Semi-solid antihistamine compositions and methods of making and using same

Abstract

The present invention provides a semi-solid composition comprising a gel component in an amount sufficient to provide a gel product with binding force, an antihistamine composition comprising an antihistamine agent, and a complexing agent wherein the complexing agent is capable of interacting with the antihistamine agent and forming an antihistamine complex. In one embodiment, the antihistamine agent includes diphenhydramine, cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine, azelastine, bilastine, rupatadine, or a derivative, a salt, or a combination thereof.

Description

[0001] This application is a divisional application of the Chinese invention patent application (application number: 2019800082360; invention name: Semi-solid antihistamine composition and preparation and use method thereof).

[0002] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 62 / 617,303, filed on January 15, 2018, and U.S. Provisional Application No. 62 / 683,523, filed on June 11, 2018. The entire contents of each of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to a semi-solid edible or chewable composition containing one or more biologically active substances. Background Art

[0004] Unless otherwise indicated by the present inventors, the materials described in this section are not prior art to the present claims and are not admitted to be prior art by inclusion in this section.

[0005] Sugar products are excellent delivery materials for nutrients such as vitamins and minerals. One popular form of confectionery for delivering nutrients is gummies. Gum is a chewable confectionery made primarily of gelling agents, monosaccharides and disaccharides, and water. Common gelling agents include pectin, starch, and gelatin. Monosaccharides include glucose, and disaccharides include sucrose. Flavoring agents are sometimes used with gelling agents and sugars to enhance the taste of the gum ingredients.

[0006] Although gummy confections have been widely used for the delivery of vitamins, they have not been used for the delivery of active pharmaceutical ingredients (APIs). One reason is that many APIs have an extremely unpleasant or bitter taste. The inclusion of the API in a gummy form makes for an unpleasant tasting product that many people do not accept. Therefore, pharmaceuticals are usually reserved for non-chewable products that minimize oral contact. Summary of the invention

[0007] The following summary is illustrative only and is not intended to be limiting in any way. In addition to the illustrative aspects, embodiments, and features described above, further aspects, embodiments, and features will become apparent by reference to the drawings and the following detailed description.

[0008] In one aspect, the semisolid pharmaceutical composition comprises a gel component, an antihistamine composition and a complexing agent, wherein the gel component has a sufficient amount to provide a cohesive gel product. The antihistamine composition comprises an antihistamine. The complexing agent can interact with the antihistamine and form an antihistamine complex.

[0009] In one embodiment, the antihistamine composition comprises acrivastine, azelastine, diphenhydramine, bilastine, bromodiphenhydramine, brompheniramine, ancithin, carbinoxamine, cetirizine, chlordiphenhydramine, chlorpheniramine, azemastine, cyclizine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimethinidine, doxylamine, ebastine, embramin, fexofenadine, hydroxyzine, loratadine, meclizine, mirtazapine, olopatadine, o-phenhydramine, antiallergic amine, phenpyramine, phenyltoloxamine, promethazine, quetiapine, rupatadine, tripelennamine, triprolidine, levocetirizine, desloratadine, pyrilamine, or its derivatives. In one embodiment, the antihistamine is an H1-antihistamine. In one embodiment, the antihistamine comprises cetirizine, diphenhydramine, loratadine or fexofenadine. In one embodiment, the antihistamine composition includes cetirizine dihydrochloride or diphenhydramine dichloride.

[0010] In one embodiment, the antihistamine composition consists essentially of cetirizine. In one embodiment, the semisolid pharmaceutical composition comprises cetirizine at a concentration of not less than about 0.05%, 0.1% or 0.2% w / w. In one embodiment, the semisolid pharmaceutical composition comprises cetirizine at a concentration of about 0.07% by weight. In one embodiment, the semisolid pharmaceutical composition comprises cetirizine at a concentration of about 0.14% by weight. In one embodiment, the semisolid pharmaceutical composition comprises cetirizine at a concentration of about 0.28% by weight.

[0011] In one embodiment, the antihistamine composition consists essentially of diphenhydramine. In one embodiment, the semisolid pharmaceutical composition comprises diphenhydramine at a concentration of not less than about 0.3%, 0.5%, or 1% w / w. In one embodiment, the semisolid pharmaceutical composition comprises diphenhydramine at a concentration of about 0.35% by weight. In one embodiment, the semisolid pharmaceutical composition comprises diphenhydramine at a concentration of about 0.71% by weight. In one embodiment, the semisolid pharmaceutical composition comprises diphenhydramine at a concentration of about 1.42% by weight.

[0012] In one embodiment, the antihistamine composition mainly includes loratadine. In one embodiment, the semi-solid pharmaceutical composition includes loratadine at a concentration of not less than about 0.05%, 0.1% or 0.2% w / w. In one embodiment, the semi-solid pharmaceutical composition includes loratadine at a concentration of about 0.07% by weight. In one embodiment, the semi-solid pharmaceutical composition includes loratadine at a concentration of about 0.14% by weight. In one embodiment, the semi-solid pharmaceutical composition includes loratadine at a concentration of about 0.28% by weight.

[0013] In one embodiment, the antihistamine composition consists essentially of fexofenadine. In one embodiment, the semisolid pharmaceutical composition comprises fexofenadine at a concentration of not less than about 0.1%, 0.2%, 0.3%, 0.4%, 0.6%, 0.8%, 1% or 1.2% w / w. In one embodiment, the semisolid pharmaceutical composition comprises fexofenadine at a concentration of about 0.2% by weight. In one embodiment, the semisolid pharmaceutical composition comprises fexofenadine at a concentration of about 0.4% by weight. In one embodiment, the semisolid pharmaceutical composition comprises fexofenadine at a concentration of about 0.6% by weight.

[0014] The complexing agent can be complexed with the antihistamine by coordination, chelation, complexation, hydrogen bonding, dipole-dipole interaction, van der Waals interaction, or a combination thereof. In one embodiment, the antihistamine complex can mask, mitigate, or reduce the taste of the antihistamine, increase the solubility or stability of the antihistamine in an aqueous matrix or a combination thereof. In one embodiment, the antihistamine complex can mask and reduce the bitter, astringent, or metallic taste of the antihistamine. In one embodiment, the antihistamine complex can increase the solubility of the antihistamine in an aqueous matrix, thereby facilitating the incorporation of the antihistamine into an aqueous gel matrix.

[0015] In one embodiment, the complexing agent comprises a protein, a peptide, an amide or polyamide, a clustered dextrin, a cyclodextrin, polydextrose, resistant starch, polyethylene glycol, a polyunsaturated hydrocarbon, a polyunsaturated fatty acid, mica, talc, zeolite, cellulose, plant particles, calcium carbonate, diatomaceous earth, chitosan, or a combination thereof.

[0016] In one embodiment, the complexing agent comprises an amide. Examples of amides include, but are not limited to, 2-deoxy-2-glucose amino N-acetyl, sialic acid N-acetyl, imino sugar N-acetyl, daunamine N-acetyl, 2-deoxy-2-galactosamine N-acetyl, chitin, pectin, and amino acids.

[0017] Plant particles can be derived from various parts of plants, such as flowers, fruits, seeds, grains, nuts, husks, roots, leaves or stems. In one embodiment, the plant particles include berry powder, husk powder, rice bran powder, including but not limited to strawberry powder, orange pulp or peel powder, lemon pulp or peel powder, citrus fruit powder, apple powder, pineapple powder, baobab fruit powder, various berry powders, including but not limited to cherry powder, raspberry powder, blackberry powder, wolfberry powder, cranberry powder or blueberry powder.

[0018] In one embodiment, the complexing agent comprises a clustered dextrin or a cyclodextrin. In one embodiment, the complexing agent comprises a cyclodextrin. In one embodiment, the cyclodextrin comprises α-dextrin, β-cyclodextrin, γ-cyclodextrin, or a combination thereof. In one embodiment, the cyclodextrin comprises primarily γ-cyclodextrin. In one embodiment, the semisolid pharmaceutical composition comprises an antihistamine and a cyclodextrin in a molar ratio of about 1:1 to about 1:100. In one embodiment, the molar ratio of the antihistamine to the cyclodextrin is about 1:1 to about 1:20. In one embodiment, the molar ratio of the antihistamine to the cyclodextrin is about 1:5.

[0019] In one embodiment, the antihistamine composition includes cetirizine, levocetirizine, diphenhydramine, loratadine or fexofenadine, and the complexing agent includes polyamide, clustered dextrin, cyclodextrin or a combination thereof. In one embodiment, the antihistamine composition includes cetirizine, and the complexing agent includes α-cyclodextrin. In one embodiment, the antihistamine composition includes cetirizine, and the complexing agent includes β-cyclodextrin. In one embodiment, the antihistamine composition includes cetirizine, and the complexing agent includes γ-cyclodextrin. In one embodiment, the antihistamine composition includes diphenhydramine, and the complexing agent includes cyclodextrin, clustered dextrin or a combination thereof. In one embodiment, the antihistamine composition includes loratadine, and the complexing agent includes cyclodextrin.

[0020] The gel composition may include gelatin, starch, pectin, gellan gum, gum arabic, carrageenan, guar gum, agar, alginate, locust bean gum, xanthan gum, or derivatives thereof. In one embodiment, the gel composition includes pectin and gelatin in a ratio of about 10:1 to about 1:1. In one embodiment, the gel composition includes gelatin and starch in a ratio of about 100:1 to about 1:100. In one embodiment, the gel composition consists essentially of starch, gelatin, alginate, or pectin. In one embodiment, the gel composition consists essentially of gelatin.

[0021] In one embodiment, the gel component mainly includes pectin. In one embodiment, the gel component includes apple pectin, citrus pectin or a combination thereof. In one embodiment, the semi-solid composition includes at least 1% pectin. In one embodiment, the semi-solid composition includes about 1% to about 5% pectin. In one embodiment, the semi-solid composition includes about 2.5% pectin. In one embodiment, the methoxy content of pectin is not less than 30%, 40% or 50%. In one embodiment, the amide content of pectin is not less than 10%, 15%, 20%, 25%, 30% or 40%. In one embodiment, the carboxyl content of pectin is not less than 25%, 30%, 35%, 40%, 50% or 60%. In one embodiment, pectin has a methyl ester of no more than 30%, 32%, 35% or 40%.

[0022] The semi-solid pharmaceutical composition may further include a herbal composition, an antioxidant composition, a vitamin composition, a mineral composition, an amino acid composition, a probiotic composition or a prebiotic composition. The herbal composition, the antioxidant composition, the vitamin composition, the mineral composition, the amino acid composition, the probiotic composition or the prebiotic composition may act synergistically with an antihistamine to relieve allergy or allergic symptoms (e.g., inflammation, urticaria, congestion, secretions and other respiratory symptoms).

[0023] In one embodiment, the herbal composition includes one or more herbs having biological activity that reduces or relieves allergy symptoms. In one embodiment, the herbal composition acts synergistically with an antihistamine, thereby being configured to enhance the antihistamine activity of the pharmaceutical composition or increase the anti-allergic activity. In one embodiment, the herbal composition may have antihistamine activity. In one embodiment, the herbal composition includes coltsfoot, quercetin, stinging nettle (Urtica dioica), bromelain, timothy grass, tinospora cordifolia stem, elderberry, sorrel, capers, verbena, gentian root, echinacea, grape seed, pycnogenol, pine bark extract, EPA, honey, cat's claw, albizzia (Albizia macrophylla), scutellaria baicalensis, goldenseal, spirulina, bitter orange (citrus), lemon, eucalyptus, frankincense, angelica, eyebright (Eurasian grass), ginkgo, milk thistle (Silybum marianum), red clover (Trifolium pratense), yarrow (Achillea millefolium), rosemary, perilla, sage, mint, turmeric, licorice, astragalus, ginseng, wormwood, Stephania macrophylla, coix seed, bitter orange, citrus, angelica dahurica, and extracts, isolates or distillates thereof.

[0024] In one embodiment, the herbal composition comprises coltsfoot, an extract thereof, or a powder thereof. In one embodiment, the herbal composition comprises nettle leaf, an extract thereof, or a powder thereof. In one embodiment, the herbal composition comprises turmeric, an extract thereof, or a powder thereof. In one embodiment, the herbal composition comprises angelica, an extract thereof, or a powder thereof. In one embodiment, the herbal composition comprises milk thistle (Silybum marianum), an extract thereof, or a powder thereof.

[0025] In one embodiment, the antioxidant composition includes vitamin E, vitamin C, beta-carotene, gallic acid, selenium, selenium yeast, phenols, anthocyanins, flavonoids, bioflavonoids, theobromine, anthracene, carotenoids, lutein, zeaxanthin, ginkgo biloba, blackberry extract, elderberry extract, cranberry extract, blueberry extract, grape seed extract, resveratrol, saffron, dragon's blood, cocoa or its derivatives. In one embodiment, the vitamin composition includes vitamin A, B, C, D, E, K or a combination thereof. In one embodiment, vitamin B includes thiamine (B1), riboflavin (B2), niacin or niacinamide (B3), pantothenic acid (B5), pyridoxine (B6), biotin (B7), folic acid or folic acid (B9), cobalamin (B12) or its derivatives. In one embodiment, the vitamin composition mainly includes vitamin C or its derivatives.

[0026] The mineral composition may have biological activity that reduces or relieves allergic symptoms. In one embodiment, the mineral composition may act synergistically with an antihistamine, thereby being configured to enhance the antihistamine activity of the pharmaceutical composition or increase the antiallergic activity. In one embodiment, the mineral component includes salts of calcium, iron, zinc, magnesium, sodium, chloride, potassium, copper, molybdenum, manganese, phosphorus, iodine, nickel or selenium, or a combination thereof. In one embodiment, the mineral composition primarily includes salts of zinc.

[0027] In one embodiment, the amino acid composition includes one or more amino acids having biological activity to reduce or relieve allergic symptoms. In one embodiment, the amino acid composition acts synergistically with an antihistamine, thereby being configured to enhance the antihistamine activity of the pharmaceutical composition or increase the anti-allergic activity. In one embodiment, the amino acid composition may have antihistamine activity. In one embodiment, the amino acid composition includes histidine, branched chain amino acids, L-5 hydroxytryptophan (5-HTP) or a derivative thereof.

[0028] In one embodiment, the prebiotic composition includes gum arabic, chicory root, wheat bran, resistant starch, manno-oligosaccharides, acacia gum, inulin, galacto-oligosaccharides, guar gum, artichoke fiber, fructooligosaccharides, or a combination thereof.

[0029] The probiotic composition includes bifidobacteria, lactic acid bacteria or a combination thereof. In one embodiment, the probiotic composition includes bifidobacterium lactis, bifidobacterium longum, lactobacillus acidophilus, lactobacillus paracasei, lactobacillus plantarum, lactobacillus rhamnosus, bacillus coagulans, bifidobacteria, bifidobacteria, lactobacillus casei, lactobacillus gasseri, lactobacillus bulgaricus or a combination thereof.

[0030] The semisolid pharmaceutical composition may further include an additive selected from sweeteners, food acids, flavoring agents, coloring agents, wetting agents, bulking agents, fatty acids, triglycerides, plasticizers, emulsifiers, thickeners, preservatives, or mixtures thereof. In one embodiment, the sweetener includes erythritol, xylitol, sugar, glucose syrup, corn syrup, high fructose corn syrup, trehalose, isomaltose, allulose, concentrated fruit juice, tapioca syrup, agave syrup, brown rice syrup, high maltose syrup, invert sugar, artificial sweetener, saccharin, saccharin salt, cyclamic acid, cyclamic acid salt, aspartame, sucralose, acesulfame potassium, rebaudioside A, rebaudioside B, rebaudioside C, rebaudioside D, rebaudioside E, dulcoside A, dulcoside B, rubusoside, stevia, steviol glycosides, mogroside IV, mogroside V, monk fruit sweetener, simonoside, monatin and its salts (monatin SS, RR, RS, SR), curculigo sweet protein, glycyrrhizic acid and its salts, miraculin Fructus melamine, monellin, mabinin, thaumatin, hernandulcin, phylloside, sarsaparin, phloridzin, trilobatin, baicalin, eudicotin, polypodoside A, pteridin A, pteridin B, cyperoside, scutellariae glycoside I, glycyrrhizin I, abrin A, cyclocorin I, sucralose, acesulfame potassium and other salts, aspartame, alitame, saccharin, neohesperidin dihydrochalcone, cyclamate, neotame, N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-α-aspartyl]-L-phenylalanine 1-methyl ester, N-[N-[3-(3-hydroxy-4-methoxyphenyl)-3-methylbutyl]-L-α-aspartyl] -L-phenylalanine 1-methyl ester, N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-α-aspartyl]-L-phenyl-alkyne-1-methyl ester, its salt, licorice or its extract or isolate or a mixture thereof.

[0031] In one embodiment, the flavoring agent comprises vanilla, chili oil, gingerol, piperine, capsaicin, peppermint oil, spearmint oil, eucalyptus oil, cinnamon oil, grapefruit oil, menthol, monomenthyl succinate, menthol glycol carbonate, menthone glycerol ketal, menthyl lactate, (-)-isopulegol, p-menthane-3,8-diol, (-)-monomenthyl glutarate, wintergreen oil (methyl salicylate), citrus oil, orange oil, bitter orange flavoring, fruit essence, rosemary oil, lavender oil, sage oil, clary sage oil, thyme oil, sandalwood oil, basil oil, coriander oil, cypress oil, fleabane oil, frankincense oil, geranium oil, anise oil, oregano oil, Dalmatian sage oil, tarragon oil, cocoa, spices, or mixtures or derivatives thereof.

[0032] In one embodiment, the semisolid pharmaceutical composition may include a sugar composition. The sugar composition may be used as a sweetener, a binder of an auxiliary gel component gel, or a combination thereof. The sugar composition may include a high glycemic index sugar. In one embodiment, the glycemic index of the high glycemic index sugar is greater than 50, 60, 70, 80, 90, 100, 120, 150, or 160. Examples of high glycemic index sugars include, but are not limited to, sucrose, glucose, dextrin, maltose, maltotriose, or maltodextrin. In one embodiment, the sugar composition includes sucrose, glucose, or a combination thereof.

[0033] In one embodiment, the sugar composition may include low-glycemic sugars. In one embodiment, the glycemic index of low-glycemic sugars is less than 50, 40, 30, 25, 20, 15 or 10. Examples of low-glycemic sugars include, but are not limited to, trehalose, palatinose, isomaltulose, tagatose, sorbose, galactose, mannose, psicose or fructose. In one embodiment, the sugar composition includes trehalose, palatinose (isomaltulose), psicose (allulose) or a combination thereof. In one embodiment, the sugar composition includes trehalose and palatinose. In one embodiment, the ratio of trehalose to palatinose is about 10:1 to 1:10. In one embodiment, the sugar composition includes palatinose and psicose. In one embodiment, the ratio of palatinose to psicose is about 1:10 to about 10:1. In one embodiment, the sugar composition includes trehalose and psicose. In one embodiment, the ratio of trehalose to psicose is about 1:10 to about 10:1. In one embodiment, the sugar composition includes trehalose, palatinose, and psicose. The ratio of the various sugars can be any ratio between the ranges.

[0034] The semisolid pharmaceutical composition may have a glycemic index of about 8 to about 170. In one embodiment, the semisolid pharmaceutical composition has a glycemic index greater than 60. In one embodiment, the semisolid pharmaceutical composition has a glycemic index greater than 90. In one embodiment, the semisolid pharmaceutical composition may have a glycemic index of about 50 to about 170. In one embodiment, the semisolid pharmaceutical composition may have a glycemic index of about 50 to about 80. The semisolid pharmaceutical composition has a glycemic index of no greater than 30. In one embodiment, the semisolid pharmaceutical composition has a glycemic index of no greater than 20. In one embodiment, the semisolid pharmaceutical composition has a glycemic index of no greater than 15. In one embodiment, the semisolid pharmaceutical composition has a glycemic index of about 8 to about 25.

[0035] The pH of the semisolid pharmaceutical composition can be from about 2 to about 6. In one embodiment, the pH of the composition is from about 2.5 to about 2.9. In one embodiment, the pH of the composition is from about 2.7 to about 2.9. In one embodiment, the pH of the composition is from about 2.6 to about 3. In one embodiment, the pH of the composition is from about 3 to about 5. In one embodiment, the pH of the composition is from about 3.0 to about 3.4. The pH of the composition can be any value between the ranges.

[0036] In one embodiment, the present invention provides a semisolid pharmaceutical composition comprising about 0.5% to about 5.0% pectin by weight, about 0.05% to about 0.3% cetirizine by weight, about 0.1% to about 12% complexing agent by weight, and about 50% to about 85% sugar composition by weight. In one embodiment, the complexing agent comprises a polyamide, a cyclodextrin or a clustered dextrin. In one embodiment, the complexing agent mainly comprises cyclodextrin. In one embodiment, the glycemic index of the pharmaceutical composition is greater than 80. In one embodiment, the glycemic index of the pharmaceutical composition is less than 30. In one embodiment, the glycemic index of the pharmaceutical composition is about 8 to about 25.

[0037] In one embodiment, the present invention provides a semisolid pharmaceutical composition comprising about 0.5% to about 5.0% pectin by weight, about 0.3% to about 1.5% diphenhydramine by weight, about 0.1% to about 12% complexing agent by weight, and about 50% to about 85% sugar composition by weight. In one embodiment, the complexing agent comprises polyamide, cyclodextrin or clustered dextrin. In one embodiment, the complexing agent mainly comprises cyclodextrin. In one embodiment, the glycemic index of the pharmaceutical composition is greater than 70. In one embodiment, the glycemic index of the pharmaceutical composition is less than 25. In one embodiment, the glycemic index of the pharmaceutical composition is about 8 to about 25.

[0038] In one embodiment, the present invention provides a semisolid pharmaceutical composition comprising about 0.5% to about 5.0% pectin by weight, about 0.05% to about 0.3% loratadine by weight, about 0.1% to about 12% complexing agent by weight, and about 50% to about 85% sugar composition by weight. In one embodiment, the complexing agent comprises polyamide, cyclodextrin or clustered dextrin. In one embodiment, the complexing agent mainly comprises cyclodextrin. In one embodiment, the glycemic index of the pharmaceutical composition is greater than 70. In one embodiment, the glycemic index of the pharmaceutical composition is less than 25. In one embodiment, the glycemic index of the pharmaceutical composition is about 8 to about 25.

[0039] In one embodiment, the present invention provides a semisolid pharmaceutical composition comprising about 0.5% to about 5.0% pectin by weight, about 0.1% to about 1% fexofenadine by weight, about 0.1% to about 12% complexing agent by weight, and about 50% to about 85% sugar composition by weight. In one embodiment, the complexing agent comprises polyamide, cyclodextrin or clustered dextrin. In one embodiment, the complexing agent mainly comprises cyclodextrin. In one embodiment, the glycemic index of the pharmaceutical composition is greater than 80. In one embodiment, the glycemic index of the pharmaceutical composition is less than 30. In one embodiment, the glycemic index of the pharmaceutical composition is about 8 to about 25. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The foregoing and other features of the present invention will become more fully apparent from the following description and appended claims, taken in conjunction with the accompanying drawings. Understanding that the drawings depict only several embodiments arranged in accordance with the present invention and are therefore not to be considered limiting of its scope, the present invention will be described with additional specificity and detail through the use of the accompanying drawings, in which: Figure 1 The chemical structures of exemplary antihistamines, cetirizine (L and D isomers) and diphenhydramine are shown; Figure 2 It was shown that trehalose can be digested slowly and release glucose compared to other foods that provide low glycemic values; Figure 3 It was shown that Palatinose is digested very slowly and has little effect on blood sugar levels, providing lower blood sugar values; Figure 4 A simplified structure of a clustered dextrin is shown, which has a ring structure with glucose side chains; Figure 5 The ring structures of α-cluster dextrin, β-cluster dextrin, and γ-cluster dextrin are shown; Figure 6 shows the ring structure of cyclodextrin complexed with cetirizine molecules to form an inclusion complex; Figure 7 shows a chromatogram and mass spectrum of a representative pharmaceutical adhesive composition of Example 12, wherein the protonated form of cetirizine eluted at 4:50 and 4:63 for the D and L stereoisomers, indicating that cetirizine is stable in the representative adhesive formulation; Figure 8 : are chromatograms and mass spectra of the adhesive sample of Example 12, showing that cetirizine is stable in a representative adhesive formulation.

[0041] Fig. 9 shows a liquid chromatography mass spectrum of a representative pharmaceutical adhesive composition produced in Example 29, wherein the cetirizine molecule elutes at 4.38, indicating that cetirizine is stable in the representative adhesive formulation; and Fig.10 The liquid chromatography mass spectrum of the representative pharmaceutical adhesive composition obtained in Example 44 is shown, wherein the protonated form of diphenhydramine molecules elutes at 3.79, indicating that diphenhydramine is stable in the representative adhesive formulation. DETAILED DESCRIPTION

[0042] In the following detailed description, reference is made to the accompanying drawings which form a part thereof. In the accompanying drawings, similar symbols generally identify similar components unless the context indicates otherwise. The illustrative embodiments described in the detailed description, drawings, and claims are not meant to be limited. Other embodiments may be utilized, and other changes may be made, without departing from the spirit or scope of the subject matter presented in the present invention. It is readily understood that the various aspects of the present invention, as generally described herein and as illustrated in the accompanying drawings, may be arranged, substituted, combined, separated, and designed in a variety of different configurations, all of which are expressly contemplated in the present invention.

[0043] The present invention generally relates to compositions, methods and processes relating to semisolid chewable compositions.

[0044] Semisolid formulations such as stickies can be used as an effective delivery mechanism for active pharmaceutical ingredients (APIs). Good-tasting pharmaceutical sticky compositions will have multiple advantages over traditional drug delivery formulations such as tablets, capsules, and syrups. Unlike tablets and capsules, stickies can be used in populations with swallowing problems such as children and the elderly. Unlike syrups, stickies can be precisely dosed. Pharmaceutical sticky compositions that are sweet and tasty to consumers have the advantage of increasing patient compliance with medication. The act of chewing and dissolving the stickies allows for the release of the API into the oral cavity and transmucosal absorption of the API. The rapid absorption of the API allows the API to bypass the liver and avoid the first-pass effect. In addition, the transmucosal absorption allowed by the stickies can provide faster symptom relief due to the rapid absorption of the API. Therefore, solving the adhesive delivery problem of API can lead to superior technology for API delivery.

[0045] However, most APIs (e.g., cetirizine, diphenhydramine, etc.) have a bitter, astringent, metallic or unpleasant taste that is unpleasant. When placed in a traditional confectionery adhesive preparation, unpleasant tastes such as bitterness and metallic tastes are retained regardless of the amount of sweetener used. Although the adhesive delivery of such antihistamine APIs would be advantageous due to rapid absorption and symptom relief, simply incorporating these APIs into traditional gummy confections will only result in unpleasant, undesirable products. In addition, the adhesive preparation is water-based, providing an aqueous matrix. Typically, the adhesive preparation includes a water content of about 12% to about 20% by weight. APIs tend to be unstable in such an aqueous environment. In addition, the API is generally not water-soluble, so it is technically impossible to evenly disperse the API in an aqueous adhesive matrix to produce a stable product.

[0046] The present invention solves the above technical problems by providing a semi-solid pharmaceutical adhesive formulation and similar products for delivering API with satisfactory taste and stability. In some embodiments, the adhesive pharmaceutical formulation provided by the present invention has excellent texture, taste and flavor, has proven solubility and stability of API, and allows rapid delivery of antihistamines to quickly relieve allergic symptoms.

[0047] Semisolid drug adhesive composition may include an antihistamine composition containing an antihistamine. Exemplary antihistamines may include acrivastine, azelastine, diphenhydramine, bilastine, bromodiphenhydramine, brompheniramine, angiotensin, carbinoxamine, cetirizine, chlordiphenhydramine, chlorpheniramine, azemastine, cyclizine, cyproheptadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimethindene, doxylamine, ebastine, embramin, fexofenadine, hydroxyzine, loratadine, meclizine, mirtazapine, olopatadine, o-phenhydramine, antiallergic amine, phenylpyramine, phenyltoloxamine, promethazine, quetiapine, rupatadine, tripelennamine, triprolidine, levocetirizine, desloratadine, pyrilamine, or derivatives thereof. The antihistamine composition may include one or more antihistamines.

[0048] In one embodiment, the antihistamine composition may include diphenhydramine, cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine, azelastine, bilastine, rupatadine or a derivative, salt or combination thereof. In one embodiment, the antihistamine includes cetirizine. In one embodiment, the antihistamine includes diphenhydramine.

[0049] Cetirizine and diphenhydramine are both APIs used as antihistamines. Cetirizine and diphenhydramine used in the present invention include all pharmaceutically useful derivative forms, such as salts. In one embodiment, cetirizine can be cetirizine hydrochloride. In one embodiment, diphenhydramine can be diphenhydramine hydrochloride.

[0050] Cetirizine and diphenhydramine can relieve allergy and cold symptoms. Cetirizine has lower signs of drowsiness as a side effect. In addition to relieving allergy symptoms, diphenhydramine can help relieve nausea and relieve motion sickness. The drowsiness-inducing effect makes diphenhydramine an effective sleep aid.

[0051] The drug sticker delivers about 1 mg to about 80 mg of the antihistamine API per dose. In one embodiment, the drug sticker delivers at least 2 mg of cetirizine hydrochloride per dose. In one embodiment, the drug sticker delivers 2.5 mg, 5 mg, or 10 mg of cetirizine hydrochloride per dose.

[0052] In one embodiment, the drug sticker delivers 8 mg of diphenhydramine hydrochloride per dose. In one embodiment, the drug sticker delivers 12.5 mg, 25 mg, or 50 mg of diphenhydramine hydrochloride per dose.

[0053] In one embodiment, the drug sticker delivers at least 2 mg of loratadine per dose. In one embodiment, the drug sticker delivers 2.5 mg, 5 mg, or 10 mg of loratadine per dose.

[0054] In one embodiment, the drug sticker delivers at least 15 mg of fexofenadine per dose. In one embodiment, the drug sticker delivers 15 mg, 30 mg, 60 mg, 90 mg, or 180 mg of fexofenadine per dose.

[0055] The weight of the drug adhesive can be about 2g to about 10g per dose. In one embodiment, the weight of the drug adhesive is about 2.5g, 3g, 3.5g, 4g, 5g, 6g, 6.5g, 7g or 7.5g per dose. The weight of each dose can be any value between the ranges.

[0056] The drug adhesive may include a sugar composition. In one embodiment, the sugar composition may serve as a sweetener, a binder for the gel component, or both. In one embodiment, the drug adhesive composition includes no less than 60% of the sugar composition. In one embodiment, the drug adhesive composition may include about 40% to about 85% of the sugar composition. In one embodiment, the drug adhesive composition may include about 75% of the sugar composition.

[0057] In one embodiment, the sugar composition may include sucrose, glucose, fructose, maltose, mannose, trehalose, palatinose, psicose, sorbose, tagatose, galactose, lactose, tagatose, sorbose, galactose, maltotriose, maltodextrin, glucosamine, N-acetylglucose, N-acetylgalactosamine or a combination or derivative thereof. In one embodiment, the sugar composition may include sucrose, glucose, fructose or a combination thereof. In one embodiment, the drug adhesive composition includes about 0.1% to about 55% mannose. In one embodiment, the drug adhesive composition includes about 0.1% to about 85% sucrose. In one embodiment, the drug adhesive composition includes about 0.1% to about 85% fructose.

[0058] In one embodiment, sugar composition includes low blood sugar. In one embodiment, the blood sugar value of low blood sugar is not more than 8,10,15,20,25,30 or 35. The example of low blood sugar includes but is not limited to L-glucose, L-sucrose, L-galactose, D-or L-isomaltose, D-or L-trehalose, D-or L-heptose, D-or L-tagatose and D-or L-sorbose. In one embodiment, sugar composition may include trehalose, palatinose, psicose, tagatose, sorbose or their combination. In certain embodiments, adhesive composition includes the low blood sugar of no less than 68% weight. In certain embodiments, adhesive composition includes the low blood sugar of about 45% weight to about 85%.

[0059] In one embodiment, the pharmaceutical adhesive composition comprises about 50% to about 85% of a sugar composition. In one embodiment, the pharmaceutical adhesive composition comprises about 5% to about 55% of trehalose. In one embodiment, the pharmaceutical adhesive composition comprises about 5% to about 55% of palatinose. In one embodiment, the pharmaceutical adhesive composition comprises about 15% to about 75% of psicose. In one embodiment, the pharmaceutical adhesive composition comprises about 5% to about 75% of sorbitol. In one embodiment, the pharmaceutical adhesive composition comprises about 5% to about 65% of tagatose.

[0060] In one embodiment, the pharmaceutical adhesive composition comprises psicose and trehalose in a ratio of about 1:10 to about 10:1. In one embodiment, the pharmaceutical adhesive composition comprises trehalose and palatinose in a ratio of about 1:10 to about 10:1. In one embodiment, the pharmaceutical adhesive composition comprises palatinose and trehalose in a ratio of about 1:10 to about 10:1. The ratio can be any value between the ranges, such as 8:1 to 1:8, 1:5 to 5:1, 4:1 to 1:4, 3:1 to 1:3, 1:2 to 2:1 or 1:1.

[0061] In one embodiment, the pharmaceutical adhesive composition may be substantially free of sucrose, fructose, glucose or their combination. In one embodiment, the adhesive composition may be substantially free of sugar substitutes. In one embodiment, the adhesive composition may be substantially free of artificial sweeteners. In one embodiment, the adhesive composition may be substantially free of sugar alcohols.

[0062] In one embodiment, the drug adhesive can be a sugar-free composition. In one embodiment, the drug adhesive can include a sugar alcohol composition. In one embodiment, the sugar alcohol composition can serve as a sweetener, a binder for the gel of the auxiliary gel component, or both. The example of sugar alcohol can include glycerol, sorbitol, mannitol, xylitol, or erythritol. In one embodiment, the drug adhesive can be a gelatin-based adhesive with a sugar substitute (e.g., stevia) as a sweetener, resulting in a sugar-free formulation.

[0063] The medicinal adhesive can comprise a food acid composition. In one embodiment, the food acid composition can play a role in imparting acidity or astringency, promoting gel component gel or both effects. In one embodiment, the food acid composition can comprise citric acid, malic acid, ascorbic acid, lactic acid, galactonic acid, glutamic acid, tartaric acid, propionic acid, butyric acid, valeric acid, gluconic acid, isocitric acid, succinic acid, fumaric acid or a combination thereof. In one embodiment, the food acid composition can comprise citric acid, malic acid or a combination thereof.

[0064] The drug adhesive may include a buffer composition. The buffer composition, when combined with one of the above acid embodiments, acts to buffer the pH of the composition, promote gelation, or both. In one embodiment, the buffer composition includes sodium citrate, potassium citrate, calcium citrate, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, and combinations thereof.

[0065] In one embodiment, the adhesive pharmaceutical formulation includes a gel component, a sugar composition, water, and a complexing component. The complexing component is complexed with the antihistamine to form an inclusion complex. When an API such as a cetirizine or diphenhydramine molecule is coordinated in the inclusion complex, the bitter taste is reduced or eliminated, thereby producing a sweet, delicious, and pleasant pharmaceutical adhesive.

[0066] In one embodiment, the pharmaceutical adhesive preparation comprises a gel component, a sugar composition and a food acid composition, a flavoring agent and a coloring agent. In one embodiment, the gel component comprises gelatin or pectin. In one embodiment, the sugar composition comprises sucrose, fructose, glucose, trehalose, palatinose or isomaltose. In one embodiment, the food acid composition comprises citric acid, malic acid or any combination thereof.

[0067] The pharmaceutical adhesive formulation includes a complexing agent configured to complex with an antihistamine. In one embodiment, the complexing agent can be a molecule composed of glucose units arranged in a ring or crown structure. Without being limited by theory, in some embodiments, a cetirizine molecule or a diphenhydramine molecule can be at least partially fitted inside the ring or crown structure to provide an inclusion complex. The formation of the inclusion complex greatly reduces the bitter taste of the resulting adhesive pharmaceutical formulation containing the API.

[0068] Cetirizine and diphenhydramine The chemical structures of cetirizine and diphenhydramine are as follows Figure 1 As shown. The structure of cetirizine is based on an internal piperazine moiety. This moiety imparts a bitter taste to the molecule since the nitrogen atom is strongly basic. The structure has dextrorotatory (D) and levorotatory (L) stereoisomers. The L stereoisomer of cetirizine is sold as levocetirizine. The L stereoisomer of cetirizine has the higher biological activity of the two isomers. Diphenhydramine has similar structural elements to cetirizine. These structural elements would include a diphenyl moiety and a tertiary amine. Both antihistamines act primarily as histamine H1 receptor inverse agonists.

[0069] Cetirizine and diphenhydramine are prescribed for allergies that frequently affect the nose, sinuses, throat, and other parts of the upper respiratory tract. Both antihistamines can relieve mild to moderate allergy symptoms, including but not limited to sneezing, runny nose, itchy or watery eyes, and an itchy throat or nose.

[0070] Antihistamines may also help relieve hives. Hives are often associated with food or drug allergies. Unlike other antihistamines, cetirizine only slightly crosses the blood-brain barrier, so it produces minimal sedation compared to many other antihistamines. Diphenhydramine, on the other hand, is a smaller molecule that easily crosses the blood-brain barrier and causes drowsiness when taken. Diphenhydramine is also prescribed to treat nausea, relieve motion sickness, and aid in sleep.

[0071] Semi-solid chewable gummy preparations Gel A large part of the texture of adhesive products comes from the gelling agent used. The gelling agent is usually a high molecular weight polymer.

[0072] Pectin is a heteropolysaccharide composed of galacturonic acid and is found in plant cell walls. Traditional pectin gels in the presence of sugars and acids, while chemically modified pectins gel in the presence of calcium or potassium ions instead of acid and are therefore effective in low-acid foods. The latter can also be used at lower solids concentrations. Pectin is water-soluble. Pectin can be used in combination with gelatin. Gelatin has a tough chew, while pectin has a distinct softness.

[0073] Gelatin is a protein made from animal collagen. The source of collagen is usually from cows and pigs, but sometimes from fish. Gelatin can be mixed with other gels (pectin, agar, starch, gum arabic). In one embodiment, gelatin can be combined with gum arabic as a gelling agent.

[0074] In one embodiment, the gel composition includes starch. In one embodiment, the starch includes amylose. For adhesive formulations, starch is often "modified". There are a variety of modification techniques, but common modification techniques are to contact the starch with acid, sodium hydroxide or potassium hydroxide, or to oxidize the starch. These treatments help the starch dissolve in water and gel to an appropriate degree.

[0075] Agar is a jelly-like substance obtained from algae. Agar is derived from the polysaccharide agarose and includes two components: a heterogeneous mixture of linear polysaccharide agarose and smaller molecules called agaropectin. When agar gel is used as a gelling agent by itself, it will ooze or squeeze out water over time. In one embodiment, agar is combined with locust bean gum as a gelling agent. Locust bean gum helps prevent the agar gel from oozing water. Locust bean gum is a galactomannan polysaccharide plant gum extracted from the seeds of the carob tree. The two polysaccharides in agar and locust bean gum work synergistically with each other to form a strong gel that does not ooze.

[0076] Carrageenan or carrageenan is a family of linear sulfated polysaccharides extracted from red edible seaweed. The linear sugar chains tend to curl up to form a helical structure. κ-carrageenan has one sulfate group per disaccharide and forms a strong, hard gel in the presence of potassium ions. Locust bean gum is often used with κ-carrageenan to prevent water from draining out of the gel (bleeding), similar to agar. Gels formed from κ-carrageenan and potassium ions are thermoreversible, meaning they melt when heated and solidify when cooled.

[0077] Alginate is a linear copolymer having homopolymer blocks of (1-4)-linked β-D-mannonate (M) (the acid form of mannose) and its C-5 diastereomer α-L-gulonic acid (G) (the acid form of gulose) residues, respectively, covalently linked together in different sequences or blocks. The monomers can appear in homopolymer blocks of continuous G residues (G blocks), continuous M residues (M blocks), or alternating M and G residues (MG blocks). When cross-linked with calcium ions, alginate forms a strong hydrogel.

[0078] Simple carbohydrates Carbohydrates are an important component of the gummy structure. Carbohydrates help hold the gummy together by interacting with the gelling agent. Carbohydrates keep the texture of the product soft and gummy by acting as humectants. Carbohydrates bind water. By binding water, carbohydrates prevent the product from crystallizing, drying out and give the product a chewy texture.

[0079] Sucrose, commonly known as table sugar, is a disaccharide consisting of one glucose unit and one fructose unit. The IUPAC name is O-α-D-glucopyranosyl-(1→2)-β-D-fructofuranoside. Sucrose is the most common carbohydrate used in gummy confectionery. Sucrose is very soluble in water. More than 2 grams of sucrose will dissolve in 1 gram of water. The interaction between sucrose and water allows sucrose to be used as a humectant in confectionery. Sucrose helps the gummy to retain moisture and maintain its texture longer. Sucrose also provides the product with sweetness. Sucrose is the raw material for invert sugar. Invert sugar is sucrose that has undergone hydrolysis to make glucose and fructose monosaccharides. Invert sugar can be used in gummy preparations.

[0080] Fructose, also known as fruit sugar, is a monosaccharide, a ketose. Fructose is also very soluble in water. Almost 4 grams of fructose will dissolve in one gram of water. Due to the interaction between fructose and water, it is used as a humectant in gummy preparations. Fructose helps the gummy ingredients retain moisture, maintain texture, and prevent crystallization. Fructose is twice as sweet as sucrose and is often used to increase sweetness.

[0081] Glucose is an aldose (a sugar with an aldehyde group or CHO) in a straight chain form. However, only 0.25% of glucose molecules exist in a straight chain form. Glucose undergoes internal cyclization as shown below to make α-D-pyranose and β-D-pyranose. In stickies, glucose is used to maintain the texture of the stickies and prevent the crystallization of sugar from the stickies.

[0082] Sucrose, sorbose, and tagatose are sugars similar to fructose. Chemically, they are ketoses, which are C3-C5 stereoisomers of fructose. Allulose has the same sweetness as sucrose (table sugar), but has almost zero calories and does not promote tooth decay. Tagatose is almost as sweet as sucrose, but has only 38% of the caloric value of sucrose and is friendlier to teeth than sucrose. Sorbitol is used to make vitamin C and has a sweetness comparable to sucrose. Through extensive experiments, processes were developed to use allulose, sorbose, or tagatose in semisolid adhesive formulations, making these sugars behave like sucrose and fructose, but without the caloric significance of sucrose.

[0083] Trehalose, also known as mycose or tremalose, is a natural α-linked disaccharide formed by an α,α-1,1-glucosidic bond between two α-glucose units. Trehalose is non-reducing. Trehalose is reported to have antioxidant effects. Trehalose is also reported to have many important neurological benefits. Trehalose is digested by trehalase in the small intestine, releasing two glucose molecules. The glucose molecules are then used by the animal's body for energy. However, the digestion of trehalose does not lead to an increase in blood glucose levels, such as Figure 2 In contrast, blood sugar levels rise slowly and last longer. In addition, there is no glucose consumption for a long time, which is very different from high glycemic index sugars. This is because trehalose is digested in the small intestine rather than in the mouth, and the possibility of trehalose causing dental caries is much lower than most carbohydrates, which is beneficial for drug delivery.

[0084] Palatinose, also known as isomaltulose, is a derivative of the natural source sucrose. Palatinose is made by enzymatic rearrangement of the α-1,2 bonds between glucose and fructose molecules to α-1,6 bonds. Palatinose is enzymatically digested by the enzyme sucrase. However, due to the rearrangement of Palatinose relative to sucrose, the sucrase hydrolysis of Palatinose is much slower. The hydrolysis products are glucose and fructose. Glucose can be used directly by the body as energy, while fructose is converted into glucose by the liver. Due to its slow and complete absorption and hydrolysis, Palatinose provides constant and long-lasting energy for the muscles and brain. As Palatinose enters the blood slowly, it is metabolized slowly by the body, resulting in a slight increase in blood sugar levels. As a result, the energy obtained from Palatinose remains in the body longer and is in constant supply for a longer period of time than, for example, glucose or sucrose. Palatinose has a limited effect on blood sugar levels and a low insulin index ( Figure 3 ). Palatinose has a low insulin index (about 30) and therefore may help stabilize insulin levels in the body. Palatinose also has a lower incidence of tooth decay.

[0085] Polydextrose Polymers of glucose can exist in a variety of forms. Some forms of polymerized glucose are ring structures. Cyclic polymers of glucose can exist in several different forms. The ring structures can be highly branched and are often referred to as clustered dextrins.

[0086] Figure 4A simplified structure of a clustered dextrin is shown. The clustered dextrin has a ring structure with long chain branches of glucose units hanging from the ring. This has the effect of forming a helical structure. Both the helical structure and the ring structure of the clustered dextrin are capable of complexing the API in current applications. Both the helical structure and the ring structure of the clustered dextrin are capable of complexing the cetirizine and diphenhydramine molecules. For cetirizine, the complexation is carried out by the phenyl group on the cetirizine being coordinated inside the helical structure.

[0087] Cyclodextrin is another form of cyclic glucose. There are three main forms of cyclodextrin: alpha, beta, and gamma. Figure 5 The ring structures of α, β and γ cyclodextrins are shown. α cyclodextrin consists of a ring of 6 glucose units connected by 1,4-α-glycosidic bonds. β cyclodextrin is a ring of seven glucose units, while γ is a ring of eight glucose units.

[0088] Alpha cyclodextrin consists of a ring of 6 glucose units, while beta has 7 glucose units on the ring and gamma has 8 glucose units on the ring. The ring structure forms a corona. The interior of the corona can be used in complexation with the API in the current application. Figure 6 The process of complexation with the cetirizine molecule is shown. Both the phenyl or 4-chlorophenyl groups are coordinated inside the ring structure. The inner cavity of the cyclodextrin is mostly hydrophobic, which is favorable for the hydrophobic aromatic system of the API. The formation of the chelate structure is endothermic, which is due to the electrostatic interaction of the π system of the aromatic part in the hydrophobic cavity and the electronic interaction with the hydrogen atoms and glycidyl ether bonds. It is these electronic interactions between the cyclodextrin system and the π system that generate the good heat of formation. Alpha, beta and gamma cyclodextrins cannot form complexes with cetirizine equally. Cetirizine forms a more stable complex with beta-cyclodextrin (K(a) = 5641 ± 358 M(-1)) than with alpha-cyclodextrin (K(a) = 1434 ± 60 M(-1)). The binding constants determined by ITC for the cetirizine-γ-cyclodextrin and cetirizine-α-cyclodextrin complexes are 1200±50 and 1434±60(-1), while the cetirizine-β-cyclodextrin complex is 5641±358 M(-1). The formation constant for β-cyclodextrin is almost four times that of α- and γ-cyclodextrin. In one embodiment, the complexing composition consists essentially of β-cyclodextrin.

[0089] Figure 6 The cyclodextrin complexes with the cetirizine molecule to form a ring structure of an inclusion complex. The interior of the cyclodextrin is able to electronically interact with the phenyl group of the cetirizine molecule. The phenyl group is an inverse quadrupole, where the interior of the aromatic ring is very electron dense, while the exterior of the ring is electron deficient. The hydrogen atoms in the hydrophobic interior of the cyclodextrin are electronically attracted to the π system of the aromatic ring. The hydrogen atoms of the aromatic ring are electronically attracted to the oxygen atoms of the cyclodextrin.

[0090] Diphenhydramine forms a complex with cyclodextrin. Its mechanism of action is similar to that of cetirizine. Diphenhydramine forms a more stable complex with β-cyclodextrin (K(a) = 4988M(-1)) than with α-cyclodextrin and g-cyclodextrin (both with K(a) = 1000 M(-1)). In one embodiment, the complexing agent includes β-cyclodextrin, which is configured to form an antihistamine complex. In some embodiments, the complexing agent includes α-cyclodextrin, γ-cyclodextrin, or a combination thereof. The coordination with diphenhydramine is similar to that of cetirizine.

[0091] Cluster dextrins also coordinate with cetirizine or diphenhydramine. Cluster dextrins have a wide range of cyclic and helical structures. Statistically, some of the cyclic and helical structures meet the criteria for complexation with cetirizine or diphenhydramine. Without being limited by theory, the complexation mechanism between cetirizine or diphenhydramine and cluster dextrin molecules is the same as the electronic interaction that occurs with alpha, beta and gamma cyclodextrins.

[0092] The adhesive pharmaceutical composition may further include a flavoring modifier. In one embodiment, the flavoring modifier includes mannitol. Mannitol is a sugar alcohol derived from an aldose called mannose. Mannitol can help mask the bitter taste. Mannitol masks the bitter taste by a mechanism involving the endothermic properties of mannitol dissolving in water. In one embodiment, the flavoring modifier includes taurine. Taurine or 2-aminoethanesulfonic acid is an organic compound widely distributed in animal tissues. When taurine concentration is 300 mM, the bitter taste can be reduced by 50%.

[0093] The present invention further provides a method for preparing a pharmaceutical adhesive composition containing an antihistamine. In one embodiment, the pharmaceutical composition can be a low-glycemic composition having a glycemic index of less than 8, 10, 15, 20, or 25. In one embodiment, the pharmaceutical composition can be a sugar-free adhesive composition.

[0094] The present invention further provides methods of treating allergies using the pharmaceutical adhesive compositions containing antihistamines.

[0095] Example Example 1. Cetirizine gelatin adhesive Ingredients: Sucrose, glucose syrup, 1.3g cetirizine hydrochloride, water, potassium sorbate, sodium benzoate, gelatin, mannitol, taurine Gelatin, mannitol, cetirizine and taurine are transferred together. The dry component mixture is added to water to provide a rubbery substance. The rubbery substance is heated at 160°F until there is no foam and it is transparent yellow. Water is mixed with potassium sorbate, sodium benzoate, glucose and sucrose. The solution is heated to 248°F. The solution is then cooled to 200°F and the gelatin solution is added. The mixture is stirred until uniform. The solution is then added to a silicone mold and the mold is placed in a refrigerator for 90 minutes. The adhesive sheet is removed from the mold to produce a product containing approximately 11 mg of cetirizine per sheet.

[0096] Example 2. Cetirizine Stickies The same procedure as in Example 1 was followed, but sucrose was replaced by palatinose.

[0097] Example 3. Cetirizine adhesive with low glycemic index adhesive matrix Proceed as in Example 1, but using palatinose instead of sucrose and using psicose syrup instead of glucose syrup.

[0098] Example 4. Cetirizine pectin stickies Ingredients: Water (heated to 200°F), Sucrose, Pectin Blend (Dextrose, Pectin, Citric Acid), Sodium Citrate, Potassium Citrate, Boiling Glucose Syrup, Cetirizine Hydrochloride, 50% Citric Acid in Water, Orange Extract, Orange Coloring Sucrose, pectin mixture, sodium citrate and potassium citrate are combined in a separate container to form mixture 1. Cetirizine hydrochloride, 50% citric acid solution, orange extract and orange colorant are combined in a separate container to form mixture 2. Add mixture 1 to hot water and bring the solution to a boil. Boiling glucose syrup is then added and heated to 83 Brix. Mixture 2 is then added. The total mixture is stirred until homogeneous. The liquid adhesive mixture is then added to a silicone mold. The adhesive pieces are removed from the mold to obtain a product including 11 mg of cetirizine per piece.

[0099] Example 5. Cetirizine Stickies Same as Example 4, but using trehalose instead of sucrose.

[0100] Example 6. Cetirizine Gel with Low Glycemic Index Same as Example 4, but trehalose was used instead of sucrose and tagatose syrup was used instead of glucose syrup.

[0101] Example 7. Low Glycemic Index Cetirizine Gel Same as Example 4, but using a mixture of palatinose and trehalose instead of sucrose.

[0102] Example 8. Cetirizine Gel with Low Glycemic Index Same as Example 4, but using a mixture of palatinose and trehalose instead of sucrose, and using psicose syrup instead of glucose syrup.

[0103] Example 9. Cetirizine Gel with Low Glycemic Index Same as Example 4, but using a mixture of palatinose and trehalose instead of sucrose, and tagatose syrup instead of glucose syrup.

[0104] Example 10. Cetirizine Gelatin Ginger Stickies Ingredients: Sucrose, concentrated ginger juice, glucose syrup, cetirizine hydrochloride, gelatin, mannitol, taurine, sodium benzoate, potassium sorbate Gelatin, cetirizine and mannitol are transferred together. The dry component mixture is added to water with dissolved potassium sorbate and sodium benzoate to provide a rubbery substance. The rubbery substance is heated to 160°F until there is no foam and it is transparent yellow. Ginger concentrate is added to a container with sucrose and glucose syrup. The mixture is heated until the Brix reaches 87.5. The mixture is cooled to 200°F and the gelatin mixture is added under stirring. The final sugar content is 84. The solution is then added to a silicone mold and the mold is placed in a refrigerator. The adhesive sheet is removed from the mold to obtain a product containing 11mg of cetirizine per sheet.

[0105] Example 11. Cetirizine pectin stickies / fructose Ingredients: Water, Sucrose, Fructose, Cluster Dextrin, Pectin Blend (Dextrose, Pectin, Citric Acid), Sodium Citrate, Potassium Citrate, (Boiled) Glucose Syrup, Cetirizine Hydrochloride, 50% Citric Acid in Water, Orange Flavor Natural Flavoring, Orange Coloring The pectin mixture, sodium citrate and potassium citrate are combined to make mixture 1. Sucrose, fructose and cluster dextrin are combined to make mixture 2. Cetirizine hydrochloride, 50% citric acid solution, orange extract and orange colorant are combined to make mixture 3. Mixture 1 is added to hot water and boiled. The pectin is fully swollen. Mixture 2 is then added, followed by boiling glucose syrup. The system is heated until the Brix is ​​83. Mixture 3 is added to provide a gummy paste. The gummy paste is then added to a silicone mold. The gummy sheet is removed from the mold to produce a product containing 11 mg of cetirizine per sheet.

[0106] Example 12. Cetirizine pectin stickies Ingredients: Water, Citrus Pectin, Sucrose, Sodium Citrate, Sucrose, Corn Syrup, Blood Orange Extract, Cetirizine Hydrochloride, 50% Citric Acid Solution (in 50% Glycerin / Water), Glycerin, Orange Color Pectin, sucrose, and sodium citrate are mixed together. The components are mixed until uniform to provide Mixture 1. In a separate container, citric acid solution, orange colorant, blood orange flavoring, and cetirizine are added. All materials are mixed and heated to 175°F to provide Mixture 2. Heat to 200°F and mix with Mixture 1. Stir the mixture until the pectin is fully swollen. The solution is boiled. Boiling corn syrup is added to the boiling Mixture 1 solution. The mixture is heated to 82 Brix, at which time Mixture 2 is added. The gummy paste is then added to a silicone mold. The gummy pieces are removed from the mold to produce a product including 11 mg of cetirizine per piece.

[0107] Example 13. Cetirizine pectin stickies Ingredients: Water, Pectin, Sucrose, Sodium Citrate, Sucrose, Cluster Dextrin, Mannitol, Coconut Oil, (Boiled) Glucose Syrup, Blood Orange Extract, Cetirizine Hydrochloride, 50% Citric Acid Solution (in 50% Glycerin / Water), Glycerin, Orange Color Pectin, sucrose, and sodium citrate are mixed until homogeneous to provide mixture 1. Sucrose, cluster dextrin, and mannitol are mixed to provide mixture 2. Citric acid solution, orange colorant, blood orange flavoring, and cetirizine are mixed and heated to 175°F to provide mixture 3. Water is heated to 200°F and mixed with mixture 1. Mixture 2 is added to the boiling mixture 1 solution. Coconut oil is then added dropwise to the boiling mixture under stirring. Boiling glucose syrup is then added to the boiling pectin / sugar / oil mixture. The mixture is heated to 82 Brix, at which point mixture 3 is added dropwise under stirring. The gummy paste is then added to a silicone mold. The gummy pieces are removed from the mold to produce a product that includes 11 mg of cetirizine per piece.

[0108] Example 14. Cetirizine pectin stickies As in Example 12, but using 5.0 g of α-cyclodextrin instead of clustered dextrin.

[0109] Example 15. Cetirizine pectin stickies As in Example 12, but using 10.0 g of α-cyclodextrin instead of clustered dextrin.

[0110] Example 16. Cetirizine pectin stickies As in Example 12, but using 15.0 g of α-cyclodextrin instead of clustered dextrin.

[0111] Example 17. Cetirizine pectin stickies As in Example 12, but using 5.0 g of β-cyclodextrin instead of clustered dextrin.

[0112] Example 18. Cetirizine pectin stickies As in Example 12, but using 10.0 g of β-cyclodextrin instead of clustered dextrin.

[0113] Example 19. Cetirizine pectin stickies As in Example 12, but using 15.0 g of β-cyclodextrin instead of clustered dextrin.

[0114] Example 20. Cetirizine pectin stickies As in Example 12, but using 5.0 g of γ-cyclodextrin instead of clustered dextrin.

[0115] Example 21. Cetirizine pectin stickies As in Example 12, but using 10.0 g of γ-cyclodextrin instead of clustered dextrin.

[0116] Example 22. Cetirizine pectin stickies As in Example 12, but using 15.0 g of gamma-cyclodextrin instead of clustered dextrin.

[0117] Example 23. Cetirizine adhesive with low glycemic index adhesive matrix Ingredients: Water, Pectin (Herbstreith and Fox), Trehalose, Sodium Citrate, Palatinose, Cluster Dextrin, Mannitol, Coconut Oil, (Boiled) Fructose Syrup, Blood Orange Extract, Cetirizine Hydrochloride, 50% Citric Acid Solution (in 50% Glycerin / Water), Glycerin, Orange Color Pectin, trehalose, and sodium citrate were mixed to provide Mix 1. In a separate container, trehalose, palatinose, cluster dextrin, and mannitol were mixed to provide Mix 2. Separately, citric acid solution, orange coloring, blood orange flavoring, and cetirizine were mixed and heated to 175° F. to provide Mix 3.

[0118] Water is heated to 200°F and mixed with Mixture 1. The mixture is stirred until the pectin is fully swollen. The solution is boiled. Mixture 2 is added to the boiling Mixture 1 solution. Coconut oil is then added to the boiling mixture under stirring. Boiling glucose syrup is then added to the boiling mixture. The mixture is heated to a Brix of 82, at which point Mixture 3 is added to provide a gummy paste. The gummy paste is then added to a silicone mold. The gummy pieces are removed from the mold to produce a product comprising 11 mg of cetirizine per piece.

[0119] Example 24. Cetirizine adhesive with low glycemic index adhesive matrix As in Example 22, but using 5.0 g of α-cyclodextrin instead of clustered dextrin.

[0120] Example 25. Cetirizine adhesive with low glycemic index adhesive matrix As in Example 22, but using 10.0 g of α-cyclodextrin instead of clustered dextrin.

[0121] Example 26. Cetirizine Adhesive Matrix with Low Glycemic Index As in Example 22, but using 15.0 g of α-cyclodextrin instead of clustered dextrin.

[0122] Example 27. Cetirizine adhesive with low glycemic index adhesive matrix As in Example 22, but using 5.0 g of β-cyclodextrin instead of clustered dextrin.

[0123] Example 28. Cetirizine adhesive with low glycemic index adhesive matrix As in Example 22, but using 10.0 g of β-cyclodextrin instead of clustered dextrin.

[0124] Example 29. Cetirizine adhesive with low glycemic index adhesive matrix As in Example 22, but using 15.0 g of β-cyclodextrin instead of clustered dextrin.

[0125] Example 30. Cetirizine adhesive with low glycemic index adhesive matrix As in Example 22, but using 5.0 g of γ-cyclodextrin instead of clustered dextrin.

[0126] Example 31. Cetirizine adhesive with low glycemic index adhesive matrix As in Example 22, but using 10.0 g of γ-cyclodextrin instead of clustered dextrin.

[0127] Example 32. Cetirizine adhesive with low glycemic index adhesive matrix As in Example 22, but using 15.0 g of gamma-cyclodextrin instead of clustered dextrin.

[0128] Example 33. Agar-cetirizine stickies Ingredients: Water, Ticagel Natural GC-581 B, Corn Syrup, Sucrose, Cetirizine Hydrochloride, 50% Citric Acid (in Water), Orange Colorant, Orange Natural Flavoring, Glycerin Ticagel was mixed with water at 175°F to provide an agar mixture. Corn syrup preheated to 175°F was mixed with the agar mixture. Sucrose was then added and the mixture was heated until the Brix reached 80. 50% citric acid, colorant, orange natural flavoring, cetirizine, and glycerin were mixed together until uniform. The mixture was then added to the paste. The paste was then deposited into a silicone mold and cured at 98°F and 18% relative humidity for 24 hours. The gummy mass was removed from the mold to produce a product containing 11 mg of cetirizine per tablet.

[0129] Example 34. Kappa carrageenan cetirizine adhesive Ingredients: Water, Kappa Carrageenan, Potassium Citrate, Sucrose, Coconut Oil, Sucrose, Glucose Syrup, Cetirizine Hydrochloride, Mannitol, Blood Orange Extract Kappa carrageenan, sucrose and potassium citrate were mixed with water and heated to 200 °F until there were no lumps. In a separate container, glucose syrup, 220 grams of sucrose and mannitol were added. They were heated until a Brix of 88 was reached. The mixture was cooled to 210 °F and the above kappa carrageenan solution was added. Cetirizine, blood orange extract and 5 grams of water were combined and added to the kappa / sugar mixture. The resulting gummy paste was then added to a silicone mold. The gummy pieces were removed from the mold to produce a product that included 11 mg of cetirizine per piece.

[0130] Example 35. Liquid chromatography mass spectrum of Example 12 7.5 grams of the sticky piece from Example 13 was added to 150 mL of PBS in a sealed container. The PBS container was placed in a water bath heated to 99°F and the water bath was placed on a shaker. The shaker was turned to half speed and the stickies were allowed to dissolve. Complete dissolution took about 90 minutes. The resulting solution was placed on the LTQ-Trackhydrazine for analysis. The protonated form of cetirizine eluted at 4:99 and 5:14 for the D and L isomers. The protonated form of cetirizine eluted at 4:99 and 5:14 for the D and L isomers. These are shown in Figure 7 and 8 The results showed that cetirizine was stable in the adhesive formulation. The adhesive blocks were removed from the mold to produce products each including 11 mg of cetirizine.

[0131] Example 36. Liquid Chromatography Mass Spectrometry of Example 29 7.5 grams of stickies from Example 29 were added to 150 mL of PBS in a sealed container. The PBS container was placed in a water bath heated to 99°F and the water bath was placed on a shaker. The shaker was turned to half speed and the stickies were allowed to dissolve. Complete dissolution took about 90 minutes. The resulting solution was placed on the LTQ-Trackhydrazine for analysis. The protonated form of cetirizine eluted at 4:38, as Fig. 9 The results showed that cetirizine was present in the sticky sample and that the cetirizine molecule was still present during the production process. The sticky blocks were removed from the mold to produce a product including 11 mg of cetirizine per block.

[0132] Example 37. Diphenhydramine hydrochloride gel Ingredients: 2.2g diphenhydramine hydrochloride, sodium benzoate, potassium sorbate, 240.0g sucrose, 283.0g glucose syrup, water, gelatin, sorbitol, organic ginger The gelatin and sorbitol are mixed and added to the water to provide a rubbery mass. The rubbery mass is heated to 160°F until free of foam and clear yellow.

[0133] 245 grams of water were mixed with diphenhydramine hydrochloride at boiling temperature, and potassium sorbate and sodium benzoate were then added to provide a boiling diphenhydramine hydrochloride solution. Glucose syrup was added. Sucrose and ginger were transferred together and the mixture was added to the diphenhydramine hydrochloride / glucose solution. The solution was heated until it reached 248°F. The solution was then cooled to 200°F. The gelatin solution was added. The solution was then added to a silicone mold and the mold was placed in a refrigerator for 90 minutes. The result was a chewy, ginger-flavored, 7.5-gram product containing 25 mg of diphenhydramine hydrochloride.

[0134] Example 38. Diphenhydramine hydrochloride gel Ingredients: 240.0g sucrose, 283.0g glucose syrup, 2.390g diphenhydramine hydrochloride, gelatin, sorbitol, water, sodium benzoate, potassium sorbate, watermelon flavoring, coconut flavoring Transfer the gelatin and sorbitol together and add the mixture to water with dissolved potassium sorbate and sodium benzoate to provide a rubbery substance. Heat the rubbery substance to 160°F until there is no foam and it is a transparent yellow color. Dissolve diphenhydramine in water and add glucose syrup under stirring. Then boil the solution. Then add the sucrose mixture to the boiling solution. Heat the solution until the Brix reaches 85. Then cool the solution to 200°F. Add the gelatin solution. Stir the mixture until uniform. Then add watermelon and coconut flavoring. Then add the solution to a silicone mold and place the mold in a refrigerator for 90 minutes. Each 7.5 grams of stickies has about 25 mg of diphenhydramine.

[0135] Example 39. Diphenhydramine gelatin Ingredients: 240.0 g sucrose, 200.1 g ginger concentrate, 100.0 g glucose syrup, 2.388 g diphenhydramine hydrochloride, 62.5 g gelatin, 18.8 g sorbitol, sodium benzoate, potassium sorbate Gelatin and sorbitol are mixed with water having dissolved potassium sorbate and sodium benzoate to provide a rubbery substance. The rubbery substance is heated to 160°F until there is no foam and it is a transparent yellow color. Ginger concentrate is mixed with sucrose and glucose syrup. The mixture is heated until the Brix reaches 87.5. The gelatin mixture is added. The temperature is maintained above 180°F, and then a mixture of 2.388g of diphenhydramine in 4.035g of water is mixed and added dropwise within 30 seconds under stirring. The solution is then added to a silicone mold, and the mold is placed in a refrigerator for 90 minutes. Each 7.5 grams of stickies contains about 25 mg of diphenhydramine.

[0136] Example 40. Diphenhydramine gelatin Ingredients: 240.3g sucrose, 200.1g ginger concentrate, 100.5g glucose syrup, 2.350g diphenhydramine hydrochloride, 62.5g gelatin, 18.8g mannitol, 21.2g taurine, sodium benzoate, potassium sorbate Gelatin and mannitol are mixed with water having dissolved potassium sorbate and sodium benzoate to obtain a rubbery substance. The rubbery substance is heated to 160°F until there is no foam and it is a transparent yellow color. Ginger concentrate is mixed with sucrose and glucose syrup. The mixture is heated to a Brix of 87.5. The gelatin mixture is added, followed by a solution of 2.350 g of diphenhydramine hydrochloride in 6.100 g of water. The final Brix is ​​84. The resulting mixture is then added to a silicone mold, and the mold is placed in a refrigerator for 90 minutes. Each 7.5 g of stickies contains approximately 20 mg of diphenhydramine.

[0137] Example 41. Diphenhydramine hydrochloride gelatin containing pectin Ingredients: 5.500 g sodium bicarbonate, 3.673 g food grade potassium hydroxide, 1.555 g diphenhydramine hydrochloride, 145.3 g citrus pectin, water, 409.1 g glucose syrup, 310.3 g sucrose, 15.0 g 50% citric acid in water, apple green food coloring Mix water, potassium hydroxide and sodium bicarbonate to provide an alkaline solution. Add pectin. Stir until homogeneous. Then add glucose syrup. Then add sucrose and heat the total mixture to 84 Brix.

[0138] The mixture was cooled to 210°F and a mixture of citric acid solution, candy apple green flavoring and diphenhydramine hydrochloride was added to provide a paste mixture. Green food coloring was then added. The stickies paste was then added to a silicone mold and cooled to room temperature. An excellent tasting sticky was produced. Each 7.5 gram sticky contained approximately 13 mg of diphenhydramine hydrochloride.

[0139] Example 42. Diphenhydramine Hydrochloride Lemon Flavor Stickies Ingredients: Water, Pectin, 100g Fructose, 3.0g Sodium Citrate, 200.0g Sucrose, 20.0g Mannitol, 20.0g β-Cyclodextrin, 410.0g Glucose Syrup, 6.0g Coconut Oil, 25.0g 50% Citric Acid Solution (50% Glycerin / Water), Turmeric Natural Yellow, 1.426g Diphenhydramine Hydrochloride, Natural Lemon Flavoring Water was added to a container and heated to 200°F. Pectin, fructose, and sodium citrate were added to a separate container to provide Mixture 1. Sucrose, 15 g of cyclodextrin, and mannitol were added to a separate container to provide Mixture 2. Citric acid solution, diphenhydramine, 5 g of cyclodextrin, and yellow colorant were mixed to a separate container to provide Mixture 3. Mixture 1 was added to hot water and allowed to dissolve. Mixture 2 was then added.

[0140] In a separate container add glucose syrup and coconut oil. Heat solution until Brix has reached 90-93. Temperature is ~245°F. Then add glucose syrup. Heat solution until Brix reaches 80. Add lemon flavoring. In a separate container, preheat Mix 3 to 175°F and add to gummy paste solution. Stir paste until homogeneous and pour into silicone mold. Then cool mold to room temperature. Contains 12 mg of diphenhydramine HCl per 7.5 g of gummy.

[0141] Example 43. Diphenhydramine Watermelon Flavor Stickies Ingredients: Water, pectin, 100g fructose, 3.0g sodium citrate, 220.0g sucrose, 20.0g mannitol, 20.2g β-cyclodextrin, 410.0g glucose syrup, 25.0g 50% citric acid solution (50% glycerol / water), carmine, 1.426g diphenhydramine hydrochloride, natural watermelon flavoring Water is added to a container and heated to 200°F. Pectin, fructose, and sodium citrate are mixed in a separate container to provide Mixture 1. Sucrose, 15 g of cyclodextrin, and mannitol are mixed in a separate container to provide Mixture 2. Citric acid solution, diphenhydramine, 5 g of cyclodextrin, and red colorant are mixed in a separate container to provide Mixture 3. Mixture 1 is added to hot water and dissolved. With constant stirring, Mixture 2 is added. The resulting mixture is mixed until all components are dissolved.

[0142] In a separate container, add glucose syrup and heat until it reaches 90-93 Brix. The temperature is ~245°F. Heat the solution until it reaches 81 Brix. Then add lemon flavoring. In a separate container, preheat Mix 3 to 175°F. Then add Mix 3 dropwise to the gummy paste solution while stirring. Stir the paste until it is homogeneous and then pour into a silicone mold. Then cool the mold to room temperature. Each 7.5 grams of gummy has 11.5 mg of diphenhydramine HCl.

[0143] Example 44. Diphenhydramine Watermelon Flavor Stickies Ingredients: Water, 105.0 g pectin, 300 g fructose, 6.0 g sodium citrate, 660.0 g sucrose, 30.2 g β-cyclodextrin, 25 g glycerol, 1230.0 g glucose syrup, 60.0 g 50% citric acid solution (50% glycerol / water), carmine, 9.2 g diphenhydramine hydrochloride, natural watermelon flavoring Water was added to a container and heated to 200° F. Diphenhydramine HCl was dissolved. Pectin, fructose, cyclodextrin, and sodium citrate were mixed into a separate container to provide Mixture 1. Sucrose and 15 g of cyclodextrin were added to a separate container to provide Mixture 2. Citric acid solution, watermelon flavoring, and red coloring were mixed into a separate container to provide Mixture 3.

[0144] While stirring, add Mixture 1 to hot water and allow to dissolve. In a separate container, add glucose syrup and bring to a boil. Add Mixture 2 to the boiling glucose syrup, then add the remaining water. Allow the sugar to disperse and heat the solution to near boiling point. Then slowly add the dissolved pectin solution to the glucose syrup solution. Heat and boil the solution until it reaches a Brix of 83, at which point cool the system to 210 – 210°F.

[0145] In a separate container, preheat Mix 3 to 175°F. Then add Mix 3 dropwise to the sticky paste solution. Stir the paste until homogeneous and then pour into a silicone mold. Then cool the mold to room temperature. Each 3.75 g sticky contains 12.5 mg of diphenhydramine hydrochloride.

[0146] Example 45. Liquid chromatography mass spectrum of Example 44 A 3.75 gram mass of stickies from Example 44 was added to 150 mL of PBS in a sealed container. The PBS container was placed in a water bath heated to 99°F and the water bath was placed on a shaker. The shaker was turned to half speed and the stickies were allowed to dissolve. Complete dissolution took about 45 minutes. The resulting solution was placed on the LTQ-Trackhydrazine for analysis. The protonated form of diphenhydramine eluted at 3.79. Data are shown in Table 1. Fig.10 The results showed that diphenhydramine was present in the adhesive sample and that diphenhydramine molecules were still present during the manufacturing process. The adhesive sheets were removed from the mold to obtain a product containing 12.5 mg of diphenhydramine per sheet.

[0147] Example 46. Diphenhydramine Orange Flavor Stickies Ingredients: Water, 105.0 g pectin, 300 g fructose, 6.0 g sodium citrate, 846.0 g sucrose, 30.2 g β-cyclodextrin, 20.0 g mannitol, glycerin, 1000.0 g glucose syrup, 60.0 g 50% citric acid solution (50% glycerol / water), chili orange, 9.4 g diphenhydramine hydrochloride, natural orange flavoring Water was added to a container and heated to 200°F. Diphenhydramine hydrochloride was added to the water and dissolved. Pectin, fructose, 15 g of cyclodextrin, and sodium citrate were added to a separate container to provide Mixture 1. Sucrose, mannitol, and 15 g of cyclodextrin were added to a separate container to provide Mixture 2. Citric acid solution, flavoring, and orange coloring were mixed to provide Mixture 3 in a separate container.

[0148] Add mixture 1 to hot water and allow to dissolve. Add glucose syrup to a separate container and bring to a boil. Add mixture 2 to the boiling glucose syrup, then add water. Disperse the sugar and heat the solution to near boiling point. Then slowly add the dissolved pectin solution to the syrup solution. Heat and boil the solution until the Brix reaches 83, at which point the system will be cooled to 210-210°F. In another container, preheat mixture 3 to 175°F. Then add mixture 3 to the gummy paste solution while stirring. Stir the paste until uniform and then pour into a silicone mold. Then cool the mold to room temperature. Each 3.75 grams of gummy contains 12.5 mg of diphenhydramine hydrochloride.

[0149] Example 47. Diphenhydramine Orange Flavor Sticky As in Example 46, but using 15.0 g of α-cyclodextrin instead of β-cyclodextrin.

[0150] Example 48. Diphenhydramine Orange Flavor Stickies As in Example 46, but using 20.0 g of α-cyclodextrin instead of β-cyclodextrin.

[0151] Example 49. Diphenhydramine Orange Flavor Stickies As in Example 46, but using 30.0 g of α-cyclodextrin instead of β-cyclodextrin.

[0152] Example 50. Diphenhydramine Orange Flavor Sticky As in Example 46, but using 15.0 g of β-cyclodextrin instead of β-cyclodextrin.

[0153] Example 51. Diphenhydramine Orange Flavor Sticky As in Example 46, but using 20.0 g of β-cyclodextrin instead of β-cyclodextrin.

[0154] Example 52. Diphenhydramine Orange Flavor Sticky As in Example 46, but using 20.0 g of γ-cyclodextrin instead of β-cyclodextrin.

[0155] Example 53. Diphenhydramine Orange Flavor Stickies As Example 46, but using 20.0 g of γ-cyclodextrin instead of β-cyclodextrin.

[0156] Example 54. Diphenhydramine Orange Flavor Sticky As Example 46, but using 30.0 g of γ-cyclodextrin instead of β-cyclodextrin.

[0157] Example 55. Diphenhydramine Orange Flavor Sticky Ingredients: Water, Pectin, 300g Fructose, Sodium Citrate, 846.0g Sucrose, 30.2g β-Cyclodextrin, 20.0g Mannitol, Glycerin, 1000.0g Glucose Syrup, 60.0g 50% Citric Acid Solution (50% Glycerin / Water), Chili Orange, 9.4g Diphenhydramine Hydrochloride, Natural Orange Flavoring Add water to a container and heat to 200°F. Add diphenhydramine hydrochloride to the water and dissolve. Add pectin, fructose, 15 g of cyclodextrin, and sodium citrate to a separate container to provide Mixture 1. Add sucrose, mannitol, and 15 g of cyclodextrin to a separate container to provide Mixture 2. Mix citric acid solution, flavoring, and orange coloring to a separate container to provide Mixture 3.

[0158] Add mixture 1 to hot water and allow to dissolve. Add glucose syrup in a separate container and bring to a boil. Add mixture 2 to the boiling glucose syrup, then add the remaining water. Allow the sugar to disperse and heat the solution to near boiling point. Then slowly add the dissolved pectin solution to the glucose syrup solution.

[0159] The solution was heated and boiled until it reached a Brix of 83, at which point the system was cooled to 210-210°F. In a separate container, Mixture 3 was preheated to 175°F. Mixture 3 was then added dropwise to the adhesive paste solution under stirring. The paste was stirred until uniform and then poured into a silicone mold. The mold was then cooled to room temperature. Each 3.75 gram sticky had 12.5 mg of diphenhydramine hydrochloride.

[0160] Example 56. Diphenhydramine Orange Flavor Stickies As in Example 53, but using 15.0 g of α-cyclodextrin instead of β-cyclodextrin.

[0161] Example 57. Diphenhydramine Orange Flavor Sticky As in Example 53, but using 20.0 g of α-cyclodextrin instead of β-cyclodextrin.

[0162] Example 58 Diphenhydramine Orange Flavor Sticky As in Example 53, but using 30.0 g of α-cyclodextrin instead of β-cyclodextrin.

[0163] Example 59. Diphenhydramine Orange Flavor Sticky As in Example 53, but using 15.0 g of β-cyclodextrin instead of β-cyclodextrin.

[0164] Example 60. Diphenhydramine Orange Flavored Stickies As Example 53, but using 20.0 g of β-cyclodextrin instead of β-cyclodextrin.

[0165] Example 61. Diphenhydramine Orange Flavored Stickies As Example 53, but using 15.0 g of gamma-cyclodextrin instead of beta-cyclodextrin.

[0166] Example 62. Diphenhydramine Orange Flavor Stickies As in Example 53, but using 20.0 g of γ-cyclodextrin instead of β-cyclodextrin.

[0167] Example 63. Diphenhydramine Orange Flavored Stickies As in Example 53, but using 30.0 g of γ-cyclodextrin instead of β-cyclodextrin.

[0168] Example 64. Diphenhydramine Orange Flavored Sticky Material Safer for Diabetics Ingredients: Water, Pectin, Isomaltulose, Sodium Citrate, Trehalose, β-Cyclodextrin, 20.0g Mannitol, 25g Glycerin, Allulose, 60.0g 50% Citric Acid Solution (50% Glycerin / Water), Chili Orange, 9.4g Diphenhydramine Hydrochloride, Natural Orange Flavor Water is added to a container and heated to 200°F. Diphenhydramine hydrochloride is added to the water and dissolved. Trehalose and isomaltulose are combined and mixed until homogeneous to provide a sugar mixture. Pectin, 300 grams of the sugar mixture, 15 g of cyclodextrin, and sodium citrate are added to a separate container to provide mixture 1. The remaining sugar mixture, mannitol, and 15 g of cyclodextrin are added to a separate container to provide mixture 2. In a separate container, citric acid solution, flavoring, and orange coloring are mixed to provide mixture 3.

[0169] Add mixture 1 to hot water and allow to dissolve. Add allulose and water in a separate container and boil. Add mixture 2 to the boiling allulose syrup, followed by water. Allow the sugar to disperse and heat the solution to near boiling point. Then add the dissolved pectin solution to the syrup solution.

[0170] The solution was heated and boiled until it reached a Brix of 83, at which point the system was cooled to 210-210°F. In a separate container, Mixture 3 was preheated to 175°F. Mixture 3 was then added dropwise to the sticky paste solution under stirring. The paste was stirred until uniform and then poured into a silicone mold. The mold was then cooled to room temperature. Each 3.75 gram sticky had 12.5 mg of diphenhydramine hydrochloride.

[0171] Example 65. Diphenhydramine Orange Flavored Sticky Material Safer for Diabetics As in Example 64, but using 15.0 g of α-cyclodextrin instead of β-cyclodextrin.

[0172] Example 66. Diphenhydramine Orange Flavored Stickies Safer for Diabetics As Example 64, but using 20.0 g of α-cyclodextrin instead of β-cyclodextrin.

[0173] Example 67. Diphenhydramine Orange Flavored Sticky Material Safer for Diabetics As in Example 64, but using 30.0 g of α-cyclodextrin instead of β-cyclodextrin.

[0174] Example 68. Diphenhydramine Orange Flavored Stickies Safer for Diabetics As in Example 64, but using 15.0 g of β-cyclodextrin instead of β-cyclodextrin.

[0175] Example 69. Diphenhydramine Orange Flavored Sticky Material Safer for Diabetics As Example 64, but using 20.0 g of β-cyclodextrin instead of β-cyclodextrin.

[0176] Example 70. Diphenhydramine Orange Flavored Sticky Material Safer for Diabetics As Example 64, but using 15.0 g of γ-cyclodextrin instead of β-cyclodextrin.

[0177] Example 71. Diphenhydramine Orange Flavored Sticky Material Safer for Diabetics As Example 64, but using 20.0 g of γ-cyclodextrin instead of β-cyclodextrin.

[0178] Example 72. Diphenhydramine Orange Flavored Sticky Material Safer for Diabetics As in Example 64, but using 30.0 g of γ-cyclodextrin instead of β-cyclodextrin.

[0179] Example 73. Diphenhydramine Orange Flavored Stickies Safer for Diabetics As in Example 64, but using tagatose instead of psicose.

[0180] Example 72. Diphenhydramine Orange Flavored Sticky Material Safer for Diabetics As Example 64, but using sorbose instead of psicose.

[0181] Example 73. Diphenhydramine Orange Flavored Stickies Safer for Diabetics As in Example 64, but using a tagatose-psicose mixture instead of psicose.

[0182] Example 74. Diphenhydramine Orange Flavored Sticky Material Safer for Diabetics As Example 64, but using a sorbitol-psicose mixture instead of psicose.

[0183] Example 75. Diphenhydramine Orange Flavored Sticky Material Safer for Diabetics As in Example 64, but using a sorbitol-tagatose mixture instead of psicose.

[0184] The present invention is not limited to the specific embodiments described in the present invention, which are intended to be illustrations of various aspects. Many modifications and variations can be made without departing from its spirit and scope, which will be apparent to those skilled in the art. In addition to the methods and devices listed in the present invention, the functionally equivalent methods and devices of the present invention will be apparent to those skilled in the art according to the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. The present invention is limited only by the terms of the appended claims and the full range of equivalents granted by these claims. It should be understood that the present invention is not limited to specific methods, reagents, compounds, compositions or biological systems, which can certainly vary. It should also be understood that the terms used in the present invention are only for the purpose of describing specific embodiments, and are not intended to be limited.

[0185] Regarding the use of substantially any plural and / or singular terms in the present invention, those skilled in the art can convert plural forms into singular forms and / or convert singular forms into plural forms according to circumstances and / or applications. For the sake of clarity, various singular / plural substitutions can be explicitly stated in the present invention.

[0186] Those skilled in the art will understand that, in general, the terms used in the present invention and especially in the appended claims (e.g., the bodies of the appended claims) are generally intended to be "open" terms (e.g., the term "including" should be interpreted as "including but not limited to", the term "having" should be interpreted as "having at least", the term "including" should be interpreted as "including but not limited to", etc.). Those skilled in the art will further understand that if a specific value of an introduced claim limitation is intended, such intent will be explicitly stated in the claim, and in the absence of such statement, no such intent is present. For example, to aid understanding, the following appended claims may include the use of the introductory phrases "at least one" and "one or more" to introduce claim limitations. However, the use of such phrases should not be interpreted as meaning that the indefinite article "a" or "an" of an introduced claim limitation limits any particular claim including the introduced claim limitation to including only one embodiment of such limitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and an indefinite article, such as "a" or "an" (e.g., "a" and / or "an" should be interpreted as "at least one" or "one or more"); this is also true when the definite article used to introduce the claim limitation is used. In addition, even if a specific number of an introduced claim limitation is explicitly recited, one skilled in the art will recognize that such limitation should be interpreted to mean at least the limited number (e.g., a bare limitation of "two limitations", without other modifiers, means at least two limitations, or two or more limitations).

[0187] Furthermore, in those cases where a convention similar to “at least one of A, B, and C, etc.” is used, generally speaking, such construction is intended to be understood by one skilled in the art for the meaning of the convention (e.g., “a system having at least one of A, B, and C” would include, but is not limited to, systems having only: A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, C together, etc.). In those cases where a convention similar to “at least one of A, B, and C, etc.” is used, generally speaking, such construction is intended to be understood by one skilled in the art for the meaning of the convention (e.g., “a system having at least one of A, B, and C” would include, but is not limited to, systems having only: A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, C together, etc.). One skilled in the art will further understand that, in fact, whether in the specification, claims, or drawings, words and / or phrases indicating two or more alternative terms should be understood to contemplate the possibility of including one, either, or both of the terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or "B" or "A and B."

[0188] In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of the Markush group.

[0189] As will be understood by those skilled in the art, for any and all purposes, such as in providing a written description, all ranges disclosed herein also include any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily identified as fully describing and making the same range be decomposed into at least equal half, one-third, one-quarter, one-fifth, one-tenth, etc. As a non-limiting example, each range discussed herein can be easily decomposed into a lower third, a middle third, and an upper third, etc. As will be understood by those skilled in the art, all languages ​​such as "at most", "at least", etc. include limited numbers and refer to the range that can be decomposed into sub-ranges subsequently, as described above. Finally, as will be understood by those skilled in the art, the range includes each individual member. Therefore, for example, a group with 1-3 units refers to a group with 1, 2 or 3 units. Similarly, a group with 1-5 cells refers to a group with 1, 2, 3, 4 or 5 cells, and the like.

[0190] The appropriate dosage and administration regimen may be selected based on a variety of factors, including the specific condition or conditions being treated, the severity of the condition or conditions, genetic characteristics, age, health status, sex, diet and body weight, the route of administration alone or in combination with pharmacological considerations, including the activity, efficacy, bioavailability, pharmacokinetic and toxicological characteristics of the specific compound used, whether a drug delivery system is used, and whether the drug is administered as part of a drug combination. Thus, the dosage regimen employed may vary widely and may necessarily deviate from the dosage regimens set forth in the present invention.

[0191] The dosage form may be administered once daily or twice daily, or once every 6 hours, or once every 4 hours, or once every 2 hours, or twice hourly, or twice a day, twice a week, or once a month.

[0192] The phrase "therapeutically effective" is intended to qualify an amount that will achieve the goal of improving disease severity and / or frequency compared to no treatment, while limiting, reducing or avoiding adverse side effects typically associated with disease treatment.

[0193] The term "pharmaceutically acceptable" used in the present invention refers to a modified noun that is applicable to a pharmaceutical product. Pharmaceutically acceptable cations include metal ions and organic ions. Other metal ions include, but are not limited to, appropriate alkali metal salts, alkaline earth metal salts, and other physiologically acceptable metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc with their usual valences. Organic ions include protonated tertiary amines and quaternary ammonium cations, some of which include trimethylamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Pharmaceutically acceptable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, lactic acid, glucuronic acid, pyruvic acid oxaloacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, etc.

[0194] It is further contemplated that one active ingredient may be in an extended release form, while an optional second, third or fourth other active ingredient, for example, may or may not be present, so that the recipient experiences, for example, a peak of the second, third or fourth active ingredient that dissipates rapidly, while the first active ingredient remains in a higher concentration in the blood for a longer period of time. Similarly, one of the active ingredients may be an active metabolite, while the other active ingredient may be in an unstable state, so that the active metabolite has an immediate effect on the subject after administration, while the unmetabolized active ingredient administered in a single dosage form may need to be metabolized before it becomes effective in the subject.

[0195] Pharmaceutical preparations may be in unit dosage form. In this form, the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form may be a packaged preparation, such as a kit or other form of packaging containing discrete quantities of the preparation, such as packaged tablets, capsules, liquids or powders in vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, plaster or lozenge, or an appropriate number of any of these packaged forms.

[0196] In summary, various embodiments of the present invention are described herein for illustrative purposes, and various modifications may be made without departing from the scope and spirit of the present disclosure. Therefore, the various embodiments disclosed herein are not intended to be limiting, and the true scope and spirit are shown by the following claims.

Claims

1. A semisolid pharmaceutical composition comprising: a gel component in an amount sufficient to provide a cohesive gel product, An antihistamine composition comprising an antihistamine, wherein: The antihistamines include diphenhydramine, cetirizine, loratadine, levocetirizine, or derivatives thereof, and a complexing agent capable of interacting with the antihistamine and forming an antihistamine complex, wherein the complexing agent comprises polyamide, clustered dextrin, or a combination thereof, and A sugar composition, wherein the sugar composition comprises palatinose, trehalose, psicose, tagatose, or a combination thereof, Herbal ingredients, amino acids, vitamins or minerals with antihistamine or antiallergic activity, From about 12% to about 20% water content by weight.

2. The semisolid pharmaceutical composition according to claim 1, wherein The antihistamine is included in a concentration of not less than about 0.05% w / w.

3. The semisolid pharmaceutical composition according to claim 1, wherein The gel composition comprises gelatin, starch, gellan gum, gum arabic, carrageenan, guar gum, agar, alginate, locust bean gum, xanthan gum or derivatives thereof.

4. The semisolid pharmaceutical composition according to claim 1, further comprising a herbal composition, an antioxidant composition, a vitamin composition, a mineral composition, an amino acid composition, a probiotic composition or a prebiotic composition.

5. The semisolid pharmaceutical composition according to claim 4, wherein The herbal composition includes coltsfoot, quercetin, stinging nettle (Urtica dioica), bromelain, timothy grass, tinospora cordifolia stem, European elderberry, sorrel, caper, verbena, gentian root, echinacea, grape seed, pycnogenol, pine bark extract, EPA, honey, cat's claw, albizzia (Albizzia julibrissin), scutellaria baicalensis, goldenseal, spirulina, bitter orange (Citrus sinensis), lemon, eucalyptus, frankincense, angelica, eyebright (Eurasian grass), ginkgo, milk thistle (Silybum marianum), red clover (Trifolium pratense), yarrow (Achillea millefolium), rosemary, perilla, sage, mint, licorice, astragalus, ginseng, wormwood, Stephania macrophylla, coix seed, bitter orange, citrus, angelica dahurica, and extracts, isolates or distillates thereof.

6. The semisolid pharmaceutical composition according to claim 4, wherein The antioxidant composition includes vitamin E, vitamin C, beta-carotene, gallic acid, selenium, selenium yeast, phenols, anthocyanins, flavonoids, bioflavonoids, theobromine, anthracene, carotenoids, lutein, zeaxanthin, ginkgo biloba, berry extract, resveratrol, saffron, dragon's blood, cocoa or its derivatives.

7. The semisolid pharmaceutical composition according to claim 4, wherein The vitamin composition includes vitamin A, B, C, D, E, K or a combination thereof.

8. The semisolid pharmaceutical composition according to claim 4, wherein The mineral composition includes a salt of calcium, iron, zinc, magnesium, sodium, chloride, potassium, copper, molybdenum, manganese, phosphorus, iodine, nickel or selenium, or a combination thereof.

9. The semisolid pharmaceutical composition according to claim 4, wherein The mineral composition mainly comprises zinc salts.

10. The semisolid pharmaceutical composition according to claim 4, wherein The amino acid composition comprises histidine, branched-chain amino acids, L-5 hydroxytryptophan (5-HTP) or derivatives thereof.

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