Melanin - metal composites for sound absorption and other applications

Abstract

Lightweight melanin composite sound protection materials that are easy to fabricate into final components, at reasonable cost, yet still offer sound protection properties on par with heavier materials are disclosed.

Description

[0001] Attorney Docket No.: 4774-0060W006

[0002] MELANIN - METAL COMPOSITES FOR SOUND ABSORPTION AND OTHER

[0003] APPLICATIONS

[0004] SPECIFICATION

[0005] CROSS REFERENCE APPLICATIONS

[0006] This application claims benefit of U.S. Provisional application no. 63 / 685,736 filed on August 22, 2024, the entirety of which is incorporated herein by reference.

[0007] BACKGROUND OF THE INVENTION

[0008] The disclosure provides lightweight melanin composite sound protection materials that are easy to fabricate into final components, at reasonable cost, yet still offer sound protection properties on par with heavier materials.

[0009] Melanin is an intriguing biomolecule with interesting material science properties. Naturally derived melanin is a heterogeneous polymer whose structure remains a matter of controversial discussion in spite of a century of research (Meredith and Sarna, 2006). Melanin extracted from cephalopods, such as cuttlefish, is generally accepted to be derived from two monomers, 5,6- dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA), which are heterogeneously arrayed. Cephalopod melanin has a number of well recognized chemical functional groups, including carboxyl, phenolic, and amine, which can react with a variety of ions. Cephalopod melanin is synthesized and retained in spherical organelles termed melanosomes.

[0010] ELBialy et al., 2019 was able to synthesize composites of fungal melanin with silver, lead or bismuth ions, and their analysis indicated that the silver atoms bound to a single oxygen in melanin, lead atom bound to two oxygens, and bismuth atom bound to three oxygens. (See Figure 2). They were also able to create a composite where all three metals were present. They demonstrated that the bismuth-melanin composites had substantial capacity to absorb gamma radiation.

[0011] The inventor has discovered that melanin, melanin derivatives, and melanin variants are capable of absorbing sound and converting it to electrical energy. This refers to all types of melanin, and especially extracts of natural melanins, which are particularly well-suited for utilization and commercial applications. Attorney Docket No.: 4774-0060W006

[0012] Sound as used herein includes all types of sounds that are in the hearing range of all animals, as well as ultrasound and supersonic sound. Humans can perceive sound in the range of 20 Hz to 20 kHz. Some animals can perceive sound at lower and higher ranges.

[0013] This invention can be used for sound absorption in noisy environments, including for consumer ear plugs and homes, and industrial environments that are noisy. It can be used to absorb sound due to large blasts such as occurs from explosions during demolition or combat.

[0014] The inventor has discovered that many types of melanin are able to absorb sound levels that are greater or equal to materials currently used for that purpose.

[0015] The electrical energy produced when sound encounters melanin can be stored in devices such as capacitors, routed to other locations, and used as any electrical energy.

[0016] The inventor has discovered that natural melanins contain a variety of proteins and other non-melanin molecules which provide assistance and support for formulation of melanin into commercially useful products by enhancing its ability to make robust structured items of defined sizes such as tiles, small chips. These proteins and non-melanin substances enhance and allow tunability of properties such as hardness, abrasion resistance, and tensile strength.

[0017] There is little written in the literature on the absorption of sound by melanin. Kono et al. 1979 reported that a specific type of melanin they synthesized was able to absorb sound. Horowitz, 1979 reported that synthetic melanin is unable to convert ultrasound into heat.

[0018] The present disclosure relates generally to composites of melanin materials and non- melanin materials such as ceramics, fibrous sheets and / or laminated plies. The inventor has appreciated that by combining certain melanin materials and non-melanin materials into ceramics, laminar configurations, and composites with advantages not attainable by either component separately can be achieved. In some cases, the resulting composite, synergistic interactions between the fibrous materials and melanin materials may arise.

[0019] Melanin composites may take many forms and have many different useful advantages. Melanin composites comprising mechanically strong melanin materials are particularly useful. In some embodiments, melanin composites are particularly well-suited as multilayer insulation (MLI) with better thermal performance than the melanin material itself. In some embodiments, Attorney Docket No.: 4774-0060W006 melanin composites with good flexibility may serve as useful insulation for garments. In other embodiments, melanin composites are highly effective sound absorbing materials useful for, for example, vehicle cladding. In further embodiments, melanin composites may serve as high stiffness-to-weight ratio materials suitable for lightweight structures, aircraft and automotive parts, and high-performance sports equipment.

[0020] The melanin composite exhibits the following features: 1. Ultra-light-weight; 2. Flexibility to fit various vehicle bodies and contours; 3. Superior sound energy absorption capability; 4. Superior strength for structural integrity; 5. Capability to resist heat and flame; 6. Ease of manufacture, maintenance and repair, and low life-cycle cost; 7. Applicability to other civilian, military, and commercial vehicle systems.

[0021] Due to the flexibility of the proposed system, the new melanin composite material can also be used, with minimum modifications, to protect commercial vehicles when necessary. The melanin composite can be further extended for other usages, for example, in a chair-based melanin composite to protect driver and passengers, or attached to office walls to protect officers, or even as a personal sound protection.

[0022] The melanins comprise a family of biopolymer pigments. Progress understanding the structure, functions, chemical and physical properties of melanins has been slow, sporadic and fragmented among many different scientific disciplines, including biology, chemistry, physics, and electronics.

[0023] There are a number of different schemes for classifying melanin. These include the following:

[0024] By color: e.g., most known melanins have been black, brown, or red, although other colors have been produced synthetically, Natural versus synthetic,

[0025] By category: Eumelanin, phaeomelanin, neuromelanin, allomelanin,

[0026] By source: animal, plant, fungal, lichen, etc., By suitability to different extraction methods, By chemical structure,

[0027] By physical properties, and

[0028] By biological functions. Attorney Docket No. : 4774-0060W006

[0029] The definition and nomenclature of melanin remains unsettled and problematic, since workers in various scientific disciplines differ somewhat in their use of the term. For instance, chemists can produce different synthetic melanins using different pathways, but vary in how they characterize the resulting substances. Also, biologists sometimes struggle with the exact definition of melanin, since many melanins extracted from different organisms have similar chemical and physical properties, but remain largely insoluble in most common solvents, and resist many types of chemical and physical analysis.

[0030] A frequently used chemical description of melanin is that it is comprised of "heteropolymers of 5-6-dihydroxyindole and 5-6-dihydroxyindole-2-carboxylic acid"(Bettinger et al., 2009).

[0031] Accordingly, it would be desirable to have lightweight melanin composite sound protection materials that are easy to fabricate into final components, at reasonable cost, yet still offer sound protection properties on par with heavier materials. Such materials would find ready use in a number of applications, including military, law enforcement, civilian; vehicle cladding especially cars and light transport vehicles; aircraft, such as jet and / or rotary wing aircraft; shipping containers, and other applications that are weight sensitive.

[0032] In addition, this disclosure relates to pharmaceutical compositions for, for example, oral administration to treat, for example, acute radiation sickness, wherein the composition comprises, for example, melanin, derivatives thereof, and pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

[0033] Most people who survive dangerous levels of radiation exposure but succumb to death several weeks afterwards die of bone marrow failure, and this is called the Hematopoietic Syndrome of the Acute Radiation Syndrome. Acute radiation syndrome (ARS), also known as radiation toxicity or radiation sickness, is an acute illness caused by irradiation of the entire body with a high dose of radiation over a short period of time. Because of differences in cell sensitivity to ionizing radiation, ARS is often divided into three components: Hematopoietic Syndrome, Gastrointestinal Syndrome, and Neurovascular Syndrome (DiCarlo, A. L., et al. 2011. Disaster Med Public Health Prep 5, Suppl 1, S32-44; and Hematopoietic Syndrome from Radiation.

[0034] US Centers for Disease Control www. bt . cdc . gov / radi ati on / arsphy si ci anfactsheet . asp) . Attorney Docket No.: 4774-0060W006

[0035] The hematopoietic stem and progenitor cells of the bone marrow are normally rapidly dividing, and are highly sensitive to the effects of ionizing radiation. Hematopoietic Syndrome will develop after about 2-8 Gray (Gy) total body irradiation, and typically results in death in a few weeks. (DiCarlo, A.L., et al. 2011. Disaster Med Public Health Prep 5, Suppl 1, S32-44. Hematopoietic Syndrome from Radiation. US Centers for Disease Control, www.bt.cdc.gov / radiation / arsphysicianfactsheet.asp). There are currently no approved antidotes. Death is primarily due to radiation damaging the bone marrow cells, which are unable to produce normal amounts of white cells, resulting usually in mortality from sepsis.

[0036] The present disclosure provides formulations and devices for the administration of melanin formulations which are novel and unique in that administration to the mouth results in rapid absorption similar to what would be achieved by intravenous injection, and can be accomplished by individuals with no medical training (e g., not a medic, pharmacist, nurse, nor physician) to severely injured or unconscious victims, even in a mass casualty situation.

[0037] Unlike potential injectable therapies for Hematopoietic Syndrome of Acute Radiation Syndrome, which would require the presence of trained medical personnel to administer the injection, the present disclosure is sufficiently simple in manufacture and administration that laymen with no medical training can administer the treatment to victims of radiation exposure, even to victims who are unconscious or unresponsive. The present disclosure can also, of course, be administered by those with medical training. Furthermore, this oral treatment is absorbed into the body and has therapeutic effect almost as quickly as an intravenous injection would. Radiation injured individuals could administer the treatment to themselves simply by putting it in their mouths and it does not require additional materials such as a drink to swallow. Patients who are incapacitated or unconscious could be given the treatment simply by the expedient method of someone placing this material in the mouth of the victim, without regard to placing the material in any specific parts of the mouth. Furthermore, while a single administration of the treatment will enhance the chances for reducing mortality and morbidity from radiation exposure, repeated administration of the compositions and methods of the disclosure is simple and would not result in any toxicity.

[0038] All references cited herein are incorporated herein by reference in their entireties. Attorney Docket No.: 4774-0060W006

[0039] BRIEF SUMMARY OF THE INVENTION

[0040] The disclosure provides a sound absorbing material formed using a composition comprising: melanin material; optionally, at least one additional non-melanin material selected from the group consisting of biological material, biological polymers, polymers, metals, radionuclides, iron, copper, zinc, cesium, radium, strontium, thorium, uranium, salts, ceramics, clothing, construction materials, existing cladding materials, poly-paraphenylene terephthalamide, and other natural materials or their synthetic mimics. The disclosure provides a sound absorbing material wherein the sound absorbing material is manufactured in a form selected from the group consisting of particles, nanoparticles, dust, beads, fibers that are woven, fibers that are non-woven, sheets, films, slabs, plates, bricks, chars, spheres, nodules, balls, graphite-like sheets and shards, liquids, gels, solids, thermoplastic solids, and thermoset solids. The disclosure provides a sound absorbing material wherein the non-melanin material is collagen. The disclosure provides a sound absorbing material wherein the non-melanin material is selected from the group consisting of a polyphenylene polymer, polyimides, polyetherimides, polyimideamides, polysulfones, epoxy resins, bismaleimide resins, bis-benzocyclobutene resins, phthalonitrile resins, polyaryletherketones, polyetherketones, liquid crystal polymers, oligomeric cyclic polyester precursors, polybenzbisoxazoles, polybenzbisthiazoles, polybenzbisimidazoles, acetylene endcapped thermosetting resins, polysulfones, polyaramides, Poly-paraphenylene terephthalamide, polyamides, polycarbonates, polyethylenes, polyesters, and combinations thereof. The disclosure provides a sound absorbing material wherein the non- melanin material is a ceramic material selected from the group consisting of alumina, boron carbide, boron nitride, mullite, silica, silicon carbide, silicon nitride, magnesium boride, multi- walled carbon nanotubes, single walled carbon nanotubes, group IVB, VB and VIB metal sulfide nanotubes, titanium boride, titanium carbide, diamond, and combinations thereof. The disclosure provides a sound absorbing material wherein the non-melanin material and the melanin material are present in a ratio selected from the group consisting of about 5 to 95, about 20 to 80, about 30 to 70, about 40 to 60, about 50 to 50, about 60 to 40 about 70 to 30 about 80 to 20, about 95 to 5 (percent by weight). The disclosure provides a sound absorbing material wherein the non-melanin material and the melanin material combine to synergistically increase the impact resistance of the sound absorbing material compared to the non- melanin materials and melanin material alone. The disclosure provides a sound absorbing material wherein the sound absorbing material is formed into an article which is Attorney Docket No.: 4774-0060W006 an item selected from the group consisting of helmets, headphones, vehicle cladding, aircraft cladding, watercraft cladding, structure cladding, equipment housing, blast protection panels, sound absorbing panels, and cargo containers.

[0041] The disclosure provides a process for forming a sound absorbing material comprising: mixing a melanin material; and optionally, at least one additional non-melanin material selected from the group consisting of polymers, metals, radionuclides, iron, copper, zinc, cesium, radium, strontium, thorium, uranium, salts, ceramics, clothing, construction materials, existing cladding materials, Poly-paraphenylene terephthalamide, other natural materials or their synthetic mimics; and shaping the resultant material into an article. The disclosure provides a process for forming a sound absorbing material wherein the sound absorbing material is manufactured in a form selected from the group consisting of particles, nanoparticles, dust, beads, fibers that are woven, fibers that are non-woven, sheets, films, plates, bricks, chars, spheres, nodules, balls, graphite-like sheets and shards, liquids, gels, solids, thermoplastic solids, and thermoset solids. The disclosure provides a process for forming a sound absorbing material wherein the step of shaping comprises using a technique selected from the group consisting of molding, compression molding, stamping, bending, thermoforming, injection molding, additive manufacturing, coining, and extruding. The disclosure provides a process for forming a sound absorbing material wherein the melanin material and the non-melanin material are mixed using a machine selected from the group consisting of a single screw extruder, a counter-rotating twin-screw extruder, a co-rotating twin-screw extruder, a Henschel mixer, and a co-kneader. The disclosure provides a process for forming a sound absorbing material wherein the non-melanin material is selected from the group consisting of a polyphenylene polymer, polyimides, polyetherimides, polyimideamides, polysulfones, epoxy resins, bismaleimide resins, bis-benzocyclobutene resins, phthalonitrile resins, polyaryletherketones, polyetherketones, liquid crystal polymers, oligomeric cyclic polyester precursors, polybenzbisoxazoles, polybenzbisthiazoles, polybenzbisimidazoles, acetylene endcapped thermosetting resins, polysulfones, polyaramides, Poly-paraphenylene terephthalamide, polyamides, polycarbonates, polyethylenes, polyesters, and combinations thereof. The disclosure provides a process for forming a sound absorbing material wherein the non-melanin material is a ceramic material selected from the group consisting of alumina, boron carbide, boron nitride, mullite, silica, silicon carbide, silicon nitride, magnesium boride, multiwalled carbon nanotubes, single walled carbon nanotubes, group IVB, VB and VIB metal sulfide Attorney Docket No.: 4774-0060W006 nanotubes, titanium boride, titanium carbide, diamond, and combinations thereof. The disclosure provides a process for forming a sound absorbing material wherein the sound absorbing material is formed into an article which is an item selected from the group consisting of helmets, headphones, fabric, vehicle cladding, aircraft cladding, watercraft cladding, structure cladding, equipment housing, blast protection panels, sound absorbing panels, and cargo containers.

[0042] The disclosure provides a composite material comprising: melanin material; optionally, at least one additional non-melanin material selected from the group consisting of polymers, metals, radionuclides, iron, copper, zinc, cesium, radium, strontium, thorium, uranium, salts, ceramics, clothing, construction materials, existing cladding materials, Poly-paraphenylene terephthalamide, and other natural materials or their synthetic mimics. The disclosure provides a composite material wherein the non-melanin material is manufactured as in a from selected from the group consisting of particles, nanoparticles, dust, beads, fibers that are woven, fibers that are non-woven, sheets, films, plates, bricks, chars, spheres, nodules, balls, graphite-like sheets and shards, liquids, gels, solids, thermoplastic solids, and thermoset solids. The disclosure provides a composite material wherein the additional non-melanin material is selected from the group consisting of a polyphenylene polymer, polyimides, polyetherimides, polyimideamides, polysulfones, epoxy resins, bismaleimide resins, bis-benzocyclobutene resins, phthalonitrile resins, polyaryletherketones, polyetherketones, liquid crystal polymers, oligomeric cyclic polyester precursors, polybenzbisoxazoles, polybenzbisthiazoles, polybenzbisimidazoles, acetylene endcapped thermosetting resins, polysulfones, polyaramides, Poly-paraphenylene terephthalamide, polyamides, polycarbonates, polyethylenes, polyesters, and combinations thereof. The disclosure provides a composite material wherein the non-melanin material is a ceramic material selected from the group consisting of alumina, boron carbide, boron nitride, mullite, silica, silicon carbide, silicon nitride, magnesium boride, multi- walled carbon nanotubes, single walled carbon nanotubes, group IVB, VB and VIB metal sulfide nanotubes, titanium boride, titanium carbide, diamond, and combinations thereof. The disclosure provides a composite material wherein the non-melanin material and the melanin material are present in a ratio selected from the group consisting of about 5 to 95, about 20 to 80, about 30 to 70, about 40 to 60, about 50 to 50, about 60 to 40 about 70 to 30 about 80 to 20, about 95 to 5 (percent by weight). The disclosure provides a composite material wherein the non-melanin material and the melanin material combine to synergistically increase the impact resistance of the sound absorbing material Attorney Docket No.: 4774-0060W006 compared to the non- melanin materials and melanin material alone. The disclosure provides a composite material wherein the material is formed into an article which is an item selected from the group consisting of helmets, fabric, vehicle cladding, aircraft cladding, watercraft cladding, structure cladding, equipment housing, blast protection panels, sound absorbing panels, and cargo containers. The disclosure provides a composite material wherein the polymer matrix is formed at least partially of a thermosetting resin. The disclosure provides a composite material wherein the non-melanin is formed at least partially of a thermoplastic. The disclosure provides a composite material wherein the non- melanin is formed at least partially of a polyarylene having one of either a rigid-rod or semi- rigid-rod structure where the structure is formed of a plurality of repeat units where 25% of the repeat units are rigid-rod repeat units having substantially parallel bonds. The disclosure provides a composite material wherein the non-melanin is formed of at least a polyphenylene polymer. The disclosure provides a composite material wherein non-melanin further comprises at least one other polymer independently selected from the group consisting of polyimides, polyetherimides, polyimideamides, polysulfones, epoxy resins, bismaleimide resins, bis- benzocyclobutene resins, phthalonitrile resins, polyaryletherketones, polyetherketones, liquid crystal polymers, oligomeric cyclic polyester precursors, polybenzbisoxazoles, polybenzbisthiazoles, polybenzbisimidazoles, acetylene endcapped thermosetting resins, polysulfones, polyaramides, Poly-paraphenylene terephthalamide, polyamides, polycarbonates, polyethylenes, and polyesters. The disclosure provides a composite material wherein the non- melanin material comprises one or more ceramic powders or particles selected from the group consisting of alumina, boron carbide, boron nitride, mullite, silica, silicon carbide, silicon nitride, magnesium boride, multi-walled carbon nanotubes, single walled carbon nanotubes, group IVB metal sulfide nanotubes, group VB metal sulfide nanotubes, group VIB metal sulfide nanotubes, titanium boride, titanium carbide and diamond. The disclosure provides a composite material further comprising at least one additive material selected from the group consisting of process aids, modifiers, colorants, fibers, adhesion promoters and fillers. The disclosure provides a composite material wherein the material is formed into an article which is an item selected from the group consisting of helmets, fabric, vehicle cladding, aircraft cladding, watercraft cladding, structure cladding, equipment housing, blast protection panels, sound absorbing panels and cargo containers. Attorney Docket No.: 4774-0060W006

[0043] The disclosure provides a process for forming a composite material comprising: mixing a melanin material; optionally, at least one additional non-melanin material selected from the group consisting of polymers, metals, radionuclides, iron, copper, zinc, cesium, radium, strontium, thorium, uranium, salts, ceramics, clothing, construction materials, existing cladding materials, Poly-paraphenylene terephthalamide, other natural materials or their synthetic mimics.; and shaping the composite material into an article. The disclosure provides a process for forming a composite material wherein the step of shaping comprises using a technique selected from the group consisting of molding, compression molding, stamping, bending, thermoforming, injection molding, additive manufacturing, coining, and extruding. The disclosure provides a process for forming a composite material wherein the melanin material and the non-melanin material are mixed using a machine selected from the group consisting of a single screw extruder, a counterrotating twin-screw extruder, a co-rotating twin-screw extruder, a Henschel mixer, and a cokneader. The disclosure provides a process for forming a composite material wherein the non- melanin material is selected from the group consisting of a polyphenylene polymer, polyimides, polyetherimides, polyimideamides, polysulfones, epoxy resins, bismaleimide resins, bis- benzocyclobutene resins, phthalonitrile resins, polyaryletherketones, polyetherketones, liquid crystal polymers, oligomeric cyclic polyester precursors, polybenzbisoxazoles, polybenzbisthiazoles, polybenzbisimidazoles, acetylene endcapped thermosetting resins, polysulfones, polyaramides, Poly-paraphenylene terephthalamide, polyamides, polycarbonates, polyethylenes, polyesters, and combinations thereof. The disclosure provides a process for forming a composite material wherein the non- melanin material is selected from the group consisting of alumina, boron carbide, boron nitride, mullite, silica, silicon carbide, silicon nitride, magnesium boride, multi-walled carbon nanotubes, single walled carbon nanotubes, group IVB, VB and VIB metal sulfide nanotubes, titanium boride, titanium carbide, diamond, and combinations thereof. The disclosure provides a process for forming a composite material wherein the non-melanin material and the melanin material are present in a ratio selected from the group consisting of about 5 to 95, about 20 to 80, about 30 to 70, about 40 to 60, about 50 to 50, about 60 to 40 about 70 to 30 about 80 to 20, about 95 to 5 (percent by weight). The disclosure provides a process for forming a composite material wherein the non-melanin material and the melanin material combine to synergistically increase the impact resistance of the sound absorbing material compared to the non- melanin materials and melanin material alone. The disclosure provides a process for forming a Attorney Docket No.: 4774-0060W006 composite material wherein the material is formed into an article which is an item selected from the group consisting of helmets, headphones, fabric, vehicle cladding, aircraft cladding, watercraft cladding, structure cladding, equipment housing, blast protection panels, sound absorbing panels, and cargo containers.

[0044] The disclosure provides a method of preparation of melanin material comprising: providing a melanin source selected from the group consisting of squid ink, cuttlefish ink, octopus ink, natural melanin, synthetic melanin, mushrooms, and combinations thereof; applying microwave radiation, thereby producing a melanin material.

[0045] The disclosure provides a method of preparation of melanin material comprising: providing a melanin source selected from the group consisting of squid ink, cuttlefish ink, octopus ink, natural melanin, synthetic melanin, mushrooms, and combinations thereof; applying microwave radiation; applying compression; thereby producing a melanin material. The disclosure provides a method wherein the compression is applied in a hydraulic press. The disclosure provides a method wherein the hydraulic press ranges in capacity from approximately 1 ton / in2 to 500 tons / in2, 1 ton / in2 to 50 tons / in2, 50 tons / in2 to 100 tons / in2, 1 ton / in2 to 100 tons / in2, 50 tons / in2 to 200 tons / in2, or 1 ton / in2 to 200 tons / in2.

[0046] The disclosure provides a pharmaceutical composition comprising: at least one melanin material; optionally, at least one additional pharmaceutically active agent; optionally, at least one additional pharmaceutically acceptable carrier, wherein the pharmaceutical composition is formulated or manufactured as a liquid, an elixir, an aerosol, a spray, a powder, a tablet, a pill, a capsule, a gel, a geltab, a nano-suspension, a nano-particle, an extended release dosage form, or a topical formulation, further wherein the pharmaceutical composition is a therapeutically effective for treating a condition in a patient.

[0047] The disclosure provides a process for making a pharmaceutical composition comprising: Providing at least one melanin material; Optionally providing at least one additional pharmaceutically active agent; Optionally providing at least one additional pharmaceutically acceptable carrier, Mixing the at least one melanin material, if present the at least one additional pharmaceutically active agent, and if present the at least one additional pharmaceutically acceptable carrier, thereby forming a pharmaceutical composition, further wherein the pharmaceutical composition is a therapeutically effective for treating a condition in a patient. Attorney Docket No.: 4774-0060W006

[0048] The disclosure provides a method of preparation of melanin material comprising: providing a melanin source selected from the group consisting of squid ink, cuttlefish ink, octopus ink, natural melanin, synthetic melanin, mushrooms, and combinations thereof; providing a metal selected from the group consisting of iron, copper, zinc, cesium, radium, strontium, thorium, uranium, and combinations thereof; applying microwave radiation to the melanin source to form a dried melanin source; mixing the metal with the dried melanin source; optionally, applying compression; thereby producing a melanin material. The disclosure provides a method wherein the compression is applied in a hydraulic press. The disclosure provides a method wherein the hydraulic press ranges in capacity from approximately 1 ton / in2 to 500 tons / in2, 1 ton / in2 to 50 tons / in2, 50 tons / in2 to 100 tons / in2, 1 ton / in2 to 100 tons / in2, 50 tons / in2 to 200 tons / in2, or 1 ton / in2 to 200 tons / in2.

[0049] The disclosure provides a pharmaceutical composition comprising: a therapeutically effective amount of an agent which is selected from the group consisting of melanin, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; and at least one pharmaceutically acceptable excipient. The disclosure provides a pharmaceutical composition wherein the composition is provided in a sublingual or buccal dosage form. The disclosure provides a pharmaceutical composition wherein the composition comprises a pharmaceutically acceptable excipient selected from the group consisting of buffer, preservative, isotonic agent, an antioxidant, and combinations thereof. The disclosure provides a pharmaceutical 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 disclosure provides a pharmaceutical composition wherein the composition comprises the agent in a dose from about 10 mg to about 450 mg.

[0050] The disclosure provides a pharmaceutical composition wherein the agent is present in an amount of from 2% to 50% of the total weight of the composition. The disclosure provides a pharmaceutical composition wherein the agent is present in an amount of from 25% to 30% of the total weight of the composition. The disclosure provides a pharmaceutical composition wherein said agent is melanin and the therapeutically effective amount of melanin comprises at least about 75 mg to about 450 mg. The disclosure provides a pharmaceutical composition wherein said therapeutically effective amount of melanin comprises about 240 mg. The disclosure provides a Attorney Docket No.: 4774-0060W006 pharmaceutical 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 disclosure provides a method for the treatment or prevention of acute radiation syndrome (ARS) in a subject in need thereof comprising: administering the composition to the subject, wherein the administration of the composition treats or prevents ARS in the subject. The disclosure provides a method wherein the pharmaceutical composition is administered transmucosally through sublingual or buccal routes of delivery. The disclosure provides a method wherein the oral mucosal membrane is selected from the group consisting of buccal, sublingual, and combinations thereof. The disclosure provides a method wherein said agent is melanin and the therapeutically effective amount of melanin comprises at least about 75 mg to about 450 mg. The disclosure provides a method wherein said therapeutically effective amount of melanin comprises about 240 mg. The disclosure provides a method wherein the composition comprises the agent in a dose from about 10 mg to about 450 mg. The disclosure provides a method wherein the agent is melanin and the 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.

[0051] The disclosure provides a kit for the treatment, amelioration or prevention of a condition selected from the group consisting of acute radiation syndrome (ARS), in a patient in need thereof comprising: (a) the composition; and (b) at least one blister package; a lidded blister; a blister card or packet; a clamshell; an intravenous (IV) package, IV packette or IV container; a bottle; a metal tube; a laminate tube; a plastic tube; a dispenser; a pressurized container; a barrier container; a package; a tray or a shrink wrap, comprising the pharmaceutical composition of (a) and instructions for use of the composition.

[0052] The disclosure provides a product of manufacture comprising a blister package; a lidded blister; a blister card or packet; a clamshell; an intravenous (IV) package, IV packette or IV container; a bottle; a metal tube; a laminate tube; a plastic tube; a dispenser; a pressurized container; a barrier container; a package; a tray or a shrink wrap comprising the composition and instructions for use of the composition.

[0053] The disclosure provides a method of producing a composition for use in mucosal delivery, the method comprising: providing a therapeutically effective amount of an agent which is selected Attorney Docket No.: 4774-0060W006 from the group consisting of melanin, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; providing at least one pharmaceutically acceptable excipient; and mixing the agent, and at least one pharmaceutically acceptable excipient to thereby produce the composition. The disclosure provides a wherein the composition is provided in a sublingual or buccal dosage form. The disclosure provides a wherein the composition comprises a pharmaceutically acceptable excipient selected from the group consisting of buffer, preservative, isotonic agent, an antioxidant, and combinations thereof. The disclosure provides a 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 disclosure provides a wherein said agent is melanin and the therapeutically effective amount of melanin comprises at least about 75 mg to about 450 mg. The disclosure provides a wherein said therapeutically effective amount of melanin comprises about 240 mg. The disclosure provides a 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.

[0054] The disclosure provides a sound absorbing material wherein the sound absorbing material converts sound energy to electrical energy. The disclosure provides a process wherein the sound absorbing material converts sound energy to electrical energy. The disclosure provides a composite material wherein the composite material converts sound energy to electrical energy. The disclosure provides a process wherein the composite material converts sound energy to electrical energy. The disclosure provides a process wherein the composite material converts sound energy to electrical energy. The disclosure provides a method wherein the melanin material converts sound energy to electrical energy.

[0055] BRIEF DESCRIPTION OF SEVERAL VIEWS OF THE DRAWINGS

[0056] The invention will be described in conjunction with the following drawings in which like reference numerals designate like elements and wherein:

[0057] Figure 1 is chemical structure of pure melanin.

[0058] Figure 2A is a chemical structure showing the chemical bonding of melanin with Silver.

[0059] Figure 2B is a chemical structure showing the chemical bonding of melanin with Lead. Attorney Docket No.: 4774-0060W006

[0060] Figure 2C is a chemical structure showing the chemical bonding of melanin with Bismuth.

[0061] Figure 3 is a chemical structure showing the chemical bonding of melanin with Bismuth.

[0062] DETAILED DESCRIPTION OF THE INVENTION

[0063] 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.

[0064] 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.

[0065] In carrying out the method of the present disclosure, the composition of the disclosure may be administered to mammalian species, such as dogs, cats, humans, etc. and as such may be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable. The dosage forms may also include the necessary carrier material, excipient, lubricant, buffer, antibacterial, bulking agent, anti-oxidants, or the like.

[0066] The terms "treating" and "treatment" used to refer to treatment of a condition in a subject includes: preventing, inhibiting or ameliorating the condition in a subject, such as slowing progression of the condition and / or reducing or ameliorating a sign or symptom of the condition; and preventing, inhibiting or ameliorating a side-effect of a condition in a subject.

[0067] "Patient" for the purposes of the present disclosure includes humans and other animals, particularly mammals. Thus the compositions and methods are applicable to both human therapy and veterinary applications. In certain embodiments the subject is a mammal, and in a preferred embodiment the subject is human.

[0068] "Pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary use as well as human pharmaceutical use. 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, Attorney Docket No.: 4774-0060W006 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.

[0069] Compositions of the disclosure include pharmaceutical compositions for oral administration to treat, for example, acute radiation sickness. The formulation will optimally reduce mortality and morbidity if administered within 72 hours of severe radiation exposure, and most optimally within 24 hours.

[0070] The systems and methods of the present disclosure takes advantage of the structure and reactivity of melanin to create novel composite materials with unexpected and useful properties, for example, high absorption of sound and x-rays, unusually light but hard, able to conduct electricity, able to exhibit semiconductor behavior such as switching and memory.

[0071] The bismuth-melanin composite, as an exemplary disclosure, is believed to be one where each bismuth atom binds to at least three oxygens in melanin, and is the basis of a family of new materials, whereby ions additional to bismuth, usually lighter and more conductive than bismuth, such as iron and copper, are incorporated, conferring enhanced sound absorption, hardness, radiation absorption and electrical properties such as conductivity, switching and memory.

[0072] Similarly, iron-melanin and copper-melanin, as examples, are each the basis of new families of materials. For example, Meredith and Sarna, 2006 points out that depending on the pH of synthesis, copper ions can bind to different functional groups in melanin. Extracts from Meredith and Sarna's's summary are: "1. At pH < 7, binding of cupric ions in eumelanin is to monodentate carboxyl groups and bidentate nitrogen-carboxyl groups ... 2. At pH 7 and above, binding is to bidentate hydroxyl (phenolic hydroxyl groups) and tri- or even tetradentate oxygen and nitrogen complexes of various types... 3. At pH 32.6, a totally new Cu(n)-melanin ESR spectrum is detected suggesting formation of a complex consisting of: two nitrogen and two oxygen ligands with the electric charge -2, three nitrogen and one oxygen ligands (the electric charge -2), or five nitrogen ligands (the electric charge either 0 or -1)...."

[0073] The systems and methods of the present disclosure has expanded in a novel direction understanding of the flexibility of melanin's reactivity to create new and useful composites, e.g., of copper melanin and bismuth-melanin, to absorb sound, etc. Parameters of synthesis, such as Attorney Docket No.: 4774-0060W006 temperature, pH, length of time for particular reagents to be in contact, and sequence of adding different ion types, are explored and controlled to optimize specific characteristics and useful functions such as sound absorption, electrical conductivity, etc.

[0074] Furthermore, the systems and methods of the present disclosure shows the practicality of using washed melanin extracted from cephalopods such as cuttlefish, which is potentially more abundantly available and relative inexpensive compared to synthetic melanin, organismic-derived melanin created in bioreactors, or melanin extracted from plant or other animal sources which often are reported to require complex chemical or enzymatic purifications.

[0075] Melanins

[0076] The melanins comprise a family of biopolymer pigments. A frequently used chemical description of melanin is that it is comprised of “heteropolymers 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, butnot 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.

[0077] 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.

[0078] 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 Attorney Docket No.: 4774-0060W006 otherwise. The term “melanin4ike” also refers to hydrogels with melanin-like pigmentation and quinoid electrophilicity. This electrophilicity can be exploited for facile coupling with biomolecules.

[0079] 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.

[0080] 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., Ann. N.Y. Acad. Sci. 507, 289 (1987), which enables the melanin to cross the bloodbrain barrier. The term melanin derivatives is also intended to include chemical derivatives of melanin, such as an esterified melanin.

[0081] 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:

[0082] (1) Naturally occurring melanins produced by whole cells that vary in their chemical and physical characteristics;

[0083] (2) Enzymatically produced melanins prepared from a variety of precursor substrates under diverse reaction conditions;

[0084] (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

[0085] (4) Melanin derivatives in which a substituent in a melanin produced in (1), (2) or

[0086] (3) above is further altered by chemical or enzymatic means.

[0087] 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.

[0088] Melanin Sources Attorney Docket No.: 4774-0060W006

[0089] Melanin and Melanindike compounds can be obtained:

[0090] -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);

[0091] -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);

[0092] -by electrochemical synthesis, e.g. (Meredith et al., 2005);

[0093] -by bioreactors created by utilization of natural or genetically altered bacteria, fungi, lichens, or viruses e.g.(della-Cioppa , 1998).

[0094] Melanin Manufacturing and Fabrication

[0095] 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.

[0096] 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.

[0097] The following procedure describes an exemplary technique for the extraction of melanin from cuttlefish (Sepia Officinalis). 100 gm of crude melanin are dissected from the ink sac of 10 cuttlefish and washed with distilled water (3x 100 ml). The melanin is collected after each wash by centrifugation (200xg for 30 minutes). The melanin granules are then stirred in 800 ml of 8M 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% Attorney Docket No.: 4774-0060W006 aqueous DMF (5x400 ml) until a constant UV baseline is achieved from the washes. Finally, the pellet is washed with acetone (3x400 ml) and allowed to air dry.

[0098] 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.

[0099] 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-dihydroxybenzylamine, 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 disclosure. Combinations of precursors can also be used.

[0100] 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 just by bubbling oxygen through a solution of a precursor for an adequate period of time.

[0101] Melanin material may be obtained by treatment of, e.g, cuttlefish ink or squid ink in a microwave, optionally with mixing. The inventor has found that microwaving can be used for the preparation of melanin formulations. For example, it was found that drying melanin in a microwave oven made possible the preparation of large amount of melanin from cuttlefish ink in a very short period of time. In an exemplary embodiment, cuttlefish ink was placed at 40°C in a conventional oven and required 18 days to reduce the material to 40% of its original weight. In a 900 watt microwave oven, the same degree of drying was achieved in 12 minutes. The disclosure provides a method for formulation of melanin by applying a hydraulic press to melanin partially Attorney Docket No.: 4774-0060W006 dried in a microwave oven. In exemplary embodiments, hydraulic presses for this use may range in capacity from, for example, about 1 ton / sq. in. to about 500 tons / sq2 approximately. In an exemplary embodiment, commercial cuttlefish ink was dried in a 900 watt microwave oven so that the product was 30% or 35% of the initial weight. Ablender was used to mix and grind the melanin. A variety of formulations were made. In one formulation, the 30% preparation was mixed with 7% iron filings, and then the blender was used to mix again. In another formulation, 35% slabs were alternated with 30% slabs to create a layered composite. Each formulation was subjected to compression in a 20 ton / in2 hydraulic press for about 20 minutes. Because the platen was approximately 3.5 in2, it is estimated that a force of approximately 3265 pounds / sq. in. was exerted on each sample formulation. The simplest situation is when a force of 1000 pounds is exerted on 1 square inch of material, resulting in 1000 psi. If a force of 1000 pounds is exerted on 4 square inches of material, this results in 250 psi. If a force of 1000 pounds is exerted on 16 square inches of material, this results in 62.5 psi. If a force of 10,000 pounds is exerted on 16 square inches of material, this results in 625 psi.

[0102] The disclosure provides for the use of formulations of melanin produced by, for example, microwaving and hydraulic press compression to produce a sound absorbing material.

[0103] The disclosure provides for the use of elemental metals mixed with melanin to create new formulations of melanin with novel properties. The metals may be, for example, iron, copper, zinc, cesium, radium, strontium, thorium, uranium, or combinations thereof. In an exemplary embodiment, elemental iron was mixed with melanin in the form of dried cuttlefish ink resulted in unexpected hardness of the material while it remains somewhat flexible. Under scanning electron microscopy it was demonstrated that the new formulation of melanin had organized into stacks of lamellae, which appeared to be composed of melanosomes. This is an entirely novel finding since, although metal ions are known to bind to the melanin, it does not appear that anyone has experimented with or reported that elemental iron can bind. This new disclosure is based on the finding that iron and other elemental metals including, for example, copper, zinc, cesium, radium, strontium, thorium, or uranium, can bind to melanin and organize it in novel ways which confer upon it new properties. For instance, the new properties conferred will include enhanced hardness, stiffness, impact resistance, electrical conductivity, capacitance, semiconductor properties, and enhanced ability to absorb radiation including x-ray and gamma ray. Attorney Docket No.: 4774-0060W006

[0104] In an exemplary embodiment, cuttlefish ink was dried using a microwave oven to 40% of its original weight. Iron filings were added so that they comprised 0.5% of the final formulation. The material felt harder than a similar sample without the 0.5% iron filings.

[0105] Scanning electron microscopy revealed multiple areas where sharply defined lamellae with 90° comer angles were seen in stacks.

[0106] In some embodiments, melanins are incorporated into other materials and used for many useful applications, such as:

[0107] 1. Melanin and melanindike compounds can be incorporated into: polymers, metals, salts, ceramics of many types, clothing, construction materials, existing armor materials including Kevlar and ceramics, other natural materials or their synthetic mimics, materials for implantation into human or mammalian living beings.

[0108] 2. A small percentage of melanin confers new or improved properties on resultant material: Another aspect of the present disclosure is that small amounts of melanin and of melanin-like substances will impart to a mixture of melanin with other substances, such as a matrix or polymer, properties which are unexpected. Generally, 1 to 5% of melanin will impart desired properties to a mixture or composite, whereas small incremental improvement in properties will be gained by increasing up to 35%. Examples of such unexpected properties are resistance to ultraviolet light, radiation, heat, flame, chemical agents and toxins, biological agents and toxins, and to abrasion.

[0109] 3. Hydration effects and control: It is another aspect of the present disclosure that the control and maintenance of hydration of melanin and melanin like substances (or non-water solvent or matrix concentration for melanins made from organic solvents) is critical for the applications described above, including armor and shielding. Published research describes the effect of hydration on electrical conductivity, and on the ability to absorb radiation from the electromagnetic spectrum. The present disclosure includes the aspect that when melanin or melanin-like substances are extracted or synthesized, manufactured or fabricated, incorporated in any way with other substances, whether by mixtures, impregnation, layering, compositing, that control and maintenance of desired levels of hydration (and non-water solvent concentration for melanins made from organic solvents) may be critical to achieving and preserving the desired combination of properties. Much of the published research on melanin in the biological, chemical, Attorney Docket No.: 4774-0060W006 physics, and electronics literature reports work done using commercially available melanin from Sigma-Aldrich Corp. (St. Louis, Missouri) which is prepared using lyophilization, thus dehydrating it. The present disclosure includes recognition that for the purposes set forth in this disclosure, such as armor and shielding, hydration and control of hydration may be critical for the properties desired in the final material, and the use of highly desiccated or lyophilized melanin may in many instances be undesirable. However, in certain aspects of the disclosure, desiccated or lyophilized melanin may be appropriate.

[0110] 4. Oxygenation effects and control: It is another aspect of the present disclosure that the control and maintenance of oxygenation, or of lack of access to oxygen, by incorporating melanin into materials that control this factor, or by restricting use to environments that control or restrict this factor, may be critical for certain characteristics to be achieved for shielding, armor, flame retardancy, heat resistance, and cold resistance.

[0111] 5. Incorporation methods for melanin into other materials includes, for example: mixtures, covalent or non-covalent binding, printing, stamping, electrochemical deposition, metallic salt binding, adhering, and layering in composites.

[0112] Composites

[0113] Process aids and modifiers are materials commonly used to facilitate polymer fabrication, to help compatibilize the mixture of polymers, ceramics, and other additives, and the like, to increase fire resistance, or to modify other properties, other than primary sound absorbing properties. Any of these material that are desirable for fabricating or using the new lightweight sound absorbing materials may be incorporated into the current disclosure, including but not limited to materials such as silicones, phthalates, bromides, and the like.

[0114] Other additives, present in amounts not exceeding 10% by weight, if any, may also be included. These materials may include, but are not limited to adhesion aides, colorants, fibers (carbon, polyaramid, polyethylene, etc.), fillers (talc, sand, microballoons) that further serve to modify the process-ability, stability, durability, or appearance of the objective sound absorbing materials.

[0115] Any suitable ceramic materials may be used in the composite composition in accordance with the current disclosure. In one embodiment the ceramic powders or particles may be selected Attorney Docket No.: 4774-0060W006 from the group consisting of alumina, boron carbide, boron nitride, mullite, silica, silicon carbide, silicon nitride, magnesium boride, multi-walled carbon nanotubes, single walled carbon nanotubes, group IVB, VB and VIB metal sulfide nanotubes, titanium boride, titanium carbide, and diamond.

[0116] The current disclosure is also directed to methods of preparing sound absorbing materials. In one embodiment, the sound absorbing material is formed by a simple process of mixing the starting materials without melt processing prior to the final molding step. This simplifies the processing, as it is not necessary to undertake the possibly complicated step of melt processing with its accompanying difficulties in dispersion and equipment wear.

[0117] Although such a simple mixing process may be used, other processes for forming the sound absorbing material of the current disclosure can also be utilized. These include melt compounding, in which the ceramic and the polymer are intimately mixed while the polymer is in the molten state. In this embodiment the mixing can be done in any suitable standard machinery such as single and twin-screw extruders (both co- and counter-rotating), Henschel mixers, co-kneaders, etc. An additional technique that can be used is solvent mixing in which the ceramic and the polymer are mixed while the polymer is dissolved in the appropriate solvent. In such an embodiment any suitable solvent may be utilized.

[0118] The current disclosure is also directed to articles made with the sound absorbing material in accordance with the above processes. Sound absorbing materials of the present disclosure may be fabricated into any suitable article, including but not limited to sheets, slabs, disks, or more complex shapes, of varying thicknesses and sizes.

[0119] Using such construction techniques, the sound absorbing materials of the present disclosure may be used together with other materials, including but not limited to woven fabrics (such as but not limited to polyaramid or polyethylene fabrics), metals, ceramics, and the like to form sound absorbing articles, such as, for example, helmets, headphones, sheets, or panels. In another example, fabric using the inventive material may be fabricated by first forming a woven fiber vest containing pockets then sewing flat or curved panels or tiles comprising the composite into the pockets. The sheets or panels may also be incorporated into a number of embodiments, such as, for example, panels for covering vehicles, aircraft, and watercraft like cars, trucks, vans, personnel carriers, limousines, trailers, helicopters, cargo planes, rail cars, boats and ships; blast / sound Attorney Docket No.: 4774-0060W006 absorbing for small buildings, especially military command posts and mobile headquarters; sound absorbing for cargo containers; sound absorbing for equipment housing, such as, for example, computers, communications equipment; and generally mobile or stationary sound protection panels. In exemplary embodiments, the sound absorbing material of the disclosure is formed into an article which is an item selected from the group consisting of, for example, helmets, headphones, fabric, vehicle cladding, aircraft cladding, watercraft cladding, structure cladding, equipment housing, blast protection panels, sound absorbing panels, and cargo containers. In exemplary embodiments, the sound absorbing material of the disclosure is formed into a from selected from the group consisting of, for examples, particles, nanoparticles, dust, beads, fibers that are woven, fibers that are non-woven, sheets, films, plates, bricks, chars, spheres, nodules, balls, graphitedike sheets and shards, liquids, gels, solids, thermoplastic solids, and thermoset solids.

[0120] In an embodiment, a structure is provided. The structure includes bonded alternating layers of at least a melanin material and at least one of a fibrous sheet, a plastic sheet, a plastic plate, a ceramic sheet, a ceramic plate, and a multilayer ply, the multilayer ply comprising multiple fibrous sheets bonded together.

[0121] In another embodiment, a structure is provided. The structure includes alternating layers of melanin material wherein said layers are bonded to each other.

[0122] In another embodiment, a structure is provided. The structure includes alternating layers of melanin material wherein said layers are joined to each other by an array of oriented nanostructures.

[0123] In yet another embodiment, a method for fabricating a melanin composite is provided.

[0124] The method includes providing a first layer, the layer comprising at least a fibrous sheet or a multilayer laminate; applying a second layer to the first layer, the layer comprising an melanin material; applying a third layer to the second layer, the layer comprising another fibrous sheet or multilayer laminate; bonding or joining the first layer to the second layer; and bonding or joining the second layer to the third layer.

[0125] In another embodiment, a method for fabricating a melanin composite is provided. The method includes providing a first layer, the layer comprising at least a fibrous sheet or a multilayer Attorney Docket No.: 4774-0060W006 laminate; applying a second layer to the first layer, the layer comprising a liquid- phase gel precursor; applying a third layer to the second layer, the layer comprising another fibrous sheet or multilayer laminate; bonding or joining the first layer to the second layer; and bonding or joining the second layer to the third layer.

[0126] In yet another embodiment, a method for fabricating a melanin composite is provided. The method includes providing two layers of melanin material, and bonding the two layers together.

[0127] In another embodiment, a method for fabricating a melanin composite is provided. The method includes providing a liquid-phase; forming a gel from the liquid-phase precursor; and optionally forming a second gel in contact with the first gel.

[0128] In an embodiment, a composition is provided. The composition includes melanin and nonmelanin material, and embedding the melanin material within the non-melanin material. Biological Polymers

[0129] The term “biological polymer” according to the disclosure, it is understood collagen and its derivatives, hyaluronic acid, its salts and its derivatives, alginates, synthetic polymers, elastin and biological polymers, and mixtures thereof. Preferably, the biological polymer may comprises compounds chosen from collagen, collagen of porcine origin, collagen of bovine origin, crosslinked collagens, hyaluronic acid, its salts and its derivatives, lactic acid polymers, methacrylate derivatives, calcium phosphate derivatives, polyacrylamides, polyurethanes, polyalkylimide gels, polyvinyl microspheres, silicones, silica (SiO2) polymers, and mixtures thereof.

[0130] Collagen is a fibrous protein, of approximately 300 kDa, which makes up the connective tissue in the animal kingdom. It may be of human or nonhuman origin, in particular of porcine or bovine origin. Collagen derivatives include, inter alia, crosslinked collagens.

[0131] The composites of the disclosure may be formed from a wide variety of polymers, including natural polymers such as carboxylmethylcellulose, cellulose acetate phthalate, ethylcellulose, methylcellulose, arabinogalactan, nitrocellulose, propylhydroxycellulose, and succinylated gelatin; and synthetic polymers such as polyvinyl alcohol, polyethylene, polypropylene, polystyrene, polyacrylamide, polyether, polyester, polyamide, polyurea, epoxy, ethylene vinyl acetate copolymer, polyvinylidene chloride, polyvinyl chloride, polyacrylate, Attorney Docket No.: 4774-0060W006 polyacrylonitrile, chlorinated polyethylene, acetal copolymer, polyurethane, polyvinyl pyrrolidone, poly(p-xylene), polymethylmethacrylate, polyvinyl acetate, polyhydroxyethyl methacrylate, and combinations thereof.

[0132] Utility and Characteristics

[0133] The following characteristics and functions for sound absorbing shielding and other applications can be achieved, in almost infinite variety of degrees and combinations:

[0134] An object to which the shock and sound absorbing material of the disclosure is installed includes, for example, a car such as passenger car, bus, or the like, home electrical appliances such as air-conditioning equipment, refrigerator, washing machine, or the like, electrical appliances such as personal computer (PC), items relating to the civil engineering field, such as items relating to roads, like expressway, motor way, general road, tunnel, or the like, and items relating to the railway like a train, sleeping car, or the like, items relating to the construction field such as house, apartment, school, station building, reinforced building, or the like, and items relating to vessels such as ferry, boat, or the like.

[0135] In the case where a vehicle is the object, the shock and sound absorbing material of the disclosure can be installed in or applied to the, for example, engine cover components such as engine head cover, engine under cover, or the like, car equipment cover components such as transmission cover, differential gear cover, motor cover or invertor cover equipped in hybrid or the electric cars, or the like, interior finishing materials such as head lining, door trim, floor mat or floor panel, seat, rear package tray, or the like, car exterior materials such as front hood, wind pressure cover, fender liner, or the like, exterior panels such as floor under panel, door panel, bonnet hood, trunk room hood, roof panel, or the like, with other possible objects or places being such as chassis frame, the space inside or outside of the reinforcement, intake duct, inside of surge tank, inside of exhaust pipe muffler, inside of tire housing, inside of tire, tire wheel, or the like.

[0136] In the case of the cover components, interior finishing materials, exterior materials, or the like, said cover panel may be a synthetic resin panel, and in the case of exterior panels, a chassis frame, or the like, said cover panel may be a metal panel.

[0137] Further, in the case of a vehicle, engine noise, road noise, exhaust noise, or the like may 1 Attorney Docket No.: 4774-0060W006 be the noise, requiring reduction.

[0138] In a case where the object to which the shock and sound absorbing material of the disclosure is to be installed is an electrical appliance, the noise source may be, for example, a compressor, motor, fans such as cooling fan, intake fan, exhaust fan, or the like, the outer panel of said consumer electrical appliances, or the like may be said cover panel.

[0139] In the case where the object to which the shock and sound absorbing material of the disclosure is to be installed relates to civil engineering field or building field, said shock and sound absorbing material may be installed on / in or applied to the following articles.

[0140] The disclosure provides a sound proof wall, for example, for a road, the surface of a tunnel wall, the casing of air-conditioner or a dynamo, the under surface of an elevated bridge or road, a room partition, wall, ceiling, wall surface of the floor of a building, the wall or roof of an underground shopping mall, or hall or football ground, a railroad train, surface of the wall of the railway, an aircraft, a ship, a heavy machine, an agricultural machine, a machine tool, or the like.

[0141] The disclosure provides a sound proof wall, for example, for an object laid under the road, a wall material, a building material, a case panel, or the like correspond to said cover panel. Further, as for said articles, the culprit noise may be driving sound of a car, a vibrational sound, driving motor sound, engine sound, mechanical sound, echoing sound, chafing sound, or the like.

[0142] The present disclosure relates to an acoustic and thermally absorbent composite material that is formed of the composition of the disclosure plus reinforcement fibers, acoustical enhancing fibers such as polyethylene terephthalate (PET) fibers or modified polyethylene terephthalate fibers, and one or more organic fibers. The composite material may be utilized in numerous structural applications such as in automobiles (head liners, hood liners, floor liners, trim panels, parcel shelves, vehicle sunshades, instrument panel structures, door inners, and the like), and in wall panels and roof panels of recreational vehicles (RV's) as well as in a number of non-structural acoustical applications such as in kitchen appliances, in office screens and partitions, in ceiling tiles, in building panels, and in basement finishing systems.

[0143] The reinforcement fibers utilized in the composite material may be any type of organic or inorganic fiber suitable for providing good structural qualities as well as good acoustical and Attorney Docket No.: 4774-0060W006 thermal properties. Non-limiting examples of reinforcement fibers that may be utilized in the composite material include glass fibers, wool glass fibers, natural fibers, metal fibers, ceramic fibers, mineral fibers, carbon fibers, graphite fibers, nanofibers, and combinations thereof. The term "natural fiber" as used in conjunction with the present disclosure refers to plant fibers extracted from any part of a plant, including, but not limited to, the stem, seeds, leaves, roots, or bast. In the composite material, the reinforcement fibers may have the same or different lengths, diameters, and / or denier. Preferably, the reinforcing fiber material is glass fibers.

[0144] The reinforcement fibers utilized in the composite material may have a length of from approximately 10-100 mm in length, and even more preferably, a length of from 25-50 mm.

[0145] Additionally, the reinforcing fibers may have diameters of from 11-25 microns, and preferably have diameters of from 12-18 microns. The reinforcing fibers may have varying lengths (aspect ratios) and diameters from each other within the composite material. The reinforcing fibers may be present in the composite material in an amount of from 20-60% by weight of the total fibers, and are preferably present in the composite material in an amount of from 30-50% by weight.

[0146] In addition, the composite material includes at least one acoustical enhancing fiber. The acoustical enhancing fiber may be any fiber that provides increased or enhanced acoustical absorbance, particularly at lower frequencies, such as, for example, frequencies below approximately 2000 Hz. Non-limiting examples of such fibers include polyethylene terephthalate (PET) fibers and modified polyethylene terephthalate fibers (such as poly 1,4 cyclohexanedimethyl terephthalate, glycol modified polyethylene terephthalate), cotton and jute fibers (cellulosic and natural), glass fibers, and polyurethane foam. Preferably, the acoustical enhancement fibers are polyethylene terephthalate fibers or modified polyethylene terephthalate fibers. The acoustical enhancing fibers may have different denier and fiber lengths to provide increased sound absorption. The acoustical enhancing fibers utilized in the composite material may have a length of from approximately 6-75 mm in length, and preferably have a length of from 18- 50 mm. In addition, the acoustical enhancing fibers may have a denier from approximately 1.5-30 denier, preferably from 1.5-6 denier. The acoustical enhancing fibers may present in the composite Attorney Docket No.: 4774-0060W006 material in an amount of from 30-70% by weight of the total fibers, and are preferably present in an amount of from 30-40% by weight.

[0147] Additionally, the composite material includes at least one organic fiber. The organic fibers present in the composite material may include polymer based thermoplastic fibers such as, but not limited to, polyester fibers, polyethylene fibers, polypropylene fibers, polyethylene terephthalate (PET) fibers, polyphenylene sulfide (PPS) fibers, polyvinyl chloride (PVC) fibers, ethylene vinyl acetate / vinyl chloride (EVA / VC) fibers, lower alkyl acrylate polymer fibers, acrylonitrile polymer fibers, partially hydrolyzed polyvinyl acetate fibers, polyvinyl alcohol fibers, polyvinyl pyrrolidone fibers, styrene acrylate fibers, polyolefins, polyamides, polysulfides, polycarbonates, rayon, nylon and butadiene copolymers such as styrene / butadiene rubber (SBR) and butadiene / acrylonitrile rubber (NBR). The organic fibers may be functionalized with acidic groups, for example, by carboxylating with an acid such as a maleated acid or an acrylic acid, or the polymer fibers may be functionalized by adding an anhydride group or vinyl acetate. The organic fibers may alternatively be in the form of a flake, granule, or a powder rather than in the form of a polymer fiber. In some embodiments, a resin in the form of a flake, granule, and / or a powder is added in addition to the organic fibers.

[0148] One or more types of organic fibers may be present in the composite material. The specific combination of the types of organic fibers present in the composite material will vary to meet the specific acoustical requirements of a particular application. The organic fibers present in the composite material may have the same or different lengths, diameters, and / or denier. For example, the organic fibers of the composite material may include a single polymeric fibrous material (such as polypropylene) in which the polymer fibers have different lengths, diameters, and / or denier. As another example, the organic fibers present in the composite material may include two or more different polymeric fibrous materials, and each of the polymers may have the same lengths and / or diameters and / or denier, or, alternatively, the polymers may have different lengths and / or diameters and / or denier. The acoustical behavior of the composite material may be fine-tuned by altering the lengths and denier of the organic polymer fibers. In addition, the ratio of the different organic fibers present in the composite material can be varied to achieve specific acoustic properties.

[0149] The organic fibers may have a length of from approximately 6-75 mm, and preferably have a length of from 18-50 mm. Additionally, the organic fibers may have a denier of from 2- 30 Attorney Docket No.: 4774-0060W006 denier, preferably from 2-18 denier, and more preferably, from 3-7 denier. The organic fibers present in the composite material may have varying lengths and diameters, depending on the desired acoustical characteristics of the composite material. The polymer fibers may be present in the composite material in an amount of from 10-50% by weight of the total fibers, and are preferably present in an amount of from 10-30% by weight.

[0150] One or more of the organic fibers may be a multicomponent fibers such as bicomponent polymer fibers, tricomponent fibers, or plastic-coated mineral fibers such as thermoplastic coated glass fibers. The bicomponent fibers may be arranged in a sheath-core, side-by-side, islands-in- the-sea, or segmented-pie arrangement. Preferably, the bicomponent fibers are formed in a sheathcore arrangement in which the sheath is formed of first polymer fibers which substantially surround the core formed of second polymer fibers. It is not required that the sheath fibers totally surround the core fibers. The first polymer fibers have a melting point lower than the melting point of the second polymer fibers so that upon heating the bicomponent fibers, the first and second polymer fibers react differently. In particular, when the bicomponent fibers are heated to a temperature that is above the melting point of the first polymer fibers (sheath fibers) and below the melting point of the second polymer fibers (core fibers), the first polymer fibers will soften or melt while the second polymer fibers remain intact. This softening of the first polymer fibers (sheath fibers) will cause the first polymer fibers to become sticky and bond the first polymer fibers to themselves and other fibers that may be in close proximity.

[0151] Numerous combinations of materials can be used to make the bicomponent polymer fibers, such as, but not limited to, combinations using polyester, polypropylene, polysulfide, polyolefin, and polyethylene fibers. Specific polymer combinations for the bicomponent fibers include polyethylene terephthalate / polypropylene, polyethylene terephthalate / polyethylene, and polypropylene / polyethylene. Other non-limiting bicomponent fiber examples include copolyester polyethylene terephthalate / polyethylene terephthalate (coPET / PET), poly 1,4 cyclohexanedimethyl terephthalate / polypropylene (PCT / PP), high density polyethylene / polyethylene terephthalate (HDPE / PET), high density polyethylene / polypropylene (HDPE / PP), linear low density polyethylene / polyethylene terephthalate (LLDPE / PET), nylon 6 / nylon 6,6 (PA6 / PA6,6), and glycol modified polyethylene terephthalate / polyethylene terephthalate (6PETg / PET). Attorney Docket No.: 4774-0060W006

[0152] The bicomponent polymer fibers may have a length of from 2-4 mm and a denier in the range of approximately 1-18 denier. It is preferred that the first polymer fibers (sheath fibers) have a melting point within the range of from about 150-400°F, and more preferably in the range of from about 170-300°F. The second polymer fibers (core fibers) have a higher melting point, preferably above about 350°F. When bicomponent fibers are used as a component of the composite material, the bicomponent fibers may be present in an amount up to 20% by weight of the total fibers, preferably in an amount up to 10% by weight.

[0153] The acoustic performance of the composite material may be altered or improved by the specific combination of fibers present in the composite material, and can therefore be tailored to meet the needs of a particular application. For example, the acoustic properties desired for specific applications can be optimized by altering the weight of the fibers, by changing the reinforcement fibers content and / or length or diameter of the reinforcement fibers, or by altering the fiber length and / or denier of the acoustical enhancing fibers or organic fibers. The thickness of the formed composite part, porosity of the formed composite part (void content), and the air flow path may be controlled by changing the basis weight of the organic fibers and / or glass content of the composite material. In addition, the use of wet use chopped strand glass in the dry-laid process as described above also contributes to the improved sound absorption of the inventive composite material because the composite materials formed by the dry-laid process described herein has a higher loft (increased porosity).

[0154] Further, the composite material provides the ability to optimize and / or tailor the physical properties (such as stiffness and / or strength) needed for specific applications by altering the weight, length, and / or diameter of the reinforcement fibers and / or organic fibers used in the composite material. In addition, composite materials formed by the processes described herein have a uniform or substantially uniform distribution of fibers, thereby providing improved strength as well as improved acoustical and thermal properties, stiffness, impact resistance, and acoustical absorbance.

[0155] Electrical Properties

[0156] The present disclosure includes the discovery that melanin can be used alone, or in composites with other materials, in harsh environments such as the vacuum and extreme cold of space where the following listed properties are desirable or necessary: Attorney Docket No.: 4774-0060W006

[0157] Photoconductivity (when light is shined on it, electricity flows), Semiconductor properties, Electricity conduction, and Paramagnetism (Nordlund, 2006).

[0158] Binding to Metals and Radioactive Substances

[0159] It has been reported that melanin binds to metals and radioactive substances (Bruenger et al., 1967) (Fogarty and Tobin, 1996) (Kasatna et al, 2003) (Taylor et al., 1964). The present disclosure includes the discovery that melanin can be used alone, or in composites with other materials to form shielding and armor and for aerospace applications, specifically because it naturally binds to a wide range of metals and to radioactive substances.

[0160] Pharmaceutical Formulations

[0161] Compositions of the disclosure include pharmaceutical compositions for, for example, oral administration to treat, for example, acute radiation sickness, wherein the composition comprises, for example, an agent which is selected from the group consisting melanin, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient. Exemplary dosages of the agent include, for example, about 75 mg, about 150 mg, about 225 mg, about 300 mg, about 450 mg.

[0162] Relative to an oral dosage form such as a tablet or capsule, buccal or sublingual delivery 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.

[0163] Compositions for buccal administration include an agent which is selected from the group consisting of melanin, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations 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.

[0164] Compositions for sublingual administration include an agent which is selected from the group consisting of melanin, pharmaceutically acceptable derivatives thereof, pharmaceutically Attorney Docket No.: 4774-0060W006 acceptable salts thereof, and combinations 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] Sublingual and / or buccal oral dosage forms are preferred for delivering certain pharmaceutically active agents to the bloodstream. For example, many pharmaceutically active Attorney Docket No.: 4774-0060W006 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.

[0170] 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.

[0171] The term "buccal delivery system" as used herein refers to a delivery system wherein an active ingredient is provided for absorption across one or more membranes in the mouth, 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.

[0172] Reference to an "active ingredient" includes a therapeutic or prophylactic agent, drug, prodrug, 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.

[0173] 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 ingredient(s) 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. Attorney Docket No.: 4774-0060W006

[0174] 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.

[0175] 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 di stearate, 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, polyglyceryl- 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.

[0176] 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, kollicoat, solutol and ludipress.

[0177] 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. Attorney Docket No.: 4774-0060W006

[0178] 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.

[0179] In another aspect, the present disclosure 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.

[0180] 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).

[0181] In a preferred embodiment, the buccal delivery system comprises a binding and gelling agent such as hydroxypropyl methocellulose.

[0182] In another embodiment, the buccal delivery 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. Attorney Docket No.: 4774-0060W006

[0183] 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; corn 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.

[0184] 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.

[0185] Formulations and solid oral dosage forms of this disclosure include disintegrating agents (di sint egrants) 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.

[0186] In some embodiments, direct compression formulations and solid oral dosage forms of this disclosure 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, Attorney Docket No.: 4774-0060W006 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.

[0187] Film

[0188] In one embodiment of the present disclosure, there is provided a film dosage composition including: a polymeric carrier matrix; a therapeutically effective amount of an agent which is selected from the group consisting of melanin, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof, and at least one pharmaceutically acceptable excipient; and a buffer in an amount to provide a pH of the composition of a value sufficient to optimize absorption of the active ingredients.

[0189] 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 than about 30 mils. Films may be in a single layer or they may be multi-layered, including laminated films.

[0190] 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).

[0191] 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 disclosure, it is preferable to use films that fall between the categories of fast Attorney Docket No.: 4774-0060W006 dissolving and moderate dissolving. Such moderate dissolving fdms 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 fdm is not easily removable once it is placed in the oral cavity of the user.

[0192] The fdms used in the pharmaceutical products may be produced by a combination of at least one polymer and a solvent, optionally including other fdlers 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 fdm may be prepared by utilizing a selected casting or deposition method and a controlled drying process. For example, the fdm may be prepared through controlled drying processes, which include application of heat and / or radiation energy to the wet fdm matrix to form a visco-elastic structure, thereby controlling the uniformity of content of the fdm. Such processes are described in more detail in commonly assigned U.S. application Ser. No. 10 / 074,272, fded 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 fdms may be extruded as described in commonly assigned U.S. application Ser. No. 10 / 856,176, fded 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.

[0193] The polymer included in the fdms 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. Attorney Docket No.: 4774-0060W006

[0194] 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 disclosure 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.

[0195] 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, poly(lactic acid) / poly(glycolic acid) / polyethyleneglycol copolymers, copolymers of polyurethane 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.

[0196] 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 Attorney Docket No.: 4774-0060W006 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 a melting 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).

[0197] The Biodel materials represent a family of various poly anhydrides which differ chemically.

[0198] Although a variety of different polymers may be used, it is desired to select polymers that provide mucoadhesive properties to the fdm, 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.

[0199] 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.

[0200] 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. Attorney Docket No.: 4774-0060W006

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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. Attorney Docket No.: 4774-0060W006

[0205] 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, anti-adherents, acidulants, softeners, resins, demulcents, solvents, surfactants, emulsifiers, elastomers and mixtures thereof. These additives may be added with the active ingredient(s).

[0206] 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: alkylcelluloses hydroxyalkylcelluloses and hydroxyalkylalkylcelluloses, such as methylcelulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxy ethylmethylcellulose, 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 acids 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 quaternized if desired; and other similar polymers.

[0207] 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. Attorney Docket No.: 4774-0060W006

[0208] 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.

[0209] 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.

[0210] 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 C12-, C14-, C16-, C18-, C20- and C22-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.

[0211] The mono- and di-glycerides are desirably derived from the types of fats described above, i.e. with Cl 2-, Cl 4-, Cl 6-, Cl 8-, C20- and C22-fatty acids.

[0212] 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.

[0213] 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.

[0214] Lecithin 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 Attorney Docket No.: 4774-0060W006 available from BASF, are also useful. Carbowax® is yet another modifier which is very useful in the present disclosure. Tweens® or combinations of surface active agents may be used to achieve the desired hydrophilic-lipophilic balance ("HLB"). The present disclosure, however, does not require the use of a surfactant and films or film-forming compositions of the present disclosure may be essentially free of a surfactant while still providing the desirable uniformity features of the present disclosure.

[0215] 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, methyl cellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, and polyvinylalcohols.

[0216] 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 doughnutshaped 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 derived from starch. Other similar substances, however, are considered well within the scope of the present disclosure.

[0217] 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.

[0218] 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.

[0219] 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 Attorney Docket No.: 4774-0060W006 or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. A nonlimiting 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.

[0220] 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.

[0221] The sweeteners may be chosen from the following non-limiting list: glucose (corn 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.

[0222] 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 antifoaming and / or de-foaming agent. The present disclosure, however, is not so limited and other anti-foam and / or de-foaming agents may suitable be used.

[0223] In another embodiment, the composition comprises antioxidant(s), for example, tocopherol and derivatives, ascorbic acid and derivatives, butylated hydroxy anisole, butylated hydroxytoluene, fumaric acid, malic acid, propyl gallate, sodium metabisulfite and derivatives, 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. Attorney Docket No.: 4774-0060W006

[0224] 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 5 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.

[0225] The transmucosal pharmaceutical formulation of the present disclosure 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.

[0226] The transmucosal pharmaceutical formulation of the present disclosure may also further include humectants, sequestering agents, moisturizers, surfactants, emollients, colorants, fragrances, flavors, or any combination thereof.

[0227] In some embodiments, the transmucosal dosage form is a liquid formulation, comprising: a therapeutically effective amount of an agent which is selected from the group consisting of melanin, pharmaceutically acceptable derivatives thereof, 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.

[0228] In one embodiment, a gel formulation of the present disclosure comprises an agent which is selected from the group consisting of melanin, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and pharmaceutically acceptable salts thereof, and combinations 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 Attorney Docket No.: 4774-0060W006 weight percent of water, between about 30 to about 70 weight percent ethanol, between about 15 and about 60 weight percent of a 10: 1 to 1 :10 (weight to weight) mixture of di ethylene 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 hydroxypropyl cellulose. 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.

[0229] 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.

[0230] The buffer of the transmucosal delivery system can be selected from the group including acetate, citrate, prolamine, carbonate and phosphate buffers.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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. Attorney Docket No.: 4774-0060W006

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] The formulations of the present disclosure may be provided in a unit dose container(s). Such containers typically comprise inner and outer surfaces, wherein the formulation of the present disclosure 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 disclosure 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.

[0240] Packaging / Treatment Kits

[0241] The present disclosure relates to a kit for conveniently and effectively carrying out the methods in accordance with the present disclosure. 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 Attorney Docket No.: 4774-0060W006 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.

[0242] 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 disclosure, and PM dosage of this disclosure, or mid-day dosage of this disclosure. 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.

[0243] Blister packs, clamshells or trays are forms of packaging used for goods; thus, the disclosure provides for blister packs, clamshells or trays comprising a composition (e g., a (the multi-ingredient combination of drugs of the disclosure) combination of active ingredients) of the disclosure. 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 disclosure. In one aspect, a blister pack of the disclosure comprises a moulded PVC base, with raised areas (the "blisters") to contain the tablets, pills, etc. comprising the combinations of the disclosure, 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.

[0244] In one aspect, a blister pack also comprises a method of packaging where the compositions comprising combinations of ingredients of the disclosure are contained in-between a card and a Attorney Docket No.: 4774-0060W006 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 disclosure are used, and they can comprise of two vacuum- formed PVC sheets meshed together at the edges, with the informative card inside.

[0245] In one aspect, blister packaging comprises at least two components (e.g., is a multiingredient combination of drugs of the disclosure): a thermoformed "blister" which houses the product (e.g., a pharmaceutical combination of the disclosure), 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, Ill.) using regular heat seal tooling. This alternative aspect, using heat seal tooling, can seal common types of thermoformed packaging.

[0246] As discussed herein, the products of manufacture of the disclosure can comprise the packaging of the therapeutic drug combinations of the disclosure, 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.

[0247] 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 disclosure 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 Attorney Docket No.: 4774-0060W006 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 disclosure'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.

[0248] In one embodiment of the disclosure, the composition is contained within one suitable container, such as a dropper, ajar, 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 disclosure 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.

[0249] Kits are also contemplated as being used in certain aspects of the present disclosure. For instance, a composition of the present disclosure 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 injection 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.

[0250] 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. Attorney Docket No.: 4774-0060W006

[0251] 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.

[0252] Pharmaceutical Dosage Forms

[0253] The compositions of the present disclosure can be processed by agglomeration, air suspension chilling, air suspension drying, balling, coacervation, coating, commination, compression, cryopelletization, encapsulation, extrusion, wet granulation, dry granulation, homogenization, inclusion complexation, lyophilization, melting, microencapsulation, mixing, molding, pan coating, solvent dehydration, sonication, spheronization, spray chilling, spray congealing, spray drying, or other processes known in the art. The compositions can be provided in the form of a minicapsule, a capsule, a tablet, an implant, a troche, a lozenge (minitablet), a temporary or permanent suspension, an ovule, a suppository, a wafer, a chewable tablet, a quick or fast dissolving tablet, an effervescent tablet, a buccal or sublingual solid, a granule, a film, a sprinkle, a pellet, a bead, a pill, a powder, a triturate, a platelet, a strip or a sachet. Compositions can also be administered as a "dry syrup", where the finished dosage form is placed directly on the tongue and swallowed or followed with a drink or beverage. These forms are well known in the art and are packaged appropriately. The compositions can be formulated for oral, nasal, buccal, ocular, urethral, transmucosal, vaginal, topical or rectal delivery.

[0254] The pharmaceutical composition of the disclosure can be coated with one or more enteric coatings, seal coatings, film coatings, barrier coatings, compress coatings, fast disintegrating coatings, or enzyme degradable coatings. Multiple coatings can be applied for desired performance. Further, the dosage form can be designed for immediate release, pulsatile release, controlled release, extended release, delayed release, targeted release, synchronized release, or targeted delayed release. For release / absorption control, solid carriers can be made of various component types and levels or thicknesses of coats, with or without an active ingredient.

[0255] Such diverse solid carriers can be blended in a dosage form to achieve a desired performance. The definitions of these terms are known to those skilled in the art. In addition, the dosage form release profile can be affected by a polymeric matrix composition, a coated matrix Attorney Docket No.: 4774-0060W006 composition, a multiparticulate composition, a coated multiparticulate composition, an ionexchange resin- based composition, an osmosis-based composition, or a biodegradable polymeric composition.

[0256] Without wishing to be bound by theory, it is believed that the release may be effected through favorable diffusion, dissolution, erosion, ion-exchange, osmosis or combinations thereof.

[0257] When formulated as a capsule, the capsule can be a hard or soft gelatin capsule, a starch capsule, or a cellulosic capsule. Although not limited to capsules, such dosage forms can further be coated with, for example, a seal coating, an enteric coating, an extended-release coating, or a targeted delayed release coating. These various coatings are known in the art, but for clarity, the following brief descriptions are provided: seal coating, or coating with isolation layers: Thin layers of up to 20 microns in thickness can be applied for variety of reasons, including for particle porosity reduction, to reduce dust, for chemical protection, to mask taste, to reduce odor, to minimize gastrointestinal irritation, etc. The isolating effect is proportional to the thickness of the coating. Water soluble cellulose ethers are preferred for this application. HPMC and ethyl cellulose in combination, or Eudragit E100, may be particularly suitable for taste masking applications. Traditional enteric coating materials listed elsewhere can also be applied to form an isolating layer.

[0258] Extended-release coatings are designed to effect delivery over an extended period of time. The extended-release coating is a pH-independent coating formed of, for example, ethyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, acrylic esters, or sodium carboxymethyl cellulose. Various extended-release dosage forms can be readily designed by one skilled in art to achieve delivery to both the small and large intestines, to only the small intestine, or to only the large intestine, depending upon the choice of coating materials and / or coating thickness.

[0259] Enteric coatings are mixtures of pharmaceutically acceptable excipients which are applied to, combined with, mixed with or otherwise added to the carrier or composition. The coating may be applied to a compressed or molded or extruded tablet, a gelatin capsule, and / or pellets, beads, granules or particles of the carrier or composition. The coating may be applied through an aqueous dispersion or after dissolving in appropriate solvent. Additional additives and their levels, and selection of a primary coating material or materials will depend on the following properties: 1. resistance to dissolution and disintegration in the stomach; 2. impermeability to gastric fluids and Attorney Docket No.: 4774-0060W006 drug / carrier / enzyme while in the stomach; 3. ability to dissolve or disintegrate rapidly at the target intestine site; 4. physical and chemical stability during storage; 5. non-toxicity; 6. easy application as a coating (substrate friendly); and 7. economical practicality.

[0260] Delayed release generally refers to the delivery so that the release can be accomplished at some generally predictable location in the lower intestinal tract more distal to that which would have been accomplished if there had been no delayed release alterations. The preferred method for delay of release is coating. Any coatings should be applied to a sufficient thickness such that the entire coating does not dissolve in the gastrointestinal fluids at pH below about 5, but does dissolve at pH about 5 and above. It is expected that any anionic polymer exhibiting a pH-dependent solubility profde can be used as an enteric coating in the practice of the present disclosure to achieve delivery to the lower gastrointestinal tract. Polymers for use in the present disclosure are anionic carboxylic polymers. Shellac, also called purified lac, a refined product obtained from the, resinous secretion of an insect. This coating dissolves in media of pH>7. Colorants, detackifiers, surfactants, antifoaming agents, lubricants, stabilizers such as hydroxy propyl cellulose, acid / base may be added to the coatings besides plasticizers to solubilize or disperse the coating material, and to improve coating performance and the coated product.

[0261] In carrying out the method of the present disclosure, the compositions of the disclosure may be administered to mammalian species, such as dogs, cats, humans, etc. and as such may be incorporated in a conventional systemic dosage form, such as a tablet, capsule, elixir or injectable. The above dosage forms will also include the necessary carrier material, excipient, lubricant, buffer, antibacterial, bulking agent (such as mannitol), anti-oxidants (ascorbic acid of sodium bisulfite) or the like.

[0262] The dose administered must be carefully adjusted according to age, weight and condition of the patient, as well as the route of administration, dosage form and regimen and the desired result.

[0263] The pharmaceutical compositions of the disclosure may be administered in the dosage forms in single or divided doses of one to four times daily. It may be advisable to start a patient on a low dose combination and work up gradually to a high dose combination. Attorney Docket No.: 4774-0060W006

[0264] Tablets of various sizes can be prepared, e.g., of about 1 to 2000 mg in total weight, containing one or both of the active pharmaceutical ingredients, with the remainder being a physiologically acceptable carrier of other materials according to accepted pharmaceutical practice. These tablets can be scored to provide for fractional doses. Gelatin capsules can be similarly formulated.

[0265] Liquid formulations can also be prepared by dissolving or suspending one or the combination of active substances in a conventional liquid vehicle acceptable for pharmaceutical administration so as to provide the desired dosage in one to four teaspoonful.

[0266] Dosage forms can be administered to the patient on a regimen of, for example, one, two, three, four, five, six, or other doses per day.

[0267] In order to more finely regulate the dosage schedule, the active substances may be administered separately in individual dosage units at the same time or carefully coordinated times. Since blood levels are built up and maintained by a regulated schedule of administration, the same result is achieved by the simultaneous presence of the two substances. The respective substances can be individually formulated in separate unit dosage forms in a manner similar to that described above.

[0268] In formulating the compositions, the active substances, in the amounts described above, may be compounded according to accepted pharmaceutical practice with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in the particular type of unit dosage form.

[0269] Illustrative of the adjuvants which may be incorporated in tablets are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate or cellulose; a disintegrating agent such as com starch, potato starch, alginic acid or the like; a lubricant such as stearic acid or magnesium stearate; a sweetening agent such as sucrose, aspartame, lactose or saccharin; a flavoring agent such as orange, peppermint, oil of wintergreen or cherry. When the dosage unit form is a capsule, it may contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets or capsules may be coated with shellac, sugar or both. A syrup of elixir may contain the active compound, water, Attorney Docket No.: 4774-0060W006 alcohol or the like as the carrier, glycerol as solubilizer, sucrose as sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange.

[0270] One embodiment of this disclosure includes methods of treating, preventing, or diagnosing a particular disease or condition by administering the disclosed compositions to a subject. In many instances, the compositions can be administered alone or can be included within a pharmaceutical composition. An effective amount of a pharmaceutical composition, generally, is defined as that amount sufficient to ameliorate, reduce, minimize, or limit the extent of the disease or condition. More rigorous definitions may apply, including elimination, eradication, or cure of the disease or condition.

[0271] The composition may be in nanoparticulate form. "Nanoparticles" are solid particles of an average particle diameter of, for example, less than about 1 micron (micrometer). One micron is 1,000 nanometers (nm). "Stabilized" nanoparticles are nanoparticles coated with a stabilizing material and having a reduced tendency for aggregation and loss of dispersion with respect to nanoparticles of the compound of the disclosure without a stabilizing coating. A nano- spray is a spray containing nanoparticles or a spray that produces nanoparticles. A nanodispersion is a dispersion containing nanoparticles. A nanosuspension is a suspension containing nanoparticles.

[0272] The liquid formulations useful herein may comprise a solvent, solution, suspension, microsuspension, nanosuspension, emulsion, microemulsion, gel or even a melt containing the active component or components. In some embodiments the nanoparticles, nanofibers, or nanofibrils may be in the form of, or within or on, granules, powders, suspensions, solutions, dissolvable films, mats, webs, tablets, or releasable forms particularly releasable dosage forms. Other particular useful forms are concentrates to which a diluting liquid is added prior to use. The product may also be sprayed onto the inner surface of a container to which a liquid is added later prior to use and the nanoparticles, nanofibers, or nanofibrils, are released into the liquid. Pharmaceutical compositions of the present disclosure can include nanoparticles, composite nanoparticles, nanosuspension, or nanocapsules of the present disclosure.

[0273] The composition may also include various antioxidants to retard oxidation of one or more active ingredient or nanoparticles, composite nanoparticles, nanosuspension, or nanocapsules. The prevention of the action of microorganisms can be brought about by preservatives such as various Attorney Docket No.: 4774-0060W006 antibacterial and antifungal agents, including but not limited to parabens (e.g., methylparabens, propylparabens), chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof.

[0274] In order to increase the effectiveness of a treatment with the nanoparticles, nanogels, composite nanoparticles, nanosuspension, or nanocapsules of the present disclosure, it may be desirable to combine these nanoparticles, composite nanoparticles, or nanocapsules with other therapies effective in the treatment of a particular disease or condition.

[0275] The formulations as described above may be administered for a prolonged period, that is, for as long as the potential for a disease or condition remains or the symptoms continue.

[0276] The disclosure will be illustrated in more detail with reference to the following Examples, but it should be understood that the present disclosure is not deemed to be limited thereto.

[0277] EXAMPLES

[0278] Example 1. In an exemplary embodiment, two slabs of melanin were produced by placing cuttlefish ink at 40°C in a conventional oven and dried for 18 days to reduce the material to 40% of its original weight. In an alternative embodiment, cuttlefish ink was placed in a 900 watt microwave oven, and dried for 12 minutes to form two slabs. Each slab was approximately 3.5 in square. One slab was 1 inch thick and 1 slab was 0.5 in. thick. Both slabs were placed together in a wood frame to create a 1.5 inch thick sample of melanin.

[0279] Example 2. Design of Experiment evaluating the effect of four oral doses of Melanin on 30-day survival CD2F1 mice irradiated with an LD-70 dose.

[0280] Experiment summary: In the Experiment, melanin is tested at the LD70 / 30 radiation dose, using one drug dose and three schedules relative to total body irradiation with Cobalt-60 gamma radiation. The time points used in the screening protocol are 1 d pre-irradiation, and 4 h and 1 d post-irradiation. In addition to drug-treated groups the experiment includes a standard positive control, 5-androstenediol (5-AED, 30 mg / kg, sc, -24 h), and its vehicle PEG-400 (Table 3). The positive control on average provides 90-100% survival in these experiments.

[0281] CD2F1 male mice are weighed, animals outside ± 10 % of the mean weight excluded, and randomized into groups of four animals per box (Table 3). There are 24 animals per treatment Attorney Docket No.: 4774-0060W006 group (6 boxes). The experimental animals receive 9.25 Gy at dose rate 0.6 Gy per / min in the AFRRI Cobalt-60 gamma radiation facility. Animals are irradiated in Lucite boxes (8 animals / box) and arranged in an array (dosimetry 02 / 28 / 2013) using plastic racks. Animals are restrained for no more than 60 min and returned to cages at the end of the irradiation period. They are monitored daily (twice a day when necessary) for 30 days and euthanized at the completion of the observation period.

[0282] Results: Thirty day survival of the PEG-400 vehicle group is 5% and 95% for the positive control, 5-AED (not shown). The naive group showed a survival of 5%. Survival of mice administered 300 mg / kg of melanin pre-TBI was 95% compared to 15% survival with PBS alone. Post-irradiation 4 h treatment with 300 mg / kg melanin resulted in survival of 70% mice compared to 15% in the vehicle group. When drug administration is delayed to 24 h, 30-day survival was 50% in the experimental mice compared to 15% in the vehicle group.

[0283] Summary: Melanin administered orally is successful in enhancing survival compared to the vehicle control using LD70 / 30 dose of radiation.

[0284] Example 3 - Preparation of bismuth-melanin

[0285] Cuttlefish ink was heated slowly to allow evaporation of some its water until it was about 50% melanin and 50% water, and was of the form of a paste. It was then centrifuged 2: 1 with distilled water at 4°C for 30 minutes at 14,000 g. This was repeated intil the total was seven washes. Attorney Docket No.: 4774-0060W006

[0286] This purified melanin was then reacted with Bismuth Trioxide (Bi203) in a 15:1 ratio in IN NaOH. The suspension was vigorously mixed in a heat bath at 100°C for 2.5 hours until most of the water has evaporated and the result was a thick paste. The paste was then further dried in a 1000 Watt microwave oven 7 times for 30 seconds each time. It was then ground into fine particles using a blender. A lyophilized sample of the resulting material determined that the final powder contained about 1% water. The powder was poured into a 4 inch x 4 inch steel mold and then compressed into a block using a hydraulic press exerting 6000 pounds on the 16 in.2area for 30 minutes. The resulting block was removed from the mold and then vacuum packed.

[0287] We note that although this procedure was developed with awareness of the synthesis reported by El-Bialy et al. 2019, there are fundamental differences. He used fungal melanin which is believed to have a somewhat different structure than cuttlefish melanin. Additionally, cuttlefish melanin exists in organelles known as melanosomes which are spherical and approximately 0.2 pm particles. It is thought that the geometry of the melanosomes only permitted linking to bismuth to occur on the exterior of each melanosome whereas in the El-Bialy synthesis it seems that all of the melanin is presumed to have been available for covalent bonding to bismuth.

[0288] Example 4 - Preparation of copper-melanin

[0289] Purified melanin was prepared as above. 100 grams of purified melanin was reacted with 500 ml of 0.4 M copper (II) chloride solution at 70°C for two hours. After letting it stand overnight, the supernatant was removed and heating was resumed until most of the water evaporated and the result was a thick paste. The new composite was further dried using a 1000 Watt microwave oven 4 times at 30 seconds each time. It was then ground into fine particles using a blender. Lyophilization of a sample of this material showed that the water content of the final paste was about 35%. The paste was then poured into a 4 inch x 4 inch steel mold and compressed using 6000 pounds to the 16 in.2area for 30 minutes. The resulting block was removed from the mold and vacuum packed. Attorney Docket No.: 4774-0060W006

[0290] While the disclosure 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. References

[0291] Kono, R, Yamaoka, T, McGinness, J. (1979). Anomalous absorption and dispersion of sound waves in diethylamine melanin. Journal of Applied Physics 50: 1236-1244.

[0292] Horowitz, D. (1979) The absorption of ultrasound in melanin and melanoma. Master's Thesis. University of Rochester. El-Bialy, HA et al., 2019. Microbial melanin physiology under stress conditions and gamma radiation protection studies Radiation Physics and Chemistry 162 , pp.178-186.

[0293] Meredith, P, Sarna, T. 2006. The physical and chemical properties of eumelanin. Pigment Cell Res. 19; 572-594.

Claims

Attorney Docket No.: 4774-0060W006CLAIMSWHAT IS CLAIMED IS:

1. A sound absorbing material formed using a composition comprising: melanin material; optionally, at least one additional non-melanin material selected from the group consisting of biological material, biological polymers, polymers, metals, radionuclides, iron, copper, zinc, cesium, radium, strontium, thorium, uranium, salts, ceramics, clothing, construction materials, existing cladding materials, poly-paraphenylene terephthalamide, and other natural materials or their synthetic mimics.

2. The sound absorbing material of claim 1, wherein the sound absorbing material is manufactured in a form selected from the group consisting of particles, nanoparticles, dust, beads, fibers that are woven, fibers that are non-woven, sheets, films, slabs, plates, bricks, chars, spheres, nodules, balls, graphite-like sheets and shards, liquids, gels, solids, thermoplastic solids, and thermoset solids.

3. The sound absorbing material of any one of claims 1 to 2, wherein the non-melanin material is collagen.

4. The sound absorbing material of any one of claims 1 to 3, wherein the non-melanin material is selected from the group consisting of a polyphenylene polymer, polyimides, polyetherimides, polyimideamides, polysulfones, epoxy resins, bismaleimide resins, bis-benzocyclobutene resins, phthalonitrile resins, polyaryletherketones, polyetherketones, liquid crystal polymers, oligomeric cyclic polyester precursors, polybenzbisoxazoles, polybenzbisthiazoles, polybenzbisimidazoles, acetylene endcapped thermosetting resins, polysulfones, polyaramides, Poly-paraphenylene terephthalamide, polyamides, polycarbonates, polyethylenes, polyesters, and combinations thereof.

5. The sound absorbing material of any one of claims 1 to 4, wherein the non-melanin material is a ceramic material selected from the group consisting of alumina, boron carbide, boron nitride, mullite, silica, silicon carbide, silicon nitride, magnesium boride, multi-walled carbon nanotubes, single walled carbon nanotubes, group IVB, VB and VIB metal sulfide nanotubes, titanium boride, titanium carbide, diamond, and combinations thereof.Attorney Docket No.: 4774-0060W0066. The sound absorbing material of any one of claims 1 to 5, wherein the non-melanin material and the melanin material are present in a ratio selected from the group consisting of about 5 to 95, about 20 to 80, about 30 to 70, about 40 to 60, about 50 to 50, about 60 to 40 about 70 to 30 about 80 to 20, about 95 to 5 (percent by weight).

7. The sound absorbing material of any one of claims 1 to 6, wherein the non-melanin material and the melanin material combine to synergistically increase the impact resistance of the sound absorbing material compared to the non- melanin materials and melanin material alone.

8. The sound absorbing material of any one of claims 1 to 7, wherein the sound absorbing material is formed into an article which is an item selected from the group consisting of helmets, headphones, vehicle cladding, aircraft cladding, watercraft cladding, structure cladding, equipment housing, blast protection panels, sound absorbing panels, and cargo containers.

9. A process for forming a sound absorbing material comprising: mixing a melanin material; and optionally, at least one additional non-melanin material selected from the group consisting of polymers, metals, radionuclides, iron, copper, zinc, cesium, radium, strontium, thorium, uranium, salts, ceramics, clothing, construction materials, existing cladding materials, Poly-paraphenylene terephthalamide, other natural materials or their synthetic mimics; and shaping the resultant material into an article.

10. The process of claim 9, wherein the sound absorbing material is manufactured in a form selected from the group consisting of particles, nanoparticles, dust, beads, fibers that are woven, fibers that are non-woven, sheets, films, plates, bricks, chars, spheres, nodules, balls, graphite- like sheets and shards, liquids, gels, solids, thermoplastic solids, and thermoset solids.

11. The process of any one of claims 9 to 10, wherein the step of shaping comprises using a technique selected from the group consisting of molding, compression molding, stamping, bending, thermoforming, injection molding, additive manufacturing, coining, and extruding.

12. The process of any one of claims 9 to 11, wherein the melanin material and the non-melanin material are mixed using a machine selected from the group consisting of a single screw extruder,Attorney Docket No.: 4774-0060W006 a counter-rotating twin-screw extruder, a co-rotating twin-screw extruder, a Henschel mixer, and a co-kneader.

13. The process of any one of claims 9 to 12, wherein the non-melanin material is selected from the group consisting of a polyphenylene polymer, polyimides, polyetherimides, polyimideamides, polysulfones, epoxy resins, bismaleimide resins, bis-benzocyclobutene resins, phthalonitrile resins, polyaryletherketones, polyetherketones, liquid crystal polymers, oligomeric cyclic polyester precursors, polybenzbisoxazoles, polybenzbisthiazoles, polybenzbisimidazoles, acetylene endcapped thermosetting resins, polysulfones, polyaramides, Poly-paraphenylene terephthalamide, polyamides, polycarbonates, polyethylenes, polyesters, and combinations thereof.

14. The process of any one of claims 9 to 13, wherein the non-melanin material is a ceramic material selected from the group consisting of alumina, boron carbide, boron nitride, mullite, silica, silicon carbide, silicon nitride, magnesium boride, multi-walled carbon nanotubes, single walled carbon nanotubes, group IVB, VB and VIB metal sulfide nanotubes, titanium boride, titanium carbide, diamond, and combinations thereof.

15. The process of any one of claims 9 to 14, wherein the sound absorbing material is formed into an article which is an item selected from the group consisting of helmets, headphones, fabric, vehicle cladding, aircraft cladding, watercraft cladding, structure cladding, equipment housing, blast protection panels, sound absorbing panels, and cargo containers.

16. A composite material comprising: melanin material; optionally, at least one additional non- melanin material selected from the group consisting of polymers, metals, radionuclides, iron, copper, zinc, cesium, radium, strontium, thorium, uranium, salts, ceramics, clothing, construction materials, existing cladding materials, Poly-paraphenylene terephthalamide, and other natural materials or their synthetic mimics.

17. The composite material of claim 16, wherein the non-melanin material is manufactured as in a from selected from the group consisting of particles, nanoparticles, dust, beads, fibers that are woven, fibers that are non-woven, sheets, films, plates, bricks, chars, spheres, nodules, balls, graphite-like sheets and shards, liquids, gels, solids, thermoplastic solids, and thermoset solids.Attorney Docket No.: 4774-0060W00618. The composite material of any one of claims 16 to 17, wherein the additional non-melanin material is selected from the group consisting of a polyphenylene polymer, polyimides, polyetherimides, polyimideamides, polysulfones, epoxy resins, bismaleimide resins, bis- benzocyclobutene resins, phthalonitrile resins, polyaryletherketones, polyetherketones, liquid crystal polymers, oligomeric cyclic polyester precursors, polybenzbisoxazoles, polybenzbisthiazoles, polybenzbisimidazoles, acetylene endcapped thermosetting resins, polysulfones, polyaramides, Poly-paraphenylene terephthalamide, polyamides, polycarbonates, polyethylenes, polyesters, and combinations thereof.

19. The composite material of any one of claims 16 to 18, wherein the non-melanin material is a ceramic material selected from the group consisting of alumina, boron carbide, boron nitride, mullite, silica, silicon carbide, silicon nitride, magnesium boride, multi-walled carbon nanotubes, single walled carbon nanotubes, group IVB, VB and VIB metal sulfide nanotubes, titanium boride, titanium carbide, diamond, and combinations thereof.

20. The composite material of any one of claims 16 to 19, wherein the non-melanin material and the melanin material are present in a ratio selected from the group consisting of about 5 to 95, about 20 to 80, about 30 to 70, about 40 to 60, about 50 to 50, about 60 to 40 about 70 to 30 about 80 to 20, about 95 to 5 (percent by weight).

21. The composite material of any one of claims 16 to 20, wherein the non-melanin material and the melanin material combine to synergistically increase the impact resistance of the sound absorbing material compared to the non- melanin materials and melanin material alone.

22. The composite material of any one of claims 16 to 21, wherein the material is formed into an article which is an item selected from the group consisting of helmets, fabric, vehicle cladding, aircraft cladding, watercraft cladding, structure cladding, equipment housing, blast protection panels, sound absorbing panels, and cargo containers.

23. The composite material of any one of claims 16 to 22, wherein the polymer matrix is formed at least partially of a thermosetting resin.

24. The composite material of any one of claims 16 to 23, wherein the non-melanin is formed at least partially of a thermoplastic.Attorney Docket No.: 4774-0060W00625. The composite material of any one of claims 16 to 24, wherein the non-melanin is formed at least partially of a polyarylene having one of either a rigid-rod or semi-rigid-rod structure where the structure is formed of a plurality of repeat units where 25% of the repeat units are rigid-rod repeat units having substantially parallel bonds.

26. The composite material of any one of claims 16 to 25, wherein the non-melanin is formed of at least a polyphenylene polymer.

27. The composite material of any one of claims 16 to 26, wherein non-melanin further comprises at least one other polymer independently selected from the group consisting of polyimides, polyetherimides, polyimideamides, polysulfones, epoxy resins, bismaleimide resins, bis- benzocyclobutene resins, phthalonitrile resins, polyaryletherketones, polyetherketones, liquid crystal polymers, oligomeric cyclic polyester precursors, polybenzbisoxazoles, polybenzbisthiazoles, polybenzbisimidazoles, acetylene endcapped thermosetting resins, polysulfones, polyaramides, Poly-paraphenylene terephthalamide, polyamides, polycarbonates, polyethylenes, and polyesters.

28. The composite material of any one of claims 16 to 27, wherein the non-melanin material comprises one or more ceramic powders or particles selected from the group consisting of alumina, boron carbide, boron nitride, mullite, silica, silicon carbide, silicon nitride, magnesium boride, multi-walled carbon nanotubes, single walled carbon nanotubes, group IVB metal sulfide nanotubes, group VB metal sulfide nanotubes, group VIB metal sulfide nanotubes, titanium boride, titanium carbide and diamond.

29. The composite material of any one of claims 16 to 28, further comprising at least one additive material selected from the group consisting of process aids, modifiers, colorants, fibers, adhesion promoters and fillers.

30. The composite material of any one of claims 16 to 29, wherein the material is formed into an article which is an item selected from the group consisting of helmets, fabric, vehicle cladding, aircraft cladding, watercraft cladding, structure cladding, equipment housing, blast protection panels, sound absorbing panels and cargo containers.

31. A process for forming a composite material comprising:Attorney Docket No.: 4774-0060W006 mixing a melanin material; optionally, at least one additional non-melanin material selected from the group consisting of polymers, metals, radionuclides, iron, copper, zinc, cesium, radium, strontium, thorium, uranium, salts, ceramics, clothing, construction materials, existing cladding materials, Polyparaphenylene terephthalamide, other natural materials or their synthetic mimics.; and shaping the composite material into an article.

32. The process of claim 31, wherein the step of shaping comprises using a technique selected from the group consisting of molding, compression molding, stamping, bending, thermoforming, injection molding, additive manufacturing, coining, and extruding.

33. The process of any one of claims 31 to 32, wherein the melanin material and the nonmelanin material are mixed using a machine selected from the group consisting of a single screw extruder, a counter-rotating twin-screw extruder, a co-rotating twin-screw extruder, a Henschel mixer, and a co-kneader.

34. The process of any one of claims 31 to 33, wherein the non-melanin material is selected from the group consisting of a polyphenylene polymer, polyimides, polyetherimides, polyimideamides, polysulfones, epoxy resins, bismaleimide resins, bis-benzocyclobutene resins, phthalonitrile resins, polyaryletherketones, polyetherketones, liquid crystal polymers, oligomeric cyclic polyester precursors, polybenzbisoxazoles, polybenzbisthiazoles, polybenzbisimidazoles, acetylene endcapped thermosetting resins, polysulfones, polyaramides, Poly-paraphenylene terephthalamide, polyamides, polycarbonates, polyethylenes, polyesters, and combinations thereof.

35. The process of any one of claims 31 to 34, wherein the non-melanin material is selected from the group consisting of alumina, boron carbide, boron nitride, mullite, silica, silicon carbide, silicon nitride, magnesium boride, multi-walled carbon nanotubes, single walled carbon nanotubes, group IVB, VB and VIB metal sulfide nanotubes, titanium boride, titanium carbide, diamond, and combinations thereof.Attorney Docket No.: 4774-0060W00636. The process of any one of claims 31 to 35, wherein the non-melanin material and the melanin material are present in a ratio selected from the group consisting of about 5 to 95, about 20 to 80, about 30 to 70, about 40 to 60, about 50 to 50, about 60 to 40 about 70 to 30 about 80 to 20, about 95 to 5 (percent by weight).

37. The process of any one of claims 31 to 36, wherein the non-melanin material and the melanin material combine to synergistically increase the impact resistance of the sound absorbing material compared to the non- melanin materials and melanin material alone.

38. The process of any one of claims 31 to 37, wherein the material is formed into an article which is an item selected from the group consisting of helmets, headphones, fabric, vehicle cladding, aircraft cladding, watercraft cladding, structure cladding, equipment housing, blast protection panels, sound absorbing panels, and cargo containers.

39. A method of preparation of melanin material comprising:- providing a melanin source selected from the group consisting of squid ink, cuttlefish ink, octopus ink, natural melanin, synthetic melanin, mushrooms, and combinations thereof;- applying microwave radiation, thereby producing a melanin material.

40. A method of preparation of melanin material comprising:- providing a melanin source selected from the group consisting of squid ink, cuttlefish ink, octopus ink, natural melanin, synthetic melanin, mushrooms, and combinations thereof;- applying microwave radiation;- applying compression; thereby producing a melanin material.

41. The method of claim 40, wherein the compression is applied in a hydraulic press.Attorney Docket No.: 4774-0060W00642. The method of claim 41 , wherein the hydraulic press ranges in capacity from approximately 1 ton / in2 to 500 tons / in2, 1 ton / in2 to 50 tons / in2, 50 tons / in2 to 100 tons / in2, 1 ton / in2 to 100 tons / in2, 50 tons / in2 to 200 tons / in2, or 1 ton / in2 to 200 tons / in2.

43. A pharmaceutical composition comprising: at least one melanin material; optionally, at least one additional pharmaceutically active agent; optionally, at least one additional pharmaceutically acceptable carrier, wherein the pharmaceutical composition is formulated or manufactured as a liquid, an elixir, an aerosol, a spray, a powder, a tablet, a pill, a capsule, a gel, a geltab, a nano-suspension, a nano-particle, an extended release dosage form, or a topical formulation, further wherein the pharmaceutical composition is a therapeutically effective for treating a condition in a patient.

44. A process for making a pharmaceutical composition comprising:Providing at least one melanin material;Optionally providing at least one additional pharmaceutically active agent; Optionally providing at least one additional pharmaceutically acceptable carrier,Mixing the at least one melanin material, if present the at least one additional pharmaceutically active agent, and if present the at least one additional pharmaceutically acceptable carrier, thereby forming a pharmaceutical composition, further wherein the pharmaceutical composition is a therapeutically effective for treating a condition in a patient.

45. A method of preparation of melanin material comprising:- providing a melanin source selected from the group consisting of squid ink, cuttlefish ink, octopus ink, natural melanin, synthetic melanin, mushrooms, and combinations thereof;- providing a metal selected from the group consisting of iron, copper, zinc, cesium, radium, strontium, thorium, uranium, and combinations thereof;- applying microwave radiation to the melanin source to form a dried melanin source;- mixing the metal with the dried melanin source;Attorney Docket No.: 4774-0060W006- optionally, applying compression; thereby producing a melanin material.

46. The method of claim 45, wherein the compression is applied in a hydraulic press.

47. The method of claim 46, wherein the hydraulic press ranges in capacity from approximately 1 ton / in2 to 500 tons / in2, 1 ton / in2 to 50 tons / in2, 50 tons / in2 to 100 tons / in2, 1 ton / in2 to 100 tons / in2, 50 tons / in2 to 200 tons / in2, or 1 ton / in2 to 200 tons / in2.

48. A pharmaceutical composition comprising:- a therapeutically effective amount of an agent which is selected from the group consisting of melanin, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, lyophilized melanin, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof; and- at least one pharmaceutically acceptable excipient.

49. The composition of claim 48 wherein the composition is provided in a sublingual or buccal dosage form.

50. The composition of claim 48, wherein the composition comprises a pharmaceutically acceptable excipient selected from the group consisting of buffer, preservative, isotonic agent, an antioxidant, and combinations thereof.

51. The composition of claim 48 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.

52. The composition of claim 48 wherein the composition comprises the agent in a dose from about 10 mg to about 450 mg,.

53. The composition of claim 48 wherein the agent is present in an amount of from 2% to 50% of the total weight of the composition.

54. The composition of claim 48 wherein the agent is present in an amount of from 25% to 30% of the total weight of the composition.Attorney Docket No.: 4774-0060W00655. The composition of claim 48 wherein said agent is melanin and the therapeutically effective amount of melanin comprises at least about 75 mg to about 450 mg.

56. The composition of claim 55 wherein said therapeutically effective amount of melanin comprises about 240 mg.

57. The composition of claim 48 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.

58. A method for the treatment or prevention of acute radiation syndrome (ARS) in a subject in need thereof comprising:- administering the composition of claim 48 to the subject, wherein the administration of the composition treats or prevents ARS in the subject.

59. The method of claim 58 wherein the pharmaceutical composition is administered transmucosally through sublingual or buccal routes of delivery.

60. The method of claim 59, wherein the oral mucosal membrane is selected from the group consisting of buccal, sublingual, and combinations thereof.

61. Amethod as defined in claim 58, wherein said agent is melanin and the therapeutically effective amount of melanin comprises at least about 75 mg to about 450 mg.

62. A method as defined in claim 61, wherein said therapeutically effective amount of melanin comprises about 240 mg.

63. A method as defined in claim 58, wherein the composition comprises the agent in a dose from about 10 mg to about 450 mg.

64. A method as defined in claim 58, wherein the agent is melanin and the 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.Attorney Docket No.: 4774-0060W00665. A kit for the treatment, amelioration or prevention of a condition selected from the group consisting of acute radiation syndrome (ARS), in a patient in need thereof comprising:(a) the composition of claim 48; and(b) at least one blister package; a lidded blister; a blister card or packet; a clamshell; an intravenous (IV) package, IV packette or IV container; a bottle; a metal tube; a laminate tube; a plastic tube; a dispenser; a pressurized container; a barrier container; a package; a tray or a shrink wrap, comprising the pharmaceutical composition of (a) and instructions for use of the composition.

66. A product of manufacture comprising a blister package; a lidded blister; a blister card or packet; a clamshell; an intravenous (IV) package, IV packette or IV container; a bottle; a metal tube; a laminate tube; a plastic tube; a dispenser; a pressurized container; a barrier container; a package; a tray or a shrink wrap comprising the composition of claim 48 and instructions for use of the composition.

67. A method of producing a composition for use in mucosal delivery of claim 48, the method comprising:- providing a therapeutically effective amount of an agent which is selected from the group consisting of melanin, pharmaceutically acceptable derivatives thereof, pharmaceutically acceptable salts thereof, and combinations thereof;- providing at least one pharmaceutically acceptable excipient; and- mixing the agent, and at least one pharmaceutically acceptable excipient to thereby produce the composition.

68. The method of claim 67 wherein the composition is provided in a sublingual or buccal dosage form.

69. The method of claim 67, wherein the composition comprises a pharmaceutically acceptable excipient selected from the group consisting of buffer, preservative, isotonic agent, an antioxidant, and combinations thereof.Attorney Docket No.: 4774-0060W00670. The method of claim 67 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.

71. A method as defined in claim 67, wherein said agent is melanin and the therapeutically effective amount of melanin comprises at least about 75 mg to about 450 mg.

72. A method as defined in claim 71, wherein said therapeutically effective amount of melanin comprises about 240 mg.

73. The method of claim 67 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.

74. The sound absorbing material of any one of claims 1 to 8, wherein the sound absorbing material converts sound energy to electrical energy.

75. The process of any one of claims 9 to 15, wherein the sound absorbing material converts sound energy to electrical energy.

76. The composite material of any one of claims 16 to 30, wherein the composite material converts sound energy to electrical energy.

77. The process of any one of claims 31 to 38, wherein the composite material converts sound energy to electrical energy.

78. The process of claim 39, wherein the composite material converts sound energy to electrical energy.

79. The method of any one of claims 40 to 42, wherein the melanin material converts sound energy to electrical energy.

Images