HOST MODULATING AND TISSUE REGENERATIVE HYDROGEL COMPOSITIONS AND METHODS OF THEIR DELIVERY TO PERIODONTAL AND PERI-IMPLANT TISSUES

Abstract

The present invention concerns a novel use of therapeutic hydrogels in nonsurgical techniques to promote healing and regeneration of tissues whose structure and functions have been diminished due to chronic inflammatory disorders. More particularly, the invention provides therapeutic and regenerative hydrogel compositions and their nonsurgical delivery to periodontal treatment sites to treat periodontal and peri-implant diseases. Furthermore, the invention concerns a novel technique which involves the injection of said sterile therapeutic biomimetic hyaluronic acid hydrogel to which are tethered at least one host modulating agent, such as tetrahydrocurcuminoids, THC, and at least one additional tissue regenerative agent into the gingival connective tissue proper. The host modulating agent potentiates the periodontal tissue regeneration at the periodontal treatment site, while the biomimetic hyaluronic acid hydrogel serves in a dual capacity as a drug, a tissue regenerative agent carrier and as a biodegradable matrix around which the new connective tissue can regenerate. The invention also concerns oral care gel and paste compositions of at least one host modulating agent tethered to the HA tissue regenerative hydrogel formulated to be used in a synergistic home-based oral care regimen.

Claims

1. A method of healing and regenerating of periodontal and peri-implant tissues lost due to chronic inflammatory diseases comprising of the steps of: a. Combining at least one host modulating agent and at least one tissue regenerative agent in a hyaluronic acid hydrogel base to form a therapeutic and tissue regenerative composition that is a sterile hydrogel or a sterile viscoelastic liquid, a nonsterile paste, a gel, a mouth rinse, or in a combination of these forms; the backbone of the hydrogel comprising of organically cross linked hyaluronic acid, or a mixture of non-crosslinked and crosslinked HA, a chemically modified hyaluronic acid, or a combination thereof, and b. delivering the biomimetic therapeutic and tissue regenerative composition to a periodontal treatment site by injecting the sterile hydrogel or viscoelastic liquid into the gingival connective tissue as in an in-office treatment following traditional mechanical treatments, and/or applying the nonsterile therapeutic and tissue regenerative paste, gel, mouthwash by brushing, rubbing or rinsing as part of home therapy and/or maintenance. Wherein, the direct injection technique of the therapeutic and biomimetic tissue regenerative hydrogel into the gingival soft tissue ensures maximal bioavailability of both the host modulating agent and the tissue regenerative agent, and the hydrogel also serves as an immediate matrix around which the periodontal wound can heal from within much more effectively as compared to compositions lacking a host modulating agent or a drug carrier agent, or methods which do no ensure maximum bioavailability.

2. A method according to claim 1 wherein the first step includes the preparation of the biomimetic hydrogel or viscoelastic liquid using hyaluronic acid as the backbone. The non-animal hyaluronic acid can be crosslinked or in mixture of crosslinked and non-crosslinked from as dictated by the desired rheology of the composition. Preparation of the HA hydrogel composition should not follow the traditional inorganic method used in dermal fillers and intra-articular injections as documented in the previous art but should follow the use of organic crosslinking or the Diels-Alder reaction. It is not the aim of this invention to limit the methods of such hydrogel preparation. One criterion for the non-crosslinked form of HA in the hydrogel preparations used in this invention is that its molecular weight be between 750 kDa to 1400 kDa, preferably 1000 kDa.

3. A method according to claim 2, wherein the combining step includes selecting the therapeutic agent from a list of host modulating substances, such as non-staining phytochemical polyphenols or any other natural or synthetic host modulating agent with known antioxidant, anti-inflammatory and anti-microbial effectiveness, such as rice bran phenolic extract, or a biologic, or methylsulfonylmethane, MSM, or a combination thereof.

4. A method according to claim 3, wherein the host modulating agent is the reduced biologically active non-staining metabolite of curcumin, such as di-. tetra-, hexa-, octahydrocurcuminoids, or a combination thereof.

5. A method according to claim 4, wherein the combining step includes the addition of at least one additional tissue regenerative agent to the HA based hydrogel selected from a group of growth factors, glycosaminoglycans, collagen, bone morphogenetic protein, stem cells, fibroblasts or a combination thereof. While HA in the hydrogel is also tissue regenerative, adding an additional tissue regenerative agent further potentiates the efficacy of the hydrogel in regenerating the alveolar bone and the attachment apparatus in addition to the gingival connective tissue.

6. A method according to claim 5, wherein the sterilized biomimetic hydrogel comprising a therapeutic combination of a host modulating agent and at least one additional tissue regenerative agent is injected directly into already anesthetized diseased gingival connective tissue using a syringe, following traditional mechanical treatments using a 30 gauge needle, or needles of various sizes depending on the viscosity of the gel.

7. A method according to claim 5, wherein the sterile therapeutic biomimetic hydrogel also contains a vasoactive agent, such as epinephrine in concentrations of known amounts in a 7.2 physiologic phosphate buffered solution.

8. A method according to claim 5, wherein the sterile therapeutic biomimetic hydrogel also contains a local anesthetic, such as lidocaine, mepivacaine, etc. in a buffered solution.

9. A method according to claim 1, wherein the first step involves the preparation of the biomimetic and therapeutic paste or a gel which is delivered to the periodontal tissues using a toothbrush to heal and regenerate lost periodontal tissues due to inflammatory periodontal and peri-implant diseases as part of a home care regimen.

10. A method in claim 9, wherein the host modulating agent in the paste or gel compositions is THC, di-, hexa-, octahydrocurcuminoids or a combination thereof.

11. The method according to claim 10, wherein the composition comprises from 0.1% to 10%, preferably 6 wt-% of non-staining and colorless THC powder.

12. The method of claim 11, wherein additional tissue regenerative agent in the composition is non-crosslinked hyaluronic acid or a mixture of crosslinked and non-crosslinked HA with an average molecular weight of 1000 kDa and it comprises from 0.001 wt-% to 20 wt-%, preferably 0.2 wt-% of the composition.

13. A method in claim 12, wherein certain other excipients, humectants, rheology modifiers, low grade abrasives, flavoring agents, sweeteners may be added to the paste or gel compositions.

14. A method in claim 1 wherein the configuring steps include encapsulating at least of one the host modulating agents in microspheres which have time release values and adding to the paste embodiment as in claim 9 and delivering it into periodontal pockets which are 5 millimeters or deeper.

15. A method according to claim 14, wherein encapsulating comprises selecting a nanosphere having a time release value for substantially continuous release of the therapeutic treatment composition over a predetermined period.

16. A method according to claim 14, wherein combining comprises mixing the tissue regenerative agent with a polymer comprising the microspheres.

17. A method according to claim 13, wherein the therapeutic treatment composition is in a toothpaste, gel, or semisolid embodiment and it is applied to the disease periodontal tissue, preferably with a soft prophylaxis cup as part as part of an in-office treatment. The patient is instructed to refrain from eating or drinking for at least 30 minutes.

18. The method in claim 1, wherein the therapeutic composition is in the form of a mouthwash and it is delivered to the diseased periodontal tissues by rinsing with said liquid composition.

19. The method in claim 1, wherein the therapeutic composition is a chewing gum, or a gummi and it is delivered to the diseased periodontal tissue by the mechanical action of the chewing cycle.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0063] FIGS. 1A through 1D are diagrammatic views illustrating the histopathologic changes of the three subdivisions of gingivitis leading to periodontitis. FIGS. 1A through 1 C, represent the initial, early, and established lesions of gingivitis, and FIG. 1D is an illustration of periodontitis.

[0064] FIG. 2A is a view illustrating the injection into the diseased periodontal connective tissue of a sterile viscoelastic liquid or gel composition of THC and HA. FIG. 2B is a diagram illustrating the delivery of a THC and HA gel, paste via a toothbrush as part of a home care regimen.

DETAILED DESCRIPTION OF THE INVENTION

[0065] Referring to FIGS. 1A through 1D, which diagrammatically illustrate the human periodontal anatomy progressing from the initial lesion of gingivitis to periodontitis. Specifically, FIG. 1A illustrates the initial lesion of gingivitis which appears as an acute inflammatory response with neutrophil infiltration 22, vascular and epithelial 14, 18 and connective tissue 16 changes. The gingival epithelium 18 shows signs of inflammation; more specifically erythema and edema. The gingival connective tissue 16 is made up of a fibrillar collagenous network and an extracellular matrix composed mainly of hyaluronic acid, HA. There is evidence now that not only does the collagen denature due to free radicals, but so does HA. Furthermore, as immune, and inflammatory cells infiltrate the ECM, they migrate by the same mechanism that bacteria use, more specifically by releasing the enzyme, hyaluronidase. The alveolar bone crest 20, the junctional epithelium 12, with forms the attachment apparatus and the periodontal ligament 34 are undamaged. FIG. 1B illustrates the human periodontium afflicted with early gingivitis. The gingival tissue 16 shows signs of inflammation with lymphocytic infiltration, vasodilation, distension of the tissue, and increased spacing between the epithelial cells, including the gingival 18, sulcular 14 and junctional epithelial cells 12, leading due increased permeability. The sulcular epithelium, SE 14 becomes ulcerated and friable and the connective tissue 16 shows increased signs of collagen and ECM disruption 35. FIG. 1C is an illustration of the chronic or established lesion of gingivitis characterized by infiltration of monocytes 26 and continued CT destruction 35. There is evidence that in the chronic phase, in addition to free radicals and super-oxides, there is also a host of proteolytic enzymes, such as zinc dependent matrix metalloproteinases, or MMPs and a progression to T cell and B cell predominance 24. If treated, by the mechanical removal of biofilm and reduction of bacterial burden, the connective tissue 16 still has the capability to repair and regenerate itself without any permanent damage. FIG. 1D illustrates the human periodontium afflicted with periodontitis. The gingival tissues 16 are inflamed, the junctional epithelial 12 and the attachment apparatus have broken down due to both bacterial and host defense factors, i.e., A. actynomycetemcomitans, ROS, MMPs, etc. There is alveolar bone 20 resorption 28 and breakdown of the periodontal ligament 34 also due to the proteolytic activities of MMPs.

[0066] Broadly speaking, periodontitis is a chronic inflammatory disease which results in progressive periodontal tissue degeneration and tooth loss. As such, it is now apparent that to treat periodontitis what is needed in not only to effectively treat the disease but also to repair/regenerate the damaged tissues. More specifically, what is needed is a treatment modality which combines therapeutic and tissue regenerative agents, goals which traditionally have fallen under the separate aegis of non-surgical and surgical periodontics. Recent advances in non-surgical injectable hydrogel formulations which are able to not only deliver therapeutic drugs to treat the disease, carry growth factors and cells necessary to regenerate damaged tissues, but also serve as an immediate tissue regenerative scaffold around which the healthy connective tissue can reform, has finally bridged the gap between therapy and regeneration. It was the recognition by the inventor that what was needed to effectively treat the periodontal lesion was not only to treat but also to regenerate the diseased gingival connective tissue, furthermore the discovery of HA injectable hydrogels is what made the hydrogel compositions and methods of delivery to the periodontal tissues as disclosed in this application mostly possible.

[0067] It was also recognized that because the success of any professional periodontal therapy hinges greatly on a patient's home oral care regimen, there was a need for oral care compositions which synergize with the antioxidant, anti-inflammatory and tissue regenerative treatment goals of the injectable in office novel therapy as disclosed in this invention. A review of the existing over the counter oral care compositions revealed that none of the current compositions support the treatment goals of the compositions disclosed in this invention. It was this recognition which made the over the counter or home-based compositions for “gum health” as disclosed in this application possible. What is meant by the term “gum health” is a composition which is formulated specifically with ingredients which synergize and potentiate the antioxidant, anti-inflammatory goals of the in-office compositions as disclosed in this application. Furthermore, the “gum health” compositions as disclosed in this application will not contain any non-specific antimicrobials, or agents which have the potential to cause or exacerbate dysbiosis, such as non-nutritive sweeteners, except for xylitol.

[0068] Another critical factor in periodontal treatment success is the effective control of underlying systemic variables, such as other chronic systemic inflammatory conditions. It was the recognition that definitive periodontal treatment success also hinges on systemic conditions, such as cardiovascular disease, osteoarthritis, uncontrolled diabetes mellitus and others, that necessitated the home care compositions to also include an effective host modulating phytochemical with a known track record of systemic anti-inflammatory activity, such as THC.

[0069] Accordingly, the present invention provides a systematic approach of methods and compositions for periodontal healing and regeneration of dysfunctional and/or lost periodontal tissue due to periodontal and peri-implant diseases. Specifically, in a first aspect, the present invention provides a method of treating periodontal and peri-implant disease and regenerating periodontal tissues by providing a sterile therapeutic biomimetic hydrogel composition with a hyaluronic acid backbone, tethered to which there is also at least one host modulating and antioxidant agent and at least one other tissue regenerative agent, and injecting the therapeutic and regenerative composition into the connective tissue of the periodontal treatment site as illustrated in FIG. 2A Wherein, the biodegradable hydrogel matrix mimics the physiologic granulation tissue providing an immediate scaffold around which the tissue can proliferative and mature resulting in definitive wound healing, as compared to compositions lacking an immediate biomimetic scaffold with an HA backbone. The host modulating agent effectively treats the inflammatory aspect of the disease and potentiates the tissue regenerative agent via a multiple mechanism as it will be illustrated in the remainder of the application. And the tissue regenerative agent works synergistically with the host modulating agent to effect maximal periodontal alveolar bone or attachment regeneration.

[0070] Various hydrogel preparations have been extensively documented in the patent literature and research studies. It is not the goal of this application to review all the various preparation modalities, but it is the goal to describe in detail the preparation modes selected to most ideally serve the novel periodontal specific goals and needs of the compositions disclosed herein. While injectable hydrogels have been used in many different applications in the field of therapeutic and regenerative medicine, to the knowledge of the inventor this is the first time that an injectable therapeutic and tissue regenerative hydrogel is used in periodontal and peri-implant therapy as disclosed in this invention. To develop a suitable hydrogel specific for the present application several factors were considered. More specifically, 1. the degradation rate and the mechanical properties of the hydrogel, which must complement the tissue growth and natural ECM of the periodontal tissues. These properties can be fine-tuned through variations in the chemical structure and density in the hydrogels which can be further controlled by choosing the type of crosslinking. Since HA is not able to form gels alone, several crosslinking methods have been considered. There are two basic types of crosslinking, namely, physical, or chemical. Nowadays, one of the most promising strategies for hydrogels preparation turns out to be click chemistry due to its high specificity, high yield, bio-orthogonality, and mild reaction conditions. Of the various click chemistry crosslinking, the Diels-Alder Reaction between furan modified HA and bismaleimide functional peptides seems to be appropriate for the application as disclosed in this invention due to the ability of this type of crosslinking to mimic the ECM. This type of crosslinking can further be subjected to thiol-ene photocoupling to allow its spatiotemporal patterning. Furthermore, the crosslinking can take place prior to injection or in situ, after the injection is delivered to the periodontal treatment sites. This can be accomplished via thermo-, photo, and/or pH sensitive hydrogels or an injection method with a double barrel syringe. There is ongoing research in quest of intelligent hydrogels with various features like stability, complex structures, biochemical cues, and responsiveness to several triggers. While certain crosslinking methods have been mentioned in the preparation of the HA hydrogels as disclosed in this invention, it is not meant to limit the scope of the possible preparation methods. It is understood within the scope of this invention, that as more advanced hydrogel preparations methods become available, they may also be utilized to prepare the hydrogel compositions as disclosed in this invention.

[0071] The material's physicochemical properties such as the degree of swelling and porosity must be chosen according to the needs of the therapeutic agents or cellular inclusions. Furthermore, Various materials can be used to form hydrogels; namely, natural, synthetic or hybrid. Due to their excellent biocompatibility, low immunogenicity the preferred material in the compositions in this application is a natural material that can be selected from the group of the following natural polymers: namely, hyaluronic acid, collagen/gelatin, chitosan, chondroitin sulfate, heparin sulfate, keratan sulfate, alginate, agar/agarose and fibrin, or a combination to form a composite or a hybrid. HA has been combined with both collagen and alginate to form hybrid hydrogels. Furthermore, HA can be derived from animal or non-animal sources. The preferred source of HA in this application is a non-animal source. Among biopolymers, hyaluronic acid (HA) represents one of the most used in the design of hydrogels for biomedical applications due to its biocompatibility, native biofunctionality, biodegradability, non-immunogenicity, cell-to-cell signaling ability, and versatility. HA-based hydrogels turn out to be versatile platforms ranging from passive and static matrices to smart, stimuli-responsive platforms with tunable properties and consequently they showed to have great potential as drug delivery systems, scaffolds for tissue engineering and regenerative medicine, and so on.

[0072] HA, whose chemically structure is depicted in the figure below, is a naturally occurring linear, non-sulfated glycosaminoglycan or polysaccharide that is widely distributed throughout the ECM of all connective tissues in humans and other animals. It is a GAG consisting of multiple repeating disaccharide units of N-acetyl-D-glucosamine and D-glucuronic acid. This polyanionic polymer has a range of molecular sizes from 1 to 10,000 kDa. HA is naturally degraded by hyaluronidase and oxidative species. Hyaluronidase has been shown to be elevated in the serum of patients diagnosed with periodontitis and osteoarthritis, providing indirect evidence that HA is depleted in the periodontal connective tissues of patients with chronic inflammatory periodontitis.

FIG. 3: Chemical Structure of Hyaluronic Acid Polymer

[0073] ##STR00001##

[0074] In the first aspect, the injectable therapeutic HA hydrogel is prepared using the Diels-Alder reaction as mentioned above according to the following steps. 1. Synthesis of furan functionalized HA. 2. Preparation of bismaleimide functional peptides. 3. Host modulating drugs are dissolved in water or ethanol. 4. Preparation of HA-furan drug loaded solution. 5. Drug loaded furan functionalized HA and bismaleimide functional peptides are mixed to form a hydrogel. All reactions performed at 37 C. 6. The hydrogel is sterilized prior to injection.

[0075] A variety of host modulating agents can be utilized in the compositions and methods of the present invention. According to one embodiment, the host modulating agent comprised within the combined composition of the invention may be selected from the group consisting of: Naturally derived polyphenolic phytochemicals, such as, non-staining tetra-, hexa-, octahydrocurcuminoids, or other non-staining polyphenols like cranberry extract, resveratrol, brown rice extract, biologics with immunomodulatory mechanisms as used currently in various other dermatological and chronic inflammatory bowel disease, arthritis, etc. Furthermore, other host modulating agents may also be selected from a variety of other herbs which have known TLR4 modulatory bioactivity. The following bioactive phytochemicals can be used in combination with THC: Parthenolide, a known inhibitor of the TLR4/NF-κB pathway, Berberine, an isoquinoline alkaloid mainly extracted from Rhizoma Coptidis, Sparstolonin B (SsnB) isolated from a Chinese herb (Sparganium stoloniferum) which was found to significantly inhibit the expression of the cytokines TNF-α, IL-6, and IL-1β induced by LPS. Atractylenolide I, a bioactive component of Rhizoma Atractylodis macrocephalae, significantly decreased LPS-induced TNF-α, IL-6, nuclear NF-kB.

[0076] In the preferred compositions, the host modulating agent is tetra-, hexa- or octahydrocurcuminoids, because these reduced forms of curcuminoids are known to have superior antioxidant bioactivity in addition to being a potent anti-inflammatory. THC also referred to as tetrahydrodiferuloylmethane, is the enzymatically reduced metabolite of curcumin, as shown in the Figure below.

FIG. 4: Chemical Structures of Curcumin, DHC, THC and its Short-Lived Modified Metabolites

[0077] ##STR00002##

In addition to its well documented activities as an anti-oxidant, anti-inflammatory, hypoglycemic, and anti-cancer, curcumin, more specifically THC, has been shown to exert its beneficial effects on the molecular and cellular levels by modulating different signaling molecules, most likely via a Toll-like receptor binding, including transcription factors in gene expression, chemokines, cytokines, tumor suppressor genes, microRNAs, growth factors, cell cycle proteins, cell surface adhesion molecules and more. Moreover, there are emerging studies which substantiate THC wound healing efficacy. Its mechanism on the molecular level has been suggested by a recent study, which showed that this biphenolic molecule is able to mediate the switch of pro-inflammatory macrophage M1 to phenotype pro-healing macrophage M2 via Il-4 and -13. Furthermore, an in vivo study showed that by incorporating Il-4 in a gelatin nanofiber, resulted in resolution of periodontal inflammation and subsequent new alveolar bone generation. Furthermore, THC most likely also has antimicrobial efficacy, especially against anaerobic, gram negative bacteria.

[0078] In the preferred compositions, THCurcuminoids should be at least 96% pure and should have ideally the following concentrations, to mimic the composition in the rhizome. The preferred extraction method to result in the preferred composition is well documented in prior art.

Tetrahydro curcuminoids 90%
Tetrahydro demethoxy curcumin 9%
Tetrahydro bisdemethoxy curcumin 1%

[0079] The host modulating agent is supplied to the site of periodontal disease in an amount effective to facilitate or accelerate tissue healing via its antioxidant and anti-inflammatory properties. Typically, the therapeutic hydrogel composition contains an effective amount of host modulating agent in the range of about 0.001 wt. % to about 10 wt. % mg/ml, preferably about 0.05 wt. % to about 6 wt. %, preferably to about 0.01 wt. % to 4 wt. % l. For example, when the host modulating agent is THC, or hexa-, or octa-hydrocurcuminoids, the composition contains an effective among of THC, in the range of about 0.01 to 10 wt. % preferably from about 0.2 to about 6 wt. %, preferably about 5 wt. % relative to their dry macromolecular components.

[0080] In addition to the HA biomimetic hydrogel, at least one other tissue regenerative agent can be supplied to the periodontal tissue site to aid in the regeneration of alveolar bone and/or attachment apparatus by selecting from a group of bone morphogenetic proteins, growth factors, mesenchymal stem cells, fibroblasts, etc. Typically, the therapeutic hydrogel composition contains an effective amount of a tissue regenerative agent in the range of about 0.00001 mg/ml to about 99 mg/ml, preferably about 0.0004 to about 9.9 mg/ml, preferably about 0.001 mg/ml to about 5 mg/ml. For example, when the tissue regenerative agent is bone morphogenetic protein, BMP, the hydrogel composition contains an effective amount of BMP in the range of about 0.1 mg/ml to 99 mg/ml, preferably about 0.3 mg/ml to about 9 mg/ml, preferably about 0.2 mg/ml.

For example, when the tissue regenerative agent is mesenchymal stem cells, MSCs the hydrogel contains an effective among of MSCs in the range of about 0.1×10.sup.6 cells/ml, to about 10×10.sup.6 cells/ml, preferably 3×10.sup.6 cells/ml.

[0081] The compositions of the invention may further comprise certain antimicrobials, such as Doxycycline used not as a host modulating agent but as an antibacterial.

[0082] The composition of the invention may optionally further comprise at least one pharmaceutically acceptable carrier, diluent, excipient, vasoactive agent, anesthetic and/or additive in a physiologic buffer.

[0083] According to one aspect, the preferred embodiment provides a sterile HA hydrogel composition comprising of an effective amount of tetrahydrocurcuminoid powder, and at least one tissue regenerative compound, such as bone morphogenetic protein in a buffered physiological sodium chloride hydrogel, pH 7.2. Each 2.25 ml syringe will contain 0.001 wt. %-10 wt. % of non-staining THC powder, with sodium chloride 17 mg, disodium hydrogen phosphate 0.32 mg, sodium dihydrogen phosphate monohydrate 0.08 mg, a vasoactive agent such as epinephrine and water for injection q.s. to 2 ml. The composition of the invention may optionally further comprise of other compounds which have been shown to potentiate the efficacy of either the polyphenol or the tissue regenerative compound, and an acceptable carrier, diluent, excipient and/or additive. The contents of the syringe are sterile and nonpyrogenic.

[0084] According to the preferred method, this hydrogel composition is administered by a non-surgical intra-gingival injection using a 30-gauge hypodermic needle following mechanical periodontal therapy as illustrated in FIG. 2A. Injection is in small aliquots as instructed. In this preferred method, the injection of the present invention is performed following mechanical treatment such as scaling and root planing.

[0085] It will be appreciated that the therapeutic treatment compositions according to the composition and methods of the present invention can occur in any form. Specifically, the therapeutic treatment compositions can occur in a solid form, like a paste or gel, in a liquid form or combinations thereof. For example, in certain applications the therapeutic treatment composition can be comprised of a host modulating agent formed as a solid nano-particulates interspersed in a gel comprising of the tissue regenerative agent(s).

[0086] In a second aspect the invention provides “gum health” hydrogel and paste compositions comprised of a multi-action non-staining polyphenol, such and white tetrahydrocurcuminoids and at least one tissue regenerative compound, such as hyaluronic acid (HA) in known and effective amounts, 0.2% to 2% w/w of crosslinked and non-crosslinked HA intended to be applied to the gingival tissues as part of a home care regimen via a toothbrush as illustrated in FIG. 2B. The intended “gum health” compositions denote paste, gel, cream, spray, powder and/or liquid formulations. These oral care formulations are preferably brushed into the gingival tissue, but may also be rubbed into the gingival tissue, or swished around the oral cavity and after they are retained for an effective amount of time, they are expectorated. For increased efficacy, the patient is instructed to not eat or drink for at least thirty minutes after the application of the above compositions. Preferably the gum health composition is in the form of a paste or a gel.

[0087] The “gum health” compositions according to the invention will generally contain further ingredients but they will not contain any traditional toothpaste ingredients which are known to cause either allergic reactions, dysbiosis or an inflammatory response. While this is not a traditional toothpaste formulation, the gum health paste and gel compositions as disclosed in this application will in addition to wound healing bioactivity, be efficient in cleaning and strengthening the hard surfaces of the enamel.

[0088] The following is a list of the essential ingredients: 1. deionized water from about 2% to 45%, 2. humectant and rheology modifiers. Suitable humectants include xylitol, glycerin in the amount of 2% to about 55% respectively. 3. abrasives such as hydrated silica in the lowest effective amount from about 3 to 15%, 4. a thickening agent such as a natural gum like guar gum, carrageenan. 5. Natural flavorings such as mint, spearmint. 6. Sweeteners: Xylitol. 7. Calcium, phosphate minerals. The composition of the invention may optionally further comprise at least one other pharmaceutically acceptable antioxidant and anti-inflammatory active ingredient from the following list: Ascorbic acid, glutathione, tocopherol, retinoic acid or Vitamin A, zinc.

[0089] The following examples further describe and demonstrate embodiments within the scope of the present invention. These examples are given for the purpose of illustration only and may not be construed to limit the scope of the present invention. The ingredients can be mixed in any conventional manner. However, it has been determined that superior results are obtained when THC is pre-mixed with a mixture of crosslinked and non-crosslinked HA gel prior to incorporation with the remaining ingredients. HA used in this embodiment can be non-animal or animal source. Furthermore, the crosslinking in this application is not as specific as for the in-office injectable hydrogel compositions. Inorganic crosslinking with glutaraldehyde as used in the formulation of dermal fillers, intra-articular injections would be acceptable.

EXAMPLES

Example 1: Preferred “Gum Health” Paste Compositions

[0090]

TABLE-US-00003 Ingredients % by weight Tetrahydrocurcuminoids, THC  6 Hyaluronic acid, HA 0.1-2 Deionized water 45 Vegetable Glycerin 30 Hydrated Silica 15 Xantham Gum 0.5-2 Cocamidopropyl betaine   0.5 Natural Menthol  2 Tocopherol or Citric Acid 0.5-2 Walnut, coconut oil   0.2 Xylitol   .sup.  0.5-7.5% Salt   0.2 Titanium dioxide    0.05 total  100%

[0091] While some of the mechanisms of the present invention rely on well-known and researched bioactivities of THC and HA separately, to the knowledge of the inventor, this is the first time that an antioxidant and anti-inflammatory host modulating agent is combined with a connective tissue regenerative agent in such a profound synergistic manner. Furthermore, as it will be disclosed in the remainder of this application, there are other mechanisms of bioactivity revealed in this invention with respect to both compounds which may not have been previously known or disclosed. It is due to the synergistic mechanisms of these two types of agents that the vicious cycle of chronic inflammation and tissue degeneration can be broken. The novelty of the invention does not rely merely on the compositions disclosed, but also on the novelty of the main delivery method of said compositions to the periodontal tissues, which overcomes the many shortcomings of delivery in the previous art of surgical periodontal tissue regeneration.