical formulation as an indirect or unintended result of the manufacturing process. Preferably, excipients are approved for or considered to be safe for human and animal administration, i.e., GRAS substances (generally regarded as safe). GRAS substances are listed by the Food and Drug administration in the Code of Federal Regulations (CFR) at 21 CFR 182 and 21 CFR 184, incorporated herein by reference. As used herein, the terms "formulate" refers to the preparation of a pharmaceutical composition in a form suitable for administration to a mammalian patient, preferably a human. Thus, "formulation" can include the addition of pharmaceutically acceptable excipients, diluents, or carriers and pH adjusting agents.

"Oral mucosal delivei>^r" refers to application of an active agent (such as a pharmaceutical composition) to one or more mucosal membranes of the oral cavity, including buccal (cheek), sublingual (under tongue), lips, gums, palates, and tongue, and passage of the active agent through the membranes covering these places and its entry into the bloodstream.

"Oral mucosal delivery vehicle" refers to a drug delivery system capable of oral mucosal delivery of at least one active agent.

The term "permeation enhancer" or "penetration enhancer" as used herein refers to an agent that improves the rate of transport of a pharmacologically active agent (e.g., beta-carotene) across the mucosal surface. Typically a penetration enhancer increases the permeability of mucosal tissue to a pharmacologically active agent. Penetration enhancers, for example, increase the rate at which the pharmacologically active agent permeates through membranes and enters the bloodstream. Enhanced permeation effected through the use of penetration enhancers can be observed, for example, by measuring the flux of the pharmacologically active agent across animal or human membranes as described in the Examples herein below. An "effective" amount of a permeation enhancer as used herein means an amount that will provide a desired increase in mucosal membranes permeability to provide, for example, the desired depth of penetration of a selected compound, rate of administration of the compound, and amount of compound delivered.

By "pharmaceutically acceptable" or "pharmacologically acceptable" is meant a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

As used herein, a "pharmaceutically acceptable carrier" is a material that is relatively nontoxic and generally inert and does not affect the functionality of the active ingredients adversely. Examples of pharmaceutically acceptable carriers are well known and they are sometimes referred to as diluents, vehicles or excipients. The carriers may be organic or inorganic in nature. In addition, the formulation may contain additives such as flavoring agents, coloring agents, thickening or gelling agents, emulsifiers, wetting agents, buffers, stabilizers, and preservatives such as antioxidants. The term "pharmaceutical composition" as used herein means a composition that is made under conditions such that it is suitable for administration to, for example, humans, e.g., it is made under GMP conditions and contains pharmaceutically acceptable excipients, e.g., without limitation, stabilizers, pH adjusting agents, bulking agents, buffers, carriers, diluents, vehicles, solubilizers, and binders.

A liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol such as glycerol, propylene glycol, or liquid polyethylene glycols and the like, vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof. The prevention of the growth of microorganisms can be accomplished by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

As used herein, the term "subject" encompasses mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalia class: humans, non- human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. Examples of non- mammals include, but are not limited to, birds, fish and the like. The term does not denote a particular age or sex.

As used herein, the terms "treating" or "treatment" of a disease include preventing the disease, i.e. preventing clinical symptoms of the disease in a subject that may be exposed to, or predisposed to, the disease, but does not yet experience or display symptoms of the disease; inhibiting the disease, i.e., arresting the development of the disease or its clinical symptoms, such as by suppressing or relieving the disease, i.e., causing regression of the disease or its clinical symptoms.

Beta-carotene

Beta-carotene is a dietary supplement and provitamin. Beta carotene is a member of a family of chemicals known as the carotenoids, which are found in many fruits and vegetables, as well as some animal products such as egg yolks. Natural extracts containing carotenoids, for example carrot extracts and red palm oil, have been used to color foods for centuries. Carotenoids were first isolated in the early 19th century, and have been synthesized for use as food colorings since the 1950s. The structure of beta carotene is:

Beta carotene is used in foods and beverages to provide color. For example, it is commonly used in margarine to provide its yellow color. In addition, beta carotene may be used in foods or beverages for its anti-oxidant effects. Because the body metabolizes beta carotene into Vitamin A, it is also added to foods or beverages as a nutrient.

Beta-carotene was available as a prescription drug, Solatene (Roche) for decades (until the mid-1990's) for the disease Erythropoietic Protoporphyria, and beta-carotene, is still routinely used as a first line treatment for that disease. It is typically used at doses of 180 to 300 mg per day. Extensive reviews over decades have revealed mat it is safe at the highest daily dose for a lifetime (in patients with erythropoietic protoporphyria), and there is no risk of hypervitaminosis A (because the body only converts, at high beta-carotene doses, enough beta carotene to Vitamin A for its requirements and not enough to cause toxicity (Bendich A.Nutr Cancer. 1988;11(4):207-14. Bendich A. J Nutr. 2004 Jan; 134(1):225S-230S.). Furthermore, careful surveillance of beta-carotene for the decades it was a prescription drug confirmed that it has no known acute toxicity.

"Derivatives¹¹ -of beta-carotene are, for example, retinol, retinoic acid, 9-cis retinoic acid, retinal and retinyl.

The term "daily dosage" for example, identifies the average amount of beta-carotene administered to a patient. However, the dosage need not be administered daily. The daily dosage is merely an average dosage that a patient receives when beta-carotene is administered over a period. The daily dosage can be administered in divided portions so that the total amount administered is the daily dosage. Typically, acceptable blood levels of beta-carotene and chemically detectable changes in blood levels will be achieved after administration of beta- carotene in the prescribed amounts for several months, i.e. three to six months.

Although the safe upper limit of the amount of beta-carotene that can be administered to a human has not yet been determined, it is believed that such an upper limit is at least 1000 mg/day. Typically for a human being, a daily dosage amount will be, for example, at least about 50 mg/day of beta-carotene. Most preferably, that amount will range from about 60 mg/day to about 350 mg/day. Particularly, the dosage will be about 300 mg/day. Guanosine Monophosphate

Guanosine Monophosphate is a nucleotide. It is derived from guanosine, which is a nucleoside. Guanosine itself is slightly water-soluble, whereas its phosphates, including guanosine monophosphate, are highly water-soluble. Guanosine and its phosphates are components of every cell. The phosphate derivatives are dephosphorylated in the body to guanosine (Ekelman, K., and K. C. Raffaele. 1993. Disodium 5'-Guanylate and Disodium 5'- Inosinate. World Health Organization. Toxicological evaluation of certain food additives and contaminants. WHO Food Additives Series, No. 32, 1993. No. 788 on Inchem www.mchem.org/documents/jecfa/jecmono/v32je06.htm Accessed 6/16/06.).

Methods for transdifferentiating mammalian cells that have been destabilized by radiation comprising the steps of: (a) contacting the cells with an amount of guanosine monophosphate effective to cause transdifferentiation of said cells; and (b) contacting said cells from step (a) with an amount effective for stabilization of an agent which causes stabilization of cells produced in step a. are disclosed in U.S. Patent No. 8,575,128, incorporated by reference in its entirety herein.

In further alternative embodiments guanosine monophosphate may be substituted for with guanosine, guanosine diphosphate (GDP), guanosine triphosphate (GTP), adenosine, cytosine, thymidine, uridine and their phosphates, or catecholamines (such as norepinephrine and epinephrine).

According to the present invention, effective amounts of these reagents would broadly range between about 0.5 and about 1,000 mg/kg body weight in a recipient subject.

The term "daily dosage" for example, identifies the average amount of guanosine monophosphate administered to a patient. However, the dosage need not be administered daily. The daily dosage is merely an average dosage that a patient receives when guanosine monophosphate is administered over a period. The daily dosage can be administered in divided portions so that the total amount administered is the daily dosage. Typically, acceptable blood levels of guanosine monophosphate and chemically detectable changes in blood levels will be achieved after administration of guanosine monophosphate in the prescribed amounts for several months, i.e. three to six months.

Although the safe upper limit of the amount of guanosine monophosphate that can be administered to a human has not yet been determined, it is believed mat such an upper limit is at least 1000 mg/day. Typically for a human being, a daily dosage amount will be, for example, at least about 50 mg/day of guanosine monophosphate. Most preferably, that amount will range from about 60 mg/day to about 350 mg/day. Particularly, the dosage will be about 300 mg/day.

The safety of guanosine monophosphate (as its disodium salt, Disodium Guanylate) has been extensively documented, because it is approved as a flavoring additive for food in the United States and in Europe (Kojima, K. 1974. Safety Evaluation of Disodium 5 -Inosinate, Disodium 5'-Guanylate and Disodium 5'-Ribonucleotide. Toxicology 2: 185-206.; Ekelman and Raffaele, 1993, above.). It has also been given to a few subjects in gram quantities with no known ill effects (Ekelman and Raffaele, 1993, above.).

Mice. Safety was documented in the xenograft experiment (Baranowitz, S., H. Ma , X. Li, Z. Yang, and R. M. Hoffman. 2007. Reduction Of Human Melanoma Growth By The Use Of Guanosine Monophosphate As A Transdifferentiation Agent In The Xenograft Metamouse Human Melanoma Model, LOX-GFP. J. Invest. Dermatol. 127 (Suppl. 1):S146 (Abstr. 875).) conducted for Dr Baranowitz. by a contract laboratory, Anticancer, Inc. There were three experimental groups where guanosine monophosphate was in the drinking water at 10 mg/ml, 20 mg/ml and 30 mg/ml respectively. Since these mice drink about 10 ml/day and weigh about 25 gm at the beginning of the experiment, this translates into 4000mg/kg body weight, 8000mg/kg, and 12000mg/kg respectively with no obvious ill effects for this 19-day experiment. This is in line with the literature on the safety of guanosine monophosphate.

Gerbils. In a prior experiment (Baranowitz, 2001. Methods For Transdifferentiation of Body Tissues. PCT Application. International Publication Number WO 01/08691 Al. International Publication Date 8 Febrary 2001. World Intellectual Property Organization) ; Baranowitz, 2003 (U.S. Patent No. 6,670,397); Baranowitz, 2005 (Australia Patent No. 782396); and Baranowitz, 2007 (U. S. Patent No. 7,176,189 B2.), guanosine in the food 1% for 8 weeks produced no obvious deleterious effects.

Other animals. Ekelman and Raffaele (1993, above) reviewed this literature for the FDA demonstrating safety in other animal models.

Disodium guanylate, the disodium salt of guanosine monophosphate, is an FDA- approved food flavoring additive. It is a purine-based nucleotide, commonly present in foods. Disodium guanylate is listed in the Center for Food Safety and Applied Nutrition (CFSAN) database maintained by FDA under an ongoing program known as the Priority-based Assessment of Food Additives (PAFA). PAFA contains administrative, chemical, and toxicological information on over 2,000 substances directly added to food, including substances regulated by FDA as direct, "secondary" direct, color additives, GRAS, and prior-sanctioned substances. Disodium guanylate is listed in the CFSAN database as a food enhancer and is designated GRAS.

The "Everything Added to Food in the United States" (EAFUS) list of substances contains ingredients added directly to food that FDA has either approved as food additives or listed or affirmed as GRAS. Information directly applicable to disodium guanylate is provided in Table 1.

Disodium guanylate is a substance currently used as a food flavoring additive in small quantities. Its pharmacology and toxicology have therefore been well characterized, and its excellent safety record in humans has been reviewed and documented by FDA. The safety of disodium guanylate has been extensively reviewed by Ekelman and Raffaele at FDA (Ekelman, K., and K. C. Raffaele. 1993. Disodium S'-Guanylate and Disodium 5'-Inosinate 1993; World Health Organization Toxicological evaluation of certain food additives and contaminants, WHO Food Additives Series, No. 32, 1993. No. 788).

Disodium guanylate is generally produced via fermentation to support a food grade label in compliance with the Food Chemical Codex (FCC) monograph for disodium guanylate

Disodium guanylate is a nucleotide that is found in RNA. It is an ester of phosphoric acid with the nucleoside guanosine. The chemical structure of disodium guanylate contains four chiral centers and is optically active. Disodium guanylate as shown below consists of the phosphate group, the pentose sugar ribose, and the nucleobase guanine.

Sodium chelate

Sodium cholate is a bile salt used as a food additive (e.g. for cheese) or a dietary supplement. It is remarkably safe, and is categorized by FDA in the its "safest" category which is known as "Generally Regarded as Safe" (GRAS). The present invention involves the use of, for example, sodium cholate to markedly enhance rapid absorption of medically significant amounts of, for example, beta-carotene and/or guanosine monophosphate through all three routes.

Cholic acid and its derivatives are represented by Formula 1:

wherein R₁, R₂, and R₃ are independently hydrogen or a hydroxy group; and X is -OH, -

or Formula 2:

wherein X is as defined in Formula 1. Cholic acid of the present invention has the chemical formula 3a, 7a, 12a- trihydroxycholan-24-oic acid, and is also termed ox bile extract, cholalic acid, cholalin or cholanic acid.

Examples of suitable cholic acid derivatives of the present invention include 3 a, 12a - dihydroxycholan-24-oic acid (deoxycholic acid), 3,7,12-trioxocholan-24-oic acid (dehydrocholic acid), 3a, 7a-dihydroxycholan-24-oic acid (chenodeoxycholic acid), 3a, 7P-dihydroxycholan- 24-oic acid (ursodesoxycholic acid), 3 a-hydroxycholan-24-oic acid (lithocholic acid), 2-[(3a, 7a,12a-trmydroxy-24-oxocholan-24-yl)amino]ethan- esulfonic acid (taurocholic acid), 2-(3a, 7a, 12 a-trihydroxy-24-oxocholan-24-yl)glycine (glycocholic acid), and so on. Alkali metal salts and other derivatives that can be prepared from these cholic acid derivatives are also within the scope of the present invention. These cholic acid derivatives have a steroid structure as a common mother nucleus, and belong to steroid acids containing a carboxyl group. Acidic materials having a steroid mother nucleus which can be extracted from the bile of humans and animals, and salts with alkali metal ions thereof are also within the scope of the present invention.

A few studies in the literature report that sodium cholate can increase buccal mucosal absorption of specific substances. Senel et al, 1994 (Senel, S, A J Hoogstraate, F Spies, J C Verhoef, A Bos-van Geest, H E Junginger, and H E Bodde, Journal of controlled release 32, no. 1 (1994): 45-56.) reported that sodium cholate could increase the mucosal permeability of fluorescein isothiocyanate by 100-200 times. Nakane et al., 19% (Nakane, Sachi, Munetaka Kakumoto, Keiji Yukimatsu, and Yie W Chien. Pharmaceutical development and technology 1, no. 3 (1996): 251-259) reported that sodium cholate increased the absorption of luteinizing hormone releasing hormone. Zhang et al., 1994 (Zhang, Jie, Suyi Niu, Charles Ebert, and Theodore H Stanley. International journal of pharmaceutics 101 , no. 1 (1994): 15-22.) reported that sodium cholate increased the buccal absorption of insulin. Other researchers have demonstrated effectiveness of other bile acids or derivatives of sodium cholate to enhance absorption of the buccal mucosa No reports have been identified in the literature which involve a combination of beta-carotene with sodium cholate to increase buccal or sublingual mucosal absorption of beta-carotene.

Mineral Component

Compositions of the present invention may also include a mineral supplement, such as magnesium. Other mineral supplements may be used, for example copper, zinc, selenium, molybdenum, manganese, chromium, iodine, iron and combinations thereof. In formulations of the present invention, divalent ions, such as calcium and magnesium, zinc, and manganese are preferred; however, there is some indication that calcium may compete for or otherwise inhibit magnesium functionality in this regard (See Abraham, cited above).

These vitamins, minerals and trace elements include, for example, Vitamin A or beta- carotene, Vitamin Bl (as Thiamin or Thiamin mononitrate), Vitamin B2 (as Riboflavin), Vitamin B3 (as Niacin), Vitamin B6 (as Pyridoxine or Pyridoxine hydrochloride), Vitamin B9 (Folic Acid), Vitamin B12 (cyanocobalamine), Vitamin H (Biotin), Vitamin C (Ascorbic Acid), Vitamin D, Vitamin E (as dl -Alpha Tocopherol Acetate), Vitamin K, Folacin, Niacinamide, Iron (as Ferrous Fumarate), Phosphorus, Pantothenic Acid (as Calcium Pantothenate), Iodine (as Potassium Iodide), Magnesium (as Magnesium Oxide), Zinc (as Zinc Oxide), Selenium (as Sodium Selenate), Copper (as Cupric Oxide), Manganese (as Manganese Sulfate), Chromium (as Chromium Chloride), Molybdenum (as Sodium Molybdate), Choline, Fluoride, Chloride, Potassium, Sodium, and mixtures thereof. Such vitamins, minerals and trace elements are commercially available from sources known by those of skill in the art. The dosage forms of the invention may be formulated using any pharrnaceutically-acceptable forms of the vitamins and/or minerals described above, including their salts, which are known by those of skill in the art.

In one embodiment, the pharmaceutical or dietary composition according to the present invention includes one or more vitamins, minerals, trace elements, or combinations thereof selected from the group consisting of Vitamin A, Vitamin C, Vitamin D, Vitamin E, Vitamin K, Thiamin, Riboflavin, Niacin, Folate, Vitamin B12, Vitamin B6, Pantothenic Acid, Biotin, Choline, Chromium, Copper, Iodine, Molybdenum, Selenium, Iron, Zinc, Magnesium, and combinations thereof.

In an exemplary embodiment of the present invention, compositions comprise gamma- tocopherol, DHA and magnesium; other compositions contain gamma-tocopherol, hesperetin, quercetin, DHA and magnesium. Ranges and approximate dosages are described below. Formulations of the invention may include one or more mineral in the range of 10-1000 mg, 20- 800 mg, 50-400 mg, 50-300 mg, 100-200 mg, less than 1000 mg, less than 800 mg, less than 400 mg, less than 250 mg, less than 200 mg, greater than 10 mg, greater than 20 mg, greater than 30 mg, greater than 50 mg, greater than 100 mg. Minerals can be substituted with reference to their DRIs and Upper Limits (Reference: Food and Nutrition Board, Institute of Medicine, Washington, D.C.), since toxicity may occur at very high doses of certain minerals. In some embodiments, the composition comprises at least one supplemental mineral or mineral source. Examples of minerals include, without limitation: chloride, sodium, calcium, iron, chromium, copper, iodine, zinc, magnesium, manganese, molybdenum, phosphorus, potassium, and selenium. Suitable forms of any of the foregoing minerals include soluble mineral salts, slightly soluble mineral salts, insoluble mineral salts, chelated minerals, mineral complexes, non-reactive minerals such as carbonyl minerals, and reduced minerals, and combinations thereof.

In certain embodiments, the composition comprises at least one supplemental vitamin. The at least one vitamin can be fat-soluble or water soluble vitamins. Suitable vitamins include but are not limited to vitamin C, vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, pantothenic acid, and biotin. Suitable forms of any of the foregoing are salts of the vitamin, derivatives of the vitamin, compounds having the same or similar activity of the vitamin, and metabolites of the vitamin. Beta-carotene and sodium chelate

Administration of beta-carotene and sodium cholate was demonstrated by Umegaki,

1995 to enhance gastrointestinal absorption of beta carotene. He showed that this resulted in increased absorption of beta-carotene into the bone marrow. (Umegaki et al., J. Nutr. 1995 125 :3081-3086. ). However, no reports have been identified in the literature which involve a combination of beta-carotene with sodium cholate to increase buccal or sublingual mucosal absorption.

Compositions of the invention include pharmaceutical compositions for oral administration to treat, for example, acute radiation sickness, wherein the composition comprises, for example, a first agent which is selected from the group consisting of beta- carotene, and pharmaceutically acceptable derivatives thereof; a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

The percentage of sodium cholate in the mixture ranges from 2%-50%, and preferably in the range of 25%-30%.

The formulation will optimally reduce mortality and morbidity if administered within 72 hours of severe radiation exposure, and most optimally within 24 hours.

The stable formulations of beta-carotene can also be used for rapid administration of beta-carotene for other therapeutic purposes (e.g. to treat liver toxicity as described in Baranowitz patent US 5670549, or treatment of Age Related Macular Degeneration as described in Baranowitz patent US5457135).

Exemplary Formulations of beta-carotene and sodium cholate are as set forth in Table 2:

Table 2

Guanosine Monophosphate and sodium cholate

Compositions of the invention include pharmaceutical compositions for oral administration to treat, for example, acute radiation sickness, wherein the composition comprises, for example, a first agent which is selected from the group consisting of guanosine monophosphate, pharmaceutically acceptable derivatives thereof, and pharmaceutically acceptable salts thereof, and a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

Exemplary Formulations of guanosine monophosphate and sodium cholate are as set forth in Table 3:

Table 3

Mycophenolate

In certain embodiments, the invention provides provides a method, use, device, or formulation that inhibits inosine monophosphate dehydrogenase (IMPDH), which catalyzes the NAD+-dependent conversion of inosine 5'-monophosphate to xanthosine 5'-monophosphate. In a certain embodiment, the invention provides a method, use, device, or formulation, wherein the IMPDH inhibitor is a mycophenolate. In a further embodiment, the invention provides a method, use, device, or formulation, wherein the mycophenolate is selected from mycophenolic acid and mycophenylate mofetil, or a pharmaceutically acceptable salt or prodrug thereof. In a further embodiment, the invention provides a method, use, device, or formulation, wherein the mycophenolate is an analog of mycophenolic acid having one or more varying substituents at the 2-, 4-, 5-, and 6-positions, or a pharmaceutically acceptable salt or prodrug thereof. In another further embodiment, the invention provides a method, use, device, or formulation, wherein the mycophenolate is a metabolite of mycophenolic acid, or a pharmaceutically acceptable salt thereof.

In an exemplary embodiment, the subj ect IMPDH inhibitor is a mycophenolate. As used herein, "mycophenolates" refers herein to mycophenolic acid and its analogs, and their pharmaceutically acceptable salts, derivatives, prodrugs, and metabolites. Exemplary mycophenolates for use in the present invention include mycophenolic acid and mycophenylate mofetil. Mycophenolic acid, or

Mycophenolate mofetil is the 2-morpholinoethyl ester of mycophenolic acid, and has the formula:

In still another aspect, the invention provides a method of treating a subj ect identified as suffering from or susceptible to a disease or, the method comprising the step of administering to the subject a therapeutic amount of a compound, wherein the compound is selected from the following: Mycophenolic Acid; Ribavarin; Mycophenolate; Mycophenylate Mofetil; BMS- 337197; VX-497 (merimepodib); VX-148; VX-944; Viramidine; Levovirin; Mizoribine; Tiazofurin; benzamide riboside, selenazofurin, 5-ethyTiyl-l-beta-D-ribofuranosylimidazole-4 carboxamide (EIC AR); and C2-MAD; wherein the compound inhibits inosine monophosphate dehydrogenase (IMPDH).

Analogs of mycophenolic acid that have high IMPDH-inhibiting activity are also useful in the practice of the present invention include compounds with varying substituents in the 2-, 4- , 5-, and 6-positions on the mycophenolate core structure, as well as pharmaceutically acceptable salts, derivatives, prodrugs, and metabolites of such mycophenolate analogs.

Therapeutic Use of Melanin Overview

Administration: The application or delivery of a drug to a mammal in need of the drug. This term is intended to include any means of administration which accomplishes the application or delivery of the drug (i. e., topical, oral, aerosol, suppository, parenteral, e. g. , intravenous, intramuscular, subcutaneous injection, e. g. , into the tissue, intraperitoneally and the like). The term is also intended to include any means necessary to accomplish such administration. The term is further intended to include the in vivo production of a drug or aggregation of a drug moderated by another substance such as an enzyme (tyrosinase) or enzyme gene (tyrosinase gene) to moderate production of a drug (melanin) or its precursors, or a concentrating hormone (MCH) subcutaneously to moderate drug (melanin) concentration.

Treatment: Treatment is defined as administration to a mammal suffering from infections or bums or administration to a mammal at risk for such infections.

Melanin: Melanins are polymers produced by polymerization of reactive intermediates.

The polymerization mechanisms include but are not limited to autoxidation, enzyme catalyzed polymerization and free radial initiated polymerization. The reactive intermediates are produced chemically or enzymatically from precursors. Suitable enzymes include, but are not limited to peroxidases and catalases, polyphenol oxidases, tyrosinases, tyrosine hydroxylases or lacases. The precursors which are connected to the reactive intermediates are hydroxylated aromatic compounds. Suitable hydroxylated aromatic compounds include, but are not limited to 1) phenols, polyphenols, aminophenols and thiophenols of aromatic or polycyclicaromatic hydrocarbons, including but not limited to phenol, tyrosine, pyrogallol, 3-aminotyrosine, thiophenol and. alpha, -naphthol; 2) phenols, polyphenols, aminophenols, and thiophenols of aromatic heterocyclic or heteropolycyclic hydrocarbons such as but not limited to 2- hydroxypyrrole, 2-pyrazole, 4- hydroxypyridine, 8-hydroxyquinoline, and 4,5- dihydroxybenzothiazole. The term melanin includes naturally occurring melanins which are usually high molecular weight polymers and low molecular weight polymers as well as melanin analogs as defined below. Naturally occurring melanin includes eumelanins, phaeomelanins, neuromelanins and allomelanins. The term melanin is also intended to include trichochromes when used hereafter. The term "melanin"is further intended to include melanin, melanin precursors, melanin analogs, melanin variants and melanin derivatives unless the context dictates otherwise.

Melanin Analog: Melanin in which a structural feature that occurs in naturally occurring or enzymatically produced melanins is replaced by an unusual substituent divergent from substituents traditionally present in melanin. An example of an unusual substituent is selinium in place of sulfur, such as selinocysteine.

Melanin Derivative: This term is intended to include any derivative of melanin which is capable of being converted to either melanin or a substance having melanin activity. An example of a melanin derivative is melanin attached to a dihydrotrigonelline carrier such as described in Bodor, N. , Ann. N. Y. Acad. Sci. 507,289 (1987) to enable the melanin to cross the blood-brain barrier. The term melanin derivatives is also intended to include chemical derivatives of melanin, such as an esterified melanin.

Melanin Variant: Melanin variants include various subsets of melanin substances that occur as families of related materials. Included in these subsets, but not limited thereto, are: (1 ) Naturally occurring melanins produced by whole cells that vary in their chemical and physical characteristics; (2) Enzymatically produced melanins prepared from a variety of precursor substrates under diverse reaction conditions; (3) Melanin analogs in which a structural feature that occurs in (1) or (2) above is replaced by an unusual substituent divergent from the traditional; and (4) Melanin derivatives in which a substituent in a melanin produced in (1), (2) or (3) above is further altered by chemical or enzymatic means.

Tyrosinase: An enzyme which, in mammals, catalyzes: (a) the hydroxylation of tyrosine to dopa (3,4-dihydroxyphenylalanine) ; (b) the oxidation of dopa to dopaquinone; and (c) may catalyze the oxidation of 5,6-dihydroxjdndole to indole-5,6- quinone. All of these reactions catalyzed by tyrosinase take place in the biosynthetic pathway which produces melanin. Tyrosinase is most commonly found in a glycosylated form in vivo.

Melanin Concentrating Hormone: Melanin concentrating hormone (MCH) is a peptide which has been isolated from fish pituitary glands, characterized and synthesized (Kawauchi, H. et al. , Nature 305,321 (1983) ). MCH has also been localized by immunohistochemistry in the brain and pituitary gland of salmon, frogs and rats (Baker, B.J. et al. , Gen. Comp. Endocrinol. 50,1423 (1983), Naito, N. et al. , Neurosci. Lett. 70,81 (1986), Skotfitsch, G. et al. , Proc. Natl. Acad. Sci. USA 83,1528 (1986) and Zamir, N. et al. , Brain Research 373,240 (1986) ). A mammalian MCH-like substance has been detected using salmon MCH antiserum directed against salmon MCH by radioimmunoassay and immunohistochemistry (Zamir, N. et al. , Proc. Natl. Acad. Sci. USA, supra). This mammalian MCH exhibits distinct chromatographic properties on both Reversed Phase High Performance Liquid Chromatography (RP-HPLC) and gel chromatography when compared to the fish enzyme. Id. The persistence of this mammalian MCH in the mammalian hypothalamo- neurohypophyseal system suggests a role for MCH in posterior pituitary function, such as the regulation of food and water intake. Id.

Other functions of this mammalian MCH peptide have also been suggested.

For example, due to the identification of MCH fibers in the human median eminence and pituitary stalk, it has been suggested that the peptide causes the aggregation or concentration of melanin in cells of the central nervous system and may be involved in the regulation of anterior pituitary function (Pelletier, G. et al. , Brain Research 423,247 (1987) ). Furthermore, Sekiya, K. et al. (Neuroscience 25,925, 1988) suggest that MCH may act as a neurotransmitter and/or neuromodulator in the central nervous system or may regulate the pituitary portal-blood system and/or the neurosecretory system in mammals.

Melanin: Naturally occurring melanins include eumelanins, phaeomelanins, neuromelanins and allomelanins. Trichochromes which are low molecular weight polymers derived from the oxidation of tyrosine are also considered melanins for the purpose of this invention.

Melanins and melanin variants are as defined above. Melanin variants are considered melanins for the purpose of this invention unless the context indicates otherwise.

The patient or subject to be treated may be any animal or human. The subject is preferably mammalian. In some embodiments the subject is a human. In other embodiments the subj ect is an animal, more preferably a non-human mammal. The non-human mammal may be a domestic pet, or animal kept for commercial purposes, e.g. a race horse, or farming livestock such as pigs, sheep or cattle. As such the invention may have veterinary applications. Non- human mammals include rabbits, guinea pigs, rats, mice or other rodents (including any animal in the order Rodentia), cats, dogs, pigs, sheep, goats, cattle (including cows or any animal in the order Bos), horse (incl uding any animal in the order Equidae), donkey, and non-human primates. The subject may be male or female. The subject may be a patient. Part A - Methods for depletion of guanosine-containine nucleosides and nucleotides: Specialized Diets and Dietary Program for Treatment of Zika and other Viral Diseases

Part A can be implemented using either or both of the following approaches.

Part Al - Administering agents which deplete guanosine-containing nucleosides and nucleotides.

One approach is that of administering agents (e.g. chemicals, or molecules such as immunoglobulins) that have the effect of reducing the content of guanosine-containing nucleosides and nucleotides in particular tissues or the whole body. One way to do mis, for example, is that used by mycophenolate and similar compounds that inhibit the IMPDH enzyme, which is necessary for the production of guanosine monophosphate, a key intermediate in the nucleotide synthesis pathway. Another approach would be to administer agents which bind to guanine, or guanosine-containing nucleosides and nucleotides, to reduce their availability.

Part A2 - Dietary restriction of guanosine intake and substances used by the body to synthesize guanosine. We describe below specialized diets that we have constructed and used which specifically reduce the dietary intake of guanosine

It utilizes diets which are low in nucleic acids and their components but which are not nucleotide-free. The diets contain approximately 3% to 50% of the amount by weight of nucleotides seen in the normal western diet (2000 mg/day, from Ekelman, K. Disodium 5'Guanylate and Disodium 5'-lnosate. WHO Food Additives Series, No. 32 (1993), and preferably 10%-40%. The percentage of nucleotides, nucleosides, and other nucleic acid components in specific foods has been published by different researchers using various analytic techniques over the years (e.g. Lassek, E, and A Montag. "Nucleic Acid Components in Carbohydrate-rich Food. " Zeitschrift flir Lebensmittel-Untersuchung und -Forschung 190, no. 1 (1990): doi: 1689090; Souci, S W, W Fachmann, H Kraut, EvaKirchhoff, and Forschungsanstalt Forschungsanstalt fur Deutsche. Food Composition and Nutrition Tables. Stuttgart: Medpharm, 2008; Brule, D, G Sarwar, and L Savoiet "Purine Content of Selected Canadian Food Products." Journal of Food Composition and Analysis 1, no. 2 (1988): 130-138.). A survey of the world literature on nucleic acid content of foods was conducted. In some cases where the individual nucleotides were not reported, the amount of total nucleotides and of guanosine-containing nucleotides could be estimated from the reported purine content. A set of diets with different percentages of nucleotides (compared to the typical Western diet) was created. These range between about 10% to 40% of the typical Western diet. A registered dietitian created these diets which were low in nucleotides but balanced for other necessary nutrients. Choosing a diet with a given percent (or range) of nucleotides is optimized by medical evaluation of the condition and needs of the individual patient. Medical evaluation may include the following: level of antibody titers such as those of anti-nuclear antibody, anti-dsDNA antibodies, anti-guanosine antibody, evaluation of the presence and degree of organ damage in kidneys, lungs, j oints, brain, and skin, subj ecti ve symptomatology such as pain, headaches, and evaluation criteria.

Additionally, it is proposed that all patients with pathogenic infections, and individuals susceptible to developing pathogenic infections, will benefit from diets in which the nucleotide level is 45% or less than the typical western diet, and in which the guanosine and guanosine- containing nucleotides are less than 45% of the typical western diet.

2. The diets initially recommended by the physician to the patient are low in their content of guanine, a nitrogenous base, and/or guanosine. a nucleoside, compared to the usual Western diet. The patient's response to the diet is evaluated overtime and diets with sequentially more nucleotide content and more palatability are recommended so that the compliance and tolerabiliry and palatability is at such a level that the patient can for years be maintained to on a reduced nucleotide diet. For instance, if the patient is started by the physician on a Step 1 diet attached, it is likely that after a period of weeks or months the patient will be advanced to a Step 2 diet which has a greater nucleotide content, reflected in a larger range of foods which can be taken, and is therefore more palatable.

(Nucleotide-free diets are described in: Rudolph, F B, A D Kulkarni, W C Fanslow, R P

Pizzini, S Kumar, and C T Van Buren. "Role of RNA As a Dietary Source of Pyrimidines and Purines in Immune Function." Nutrition 6, no. 1 (1990): 45-52; Kulkarni, A D, F B Rudolph, and C T Van Buren. "The Role of Dietary Sources of Nucleotides in Immune Function: A Review." The Journal of nutrition 124, no. 8 Suppl (1994): 1442S-1446S.: 45-52).

The inventor's reduced nucleotide diets are fundamentally different from nucleotide-free diets. The nucleotide-free diets used in published animal experiments were almost entirely devoid of nucleotides and were said to contain a level of only 0.001% (Rudolph, F B, A D Kulkarni, W C Fanslow, R P Pizzini, S Kumar, and C T Van Buren. "Role of RNA As a Dietary Source of Pyrimidines and Purines in Immune Function." Nutrition 6, no. 1 (1990): 45-52).

The inventor has conducted extensive analysis of the nucleotide content of human foods from a variety of sources, and evaluated the nutritional content and palatability of potential nucleotide-free diets. The inventor has concluded that it is not practical for most people to stay- on a nucleotide-free diet in a compliant manner for the period of months required to obtain substantial clinical benefit from this approach. A nucleotide-free diet is unlikely to be sufficiently palatable for extended use and would deter compliance. Also, use of a nucleotide- free diet for months in humans would likely lead to other dietary deficiencies.

As set forth above, the invention provides treatment of a patient with a diet which contains approximately 3% to 50% of the amount by weight of nucleotides seen in the normal western diet, which contains about 2000 mg/day of nucleotides. In exemplary embodiments, the diet of the invention contains a nucleotide content of about 1000 mg/day, of about 750 mg/day, of about 500 mg/day, of about 250 mg/day, of about 100 mg/day, of about 75 mg/day, of about 50 mg/day, of about 25 mg/day. In exemplary embodiments, the diet of the invention contains a nucleotide content compared to the normal Western diet of about 50%, of about 40%, of about 30%, of about 20%, of about 10%, of about 5%, of about 3%. In exemplary embodiments, the diet of the invention contains a nucleotide content compared to the normal Western diet of 3- 50%, of about 10-40%, of about 20-30%, of about 3-40%, of about 3-30%, of about 10-30%, of about 10-20%.

2. Example diets: The nucleotide content of one Example Diet is about 28±5% of the typical Western diet. The nucleotide content of another Example Diet is about 43±5% of the typical Western diet.

3. The diet program is comprised of a period of months, e.g. 6 months, during which a physician and a dietician evaluate and work to optimize diet treatment for each pathogenic infection patient.

a. The physician initially evaluates the severity of the patient's disease based on signs and symptoms, laboratory tests, evidence of organ damage, etc., and then recommends a specific diet. The patient is followed over the next few months with repeat followup disease evaluations and diet adjustments by the physician. The patient may be asked to keep, as individually necessary, logs of sy mptoms such as headaches, skin rashes, joint pains, etc. These logs are periodically reviewed by the physician.

b. The dietician has an initial meeting with the patient in which the practical aspects of the diet program are explained in detail. This first visit includes describing weighing the foods to be included in the diet, characterizing the portion size for each type of food, keeping a food log, advising on the effect of cooking on food nucleotide content, etc. The patient will have one or more followup visits, as well as occasional other phone, email or other communications with the patient to answer questions and direct the treatment. c. Depending on the severity of the patient's disease, an initial diet will be selected. As the patient stabilizes clinically or based on laboratory testing, the patient will be moved through a series of diets with increasing nucleotide content but which are still substantially lower compared to the typical Western diet. It is believed that for each patient there is a threshold for reactivity, and mat if the diets are below that threshold the patient will have successfully minimized signs, symptoms, and progression of the pathogenic infection. The goal of the program is then to put the patient on a convenient and palatable maintenance diet which they can pragmatically follow for a period of years.

Part B - Methods for administering melanin, and/or increasing the body content of melanin bv modulation of metabolic processes.

Melanin from different sources and in different formulations has been shown to have some therapeutic activity against some viruses, bacteria, fungi and parasites, but is not used clinically at all as far as the inventor has been able to determine. Additionally, melanin is very hard (Majerus, M. E. N., Melanism, New York: Oxford University Press, 1998) and has been shown to represent a physical barrier to pathogens both on the skin (Tang, Huaping. Regulation and function of the melanization reaction in Drosophila .Fly 3 (2009): 105-111) and internally. It is amenable to a wide range of administration methods including topical and parenteral. It is generally considered to be non-toxic itself except to pathogens. Melanin has also been produced from genetically modified organisms including fungi and bacteria

The present invention involves the use of one or more methods from each of Part A and part B. A method from Part A and a method from Part B can be administered together (e.g. in a single formulation, or singly at the same time), or sequentially in any order (e.g. A method from part A followed by a method from part B, or a method from part B followed by a method from part A)

Guanosine - depleting chemicals such as mycophenolate are active against microbes in much lesser doses than those currently used for its main indication that of immunosuppression for transplantation.

The present invention has the further advantage that it is unlikely that the Zika virus or other organisms will be able to develop a resistance to both of the different types of attack represented by Part A and Part B together. Another advantage of the present invention is mat any microbes which were to develop resistance would still be susceptible to other available therapies. The present invention is directed to therapeutic uses of melanin, melanin precursors, melanin derivatives, melanin analogs and related substances. One particular aspect of the invention relates to the treatment or prevention of infections by the administration of active substances which cause an increased melanin concentration in the patient's infected tissues. Such substances include melanin, melanin precursors, melanin derivatives, melanin analogs, melanin variants, melanin-concentrating hormone (MCH), tyrosinase, tyrosinase gene and combinations thereof.

In one aspect, the present invention a method for treating or preventing pathogenic infections in a mammal comprising administering to a mammal in need of such treatment an amount effective for treating said infections of an agent which causes an increased concentration of melanin and related substance in said infections.

In another aspect, the present invention provides a method for preventing pathogenic infections in a mammal comprising administering to a mammal in need of such treatment an amount of an agent effective to prevent said infections of an agent which causes an increased concentration of melanin and related substances in said infections.

In yet another aspect the present invention provides a pathogenic infection-healing device selected from a patch, a strip, a dressing or a band comprising an amount of melanin or related substance effective to treat a infections in a mammal.

In yet another aspect the present invention provides a pharmaceutical formulation for treating or preventing pathogenic infections in a mammal comprising mineral oil and an infection treating effective amount of an agent which causes an increase in the concentration of melanin in said infected tissues.

In a further aspect, the present invention provides a pharmaceutical formulation for treating or preventing pathogenic infections in a mammal comprising another topical antibacterial cream or ointment and a infection-healing effective amount of an agent which causes an increased concentration of melanin and related substances in said infections.

In a still further aspect, the present invention provides a method for treating or preventing pathogenic infections in a mammal comprising administering to a mammal in need of such treatment an amount effective to treat said infections of a pharmaceutical formulation which causes an increase in the concentration of melanin in said infected tissues wherein said agent is selected from melanin, melanin precursors, melanin derivatives, melanin analogs, melanin variants, tyrosinase, tyrosinase gene, melanin concentration hormone and mixtures thereof. In a still further aspect, the present invention provides a pharmaceutical formulation for treating or preventing pathogenic infections in a mammal comprising an emollient selected from ammonium lactate, ichthammol ointment and lanolin and an infection-healing effective amount of an agent which causes an increased concentration of melanin and related substances in said infections.

These and other aspects of the present invention will be apparent to those of ordinary skill in the art in light of the present description and claims.

Melanins Melanin is a pigment which is found in many cells and organisms (Majerus, M. E. N.,

Melanism, New York: Oxford University Press 1998). It is resistant to analysis and degradation by chemical and physical agents (Prota, G., Melanins And Melanogenesis, New York: Academic Press, 1992). Therefore the complete structures of many melanins remain unknown, although a few have been identified and even synthesized (Prota, G., Melanins And Melanogenesis, New York: Academic Press, 1992).

Melanin is naturally found in small packets called melanosomes (Prota, G. , Melanins And York: Academic Press, 1992), which are membrane- enclosed vesicles. Melanin is a hard substance (Majerus, M. E. N., Melanism, New York: Oxford University Press, 1998). The presence of many small melanosomes strengthens cells. The melanin in cells is separated by membranes and other cytoplasmic components, This arrangement permits flexibility in movement while preserving hardness to resist pressure.

Melanin is normally present in mammalian skin in cells called melanocytes (Prota, G. , Melanins And Melanogenesis, New York: Academic Press, 1992). Melanocytes are most numerous in the epidermis and dermis of the skin, but are present in other tissues such as the eye, some nerves, the brain, and some blood cells.

In the epidermis there is approximately 1 melanocyte to 36 keratinocytes. In the dermis the ratio of melanocytes to fibroblasts is much more variable. Melanin is often found in healed skin (Majerus, M. E. N., Melanism, New York: Oxford University Press, 1998).

Mammalian colors are determined chiefly by two types, eumelanins and phaeomelanins. Eumelanins are derived from the precursor tyrosine and are generally insoluble and black or brown in color. Phaeomelanins have as their precursors tyrosine and cy steine and are generally alkali-soluble and lighter in color. Allomelanins ("alio" meaning other) are formed from nitrogen-free precursors, primarily catechol and 1,8- dihydroxynaphthalene (see The Merck Index, Tenth Edition, page 827, item 5629, Melanins). Quinones are the usual intermediates in allomelanin synthesis. The synthesis of melanins occurs in nature as well as being produced synthetically. A further group of low molecular weight yellow, red and violet pigments is known as trichochromes. The trichochromes are usually classified with the melanins, since they serve as pigments and are derived from the oxidation of tyrosine.

The enzyme, tyrosinase, plays a key role in the synthesis of melanin and its derivatives. In mammals, tyrosinase is a glycosy lated enzyme found in melanocytes. It has been theorized that tyrosinase functions by means of separate catalytic sites; one site for tyrosinase hydroxylase activity, another site for dopa oxidase activity, and a third independent site for dopa as a cofactor. (Hearing, V. J. et al. , Biochem. J. , 157: 549 (1976)). Tyrosinase may also play a role in catalyzing the oxidation of 5,6-dihydroxyindole to indole-5,6-quinone. (Korner, A. M. et al. , Science 217,1163 (1982)). In vivo, mammalian tyrosinase undergoes extensive modification. When initially synthesized, tyrosinase has an apparent molecular weight of about 55,000. Glycosylation of the enzyme occurs as it is transferred through the Golgi complex and delivered to the melanocytes. (Imokawa, G. et al. , J. Invest. Derm. , 85,165 (1985)). During this modification of tyrosinase, sialic acid and 4 mol of asparagine-linked carbohydrate chains (containing mannose, glucosamine, galactose and are added to each mole of tyrosinase. (Ferrini, V. et al. , Int. J. Biochem. 19,229 (1987)). The glycosylated tyrosinase has an apparent molecular weight of about 70,000. (Laskin, J. D. et al. , J. Biol. Che 261, 16626 (1986)). The glycosylated tyrosinase is delivered to the melanocytes by coated vesicles. In the melanocytes, the tyrosinase is membrane bound and aggregates into a high molecular weight form. In vivo, tyrosinase is under active metabolic control involving an active degradation system which results in a biological half-like of about ten hours. (Jimenez, M. et al. , Fed. Proc. Fedn. Am. Socs. Exp. Biol. 45,1714 (1986)).

The melanins comprise a family of biopolymer pigments. A frequently used chemical description of melanin is that it is comprised of '¾eteropolymers of 5-6-dihydroxyindole and 5- 6-dihydroxyindole-2-carboxylic acid" (Bettinger et al., 2009). Melanins are polymers produced by polymerization of reactive intermediates. The polymerization mechanisms include, but are not limited to, autoxidation, enzyme-catalyzed polymerization and free radical initiated polymerization. The reactive intermediates are produced chemically, electrochemically, or enzymatically from precursors. Suitable enzymes include, but are not limited to, peroxidases, catalases, polyphenol oxidases, tyrosinases, tyrosine hydroxylases, and laccases. The precursors that are connected to the reactive intermediates are hydroxylated aromatic compounds. Suitable hydroxylated aromatic compounds include, but are not limited to 1) phenols, polyphenols, aminophenols and thiophenols of aromatic or polycyclicaromatic hydrocarbons, including, but not limited to, phenol, tyrosine, pyrogallol, 3-aminotyrosine, thiophenol and a-naphthol; 2) phenols, polyphenols, aminophenols, and thiophenols of aromatic heterocyclic or heteropoly cyclic hydrocarbons such as, but not limited to, 2-hydroxypyrrole,4-hydroxy-l,2-pyrazole, 4- hydroxypyridine, 8-hydroxyquinoline, and 4,5-dihydroxybenzothiazole.

The term melanin includes naturally occurring melanin polymers as well as melanin analogs as defined below. Naturally occurring melanins include eumelanins, phaeomelanins, neuromelanins and allomelanins.

As used here, the term "melanin" refers to melanins, melanin precursors, melanin analogs, melanin variants, melanin derivatives, and melanin-like pigments, unless the context dictates otherwise. The term "melanin-like" also refers to hydrogels with melanin-like pigmentation and quinoid electrophilicity. This electrophilicity can be exploited for facile coupling with biomolecules.

As used herein, the term "melanin analog" refers to a melanin in which a structural feature that occurs in naturally-occurring or enzymatically-produced melanins is replaced by a substituent divergent from substituents traditionally present in melanin. An example of such a substituent is a selenium, such as selenocysteine, in place of sulfur.

As used herein, the term "melanin derivative" refers to any derivative of melanin which is capable of being converted to either melanin or a substance having melanin activity. An example of a melanin derivative is melanin attached to a dihydrotrigonelline carrier such as described in Bodor,N., Αnn, Ν.Υ. Acad. Sci. 507, 289 (1987), which enables the melanin to cross the blood- brain barrier. The term melanin derivatives is also intended to include chemical derivatives of melanin, such as an esterified melanin.

As used herein, the term "melanin variant" refers to various subsets of melanin substances that occur as families of related materials. Included in these subsets, but not limited thereto, are:

(1) Naturally occurring melanins produced by whole cells that vary in their chemical and physical characteristics;

(2) Enzymatically produced melanins prepared from a variety of precursor substrates under diverse reaction conditions;

(3) Melanin analogs in which a structural feature that occurs in (1) or (2) above is replaced by an unusual substituent divergent from the traditional; and (4) Melanin derivatives in which a substituent in a melanin produced in (1), (2) or

(3) above is further altered by chemical or enzymatic means.

As used herein, the term "Melanin-like substances" refers to heteropolymers of 5-6- dihydroxyindole and 5-6-dihydroxyindole-2-carboxylic acid which have one or more properties usually associated with natural melanins, such as UV absorption or semiconductor behavior. Melanin Sources

Melanin and Melanin-like compounds can be obtained:

-by extraction and purification from natural sources, e.g. cephalopods such as cuttlefish (e.g. Sepia) or squid (e.g. Loligo), bird feathers (e.g. from species with black strains such as Silkie chickens);

-by chemical synthesis, whether water or non-water based e.g. (Deziderio, 2004) (daSilva et al., 2004; Lawrie et al., 2008; Pezzella et al., 2006);

-by electrochemical synthesis, e.g. (Meredith et al., 2005);

-by bioreactors created by utilization of natural or genetically altered bacteria, fungi, lichens, or viruses e.g.(della-Cioppa , 1998).

Melanin Manufacturing and Fabrication

Melanin and melanin-like compounds can be manufactured as particles, nanoparticles, dust, beads, or fibers that are woven or non- woven e.g. by methods as described by (Greiner and Wendorff, 2007), sheets e.g. (Meredith et al., 2005), films (daSilva et al., 2004), plates, bricks, chars, spheres, nodules, balls, graphite-like sheets and shards, liquids, gels, or solids (e.g. thermoplastic or thermoset), and by common chemical engineering molding and fabrication methods or custom methods. Sheets can range from one molecular layer to several millimeters. Fibers can range from nanometers to several millimeters.

The melanin material may be natural or synthetic, with natural pigments being extracted from plant and animal sources, such as squid, octopus, mushrooms, cuttlefish, and the like. In some cases, it may be desirable to genetically modify or enhance the plant or animal melanin source to increase the melanin production. Melanins are also available commercially from suppliers.

The following procedure describes an exemplary technique for the extraction of melanin from cuttlefish (Sepia Officinalis). lOOgmofcmde melanin are dissected from the ink sac of 10 cuttlefish and washed with distilled water (3* 100 ml). The melanin is collected after each wash by centiifugation (200*g for 30 minutes). The melanin granules are then stirred in 800 ml of 8 M Urea for 24 hours to disassemble the melanosomes. The melanin suspension is spun down at 22,000xg for 100 minutes and then washed with distilled water (5x400 ml). The pellet is washed with 50% aqueous DMF (5x400 ml) until a constant UV baseline is achieved from the washes. Finally, the pellet is washed with acetone (3*400 ml) and allowed to air dry.

Synthetic melanins may be produced by enzymatic conversion of suitable starting materials, as described in more detail hereinbelow. The melanins may be formed in situ within the porous particles or may be preformed with subsequent absorption into the porous particles.

Suitable melanin precursors include but are not limited to tyrosine, 3,4-dihydroxy phenylalanine (dopa), D-dopa, catechol, 5-hydroxyindole, tyramine, dopamine, m-aminophenol, o-aminophenol, p-aminophenol, 4-aminocatechol, 2-hydroxyl-l,4-naphthaquinone (henna), 4- methyl catechol, 3,4-dmydroxybenzylamine, 3,4-dihydroxybenzoic acid, 1,2- dihydroxynaphthalene, gallic acid, resorcinol, 2-chloroaniline, p-chloroanisole, 2-amino-p- cresol, 4,5-dihydroxynaphthalene 2,7-disulfonic acid, o-cresol, m-cresol, p-cresol, and other related substances which are capable of being oxidized to tan, brown, or black melanin-like compounds capable of absorbing ultraviolet radiation when incorporated in the polymeric particle matrix of the present invention. Combinations of precursors can also be used.

The melanin precursor is dissolved in an aqueous solution, typically at an elevated temperature to achieve complete solution. A suitable amount of the enzyme tyrosinase (EC 1.14.18.1) is added to the solution, either before or after the melanin precursor. The concentration of tyrosinase is not critical, typically being present in the range from about 50 to about 5000 U/ml. The solution is buffered with an acetate, phosphate, or other suitable buffer, to a pH in the range from about 3 to 10, usually in the range from about 5 to 8, more usually being about 7. Melaninlike pigments can be obtained using suitable precursors even in the absence of an enzyme j ust by bubbling oxygen through a solution of a precursor for an adequate period of time.

Melanin material may be obtained by treatment of, e.g, cuttlefish ink or squid ink in a microwave, optionally with mixing.

Topical Administration of Melanin

Presented below are non limiting categories of topical agents and specific examples of commercially available products into which melanin and related substance may be incorporated. Burn Treatments Silver Sulfadiazine Cream 1 % (catalog number. 32886 Henry Schein, Inc.) Emollients Ammonium Lactate Cream (catalog number. 1027036, Henry Schein, Inc.) Ichthammol Ointment-20% (catalog number 1020956, Henry Schein, Inc.) Lanolin (catalog number 1021756, Henry Schein, Inc. Sun Screen Products Zinc Oxide and ointment (catalog number 4711456, Henry Schein, Inc.) Antibiotics and Antibacterials Bacitracin Ointment (catalog number 4706972, Henry Schein, Inc.) Clindamycin Topical solution (catalog number 1028791, Henry Schein, Inc.) Cream (catalog number 1027125, Henry Schein, Inc.) Erythromycin topical solution (catalog number 4207358, Henry Schein, Inc.) Gentamycin ointment (catalog number 4733872, Henry Schein, Inc.) Nystatin cream (catalog number 4201056, Henry Schein, Inc.) and Antiseborreics Clotrimazole Betamethasone cream (catalog number 1025190, Henry Schein, Inc.) Ketoconoizole Cream (catalog number 1024347, Henry Schein, Inc.) Miconiazole Nitrate Cream (catalog number 2723761, Henry Schein, Inc.) Nystatin Ointment (catalog number 1020986, Henry Schein, Inc.) Antiseptics Alcohol, Isopropyl 91 % (catalog number Henry Schein, Inc.) Hydrogen Peroxide (catalog number 1023516, Henry Schein, Inc.) Isopropyl alcohol 70% (catalog number 1024716, Henry Schein, Inc.) Povidone Ointment (catalog number 4722656, Henry Schein, Inc.).

Retinoids

In certain embodiments, the invention is directed to the treatment of Zika virus and other viruses with, for example, the following retinoids and pro-retinoids: all-trans-retinoic acid, 13- cis-retinoic acid, retinol, retinal, and beta-carotene.

Deficiencies of vitamin A have been extensively documented in association with both viral and bacterial diseases (Ross AC, Stephensen CB. Vitamin A and retinoids in antiviral responses. FASEB J. 1996 Jul;10(9):979-85.)Retmoids havebeen documentedmmeUterature to inhibit several viruses including Measles, Mumps, Epstein-Barr, HIV, and Hepatitis C.

The term "retinoid" includes, for example: (1) retinol; (2) esters of retinol with carboxylic acids of 1 to 24 carbon atoms, such as retinyl acetate, retinyl propionate, retinyl buryrate, retinyl octanoate, retinyl laurate, retinyl palmitate, retinyl oleate, retinyl linoleate, and the like; (3) esters of retinol having an alpha-hydroxy carboxylic acid; (4) ether derivatives of retinol, including C_1-24 alkyl ether, ethers derived from glycolic acid, as well as glycolate ester and amide, such as retinyl glycolyl ether; (5) retinaldehyde; (6) retinoic acid; (7) esters of retinoic acid with alcohols of 1 to 24 carbon atoms; (8) isotretinoin as well as synthetic retinoid mimics, and derivatives of the foregoing, as well as others mat bind to RAR receptors; (9) cis- and trans-isomers of the foregoing retinoids; (10) salts of the foregoing retinoids; and (11) mixtures of the any of the foregoing compounds. A preferred retinoid for use in a composition according to the present invention is retinol, including the cis- or trans-isomer of retinol, typically the trans isomer. In some embodiments, a composition of the invention may comprise a retinoid (e.g., retinol) in an amount about 0.001 wt % to about 10 wt % based on the total weight of the composition. Typically, the retinoid (e.g., retinol) is present in an amount about 0.01 wt % to about 5 wt %, or about 0.1 wt % to about 2.5 wt %, based on the total weight of the composition. The amount of retinoid may be adjusted, based upon the potency of the retinoid, without departing from the present invention.

Exemplary retinoids include, without limitation, retinoic acid (e.g. , all-trans, or 9-cis, or 13-cis), and derivatives thereof, retinaldehyde, retinol (Vitamin A) and esters thereof, such as retinyl palmitate, retinyl acetate and retinyl propionate, and salts thereof. Particular mention may be made of retinol. When present, the retinoids will typically be included in amounts from about 0.0001% to about 5% by weight, more typically from about 0.01% to about 2.5% by weight, or from about 0.1% to about 1.0% by weight. Compositions according to this embodiment will typically include an antioxidant such as ascorbic acid and/or BHT and/or a chelating agent such as EDTA or a salt thereof (e.g., disodium EDTA).

Viruses

A non-exhaustive list of viruses and their species which can be deactivated and therefore prevented from multiplication by the compositions of the present invention is as follows: Abadina virus (Reoviridae), Abelson murine leukemia virus (Retroviridae), Abras virus (Bunyaviridae), Absettarov virus (Flaviviridae), AbuHammad virus (Bunyaviridae), AbuMina virus (Bunyaviridae), Acado virus (Reoviridae), Acara virus (Bunyaviridae), Acciptrid herpesvirus (Herpesviridae), Acheta domestica densovirus (Parvoviridae), Acrobasis zelleri entomopoxvirus (Poxviridae), Adelaide River virus (Rhabdoviridae), Adeno-associated virus (Parvoviridae), Aedes aegypti densovirus (Parvoviridae), Aedes aegypti entomopoxvirus (Poxviridae), Aedes albopictus densovirus (Parvoviridae), Aedes pseudoscutellaris densovirus (Parvoviridae), African green monkey cytomegalovirus (Herpesviridae), African green monkey HHV-like virus (Herpesviridae), African green monkey polyomavirus (Papovaviridae), African horse sickness viruses (Reoviridae), African swine fever virus, African swine fever-like viruses, AG-virus (Bunyaviridae), AG-virus, (Bunyaviridae), Agaricus bisporus virus, Aguacate virus (Bunyaviridae), Ahlum water-borne virus (Tombusviridae), Aino virus (Bunyaviridae), Akabane virus (Bunyaviridae), AKR (endogenous) murine leukemia virus (Retroviridae), Alajuela virus (Bunyaviridae), Alcelaphine herpesvirus (Herpesviridae), Alenquer virus (Bunyaviridae), Aleutian disease virus (Parvoviridae), Aleutian mink disease virus (Parvoviridae), Alfuy virus (Flaviviridae), Allerton virus (Herpesviridae), Allitrichheφesvirus (Herpesviridae), Allomyces arbuscula virus, Almeirim virus (Reoviridae), Almpiwar virus (Rhabdoviridae), Altamira virus, (Reoviridae), Amapari virus (Arenaviridae), American ground squirrel herpesvirus, (Herpesviridae), Amsactamoorei entomopoxvirus (Poxviridae), Amyelosis chronic stunt virus (Caliciviridae), Ananindeua virus (Bunyaviridae), Anatid herpesvirus (Herpesviridae), Andasibe virus (Reoviridae), Anhanga virus (Bunyaviridae), Anhembi virus (Bunyaviridae), Anomala cuprea entomopoxvirus (Poxviridae), Anopheles A virus (Bunyaviridae), Anopheles virus (Bunyaviridae), Antequera virus (Bunyaviridae), Aotine herpesvirus (Herpesviridae), Apeu virus (Bunyaviridae), Aphodius tasmaniae entomopoxvirus (Poxviridae), Apoi virus (Flaviviridae), Aransas Bay virus (Bunyaviridae), Arbia virus (Bunyaviridae), Arboledas virus (Bunyaviridae), Arbroath virus (Reoviridae), Argentine turtle herpesvirus (Herpesviridae), Arkonam virus (Reoviridae), Aroa virus (Flaviviridae), Arphia conspersa entomopoxvirus (Poxviridae), Aruac virus (Rhabdoviridae), Arumowot virus (Bunyaviridae), Asinine herpesvirus (Herpesviridae), Atlantic cod ulcus syndrome virus (Rhabodoviridae), Atlantic salmon reo virus Australia (Reoviridae), Atlantic salmon reo virus Canada (Reoviridae), Atlantic salmon reovirus USA (Reoviridae), Atropa belladonna virus (Rhabdoviridae), Aucuba bacill iform virus, Badnavirus, Aujeszky's disease virus (Herpesviridae), Aura virus (Togaviridae), Auzduk disease virus (Poxviridae), Avalon virus (Bunyaviridae), Avian adeno-associated virus (Parvoviridae), Avian carcinoma, Mill Hill virus (Retroviridae), Avian encephalomj'elitis virus (Picomaviridae), Avian infectious bronchitis virus (Coronaviridae), Avian leukosis virus-RSA (Retroviridae), Avian myeloblastosis virus (Retroviridae), Avian myelocytomatosis virus (Retroviridae), Avian nephrites virus (Picornaviridae), Avian paramyxovirus (Paramyxoviridae), Avian reovirus (Reoviridae), B virus (Parvoviridae), B-lymphotropic papovavirus (Papovaviridae), Babahoya virus (Bunyaviridae), Babanki virus (Togaviridae), Baboon herpesvirus (Herpesviridae), Baboon polyomavirus (Papovaviridae), Bagaza virus (Flaviviridae), Bahia Grande virus (Rhabdoviridae), Bahig virus (Bunyaviridae), Bakau virus (Bunyaviridae), Baku virus (Reoviridae), Bald eagle herpesvirus (Herpesviridae), Bandia virus (Bunyaviridae), Bangoran virus (Rhabdoviridae), Bangui virus (Bunyaviridae), Banzi virus (Flaviviridae), Barman Forest virus (Togaviridae), Barranqueras virus (Bunyaviridae), Barur virus (Rhabdoviridae), Batai virus (Bunyaviridae), Batama virus (Bunyaviridae), Batken virus (Bunyaviridae), Bauline virus (Reoviridae), Beak and feather disease virus (Circoviridae), BeAn virus (Rhabdoviridae), BeAr virus (Bunyaviridae), Bebaru virus (Togaviridae), Belem virus (Bunyaviridae), Belmont virus ((Bunyaviridae)), Belterra virus (Bunyaviridae), Benevides virus (Bunyaviridae), Benfica virus (Bunyaviridae), Berne virus, (Coronaviridae), Berrimah virus (Rhabdoviridae), Bertioga virus (Bunyaviridae), Bhanja virus (Bunyaviridae), Bimbo virus (Rhabdoviridae), Bimiti virus (Bunyaviridae), Birao virus (Bunyaviridae), BivensArm virus (Rhabdoviridae), BK virus (Papovaviridae), Bluetongue viruses (Reoviridae), Bobaya virus (Bunyaviridae), Bobia virus (Bunyaviridae), Bobwhite quail herpesvirus (Herpesviridae), Boid herpesvirus (Herpesviridae), Bombyx mori densovirus (Parvoviridae), Boolarra virus (Nodaviridae), Boraceia virus (Bunyaviridae), Border disease virus (Flaviviridae), Boma disease virus, Botambi virus (Bunyaviridae), Boteke virus, (Rhabdoviridae), Bouboui virus (Flaviviridae), Bovine adeno- associated virus (Parvoviridae), Bovine adenoviruses (Adenoviridae), Bovine astrovirus (Astroviridae), Bovine coronavirus (Coronaviridae), Bovine diarrhea virus (Flaviviridae), Bovine encephalitis herpesvirus (Herpesviridae), Bovine enteric calicivirus (Caliciviridae), Bovine enterovirus (Picornaviridae), Bovine ephemeral fever virus (Rhabdoviridae), Bovine herpesvirus (Herpesviridae), Bovine immunodeficiency virus (Retroviridae), Bovine leukemia virus (Retroviridae), Bovine mamillitis virus (Herpesviridae), Bovine papillomavirus (Papovaviridae), Bovine papular stomatitis virus (Poxviridae), Bovine parainfluenza virus (Paramyxoviridae), Bovine parvovirus (Parvoviridae), Bovine polyomavirus (Papovaviridae), Bovine respiratory syncytial virus (Paramyxoviridae), Bovine rhinovirus (Picornaviridae), Bovine syncytial virus (Retroviridae), Bozo virus (Bunyaviridae), Broadhaven virus (Reoviridae), Bruconha virus (Bunyaviridae), Brus Laguna virus (Bunyaviridae), Budgerigar fledgling disease virus (Papovaviridae), Buenaventura virus (Bunyaviridae), Buffalopox virus (Poxviridae), Buggy Creek virus (Togaviridae), Buj am virus (Bunyaviridae), Bukalasa bat virus (Flaviviridae), Bunyamwera virus (Bunyaviridae), Bunyip creek virus (Reoviridae), Bushbush virus (Bunyaviridae), Bussuquara virus (Flaviviridae), Bwamba virus (Bunyaviridae), Cache Valley virus (Bunyaviridae), Cacipacore virus (Flaviviridae), Caddo Canyon virus (Bunyaviridae), Caimito virus (Bunyaviridae), Calchaqui virus (Rhabdoviridae), California encephalitis virus (Bunyaviridae), California harbor seal pox virus (Poxviridae), Callistephus chinensis chlorosis virus (Rhabdoviridae), Callitrichine herpesvirus (Herpesviridae), Camel contagious ecthyma virus (Poxviridae), Camelpox virus (Poxviridae), Camptochironomus tentans entomopoxvirus (Poxviridae), Cananeia virus (Bunyaviridae), Canarypox virus (Poxviridae), Candiru virus (Bunyaviridae), Canid herpesvirus (Herpesviridae), Caninde virus (Reoviridae), Canine adeno-associated virus (Parvoviridae), Canine adenovirus (Adenoviridae), Canine calicivirus (Caliciviridae), Canine coronavirus (Coronaviridae), Canine distemper virus (Paramyxoviridae), Canine herpesvirus (Herpesviridae), Canine minute virus (Parvoviridae), Canine oral papillomavirus (Papovaviridae), Canine parvovirus (Parvoviridae), Carina yellow mottle virus (Badnavirus), Cape Wrath virus (Reoviridae), Capim virus (Bunyaviridae), Caprine adenovirus

Caprine arthritis encephalitis virus (Retroviridae), Caprine heφesvirus

Capuchin herpesvirus AL- Capuchin ηβφββνίηκ

AP- Carajas virus (Rhabdoviridae), Caraparu virus (Bunyaviridae), Carey

Island virus (Flaviviridae), Casphalia extranea densovirus (Parvoviridae), Catu virus (Bunyaviridae), Caviid heφesvirus ((Herpesviridae)), CbaAr virus (Bunyaviridae), Cebine heφesvirus (Heφesviridae), Cercopithecine heφesvirus (Herpesviridae), Cervid herpesvirus (Herpesviridae), CG-virus (Bunyaviridae), Chaco virus (Rhabdoviridae), Chagres virus (Bunyaviridae), Chamois contagious ecthyma virus (Poxviridae), Chandipura virus (Rhabdoviridae), Changuinola virus (Reoviridae), Charleville virus (Rhabdoviridae), Chelonid heφes virus (Herpesviridae), Chelonid herpesvirus Chelonid heφes virus

virus (Reoviridae), Chick syncytial virus (Retroviridae), Chicken anemia virus (Circoviridae), Chicken parvovirus (Paruoviridae), Chikungunya virus

Chilibre virus (Bunyaviridae), Chim virus (Bunyaviridae), Chimpanzee

attenuatus entomopoxvirus (Poxviridae), Chironomus luridus entomopoxvirus (Poxviridae), Chironomus plumosus erltomopoxvirus (Poxviridae), Chobar Gorge virus (Reoviridae), Choristoneura biennis entomopoxvirus (Poxviridae), Choristoneura conflicta entomopoxvirus (Poxviridae), Choristoneura diversuma entomopoxvirus (Poxviridae), Chorizagrotis auxiliars entomopoxvirus (Poxviridae), Chub reovirus Germany (Reoviridae), Ciconiid h^esvirus (Heφesviridae), Clo Mor virus (Bunyaviridae), CoAr-virus (Bunyaviridae), Coastal Plains virus

( , Cocal virus (Rhabdoviridae), Coital exanthema virus ColAn-virus (Bunyaviridae),

Colocasia bobone disease virus, (Rhabdoviridae), Colorado tick fever virus, (Reoviridae), Columbia SK virus, (Picornaviridae), Columbid herpesvirus, (Herpesviridae), Connecticut virus, (Rhabdoviridae), Contagious ecthyma virus, (Poxviridae), Contagious pustular dermatitis virus, (Poxviridae), Corfu virus, (Bunyaviridae), Corriparta virus, (Reoviridae), Cotia virus,

Cowpox virus, (Poxviridae), Crimean-Congo hemorrhagic fever virus,

CS1RO village virus, (Reoviridae), Cynara virus, (Rhabdoviridae), Cyprinid

(Herpesviridae), Dabakala virus, (Bunyaviridae), D'Aguilar virus, (Reoviridae),

Dakar bat virus, (Flaviviridae), DakArk virus, (Rhabdoviridae), Deer papillomavirus, (Papovaviridae), Demodema boranensis entomopoxvirus, (Poxviridae), Dengue virus, (Flaviviridae), Dengue virus group, (Flaviviridae), Dependovirus, (Parvoviridae), Dera Ghazi Khan virus, (Bunyaviridae), Dera Ghazi Khan virus Group, (Bunyaviridae), Dermolepida albohirtum entomopoxvirus, (Poxviridae), Dhori virus, (Orthomyxoviridae), Diatraea saccharalis densovinis, (Parvoviridae), Dobrava-Belgrade virus, (Bunyaviridae), Dolphin distemper virus, (Paramyxoviridae), Dolphinpox virus, (Poxviridae), Douglas virus, (Bunyaviridae), Drosophila C virus, (Picornaviridae), Dry Tortugas virus, (Bunyaviridae), duck adenovirus, (Adenoviridae), Duck adenovirus, (Adenoviridae), Duck astrovirus, (Astroviridae), Duck hepatitis B virus, (Hepadnaviridae), Duck plague herpesvirus syn. anatid herpesvirus, (Herpesviridae), Dugbe virus, (Bunyaviridae), Duvenhage virus, (Rhabdoviridae), Eastern equine encephalitis virus, (Togaviridae), Ebola virus Filoviridae, Echinochloahojablanca virus; Genus Tenui virus, Echinochloa ragged stunt virus, (Reoviridae), ectromelia virus, (Poxviridae), Edge Hill virus, (Flaviviridae), Egtved virus syn. viral hemorrhagic septicemia virus, (Rhabdoviridae), Elapid herpesvirus, (Herpesviridae), Elephant loxondontal herpesvirus, (Herpesviridae), Elephant papillomavirus, (Papovaviridae), Elephantid herpesvirus, (Herpesviridae), Ellidaey virus, (Reoviridae), Embu virus, (Poxviridae), Encephalomyocarditis virus, (Picornaviridae), Enseada virus, (Bunyaviridae), Entamoeba virus, (Rhabdoviridae), Entebbe bat virus, (Flaviviridae), Epizootic hemorrhagic disease viruses, (Reoviridae), Epstein- Barr virus, (Herpesviridae), Equid herpesvirus, (Herpesviridae), Equid herpesvirus, (Nerpesviridae), Equid heφesvirus, (Heφesviridae), Equine abortion herpesvirus, (Herpesviridae), Equine adeno-associated virus, (Parvoviridae), Equine adenovirus, (Adenoviridae), Equine arteritis virus, (Arteri virus), Equine cytomegalovirus, (Herpesviridae), Equine encephalosis viruses, (Reoviridae), Equine herpesvirus, (Herpesviridae), Equine infectious anemia virus, (Retroviridae), Equine papillomavirus, (Papovaviridae), Equine rhinopneumonitis virus, (Herpesviridae), Equine rhinovirus, (Picornaviridae), Eret-virus, (Bunyaviridae), Erinaceid herpesvirus, (Herpesviridae), Erve virus, (Bunyaviridae), Erysimum latent virus, Tymovirus, Esocid herpesvirus, (Herpesviridae), Essaouira virus, (Reoviridae), Estero Real virus, (Bunyaviridae), Eubenangee virus, (Reoviridae), Euonymus fasciation virus, (Rhabdoviridae), European bat virus, (Rhabdoviridae), European brown hare syndrome virus, (Caliciviridae), European elk papillomavirus, (Papovaviridae), European ground squirrel cytomegalovirus, (Herpesviridae), European hedgehog herpesvirus, (Herpesviridae), Everglades virus, (Togaviridae), Eyach virus, (Reoviridae), Facey's Paddock virus, (Bunyaviridae), Falcon inclusion body disease, (Herpesviridae), Falconid herpesvirus, (Herpesviridae), Farallon virus, (Bunyaviridae), Felid herpesvirus, (Herpesviridae), Feline calicivirus, (Caliciviridae), Feline herpesvirus, (Herpesviridae), Feline immunodeficiency virus, (Retroviridae), Feline infectious peritonitis virus, (Coronaviridae), Feline leukemia virus, (Retroviridae), Feline parlleukopenia virus, (Parvoviridae), Feline parvovirus, (Parvoviridae), Feline syncytial virus, (Retroviridae), Feline viral rhinotracheitis virus, (Herpesviridae), Fetal rhesus kidney virus, (Papovaviridae), Field mouse

, (Herpesviridae), Figulus subleavis entomopoxvirus, (Poxviridae), Fiji disease virus, (Reoviridae), Fin V-virus, (Bunyaviridae), Finkel-Biskis-Jinkins murine sarcoma virus, (Retroviridae), Flanders virus, (Rhabdoviridae), Flexal virus, (Arenaviridae), Flock house virus, Nodaviridae, Foot-and-mouth disease virus A, (Picornaviridae), Foot-and-mouth disease virus ASIA, (Picornaviridae), Foot-and-mouth disease virus, (Picornaviridae), Forecariah virus, (Bunyaviridae), Fort Morgan virus, (Togaviridae), Fort Sherman virus, (Bunyaviridae), Foula virus, (Reoviridae), Fowl adenoviruses, (Adenoviridae), Fowl calicivirus, (Caliciviridae), Fowlpox virus, (Poxviridae), Fraser Point virus, (Bunyaviridae), Friend murine leukemia virus, (Retroviridae), Frijoles virus, (Bunyaviridae), Frog herpesvirus, (Herpesviridae), Fromede virus, (Reoviridae), Fujinami sarcoma virus, (Retroviridae), Fukuoka virus, (Rhabdoviridae), Gabek Forest virus, (Bunyaviridae), Gadget's Gully virus, (Flaviviridae), Galleria mellonella densovirus, (Parvoviridae), Gallid herpes virus, (Herpesviridae), Gamboa virus, (Bunyaviridae), Gan Gan virus, (Bunyaviridae), Garba virus, (Rhabdoviridae), Gardner- Arnstein feline sarcoma virus, (Retroviridae), Geochelone carbonaria herpesvirus, (Herpesviridae), Geochelone chilensis heφesvirus, (Herpesviridae), Geotrupes sylvaticus entomopoxvirus, (Poxviridae), Gerbera symptomless virus, (Rhabdoviridae), Germiston virus, (Bunyaviridae), Getah virus, (Togaviridae), Gibbon ape leukemia virus, (Retroviridae), Ginger chlorotic fleckvirus, Sobemovirus, Glycine mottle virus, Tombusviridae, Goat herpesvirus, (Herpesviridae), Goatpox virus, (Poxviridae), Goeldichironomus holoprasimus entomopoxvirus, (Poxviridae), Golden shiner reovirus, (Reoviridae), Gomoka virus, (Reoviridae), Gomphrena virus, (Rhabdoviridae), Gonometa virus, (Picornaviridae), Goose adenoviruses, (Adenoviridae), Goose parvovirus, (Parvoviridae), Gordil virus Gorilla, (Herpesviridae), Gossas virus,

(Rhabdoviridae), Grand Arbaud virus,

Gray Lodge virus, (Rhabdoviridae), Gray patch disease agent of green sea turtle, Great Island virus, (Reoviridae), Great

Saltee Island virus, (Reoviridae), Great Saltee virus, (Bunyaviridae), Green iguana herpesvirus, (Herpesviridae), Green lizard

(Heφesviridae), Grey kangaroopox virus, (Poxviridae), Grimsey virus, (Reoviridae), Ground squirrel hepatitis B virus, (Hepadnaviridae), GroupA-K rotaviruses, (Reoviridae), Gruid herpesvirus, (Herpesviridae), GUU-virus, (Bunyaviridae), Guajara virus, (Bunyaviridae), Guama virus, (Bunyaviridae), Guanarito virus, (Arenaviridae), Guaratuba virus, (Bunyaviridae), Guaroa virus, (Bunyaviridae), Guinea pig cytomegalovirus,

Guinea pig h^esvirus, (Herpesviridae), Guinea pig type C oncovirus, (Retroviridae), Gumbo Limbo virus, (Bunyaviridae), Gurupi virus, (Reoviridae), H- virus, (Parvoviridae), H virus, (Bunyaviridae), Hamster herpesvirus, (Herpesviridae), Hamster polyomavirus, (Papovaviridae), Hantaan virus, (Bunyaviridae), Hanzalova virus, (Flaviviridae), Hardy-Zuckerman feline sarcoma virus, (Retroviridae), Hare fibroma virus, (Poxviridae), Hart Park virus, (Rhabdoviridae), Hartebeest herpesvirus, (Herpesviridae), Harvey murine sarcoma virus, (Retroviridae), Hazara virus, (Bunyaviridae), HB virus, (Parvoviridae), virus,

(Picornaviridae), Hepatitis virus, (Hepadnaviridae), Hepatitis virus, (Flaviviridae),

M, Herpesvirus papio, (Herpesviridae), Herpesvirus platyrrhinae type,

(Herpesviridae),

pottos, (Herpesviridae), Herpesvirus saimiri, (Herpesviridae), Herpesvirus salmonis, (Herpesviridae), Herpesvirus sanguinus,

scophthalmus, sylvilagus, (Herpesviridae), Herpesvirus T,

(Herpesviridae), Herpesvirus tarnarinus, (Herpesviridae), Highlands J virus,

Hirame rhabdovirus, (Rhabdoviridae), Hog cholera virus, (Flaviviridae), Ho Jo virus, (Bunyaviridae), Hepatitis delta virus, Satellites, Deltavirus, Hsiung aplow

(Herpesviridae), Hepatitis E virus, (Caliciviridae), Hepatopancreatic parvo-like virus of shrimps, (Parvoviridae), Heron hepatitis B virus, (Hepadnaviridae),

(Heφesviridae),

simiae virus,

Herpes simplex virus, (Herpesviridae), virus B,

aotus, ateles strain, (Herpesviridae),

cuniculi, (Herpesviridae), Herpesvirus cyclopsis, Huacho virus,

(Reoviridae), Hughes virus, (Bunyaviridae), Human adenoviruses, (Adenoviridae), Human astrovirus, (Astroviridae), Human calicivirus, (Caliciviridae), Human caliciviruses, (Caliciviridae), Human coronavirus E, (Coronaviridae), Human coronavirus OC, (Coronaviridae), Human coxsackievirus, (Picornaviridae), Human cytomegalovirus, (Herpesviridae), Human echovirus, (Picornaviridae), Human enterovirus, (Picornaviridae), Human foamy virus, (Retroviridae), Human

Human herpesvirus, Neφesviridae, Human h^esvirus, (Heφesviridae), Human immunodeficienc ' virus, (Retroviridae), Human papillomavirus, (Papovaviridae), Human parainfluenza virus, (Paramyxoviridae), Human poliovirus, (Picornaviridae), Human respirator}' syncytial virus, (Paramyxoviridae), Human rhinovirus, (Picornaviridae), Human spumavirus, (Retroviridae), Human T-lymphotropic virus, (Retroviridae), Humpty Doo virus, (Rhabdoviridae), HV-virus, (Bunyaviridae), Hypr virus, (Flaviviridae), Laco virus, (Bunyaviridae), Ibaraki virus, (Reoviridae), Icoaraci virus, (Bunyaviridae), Ictalurid heφesvirus, (H^esviridae), Len virus, (Reoviridae), Me virus, (Reoviridae), virus, Ilesha virus,

(Bunyaviridae), Ilheus virus, (Flaviviridae), Inclusion body rhinitis virus, (Herpesviridae), Infectious bovine rhinotracheitis virus, (Herpesviridae), Infectious bursal disease virus, Birnaviridae, Infectious hematopoietic necrosis virus, (Rhabdoviridae), Infectious laryngotracheitis virus, (Herpesviridae), Infectious pancreatic necrosis virus, Birnavirzdae, InfluenzaA virus (A/PR//(HN), (Orthomyxoviridae), Influenza B virus (B/Lee/), (Orthomyxoviridae), Influenzae virus (C/California/), (Orthomyxoviridae), Ingwavuma virus, (Bunyaviridae), Inini virus, (Bunyaviridae), Inkoo virus, (Bunyaviridae), Inner Frame virus, (Reoviridae), Ippy virus, (Arenaviridae), Irituia virus, (Reoviridae), Isfahan virus, (Rhabdoviridae), Israel turkey meningoencephalitis virus, (Flaviviridae), Issyk-Kul virus, (Bunyaviridae), Itaituba virus, (Bunyaviridae), Itaporanga virus, (Bunyaviridae), Itaqui virus, (Bunyaviridae), Itimirim virus, (Bunyaviridae), Itupiranga virus, (Reoviridae), Jaagsiekte virus, (Retroviridae), Jacareacanga virus, (Reoviridae), Jamanxi virus, (Reoviridae), Jamestown Canyon virus, (Bunyaviridae), Japanaut virus, (Reoviridae), Japanese encephalitis virus, (Flaviviridae), Jan virus, (Reoviridae), JC virus, (Papovaviridae), Joa virus, (Bunyaviridae), Joinj akaka virus, (Rhabdoviridae), Juan Diaz virus, (Bunyaviridae), Jugra virus, (Flaviviridae), Juncopox virus, (Poxviridae), Junin virus, (Arenaviridae), Junonia coenia densovirus, (Parvoviridae), Jurona virus, (Rhabdoviridae), Jutiapa virus, (Flaviviridae), K virus, (Papovaviridae), K virus, (Bunyaviridae), Kachemak Bay virus, (Bunyaviridae), Kadarn virus, (Flaviviridae), Kaeng Khoi virus, (Bunyaviridae), Kaikalur virus, (Bunyaviridae), Kairi virus, (Bunyaviridae), Kaisodi virus, (Bunyaviridae), Kala Iris virus, (Reoviridae), Kamese virus, (Rhabdoviridae), Karnmavanpettai virus, (Reoviridae), Kannamangalam virus, (Rhabdoviridae), Kao Shuan virus, (Bunyaviridae), Karimabad virus, (Bunyaviridae), Karshi virus, (Flaviviridae), Kasba virus, (Reoviridae), Kasokero virus, (Bunyaviridae), Kedougou virus, (Flaviviridae), Kemerovo virus, (Reoviridae), Kenai virus, (Reoviridae), Kennedya virus Y, Poryviridae, Kern Canyon virus, (Rhabdoviridae), Ketapang virus, (Bunyaviridae), Keterah virus, (Bunyaviridae), Keuraliba virus, (Rhabdoviridae), Keystone virus, (Bunyaviridae), Kharagysh virus, (Reoviridae), Khasan virus, (Bunyaviridae), Kilham rat virus, (Parvoviridae), Kimberley virus, (Rhabdoviridae), Kindia virus, (Reoviridae), Kinkajou herpesvirus, (Herpesviridae), Kirsten murine sarcoma virus, (Retroviridae), Kismayo virus, (Bunyaviridae), Klamath virus, (Rhabdoviridae), Kokobera virus, (Flaviviridae), Kolongo virus, (Rhabdoviridae), Koolpinyah virus, (Rhabdoviridae), Koongol virus, (Bunyaviridae), Kotonkan virus, (Rhabdoviridae), Koutango virus, (Flaviviridae), Kowanyama virus, (Bunyaviridae), Kumlinge virus, (Flaviviridae), Kunjin virus, (Flaviviridae), Kwatta virus, (Rhabdoviridae), Kyzylagach virus, (Togaviridae), La Crosse virus, (Bunyaviridae), La Joya virus, (Rhabdoviridae), La-Piedad- Michoacan-Mexico virus, (Paramyxoviridae), Lacertid ΙιβφββνϊηΒ, (Heφesviridae), Lactate dehydrogenase-elevating virus, (Arterivirus), Lagos bat virus, (Rhabdoviridae), Lake Clarendon virus, (Reoviridae), Lake Victoria cormorant herpesvirus, (Herpesviridae), Langat virus, Flaviviridae, Langur virus, (Retroviridae), Lanjan virus, (Bunyaviridae), Lapine parvovirus, (Parvoviridae), Las Maloyas virus, (Bunyaviridae), Lassa virus, (Arenaviridae), Lato river virus, (Tombusviridae), Le Dan tec virus, (Rhabdoviridae), Leanyer virus, (Bunyaviridae), Lebombo virus, (Reoviridae), Lednice virus, (Bunyaviridae), Lee virus, (Bunyaviridae), Leporid heφesvirus, Leucorrhinia dubia densovirus, (Parvoviridae), Lipovnik virus,

(Reoviridae), ϋνβφοοΐ vervet monkey virus, (Heφesviridae), Llano Seco virus, (Reoviridae), Locus ta migratona entomopoxvirus, (Poxviridae), Lokem virus, (Bunyaviridae), Lone Star virus,

Lorisine h^esvirus, (Herpesviridae), Louping ill virus, Flaviviridae, Lucke frog (Herpesviridae), Lum virus, (Parvoviridae), Lukuni virus, (Bunyaviridae),

Lumpy skin disease virus, (Poxviridae), Lundy virus, (Reoviridae), Lymantria dubia densovirus, (Parvoviridae), Lymphocytic choriomeningitis virus, (Arenaviridae), Machupo virus, (Arenaviridae), Madrid virus, (Bunyaviridae), Maguari

virus, (Bunyaviridae), Main Drain virus, (Bunyaviridae), Malakal virus, (Rhabdoviridae), Malignant catarrhal fever virus of European cattle, (Herpesviridae), Malpais Spring virus, (Rhabdoviridae), Malva silvestris virus, (Rhabdoviridae), Manawa virus, (Bunyaviridae), Manawatu virus, (Nodaviridae), Manitoba virus, (Rhabdoviridae), Manzanilla virus, (Bunyaviridae), Map turtle h^esvirus, (Heφesviridae), Mapputta virus, (Bunyaviridae), Maprik virus, (Bunyaviridae), Maraba virus, (Rhabdoviridae), Marburg virus, (Filoviridae), Marco virus, (Rhabdoviridae), Marek's disease herpesvirus, (Herpesviridae), Marituba virus, (Bunyaviridae), Marmodid heφesvirus, Marmoset cytomegalovirus,

(Herpesviridae), Marmoset herpesvirus,

Marmosetpox virus, (Poxviridae), Marrakai virus, (Reoviridae), Mason-Pfizer monkey virus, (Retroviridae), Masou salmon reovirus, (Reoviridae), Matruh virus, (Bunyaviridae), Matucare virus, (Reoviridae), Mayaro virus, (Togaviridae), Mboke virus, (Bunyaviridae), Meaban virus, (Flaviviridae), Measles (Edmonston) virus, (Paramyxoviridae), Medical Lake macaque Ιιβφββνϊηκ, (Herpesviridae), Melanoplus sanguinipes entomopoxvirus, (Poxviridae), Melao virus, (Bunyaviridae), Meleagrid herpesvirus, O^^esviridae), Melilotus latent virus, (Rhabdoviridae), Melolontha melolontha entomopoxvirus, (Poxviridae), Mengovirus, (Picornaviridae), Mermet virus, (Bunyaviridae), Mice minute virus, (Parvoviridae), Mice pneumotropic virus, (Papovaviridae), Microtus pennsylvanicus herpesvirus, (Herpesviridae), Middelburg virus, (Togaviridae), Miller's nodule virus, (Poxviridae), Mill Door virus, (Reoviridae), Minatitlan virus, (Bunyaviridae), Mink calicivirus, (Caliciviridae), Mink enteritis virus, (Parvoviridae), Minnal virus, (Reoviridae), Mirabilis mosaic virus, Caulimovirus, Mirim virus, (Bunyaviridae), Mitchell river virus, (Reoviridae), Mobala virus, (Arenaviridae), Modoc virus, (Flaviviridae), Moju virus, (Bunyaviridae), Mqjui dos Campos virus, (Bunyaviridae), Mokola virus, (Rhabdoviridae), Molluscum contagiosum virus, (Poxviridae), Molluscum-likepox virus, (Poxviridae), Moloney murine sarcoma virus, (Retroviridae), Moloney' virus, (Retroviridae), Monkey pox virus, (Poxviridae), Mono Lake virus, (Reoviridae), Montana myotis leukoencephalitis virus, (Flaviviridae), Monte Dourado virus, (Reoviridae), Mopeia virus, (Arenaviridae), Moriche virus, (Bunyaviridae), Mosqueiro virus, (Rhabdoviridae), Mossuril virus, (Rhabdoviridae), Mount Elgon bat virus, (Rhabdoviridae), Mouse cytomegalovirus, (Herpesviridae), Mouse Elberfield virus, (Picomaviridae), Mouse herpesvirus strain, (Herpesviridae), Mouse mammary tumor virus, (Retroviridae), Mouse thymic herpesvirus, (Herpesviridae), Movar herpesvirus, (Herpesviridae), Mucambo virus, (Togaviridae), Mudj inbarry virus, (Reoviridae), Muir Springs virus, (Rhabdoviridae), Mule deerpox virus, (Poxviridae), Multimammate mouse papillomavirus, (Papovaviridae), Mumps virus, (Paramyxoviridae), Murid herpesvirus, (Herpesviridae), Murine adenovirus, (Adenoviridae), Z murine adenovirus, (Adenoviridae), Murine hepatitis virus, (Coronaviridae), Murine herpesvirus, (Herpesviridae), Murine leukemia virus, (Retroviridae), Murine parainfluenza virus, (Paramyxoviridae), Murine poliovinis, (Picomaviridae), Murine polyomavirus, (Papovaviridae), Murray Valley encephalitis virus, (Flaviviridae), Murre virus, (Bunyaviridae), Murutucu virus, (Bunyaviridae), Mykines virus, (Reoviridae), Mynahpox virus, (Poxviridae), Myxoma virus, (Poxviridae), Nairobi sheep disease virus, (Bunyaviridae), Naranjal virus, (Flaviviridae), Nasoule virus, (Rhabdoviridae), Navarro virus, (Rhabdoviridae), Ndelle virus, (Reoviridae), Ndumu virus, (Togaviridae), Neckar river virus, (Tombusviridae), Negjshi virus, (Flaviviridae), Nelson Bay virus, New Minto virus, (Rhabdoviridae), Newcastle disease virus, (Paramyxoviridae), Ngaingan virus, (Rhabdoviridae), Ngari virus, (Bunyaviridae), Ngoupe virus, (Reoviridae), Nile crocodilepox virus, (Poxviridae), Nique virus, (Bunyaviridae), Nkolbisson virus, (Rhabdoviridae), Nola virus, (Bunyaviridae), North Clett virus, (Reoviridae), North End virus, (Reoviridae), Northern cereal mosaic virus, (Rhabdoviridae), Northern pike herpesvirus, (Heipesviridae), Northway virus, (Bunyaviridae), NorwaLk virus, (Caliciviridae), Ntaya virus, (Flaviviridae), Nugget virus, (Reoviridae), Nyabira virus, (Reoviridae), Nyamanini virus, Unassigned, Nyando virus, (Bunyaviridae), Oak- Vale virus, (Rhabdoviridae), Obodhiang virus, (Rhabdoviridae), Oceanside virus, (Bunyaviridae), Ockelbo virus, (Togaviridae), Odrenisrou virus, (Bunyaviridae), Oedaleus senegalensis entomopoxvirus, (Poxviridae), Oita virus, (Rhabdoviridae), Okhotskiy virus, (Reoviridae), Okola virus, (Bunyaviridae), Olifantsvlei virus, (Bunyaviridae), Omo virus, (Bunyaviridae), Omsk hemorrhagic fever virus, (Flaviviridae), Onchorhynchus masou herpesvirus, (Herpesviridae), O'nyong-nyong virus, (Togaviridae), Operophtera brurnata entomopoxvirus, (Poxviridae), Orangutan heφesvirus,

Orf virus, (Poxviridae), Oriboca virus, (Bunyaviridae), Oriximina virus, Oropouche virus, (Bunyaviridae), Orungo

virus, (Reoviridae), Oryctes rhinoceros virus, Unassigned, Ossa virus, (Bunyaviridae), Ouango virus, (Rhabdoviridae), Oubi virus, (Bunyaviridae), Ourem virus, (Reoviridae), Ovine adeno- associated virus, (Parvoviridae), Ovine adenoviruses, (Adenoviridae), (Astroviridae), Ovine heφesvirus, Ovine pulmonary adenocarcinoma virus, (Retroviridae), Owl

hepatosplenitis herpesvirus, P virus, (Bunyaviridae), Pacheco's disease virus,

(Heφesviridae), Pacora virus, (Bunyaviridae), Pacui virus, (Bunyaviridae), Pahayokee virus, (Bunyaviridae), Palestina virus, (Bunyaviridae), Palyam virus, (Reoviridae), Pan herpesvirus, (Herpesviridae), Papio Epstein-Barr heφesviπιs,

Para virus, (Bunyaviridae), Pararnushir virus, (Bunyaviridae), Parana virus, (Arenaviridae), Parapoxvirus ofreddeerinNew Zealand, (Poxviridae), Paravaccinia virus,

Parma

φ (Herpesviridae), Paroo river virus, (Reoviridae), Parrot h^esvirus, Parry Creek virus, (Rhabdoviridae), Pata virus, (Reoviridae), Pates monkey

pH delta,

PathumThani virus, (Bunyaviridae), Patois virus, (Bunyaviridae), Peaton virus,

Percid heφesviπιs, (Heφesviridae), Perdicid heφesvirus, (Herpesviridae),

Perinet virus, (Rhabdoviridae), Peripianata fuliginosa denso virus, (Parvoviridae), Peste-des- petits-ruminants virus, (Paramyxoviridae), Petevo virus, (Reoviridae), Phalacrocoracid heφesvirus,

Pheasant adenovirus, (Adenoviridae), Phnom-Penh bat virus, (Flaviviridae), Phocid Ιι ΐ Phocine (seal) distemper virus,

(Paramyxoviridae), Pichinde virus, (Arenaviridae), Picola virus, (Reoviridae), Pieris rapae densovirus, (Parvoviridae), Pigeon herpesvirus, Pigeonpox virus, (Poxviridae),

Badnavirus Pity virus, Pisum virus, Pixuna virus,

(Togaviridae), Playas virus, (Bunyaviridae), Pleuronectid herpesvirus,

Pneumonia virus of mice, (Paramyxoviridae), Pongine heφesvinιs,

, Pongola virus, (Bunyaviridae), Ponteves virus, (Bunyaviridae), Poovoot virus, (Reoviridae), Porcine adenoviruses, (Adenoviridae), Porcine astrovirus, (Astroviridae), Porcine circo virus, Circoviridae, Porcine enteric calicivirus, (Caliciviridae), Porcine enterovirus, (Picornaviridae), Porcine epidemic diarrhea virus, (Coronaviridae), Porcine hemagglutinating encephalomyelitis virus, (Coronaviridae), Porcine parvovirus, (Parvoviridae), Porcine respirator}' and reproductive syndrome, (Arteri virus), Porcine rubulavirus, (Paramyxoviridae), Porcine transmissible gastroenteritis virus, (Coronaviridae), Porcine type C oncovirus, (Retroviridae), Porton virus, (Rhabdoviridae), Potosi virus, (Bunyaviridae), Powassan virus, (Flaviviridae), Precarious Point virus, (Bunyaviridae), Pretoria virus, (Bunyaviridae), Primate calicivirus, (Caliciviridae), Prospect Hill virus, (Bunyaviridae), Pseudaletia includens densovirus, (Parvoviridae), Pseudocowpox virus, (Poxviridae), Pseudolumpy skin disease virus, (Herpesviridae), Pseudorabies virus, (Herpesviridae), Psittacid herpesvirus, (Herpesviridae), Psittacinepox virus, (Poxviridae), Puchong virus, (Rhabdoviridae), Pueblo Viejo virus, (Bunyaviridae), Puffin Island virus, (Bunyaviridae), Punta Salinas virus, (Bunyaviridae), Punta Toro virus, (Bunyaviridae), Purus virus, (Reoviridae), Puumala virus, (Bunyaviridae), Qalyub virus, (Bunyaviridae), Quailpox virus, (Poxviridae), Quokkapox virus, (Poxviridae), Rabbit coronavirus, (Coronaviridae), Rabbit fibroma virus, (Poxviridae), Rabbit hemorrhagic disease virus, (Caliciviridae), Rabbit kidney vacuolating virus, (Papovaviridae), Rabbit oral papillomavirus, (Papovaviridae), Rabbitpox virus, (Poxviridae), Rabies virus, (Rhabdoviridae), Raccoon parvovirus,

, Raccoonpox virus, (Poxviridae), Radi virus, (Rhabdoviridae), Rangifer tarandus

, Ranid hropesvirus,

Raphanus virus,

Rat coronavirus, (Coronaviridae), Rat cytomegalovirus, (

Rat virus, R, (Parvoviridae), Raza virus, (Bunyaviridae), Razdan virus, (Bunyaviridae), Red deer

Red kangaroopox virus, (Poxviridae), Reed Ranch virus,

Reindeer papillomavirus, (Papovaviridae),

calicivirus, (Caliciviridae), Resistencia virus, (Bunyaviridae), Restan virus,

Reticuloendotheliosis virus, (Retroviridae), Rhesus HHV-like virus, (Herpesviridae), Rhesus leukocyte associated herpesvirus strain, (Herpesviridae), Rhesus monkey cytomegalovirus,

Rhesus monkey papillomavirus, (Papovaviridae), Rheumatoid arthritis virus, (Parvoviridae), Rift Valley fever virus, (Bunyaviridae), Rind^est virus

Rio Bravo virus, (Flaviviridae), Rio Grande virus, (Bunyaviridae), RML virus, (Bunyaviridae), Rochambeau virus, (Rhabdoviridae), Rocio virus, (Flaviviridae), Ross River virus, (Togaviridae), Rost Islands virus, (Reoviridae), Rous sarcoma virus, (Retroviridae), Royal farm virus, (Flaviuiridae), RT parvovirus, (Parvoviridae), Rubella virus, (Togaviridae), Russian spring summer encephalitis virus, (Flaviviridae), S-virus, (Reoviridae), SA virus, (Herpesviridae), Sabio virus, (Arenaviridae), Sabo virus, (Bunyaviridae), Saboya virus, (Flaviviridae), Sacbrood virus, (Picornaviridae), Sagjyama virus, (Togaviridae), Saimiriine herpesvirus, (Herpesviridae), SaintAbb's Head virus, (Reoviridae), Saint-Floris virus, (Bunyaviridae), Sakhalin virus, (Bunyaviridae), Sal Vieja virus, (Flaviviridae), Salanga virus, (Bunyaviridae), Salangapox virus, (Poxviridae), Salehabad virus, (Bunyaviridae), Salmonid h^es virus, (Herpesviridae), Salmonis virus, (Rhabdoviridae), Sambucus vein clearing virus, (Rhabdoviridae), SanAngelo virus, (Bunyaviridae), San Juan virus, (Bunyaviridae), San Miguel sealion virus, (Caliciviridae), San Perlita virus, (Flaviviridae), Sand rat nuclear inclusion agents, (Herpesviridae), Sandfly fever Naples virus, (Bunyaviridae), Sandfly fever Sicilian virus, (Bunyaviridae), Sandjimba virus, (Rhabdoviridae), Sango virus, (Bunyaviridae), Santa Rosa virus, (Bunyaviridae), Santarem virus, (Bunyaviridae), Sapphire II virus, (Bunyaviridae), Saraca virus, (Reoviridae), Sarracenia purpurea virus, (Rhabdoviridae), Sathuperi virus, (Bunyaviridae), Saumarez Reef virus, (Flaviviridae), Sawgrass virus, (Rhabdoviridae), Schistocerca gregaria entomopoxvirus, (Poxviridae), Sciurid herpesvirus, (Heφesviridae), Sciurid heφesvirus, (Herpesviridae), Seal pox virus, (Poxviridae), Seletar virus, (Reoviridae) Semliki Forest virus, (Togaviridae), Sena Madureira virus, (Rhabdoviridae), Sendai virus, (Paramyxoviridae), Seoul Virus, (Bunyaviridae), Sepik virus, (Flaviviridae), Serra do Navio virus, (Bunyaviridae), Shamonda virus, (Bunyaviridae), Shark River virus, (Bunyaviridae), Sheep associated malignant catarrhal fever of, Sheep papillomavirus, (Papovaviridae), Sheep pulmonary adenomatosis associated Sheeppox virus, (Poxviridae), Shiant

Islands virus, (Reoviridae), Shokwe virus, (Bunyaviridae), Shope fibroma virus, (Poxviridae), Shuni virus, (Bunyaviridae), Sibine fusca densovirus, (Parvoviridae), Sigma virus, (Rhabdoviridae), Sikte water-borne virus, (Tombusviridae), Silverwater virus, (Bunyaviridae), virus, (Bunyaviridae), Simian adenoviruses, (Adenoviridae), Simian agent virus, (Papovaviridae), Simian enterovirus, (Picornaviridae), Simian foamy virus, (Retroviridae), Simian hemorrhagic fever virus, (Arterivirus), Simian hepatitis A virus, (Picornaviridae), Simian immunodeficiency virus, (Retroviridae), Simian parainfluenza virus, (Paramyxoviridae), Simian rotavirus SA, (Reoviridae), Simian sarcoma virus, (Retroviridae), Simian T- lymphotropic virus, (Retroviridae), Simian type D virus, (Retroviridae), Simian vancella Ιιβφββνϊηιβ, (Herpesviridae), Simian virus, (Papovaviridae), Simulium vittatum densovirus, (Parvoviridae), Sindbis virus, (Togaviridae), Sixgun city virus, (Reoviridae), Skunkpox virus, (Poxviridae), Smelt reovinis, (Reoviridae), Snakehead rhabdovirus, (Rhabdoviridae), Snowshoe hare virus, (Bunyaviridae), Snyder-Theilen feline sarcoma virus, (Retroviridae), Sofyn virus, (Flaviviridae), Sokoluk virus, (Flaviviridae), Soldado virus, (Bunyaviridae), Somerville virus, (Reoviridae), Sparrowpox virus, (Poxviridae), Spectacled caimanpox virus, (Poxviridae), SPH virus, (Arenaviridae), Sphenicid Ιιβ ββνϊηΒ, (Herpesviridae), Spider monkey herpesvirus, (Herpesviridae), Spondweni virus, (Flaviviridae), Spring viremia of carp virus, (Rhabdoviridae), Squirrel fibroma virus, (Poxviridae), Squirrel monkey herpesvirus, (Herpesviridae), Squirrel monkey retrovirus, (Retroviridae), SR-virus, (Bunyaviridae), Sripur virus, (Rhabdoviridae), StAbbs Head virus, (Bunyaviridae), St. Louis encephalitis virus, (Flaviviridae), Starlingpox virus, (Poxviridae), Stratford virus, (Flaviviridae), Strigid herpesvirus, (Herpesviridae), Striped bass reovirus, (Reoviridae), Striped Jack nervous necrosis virus, (Nodaviridae), Stump-tailed macaque virus, (Papovaviridae), Suid heφesvirus, (Herpesviridae), Sunday Canyon virus, (Bunyaviridae), Sweetwater Branch virus, (Rhabdoviridae), Swine cytomegalovirus, (Herpesviridae), Swine infertility and respiratory syndrome virus, (Arteri virus). Swinepox virus, (Poxviridae), Tacaiuma virus, (Bunyaviridae), Tacaribe virus, (Arenaviridae), Taggart virus, (Bunyaviridae), Tahyna virus, (Bunyaviridae), Tai virus, (Bunyaviridae), Taiassui virus, (Bunyaviridae), Tamana bat virus, (Flaviviridae), Tamdy virus, (Bunyaviridae), Tamiami virus, (Arenaviridae), Tanapox virus, (Poxviridae), Tanga virus, (Bunyaviridae), Tanjong Rabok virus, (Bunyaviridae), Taro bacilliform virus, (Badnavirus), Tataguine virus, (Bunyaviridae), Taterapox virus, (Poxviridae), Tehran virus, (Bunyaviridae), Telok Forest virus, (Bunyaviridae), Tembe virus, (Reoviridae), Tembusu virus, (Flaviviridae), Tench reovirus, (Reoviridae), Tensaw virus, (Bunyaviridae), Tephrosia symptomless virus, (Tombusviridae), Termeil virus, (Bunyaviridae), Tete virus, (Bunyaviridae), Thailand virus, (Bunyaviridae), Theiler's murine encephalomyelitis virus, (Picornaviridae), Thermoproteus virus, Lipothrixviridae, Thiafora virus, (Bunyaviridae), Thimiri virus, (Bunyaviridae), Thogoto virus, (Orthomyxoviridae), Thormodseyj arklettur virus, (Reoviridae), Thottapalayam virus, (Bunyaviridae), Tibrogargan virus, (Rhabdoviridae), Tick-borne encephalitis virus, (Flaviviridae), Tillamook virus, (Bunyaviridae), Tilligerry virus, (Reoviridae), Timbo virus, (Rhabdoviridae), Tilmboteua virus, (Bunyaviridae), Tilmaroo virus, (Bunyaviridae), Tindholmur virus, (Reoviridae), Tlacotalpan virus, (Bunyaviridae), Toscana virus, (Bunyaviridae), Tradescantia/Zebrina virus, Poryviridae, Trager duck spleen necrosis virus, (Retroviridae), Tree shrew adenovirus, (Adenoviridae), Tree shrew herpes vims, (Herpesviridae), Triatoma virus, (Picornaviridae), Tribec virus, (Reoviridae), Trivittatus virus, (Bunyaviridae), Trombetas virus, (Bunyaviridae), Trubanarnan virus, (Bunyaviridae), Tsuruse virus, (Bunyaviridae), Tucunduba virus, (Bunyaviridae), Tumor virus X, (Parvoviridae), Tupaia virus, (Rhabdoviridae), Tupaiid h^es virus, (Herpesviridae), Turbot herpesvirus, (Herpesviridae), Turbot reovirus, (Reoviridae), Turkey' adenoviruses, (Adenoviridae), Turkey coronavirus, (Coronaviridae), Turkey herpesvirus, (Herpesviridae), Turkey rhinotracheitis virus, (Paramyxoviridae), Turkeypox virus, (Poxviridae), Turlock virus, (Bunyaviridae), Turuna virus, (Bunyaviridae), Tyuleniy virus, (Flaviviridae) Uasin Gishu disease virus, (Poxviridae), Uganda S virus, (Flaviviridae), Ulcerative disease rhabdovirus, (Rhabdoviridae), Umatilla virus, (Reoviridae), Umbre virus, (Bunyaviridae), Una virus, (Togaviridae), Upolu virus, (Bunyaviridae), UR sarcoma virus, (Retroviridae), Urucuri virus, (Bunyaviridae), Usutu virus, (Flaviviridae), Uting a virus, (Bunyaviridae), Utive virus, (Bunyaviridae), Uukuniemi virus, (Bunyaviridae) Vaccinia subspecies, (Poxviridae), Vaccinia virus, (Poxviridae), Vaeroy virus, (Reoviridae), Varicella-zoster virus, (H^esviridae), Variola virus, (Poxviridae), Vellore virus, (Reoviridae), Venezuelan equine encephalitis virus, (Togaviridae), Vesicular exanthema of swine virus, (Caliciviridae), Vesicular stomatitis Alagoas virus, Rkabdoviridae, Vesicular stomatitis Indiana virus, (Rhabdoviridae), Vesicular stomatitis New Jersey virus, (Rhabdoviridae), Vilyuisk virus, (Picornaviridae), Vinces virus, (Bunyaviridae), Viper retrovirus, (Retroviridae), Viral hemorrhagic septicemia virus, (Rhabdoviridae), Virgin River virus, (Bunyaviridae), Virus ΙΠ, (Herpesviridae), Visna/maedi virus, (Retroviridae), Volepoxvirus, (Poxviridae), Wad Medani virus, (Reoviridae), Wallal virus, (Reoviridae), Walleye epidermal hyperplasia, (Herpesviridae), Wanowrie virus, (Bunyaviridae), Warrego virus, (Reoviridae), Weddel water-borne virus, Tombusviridae, Weldona virus, (Bunyaviridae), Wesselsbron virus, (Flaviviridae), West Nile virus, (Flaviviridae), Western equine encephalitis virus, (Togaviridae), Wexford virus, (Reoviridae), Whataroa virus, (Togaviridae), Wildbeest herpesvirus, (Herpesviridae), Witwatersrand virus, (Bunyaviridae), Wongal virus, (Bunyaviridae), Wongorr virus, (Reoviridae), Woodchuck hepatitis B virus, (Hepadnaviridae), Woodchuck herpesvirus marmota, (Herpesviridae), Woolly monkey sarcoma virus, (Retroviridae), Wound tumor virus, (Reoviridae), WVU virus, (Reoviridae), WW virus, (Reoviridae), Wyeomyia virus, (Bunyaviridae), Xiburema virus, (Rhabdoviridae), Xingu virus, (Bunyaviridae), Y sarcoma virus, (Retroviridae), Yaba monkey tumor virus, (Poxviridae), Yaba-virus, (Bunyaviridae), Yaba- virus, (Bunyaviridae), Yacaaba virus, (Bunyaviridae), Yaounde virus, (Flaviviridae), YaquinaHead virus, (Reoviridae), Yata virus, (Rhabdoviridae), Yellow fever virus, (Flaviviridae), Yogue virus, (Bunyaviridae), Yokapox virus, (Poxviridae), Yokase virus, (Flaviviridae), Yucca baciliform virus, Badnavirus, Yug Bogdanovac virus, (Rhabdoviridae), Zaliv Terpeniya virus, (Bunyaviridae), Zea mays virus, (Rhabdoviridae), Zegla virus, (Bunyaviridae), Zika virus, (Flaviviridae), Zirqa virus,

(Bunyaviridae).

Pathogenic Infections

In a preferred embodiment the pathogen is an intracellular pathogen, i.e. a pathogen capable of growing and reproducing inside the cells of a host. Bacterial examples include but are not limited to Francisella tularensis, Listeria monocytogenes, Salmonella, Brucella, Legionella, Mycobacterium, Nocardia, Rhodococcus equi, Yersinia, Neisseria meningitidis, Chlamydia, Rickettsia, Coxiella, Mycobacterium, such as Mycobacterium leprae and Treponema pallidum. Fungal examples include but are not limited to Histoplasma capsulatum, Cryptococcus neoformans and Pneumocystis jirovecii. Examples of protozoa include but are not limited to Apicomplexans (e.g. Plasmodium spp., Toxoplasma gondii and Cryptosporidium parvum) and Trypanosomatids (e.g. Leishmania spp. and Trypanosoma cruzi).

The following is an exemplary- but non-limiting discussion of various disease agents that could be the subject of prevention and/or treatment in accordance with the present invention. Bacterial Pathogens

There are hundreds of bacterial pathogens in both the Gram-positive and Gram-negative families that cause significant illness and mortality around the word, despite decades of effort developing antibiotic agents. Indeed, antibiotic resistance is a growing problem in bacterial disease.

One of the bacterial diseases with highest disease burden is tuberculosis, caused by the bacterium Mycobacterium tuberculosis, which kills about 2 million people a year, mostly in sub- Saharan Africa. Pathogenic bacteria contribute to other globally important diseases, such as pneumonia, which can be caused by bacteria such as Streptococcus and Pseudomonas, and food borne illnesses, which can be caused by bacteria such as Shigella, Campylobacter, and Salmonella Pathogenic bacteria also cause infections such as tetanus, typhoid fever, diphtheria, syphilis, and leprosy.

Conditionally pathogenic bacteria are only pathogenic under certain conditions, such as a wound facilitates entry of bacteria into the blood, or a decrease in immune function. For example, Staphylococcus or Streptococcus are also part of the normal human flora and usually exist on the skin or in the nose without causing disease, but can potentially cause skin infections, pneumonia, meningitis, and even overwhelming sepsis, a systemic inflammatory response producing shock, massive vasodilation and death. Some species of bacteria, such as Pseudomonas aeruginosa, Burkholderia cenocepacia, and Mycobacterium avium, are opportunistic pathogens and cause disease mainly in people suffering from immunosuppression or cystic fibrosis.

Other bacteria invariably cause disease in humans, such as obligate intracellular parasites (e.g., Chlamydophila, Ehrlichia, Rickettsia) that are capable of growing and reproducing only within the cells of other organisms. Still, infections with intracellular bacteria may be asymptomatic, such as during the incubation period. An example of intracellular bacteria is Rickettsia One species of Rickettsia causes typhus, while another causes Rocky Mountain spotted fever. Chlamydia, another phylum of obligate intracellular parasites, contains species that can cause pneumonia or urinary tract infection and may be involved in coronary heart disease. Mycobacterium, Brucella, Francisella, Legionella, and Listeria can exist intracellular, though they are facultative (not obligate) intracellular parasites.

Gram-positive bacteria include Staphylococcus aureus; Staphylococcus epidermidis; Staphylococcus saprophyticus; Streptococcus pyogenes (Lancefield group A, beta-hemolytic); Streptococcus agalactiae (Lancefield group B, beta-hemolytic); Streptococcus Viridans group (most are alpha-hemolytic) including, for example, the Mitus group (S. mitus, S. sanguis, S. parasanguis, S. gordonii, S. crista, S. infantis, S. oralis, S. peroris), the Salivarius group (S. salivarius, S. vestibularis, S. thermophilus), the Mutans group (S. mutans, S. sobrinus, S. criceti, S. rattus, S. downei, S. macacae), and the Anginosus group (S. anginosus, S. constellatus, S. intermedins); Streptococcus, e.g., S. bovis, S. equinus (Lancefield group D, alpha-hemolytic); Streptococcuspneumoniae (no Lancefield antigen; alpha-hemolytic); Peptostreptococcus and Peptococcus; Entercoccus faecalis; Enterococcus faeccium; Cornybacterium diphtheria; Bacillus anthracis; Bacillus cereus; Clostridium C. botulinum (more rarely, C. baratii and C. butyricum); Clostridium tetani; Clostridium perfiingens; Clostridium difficile; Clostridium sordellii; Listeria monocytogenes; Actinomyces israelii; Nocardia asteroids; Streptomyces.

Gram-negative bacteria include Neisseria meningitides; Neisseria gonorrhoeae;

Moraxella (subgenera Branhamella) catarrhalis; Kingella (most commonly kingae); Acinetobacter baumannii, Oligellaureolytica; Oligella urethralis; Escherichia coli; Shigella (S. dysenteriae, S. flexneri, S. boydii, S. sonnei); Salmonella non typhoidal, including S. enterica serotype enteritidis, S. enterica serotype typhimurium, S. enterica serotype Choleraesuis, S. bongori, Salmonella S. enterica serotype Typhi; Yersinia enterocolitica, Klebsiella pneumoniae; Proteus mirabilis; Enterobacter; Cronobacter (formerly called Enterobacter sakazakii); Serratia; Edwardsiella; Citrobacter; Hafnia; Providencia; Vibrio cholera; Vibrio parahemolyticus; Campylobacter; Helicobacter (formerly called Campylobacter) pylori, Pseudomonas aeruginosa; Burkholderia cepacia; Burkholderia mallei; Burkholderia pseudomallei; Stenotrophomonas maltophilia; Bacteroides fragilis, Bacteroides melaninogenicus; Fusobacterium; Haemophilus influenza; Haemophilus ducreyi; Gardnerella (formerly called Haemophilus) vaginalis;

Bordetella pertussis; Legionella; Yersinia pestis; Francisella tularensis; Brucella B. melitensis (infects sheep/goats); B. abortus (abortions in cows); B. suis (pigs); B. canis (dogs); B. maris

(marine animals); Pasteurella multocida; Streptobacillus moniliformis; Spirillum minus;

Treponema pallidum; Treponema pallidum subspecies pertenue; Treponema pallidum subspecies endemicum; Treponema pallidum subspecies carateum; Borrelia burgdorferi;

Borrelia; Leptospira; Chlamydia trachomatis; Chlamydia pneumonia; Chlamydia psittaci; Rickettsiae rickettsia; Rickettsiae akari; Rickettsiae prowazekii; Rickettsiae typhi; Rickettsiae tsutsugamushi; Rickettsiae parkeri; Rickettsiae africae; Rickettsia conorii; Rickettsia australis;

Rickettsia siberica; Rickettsia japonica; Bartonella Quintana; Bartonella henselae; Bartonella bacilliformis; Coxiella burnetii; Ehrlichia; Anaplasma phagocytophilum; Neorickettsia;

Orientia; Klebsiella granulomatis (formerly called Calymmatobacterium granulomatis); Capnocytophaga.

Other bacteria include Mycobacterium tuberculosis; Mycobacterium bovis;

Mycobacterium leprae; Mycobacterium avium-intracellulare or avium complex (MAI or MAC);

Mycobacterium ulcerans; Mycobacterium kansasii; Mycobacterium marinum; Mycobacterium scrofulaceum; Mycobacterium fortuitum; Mycobacterium chelonei; Mycobacterium abscessus; Mycoplasma pneumonia; Ureaplasma urealj'ticum.

Viral Pathogens

Vaccines may be developed for any viral pathogen for which protective antibodies are available. Viruses include DNA and RNA viruses. These include respirator}' viruses such as Adenoviruses, Avian influenza, Influenza virus type A, Influenza virus type B, Measles, Parainfluenza virus, Respiratory syncy tial virus (RSV), Rhinoviruses, and SARS coronavinis, gastro-enteric viruses such as Coxsackie viruses, enteroviruses such as Poliovirus and Rotavirus, hepatitis viruses such as Hepatitis B virus, Hepatitis C virus, Bovine viral diarrhea virus (surrogate), herpes viruses such as Herpes simplex 1, Herpes simplex 2, Human cytomegalovirus, and Varicella zoster virus, retroviruses such as Human immunodeficiency virus 1 (HIV-1), and Human immunodeficiency virus 2 (HIV-2), as well as Dengue virus, Hantavirus, Hemorrhagic fever viruses, Lymphocytic choriomeningitis virus, Smallpox virus, Ebola virus, Rabies virus, West Nile virus (WNV) and Yellow fever virus. Examples of viruses include Parvoviridae; Papovaviridae (Human papilloma virus (HPV); BK polyomavirus; JC polyomavirus); Adenoviridae (Adenovirus, types 40 and 41); Herpesviridae (simplex virus type 1 (HHV -1); Herpes simplex virus type 2 (HHV -2); Macacine herpesvirus 1; Varicella-zoster virus (VZV; HHV-3); Epstein-Barr virus (EBV; HHV-4); Cytomegalovirus (CMV; HHV-5); Human Herpesvirus 6 (HHV-6); HHV-7; Kaposi's sarcoma- associated herpesvirus (HHV-8); Hepadnaviridae (Hepatitis B virus); Poxviridae (Smallpox (Variola major); Alastrim (Variola minor); Vaccinia; Cowpox; Monkeypox; Goat pox, pseudocowpox virus, bovine papular stomatitis virus, tanapox, volepox and related pox viruses such as avipox, buffalopox, racoonpox, squirrelpox, etc.); Molluscum contagiosum; Picornaviridae (Polio virus; Coxsackie A virus; Coxsackie B; virus; Foot and mouth disease; ECHO virus; Hepatitis A virus; Rhinovirus); Astroviridae; Caliciviridae (Norwalk virus; Norovirus; Sapoviruses; Hepatitis E virus); Reoviridae (Rotavirus); Togaviridae (Alpha viruses; Western equine encephalitis (WEE) virus; Eastern equine encephalitis (EEE) virus; Venezuelan equine encephalitis (VEE) virus; Chikungunya virus; Rubivirus (rubella)); Flaviviridae (Y ellow fever virus; Dengue virus; St. Louis encephalitis virus; Japanese encephalitis virus; Tick-borne encephalitis virus; Omsk hemorrhagic fever virus; Al Khumra virus; Kyasanur Forest disease virus; Louping ill virus; West Nile virus; Kunjin virus; Murray Valley fever virus; Powassan virus; Hepatitis C virus; Hepatitis G virus); Coronoviridae (Respiratory illness (cold); Severe Acute Respiratory Syndrom)-corona virus (S ARS-CoV)); Bunyaviridae (California encephalitis virus; La Crosse virus; Rift Valley fever virus; Phleboviruses; Sandfly fever virus; Nairovirus; Hantavirus); Orthomyxoviridae (Influenza virus (types A, B & C); Paramyxoviridae (Parainfluenza virus; Respiratory syncytial virus (RSV); Hendra virus disease (formerly equine morbillivirus); Nipah virus encephalitis; Mumps Measles; Newcastle disease virus); Rhabdoviridae (Rabies virus); Filoviridae (Marburg virus (acute hemorrhagic fever); Ebola virus (acute hemorrhagic fever)); Arenaviridae (Lymphocytic choriomeningitis virus; Lassa fever virus; Lujo virus; Chapare virus; Junin virus; Machupo virus; Guanarito virus; Sabia virus); Retroviridae (Human Immunodeficiency virus (HIV) types I and II; Human T-cell leukemia virus (HLTV) type 1; Human T-cell leukemia virus (HLTV) type Π; Spumaviruses; Xenotropic murine leukemia virus-related (XMRV).

Fungal Pathogens

Pathogenic fungi are fungi that cause disease in humans or other organisms. The following are but a few examples. Candida species are important human pathogens that are best known for causing opportunist infections in immunocompromised hosts (e.g., transplant patients, AIDS sufferers, and cancer patients). Infections are difficult to treat and can be very serious. Aspergillus can and does cause disease in three major ways: through the production of mycotoxins; through induction of allergenic responses; and through localized or systemic infections. With the latter two categories, the immune status of the host is pivotal. The most common pathogenic species are Aspergillus fumigatus and Aspergillus flavus. Cryptococcus neoformans can cause a severe form of meningitis and meningo-encephalitis in patients with HTV infection and AIDS. The majority of Cryptococcus species lives in the soil and do not cause disease in humans. Cryptococcus laurentii and Cryptococcus albidus have been known to occasionally cause moderate-to-severe disease in human patients with compromised immunity. Cryptococcus gattii is endemic to tropical parts of the continent of Africa and Australia and can cause disease in non-i mmunocompromised people. Histoplasma capsulatum can cause histoplasmosis in humans, dogs and cats. Pneumocystis jirovecii (or Pneumocystis carinii) can cause a form of pneumonia in people with weakened immune systems, such as premature children, the elderly, transplant patients and AIDS patients. Stachybotrys chartarum or "black mold" can cause respiratory damage and severe headaches. It frequently occurs in houses in regions that are chronically damp.

Examples include Malassezia furfur; Exophiala werneckii; Microsporum species; Trichophyton species; Epidermophyton floccosum; Sporothrix schenckii; Phialophora verrucosa; Cladosporium carrinonii; Fonsecaea species; Cocci dioides; Histoplasma capsulatum;

Blastomyces dermatitidis; Cryptococcus neoformans; Cryptococcus gattii; Candida albicans;

Aspergillus fumigatus; Aspergillus flavus; Aspergillus niger; Rhizopus; Rhizomucor; Mucor;

Exserohilum.

Parasites

Parasite presents a maj or health issue, particularly in under-developed countries around the world. Significant pathogenic parasites include worms (roundworms, flatworms) and protozoa Entamoeba histolytica; Giardia lamblia; Trichomonas vaginalis; Plasmodium falciparum; Plasmodium malariae; Plasmodium ovale; Plasmodium vivax; Trypanosoma cruzi; Ascaris lumbricoides; Trichinella spiralis; Toxoplasma gondii; Leishmania donovani; Leishmania tropica; Leishmania braziliensis; Schistosoma mansoni; Schistosoma japonicum; Schistosoma haematobium; Cyclospora cayetanesis; Cry^ptosporidium, e.g., C. parvum, C. hominis; Cystoisospora species (formerly called Isospora species), e.g., C. belli; Naegleria fowled; Acanthamoeba species; Sappiniadiploidea; Sappiniapedata; Balamuthiamandrillaris; Pneumoc>'Stis jiroveci (formerly called Pnenmoc>'Stis carinii); Plasmodium knowlesi; Babesia microti; Babesia divergens; Babesia duncani; Babesia (no species name yet but designated MO- 1); Trypanosoma brucei rhodesiense; Trypanosoma brucei gambiense; Balantidium coli; Dientamoeba fragilis; Phylum: Microsporidia; Sarcocystis; Baylisascaris; Necator americanus; Ancylostoma duodenale; Strongloides stercoralis; Trichinella pseudospiralis; Trichinella nelsoni; Trichinella britovi; Trichinella nativa; Trichuris trichiura; Enterobius vermicularis; Anisakis simplex; Pseudoterranova decipiens; Trichostrongylus; Oesophagostomum, e.g., O. bifurcom; Angiostrongylus; Capillaria; Dirofilaria; Loaboa; Onchocerca volvulus; Wuchereria bancrofti; Brugiamalayi; Brugiatimori; Mansonella, M. perstans; M. streptocerca; M. ozzardi; Dracunculus mediensis; Cutaneous larva migrans (commonly Ancylostoma braziliense=dog hookworm; also A. caninum, A. ceylanicum, and Uncinaria stenocephala); Visceral larva migrans (most commonly Toxocara canis=dog roundworm, less commonly Toxocara cati=cat roundworm, Baylisascaris procyoni s=raccoon roundworm) or ocular larva migrans or neural larva migrans (B. procyonis); Gnathostoma G. spinigerum and G. hispidum; Dicrocoelium dendriticum; Echinostoma, e.g., E. hortense, E. macrorchis, E. revolutum, E. ilocanu, and E. perfoliatum; Thelazia; Shistosomajaponicum; Shistosomamansoni; Shistosoma haematobium; Shistosoma intercalatum; Shistosoma mekongi; Austrobilharzia variglandis and other schistosomes; Taenia solium; Taenia saginata; Taenia multiceps; Taenia serialis; Taenia asiatica; Diphyllobothrium latum; Hymenolepsis nana; Echinoccoccus; Paragonimus; Clonorchis sinensis; Dipylidium caninum; Fasciola, F. hepatica; F. gigantica; Fasciolopsis buski; Heterophyes heterophyes; Hymenolepsis, H. nana, H. dimnuta; Opisthorchis; Bertiella, e.g., B. studeri and B. mucronata; Macracanthorhynchus hirudinaceous; Moniliformis moniliformis; Bolbosoma species; Metagonimus yokogawai; Dioctophyme renal e; Mesocestoides, e.g. , M. lineatus and M. variabilis; Philophthalmus, e.g., P. lacrymosus, P. gralli, P. palpebrarum; Spirometra, e.g., S. mansoni, S. ranarum, S. mansonoides, S. erinacei; Sparganum proliferum.

Pharmaceutical Compositions

Compositions of the invention include pharmaceutical compositions for oral administration to treat, for example, acute radiation sickness, wherein the composition comprises, for example, a first agent which is selected from the group consisting of beta- carotene, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, guanosine monophosphate, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

Exemplar}' dosages of the first agent include, for example, about 75 mg, about 150 mg, about 225 mg, about 300 mg, about 450 mg. Exemplary dosages of the second agent include, for example, about 75 mg, about 150 mg, about 225 mg, about 300 mg, about 450 mg. Exemplary dosages of the third agent include, for example, about 75 mg, about 150 mg, about 225 mg, about 300 mg, about 450 mg.

In exemplary embodiments, the ratio of the first to the second to the third agent can be as is shown in the Table below:

Relative to an oral dosage form such as a tablet or capsule, buccal or sublingual deliver}' provides for rapid absorption, faster onset of therapeutic action and avoidance of liver or gut wall first pass metabolism. For patients who have difficulty in swallowing tablets, capsules or other solids or those who have intestinal failure, the buccal or sublingual delivery route is preferred.

Compositions for buccal administration include a first agent which is selected from the group consisting of beta-carotene, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, guanosine monophosphate, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient, for example, a solid dosage form. The solid dosage form disintegrates in an oral cavity with minimal liquid exposure and at body temperature, and ideally adheres to the body tissue of the oral cavity via direct adhesion to tissue or entrapment of the dosage form in-between the gum and inner cheek.

Compositions for sublingual administration include a first agent which is selected from the group consisting of beta-carotene, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, guanosine monophosphate, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient to form a solid dosage form The solid dosage form disintegrates in an oral cavity at body temperature under the tongue.

The solid dosage forms can provide immediate release or controlled release or a combination thereof, wherein the dosage form disintegrates or melts in the oral cavity at body temperature with or without the aid of fluids, salivary fluids, mechanical erosion, or combinations thereof.

Alternatively, the dosage form can be sprayed into the oral cavity in the form of a solution spray or a dry powder. In another embodiment, the pharmaceutical composition can be deposited in the oral cavity of a subject in the form of a gel.

Generally, the composition can be adhesive towards the body tissue lining the patient's oral cavity. The dosage form can be, but is not limited to, tablets, a bioadhesive patch or film, gels, sponges, lozenges, hard candies, wafers, lollipops, sprays, gums, pills, pellets, spheres, combinations thereof, and other forms known to those of skill in the art.

Buccal and sublingual oral dosage forms are dosage forms that are intended to be held in the mouth or under the tongue until they have completely dissolved. Unlike most oral dosage forms in which the pharmaceutically active ingredient is delivered to the gastrointestinal tract of the patient for absorption of the drug through the stomach or intestinal epithelium, sublingual and/or buccal dosage forms are designed to release the pharmaceutically active ingredients in the mouth for absorption through oral mucosa Buccal dosage forms are intended to be inserted into the buccal pouch (a space generally defined between a cheek and the gums) and dissolve or erode relatively slowly, whereas sublingual oral dosage forms are intended to be held under the tongue and dissolve more rapidly. As a result, buccal dosage forms, including mucoadhesive formulations, are generally formulated with excipients to optimize drug release into and through oral mucosa and to minimize release of the drug into the gastrointestinal tract. Otherwise, buccal and sublingual dosage forms are substantially similar, the differences being more a matter of degree than of kind.

Sublingual and/or buccal oral dosage forms are preferred for delivering certain pharmaceutically active agents to the bloodstream. For example, many pharmaceutically active agents that are metabolized in the small intestine and/or liver (pharmaceutically active agents exhibiting what is known as "the first pass effect") can be more effectively administered sublingually or bucally through oral mucosal tissue.

Sublingual and/or buccal oral dosage forms also may provide a faster onset of therapeutic effect and/or improved bioavailability of certain pharmaceutically active agents that can be absorbed through the oral mucosa, thereby bypassing gastrointestinal and hepatic metabolism processes. In addition, such dosage forms may be preferred for administering certain pharmaceutically active agents to achieve better patient acceptance and compliance, especially among those patients that have difficulty swallowing. Buccal and/or sublingual dosage forms may also be employed in some cases to overcome problems with pharmaceutically active agents that are poorly absorbed from the gastrointestinal tract and which may not be effectively administered transdermally, subcutaneously or intravenously.

The term "buccal delivery system" as used herein refers to a deliver}' system wherein an active ingredient is provided for absorption across one or more membranes in the moum, including the buccal mucosa, buccal gingiva, mucous membrane of the tongue, sublingual membrane and the soft palate. The term encompasses all suitable dosage forms capable of manufacture using a normal dry powder process and compression using a standard tabletting machine.

Reference to an "active ingredient" includes a therapeutic or prophylactic agent, drug, pro-drug, drug complex, drug intermediate, diagnostic agent, enzyme, medicine, plant extract, herbal concoction, phytochemical, proteins, antibody, nanobody, antibody fragment, antibody' directed enzyme pro-drug therapy (ADEPT), bioactive compound, nutraceutical or dietary supplement.

The term "matrix" as used herein refers to a solid or semi-solid monolithic material containing one or more dissolved or dispersed active ingredients closely associated with a surrounding, rate-controlling heterogeneous material where the active ingredients) are released when the matrix is placed in direct contact with a moist diffusion membrane. The solid or semisolid monolithic material can include a range of materials known in the art of pharmaceutical drug delivery to emulsify, solubilize, complex or deliver any biologically active lipophilic or hydrophilic compound across a membrane.

The person skilled in the art will know which polyethylene glycol (PEG) is suitable to provide the desired pharmacokinetics for the delivery system. For example, the choice of PEG will be related to whether zero or first order release is desired. In a particularly preferred embodiment, the base is PEG 1450.

The polyethylene glycol can be used in the form of a PEG-fatty acid ester having surfactant properties. Examples of suitable PEG-fatty acid esters include PEG-10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, PEG- 1450, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, pofyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, a poloxamer, and mixtures thereof.

A person skilled in the art will understand that amount of the suspending agent is sufficient to improve the texture and consistency' of the delivery system Suitable examples of such suspending agents are those in the gum-yielding plant group such as tetragonolobus, Acacia glaucophylla, Acacia abyssinica, Acacia nilotica, Acacia gummifera and Acacia arabica Other suitable suspending agents include silica gel and suspension polymers such as kollidon, cremaphor, koUicoat, solutol and ludipress.

The person skilled in the art will understand that the flowing agent (also known as lubricant) is present in an amount sufficient for the prevention of adhesion, especially during the manufacturing process. A suitable example of a flowing agent is magnesium stearate. The buccal delivery system comprises a sufficient amount of a sweetener to improve the organoleptic properties of the dosage form. Examples of suitable sweeteners include sucrose, sucralose; zinc gluconate; ethyl maltitol; glycine; acesulfame-K; aspartame; saccharin; fructose; xylitol; honey; corn syrup, golden syrup, misri, spray dried licorice root; glycerrhizine; dextrose; sodium gluconate; stevia powder; glucono delta-lactone; ethyl vanillin; vanillin; normal and high-potency sweeteners or syrups or salts thereof. Preferably, a high-intensity sweetener selected from the group consisting of aspartame, sucralose, and acesulfame-K is used.

In another aspect, the present invention provides a method of manufacturing a dosage formulation capable of delivering one or more active ingredients across one or more membranes within the buccal cavity.

The buccal delivery system may further comprise one or more other pharmaceutically acceptable carriers and/or excipients, such as but not limited to binding agents, flavoring agents, colouring agents, solubility enhancers, disintegrants, fillers, proteins, co-factors, emulsifiers, and solubilizing or complexing agents. In a preferred embodiment, these excipients will improve delivery of the active ingredient across a membrane. Suitable excipients will be known to those skilled in the art. One typical example of an emulsifier which may be suitable is tocopherol polyethylene glycol 1000 succinate (TPGS). Examples of complexing agents are compounds containing amine groups or other nitrogen functional groups such as amino acids, proteins, amine functional sterols and phospholipids containing amine functional groups. Suitable surfactants may be amphoteric, zwitterionic, or cationic. Preferred complexing agents of this type include water-soluble cationic polymers with a quaternary ammonium functional group on the polymer backbone and water-soluble, cationic guar (jaguar gums).

In a preferred embodiment, the buccal delivery system comprises a binding and gelling agent such as hydroxypropyl methocellulose.

In another embodiment, the buccal deli very system further comprises a colouring agent which may be a dye or a pigment. Suitable colouring agents are well known in the art and include curcumin, carotenoids, sunset yellow, tartrazine, indigo dyes, quino-phthalene dyes and triphenyl methane dyes.

In a preferred embodiment, the buccal delivery system further comprises a flavoring agent for improving organoleptic properties. Suitable flavoring agents are well known in the art and include almond oil; babassu oil; borage oil; blackcurrant seed oil; canola oil; castor oil; coconut oil; com oil; cottonseed oil; evening primrose oil; grapeseed oil; groundnut oil; mustard seed oil; olive oil; palm oil; palm kernel oil; peanut oil; grapeseed oil; safflower oil; sesame oil; shark liver oil; soybean oil; sunflower oil; hydrogenated castor oil; hydrogenated coconut oil; hydrogenated palm oil; hydrogenated soybean oil; hydrogenated vegetable oil; hydrogenated cottonseed and castor oil; partially hydrogenated soybean oil; soy oil; glyceryl tricaproate; glyceryl tricaprylate; glyceryl tricaprate; glyceryl triundecanoate; glyceryl trilaurate; glyceryl trioleate; glyceryl trilinoleate; glyceryl trilinolenate; glyceryl tricaprylate/caprate; glyceryl tricaprylate/caprate/laurate; glyceryl tricaprylate/caprate/linoleate; glyceryl tricaprylate/caprate/stearate; saturated polyglycolized glycerides; linoleic glycerides; caprylic/capric glycerides; modified triglycerides; fractionated triglycerides; safrole, vanillin, citric acid, malic acid and phosphoric acid or salts and/or mixtures thereof.

In an alternative embodiment, the buccal dosage forms are useful as sustained release compositions. The term "sustained release" (also referred to as "extended release") is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period.

Formulations and solid oral dosage forms of this invention include disintegrating agents

(disintegrants) such as sodium carboxylmethyl cellulose, crospovidone and the like in amounts sufficient to achieve a desirable and efficient disintegration rate that optimizes absorption of the pharmaceutically active agent, minimizes patient discomfort and inconvenience, or achieves a desired balance of absorption efficiency and reduced discomfort and/or inconvenience. Examples of suitable amounts of disintegrating agents, such as crospovidone (e.g., Polyplasdone XL, ISP) may range from about 2 to about 50% based on the weight of the direct compression formulation and/or oral dosage form

In some embodiments, direct compression formulations and solid oral dosage forms of this invention may further comprise other optional ingredients as desired, including natural and/or artificial sweeteners such as aspartam, taste-masking agents and/or flavorants such as menthol, and colorants (e.g., red iron oxide dye). Glidants, lubricants such as magnesium stearate, and other processing aids may be employed as needed or desired to facilitate handling and/or compression into tablets or other oral dosage forms.

Film

In one embodiment of the present invention, there is provided a film dosage composition including: a polymeric carrier matrix; a therapeutically effective amount ofa first agent which is selected from the group consisting of beta-carotene, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, guanosine monophosphate, pharmaceutically acceptable derivatives thereof, and pharmaceutically acceptable salts thereof, and combinations thereof; a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient; and a buffer in an amount to provide apH of the composition of a value sufficient to optimize absorption of the active ingredients.

It will be understood that the term "film" includes thin films and sheets, in any shape, including rectangular, square, or other desired shape. The films described herein may be any desired thickness and size such that it may be placed into the oral cavity of the user. For example, the films may have a relatively thin thickness of from about 0.1 to about 10 mils, or they may have a somewhat thicker thickness of from about 10 to about 30 mils. For some films, the thickness may be even larger, i.e., greater man about 30 mils. Films may be in a single layer or they may be multi-layered, including laminated films.

Oral dissolving films generally fall into three main classes: fast dissolving, moderate dissolving and slow dissolving. Fast dissolving films generally dissolve in about 1 second to about 30 seconds in the mouth. Moderate dissolving films generally dissolve in about 1 to about 30 minutes in the mouth, and slow dissolving films generally dissolve in more than 30 minutes in the mouth. Fast dissolving films may consist of low molecular weight hydrophilic polymers (i.e., polymers having a molecular weight between about 1,000 to 9,000, or polymers having a molecular weight up to 200,000). In contrast, slow dissolving films generally have high molecular weight polymers (i.e., having a molecular weight in the millions).

Moderate dissolving films tend to fall in between the fast and slow dissolving films. Moderate dissolving films dissolve rather quickly, but also have a good level of mucoadhesion. Moderate dissolving films are also flexible, quickly wettable, and are typically non-irritating to the user. For the instant invention, it is preferable to use films that fall between the categories of fast dissolving and moderate dissolving. Such moderate dissolving films provide a quick enough dissolution rate, most desirably between about 1 minute and about 20 minutes, while providing an acceptable mucoadhesion level such that the film is not easily removable once it is placed in the oral cavity of the user.

The films used in the pharmaceutical products may be produced by a combination of at least one polymer and a solvent, optionally including other fillers known in the art. The solvent may be water, a polar organic solvent including, but not limited to, ethanol, isopropanol, acetone, or any combination thereof. In some embodiments, the solvent may be a non-polar organic solvent, such as methylene chloride. The film may be prepared by utilizing a selected casting or deposition method and a controlled drying process. For example, the film may be prepared through controlled drying processes, which include application of heat and/or radiation energy to the wet film matrix to form a visco-elastic structure, thereby controlling the uniformity of content of the film. Such processes are described in more detail in commonly assigned U.S. application Ser. No. 10/074,272, filed on Feb. 14, 2002, and published as U.S. Patent Publication No. 2003/0107149 Al , the contents of which are incorporated herein by reference in their entirety. Alternatively, the films may be extruded as described in commonly assigned U.S. application Ser. No. 10/856,176, filed on May 28, 2004, and published as U.S. Patent Publication No.2005/0037055 Al , the contents of which are incorporated herein by reference in their entirety.

The polymer included in the films may be water-soluble, water-swellable, water- insoluble, or a combination of one or more either water-soluble, water-swellable or water- insoluble polymers. The polymer may include cellulose or a cellulose derivative. Specific examples of useful water-soluble polymers include, but are not limited to, polyethylene oxide, pullulan, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, carboxymethyl cellulose, polyvinyl alcohol, sodium alginate, polyethylene glycol, xanthan gum, tragancanth gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methylmethacrylate copolymer, carboxyvinyl copolymers, starch, gelatin, and combinations thereof. Specific examples of useful water-insoluble polymers include, but are not limited to, ethyl cellulose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, hydroxypropyl methyl cellulose phthalate and combinations thereof. For higher dosages, it may be desirable to incorporate a polymer that provides a high level of viscosity as compared to lower dosages.

As used herein the phrase "water-soluble polymer" and variants thereof refer to a polymer that is at least partially soluble in water, and desirably fully or predominantly soluble in water, or absorbs water. Polymers that absorb water are often referred to as being water- swellable polymers. The materials useful with the present invention may be water-soluble or water-swellable at room temperature and other temperatures, such as temperatures exceeding room temperature. Moreover, the materials may be water-soluble or water-swellable at pressures less than atmospheric pressure. Desirably, the water-soluble polymers are water-soluble or water-swellable having at least 20 percent by weight water uptake. Water-swellable polymers having a 25 or greater percent by weight water uptake are also useful. In some embodiments, films formed from such water-soluble polymers may be sufficiently water-soluble to be dissolvable upon contact with bodily fluids.

Other polymers useful for incorporation into the films include biodegradable polymers, copolymers, block polymers and combinations thereof. It is understood that the term "biodegradable" is intended to include materials that chemically degrade, as opposed to materials that physically break apart (i.e., bioerodable materials). Among the known useful polymers or polymer classes which meet the above criteria are: poly(glycolic acid) (PGA), poly(lactic acid) (PLA), polydioxanes, polyoxalates, poly(.alpha. -esters), polyanhydrides, polyacetates, polycaprolactones, poly(orthoesters), polyamino acids, polyaminocarbonates, polyurethanes, polycarbonates, polyamides, poly(alkyl cyanoacrylates), and mixtures and copolymers thereof. Additional useful polymers include, stereopolymers of L- and D-lactic acid, copolymers of bis(p-carboxyphenoxy)propane acid and sebacic acid, sebacic acid copolymers, copolymers of caprolactone, polyOactic acid)/poly(glycolic acidypolyethyleneglycol copolymers, copolymers of polj'urethane and (poly(lactic acid), copolymers of polyurethane and poly(lactic acid), copolymers of .alpha -amino acids, copolymers of .alpha -amino acids and caproic acid, copolymers of alpha-benzyl glutamate and polyethylene glycol, copolymers of succinate and poly(glycols), polyphosphazene, polyhydroxy-alkanoates and mixtures thereof. Binary and ternary systems are contemplated.

Other specific polymers useful include those marketed under the Medisorb and Biodel trademarks. The Medisorb materials are marketed by the Dupont Company of Wilmington, Del. and are generically identified as a "lactide/glycolide co-polymer" containing "propanoic acid, 2- hydroxy-polymer with hydroxy-polymer with hydroxyacetic acid." Four such polymers include lactide/glycolide 100 L, believed to be 100% lactide having a melting point within the range of 338°F-347° F (170 C); lactide/glycolide 100 L, believed to be 100% glycolide having amelting point within the range of 437°F-455°F (225C-235C); lactide/glycolide 85/15, believed to be 85% lactide and 15% glycolide with a melting point within the range of 338°F-347°F (170C- 175C); and lactide/glycolide 50/50, believed to be a copolymer of 50% lactide and 50% glycolide with a melting point within the range of 338°F-347°F (170C-175C).

The Biodel materials represent a family of various polyanhydrides which differ chemically.

Although a variety of different polymers may be used, it is desired to select polymers that provide mucoadhesive properties to the film, as well as a desired dissolution and/or disintegration rate. In particular, the time period for which it is desired to maintain the film in contact with the mucosal tissue depends on the type of active contained in the composition. Some actives may only require a few minutes for delivery through the mucosal tissue, whereas other actives may require up to several hours or even longer. Accordingly, in some embodiments, one or more water-soluble polymers, as described above, may be used to form the film In other embodiments, however, it may be desirable to use combinations of water-soluble polymers and polymers that are water-swellable, water-insoluble and/or biodegradable, as provided above. The inclusion of one or more polymers that are water-swellable, water- insoluble and/or biodegradable may provide films with slower dissolution or disintegration rates than films formed from water-soluble polymers alone. As such, the film may adhere to the mucosal tissue for longer periods or time, such as up to several hours, which may be desirable for delivery of certain active components.

Desirably, the individual film dosage has a small size, which is between about 0.5-1 inch by about 0.5-1 inch. Most preferably, the film dosage is about 0.75 inches.times.0.5 inches. The film dosage should have good adhesion when placed in the buccal cavity or in the sublingual region of the user. Further, the film dosage should disperse and dissolve at a moderate rate, most desirably dispersing within about 1 minute and dissolving within about 3 minutes. In some embodiments the film dosage may be capable of dispersing and dissolving at a rate of between about 1 to about 1.5 minutes.

For instance, in some embodiments, the films may include polyethylene oxide alone or in combination with a second polymer component. The second polymer may be another water- soluble polymer, a water-swellable polymer, a water-insoluble polymer, a biodegradable polymer or any combination thereof. Suitable water-soluble polymers include, without limitation, any of those provided above. In some embodiments, the water-soluble polymer may include hydrophilic cellulosic polymers, such as hydroxypropyl cellulose and/or hydroxypropylmethyl cellulose. In accordance with some embodiments, polyethylene oxide may range from about 20% to 100% by weight in the polymer component, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight. In some embodiments, one or more water-swellable, water-insoluble and/or biodegradable polymers also may be included in the polyethylene oxide-based film Any of the water- swellable, water-insoluble or biodegradable polymers provided above may be employed. The second polymer component may be employed in amounts of about 0% to about 80% by weight in the polymer component, more specifically about 30% to about 70% by weight, and even more specifically about 40% to about 60% by weight. The molecular weight of the polyethylene oxide also may be varied. In some embodiments, high molecular weight polyethylene oxide, such as about 4 million, may be desired to increase mucoadhesivity of the film. In some other embodiments, the molecular weight may range from about 100,000 to 900,000, more specifically from about 100,000 to 600,000, and even more specifically from about 100,000 to 300,000. In some embodiments, it may be desirable to combine high molecular weight (600,000 to 900,000) with low molecular weight (100,000 to 300,000) polyethylene oxide in the polymer component.

A variety of optional components and fillers also may be added to the films. These may include, without limitation: surfactants; plasticizers; polyalcohols; anti-foaming agents, such as silicone-containing compounds, which promote a smoother film surface by releasing oxygen from the film; thermo-setting gels such as pectin, carageenan, and gelatin, which help in maintaining the dispersion of components; inclusion compounds, such as cyclodextrins and caged molecules; coloring agents; and flavors. In some embodiments, more than one active components may be included in the film

Additives may be included in the films. Examples of classes of additives include excipients, lubricants, buffering agents, stabilizers, blowing agents, pigments, coloring agents, fillers, bulking agents, sweetening agents, flavoring agents, fragrances, release modifiers, adjuvants, plasticizers, flow accelerators, mold release agents, polyols, granulating agents, diluents, binders, buffers, absorbents, glidants, adhesives, and -adherents, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers and mixtures thereof. These additives may be added with the active ingredient(s).

Useful additives include, for example, gelatin, vegetable proteins such as sunflower protein, soybean proteins, cotton seed proteins, peanut proteins, grape seed proteins, whey proteins, whey protein isolates, blood proteins, egg proteins, acrylated proteins, water-soluble polysaccharides such as alginates, carrageenans, guar gum, agar-agar, xanthan gum, gellan gum, gum arabic and related gums (gum ghatti, gum karaya, gum tragancanth), pectin, water-soluble derivatives of cellulose: alkyl celluloses hydroxyalkylcelluloses and hydroxyalkylalkylcelluloses, such as methylcelulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, hydroxybutylmethylcellulose, cellulose esters and hydroxyalkylcellulose esters such as cellulose acetate phthalate (CAP), hydroxypropylmethylcellulose (HPMC); carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters such as carboxymethylcellulose and their alkali metal salts; water-soluble synthetic polymers such as polyacrylic acids and polyacrylic acid esters, polymethacrylic adds and polymethacrylic acid esters, polyvinylacetates, polyvinylalcohols, polyvinylacetatephthalates (PVAP), polyvinylpyrrolidone (PVP), PVY/vinyl acetate copolymer, and polycrotonic acids; also suitable are phthalated gelatin, gelatin succinate, crosslinked gelatin, shellac, water-soluble chemical derivatives of starch, cationically modified acrylates and methacrylates possessing, for example, a tertiary or quaternary amino group, such as the diethylaminoethyl group, which may be quatemized if desired; and other similar polymers.

Such extenders may optionally be added in any desired amount desirably within the range of up to about 80%, desirably about 3% to 50% and more desirably within the range of 3% to 20% based on the weight of all film components.

Further additives may flow agents and opacifiers, such as the oxides of magnesium aluminum, silicon, titanium, etc. desirably in a concentration range of about 0.02% to about 3% by weight and desirably about 0.02% to about 1% based on the weight of all film components.

Further examples of additives are plasticizers which include polyalkylene oxides, such as polyethylene glycols, polypropylene glycols, polyethylene-propylene glycols, organic plasticizers with low molecular weights, such as glycerol, glycerol monoacetate, diacetate or triacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, tributyl citrate, and the like, added in concentrations ranging from about 0.5% to about 30%, and desirably ranging from about 0.5% to about 20% based on the weight of the polymer.

There may further be added compounds to improve the texture properties of the starch material such as animal or vegetable fats, desirably in their hydrogenated form, especially those which are solid at room temperature. These fats desirably have a melting point of 50°C or higher. Preferred are tri-glycerides with and -fatty acids. These fats

can be added alone without adding extenders or plasticizers and can be advantageously added alone or together with mono- and/or di-glycerides or phosphatides, especially lecithin. The mono- and di-glycerides are desirably derived from the types of fats described above, i.e. with

and C22-fatty acids.

The total amounts used of the fats, mono-, di-glycerides and/or lecithins are up to about 5% and preferably within the range of about 0.5% to about 2% by weight of the total film composition. It further may be useful to add silicon dioxide, calcium silicate, or titanium dioxide in a concentration of about 0.02%) to about 1% by weight of the total composition. These compounds act as flow agents and opacifiers.

Lecithm is one surface active agent for use in the films described herein. Lecithin may be included in the feedstock in an amount of from about 0.25% to about 2.00% by weight. Other surface active agents, i.e. surfactants, include, but are not limited to, cetyl alcohol, sodium lauryl sulfate, the Spans® and Tweens® which are commercially available from ICI Americas, Inc. Ethoxylated oils, including ethoxylated castor oils, such as Cremophor EL which is commercially available from BASF, are also useful. Carbowax® is yet another modifier which is very useful in the present invention. Tweens®! or combinations of surface active agents may be used to achieve the desired hydrophilic-lipophilic balance ("HLB"). The present invention, however, does not require the use of a surfactant and films or film-forming compositions of the present invention may be essentially free of a surfactant while still providing the desirable uniformity features of the present invention.

Other ingredients include binders which contribute to the ease of formation and general quality of the films. Non-limiting examples of binders include starches, pregelatinize starches, gelatin, polyvinylpyrrolidone, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvmylalcohols.

Further potential additives include solubility enhancing agents, such as substances that form inclusion compounds with active components. Such agents may be useful in improving the properties of very insoluble and/or unstable actives. In general, these substances are doughnut- shaped molecules with hydrophobic internal cavities and hydrophilic exteriors. Insoluble and/or instable actives may fit within the hydrophobic cavity, thereby producing an inclusion complex, which is soluble in water. Accordingly, the formation of the inclusion complex permits very insoluble and/or instable actives to be dissolved in water. A particularly desirable example of such agents are cyclodextrins, which are cyclic carbohydrates deri ved from starch. Other similar substances, however, are considered well within the scope of the present invention.

Suitable coloring agents include food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors are dyes, their corresponding lakes, and certain natural and derived colorants. Lakes are dyes absorbed on aluminum hydroxide.

Other examples of coloring agents include known azo dyes, organic or inorganic pigments, or coloring agents of natural origin. Inorganic pigments are preferred, such as the oxides or iron or titanium, these oxides, being added in concentrations ranging from about 0.001 to about 10%, and preferably about 0.5 to about 3%, based on the weight of all the components.

Flavors may be chosen from natural and synthetic flavoring liquids. An illustrative list of such agents includes volatile oils, synthetic flavor oils, flavoring aromatics, oils, liquids, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. Anon-limiting representative list of examples includes mint oils, cocoa, and citrus oils such as lemon, orange, grape, lime and grapefruit and fruit essences including apple, pear, peach, grape, strawberry, raspberry', cherry, plum, pineapple, apricot or other fruit flavors.

Other useful flavorings include aldehydes and esters such as benzaldehyde (cherry, almond), citral i.e., alphacitral (lemon, lime), neral, i.e., beta-citral (lemon, lime), decanal (orange, lemon), aldehyde C-8 (citrus fruits), aldehyde C-9 (citrus fruits), aldehyde C-12 (citrus fruits), tolyl aldehyde (cherry, almond), 2,6-dimethyloctanol (green fruit), and 2-dodecenal (citrus, mandarin), combinations thereof and the like.

The sweeteners may be chosen from the following non-limiting list: glucose (com syrup), dextrose, invert sugar, fructose, and combinations thereof, saccharin and its various salts such as the sodium salt; dipeptide sweeteners such as aspartame; dihydrochalcone compounds, glycyrrhizin; Stevia Rebaudiana (Stevioside); chloro derivatives of sucrose such as sucralose; sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener 3,6-dihydro-6-methyl-l-l-l,2,3- oxathiazin-4-one-2,2-dioxide, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof, and natural intensive sweeteners, such as Lo Han Kuo. Other sweeteners may also be used.

Anti-foaming and/or de-foaming components may also be used with the films. These components aid in the removal of air, such as entrapped air, from the film-forming compositions. Such entrapped air may lead to non-uniform films. Simethicone is one particularly useful anti-foaming and/or de-foaming agent. The present invention, however, is not so limited and other anti-foam and/or de-foaming agents may suitable be used.

In another embodiment, the composition comprises antioxidants), for example, tocopherol and derivatives, ascorbic acid and derivatives, butylated hydroxyanisole, butylated hydroxy tol uene, fumaric acid, malic acid, propyl gallate, sodium metabisulfite and deri vatives, is a concentration of about 0.01 to about 5 weight percent; more preferred is a concentration of about 0.1 to about 0.5 weight percent, depending on the type of antioxidant used, as known by the one skilled in the art. In another embodiment, the composition comprises buffering agent(s), for example, carbonate buffers, citrate buffers, phosphate buffers, acetate buffers, hydrochloric acid, lactic acid, tartaric acid, inorganic and organic bases, is a concentration of about 1 to about 10 weight percent, more preferred is a concentration of about 2 to about S weight percent, depending on the type of buffering agent(s) used, as known by the one skilled in the art. The preferred concentration range of said buffering agents are those enabling design of compositions having a pH close to the physiologic pH of the mucosal membranes, between about pH 2.0 and about pH 10.0, preferably between about pH 3.0 and pH 7.0. Concentrations of the buffering agent(s) may vary, however, as known by the one skilled in the art. The buffering agent may replace up to 100% of the water amount within the composition.

The transmucosal pharmaceutical formulation of the present invention may also further include preservatives such as benzalkonium chloride and derivatives, benzoic acid, benzyl alcohol and derivatives, bronopol, parabens, centrimide, chlorhexidine, cresol and derivatives, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric salts, thimerosal, sorbic acid and derivatives. The preservative is present from about 0.01 to about 10% w/w depending on the type of compound used, as known by the one skilled in the art.

The transmucosal pharmaceutical formulation of the present invention may also further include humectants, sequestering agents, moisturizers, surfactants, emollients, colorants, fragrances, flavors, or any combination thereof.

In some embodiments, the transmucosal dosage form is a liquid formulation, comprising: a therapeutically effective amount of a first agent which is selected from the group consisting of beta-carotene, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, guanosine monophosphate, pharmaceutically acceptable derivatives thereof, and pharmaceutically acceptable salts thereof, and combinations thereof; a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient, aqueous solvent; and a polar organic solvent, wherein the polar organic solvent is present in an amount sufficient to enhance the solubility' of the active ingredients thereof in the water.

In one embodiment, a gel formulation of the present invention comprises a first agent which is selected from the group consisting of beta-carotene, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, guanosine monophosphate, pharmaceutically acceptable derivatives thereof, and pharmaceutically acceptable salts thereof, and combinations thereof; a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient, of between about 0.01 to about 5 weight percent. The primary vehicle may comprise between about 10 to about 60 weight percent of water, between about 30 to about 70 weight percent ethanol, between about 15 and about 60 weight percent ofa l0:l to l:10 (weight to weight) mixture of diethylene glycol mono ethyl ether and propylene glycol, and between about 0.1 and about 2 weight percent of lauryl alcohol, myristyl alcohol, oleyl alcohol, lauric acid, myristic acid, or oleic acid. The primary vehicle may be gellified with between about 0.5 and about 5 weight percent of hydroxj-propylcellulose. The apparent pH of the gel is between about pH 2.0 and about pH 10.0, or preferably between about pH 3.0 and pH 7.0.

In addition, the transmucosal delivery system of the pharmaceutical composition can include a buffer to maintain the pH of the formulation and a pharmaceutically acceptable thickening agent. The pharmaceutical composition can further include one or more pharmaceutical excipients and even further include a pharmaceutically acceptable preservative.

The buffer of the transmucosal deliver}' system can be selected from the group including acetate, citrate, prolamine, carbonate and phosphate buffers.

The thickening agent of the transmucosal delivery system can be selected from the group including methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.

The formulation may further comprise a sweetener suitable for sublingual and buccal delivery systems. The sweetener may be, but is not limited to, mannitol, saccharin or saccharin sodium. The formulation may further comprise a flavoring agent Preferably, the flavoring agent is menthol. The formulation may further comprise a thickening agent The thickening agent may be, but is not limited to, methyl cellulose, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer, polyvinyl alcohol, alginates, acacia, chitosans and combinations thereof.

The formulation may further comprise a humectant suitable for nasal delivery system. The humectant may be, but not limited to, sorbitol, glycerol, mineral oil, vegetable oil and combinations thereof.

In some embodiments, the transmucosal carrier of the transmucosal dosage unit is preferably an aqueous solution. Further, the aqueous solution can be selected from the group including aqueous gels, aqueous suspensions, aqueous liposomal dispersions, aqueous emulsions, aqueous microemulsions, aqueous nanoparticles and combinations thereof. Alternatively, the carrier of the transmucosal dosage unit is a nonaqueous solution. The non-aqueous solution can be selected from a group including non-aqueous gels, non-aqueous suspensions, non-aqueous liposomal dispersions, nonaqueous emulsions, non-aqueous microemulsions, non-aqueous nanoparticles and combinations thereof.

The carrier of the transmucosal dosage unit can also be a combination of an aqueous solution and a non-aqueous solution. The formulation may be partially pressurized. Alternatively, the carrier of the transmucosal dosage unit is a powder formulation.

The powder formulation can be selected from, but not limited to, a simple powder mixtures, powder microspheres, coated powder microspheres, liposomal dispersions and combinations thereof. Preferably, the powder formulation is simple powder mixture.

In some embodiments the oral transmucosal dosage form is chosen from: a chewing gum, a patch, a gel, a lozenge, a tablet, a troche, a pastille, a sachet, and a rapid disintegrating tablet.

The formulations of the present invention may be provided in a unit dose container(s). Such containers typically comprise inner and outer surfaces, wherein the formulation of the present invention is contained by the inner surface of the container. In selected embodiments, the container is a packet or a vial, and the inner surface of the container may further comprise a liner. For example, in one embodiment, the container is a flexible, foil packet and the liner is a polyethylene liner. Alternatively, or in addition, the formulations of the present invention may be provided in a multiple dose container(s). Such multiple dose containers typically comprise inner and outer surfaces, wherein the gel for pharmaceutical drug delivery is contained by the inner surface of the container. Multiple dose containers may, for example, dispenses fixed or variable metered doses. Multiple dose containers may, for example, be a stored-energy metered dose pump or a manual metered dose pump.

Packaging/Treatment Kits

The present invention relates to a kit for conveniently and effectively carrying out the methods in accordance with the present invention. Such kits may be suited for the delivery of, for example, solid oral forms such as tablets or capsules. Such a kit may include a number of unit dosages. Such kits can include a means for containing the dosages oriented in the order of their intended use. An example of a means for containing the dosages in the order of their intended uses is a card. An example of such a kit is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms. If desired, the blister can be in the form of a childproof blister, i.e., a blister that is difficult for a child to open, yet can be readily opened by an adult. If desired, a memory aid can be provided, for example in the form of numbers, letters, or other markings or with a calendar feature and/or calendar insert, designating the days and the sections of a day in the treatment schedule in which the dosages can be administered, such as an AM dose is packaged with a "mid day" and a PM dose.; or an AM dose is packaged with a PM dose. Alternatively, placebo dosages, or vitamin or dietary supplements, either in a form similar to or distinct from the pharmaceutical active dosages, can be included.

In one aspect, the package, kit or container comprises a "blister package" (also called a blister pack, or bubble pack). In one aspect, the blister package consists two or more separate compartments: Am dosage of this invention, and PM dosage of this invention, or mid-day dosage of this invention. This blister package is made up of two separate material elements: a transparent plastic cavity shaped to the product and its blister board backing. These two elements are then joined together with a heat sealing process which allows the product to be hung or displayed. Exemplary types of "blister packages" include: Face seal blister packages, gang run blister packages, mock blister packages, interactive blister packages, slide blister packages.

Blister packs, clamshells or trays are forms of packaging used for goods; thus, the invention provides for blister packs, clamshells or trays comprising a composition (e.g. , a (the multi-ingredient combination of drugs of the invention) combination of active ingredients) of the invention. Blister packs, clamshells or trays can be designed to be non-reclosable, so consumers can tell if a package has already opened. They are used to package for sale goods where product tampering is a consideration, such as the pharmaceuticals of the invention. In one aspect, a blister pack of the invention comprises a moulded PVC base, with raised areas (the "blisters") to contain the tablets, pills, etc. comprising the combinations of the invention, covered by a foil laminate. Tablets, pills, etc. are removed from the pack either by peeling the foil back or by pushing the blister to force the tablet to break the foil. In one aspect, a specialized form of a blister pack is a strip pack.

In one aspect, a blister pack also comprises a method of packaging where the compositions comprising combinations of ingredients of the invention are contained in-between a card and a clear PVC. The PVC can be transparent so the item (pill, tablet, geltab, etc.) can be seen and examined easily; and in one aspect, can be vacuum-formed around a mould so it can contain the item snugly and have room to be opened upon purchase. In one aspect, the card is brightly colored and designed depending on the item (pill, tablet, geltab, etc.) inside, and the PVC is affixed to the card using pre-formed tabs where the adhesive is placed. The adhesive can be strong enough so that the pack may hang on a peg, but weak enough so that this way one can tear open the join and access the item. Sometimes with large items or multiple enclosed pills, tablets, geltabs, etc., the card has a perforated window for access. In one aspect, more secure blister packs, e.g. , for items such as pills, tablets, geltabs, etc. of the invention are used, and they can comprise of two vacuum-formed PVC sheets meshed together at the edges, with the informative card inside.

In one aspect, blister packaging comprises at least two components (e.g., is a multi- ingredient combination of drugs of the invention): a thermoformed "blister" which houses the product (e.g. , a pharmaceutical combination of the invention), and then a "blister card" that is a printed card with an adhesive coating on the front surface. During the assembly process, the blister component, which is most commonly made out of PVC, is attached to the blister card using a blister machine. This machine introduces heat to the flange area of the blister which activates the glue on the card in that specific area and ultimately secures the PVG blister to the printed blister card. The thermoformed PVG blister and the printed blister card can be as small or large. Conventional blister packs can also be sealed (e.g., using an AERGO 8 DUO®, SCA Consumer Packaging, Inc., DeKalb, 111.) using regular heat seal tooling. This alternative aspect, using heat seal tooling, can seal common types of thermoformed packaging.

As discussed herein, the products of manufacture of the invention can comprise the packaging of the therapeutic drug combinations of the invention, alone or in combination, as "blister packages" or as a plurality of packettes, including as lidded blister packages, lidded blister or blister card or packets, or a shrink wrap.

In one aspect, laminated aluminum foil blister packs are used, e.g. , for the preparation of drugs designed to dissolve immediately in the mouth of a patient. This exemplary process comprises having the drug combinations of the invention prepared as an aqueous solution(s) which are dispensed (e.g., by measured dose) into an aluminum (e.g., alufoil) laminated tray portion of a blister pack. This tray is then freeze-dried to form tablets which take the shape of the blister pockets. The alufoil laminate of both the tray and lid fully protects any highly hygroscopic and/or sensitive individual doses. In one aspect, the pack incorporates a child-proof peel open security laminate. In one aspect, the system give tablets an identification mark by embossing a design into the alufoil pocket that is taken up by the tablets when they change from aqueous to solid state. In one aspect, individual 'push-through' blister packs/packettes are used, e.g., using hard temper aluminum (e.g., alufoil) lidding material. In one aspect, hermetically- sealed high barrier aluminum (e.g., alufoil) laminates are used. In one aspect, any of the invention's products of manufacture, including kits or blister packs, use foil laminations and strip packs, stick packs, sachets and pouches, peelable and non-peelable laminations combining foil, paper, and film for high barrier packaging.

In one embodiment of the invention, the composition is contained within one suitable container, such as a dropper, a jar, or a tube with a suitable small orifice size, such as an extended tip tube, made of any pharmaceutically suitable material. The formulations according to embodiments of the invention can be filled and packaged into a plastic squeeze bottle or tube. Optionally, an applicator can be provided in or attached to the container, or separately from the container.

Kits are also contemplated as being used in certain aspects of the present invention. For instance, a composition of the present invention can be included in a kit. A kit can include a container. Containers can include a bottle, a metal tube, a laminate tube, a plastic tube, a dispenser, a pressurized container, a barrier container, a package, a compartment, or other types of containers such as inj ection or blow-molded plastic containers into which the dispersions or compositions or desired bottles, dispensers, or packages are retained. The kit and/or container can include indicia on its surface. The indicia, for example, can be a word, a phrase, an abbreviation, a picture, or a symbol.

The containers can dispense a pre-determined amount of a composition. In other embodiments, the container can be squeezed (e.g., metal, laminate, or plastic tube) to dispense a desired amount of the composition. The composition can be dispensed as a spray, foam, an aerosol, a liquid, a gel, a fluid, or a semi-solid. The containers can have spray, pump, or squeeze mechanisms. A kit can also include instructions for using the kit and/or compositions. Instructions can include an explanation of how to apply, use, and maintain the compositions.

Other means for containing said unit dosages can include bottles and vials, wherein the bottle or vial comprises a memory aid, such as a printed label for administering said unit dosage or dosages. The label can also contain removable reminder stickers for placement on a calendar or dayminder to further help the patient to remember when to take a dosage or when a dosage has been taken.

Topical Formulations

The term "topical" as employed herein relates to the use of a compound, derivative or analogue as described herein, incorporated in a suitable pharmaceutical carrier, and applied at the site for exertion of local action. Accordingly, such topical compositions including those forms in which the compound is applied externally by direct contact with the skin surface to be treated. Conventional forms for this purpose include ointments, liniments, creams, shampoos, lotions, pastes, jellies, sprays, aerosols, soaps, and the like, and may be applied in patches or impregnated dressings depending on the part of the body to be treated. The term "ointment" embraces formulations (including creams) having oleaginous, absorption, water-soluble and emulsion-type bases, e.g., petrolatum, lanolin, polyethylene glycols, as well as mixtures of these.

For topical use, the agent of the invention can be advantageously formulated using ointments, creams, liniments or patches as a carrier of the active ingredients. Also, these formulations may or may not contain preservatives, depending on the dispenser and nature of use. Such preservatives include those mentioned above, and methyl-, propyl-, or butyl- parahydroxybenzoic acid, betain, chlorhexidine, benzalkonium chloride, and the like. Various matrices for slow release delivery may also be used. Typically, the dose to be applied is in the range of about 0.1 ng to about 100 mg per day, or about 1 ng to about 10 mg per day, or about 10 ng to about 1 mg per day depending on the formulation. Non-limiting examples of topical products can include, without limitation, application stick, mascara, eyebrow coloring products, eye shadow or other eye lid coloring products, eyeliner, make-up removal products, antiaging products, facial or body powder, nail polish, mousse, sprays, styling gels, nail conditioner, bam and shower gels, shampoos, conditioners, cream rinses, hair dyes and coloring products, hair conditioners, sun tanning lotions and creams and sprays, sunscreens and sunblocks, skin conditioners, cold creams, moisturizers, hair sprays, soaps, body scrubs, exfoliants, astringents, depilatories and permanent waving solutions, antidandruff formulations, antisweat and antiperspirant compositions, shaving, preshaving and after shaving products, moisturizers, deodorants, cold creams, cleansers, skin gels, and rinses.

Furthermore, the topical product can be applied topically through the use of a patch or other delivery device. Delivery devices can include, but are not limited to, those that can be heated or cooled, as well as those that utilize iontophoresis or ultrasound.

For instance, the topical product can be applied, for example, by applying a composition in the form of a skin lotion, clear lotion, milky lotion, cream, gel, foam, ointment, paste, emulsion, spray, conditioner, tonic, cosmetic, application stick, pencil, foundation, nail polish, after-shave, or the like which is intended to be left on the skin or other keratinous tissue (i.e., a "leave-on" composition). After applying the composition to the keratinous tissue (e.g., skin), it in one embodiment, it is left on for a period of at least about 15 minutes, or at least about 30 minutes, or at least about 1 hour, or for at least several hours, e.g., up to about 12 hours. In one embodiment, the topical product is left on overnight. In another embodiment, the topical product is left on all day. Any part of the external portion of the face, hair, and/or nails can be treated, (e.g., face, lips, under-eye area, eyelids, scalp, neck, torso, arms, legs, chest, hands, legs, feet, fingernails, toenails, scalp hair, eyelashes, eyebrows, etc.).

Any suitable method can be used to apply the topical product, including but not limited to for example using the palms of the hands and/or fingers or a device or implement (e.g., a cotton ball, swab, pad, applicator pen, spray applicator, ey ebrow brush, eyebrow brush pencil, pencil, mascara brush, etc.) Another approach to ensure a continuous exposure of the keratinous tissue to at least a minimum level of the topical product is to apply the compound by use of a patch applied, e.g., to the face. The patch can be occlusive, semi-occlusive or non-occlusive, and can be adhesive or non-adhesive. The topical product can be contained within the patch or be applied to the skin prior to application of the patch. The patch can also include additional actives such as chemical initiators for exothermic reactions. The patch can be left on the for any suitable period of time. For example, a period of at least about 5 minutes, or at least about 15 minutes, or at least about 30 minutes, or at least about 1 hour, or at night as a form of night therapy, or in another embodiment all day.

Administration

The pharmaceutical compositions may be optimized for particular types of delivery. For example, pharmaceutical compositions for oral delivery are formulated using pharmaceutically acceptable carriers that are well known in the art. The carriers enable the agents in the composition to be formulated, for example, as a tablet, pill, capsule, solution, suspension, sustained release formulation; powder, liquid or gel for oral ingestion by the subject.

The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as set out above. Preferably the compositions are administered by the oral, intranasal or respiratory route for local or systemic effect. Compositions in preferably sterile pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face mask, tent or intermittent positive pressure breathing machine. Solution, suspension or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

Typically, the composition may be applied repeatedly for a sustained period of time topically on the part of the body to be treated, for example, the eyelids, eyebrows, skin or scalp. The dosage regimen will generally involve regular, such as daily, administration for a period of treatment of at least one month, or at least three months, or at least six months.

Alternatively, the composition may be applied intermittently, or in a pulsed manner. Accordingly, an alternative embodiment of the invention is to apply the composition on an intermittent or pulsed dosage schedule. For example, the composition of the invention may be used for two or more days, stopped, then restarted again at a time from between 2 weeks to 3 months later, and at even more long-spaced intervals in the case of the scalp.

The treatments may include various "unit doses." Unit dose is defined as containing a predetermined-quantity of the therapeutic composition. The quantity to be administered, and the particular route and formulation, are within the skill of those in the clinical arts. A unit dose need not be administered as a single injection but may comprise continuous infusion over a set period of time. Alternatively, the amount specified may be the amount administered as the average daily, average weekly, or average monthly dose.

The invention will be illustrated in more detail with reference to the following Examples, but it should be understood that the present invention is not deemed to be limited thereto.

EXAMPLES

Example 1.

Prevention and treatment of a male at risk for Zika infection

In this example, the new method prevents or minimizes infection of humans by Zika virus. Here, a male at risk for being stung by an Aedes mosquito takes the following steps. He starts taking daily low dose oral mycophenolate one week before he travels to a Zika infested area and continues taking it while in the area. He applies a melanin containing lotion daily to skin not covered by clothing.

The use of these methods inhibits the infection in the following ways.

1. The lotion containing melanin is applied to the skin and is partially absorbed into the epidermis and dermis. It rapidly evaporates to leave a thin tough film. The external film of melanin minimizes or entirely prevents the entry of the virus in the skin from the stinger of the Aedes mosquito vector. If any virus is successfully injected into the epidermis or dermis, the absorbed melanin, which is toxic to the virus but not to human cells, eliminates or reduces the amount of live virus which has been introduced.

2. It has been demonstrated that three types of cells in the skin are normally susceptible to infection by the Zika virus: epidermal keratinocytes, dermal fibroblasts, and (dermal) macrophages. It has also been demonstrated that mycophenolate dramatically reduces guanosine levels in all three cell types. Thus because of relative depletion of guanosine in these cells, there is reduced (or absent) replication of the viral RNA in these cells as the guanosine necessary for replication of RNA is in short supply. Thus viral particles injected are only able to reproduce at a lower amount, or not at all, minimizing or terminating the infective load.

3. If in spite of the prior steps, the virus is successful in penetrating to the blood stream and causing a viremia, the systemic mycophenolate directly inhibits the the replication of the Zika virus in the blood and throughout the body.

4. Note that since a very small amount of antigen is known to trigger the immune system responses, it is likely mat even if the injected viral load is partially destroyed and the ability of remaining virus particles to replicate is limited, there is likely to be adequate viral antigen to stimulate the normal antiviral responses of the innate and adaptive immune systems.

Example 2.

Prevention and treatment of a female at risk for pregnancy and Zika infection.

Here, a female who is sexually active and may become pregnant is at risk for being stung by an Aedes mosquito and takes the following steps. She starts on a reduced guanosine diet designed for women who are pregnant or may become pregnant, one week before she travels to a Zika infested area and continues adhering to this diet while in the area. She applies a melanin containing lotion daily to skin not covered by clothing.

1. The lotion containing melanin is applied to the skin and is partially absorbed into the epidermis and dermis. It rapidly evaporates to leave a thin tough film. The external film of melanin minimizes or entirely prevents the entry of the virus in the skin from the stinger of the Aedes mosquito vector. If any virus is successfully injected into the epidermis or dermis, the absorbed melanin, which is toxic to the virus but not to human cells, eliminates or reduces the amount of live virus which has been introduced.

2. It has been demonstrated that three types of cells in the skin are normally susceptible to infection by the Zika virus: epidermal keratinocytes, dermal fibroblasts, and (dermal) macrophages.The reduced guanosine diet reduces guanosine levels in all three cell types. Thus because of relative depletion of guanosine in these cells, there is reduced (or absent) replication of the viral RNA in these cells as the guanosine necessary for replication of RNA is in short supply. Thus viral particles injected are only able to reproduce at a lower amount, or not at all, minimizing or terminating the infective load. 3. If in spite of the prior steps, the virus is successful in penetrating to the blood stream and causing a viremia, the relative lack of guanosine caused by the reduced diet limits the ability of the virus to replicate.

4. The above steps are successful in interdicting the infection sufficiently that an embryo or fetus is not damaged by the maternal viral infection.

Example 3

Treatment of a patient with multi-drug resistant tuberculosis.

A traveler from the US contracts multi-drug resistant tuberculosis while in India There are no known effective antibiotics. The patient is administered 3 ounces (about 90 gm) of cuttlefish ink (which contains melanin) mixed in his regular food twice per day for two weeks. Then mycophenolate mofetil 250mg twice per day is added. The regimen is continued for 3 months leading to cure of the multi drug-resistant tuberculosis.

Example 4

Treatment of a patient with infectious pulmonary aspergillosis.

As asthma patient contracts infectious pulmonary aspergillosis, a fungal disease. The patient is administered 2 grams of melanin (1 gm/capsule) mixed in his regular food twice per day for two weeks. Then mycophenolate mofetil 250mg twice per day is added. The regimen is continued for 3 months leading to cure of the aspergillosis.

Example 5

Diets with reduced guanosine content

These invented diets are low in nucleic acids and their components but are not nucleotide-free. The diets contain approximately 3% to 50% of the amount by weight of nucleotides seen in the normal western diet (2000 mg/day, from Ekelman, K. Disodium 5'Guanylate and Disodium 5 -Inosate. WHO Food Additives Series, No. 32 (1993), and preferably 10%-40%.

The inventor has conducted extensive analysis of the nucleotide content of human foods from a variety of sources, and evaluated the nutritional content and palatability of potential nucleotide-free diets. The inventor has concluded that it is not practical for most people to stay on a nucleotide-free diet in a compliant manner for the period of months required to obtain substantial clinical benefit from this approach. A nucleotide-free diet is unlikely to be sufficiently palatable for extended use and would deter compliance. Also, use of a nucleotide- free diet for months in humans would likely lead to other dietary deficiencies. As set forth above, the invention provides treatment of a patient with a diet which contain approximately 3% to 50% of the amount by weight of nucleotides seen in the normal western diet, which contains about 2000 mg/day of nucleotides. In exemplary embodiments, the diet of the invention contains a nucleotide content of about 1000 mg/day, of about 750 mg/day, of about 500 mg/day, of about 250 mg/day, of about 100 mg/day, of about 75 mg/day, of about 50 mg/day, of about 25 mg/day. In exemplar}' embodiments, the diet of the invention contains a nucleotide content compared to the normal Western diet of about 50%, of about 40%, of about 30%, of about 20%, of about 10%, of about 5%, of about 3%. In exemplary embodiments, the diet of the invention contains a nucleotide content compared to the normal Western diet of 3- 50%, of about 10^0%, of about 20-30%, of about 3-40%, of about 3-30%, of about 10-30%, of about 10-20%.

Example 6

Diets with reduced euanosine content optimized for women who are pregnant or may become pregnant.

The diets in Example 5 are modified to make them appropriate for women who are pregnant. The modified diets contains additional calcium, trace minerals, and B vitamin supplements. A supplement like Ensure or Boost would be added tot he diet. There would be additional fatty acids and protein.

Example 7

In vitro demonstration of method efficacy

Using methods similar to those of Diamond et al, 2002, (Diamond, M., Zachariah, M, and Harris, E.. "Mycophenolic Acid Inhibits Dengue Virus Infection by Preventing Replication of Viral RNA." Virology 304, no. 2 (2002): 211-221) mycophenolate and melanin are shown together, or when administered sequentially, to inhibit the replication of the Zika virus in vitro. For example, Zika virus is added to monolayers of hepatoma cells or hamster kidney cells at several different doses. They are incubated for 2 hours at a temperature of 37C. The cells are washed several times. Mycophenolate or melanin or both are added to the cells after they are exposed to Zika. After 72 hours the cells are harvested. RNA, viral antigen, and virion are quantitated. The results show that mycophenolate and melanin together inhibit almost all replication of the Zika vrus. Depending on the type of cells used, the dose of Zika virus, the doses of mycophenolate and/or melanin, the viral replication is inhibited in various degrees. While the invention has been described in detail and with reference to specific examples thereof, it will be apparent to one skilled in the art that various changes and modifications can be made therein without departing from the spirit and scope thereof.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A pharmaceutical oral mucosal delivery composition comprising:

- a therapeutically effective amount of a first agent which is selected from the group consisting of beta-carotene, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof;

- a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof;

- a therapeutically effective amount of a third agent which is selected from the group consisting of mycophenolic acid, mycophenolate mofetil, derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; and

- at least one pharmaceutically acceptable excipient.

2. The oral mucosal delivery composition of claim 1 wherein the composition is provided in a sublingual or buccal dosage form.

3. The oral mucosal delivery composition of any one of claims 1-2, wherein the composition comprises at least one pharmaceutically acceptable excipient selected from the group consisting of buffer, preservative, isotonic agent, an antioxidant, and combinations thereof.

4. The oral mucosal delivery composition of any one of claims 1-3 wherein the dosage form is selected from the group consisting of a tablet, a chewing gum, a gel, a patch, a lozenge, a troche, a pastille, a sachet, and a rapid disintegrating tablet.

5. The oral mucosal delivery composition of any one of claims 1-4 wherein the composition comprises the first agent in a dose from about 10 mg to about 450 mg, the second agent in a dose from about 10 mg to about 450 mg, and the third agent in a dose from about 10 mg to about 450 mg.

6. The oral mucosal delivery composition of any one of claims 1-5 wherein the first agent is beta-carotene and the first agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg.

7. The oral mucosal delivery composition of any one of claims 1-6 wherein the second agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg.

8. The oral mucosal delivery composition of any one of claims 1-7 wherein the third agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg.

9. The oral mucosal delivery composition of any one of claims 1-8 wherein the first agent is present in an amount of from 2% to 50% of the total weight of the composition.

10. The oral mucosal deliver}' composition of any one of claims 1-9 wherein the first agent is present in an amount of from 25% to 30% of the total weight of the composition.

11. The oral mucosal delivery composition of any one of claims 1-10 wherein said first agent is beta-carotene and the therapeutically effective amount of beta-carotene comprises at least about 75 mg to about 450 mg.

12. The oral mucosal delivery composition of any one of claims 1-11 wherein said therapeutically effective amount of beta-carotene comprises about 240 mg.

13. The oral mucosal delivery composition of any one of claims 1-12 wherein the second agent is present in an amount of from 2% to 50% of the total weight of the composition.

14. The oral mucosal delivery composition of any one of claims 1-13 wherein the second agent is present in an amount of from 25% to 30% of the total weight of the composition.

15. The oral mucosal delivery composition of any one of claims 1-14 wherein the third agent is present in an amount of from 2% to 50% of the total weight of the composition.

16. The oral mucosal delivery composition of any one of claims 1-15 wherein the third agent is present in an amount of from 25% to 30% of the total weight of the composition.

17. The oral mucosal delivery composition of any one of claims 1-16 wherein the weight ratio of the first agent to the second agent is selected from the group consisting of about 10: 1, about 5:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:5, and about 1:10.

18. The oral mucosal delivery composition of any one of claims 1-17 wherein the weight ratio of the first agent to the second agent to the third agent is selected from the group consisting of about 1:1:1, about 0.01:1:1, about 1:1:0.01, about 1:0.1:1, about 0.01:0.1:1, about 1:0.1:0.01, about 1:0.9:1, about 0.01:0.9:1, and about 1:0.9:0.01.

19. The oral mucosal delivery composition of any one of claims 1-18 wherein the composition further comprises at least one flavoring agent, artificial coloring, sweetener, lubricating agent, disintegration agent, permeation enhancer, lubricating agent, diluent, base, buffering agent, or combinations thereof.

20. A pharmaceutical oral mucosal delivery composition comprising:

- a therapeutically effective amount of a first agent which is selected from the group consisting of beta-carotene, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, guanosine monophosphate, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; - a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof;

- a therapeutically effective amount of a third agent which is at least one mineral selected from the group consisting of calcium, chromium, copper, iodine, iron, magnesium, manganese, phosphorus, potassium, selenium, zinc, derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof;

and

- at least one pharmaceutically acceptable excipient.

21. The oral mucosal delivery composition of claim 20 wherein the composition is provided in a sublingual or buccal dosage form.

22. The oral mucosal delivery composition of any one of claims 20-21, wherein the composition comprises at least one pharmaceutically acceptable excipient selected from the group consisting of buffer, preservative, isotonic agent, an antioxidant, and combinations thereof.

23. The oral mucosal delivery composition of any one of claims 20-22 wherein the dosage form is selected from the group consisting of a tablet, a chewing gum, a gel, a patch, a lozenge, a troche, a pastille, a sachet, and a rapid disintegrating tablet.

24. The oral mucosal delivery composition of any one of claims 20-23 wherein the composition comprises the first agent in a dose from about 10 mg to about 450 mg, the second agent in a dose from about 10 mg to about 450 mg, and the third agent in a dose from about 10 mg to about 450 mg.

25. The oral mucosal delivery composition of any one of claims 20-24 wherein the first agent is beta-carotene and the first agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg.

26. The oral mucosal delivery composition of any one of claims 20-25 wherein the second agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about

225 mg, about 300 mg, and about 450 mg.

27. The oral mucosal delivery composition of any one of claims 20-26 wherein the third agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg.

28. The oral mucosal delivery composition of any one of claims 20-27 wherein the first agent is guanosine monophosphate and the first agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450.

29. The oral mucosal delivery composition of any one of claims 20-28 wherein the first agent is present in an amount of from 2% to 50% of the total weight of the composition.

30. The oral mucosal delivery composition of any one of claims 20-29 wherein the first agent is present in an amount of from 25% to 30% of the total weight of the composition.

31. The oral mucosal delivery composition of any one of claims 20-30 wherein said first agent is beta-carotene and the therapeutically effective amount of beta-carotene comprises at least about 75 mg to about 450 mg.

32. The oral mucosal delivery composition of any one of claims 20-31 wherein said therapeutically effective amount of beta-carotene comprises about 240 mg.

33. The oral mucosal delivery composition of any one of claims 20-32 wherein said therapeutically effective amount of guanosine monophosphate comprises at least about 75 mg to about 450 mg.

34. The oral mucosal delivery composition of any one of claims 20-33 wherein said first agent is guanosine monophosphate and the therapeutically effective amount of guanosine monophosphate comprises about 240 mg.

35. The oral mucosal delivery composition of any one of claims 20-34 wherein the second agent is present in an amount of from 2% to 50% of the total weight of the composition.

36. The oral mucosal delivery composition of any one of claims 20-35 wherein the second agent is present in an amount of from 25% to 30% of the total weight of the composition.

37. The oral mucosal delivery composition of any one of claims 20-36 wherein the third agent is present in an amount of from 2% to 50% of the total weight of the composition.

38. The oral mucosal delivery composition of any one of claims 20-37 wherein the third agent is present in an amount of from 25% to 30% of the total weight of the composition.

39. The oral mucosal delivery composition of any one of claims 20-38 wherein the concentration of the second agent is from about 0.01% to about 90% of the dry matter weight of the composition.

40. The oral mucosal delivery composition of any one of claims 20-39 wherein the weight ratio of the first agent to the second agent is selected from the group consisting of about 10:1, about 5:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:5, and about 1:10.

41. The oral mucosal delivery composition of any one of claims 20-40 wherein the weight ratio of the first agent to the second agent to the third agent is selected from the group consisting of about 1:1:1, about 0.01:1:1, about 1:1:0.01, about 1:0.1:1, about 0.01:0.1:1, about 1:0.1:0.01, about 1:0.9:1, about 0.01:0.9:1, and about 1:0.9:0.01.

42. The oral mucosal delivery composition of any one of claims 20-41 wherein the composition further comprises at least one flavoring agent, artificial coloring, sweetener, lubricating agent, disintegration agent, permeation enhancer, lubricating agent, diluent, base, buffering agent, or combinations thereof.

43. A pharmaceutical oral mucosal delivery composition comprising:

- a therapeutically effective amount of a first agent which is selected from the group consisting of beta-carotene, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, guanosine monophosphate, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof;

- a therapeutically effective amount of a second agent which is selected from the group consisting of cholic acid, derivatives thereof, and pharmaceutically acceptable salts thereof;

- a therapeutically effective amount of at least one third agent which is selected from the group consisting of melanin, melanin precursors, melanin derivatives, melanin analogs and related substances, and combinations thereof;

and

- at least one pharmaceutically acceptable excipient.

44. The oral mucosal delivery composition of claim 43 wherein the composition is provided in a sublingual or buccal dosage form.

45. The oral mucosal delivery composition of any one of claims 43-44, wherein the composition comprises at least one pharmaceutically acceptable excipient selected from the group consisting of buffer, preservative, isotonic agent, an antioxidant, and combinations thereof.

46. The oral mucosal delivery composition of any one of claims 43-45 wherein the dosage form is selected from the group consisting of a tablet, a chewing gum, a gel, a patch, a lozenge, a troche, a pastille, a sachet, and a rapid disintegrating tablet.

47. The oral mucosal delivery composition of any one of claims 43-46 wherein the composition comprises the first agent in a dose from about 10 mg to about 450 mg, the second agent in a dose from about 10 mg to about 450 mg, and the third agent in a dose from about 10 mg to about 450 mg.

48. The oral mucosal delivery composition of any one of claims 43-47 wherein the first agent is beta-carotene and the first agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg.

49. The oral mucosal delivery composition of any one of claims 43-48 wherein Ihe second agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450 mg.

50. The oral mucosal delivery composition of any one of claims 43-49 wherein the third agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about

225 mg, about 300 mg, and about 450 mg.

51. The oral mucosal delivery composition of any one of claims 43-50 wherein the first agent is guanosine monophosphate and the first agent is present in an amount selected from the group consisting of about 75 mg, about 150 mg, about 225 mg, about 300 mg, and about 450.

52. The oral mucosal delivery composition of any one of claims 43-51 wherein the first agent is present in an amount of from 2% to 50% of the total weight of the composition.

53. The oral mucosal delivery composition of any one of claims 43-52 wherein the first agent is present in an amount of from 25% to 30% of the total weight of the composition.

54. The oral mucosal delivery composition of any one of claims 43-53 wherein said first agent is beta-carotene and the therapeutically effective amount of beta-carotene comprises at least about 75 mg to about 450 mg.

55. The oral mucosal delivery composition of any one of claims 43-54 wherein said therapeutically effective amount of beta-carotene comprises about 240 mg.

56. The oral mucosal delivery composition of any one of claims 43-55 wherein said therapeutically effective amount of guanosine monophosphate comprises at least about 75 mg to about 450 mg.

57. The oral mucosal delivery composition of any one of claims 43-56 wherein said first agent is guanosine monophosphate and the therapeutically effective amount of guanosine monophosphate comprises about 240 mg.

58. The oral mucosal delivery composition of any one of claims 43-57 wherein Ihe second agent is present in an amount of from 2% to 50% of the total weight of the composition.

59. The oral mucosal delivery composition of any one of claims 43-58 wherein the second agent is present in an amount of from 25% to 30% of the total weight of the composition.

60. The oral mucosal delivery composition of any one of claims 43-59 wherein the third agent is present in an amount of from 2% to 50% of the total weight of the composition.

61. The oral mucosal delivery composition of any one of claims 43-60 wherein the third agent is present in an amount of from 25% to 30% of the total weight of the composition.

62. The oral mucosal delivery composition of any one of claims 43-61 wherein the concentration of the second agent is from about 0.01% to about 90% of the dry matter weight of the composition.

63. The oral mucosal delivery composition of any one of claims 43-62 wherein the weight ratio of the first agent to the second agent is selected from the group consisting of about 10:1, about

5:1, about 3:1, about 2:1, about 1:1, about 1:2, about 1:3, about 1:5, and about 1:10.

64. The oral mucosal delivery composition of any one of claims 43-63 wherein the weight ratio of the first agent to the second agent to the third agent is selected from the group consisting of about 1:1:1, about 0.01:1:1, about 1:1:0.01, about 1:0.1:1, about 0.01:0.1:1, about 1:0.1:0.01, about 1:0.9:1, about 0.01:0.9:1, and about 1:0.9:0.01.

65. The oral mucosal delivery composition of any one of claims 43-64 wherein the composition further comprises at least one flavoring agent, artificial coloring, sweetener, lubricating agent, disintegration agent, permeation enhancer, lubricating agent, diluent, base, buffering agent, or combinations thereof.