Compositions Comprising Proanthocyanidins and Zinc for Treating and / or Preventing Inflammation - Patent application

Abstract

A composition for treating and / or preventing inflammation in a subject is provided, comprising A-type proanthocyanidins (PAC-A) and zinc. The composition can comprise 0.001% to 10% by weight of PAC-A and 0.01% to 25% by weight of a zinc-containing compound. A method for preventing and / or treating inflammation in a subject is provided, comprising administering a composition comprising A-type proanthocyanidins (PAC-A) and zinc. The composition can also be used in the manufacture of a medicament for treating inflammation. For example, inflammation can be associated with the oral cavity, skin membrane, or gastrointestinal tract. For example, a process for producing an oral gel product is provided, comprising providing a gel base and mixing a zinc-containing compound and an A-type proanthocyanidins (PAC-A)-containing extract into the gel base to form an oral gel product.

Description

[Technical field]

[0001] The present invention relates generally to compositions for treating and / or preventing inflammation. Specifically, the present invention relates to compositions comprising proanthocyanidins and zinc for reducing inflammation in a subject. [Background technology]

[0002] Inflammation is part of the body's biological response to harmful stimuli, such as bacteria or toxins. If left untreated, inflammation can lead to severe inflammatory diseases or illnesses in various body tissues, such as epithelial, periodontal, or gastrointestinal tissues. For example, periodontal disease is an inflammatory disease of the gums and periodontal tissues caused by bacterial biofilms, such as gram-negative and anaerobic bacteria, in contact with the periodontal tissues. It is estimated that approximately 80% of dogs and 70% of cats have periodontal disease by the age of 2, and severe periodontitis affects nearly 20% of adults. If left untreated, inflammation caused by periodontal disease can lead to gum degradation, alveolar bone degradation, tooth loss, and blood infections.

[0003] Conventional solutions used to reduce inflammation include synthetic drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) or steroids. However, these synthetic drugs may have adverse reactions with other drugs such as blood thinners and cannot be taken by people with heart disease and pregnant women. Polyphenols are known as natural alternatives to treat inflammation such as anti-inflammatory formulations in Canadian Patent No. 2.532.596. However, large amounts of natural extracts may be required to achieve an effective dose of polyphenols. Cranberries are a known source of polyphenols as described in Canadian Patent No. 2.730.716 and have been described for their antibacterial and antibacterial properties in WO 1996 / 028135.

[0004] Alternative methods for treating oral inflammation, such as gingival inflammation, include preventing plaque and tartar, or reducing bad breath through the proliferation of bacterial film.Therefore, the usual treatment of periodontal disease is directed at bacterial infection, not tissue inflammation.However, reducing bacterial infection can only partially reduce gingival inflammation, and may risk recurrence of bacterial infection when immune system is involved in fighting inflammation.

[0005] Thus, a need exists for improved compositions for preventing and / or treating inflammation and bacterial proliferation in a subject. Summary of the Invention

[0006] The present technology allows for the preparation and use of compositions containing combinations of active ingredients that have a synergistic effect towards reducing inflammation in a subject. It has been found that the combination of zinc and proanthocyanidin (PAC-A) allows the composition to be used to treat inflammation.

[0007] In one embodiment, a composition for treating and / or preventing inflammation in a subject is provided, comprising A-type proanthocyanidin (PAC-A) and zinc. For example, the composition can comprise at least 0.001% by weight of PAC-A based on the total weight of the composition. For example, the composition can comprise at least 0.01% by weight of PAC-A. For example, the composition can comprise at least 0.1% by weight of PAC-A. For example, the composition can comprise at least 1% by weight of PAC-A. For example, the composition can comprise at least 10% by weight of PAC-A. Optionally, the composition can comprise 0.001% to 10% by weight of PAC-A.

[0008] The composition may include a PAC-A-containing extract to provide PAC-A. The PAC-A-containing extract may include 5% to 15% by weight of PAC-A based on the total weight of the PAC-A-containing extract. For example, the composition may include 0.05% to 15% by weight of the PAC-A-containing extract based on the total weight of the composition. Optionally, the composition may include 0.05% to 6% by weight of the PAC-A-containing extract. Further optionally, the composition may include 1% to 3% by weight of the PAC-A-containing extract.

[0009] In some embodiments, the PAC-A-containing extract can be isolated from a natural source. For example, the PAC-A-containing extract can be provided as a PAC-A-containing cranberry extract. In another example, the PAC-A-containing extract can be an insoluble extract. In another example, the PAC-A-containing extract can be a soluble extract. Optionally, the PAC-A-containing extract can be a dried cranberry powder.

[0010] The composition can also include a zinc-containing compound to provide zinc.For example, the zinc-containing compound can be a zinc salt.For example, the zinc salt can be selected from the group consisting of zinc citrate, zinc lactate, zinc gluconate, zinc aspartate, zinc methionine, zinc oxide, zinc phosphate, zinc salicylate, and zinc chloride.Optionally, the zinc salt can be zinc citrate.

[0011] In some embodiments, the composition may include at least 0.01% by weight of a zinc-containing compound. For example, the composition may include 0.01% to 25% by weight of a zinc-containing compound. For example, the composition may include 0.01% to 10% by weight of a zinc-containing compound. For example, the composition may include 0.01% to 1% by weight of a zinc-containing compound.

[0012] In some embodiments, the composition can be configured for oral administration, for example, the composition can be edible.

[0013] In some embodiments, the compositions may be configured for topical application.

[0014] In some embodiments, the compositions may be configured for chewable delivery.

[0015] In some embodiments, the composition further comprises a gel base.

[0016] In some embodiments, the composition can be an oral care product, for example, the oral care product can be a mouthwash, a dentifrice, a paste, a spray, a dental lozenge, a gum, or a lozenge.

[0017] In some embodiments, the composition can be a skin care product. For example, the skin care product can be a gel, lotion, cream, or spray configured for topical application to the skin membrane.

[0018] In some embodiments, the composition can be a gastrointestinal care product. For example, the gastrointestinal care product can be a paste, powder, capsule, gummy, liquid, suppository, or chewable substance.

[0019] In some embodiments, the composition may be a paste, powder, gel, liquid, or chewable substance.

[0020] In another aspect, a method for preventing and / or treating inflammation in a subject is provided, comprising administering a composition comprising A-type proanthocyanidins (PAC-A) and zinc.For example, inflammation can be associated with oral cavity, skin membrane, or gastrointestinal tract.For example, inflammation can be associated with at least one of gingivitis, periodontitis, muscle pain, acne, allergy, dermatitis, psoriasis, eczema, heat rash, photosensitivity, abrasion, stomatitis, lesion, and gastrointestinal inflammation.For example, inflammation can be associated with dermatitis.For example, inflammation can be associated with periodontitis.

[0021] In some embodiments, the compositions may be administered orally, hi other embodiments, the compositions may be administered topically.

[0022] In some embodiments, the method may include multiple exposures to the composition.

[0023] The subject can be a mammal. For example, the subject can be a human. For example, the subject can be an animal. For example, the subject can be a dog, cat, or horse.

[0024] According to another aspect, there is provided an oral care product for reducing and / or preventing inflammation associated with the oral cavity in a subject, the oral care product comprising A-type proanthocyanidin (PAC-A) and zinc.

[0025] In some embodiments, the inflammation is associated with periodontal disease or stomatitis.

[0026] In some embodiments, the oral care products include from 0.001% to 10% by weight of PAC-A, optionally from about 0.0035% to about 0.42% PAC-A.

[0027] In some embodiments, PAC-A is provided as a PAC-A-containing extract.

[0028] In some embodiments, the oral care product comprises 0.05% to 15% by weight of the PAC-A-containing extract, optionally about 1% to about 3% by weight of the PAC-A-containing extract. In some embodiments, the oral care product comprises about 0.01% to about 25% by weight of the zinc-containing compound, optionally about 0.1% to about 10% by weight of the zinc-containing compound, further optionally about 0.1% to about 1% by weight of the zinc-containing compound. For example, the zinc-containing compound is a zinc salt, such as zinc citrate. The PAC-A-containing extract can be provided as a cranberry extract. For example, the cranberry extract can be one of a dried cranberry powder, a soluble cranberry extract, and an insoluble cranberry extract.

[0029] In another aspect, there is provided a use of a composition as defined herein for preventing and / or treating inflammation.

[0030] In another aspect, there is provided a use of a composition as defined herein for the manufacture of a medicament for the treatment of inflammation.

[0031] In another aspect, a process for producing an oral gel product is provided. The process includes providing a gel base and mixing a zinc-containing compound and a proanthocyanidin type A (PAC-A)-containing extract with the gel base to form an oral gel product. For example, the mixing can be performed to form an oral gel product having 0.001% to 10% by weight of PAC-A. For example, the mixing can be performed to form an oral gel product having 0.01% to 10% by weight of the zinc-containing compound.

[0032] In some embodiments, the PAC-A-containing extract is a PAC-A-containing cranberry extract.

[0033] In some embodiments, the zinc-containing compound is a zinc salt.

[0034] In some embodiments, the process can include maintaining a temperature during mixing of the PAC-A-containing extract and the zinc-containing compound into the gel base that prevents degradation of the PAC-A.

[0035] In addition, the methods / processes described herein can include at least one additional feature / step derived from the definition of the composition comprising PAC-A and zinc provided herein.

[0036] While the present invention will be described in conjunction with exemplary embodiments, it will be understood that it is not intended to limit the scope of the present invention to such embodiments. On the contrary, it is intended to cover all alternatives, modifications, and equivalents that may be included as defined by this description. The objects, advantages, and other features of the present invention will become more apparent and be better understood upon reading the following non-limiting description of the invention, given with reference to the accompanying drawings. [Brief description of the drawings]

[0037] [Figure 1] FIG. 2 is a bar graph showing interleukin-6 (IL-6) production (pg / ml) by a human organotypic model under inflammatory stress (bacterial lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (Poly I:C)) when treated with the formulations of Table 1. [Diagram 2] 1 is a bar graph showing interleukin-8 (IL-8) production (pg / ml) by a human organotypic model under inflammatory stress (LPS / poly I:C) when treated with the formulations of Table 1. [Diagram 3] 1 is a bar graph showing the mean expression levels (fold increase) of the gene encoding IL-6 in a human organotypic model under inflammatory stress (LPS / Poly I:C) when treated with the formulations of Table 1. [Figure 4] 1 is a bar graph showing the mean expression levels (fold increase) of the gene encoding IL-8 in a human organotypic model under inflammatory stress (LPS / Poly I:C) when treated with the formulations of Table 1. [Diagram 5] FIG. 1 is a bar graph showing IL-6 production (pg / ml) by a human organotypic model under inflammatory stress (LPS / Poly I:C) when treated with various concentration levels of PAC-A-containing extract (0%, 0.1%, 1%, 3%, 6%, and HBSS), which is PAC-A enriched cranberry powder. [Figure 6]1 is a bar graph showing IL-6 and IL-8 production (pg / ml) by a human organotypic model under inflammatory stress (LPS / Poly I:C) when treated with formulations 2A, 2C, 2G, and 2H identified in Table 2. [Figure 7] 1 is a bar graph showing IL-8 production (pg / ml) by a human organotypic model under inflammatory stress (LPS / Poly I:C) when treated with the formulations of Table 2. [Figure 8] 1 is a bar graph showing the mean expression levels (fold increase) of the gene encoding IL-6 in a human organotypic model under inflammatory stress (LPS / Poly I:C) when treated with the formulations of Table 2. [Figure 9] 1 is a bar graph showing the mean expression levels (fold increase) of the gene encoding IL-8 in a human organotypic model under inflammatory stress (LPS / Poly I:C) when treated with the formulations of Table 2. [Figure 10] 1 is a bar graph showing IL-6 production (pg / ml) by a human organotypic model (gingival model) under inflammatory stress (LPS / Poly I:C) when treated with the formulations of Table 3. [Figure 11] 1 is a bar graph showing IL-6 production (pg / ml) by a human organotypic model (gingival model) under inflammatory stress (LPS / Poly I:C) when treated with the formulations of Table 4. [Figure 12] 6 is a bar graph showing IL-6 production (pg / ml) by a human organotypic model (gingival model) under inflammatory stress (LPS / Poly I:C) when treated with the formulations of Table 5. [Figure 13] 1 is a bar graph showing the antioxidant values ​​(measured as antioxidant capacity TEAC) of different test gels containing various active ingredients. [Figure 14] FIG. 1 is a bar graph showing IL-6 production (pg / ml) by a skin model under inflammatory stress when treated with a cream formulation containing at least one of 1 wt. % PAC-rich cranberry and 0.2 wt. % zinc subjected to heat treatment at various temperatures for 30 minutes. [Figure 15]1 is a bar graph showing IL-6 production (pg / ml) by a human organotypic model (gingival model) when treated with a gel formulation comprising at least one copper and PAC rich cranberry. [Figure 16] 1 is a bar graph showing IL-6 production (pg / ml) by a human organotypic model (gingival model) when treated with gel formulations made with soluble and insoluble fractions of cranberry along with variations in zinc source, zinc concentration, and temperature the gels are exposed to when prepared. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0038] The examples, variants and preferred embodiments of the present invention are described below.In one aspect, a composition for treating and / or preventing inflammation in a subject is provided, which comprises the synergistic combination of A-type proanthocyanidin (PAC-A) and zinc ion.More specifically, it has been surprisingly found, as demonstrated herein, that zinc ion acts as an enhancer of the anti-inflammatory ability of PAC-A, and the combination of zinc and PAC-A-containing compound / extract can treat and / or prevent inflammation in a subject.

[0039] In some embodiments, the composition can be used as a dental product for the treatment and / or prevention of inflammation associated with the oral cavity in a subject, such as an animal.

[0040] In the context of this specification, the term "treatment" of inflammation can include reducing inflammation in a subject.

[0041] A-type proanthocyanidins Proanthocyanidins (PACs) are a class of polyphenols produced by natural sources such as cranberries and blueberries and other members of the Ericaceae family, as well as other plants such as aronia (chokeberry), cinnamon and cinnamon, grapes and grape seed oil, strawberry, avocado, green tea, and haskap berry. PACs have high antioxidant capacity, as well as anti-inflammatory and antibacterial properties. PACs can bind to bacteria and prevent them from clinging to mucous membranes, thus preventing biofilm growth or colonization in subjects. In this context, the term "subject" refers to living vertebrates such as mammals, including, but not limited to, humans, domestic animals such as dogs or cats, farm or livestock animals such as horses, and zoo animals.

[0042] A-type proanthocyanidins (PAC-A) are a subclass of PACs with antibacterial and anti-inflammatory properties that can be found in natural sources, such as from Vaccinium oxycoccos and Vaccinium macrocarpon (cranberry). For example, PAC-A can be included in a PAC-A-containing extract that is derived from a PAC-A-containing natural source. In another example, PAC-A can be synthesized so that a PAC-A-containing extract with a controlled concentration of synthetic PAC-A can be prepared. If the PAC-A-containing natural source includes cranberry, the PAC-A-containing extract can be referred to as a PAC-A-containing cranberry extract. The PAC-A-containing extracts encompassed herein can include soluble PAC-A-containing extracts, insoluble PAC-A-containing extracts, or combinations thereof. Soluble extracts can be useful in formulations in gels or dissolved in liquid formulations for topical application, such as in sprays, or for oral intake. For example, the soluble portion of the dried cranberry powder (soluble extract) may consist of shorter chain PAC-A polymers than the insoluble portion of the dried cranberry powder (insoluble extract). In another example, the PAC-A-containing extract may be dried cranberry powder (including soluble and insoluble portions) obtained from a whole PAC-A-containing natural source, i.e., cranberry. Pure dried cranberry powder may contain up to about 7% PAC-A by weight. For example, a PAC-A-containing extract derived from a natural source may have a PAC-A concentration ranging from about 1% to about 15% by weight based on the total weight of the PAC-A-containing extract. For example, a dried cranberry powder may have a PAC-A concentration of at least 5%, at least 6%, or at least 7% by weight. However, it should be understood that the PAC-A-containing extract may be prepared or synthesized according to any known technique for increasing PAC-A concentration. It should be noted that the present technique is not limited to a specific PAC-A concentration in the PAC-A-containing extract. A synergistic effect towards the treatment of inflammation may be observed for compositions comprising zinc and at least 0.001% by weight PAC-A, at least 0.01% PAC-A, at least 1% PAC-A, or at least 10% PAC-A based on the total weight of the composition.For example, the composition can include about 0.001% to about 10% by weight of PAC-A, based on the total weight of the composition.

[0043] In the context of this specification, the term "extract" or "PAC-A-containing extract" is intended to include PAC-A-containing compounds resulting from physical and / or chemical processing of a PAC-A-containing natural source to recover its PAC-A content in the resulting extract. The physical and / or chemical processing can be adjusted to obtain a higher PAC-A concentration in the resulting extract (such as a soluble extract, an insoluble extract, or dried cranberries). The soluble extract comprises a solution of solubilized cranberry pomace and can be prepared by dehydration of the filtrate. The insoluble extract comprises a non-solubilized fraction of the aforementioned soluble cranberry pomace and can be prepared by dehydration. The dried cranberries can be further ground to produce a pure dried cranberry powder that can be used as a PAC-A-containing extract.

[0044] PAC polymers have reactive bonding sites on their terminal units that can accommodate large ions. For example, the reactive site of the PAC-A polymer can accommodate a zinc ion, thereby forming a PAC-A / zinc complex. Specifically, PAC is a polymer consisting of two flavanol subunits, namely, catechin and epicatechin, linked by two different types of bonds. The bond in B-type proanthocyanidins (PAC-B) is a single covalent bond between carbons C4 and C8 (b-type bond), while the bond in A-type proanthocyanidins (PAC-A) is a second interflavanol bond between the oxygen of carbon C2 and carbon C7 (a-type bond). The a-type bond between catechin and epicatechin in PAC-A allows the attachment of a zinc ion (Zn 2+ ) and thus bring them together in the PAC-A / zinc complex.

[0045] It should be noted that commercially available cranberry extracts / products, such as cranberry powder, may not contain PAC-A depending on the method of production of the cranberry extract / product. In addition, the PAC-A concentration in cranberry extracts may vary depending on the type of extract. It should be further noted that subjecting cranberry sources or extracts to heat treatment at a certain temperature may degrade PAC-A and make the cranberry extract inefficient for the purpose of the present invention, which targets the synergistic effect between zinc ions and PAC-A. Experimental results are provided to show that exposure to excessive temperature may hinder the anti-inflammatory function of the synergistic combination of PAC-A and zinc in the composition. The compositions encompassed herein are prepared according to techniques that do not expose PAC-A-containing extracts to any heat that causes a reduction or inhibition of the synergistic effect toward inflammation when combined with zinc-containing ingredients.

[0046] zinc Zinc ions are known to have antibacterial properties and can be used in oral hygiene products such as mouthwashes or sprays and dentifrices to control plaque, inhibit tartar formation, and reduce bad breath.

[0047] However, it is shown herein that zinc ions provided by zinc-containing compounds, also referred to as zinc-based compounds, can be employed as an enhancer of the anti-inflammatory ability of PAC-A in combination with PAC-A-containing extracts.The zinc-containing compounds encompassed herein can be or include, but are not limited to, zinc salts or combinations thereof.Zinc salts include zinc citrate, zinc lactate, zinc gluconate, zinc aspartate, zinc methionine, zinc oxide, zinc phosphate, zinc salicylate, zinc chloride, and any combination thereof.

[0048] It should be noted that the concentration of the zinc-containing compound in the composition may be limited by the viability of the target zone being treated.

[0049] Enhancement of the effect of PAC-A It was found that the effect of PAC-A-containing extract in reducing / suppressing the in vitro expression of inflammation-related interleukin-6 (IL-6) and interleukin-8 (IL-8) genes was favorably altered in the presence of zinc ions.As seen in the Examples section, it was found that a composition containing 3% by weight of PAC-A-containing cranberry extract (dried cranberry powder) was optimal for reducing the expression of interleukin-6 and interleukin-8 genes and the production of IL-6 and IL-8 without the use of enhancers, and thus optimal for reducing inflammation in tissues of a subject.When PAC-A-containing cranberry extract was combined with zinc citrate, the concentration of PAC-A-containing cranberry extract could be reduced while still showing substantially similar suppression of IL-6 and IL-8 gene expression and IL-6 and IL-8 production, thus indicating that zinc ions could be an enhancer of the anti-inflammatory properties of PAC-A.

[0050] Thus, a composition combining PAC-A with zinc can utilize a smaller amount of PAC-A than would normally be required to reduce inflammation in a subject's tissue.As seen in the Examples section, the use of zinc ions as an enhancer can reduce the total concentration of PAC-A-containing extract required in an effective dosage to at least 1% by weight of PAC-A-containing extract in the composition, while maintaining similar levels of IL-6 and IL-8 gene expression and IL-6 and IL-8 production as the optimal level of 3% by weight of PAC-A when used without an enhancer.In some embodiments, the use of zinc as an enhancer can reduce the concentration of PAC-A-containing extract in the composition to at least about 0.05% by weight.As seen in the Examples section, the enhancing effect of zinc was demonstrated in extracts containing PAC-A, but not in extracts containing B-type proanthocyanidins (PAC-B), such as blueberry extract. While the a-type bond in the PAC-A polymer creates a reactive site that can stably bind zinc ions along with a second PAC-A polymer, the single bond b-type bond between epicatechin and catechin in the PAC-B polymer does not.

[0051] In another example, a composition containing at least 1% by weight of a PAC-A-containing extract and at least 0.01% by weight of a zinc-containing compound has been shown to reduce the expression of interleukin-6 and interleukin-8 genes and the production of IL-6 and IL-8, thus reducing inflammation. Including at least 0.01% by weight of a zinc-containing compound with a PAC-A-containing extract has been shown to increase the anti-inflammatory properties of PAC-A. Using zinc ions as an enhancer of the anti-inflammatory properties of PAC-A reduces the total concentration of anti-inflammatory PAC-A compounds required in an effective dose of the composition. Since most PAC-A-containing ingredients or extracts are brightly colored (e.g., cranberry), reducing the amount of PAC-A-containing ingredients facilitates the creation of a colorless or easily dyed formulation. Furthermore, using zinc ions as an enhancer of the anti-inflammatory capabilities of PAC-A allows for an anti-inflammatory composition with higher efficacy than a formulation that does not contain zinc ions.

[0052] In some embodiments, the composition comprises at least about 0.05% to about 15% by weight of a PAC-A-containing extract, about 0.05% to about 6% by weight of a PAC-A-containing extract, or about 1% to about 3% by weight of a PAC-A-containing extract, and can achieve a PAC-A concentration of at least 0.001% by weight, at least 0.01% by weight, at least 1% by weight, or at least 10% by weight in the composition (depending on the PAC-A concentration of the PAC-A-containing extract). For example, the composition can comprise about 0.001% to about 10% PAC-A, optionally about 0.0035% to about 0.42% PAC-A, based on the total weight of the composition. The PAC-A-containing extract can be derived from a natural source, such as cranberry. The PAC-A-containing extract can be soluble or insoluble. In some embodiments, the PAC-A-containing extract is a dried cranberry powder.

[0053] In some embodiments, the composition comprises about 0.01% to about 25% by weight of a zinc-containing compound, e.g., about 0.01% to about 10% by weight of a zinc-containing compound, optionally 0.01% to 1% by weight of a zinc-containing compound. For example, the composition can comprise up to 3%, up to 2%, or up to 1% by weight of a PAC-A-containing extract, and up to 0.6%, up to 0.2%, or at least 0.01% by weight of a zinc salt, such as zinc citrate.

[0054] Other Effects It should be noted that the active ingredients described herein, i.e., PAC-A and zinc ions, can provide more than just anti-inflammatory functions / effects. It is not intended to limit the application of the compositions described herein to the treatment of inflammation, and the compositions may further be used for antioxidant functions, to reduce / prevent bacterial growth, or to support an immune response.

[0055] Delivery method Compositions comprising PAC-A and zinc can be used to treat a variety of diseases or conditions caused by oral inflammation (including periodontal disease such as periodontitis or gingivitis and stomatitis), skin inflammation (including acne, urticaria (allergy), dermatitis, psoriasis, eczema, heat rash, photosensitivity, abrasions and lesions), and / or gastrointestinal inflammation (including pharyngitis or inflammatory bowel disease). Thus, delivery methods of the compositions can include, for example, topical application on the affected tissue, oral administration, or chewable delivery. In this context, the term "topical application" refers to a formulation configured for application to body surfaces including the oral cavity (mouth, gums, etc.) and dermal membranes (skin) for delivery of the active agent through dermal, sublingual, buccal, or oral mucosal absorption. The term "oral administration" refers to a formulation configured for delivery of the active agent to the gastrointestinal tract for absorption. The term "chewable delivery" refers to a formulation configured to be chewed for topical delivery to the oral cavity, such as a gum or soft dental lozenge. The compositions described herein can be delivered to tissues (before or during the diseased / inflamed condition) via a variety of delivery methods, including, but not limited to, gels, dentifrices, dental lozenges, lotions, sprays, creams, gums, beverages, tablets, lozenges, capsules, syrups, capsules, aqueous or oil suspensions, and the like.

[0056] In some embodiments, particularly compositions configured for oral administration, chewable delivery, or topical application to the oral cavity, the composition may consist entirely of edible ingredients such as dried cranberry powder and zinc citrate.

[0057] In some embodiments, the composition is adapted for topical application to the oral cavity or oral mucosa, including the gums and oral cavity. For example, in periodontitis, inflammation of the gums is the main cause of bone density loss. Matrix metalloproteinases produced by inflammation cause the degradation of alveolar bone by chelating calcium. Therefore, reducing inflammation in the subject's gums reduces the potential loss of alveolar bone. Compositions adapted for topical application to the oral cavity or oral mucosa can include gels, dentifrices, mouth sprays, mouthwashes, lozenges, and the like.

[0058] In some embodiments, the composition is configured for topical application to the skin membrane (skin). For example, inflammatory acne can result from clogged pores. Treating inflammation of the skin can reduce the swelling and redness of the clogged pores. Muscle pain can also be caused by inflammation of muscle tissue, and reducing inflammation in affected tissue can reduce the associated muscle pain. The composition configured for topical application to the skin membrane can include a gel, lotion, cream, or spray. In other embodiments, the composition can be used in cosmetics such as scar or skin regeneration creams, makeup primers, concealers, etc.

[0059] In some embodiments, the composition is configured for oral administration. For example, pharyngitis is caused by inflammation of the pharynx (i.e., the part of the throat between the mouth / nasal cavity and the esophagus / trachea), which can cause pain and swelling in the throat. Reducing inflammation in the pharynx can reduce the associated symptoms. Oral administration for delivery of the composition to the gastrointestinal tract can include compositions in the form of gels, sprays, beverages, tablets, lozenges, capsules, water or oil suspensions, syrups, etc.

[0060] In some embodiments, the composition is configured for chewable delivery, such as for delivery to the oral mucosa to treat periodontal disease. Chewable delivery is particularly useful for non-human subjects to maximize the time of exposure to the oral mucosa. For example, the composition can be in the form of a dental soft candy for administration to the oral mucosa of domestic animals, such as dogs or cats. In other embodiments, such as for human subjects, the composition can be in the form of a chewing gum for prolonged exposure to the oral mucosa.

[0061] For example, the composition can be an oral care product that includes up to 3%, up to 2%, or up to 1% by weight of a PAC-A-containing extract, such as dried cranberry powder, and up to 0.6%, up to 0.2%, or at least 0.01% by weight of a zinc salt, such as zinc citrate. In another example, the composition can be a skin care product that includes up to 3%, up to 2%, or up to 1% by weight of a PAC-A-containing extract, such as dried cranberry powder, and up to 0.6%, up to 0.2%, or at least 0.01% by weight of a zinc salt, such as zinc citrate.

[0062] In some embodiments, the composition may contain other compounds that are beneficial to the health of subjects or improve the palatability of the composition.For example, the composition may contain natural extracts that contain PAC-B antioxidants, such as the extracts isolated from blueberry, aronia (chokeberry), haskap berry, green tea, strawberry, grape and grape seed oil, grapefruit, lemon, and cherry.In some embodiments, the composition may contain compounds such as vitamin C, vitamin D, vitamin E, omega-3 fatty acid, omega-6 fatty acid, sodium hexametaphosphate, pyrophosphate, dicalcium phosphate, citric acid, lactoperoxidase, glucose oxidase, lysozyme, and / or protease.In some embodiments, agents such as humectants, thickeners, waxes, flours, starches, emulsifiers, and / or oils may be used as part of the delivery system of the composition.

[0063] Exemplary Implementations Examples of dental gel products are provided below:

[0064] [Table 1]

[0065] Examples of dental soft candy compositions are provided below:

[0066] [Table 2]

[0067] Examples of health drink compositions are provided below:

[0068] [Table 3]

[0069] Examples of lotion compositions are provided below:

[0070] [Table 4]

[0071] Examples of cream compositions are provided below:

[0072] [Table 5]

[0073] It should be noted that other products can be produced to provide the composition to a subject.For example, a capsule containing the composition encompassed herein can be used to treat gastrointestinal inflammation.Optionally, the composition in the capsule can comprise at least 80% by weight of a PAC-A-containing extract and 1% by weight of zinc citrate.For example, the composition in the capsule can comprise about 99% by weight of dried cranberry powder and about 1% by weight of zinc citrate.

[0074] Experimental Results Example 1 - Effect of a composition containing PAC and zinc on an in vitro organotypic model - Detection of inflammatory cytokines (IL-6 and IL-8) In vitro assays were performed to demonstrate the enhanced anti-inflammatory effect of PAC-A and zinc compositions on an artificial human organotypic model. The EpiGingival™ three-dimensional organotypic model (GIN-112 from MaTtek™) was used to determine the inhibitory effect of the synergistic combination of PAC-A and zinc ions on inflammatory cytokine production. The organotypic model is equivalent to the human oral mucosa formed by a multilayer of highly differentiated human keratinocytes. Briefly, human epithelial cells isolated from healthy volunteers were deposited on the surface of a porous membrane soaked in a culture medium containing growth factors. A cellular multilayer was formed with an air-liquid interface with the apical (top) part of the model in contact with the environment (air) while the basolateral part supported by the porous membrane was in contact with the culture medium. The models were incubated overnight (37° C., 5% CO2) and then inoculated with immune stimulating medium containing 10 μg / mL polyinosinic:polycytidylic acid (Poly I:C) and 2 μg / mL bacterial lipopolysaccharide (LPS) to induce an inflammatory response. Prior to a 24-hour incubation period (37° C., 5% CO2), 40 μL of the formulations shown in the table were deposited on the surface of the organotypic models.

[0075] The organotypic models were rinsed with cold PBS to remove residual traces of gel and stored in RNAlater®. In addition to the detection of inflammatory cytokines (IL-6 and IL-8) in the culture medium, an analysis of the expression of genes encoding inflammatory cytokines was performed. The organotypic models were transferred to Precellys®-type tubes containing CK14 ceramic beads with 600 μL of cold RLT buffer (EZNA kit, Omega®). The samples were homogenized with a Precellys® homogenizer at 6500 rpm for 30 seconds. The cell lysates were then used to extract RNA using the Omega® EZNA kit according to the manufacturer's recommendations. The RNA was then eluted in 60 μL of elution buffer. The RNA was then eluted with Qiagen® Retrotranscriptase (RT) according to the manufacturer's instructions. 2 500 ng of RNA was transcribed into complementary DNA (cDNA) using the First Strand PCR product. Amplification was carried out using a thermocycler (Mx3000p, Stratagene®) using primers from Qiagen® up to a volume of 20 μL. Samples were denatured with an initial cycle of 10 min at 95°C, followed by 40 cycles of alternating denaturation at 95°C for 15 s and denaturation at 60°C. Fluorescence was measured at the end of each cycle. Expression of the housekeeping genes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and β-glucuronidase (GUSB) was also monitored. The delta-delta Ct method (ΔΔCt) was used to quantify the expression of each of the genes. The samples serving as the reference basis for the calculations were RNA extracted from cells in contact only with the complete medium Hank's Balanced Salt Solution (HBSS).

[0076] The following formulations were tested:

[0077] [Table 6]

[0078] [Table 7]

[0079] [Table 8]

[0080] [Table 9]

[0081] [Table 10]

[0082] Referring now to Figures 1-4, the results showed that formulations containing 3% PAC-A in cranberry extract (Formulations 1B and 1C) and 3% PAC-B in blueberry extract (Formulation 1D) significantly reduced IL-6 and IL-8 gene expression and IL-6 and IL-8 production compared to the control formulation containing HBSS (Formulation 1A). No significant differences were found between formulations containing only PAC-A in cranberry extract or only PAC-B in blueberry extract. The formulation containing 0.2% zinc citrate (Formulation 1E) did not produce any significant differences in IL-6 or IL-8 gene expression or IL-6 or IL-8 production.

[0083] Referring now to FIG. 5, a bar graph shows IL-6 production (pg / ml) by human organotypic models under inflammatory stress (LPS / poly I:C) when treated with 0%, 0.1%, 1%, 3%, and 6% PAC-A-containing cranberry extract, including a formulation containing HBSS as a control. The lowest optimal concentration of PAC-A-containing extract without the use of enhancers to reduce the production of IL-6 was found to be at least 3%. There was a significant reduction in IL-6 production between the formulation containing 1% PAC-A-containing extract and the formulation containing 3% PAC-A-containing extract, and the production of IL-6 was not significantly reduced when a formulation with an increased PAC-A concentration of 6% was applied. Therefore, a concentration of 3% PAC-A-containing extract was used as a positive control in subsequent experiments.

[0084] 6-9, results confirm that IL-6 and IL-8 gene expression and cytokine concentration levels are significantly reduced in organotypic models treated for 24 hours with a formulation containing 3% PAC-A containing cranberry extract (Formulation 2A). Comparison of IL-6 production in organotypic models treated with Formulations 2B and 2D indicates that the anti-inflammatory function of the cranberry PAC-A composition (2B) is comparable to that of the 0.5% hydrocortisone composition.

[0085] Thus, the experiments indicate that the PAC-A-containing cranberry extract produces most of the anti-inflammatory effect, as the reduction in inflammatory cytokine production is more pronounced when the concentration of cranberry extract is higher.

[0086] A formulation containing 3% Aronia berry (chokeberry) extract (formulation 2C) was also tested in the organotypic model. With reference to Figures 6 and 7, the results showed that the formulation containing Aronia berry extract with PAC (formulation 2C) resulted in a reduction in the production of IL-6 and IL-8 compared to the gel base, but the anti-inflammatory properties of Aronia berry were not as pronounced as those of cranberry extract. With reference to Figures 5, 17, and 18, the trends observed for IL-6 and IL-8 gene expression, as well as IL-6, IL-8, TNF-α, and NF-κB production, appeared to be similar, so further testing was performed based on the evaluation of IL-6 production only.

[0087] Referring now to Figure 10, similar to the results shown in Figures 5 and 6, the formulation containing 3 wt% PAC-A in cranberry extract (Formulation 3B) produced significantly less inflammatory cytokines than the formulation containing only 1 wt% PAC-A in cranberry extract (Formulation 3C). However, when 0.2 wt% zinc citrate was combined with 1 wt% PAC-A in cranberry extract (Formulation 3E), IL-6 cytokine production was significantly reduced to a production level equivalent to that of the formulation containing 3 wt% PAC-A in cranberry extract. The results indicate that zinc acts as an enhancer of the anti-inflammatory ability of PAC-A, since the formulation containing only 0.2 wt% zinc citrate (Formulation 1D) did not significantly reduce IL-6 cytokine production compared to the HBSS control (Figure 1). Comparison of the resulting IL-6 production in organotypic models treated with a formulation containing 1% PAC-A containing cranberry extract and 0.2% zinc citrate (Formulation 3E) and a formulation containing 1% PAC-B containing blueberry extract and 0.2% zinc citrate (Formulation 5G, FIG. 12) surprisingly shows that the enhancing effect of zinc ions is present in the cranberry extract containing PAC-A but not in the blueberry extract containing PAC-B.

[0088] Further experiments were performed using various levels of zinc citrate, including 0.6%, 0.05%, and 0.0125% by weight, as shown in Figure 11. IL-6 production was significantly reduced in a formulation containing 3% by weight PAC-A cranberry extract and 0.6% by weight zinc citrate (Formulation 4F). Formulations 4G and 4H containing 0.05% or less by weight zinc citrate did not show the enhancing effect shown by formulations containing at least 0.2% by weight zinc citrate (Formulations 3E and 4F).

[0089] Formulations containing soluble and insoluble PAC-A-containing cranberry extracts were also applied to organotypic models. There was no significant difference between IL-6 cytokine production in models treated with 3% by weight of PAC-A-containing cranberry extract (formulation 4B) and models treated with either soluble or insoluble PAC-A-containing cranberry extract (formulations 4C and 4D, respectively).

[0090] Example 2 - Effect of a composition containing PAC and zinc using the H-ORAC assay - Antioxidant capacity study The antioxidant capacity of gels containing separate active ingredients and several mixtures of ingredients was evaluated by using Trolox Equivalent Antioxidant Capacity (TEAC) and Hydrophilic-Oxygen Radical Absorbance Capacity (H-ORAC) potentials. Table 6 provides a summary of the TEAC results for neutral gels containing separate ingredients (cranberry, blueberry, zinc citrate), mixtures of ingredients, and a reference neutral gel (Gel 4) that was evaluated at 595 TEAC.

[0091] [Table 11]

[0092] With reference to Table 6 and Figure 13, the gel made with 0.2 wt% zinc citrate was found to have a TEAC value just below that measured for the neutral gel. The gel made with 1 wt% cranberry powder had a measured TEAC value of 1018. When 0.2 wt% zinc citrate was added to 1 wt% cranberry powder, the antioxidant capacity value was measured at 1997 TEAC, which is 185 TEAC higher than when only 3 wt% cranberry powder was used as a positive control. This supports the idea that using zinc or a zinc-based compound such as zinc citrate and PAC-rich cranberry powder increases the antioxidant capacity of the system.

[0093] No synergistic effect was observed when using PAC-rich blueberry powder. Thus, synergistic effects in terms of increased antioxidant capacity / potency are observed when using cranberry proanthocyanidins, i.e., PAC-A.

[0094] Example 3 - Effect of a composition containing PAC and zinc on a skin model - Study of the anti-inflammatory effect by detecting inflammatory cytokines (IL-6) Another series of experiments was carried out to measure the anti-inflammatory effect of PAC-rich cranberry powder and zinc citrate in different vehicles applied to different types of human tissue. In this case, the active ingredients were provided in an oily commercial skin cream and applied to a skin model (MaTtek EpiDerm™). Two hypotheses were tested in this series of experiments. The first hypothesis was that the cranberry-zinc synergy is independent of the vehicle and tissue model. The second hypothesis is that the synergy is temperature dependent.

[0095] With reference to FIG. 14, a commercial skin cream enriched with PAC-rich cranberry powder (1 wt%) was found to have a significantly different anti-inflammatory effect than the neutral cream used as a reference. A cream enriched only with zinc citrate (0.2 wt%) did not produce any significant difference in anti-inflammatory effect compared to the neutral cream. A significantly different and higher anti-inflammatory effect was observed when a combination of 1.0 wt% PAC-rich cranberry powder and 0.2 wt% zinc citrate was added to the cream (without heat treatment). This cream was found to be the most effective when compared to other creams. This suggests that synergy can be observed in a different medium than gel. It also suggests that synergy works when used in different types of human tissues (e.g., gingival model and skin model) and in different media.

[0096] In the second half of the experiment, the same commercial cream was supplemented with 1.0 wt. % PAC-containing cranberry powder and 0.2 wt. % zinc citrate, but heated to a temperature of 75° C. for a duration of 30 minutes. Still referring to FIG. 14, the cream sample did not show any synergistic anti-inflammatory response, thereby indicating that temperature may be detrimental to the PAC-A-zinc synergy.

[0097] Example 4 - Effect of a composition containing PAC and copper on a gingival model - Study of the anti-inflammatory effect by detecting inflammatory cytokines (IL-6) Another series of experiments was carried out to evaluate the effect of metal ions different from zinc. These tests were carried out using gel as a vehicle and a gingival tissue model (MaTtek EpiGingival™) as described in Example 1. Copper (2+) citrate was used instead of zinc citrate. The concentration of copper used (0.1046 wt%) was used to have the same concentration of copper and zinc ions. Cu 2+ However, the atomic radius, atomic weight, and electron distribution of Zn 2+IL-6 production was chosen as a surrogate because it is very close to Zn. With reference to FIG. 15, when copper was used alone in the gel, there was no significant difference between this gel and the neutral gel (gel base). When a gel was made with cranberry and copper citrate, IL-6 production was not significantly different from that of the gel made with copper alone or the neutral gel. This data supports the conclusion that Zn 2+ This supports the hypothesis that ions alone have an enhancer effect with cranberry.

[0098] Example 5 - Effect of a composition containing PAC and zinc on a gingival model - Study of the anti-inflammatory effect by detecting inflammatory cytokines (IL-6) Another series of experiments was carried out on the gingival model (MaTtek EpiGingival™) described in Example 1 to characterize the role of soluble and insoluble fractions of cranberry in the observed synergistic effect on reducing inflammation. Separation of soluble and insoluble fractions of PAC-A-containing cranberry extract was carried out, and two different gel samples were made using soluble and insoluble fraction concentrations of cranberry powder of 1% by weight, respectively, and zinc citrate concentration of 0.2% by weight. With reference to FIG. 16, the gel sample made with soluble fraction showed anti-inflammatory results significantly different from the neutral gel, while the gel sample made with only insoluble fraction did not show anti-inflammatory results. Therefore, the insoluble fraction did not seem to provide the same synergistic effect as the soluble fraction. Gels made with 1 wt% soluble fraction only and 0.2 wt% zinc citrate did not achieve as strong a synergistic effect as when whole cranberry powder was used. In other experiments, gels made with 1 wt% whole cranberry powder and 0.2 wt% zinc citrate have the same effect as 3 wt% cranberry powder. In this case, the 3 wt% cranberry gel and the gels made with 1 wt% soluble and insoluble cranberry fractions with 0.2 wt% zinc citrate were all significantly different from neutral, suggesting that both fractions may exhibit synergistic effects.

[0099] The upper limit of zinc utilization is being further tested. For example, a concentration of 5% by weight of zinc citrate has been used. The hypothesis is that Zn2+ The ions supplement the antioxidant capacity of PAC when used. 5% by weight of zinc citrate is equivalent to 1,745% by weight of Zn in the gel. 2+ The maximum concentration of zinc ions corresponds to the upper limit of zinc concentration at which precipitates in the gel are formed and / or degradation of the in vitro tissue model tested is observed. Still referring to FIG. 16, the gel with 5% by weight zinc citrate and 1% by weight cranberry did not produce better results than the gel made with soluble cranberry fraction. Viability assays were performed on the gingival model after its addition of the maximum zinc concentration and it was found that the viability was significantly reduced. This may have affected the production of interleukin IL-6 on the model. The very high concentration of zinc ions may possibly explain the low synergism. Since only 1% by weight cranberry powder was used, PAC was the limiting reactant. This exemplary set of experiments represents the only case where proanthocyanidins (PAC) were used as reactants with limiting concentrations. This means that zinc does not supplement the antioxidant capacity of PAC as previously assumed. Otherwise, a great synergism would have been observed.

[0100] Different zinc salts have been used to understand if citrate ions are necessary for synergy to occur. Gels were made with 1% cranberry powder and 0.0875% zinc oxide by weight. This concentration is equivalent to 0.2% zinc citrate by weight. 2+ The ionic concentrations are shown in Table 1. This gel shows similar results to the soluble cranberry and zinc citrate gels. These results indicate that zinc oxide can act as an enhancer to obtain similar effects to gels made with higher concentrations of PAC-A-containing extracts (see previously reported results).

[0101] The effect of heat on the system has been studied again. Gels made with 1.0 wt% cranberry and 0.2 wt% zinc citrate gel were placed in a 70°C water bath for 30 minutes. This heating regimen is used to try to denature the maximum amount of PAC in the cranberry. It is hypothesized that by varying the concentration of PAC, the synergy should be less effective. The results of this test could be compared with the soluble and insoluble fractions performed in the same model. When applied to the gingival model, the cooled gel did not show significantly different results than the neutral gel. This means that the synergy may be reduced and possibly inactivated when the medium is heated. When the synergy is reduced by heating, this is most likely not due to the complete decomposition of the PAC.

[0102] In the above description, the term "about" means within an acceptable error range for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined, i.e., the limitations of the measurement system. It is generally accepted that a measure of accuracy of 10% is acceptable and encompasses the term "about."

[0103] The use of the words "a" or "an" when used in conjunction with the term "comprising" in the claims and / or specification may mean "one," but is also consistent with the meaning of "one or more," "at least one," and "one or more."

[0104] In the above description, the embodiments are examples or implementations of the present invention. The various appearances of "one embodiment," "embodiments," or "some embodiments" do not necessarily all refer to the same embodiment. Although various features of the present invention may be described in the context of a single embodiment, the features may also be provided separately or in any suitable combination. Conversely, although the present invention may be described herein in the context of separate embodiments for clarity, the present invention may also be implemented in a single embodiment. Furthermore, it should be understood that the present invention is not limited in its application to the details of construction and arrangement of components set forth in the following description or illustrated in the drawings. The present invention is capable of other variations or embodiments and can be practiced or carried out in various ways. It should also be understood that the phraseology and terminology used herein are for the purpose of description and should not be regarded as limiting. The use of "including," "comprising," or "having" and variations thereof herein is intended to encompass the items listed thereafter and equivalents thereof, as well as additional preferred items.

[0105] It is to be understood that any one of the above-mentioned embodiments of each composition, product, method, process, and use of the combination of a PAC-A-containing extract and a zinc-containing agent may be combined with any other of those embodiments, except where the two embodiments cannot clearly be combined due to their mutual exclusivity.

Claims

1. A composition for treating and / or preventing inflammation in a subject, comprising A-type proanthocyanidin (PAC-A) and zinc.

2. 10. The composition of claim 1, comprising at least 0.001 wt. %, or at least 0.01 wt. %, or at least 0.1 wt. %, or at least 1 wt. %, or at least 10 wt. % of PAC-A, based on the total weight of the composition.

3. The composition described in claim 1, comprising 0.001 wt% to 10 wt% of PAC-A relative to the total weight of the composition.

4. 4. The composition of claim 1, further comprising a PAC-A-containing extract to provide PAC-A.

5. 5. The composition of claim 4, wherein the PAC-A-containing extract comprises 1% to 15% by weight of PAC-A, based on the total weight of the PAC-A-containing extract.

6. 5. The composition of claim 4, comprising 0.05% to 15%, or 0.05% to 6%, or 1% to 3% by weight of the PAC-A-containing extract, based on the total weight of the composition.

7. The PAC-A-containing extract is isolated from a natural source, and / or provided as a PAC-A-containing cranberry extract; and / or an insoluble or soluble extract; and / or Dried cranberry powder The composition of claim 4.

8. The composition of any one of claims 1 to 3, further comprising a zinc-containing compound to provide the zinc.

9. 9. The composition of claim 8, wherein the zinc-containing compound is a zinc salt preferably selected from the group consisting of zinc citrate, zinc lactate, zinc gluconate, zinc aspartate, zinc methionine, zinc oxide, zinc phosphate, zinc salicylate, and zinc chloride, more preferably the zinc salt is zinc citrate.

10. 9. The composition of claim 8, comprising at least 0.01 wt. %, alternatively 0.01 wt. % to 25 wt. %, alternatively 0.01 wt. % to 10 wt. %, alternatively 0.01 wt. % to 1 wt. % of said zinc-containing compound.

11. 4. The composition of any one of claims 1 to 3, wherein the composition is adapted for oral administration, adapted for topical application, or adapted for chewable delivery.

12. The composition according to any one of claims 1 to 3, further comprising a gel base.

13. The composition comprises: i. an oral care product, preferably selected from the group consisting of a mouthwash, a dentifrice, a paste, a spray, a dental soft candy, a gum, or a lozenge; or ii. a skin care product, preferably selected from a gel, lotion, cream, or spray adapted for topical application to the skin membrane; or iii. A gastrointestinal care product, preferably selected from a paste, powder, capsule, gummy, liquid, suppository, or chewable material; The composition according to any one of claims 1 to 3.

14. The composition of any one of claims 1 to 3, wherein the composition is a paste, powder, gel, liquid, or chewable substance.

15. The composition according to any one of claims 1 to 3, wherein the subject is a human or an animal, preferably selected from a dog, a cat or a horse.

16. A method for preventing and / or treating inflammation in a subject, comprising administering a composition comprising A-type proanthocyanidin (PAC-A) described in any one of claims 1 to 3 and zinc.

17. 17. The method of claim 16, wherein the inflammation is associated with the oral cavity, skin membrane, or gastrointestinal tract, particularly associated with at least one of gingivitis, periodontitis, muscle pain, acne, allergies, dermatitis, psoriasis, eczema, heat rash, photosensitivity, abrasions, stomatitis, lesions, and gastrointestinal inflammation, and more particularly associated with dermatitis or periodontitis.

18. 17. The method of claim 16, wherein the composition is administered orally or topically.

19. 17. The method of claim 16, wherein the subject is a human or an animal, preferably selected from dogs, cats, and horses.

20. 17. The method of claim 16, further comprising multiple exposures to the composition.

21. Use of a composition according to any one of claims 1 to 3 for the manufacture of a medicament for the prevention and / or treatment of inflammation or for the treatment of inflammation.

22. 1. A process for producing an oral gel product, comprising: Providing a gel base; and mixing a zinc-containing compound and an A-type proanthocyanidin (PAC-A)-containing extract with the gel base to form the oral gel product.

23. 23. The process of claim 22, wherein the blending is carried out to form the oral gel product having 0.001% to 10% by weight of PAC-A.

24. 23. The process of claim 22, wherein the PAC-A-containing extract is a PAC-A-containing cranberry extract.

25. 25. The process of any one of claims 22 to 24, wherein the zinc-containing compound is a zinc salt.

26. 25. The process of any one of claims 22 to 24, wherein the mixing is carried out to form the oral gel product having from 0.01% to 10% by weight of the zinc-containing compound.

27. 25. The process of any one of claims 22 to 24, comprising maintaining a temperature that prevents decomposition of the PAC-A during mixing of the PAC-A-containing extract and the zinc-containing compound into the gel base.

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