Oral delivery compositions for treating dermatitis disorders in mammals

Abstract

A composition for treating atopic dermatitis in animals containing active compositions of ceramides for skin barrier protection, omega 3 and omega 6 fatty acids for reducing pruritus and botanical extracts for inhibiting 5-lipoxygenase activity, histamine release while modulating the immune system. The active compositions are placed in a soft dough oral delivery system.

Claims

1. An oral ingestible composition for treating atopic dermatitis in a mammal, the composition comprising: active ingredients mixed throughout a soft dough carrier base, wherein the active ingredients are present in the composition in an amount therapeutically effective to treat atopic dermatitis, and wherein the active ingredients comprise: ceramide in an amount of from about 0.01% to about 1.0% w/w of the composition; a lipoxygenase inhibitor comprising at least one of black cumin (Nigella sativa) and ginger root (Zingibar officinale) extract; licorice (Glycyrrhiza glabra) extract; triptolide; vitamins selected from the group consisting of vitamin A, vitamin C, vitamin D, vitamin E, vitamin K, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B9, and vitamin B12; minerals selected from the group consisting of zinc, manganese, copper, and molybdenum; and polyunsaturated fatty acids selected from the group consisting of omega-3 fatty acids and omega-6 fatty acids in an amount of from about 8.0% to about 15% w/w of the composition; and wherein the soft dough carrier base comprises flour, an emulsifier, a starch, an oil, a softening agent, and water.

2. A method of treating atopic dermatitis in a mammal comprising administering the composition of claim 1 to the mammal.

Description

DETAILED DESCRIPTION OF THE INVENTION

(1) The present invention employs the use of a soft food delivery system for the oral administration of ceramide in concert with another ingredient, which together forms a synergistic beneficial therapeutic effect on the animal.

(2) Ceramides

(3) Ceramides are a complex family of waxy lipid molecules. A ceramide is composed of sphingosine and a fatty acid. Sphingosine (2-amino-4-octadecene-1,3-diol) is an 18-carbon amino alcohol with an unsaturated hydrocarbon chain. A fatty acid is a carboxylic acid with a long aliphatic tail (chain), which is either saturated or unsaturated. Ceramides are found in high concentrations within the cell membrane of cells. They are one of the component lipids that make up sphingomyelin, one of the major lipids in the lipid bilayer. Ceramides and other sphingolipids found in the cell membrane play a structural role in cells, but can also participate in a variety of cellular signaling include regulating differentiation and proliferation of cells. Adding sugar molecules to the ceramide compound creates a group of molecules called glycosylceramides. When the sugar is glucose, the molecule is called a glucosylceramide. Glucosylceramide is a major constituent of skin lipids, where it is essential for lamellar body formation in the stratum corneum and to maintain the water permeability barrier of the skin. In addition, the epidermal glucosylceramides (together with sphingomyelin) are the source of the unusual complex ceramides that are found in the stratum corneum, including those with estolide-linked fatty acids.

(4) Oral ceramides from Konjac root have been used in Japan and appear to be safe. In 2004, New Dietary Ingredient (NDI) Notification was submitted pursuant to 21 C.F.R. 0 190.6 and Section 8 of the Dietary Supplement Health and Education Act. This Notification concerned the new dietary ingredient phyto-derived Ceramides, a type of lipids which are constituents of sphingolipids, and for this Notification, derived from either wheat or rice. Oral application of glycosylceramide has been used in one published case study of on a dog (Manoru). The results concluded that oral supplementation can improve CAD.

(5) Providing building blocks of ceramides and omega fatty acids to help the barrier function of the skin is important, but blocking the underlying causes of atopic dermatitis in animals is also required. Use of certain botanical extracts is a safe way of treating animals to block underlying causes of atopic dermatitis. However, the specific botanical extracts used are the challenge. Examples of suitable glycosylceramides sources include konjac tuber, rice, corn, apple, sugar beet and wheat. The term ceramide includes all ceramides, whether naturally or synthetically derived, i.e., animal or vegetable.

(6) The oral ceramide may be included in an amount of from about 0.01% to about 1.0% w/w of the viscoelastic mass, preferably from about 0.02% to about 0.10% w/w, and more preferably from about 0.04% to about 0.08% w/w.

(7) Lipoxygenase Inhibitor

(8) Black Cumin (Nigella sativa) has been shown to be effective in helping treat a number of immune-related disorders including psoriasis (Sharrif). While it has numerous compounds, nigellone, one of its major actives, has been shown to inhibit the release of histamine from mast cells (Chakravarty). It also inhibits 5-lipoxygenase product formation and has anti-inflammatory activity (El-Dakhakhny). Black cumin also is an Association of American Feed Control Officials (AFFCO) approved ingredient. Black Cumin can be provided in the form of an extract such as an oil, a powder, or other forms.

(9) Ginger root extract (Zingibar officinale) has been used as a calming agent in nutraceutical supplements, but the anti-inflammatory properties of ginger have been known and valued for centuries. Ginger has lipoxygenase inhibition action (Grzanna) and has antihistamine activity (Supinya). Formulas containing ginger have been efficacious and safe to treat recalcitrant atopic dermatitis (Kobayashi). Ginger is an AAFCO approved ingredient.

(10) Other lipoxygenase inhibitors from herbal sources include catechins such as epicatechin, epigallocatechin gallate, epigallocatechin and others from tea (Camellia sinensis) allicin from garlic (Allium sativum); caffeic acid from dandelion (Taraxacum officinale) (Subhuiti). These herbals are safe and are AFFCO approved ingredients. The amount of the herbal extract included in the viscoelastic mass can be adapted to the specific needs of the target animal.

(11) The lipoxygenase inhibitors may be included in an amount of from about 0.001% to about 10.0% w/w of the viscoelastic mass, preferably from about 0.01% to about 5% w/w, and more preferably from about 1.0% to about 3.5% w/w.

(12) Antihistamine

(13) Licorice (Glycyrrhiza glabra) is a traditional botanical that has been used as an anti-allergy agent, anti-inflammatory agent, and anti-asthmatic agent. Research shows that licorice works through IgE production inhibitory actions and through antihistamine activity (Saeedi). Licorice has been effective for treating atopic dermatitis and also is an approved AFFCO approved ingredient (Yong-Wook). Licorice components given orally have been shown to reduce allergan-induced scratching behavior in animals (Saeedi).

(14) Extracts of basil, ginger, thyme, origanum and caraway are also known to have antihistamine capability. These are all natural compounds and are AFFCO approved. The amount of the licorice or other listed herbal extract included in the viscoelastic mass can be adapted to the specific needs of the target animal. As an example, licorice extract may be included in an amount of from about 0.001% to about 7.0% w/w of the viscoelastic mass, preferably from about 0.01% to about 5.0% w/w, and more preferably about 1.0% to about 2.0% w/w.

(15) Immunomodulator

(16) Treatment of atopic dermatitis is commonly done with drugs, like cyclosporine, that decrease the activity of the immune system. There can be undesirable side effects when using drugs like cyclosporine. The use of botanical extracts that would decrease the activity of the immune system without side effects is therefore desirable for atopic dermatitis. Extracts from Tripterygium wilfordii containing triptolide, has a long history of use in traditional Chinese medicine to treat immune-related disorders. These extracts have been used to treat inflammation including atopic dermatitis. Triptolide appears to have a suppressive effect on the immune system, and it inhibits the development and spread of inflammation.

(17) Triptolide inhibits the transcription of the p40 gene encoding the shared subunit of IL-12 and IL-23 in APCs (Yan). The immunosuppressive effect of triptolide on T cells has been somewhat characterized. It inhibits T cell activation and cytokine gene transcription in T cells and suppresses the expression of genes for transcription factors, signal transduction pathway regulators, DNA binding protein, and MAPK in Jurkat cell. In addition, triptolide inhibits lymphocyte activation and T cell expression of IL-2 at the level of transcription by inhibiting NF-B transcriptional activation.

(18) However, little is known about the effect of triptolide on accessory cells, particularly the professional APCs, such as dendritic cells (DCs) and macrophages. It has been suggested that DCs are a primary target of the immunosuppressive activity of triptolide. At high concentrations (20 ng/ml) triptolide induces apoptosis of DCs through sequential p38 MAP kinase phosphorylation and caspase 3-activation. It has also been shown that triptolide inhibits DC-mediated chemoattraction of neutrophils and T cells through inhibiting Stat3 phosphorylation and NF-B activation. Triptolide prevents the differentiation of immature monocyte-derived DC (MoDC) by inhibiting CD1a, CD40, CD80, CD86, and HLA-DR expression, and by reducing the capacity of MoDC to stimulate lymphocyte proliferation in allogeneic MLR. However, expression of surface CD14 and phagocytic capacity of MoDC was enhanced by triptolide. Therefore, the suppression of DC differentiation, maturation, and function of immature DCs by triptolide may explain some of its immunosuppressive properties.

(19) The amount of triptolide included in the viscoelastic mass can be adapted to the specific needs of the target animal. As an example, triptolide may be included in an amount of from about 0.001% to about 1% w/w of the viscoelastic mass, preferably from about 0.005% to about 0.05% w/w, and more preferably from about 0.01% to about 0.03% w/w.

(20) Other immunomodulators that are from natural herbal sources include garlic, turmeric, and tea. These are AFFCO-approved ingredients. Vitamins A, C, and E are also known to be immunomodulators. These are also all AFFCO approved ingredients.

(21) Polyunsaturated Fatty Acids

(22) Omega-3 and omega-6 fatty acids (also called -3 and -6 fatty acids or n-3 and n-6 fatty acids) are polyunsaturated fatty acids (PUFAs) with a double bond (CC) at the third or sixth carbon atom from the end of the carbon chain for the omega 3 and omega 6, respectively. The fatty acids have two ends, the carboxylic acid (COOH) end, which is considered the beginning of the chain, thus alpha, and the methyl (CH3) end, which is considered the tail of the chain, thus omega. The way in which a fatty acid is named is determined by the location of the first double bond, counted from the methyl end, that is, the omega (-) or the n-end.

(23) The three types of omega-3 fatty acids involved in mammalian physiology are -linolenic acid (ALA), found in plant oils, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), both commonly found in marine oils. Marine algae and phytoplankton are primary sources of omega-3 fatty acids. Common sources of plant oils containing the omega 3 ALA fatty acid include walnut, edible seeds, clary sage seed oil, algal oil, flaxseed oil, Sacha Inchi oil, Echium oil, and hemp oil, while sources of animal omega-3 EPA and DHA fatty acids include fish oils, egg oil, squid oils, and krill oil. Omega 3 and omega 6 fatty acids are selected from the group consisting of plant oils, fish oils, animal oils, algea sources and crustacean sources. Evening primrose oil is an excellent source of omega 6 polyunsaturated fatty acids. Linoleic acid (18:2, n-6), the shortest-chained omega-6 fatty acid, is one of many essential fatty acids and is categorized as an essential fatty acid because mammals cannot synthesize it. Mammalian cells lack the enzyme omega-3 desaturase and therefore cannot convert omega-6 fatty acids to omega-3 fatty acids.

(24) The amount of omega 3 and omega 6 polyunsaturated fatty acids included in the viscoelastic mass can be adapted to the specific needs of the target animal. As an example, omega 3 and omega 6 polyunsaturated fatty acids may be included in an amount of from about 0.001% to about 25% w/w of the viscoelastic mass, preferably from about 1.0% to about 20.0% w/w, and more preferably from about 8.0% to about 15.0% w/w.

(25) There are also a number of minerals and vitamins that help maintain the immune system. These include zinc, vitamin A, vitamin B12, vitamin E, vitamin C. These vitamins and minerals act as cofactors in enzymatic reactions that are required by the immune system to help maintain normal skin health (Kumary). These vitamins and minerals are a key aspect in formulations that address skin health of dogs.

(26) Vitamins

(27) The composition may include one or more vitamins. Vitamins are necessary for literally tens of thousands of different chemical reactions in the body. They often work in conjunction with minerals and enzymes to assure normal digestion, reproduction, muscle and bone growth and function, healthy skin and hair, clotting of blood, and the use of fats, proteins, and carbohydrates by the body. For example, vitamin E isomers (mixed tocopherols) are antioxidants that help protect animals from free radical damage. Vitamin deficiencies can occur in an animal if poor quality food is provided to the animal. Vitamin deficiencies can also occur if an animal is under stress. Ill or recovering animals that may have a poor appetite typically need a vitamin supplement since they are not receiving their daily requirements through the food they eat. Animals in other situations such as stress from travel, showing, training, hunting, breeding, or lactation can also benefit from vitamin supplementation. Older animals can also benefit from vitamin supplementation. Older animals tend to absorb fewer vitamins, minerals, and electrolytes through the intestinal tract, and lose more of them through the kidneys and urinary tract. Also, some older animals eat less (due to conditions such as oral disease) and may not receive their daily needs of vitamins and minerals. These same old animals are often the ones that will also be given solid medications to treat other conditions. Another issue that may increase the need for vitamin supplementation in animals is that commercial feeds typically involve a heating process that can destroy vitamins present in the feed. The viscoelastic mass of the delivery system described below does not involve heat for manufacture and is therefore able to provide vitamins that are not degraded.

(28) Any vitamin known in the art may be included in the composition of the present invention. Particular vitamins may be provided according to the nutritional requirements of the target animal. Suitable vitamins include both water soluble and/or fat soluble vitamins. Exemplary water soluble vitamins include any or all of the B vitamins (Vitamin B.sub.1, B.sub.2, B.sub.3, B.sub.4, B.sub.5, B.sub.6, B.sub.7, B.sub.8, B.sub.9, B.sub.10, B.sub.11, and B.sub.12) and/or Vitamin C (ascorbic acid). Exemplary fat soluble vitamins include Vitamin A, Vitamin D, Vitamin E, and Vitamin K. As stated above, vitamins A, C, and E also function as immunomodulators. The fat-soluble vitamins may be provided as an element of oils utilized in the present invention, such as, for example, canola oil, corn oil, soybean oil, and vegetable oil. The amount of the vitamins included in the viscoelastic mass can be adapted to the specific needs of the target animal. As an example, each vitamin may be included in an amount of from about 0.001% to about 10.0% w/w of the viscoelastic mass, preferably from about 0.01% to about 5.0% w/w, and more preferably from about 0.5% to about 1% w/w.

(29) Minerals

(30) Minerals play important roles in many biochemical functions in the body. Deficiencies of minerals can lead to problems in the immune system. However supplementation of zinc and copper can help correct these problems. As absorption of chelated minerals to amino acids or other substances is enhanced, this invention uses chelated minerals. This invention uses chelated copper, zinc, manganese and molybdenum to benefit the immune system. The preferred concentration of copper is from 0.1 mg to 2 mg/kilogram; for zinc is from 100 mg to 300 mg/kilogram; and for manganese is from 0.05 mg to 0.2 mg/kilogram.

(31) A typical formulation for a dog is:

(32) TABLE-US-00001 Ingredient Quantity/Concentration Ceramide 0.0625% w/w Nigella sativa 0.63% w/w Zingibar officinale 0.63% w/w Licorice 6.3% w/w Triptolide 0.025% w/w Omega-3 PUFA 12.5% w/w Vitamin A 150 IU/g Vitamin B12 0.00010% w/w Vitamin C 0.005% w/w Vitamin E 2.5 IU/g Copper 0.0625% w/w Manganese 0.0275% w/w
A typical formulation for a cat is:

(33) TABLE-US-00002 Ingredient Quantity/Concentration Ceramide 0.02% w/w Nigella sativa 0.20% w/w Zingibar officinale 0.20% w/w Licorice 2.3% w/w Triptolide 0.008% w/w Omega-3 PUFA 4.1% w/w Vitamin A 50 IU/g Vitamin B12 0.00003% w/w Vitamin C 0.0016% w/w Vitamin E 0.8 IU/g Copper 0.002% w/w Manganese 0.009% w/w
Delivery System

(34) The base composition of the delivery system is comprised of a base powder, lecithin, glycerol, molasses, sugar, starch, mixed tocopherols, sodium chloride, preservatives and water mixed together to form a soft dough composition and extruded. The composition of the present invention comprises a viscoelastic mass. The viscoelastic mass is an edible, dough-like composition that is capable of being folded, wrapped, or rolled around a medicine or otherwise manipulated to surround the medicine to conceal or mask the flavor of the medicine. The viscoelastic mass comprises a carrier base and one or more effector components.

(35) Base Powder: The base powder generally provides structural integrity to the mass. The base powder may comprise a plant powder, an animal powder, or both a plant and an animal powder. Plant powders are powders derived from plants, such as flours or other powders. The flours may be whole flours or flours which have had fractions, such as the germ fraction or the husk fraction, removed. Non-limiting examples of suitable plant powders include soy flour, wheat flour, whole wheat flour, whole wheat fine flour, wheat feed flour, wheat gluten, pre-gel wheat flour, soy protein concentrate, oat flour or powder, barley powder or flour, brown rice flour or powder, dried whey powder, carrot powder, cherry powder, pineapple powder, and alfalfa herb powder. Animal powders are powders derived from animals and can include dehydrated meat byproducts, such as liver powder. In a preferred version of the invention, the base powder comprises an animal powder and a plant flour, which can be mixed with a fluid lubricant. The powder is preferably included in an amount of from about 0% to about 50% w/w of the viscoelastic mass.

(36) Starch: The delivery system may include a starch. As used herein, starch refers to any substance comprised of more than about 80%, 90%, 95%, or even 99% amylase and amylopectin by weight. Starches from various sources are known in the art. Suitable starches can be obtained from tuberous foodstuffs, such as potatoes, tapioca, and the like. Other suitable starches can be obtained upon grinding cereal grains such as corn, oats, wheat, milo, barley, rice, and others. The starch may be included in an amount of from about 0% to about 2% w/w of the composition, such as from about 1% to about 15% w/w or from about 5% to about 9% w/w.

(37) Emulsifiers: The composition may include an emulsifier. Suitable emulsifiers include nonionic surfactants, such as polyoxyethylated castor oil, polyoxyethylated sorbitan monooleate, sorbitan monostearate, ethyl alcohol, glycerol monostearate, polyoxyethylene stearate, and alkylphenol polyglycol ethers; ampholytic surfactants, such as disodium N-lauryl-B-iminodipropionate and lecithin; and anionic surfactants, such as sodium lauryl sulphate, fatty alcohol ether sulphates, and mono/dialkyl polyglycol ether orthophosphoric ester monoethanolamine salt. A preferred emulsifier is lecithin, such as soy lecithin. The emulsifier may be included in an amount of from about 0% to about 20% w/w of the composition, such as from about 4% to about 16% w/w or from about 6% to about 10% w/w.

(38) Softening Agents: In order to provide an edible soft chew, the composition preferably includes a softening agent. Examples of suitable softening agents include glycerol and propylene glycol, wetting agents such as cetyl alcohol and glycerol monostearate, and other humectants. Glycerin is a preferred softening agent and can maintain the softness of the composition over the shelf life of the product. The softening agent may be included in an amount of from about 0% to about 50% w/w of the composition, such as from about 5% to about 25% w/w or from about 9% to about 14% w/w.

(39) Flavorings: A flavoring is preferably included in the composition to enhance the palatability of the mass and to mask the flavor of any medicine included therewith. The flavoring is preferably food grade quality. Sweeteners constitute one type of suitable flavoring. Examples of suitable sweeteners include such sugars as xylose, ribose, sucrose, mannose, galactose, fructose, dextrose, and maltose. Other suitable sweeteners include molasses, honey, maple syrup, and fruit flavoring. The sweeteners may be in powdered, granulated, or liquid form. Natural or synthetic sweeteners are suitable. Preferred sweeteners include powdered sugar and dry molasses. Other suitable flavorings include carob, peanuts, garlic, and herbs such as, parsley, celery, peppermint, and spearmint. Natural and synthetic flavoring oils can also be included as a flavoring. Examples of flavoring oils include anise oil, spearmint oil, peppermint oil, cinnamon oil, wintergreen oil, citrus oils, such as lemon, orange, grape, lime, and grapefruit oils. Other suitable flavorings include fruit essences such as apple, strawberry, cherry, and pineapple essences, among others. The flavoring may be included in an amount of from about 0% to about 20% w/w of the viscoelastic mass, such as from about 2% to about 15% w/w, or from about 5% to about 10% w/w.

(40) Antioxidants: The composition preferably includes an antioxidant. Examples of suitable antioxidants include alpha-tocopherol, alpha-tocopherol acetate, butylated hydroxytoluene (BHT), ascorbic acid, mixed tocopherols, propyl gallate, and mixtures thereof. The antioxidant may be included in an amount of from about 0% to about 0.3% w/w of the composition, such as from about 0.025% to about 0.2% w/w, or from about 0.05% to 0.15% w/w.

(41) Preservatives: The composition preferably includes a preservative to prevent or retard growth of microorganisms and fungi. Suitable preservatives include potassium sorbate, methylparaben, propylparaben, sodium benzoate, calcium propionate, or combinations thereof. A preferred preservative comprises a combination of potassium sorbate, methylparaben, and propylparaben. The preservatives may be included in an amount of from about 0% to about 1% w/w of the viscoelastic mass, such as from about 0.03% to about 0.75% w/w or from about 0.05% to about 0.75% w/w.

(42) Salts: The composition preferably includes one or more salts comprising mono- and/or divalent cations for proper gelation of the mass. Suitable sources of mono- and divalent cations include sodium, potassium or calcium salts such as sodium chloride, potassium chloride, calcium chloride, or potassium citrate, among others. Such a salt may be included in an amount of from about 0% to about 5% w/w of the viscoelastic mass, such as from about 0.1% to about 2.5% w/w or from about 0.4% to about 0.6% w/w.

(43) Water and Oil: The composition preferably includes water in an amount of from about 1% to about 50% w/w of the viscoelastic mass, such as from about 1% to about 30% w/w or about 5% to about 15% w/w. The composition preferably includes an oil in an amount of from about 1% to about 50% w/w of the composition, such as from about 1% to about 30% w/w or about 5% to about 15% w/w. Suitable oils include, for example, canola oil, corn oil, soybean oil, and vegetable oil, among others.

(44) Amounts of Components: The amounts of each of the components in the composition may be varied from the amounts described herein depending upon the nature of the delivery drug, the weight and condition of the animal to be treated, and the unit dosage desired. Those of ordinary skill in the art will be able to adjust dosage amounts as required.

(45) Preparation: The individual ingredients in the composition of the invention are mixed together in a standard mixing apparatus. The dry powders are mixed initially. This is followed by the addition of liquid materials to create a soft dough that is easily pliable by hand. The materials are mixed until the dough composition has reached a satisfactory pliability texture level and no dry materials are present. The dough is then transferred to an extruder device hopper. The extruder device hopper feeds the soft dough through an extrusion port, and a knife blade chops the extruded dough composition to a desired length and weight. The cut pieces of the invention are subsequently packaged.

(46) The extruded dough can form any cross-sectional shape depending on the extrusion port design. Suitable shapes include rectangles, squares, circles, triangles, or other specific shapes such as animal or bone shapes. A preferred cross-sectional shape is a thin rectangle. The extruded dough can also have any length, which is determined by the distance between the knife cuts as the dough leaves the extrusion port. The size of the final product may be varied depending on the size of the target animal and the size of the solid medication to be wrapped. In a preferred version of the invention, the viscoelastic mass takes the form of a sheet, i.e., having a depth less than about half the magnitude of the length and width, such as a depth less than about a quarter the magnitude of the length and width.

(47) The extruded dough can be in any shaped designed depending on the extrusion port design. These shape range from a shapeless mass, cylinders, rectangles, squares, circles, triangles, or other specific shapes such as animals or bones shapes.

(48) Use: The composition can take any of several semi-solid of soft dough format in the shape of pills, tablets or boluses. The composition can be administered to any animal, including mammals, in need of nutritional supplementation and/or a particular medication. Non-limiting examples of suitable animals include, dogs, cats, horses, cows, pigs, goats, and sheep, among others. The composition is preferably used with dogs.

Example 1

(49) Ingredients as found in Table 1 were mixed together by first mixing the dry materials in a mixing device followed by mixing in the liquid ingredients to create a base composition. The mixing resulted in a soft dough that was extruded through an extrusion device. The dye shape on the extruder resulted in cylinder shaped pieces that were cut into 8 grams pieces. The extruded shaped material was packaged.

(50) TABLE-US-00003 TABLE 1 Base composition of Soft Dough Delivery System Ingredient % w/w Soy Flour 9.80% Soy Lecithin 8.00% Pregelatinized Starch 7.00% Dry Molasses 14.00% Soy Oil 7.90% Glycerine 11.00% Poultry Liver Powder 12.00% Potassium Sorbate 0.50% Sodium Chloride USP 0.50% Powder Sugar 5.00% Mixed Tocopherols 0.10% Whole Wheat Fine Flour 15.50% Water 8.50% Methylparaben 0.1 Propylparaben 0.1

Example 2

(51) Palatability trials were conducted on the base composition found in table 1. Twenty dogs were given single 8 gram pieces of the composition. All of the dogs consumed the composition within 10 seconds. This indicated that the base composition of the invention was palatable to the dog.

Example 3

(52) Active ingredients found in Table 2 were mixed into base compositions of Table 1 to create 100 lbs of total mixture. The composition was extruded and cut into 8 gram pieces as described in Example 1. Twenty dogs were given single 8 grams pieces of the base composition with active ingredients. All of the dogs consumed the oral dose within 10 seconds. This indicates that the active ingredients for treating atopic dermatitis were successfully masked by the base composition of the invention.

(53) TABLE-US-00004 TABLE 2 Active Ingredients Black Seed Oil 6.3 lbs Ginger Powder 0.63 lbs Licorice powder 6.3 lbs Omega 3 DHA beadlets 12.5 lbs MEG-3 DHA Powder Konjac Ceramides 0.0625 lbs Zin Pro 180 (zinc) 0.15 lbs Vitamin A 500,000 IU, 0.03 lbs Vitamin B-12 (1%) 0.01 lbs Vitamin E 50% (500 IU) 0.25 lbs Ascorbic Acid (99-100%) 0.7 lbs

Example 4

(54) A clinical trial was set up to examine the efficacy of the invention. Dogs with diagnosed with non-seasonal atopic dermatitis using the William's clinical criteria [Williams, R R, et al] were selected and based on being >1 year of age and >5 lbs weight but otherwise being healthy. Exclusion criteria for the trial included clinical evidence of active ectoparasite infestation, bacterial, fungal skin infection, pyoderma, malassezia dermatitis or mange; concurrent or within 21 days use of immunosuppressant, glucocorticoids, antihistamines, anti-inflammatory (NSAIDs) or antibiotic treatment; if the dogs had been using essential fatty acid supplement within 21 days before the start of the trial; dogs with hypothyroidism, active or uncontrolled flea allergy and food allergy were excluded.

(55) The dose was administered in the form of two soft chew with actives as in example 3 twice daily with or without food for eight weeks. During the trial animals were evaluated at day 0, at two weeks, 4 weeks and at final visit at 8 weeks.

(56) The direct effect of treatment was measured by the CADESI. This index is based on the presence and intensity clinical indicators such as erythema, lichenification, alopecia (hair loss) and excoriation on different skin areas. A of score 0 indicates no visible problems are present while a score of 1 or 2 indicates mild or moderate condition and a score of 5 indicates the most severe conditions.

(57) Results: Prior to treatment, the dog has a skin lesion that is erythematous and inflamed. There was lichenification of skin with alopecia. A CADESI score of 4 was given to this animal before treatment. After 8 weeks of oral treatment, there was a reduction in the amount of erythematous skin tone and a reduction in lesion size. While alopecia has not improved at lesion site at this time point in the trial, that may be due to damage of hair follicles that ultimately can grow back. The reduction in erythema redness that is very evident after the treatment that might be accounted for by a reduction in rubbing or scratching of the skin by the dog, especially as concurrent skin health improves. There was an improvement in the CADESI score to a level of 2 after the treatment with the invention. The improvement in CADESI score in this animal is consistent with the efficacy of the invention.

Example 5

(58) The same trial set up as found in example #4 was carried out in another dog. Prior to treatment, there was a lichenified lesion present with diffuse thickening and hardening of skin, along with alopecia. The alopecia might have been the result of excessive pruritus and scratching. However there is no erythematous lesion in this case. The CADESI value was evaluated to be 5 before treatment. After 8 weeks of treatment with the invention, there was visible growth in hair at lesion site and reduction in scabbed and lichenified skin. The CADESI score was evaluated to be 2. This shows skin health improvement when using the invention. These improvements in CADESI score results are consistent with the efficacy of the invention.

(59) Any version of any component or method step of the invention may be used with any other component or method step of the invention. The elements described herein can be used in any combination whether explicitly described or not.

(60) All combinations of method steps as used herein can be performed in any order, unless otherwise specified or clearly implied to the contrary by the context in which the referenced combination is made.

(61) As used herein, the singular forms a, an, and the include plural referents unless the content clearly dictates otherwise.

(62) Numerical ranges as used herein are intended to include every number and subset of numbers contained within that range, whether specifically disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 2 to 8, from 3 to 7, from 5 to 6, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.

(63) All patents, patent publications, and peer-reviewed publications (i.e., references) cited herein are expressly incorporated by reference in their entirety to the same extent as if each individual reference were specifically and individually indicated as being incorporated by reference. In case of conflict between the present disclosure and the incorporated references, the present disclosure controls.

(64) The devices, methods, compounds and compositions of the present invention can comprise, consist of, or consist essentially of the essential elements and limitations described herein, as well as any additional or optional steps, ingredients, components, or limitations described herein or otherwise useful in the art.

(65) While this invention may be embodied in many forms, what is described in detail herein is a specific preferred embodiment of the invention. The present disclosure is an exemplification of the principles of the invention is not intended to limit the invention to the particular embodiments illustrated. It is to be understood that this invention is not limited to the particular examples, process steps, and materials disclosed herein as such process steps and materials may vary somewhat. It is also understood that the terminology used herein is used for the purpose of describing particular embodiments only and is not intended to be limiting since the scope of the present invention will be limited to only the appended claims and equivalents thereof.

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