Oral hydrogel compositions and uses

Abstract

The present invention relates to oral hydrogel compositions, and more particularly, to thermosensitive gel compositions which undergo a sol-gel transition in the oral cavity, and which optionally comprise a therapeutically active agent for sustained release.

Description

[0001] This application is an international application claiming priority and interest in U.S. Provisional Application No. 63 / 109,169, filed November 3, 2020, the contents of which are incorporated herein by reference in their entirety.

[0002] This invention relates to oral hydrogel compositions, and more particularly to thermosensitive gel compositions that interact with mucins in the oral cavity and undergo a sol-gel transition, and optionally contain a therapeutically active substance for sustained release. Background Technology

[0003] The oral cavity is susceptible to a variety of conditions, including periodontal disease (including gingivitis and periodontitis), tooth decay, tooth hypersensitivity, halitosis, and oral infections (such as fungal or bacterial infections of the oral mucosa).

[0004] Tooth erosion involves demineralization and damage to tooth structure caused by acid erosion from non-bacterial sources. Erosion is initially found in the enamel and can progress to the underlying dentin if left unchecked. Saliva typically has a pH of 7.2 to 7.4. When the pH decreases and the concentration of hydrogen ions becomes relatively high, the enamel can be microscopically eroded, resulting in a porous, spongy, rough surface. If saliva remains acidic for an extended period, remineralization may not occur, and the tooth will continue to lose minerals, leading to weakening and eventually structural loss.

[0005] Dentin hypersensitivity is an acute, localized toothache caused by physical stimulation of the dentin surface, such as thermal (hot or cold), osmotic, tactile, or a combination of thermal, osmotic, and tactile stimuli, in response to exposure of dentin. Exposure of dentin (often attributed to gingival recession or enamel loss) usually leads to hypersensitivity.

[0006] Oral bacteria are a major cause of dental diseases, including tooth decay, gingivitis, periodontitis, and halitosis. Bacteria associated with dental plaque convert sugars into glucans, insoluble polysaccharides that provide the adhesive properties of plaque. Anaerobic bacteria in plaque metabolize the sugars to produce acids that dissolve tooth minerals, thereby damaging tooth enamel and ultimately leading to tooth decay.

[0007] Dental plaque is a sticky biofilm or clump of bacteria that typically exists between teeth, along the gum line, and below the gum line margin. Dental plaque can cause tooth decay and periodontal problems such as gingivitis and periodontitis. Tooth decay, cavities, or tooth demineralization are caused by acids produced by bacteria that break down sugars.

[0008] Periodontal disease is a common condition affecting most of the population, especially the elderly. Gingivitis, often caused by poor oral hygiene, is the mildest form of periodontal disease, causing the gums (or gingiva) to become red, swollen, and bleed easily. While gingivitis can be reversed with professional treatment and good home oral care, untreated gingivitis can develop into periodontitis. Over time, plaque can spread and grow below the gum line. Toxins produced by bacteria in the plaque inflame the gums and stimulate a chronic inflammatory response, which then breaks down and destroys the tissues and bone that support the teeth. As a result, the gums separate from the teeth, forming infected pockets (spaces between the teeth and gums). As the disease progresses, these pockets deepen and more gum tissue and bone are destroyed. Often, the symptoms of this destructive process are very mild. Eventually, the teeth may become loose and may have to be removed. Because the environments of the oral cavity and the periodontal cavity are significantly different, periodontal disease is more difficult to treat than tooth decay. For example, while the oral cavity is essentially an aerobic environment constantly filled with saliva, the periodontal microenvironment is more anaerobic and filled with a plasma filtrate known as "gingival crevicular fluid." The growth of microorganisms within the periodontal microenvironment can lead to periodontal disease, and as periodontal disease becomes more established, the microenvironment becomes more anaerobic and the flow of gingival crevicular fluid increases.

[0009] Various antibacterial agents can inhibit bacterial growth and thus reduce biofilm formation on the oral cavity surface. In many cases, these antibacterial agents are cationic, such as quaternary ammonium surfactants like hexadecylpyridine chloride. (CPC), biguanides such as chlorhexidine, metal cations such as zinc or stannous ions, and guanidines such as arginine. Soluble zinc salts (e.g., zinc citrate) and stannous ion sources (e.g., stannous fluoride and stannous chloride) have shown excellent clinical benefits, particularly in reducing gingivitis.

[0010] Hyaluronic acid (also known as hyaluronan or hyaluronate) is an anionic, non-sulfated glycosaminoglycan (GAG) widely distributed throughout the connective tissues of vertebrates, and is the most abundant high-molecular-weight glycosaminoglycan in the extracellular matrix of soft periodontal tissues. Hyaluronic acid has been found effective in treating inflammatory processes in medical fields such as orthodontics, dermatology, and ophthalmology, and has also been found to have anti-inflammatory and antibacterial properties in the treatment of gingivitis and periodontitis.

[0011] Although medicated toothpaste and mouthwash are commonly used, their effects are often short-lived because the active agents can be quickly flushed out of the mouth due to rinsing, eating, or drinking, and / or the effective concentration of the active agents can become ineffective due to rapid dilution by saliva. Delivering toothpaste and mouthwash into the tight periodontal cavity located between the tooth root and gum is particularly difficult.

[0012] The use of oral gels is known, most commonly in the form of gels used for teeth cleaning and whitening. Common polymers present in such gels include poloxamer (polyethylene glycol-polypropylene glycol block copolymer), gums (e.g., carrageenan, xanthan gum, guar gum, guilarin, gellan gum), polyacrylate polymers, vinyl polymers and copolymers (e.g., povidone, cross-povidone), polyethylene glycol, polyethylene glycol / polypropylene glycol copolymers, polyvinyl alcohol, modified cellulose polymers (e.g., carboxymethyl cellulose, hydroxypropyl methyl cellulose), polyvinyl ether, and methyl vinyl ether / maleic anhydride copolymers.

[0013] In particular, poloxamers are widely used in the biomedical field due to their ability to undergo reverse thermal gelation. Their self-assembly process occurs through micellization, which is characterized by its critical micellization concentration and critical micellization temperature. These parameters (depending on the specific poloxamer used) can be tuned to obtain materials with final properties suitable for a wide range of applications. However, one of the drawbacks associated with poloxamer gels used for delivery applications is their lack of adhesiveness, resulting in short residence times. Another disadvantage of poloxamers is their rapid dissolution in aqueous media. Therefore, blending poloxamers with mucosal adhesion polymers capable of forming entanglements or non-covalent bonds with mucus covering epithelial tissue is one approach to improve adhesion and residence time.

[0014] Therefore, there is still a need for effective delivery of oral care agents into the oral cavity, especially into the periodontal cavity, preferably with long-term continuous delivery. Summary of the Invention

[0015] This disclosure provides a liquid thermosensitive hydrogel comprising: (a) a linear polyethylene glycol (PEG) / polypropylene glycol (PPG) triblock copolymer (e.g., poloxamer 407), (b) a linear PEG / PPG triblock copolymer and a polypropylene glycol (PPG)-SMDI copolymer (e.g., ExpertGel 312 or 412), and (c) an aqueous or non-aqueous polyol carrier. In certain embodiments, the hydrogel further comprises one or more of the following: (d) a polyethylene glycol (PEG) polymer, (e) a polyacrylic acid or polyacrylate polymer (e.g., acrylic homopolymer), (f) a high molecular weight hyaluronic acid or alkali metal hyaluronic acid salt polymer (>100,000 Da), and (g) one or more active agents (e.g., antibacterial agents). The hydrogel according to the invention possesses unique properties at or around room temperature; it is a free-flowing liquid, but upon exposure to typical human oral temperatures or mucin proteins or oral mucosa, it transforms into a high-viscosity mucosal adhesion gel (e.g., viscosity of at least 1000 mPa⁻¹). In embodiments in which the hydrogel contains an active ingredient, the ingredient is preferably uniformly distributed throughout the hydrogel, such that upon gelation and mucosal adhesion in the oral cavity, the gel will gradually release the active ingredient in a predictable and continuous manner. Preferably, the viscosity of the liquid composition is low enough to allow for easy application via a syringe with a narrow-aperture needle, which would be necessary, for example, for injection into the periodontal space (viscosity < 1000 mPa⁻¹). As used herein, the term "liquid thermosensitive hydrogel" means a material that is liquid under ambient conditions and transforms into a gel (hydrogel) upon exposure to elevated temperatures.

[0016] In another aspect, this disclosure provides oral care compositions comprising the hydrogel and methods of using the same. Detailed Implementation

[0017] This disclosure provides a liquid thermosensitive hydrogel formulated to provide transient intraoral swelling and mucosal adhesion through a significant increase in viscosity (e.g., a viscosity increase of at least 100-fold). Unbound by theory, the rapid viscosity change is thought to be achieved through at least two mechanisms: (1) thermosensitive gelation of linear and cross-linked poloxamer systems, and (2) rheological synergy via the attraction between polymers (e.g., polyacrylates) and oligosaccharides of oral mucin proteins. The continuous flow of saliva and / or gingival crevicular fluid will degrade the structure of such a gel over time, allowing for the controlled release of polymers within the gel and / or active ingredients embedded in a polymer matrix.

[0018] Unbound by theory, it is believed that the carboxyl and hydroxyl groups of polyacid polymers form hydrogen bonds with the hydroxyl groups of glycosylated oral mucoproteins. This entanglement alters the microstructure and pore size of the epithelial layer, thereby increasing the density of this natural layer. Furthermore, compaction provides a greater barrier against bacteria or can be used to further amplify and trap active substances within the mucosa. Additionally, the localization of these polymer matrices in contact with damaged tissue areas has the potential to act as an exogenous scaffold for cell infiltration, thereby enhancing wound healing. The inclusion of high molecular weight hyaluronic acid (MW > 100,000 Da, e.g., 200 kDa to 1 MDa, or 250 kDa to 350 kDa) in the composition, such as neutralized sodium hyaluronate, can also promote healing and anti-inflammatory effects. Hyaluronic acid is thought to competitively bind to lipopolysaccharide (LPS) receptors, thereby attenuating the production of downstream inflammatory cytokines. Hyaluronic acid (a natural product produced during wound healing) can also promote cell migration, thereby accelerating the rate of tissue repair.

[0019] Various active ingredients can be dissolved or suspended in a liquid hydrogel, thereby embedding the active substances within the resulting oral gel. Cationic compounds such as CPC and chlorhexidine can be used to provide antibacterial properties, preservatives, resistance to bacterial invasion, and additional gel structural construction via ionic interactions with polyacrylates. Metal oxides such as zinc oxide and metal phosphates such as hydroxyapatite can be included, providing emulsification and volume to the gel structure. Polyphenols and other hydrophobic active substances, such as eugenol, curcumin, and salicylic acid, can also be included. The amphiphilic nature of the polymers in the compositions of the present invention can be used to dissolve and multivalently chelate hydrophobic or water-sensitive active substances (e.g., antibiotics, dyes, anti-inflammatory agents, peroxides) in highly aqueous formulations.

[0020] The compositions according to this disclosure can be formulated as, for example, mucosal adhesive tablets, instant tablets, films, porous thin tablets, gels, ointments, water-based pastes, anhydrous pastes, powders, patches, nonwoven microfiber sheets, liquid band-aids, structured mouthwashes, mouthwashes, serums, sprays, thin tablets, mucosal adhesive powders, and mucosal adhesive coatings. In certain embodiments, this disclosure provides viscous gels that can be injected into periodontal pockets or applied directly to oral wounds, such as alveolar bone or damaged tooth surfaces after tooth extraction. Without being bound by theory, it is thought that the complex cross-linked polymer network of the gel acts as a barrier against infection by physically preventing oral (e.g., saliva) bacteria or fungi from entering the wound site. In some embodiments, the viscous gel also contains antibacterial and / or antifungal ingredients, antiseptics, or wound-healing ingredients, and such ingredients act as part of the barrier and are slowly released into oral tissues as the gel matrix degrades over time. Such ingredients include, for example, hyaluronic acid (or its salts), chlorhexidine gluconate, and hexadecylpyridine chloride. And zinc salts (e.g., zinc oxide).

[0021] In a first aspect, this disclosure provides a liquid thermosensitive hydrogel (hydrogel 1) comprising (a) a linear polyethylene glycol (PEG) / polypropylene glycol (PPG) triblock copolymer (e.g., poloxamer 407), (b) a linear PEG / PPG triblock copolymer and a polypropylene glycol (PPG)-SMDI copolymer (e.g., ExpertGel 312 or 412), and (c) an aqueous or non-aqueous polyol carrier. In a particular embodiment, this disclosure also provides:

[0022] 1.1. Hydrogel 1, wherein (a) the PEG / PPG triblock copolymer has the structure HO-[CH2CH2O] a [-CH(CH3)CH2O-] b [CH2CH2O] a -H, where a is an integer from 50 to 130 and b is an integer from 30 to 80.

[0023] 1.2. Hydrogel 1.1, wherein (a) the PEG / PPG triblock copolymer has the structure described above, wherein a is an integer from 75 to 125 and b is an integer from 50 to 70, or wherein a is an integer from 85 to 115 and b is an integer from 55 to 65, or wherein a is an integer from 90 to 110 and b is an integer from 55 to 60, or wherein a is an integer from 95 to 105 and b is an integer from 55 to 57, or wherein a is an integer from 98 to 101 and b is about 56.

[0024] 1.3. Hydrogel 1.1 or 1.2, wherein (a) the PPG core of the PEG / PPG triblock copolymer (i.e., [-CH(CH3)CH2O-]). b The molecular weight is approximately 2500 Da to 5000 Da, or approximately 3000 Da to 4500 Da, or approximately 3500 Da to 4100 Da, or approximately 3500 Da to 3700 Da, or approximately 3700 Da to 4100 Da, or approximately 3600 Da, or approximately 4000 Da.

[0025] 1.4. The hydrogel of any one of 1.1 to 1.3, wherein (a) the polyethylene oxide content of the PEG / PPG triblock copolymer is about 60% to 80% by weight, for example about 70% by weight.

[0026] 1.5. The hydrogel of any one of 1.1 to 1.4, wherein (a) the PEG / PPG triblock copolymer has a molecular weight of 5,000 Da to 25,000 Da, or about 7,000 Da to 20,000 Da, or about 8,000 Da to 16,000 Da, or about 9,000 Da to 15,000 Da, or about 9,840 Da to 14,600 Da.

[0027] 1.6. Hydrogels 1.1 to 1.5, wherein (a) the HLB (hydrophilic-lipophilic balance) value of the PEG / PPG triblock copolymer is 18 to 22.

[0028] 1.7. Hydrogels 1.1 to 1.6, wherein (a) the PEG / PPG triblock copolymer is poloxamer 407.

[0029] 1.8. Hydrogel 1, or any one of 1.1.1 to 7, wherein the hydrogel contains (a) a PEG / PPG triblock copolymer in an amount of 0.1% to 20% by weight, for example 1% to 10% by weight, or 2% to 8% by weight, or 3% to 7% by weight, or 4% to 6% by weight, or about 5% by weight.

[0030] 1.9. Hydrogel 1, or any one of 1.1 to 1.8, wherein (b) the linear PEG / PPG triblock copolymer and PPG-SMDI copolymer consist of a linear PEG / PPG triblock copolymer portion, a PPG portion and an SMDI portion (e.g., a poloxamer 338 or 407 portion, a PPG-12 portion and an SMDI portion).

[0031] 1.10. Hydrogel 1.9, wherein component (b) is a mixture of a copolymer of PPG and SMDI and a linear PEG / PPG triblock copolymer.

[0032] 1.11. Hydrogel 1.9, wherein component (b) is a linear PEG / PPG triblock copolymer covalently linked to a copolymer of PPG and SMDI (e.g., poloxamer 338 or 407 covalently linked to a PPG-12 / SMDI copolymer).

[0033] 1.12. Hydrogel 1.9, wherein component (b) is a linear PEG / PPG triblock copolymer crosslinked with a copolymer of PPG and SMDI (e.g., poloxamer 338 or 407 crosslinked with a PPG-12 / SMDI copolymer).

[0034] 1.13. Hydrogel 1.9, wherein PPG (e.g., PPG-12) is condensed with SMDI.

[0035] 1.14. Hydrogel 1.9, wherein a linear PEG / PPG triblock copolymer is condensed with SMDI (e.g., poloxamer 338 or 407 condensed with SMDI).

[0036] 1.15. Hydrogel 1.9, wherein both the linear PEG / PPG triblock copolymer and PPG are condensed with SMDI (e.g., wherein the condensation occurs between the hydroxyl ends of SMDI and the PEG / PPG triblock copolymer, such as poloxamer 338 or poloxamer 407, and / or PPG, such as PPG-12).

[0037] 1.16. Hydrogels of any one of 1.9 to 1.12, wherein the average n value of PPG (the average number of moles of propylene oxide in the polymer) is 3 to 70.

[0038] 1.17. Hydrogel 1.16, wherein the average n value of PPG is 3 to 30, or 3 to 20, or 7 to 16, or 9 to 15, or about 12 (e.g., PPG-12).

[0039] 1.18. Hydrogels of any one of 1.9 to 1.17, wherein component (b) is a linear PEG / PPG triblock copolymer having the structure HO-[CH2CH2O]. a [-CH(CH3)CH2O-] b [CH2CH2O] a -H, where a is an integer from 100 to 200 and b is an integer from 30 to 80.

[0040] 1.19. Hydrogel 1.18, wherein component (b) is a linear PEG / PPG triblock copolymer having the structure described above, wherein a is an integer from 125 to 175 and b is an integer from 30 to 70, or wherein a is an integer from 135 to 165 and b is an integer from 40 to 60, or wherein a is an integer from 140 to 150 and b is an integer from 40 to 50, or wherein a is about 141 and b is about 44.

[0041] 1.20. Hydrogel 1.18 or 1.19, wherein the PPG core molecular weight of the linear PEG / PPG triblock copolymer of component (b) is about 2000 Da to 5000 Da, or about 2500 Da to 4000 Da, or about 3000 Da to 3500 Da, or about 3300 Da.

[0042] 1.21. Hydrogels 1.18 to 1.20, wherein the polyethylene oxide content of the linear PEG / PPG triblock copolymer of component (b) is about 70% to 90% by weight, for example about 80% by weight.

[0043] 1.22. Hydrogels 1.18 to 1.21, wherein component (b) is a linear PEG / PPG triblock copolymer of poloxamer 338.

[0044] 1.23. Hydrogels of any one of 1.9 to 1.17, wherein component (b) is a linear PEG / PPG triblock copolymer having the structure HO-[CH2CH2O]. a [-CH(CH3)CH2O-] b [CH2CH2O] a -H, where a is an integer from 50 to 130 and b is an integer from 30 to 80.

[0045] 1.24. Hydrogel 1.23, wherein component (b) is a linear PEG / PPG triblock copolymer having the structure described above, wherein a is an integer from 75 to 125 and b is an integer from 50 to 70, or wherein a is an integer from 85 to 115 and b is an integer from 55 to 65, or wherein a is an integer from 90 to 110 and b is an integer from 55 to 60, or wherein a is an integer from 95 to 105 and b is an integer from 55 to 60, or wherein a is an integer from 98 to 101 and b is about 56.

[0046] 1.25. Hydrogel 1.23 or 1.24, wherein the PPG core molecular weight of the linear PEG / PPG triblock copolymer of component (b) is about 2500 Da to 5000 Da, or about 3000 Da to 4500 Da, or about 3500 Da to 4100 Da, or about 3500 Da to 3700 Da, or about 3700 Da to 4100 Da, or about 3600 Da, or about 4000 Da.

[0047] 1.26 Hydrogel 1.23 to 1.25, wherein the polyethylene oxide content of the linear PEG / PPG triblock copolymer of component (b) is about 60% to 80% by weight, for example about 70% by weight.

[0048] 1.27. Hydrogels of any one of 1.23 to 1.26, wherein the linear PEG / PPG triblock copolymer of component (b) has a molecular weight of 5,000 Da to 25,000 Da, or about 7,000 Da to 20,000 Da, or about 8,000 Da to 16,000 Da, or about 9,000 Da to 15,000 Da, or about 9,840 Da to 14,600 Da.

[0049] 1.28. Hydrogels 1.23 to 1.27, wherein the HLB (hydrophilic-lipophilic balance) value of component (b) PEG / PPG triblock copolymer is 18 to 22.

[0050] 1.29. Hydrogels 1.23 to 1.28, wherein the linear PEG / PPG triblock copolymer of component (b) is poloxamer 407.

[0051] 1.30. Hydrogels 1.1 to 1.29, wherein component (b) is ExpertGel412 (e.g., a poloxamer 407 / PPG-12 / SMDI copolymer).

[0052] 1.31. Hydrogels 1.1 to 1.29, wherein component (b) is ExpertGel312 (e.g., a poloxamer 338 / PPG-12 / SMDI copolymer).

[0053] 1.32. Hydrogels 1.18 to 1.31, wherein the hydrogel contains component (b) (e.g., ExpertGel 312 or ExpertGel 412) in an amount of 1% to 20% by weight, such as 5% to 15% by weight, or 5% to 10% by weight, or 8% to 12% by weight, or about 10% by weight.

[0054] 1.33. Hydrogel 1, or any one of 1.1 to 1.32, wherein the carrier comprises water, ethanol, glycerol, propylene glycol, sorbitol and xylitol, or mixtures thereof.

[0055] 1.34. Hydrogel 1.33, wherein the carrier comprises water, ethanol, glycerol, propylene glycol, and mixtures thereof.

[0056] 1.35. Hydrogel 1.34, wherein the carrier is water (e.g., without any polyol humectants).

[0057] 1.36. Hydrogel 1.34, wherein the carrier is a non-aqueous polyol carrier (i.e., no water is added except for the inherent water content of any polyol carrier).

[0058] 1.37. Hydrogel 1.36, wherein the hydrogel is prepared with water, but is freeze-dried to remove all or substantially all of the water from the hydrogel.

[0059] 1.38. Hydrogel 1, or any one of 1.1 to 1.36, wherein the hydrogel contains a carrier (e.g., water or a water / polyol mixture) in an amount of 50% to 90% by weight, such as 60% to 90% by weight, or 70% to 90% by weight, or 80% to 90% by weight, or 50% to 70%, or 60% to 80% by weight, or 70% to 80% by weight, or 70% to 90% by weight.

[0060] 1.39. Hydrogel 1, or any one of 1.1 to 1.38, wherein the hydrogel further comprises one or more of the following: (d) a polyethylene glycol (PEG) polymer, (e) a polyacrylic acid or polyacrylate polymer (e.g., an acrylic homopolymer), (f) a high molecular weight hyaluronic acid or alkali metal hyaluronic acid salt polymer (>100,000 Da), and (g) one or more active agents (e.g., an antibacterial agent).

[0061] 1.40. Hydrogels 1.14 to 1.39, wherein the hydrogel further comprises a polyethylene glycol (PEG) polymer.

[0062] 1.41. Hydrogel 1.40, wherein the average molecular weight of the PEG polymer is 400 to 20,000 (i.e., PEG-400 to PEG-20,000).

[0063] 1.42. Hydrogel 1.41, wherein the average molecular weight of the PEG polymer is from 2,000 to 12,000 (e.g., PEG-2000 to PEG-12000).

[0064] 1.43. Hydrogel 1.41 or 1.42, wherein the average molecular weight of the PEG polymer is from 6,000 Da to 10,000 Da (e.g., PEG-6000 to PEG-10000).

[0065] 1.44. Hydrogels 1.40 to 1.43, wherein the hydrogel comprises PEG-6000, PEG-8000, PEG-10000, or combinations thereof.

[0066] 1.45. Hydrogels 1.40 to 1.44, wherein the hydrogel contains PEG polymer in an amount of 0.1% to 3% by weight, for example 0.1% to 2% by weight, or 0.1% to 1% by weight, or 0.1% to 0.5% by weight, or 0.5% to 1% by weight.

[0067] 1.46. Hydrogel 1, or any one of 1.1 to 1.45, wherein the hydrogel further comprises a polyacrylic acid or polyacrylate polymer (e.g., an acrylic homopolymer), such as carbomer homopolymer type A.

[0068] 1.47. Hydrogel 1.46, wherein the polyacrylic acid or polyacrylate polymer is a crosslinked polymer, for example, crosslinked with allyl sucrose or allyl pentaerythritol.

[0069] 1.48. Hydrogel 1.47, wherein the polyacrylic acid or polyacrylate polymer is a highly crosslinked polymer, for example having a viscosity of 29,000 mPa-s to 40,000 mPa-s, such as carbomer 974P NF.

[0070] 1.49. Hydrogel 1.47, wherein the polyacrylic acid or polyacrylate polymer is a highly crosslinked polymer, for example having a viscosity of 4,000 mPa-s to 11,000 mPa-s, such as carbomer 971P NF.

[0071] 1.50. Hydrogel 1.46 to 1.49, wherein the hydrogel contains a polyacrylic acid or polyacrylate polymer in an amount of 0.05% to 5% by weight, for example 0.1% to 2% by weight, or 0.1% to 1% by weight, or 0.1% to 0.5% by weight, or about 0.3% by weight.

[0072] 1.51. Hydrogel 1, or any one of 1.1 to 1.50, wherein the hydrogel further comprises high molecular weight hyaluronic acid or alkali metal hyaluronic acid polymer (>100,000 Da).

[0073] 1.52. Hydrogel 1.51, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronic acid salt polymer is from 200,000 Da to 1,500,000 Da, for example 300,000 Da to 1,200,000 Da, or 300,000 Da to 700,000 Da, or 700,000 Da to 1,100,000 Da, or 300,000 Da to 450,000 Da, or 350,000 Da. Up to 600,000 Da, or 900,000 Da to 1,100,000 Da, or 250,000 Da to 700,000 Da, or 250,000 Da to 500,000 Da, or 250,000 Da to 350,000 Da, or about 290,000 Da, or about 315,000 Da, or about 370,000 Da, or about 480,000 Da, or about 1,000,000 Da.

[0074] 1.53. Hydrogel 1.51 or 1.52, wherein the hyaluronic acid or alkali metal hyaluronic acid salt polymer is a sodium hyaluronate polymer.

[0075] 1.54. The hydrogel of any one of 1.51 to 1.53, wherein the hydrogel comprises hyaluronic acid or alkali metal hyaluronic acid polymer in an amount of 0.01% to 10% by weight, such as 0.01% to 5% by weight, 0.05% to 5% by weight, 0.1% to 2% by weight, or 0.1% to 1% by weight, or 0.3% to 0.5% by weight, or about 0.4% by weight; and optionally, wherein the weight ratio of component (a) linear PEG / PPG triblock copolymer (e.g., poloxamer 407) to hyaluronic acid or alkali metal hyaluronic acid polymer is 10:1 to 30:1, such as 10:1 to 25:1, or 10:1 to 20:1, or 10:1 to 15:1, or about 12.5:1.

[0076] 1.55. Hydrogel 1, or any one of 1.1 to 1.54, wherein the hydrogel further comprises one or more active agents (e.g., antimicrobial agents or antifungal agents).

[0077] 1.56. Hydrogel 1.55, wherein the active agent is selected from zinc salts, stannous salts, quaternary ammonium compounds, guanidines, amino acids, amino acid complexes, fluoride ion sources, tetrahydrocurcumin, vitamins, antibacterial agents, antifungal agents, antisensitizing agents, anti-inflammatory agents, anesthetics (e.g., local anesthetics), essential oils, and combinations thereof.

[0078] 1.57. Hydrogel 1.56, wherein the active agent is selected from zinc oxide, zinc citrate, zinc sulfate, zinc chloride, zinc phosphate, zinc lactate, zinc pyrophosphate, zinc salicylate, zinc pyridinecarboxylate, stannous chloride, stannous fluoride, stannous pyrophosphate, and hexadecylpyridine chloride. Ammonium benzoyl chloride, chlorhexidine (e.g., chlorhexidine gluconate), arginine (e.g., arginine carbonate, arginine bicarbonate, arginine hydrochloride), lysine, histidine, zinc-dilysine-chloride complex, zinc-diarginine-chloride complex, sodium fluoride, sodium monofluorophosphate, fluorinated amine, tetrahydrocurcumin, eugenol, nicotinamide, riboflavin, sodium nitrate, potassium nitrate, strontium nitrate, eucalyptol, thymol, menthol, hydrogen peroxide, doxycycline, minocycline, ketoconazole, or combinations thereof.

[0079] 1.58. Hydrogel 1.57, wherein the active agents are zinc oxide and hexadecylpyridine chloride. Chlorhexidine gluconate, eugenol, or a combination thereof.

[0080] 1.59. Hydrogels 1.56 to 1.58, wherein each active agent is present in an amount of 0.01% to 5% by weight, for example 0.05% to 2.5% by weight, or 0.1% to 1% by weight, or 0.05% to 0.5% by weight.

[0081] 1.60. Hydrogel 1.58, wherein the hydrogel contains 0.1% to 1% by weight, for example, about 0.5% by weight of zinc oxide; and / or 0.01% to 0.2% by weight, for example, about 0.015% by weight or about 0.075% by weight of hexadecylpyridine chloride. And / or in amounts of 0.1% to 5%, such as about 2.5% or about 5% chlorhexidine gluconate; and / or in amounts of 0.1% to 0.5%, such as about 0.3% eugenol.

[0082] 1.61. Hydrogel 1, or any one of 1.1 to 1.60, wherein the hydrogel comprises (a) a linear polyethylene glycol (PEG) / polypropylene glycol (PPG) triblock copolymer (e.g., poloxamer 407), (b) a linear PEG / PPG triblock copolymer and a polypropylene glycol (PPG)-SMDI copolymer (e.g., ExpertGel 312 or 412), (c) an aqueous or non-aqueous polyol carrier, (d) a polyacrylic acid or polyacrylate polymer (e.g., acrylic homopolymer), and (e) a high molecular weight hyaluronic acid or alkali metal hyaluronic acid salt polymer (>100,000 Da); for example, wherein the hydrogel does not contain a polyethylene glycol polymer.

[0083] 1.62. Hydrogel 1.61, wherein the hydrogel comprises (a) poloxamer 407, (b) a poloxamer 407 or 338 and a PPG-12 / SMDI copolymer, (c) water, (d) carbomer 971P or 974P, and (e) sodium hyaluronate with a molecular weight of 350,000 Da to 600,000 Da, or 250,000 Da to 250,000 Da, wherein the poloxamer and PPG-12 / SDMI copolymer of component (b) are ExpertGel 312 or ExpertGel 412.

[0084] 1.63. Hydrogel 1.62, wherein the hydrogel comprises 1% to 10% by weight of poloxamer 407, 0.1% to 0.5% by weight of carbomer 971P or 974P, 1% to 10% by weight of ExpertGel 312 or ExpertGel 412, and 0.01% to 1% by weight of sodium hyaluronate polymer and 70% to 90% by weight of water.

[0085] 1.64. Hydrogel 1.62 or 1.63, wherein the weight ratio of poloxamer 407 to ExpertGel 312 or ExpertGel 412 is 1:1.5 to 1:2.5, or about 1:2.

[0086] 1.65. Hydrogels 1.62, 1.63 or 1.64, wherein the weight ratio of poloxamer 407 to carbomer 971P or 974P is 15:1 to 20:1, or about 17:1.

[0087] 1.66. A hydrogel of 1.62 to 1.65, wherein the weight ratio of poloxamer 407 to carbomer 971P or 974P to ExpertGel 312 or ExpertGel 412 is (15 to 20):1:(30 to 40), optionally wherein the weight of poloxamer 407 is about 17:1:33.

[0088] 1.67. Hydrogels 1.62 to 1.66, wherein the hydrogel comprises 8% to 12% by weight of poloxamer 407 (e.g., about 10% by weight), 0.2% to 0.4% by weight of carbomer 971P or 974P (e.g., about 0.3% by weight), 4% to 6% by weight of ExpertGel 312 or ExpertGel 412 (e.g., about 5% by weight), and 0.3% to 0.7% by weight of sodium hyaluronate polymer (e.g., about 0.4% by weight) and 80% to 90% by weight of water (e.g., 80% to 85% by weight).

[0089] 1.68. Hydrogels from 1.62 to 1.67, wherein the hydrogel further comprises 0.1% to 1% by weight (e.g., about 0.5% by weight) of zinc oxide and / or 0.01% to 0.2% by weight (e.g., about 0.015% by weight or 0.075% by weight) of hexadecylpyridine chloride. And / or chlorhexidine gluconate in amounts from 1% to 10% by weight (e.g., 2.5% or 5% by weight).

[0090] 1.69. Hydrogel 1, or any one of 1.1 to 1.68, further comprising, in a total amount of 0.1% to 5%, one or more surfactants, such as anionic surfactants, cationic surfactants, nonionic surfactants, or amphoteric surfactants.

[0091] 1.70. Hydrogel 1.69, wherein one or more surfactants are selected from cocamidopropyl betaine, sodium lauryl sulfate, sodium lauryl ether sulfate, ammonium lauryl sulfate, coconut monoethanolamide, coconut diethanolamide, lauramidopropyl dimethylamine oxide, myristamidopropyl dimethylamine oxide, decyl glucoside, sodium N-cocoyl-N-methyltaurate, sodium cocoyl isoethylene disulfonate, and sodium dioctyl sulfosuccinate.

[0092] 1.71. Hydrogel 1.70, wherein one or more surfactants are each present in an amount of 0.1% to 5%, for example 0.5% to 2.5%, or 1% to 1.5%, or about 1.5%.

[0093] 1.72. Hydrogel 1, or any one of 1.1 to 1.71, further comprising one or more preservatives (e.g., benzyl alcohol), colorants, flavoring agents (e.g., eugenol), sweeteners, buffers (e.g., acids or bases, such as sodium carbonate or sodium bicarbonate), antioxidants (e.g., p-hydroxyacetophenone, ascorbic acid, beta-carotene, retinol, α-tocopherol, propyl gallate, tert-butylhydroquinone, butylated hydroxyanisole, butylated hydroxytoluene), or other oral care ingredients, for example, each in an amount less than 0.5% by weight, or less than 0.3% by weight, or less than 0.1% by weight, or less than 0.05% by weight.

[0094] 1.73. Hydrogel 1, or any one of 1.1 to 1.72, wherein the pH of the hydrogel is 5.5 to 9.5, for example 5.5 to 6.5, or 5.5 to 6.0, or 6.0 to 7.0, or 7.0 to 9.5, or 8.0 to 9.5, or 8.5 to 9.5 (e.g., 9.0).

[0095] 1.74. Hydrogel 1, or any one of 1.1 to 1.73, wherein the hydrogel is fluid at ambient temperature but transforms into a viscous gel in the oral cavity (e.g., in the periodontal cavity or oral mucosa).

[0096] 1.75. Hydrogel 1.74, wherein the viscosity (e.g., Brookfield viscosity) of the hydrogel at a temperature below 30°C (e.g., at 20°C to 30°C or at about 25°C) and / or in the absence of mucin (e.g., on the exterior of the oral cavity) is less than 15,000 mPa-s, for example less than 10,000 mPa-s, or less than 5,000 mPa-s, or less than 1,000 mPa-s, or less than 500 mPa-s, or less than 200 mPa-s and is at least 1 mPa-s.

[0097] 1.76. Hydrogel 1.74 or 1.75, wherein the maximum instantaneous viscosity of the hydrogel at a temperature below 30°C (e.g., at 20°C to 30°C or at about 25°C) and / or in the absence of mucin (e.g., on the exterior of the oral cavity) is less than 10,000 Pa-s, for example less than 8,000 Pa-s, or less than 5,000 Pa-s, or less than 3,000 Pa-s, or less than 2,500 Pa-s, or less than 2,000 Pa-s and is at least 100 Pa-s.

[0098] 1.77. Hydrogels 1.74, 1.75 or 1.76, wherein the hydrogel has a G' / G” ratio of less than 3.0, for example less than 2.0, or less than 1.0, or less than 0.75, or less than 0.50 at temperatures below 30°C (e.g., at 20°C to 30°C or at about 25°C) and / or in the absence of mucin (e.g., in the external oral cavity).

[0099] 1.78. Hydrogels 1.74, 1.75, 1.76 or 1.77, wherein the hydrogel is initiated to transform into a viscous gel at a temperature above 30°C and below 40°C, for example at a temperature of 35°C to 39°C, or at a temperature of 36°C to 38°C (e.g., at about 37°C) and / or at a pH of 6.5 or greater (e.g., 7.0 or greater), and / or wherein the hydrogel is initiated to transform into a viscous gel upon exposure to oral mucin (e.g., oral human mucin).

[0100] 1.79. Hydrogel 1.78, wherein the viscosity (e.g., Brookfield viscosity) of the resulting viscous gel is at least 1000 mPa-s and / or as high as about 5,000,000 mPa-s, for example 2000 mPa-s to 2,000,000 mPa-s, or 10,000 mPa-s to 1,600,000 mPa-s, or 50,000 mPa-s to 1,400,000 mPa-s, or 200,000 mPa-s to 1,200,000 mPa-s, or about 1,000,000 mPa-s.

[0101] 1.80. Hydrogel 1.78 or 1.79, wherein the maximum instantaneous viscosity of the resulting viscous gel is at least 9,000 Pa-s and / or as high as about 50,000 Pa-s, for example 10,000 mPa-s to 35,000 mPa-s, or 10,000 mPa-s to 25,000 mPa-s, or 10,000 mPa-s to 20,000 mPa-s, or 10,000 mPa-s to 15,000 mPa-s.

[0102] 1.81. Hydrogel 1.78, 1.79 or 1.80, wherein the resulting viscous gel has a G' / G” ratio of at least 1.0, for example 1.0 to 6.0, or 1.5 to 6.0, or 2.0 to 6.0, or 2.5 to 6.0, or 3.0 to 6.0, or 3.2 to 6.0, or 3.5 to 6.0, or 4.0 to 6.0.

[0103] 1.82. Hydrogel 1.74 to 1.81, wherein the resulting viscous gel adheres to the mucous lining of the oral cavity (e.g., periodontal cavity).

[0104] 1.83. Hydrogels 1.74 to 1.82, wherein the resulting viscous gel interacts with mucin to enhance adhesion to mucosal surfaces of the oral cavity (e.g., periodontal cavity or oral mucosa), for example due to rheological synergy with mucin.

[0105] 1.84. Hydrogels from 1.74 to 1.83, wherein the resulting viscous gel slowly releases any active agent and / or any hyaluronic acid or alkali metal hyaluronic acid salt in a continuous manner (e.g., at a rate of 1% to 20% of the active agent content per day for at least 1 day, for example, 1 to 30 days).

[0106] In another embodiment of the first aspect, this disclosure provides a solid or semi-solid hydrogel (hydrogel 1A) formulated according to hydrogel 1 or any of 1.1 to 1.84 (those embodiments containing water), followed by an additional processing step of dehydrating or freeze-drying the hydrogel to remove all or substantially all of the water from the composition to produce a solid or semi-solid pellet, such as a tablet or thin tablet. After reconstitution with water (or saliva, e.g., in the oral cavity), hydrogel 1A behaves as expected for hydrogel 1 (or any of 1.1 to 1.84) by conversion to a viscous gel (either via a completely liquid fluid phase or via a low- or medium-viscosity gel that rapidly transforms into a high-viscosity gel).

[0107] In a second aspect, this disclosure provides a solid or semi-solid non-aqueous or low-water thermosensitive hydrogel (hydrogel 2) comprising (a) a linear polyethylene glycol (PEG) / polypropylene glycol (PPG) triblock copolymer (poloxam) and (b) a polyol carrier, wherein the water content does not exceed 50% by weight. In a particular embodiment, this disclosure also provides:

[0108] 2.1. Hydrogel 2, wherein the PEG / PPG triblock copolymer has the structure HO-[CH2CH2O] a [-CH(CH3)CH2O-] b [CH2CH2O] a -H, where a is an integer from 50 to 130 and b is an integer from 30 to 80.

[0109] 2.2. Hydrogel 2.1, wherein the PEG / PPG triblock copolymer has the structure described above, wherein a is an integer from 75 to 125 and b is an integer from 50 to 70, or wherein a is an integer from 85 to 115 and b is an integer from 55 to 65, or wherein a is an integer from 90 to 110 and b is an integer from 55 to 60, or wherein a is an integer from 95 to 105 and b is an integer from 55 to 57, or wherein a is an integer from 98 to 101 and b is about 56.

[0110] 2.3. Hydrogel 2.1 or 2.2, wherein the PPG core molecular weight of the PEG / PPG triblock copolymer is about 2500 Da to 5000 Da, or about 3000 Da to 4500 Da, or about 3500 Da to 4100 Da, or about 3500 Da to 3700 Da, or about 3700 Da to 4100 Da, or about 3600 Da, or about 4000 Da.

[0111] 2.4. The hydrogel of any one of 2.1 to 2.3, wherein the polyethylene oxide content of the PEG / PPG triblock copolymer is about 60% to 80% by weight, for example about 70% by weight.

[0112] 2.5. The hydrogel of any one of 2.1 to 2.4, wherein (a) the PEG / PPG triblock copolymer has a molecular weight of 5,000 Da to 25,000 Da, or about 7,000 Da to 20,000 Da, or about 8,000 Da to 16,000 Da, or about 9,000 Da to 15,000 Da, or about 9,840 Da to 14,600 Da.

[0113] 2.6. Any one of the hydrogels 2.1 to 2.5, wherein (a) the HLB (hydrophilic-lipophilic balance) value of the PEG / PPG triblock copolymer is 18 to 22.

[0114] 2.7. The hydrogel 2.1 to 2.6, wherein the PEG / PPG triblock copolymer is poloxamer 407.

[0115] 2.8. Hydrogel 2, or any one of 2.1.2 to 7, wherein the hydrogel contains a PEG / PPG triblock copolymer in an amount of 0.1% to 20% by weight, for example 1% to 10% by weight, or 2% to 8% by weight, or 3% to 7% by weight, or 4% to 6% by weight, or about 5% by weight, or 10% to 30% by weight, or about 20% by weight.

[0116] 2.9. Hydrogel 2, or any one of 2.1 to 2.8, wherein the carrier is selected from water, ethanol, glycerol, propylene glycol, sorbitol and xylitol, or mixtures thereof.

[0117] 2.10. Hydrogel 2.9, wherein the carrier is selected from glycerol, sorbitol, propylene glycol and mixtures thereof.

[0118] 2.11. Hydrogel 2.10, wherein the carrier is propylene glycol or a mixture of ethanol / propylene glycol or a mixture of sorbitol / glycerol or sorbitol.

[0119] 2.12. Hydrogel 2, or any one of 2.1 to 2.11, wherein the hydrogel contains 0% to 40% by weight of water, or 0% to 30% by weight of water, or 0% to 20% by weight of water, or 0% to 10% by weight of water, or wherein the hydrogel is anhydrous.

[0120] 2.13. Hydrogel 2, or any one of 2.1 to 2.12, wherein the hydrogel is a paste, tablet, powder, spray, serum, patch, nonwoven microfiber sheet, foaming mousse, or thin tablet.

[0121] 2.14. Hydrogel 2, or any one of 2.1 to 2.13, wherein the hydrogel contains a carrier in an amount of 20% to 90% by weight, for example 30% to 90% by weight, or 40% to 90% by weight, or 50% to 90% by weight, or 60% to 90% by weight, or 70% to 80% by weight, or 70% to 90% by weight.

[0122] 2.15. Hydrogel 2, or any one of 2.1 to 2.14, wherein the hydrogel further comprises one or more of the following: (c) a linear PEG / PPG triblock copolymer and a polypropylene glycol (PPG)-SMDI copolymer, (d) a polyethylene glycol (PEG) polymer, (e) a polyacrylic acid or polyacrylate polymer (e.g., an acrylic homopolymer), (f) a high molecular weight hyaluronic acid or alkali metal hyaluronic acid polymer (>100,000 Da), and (g) one or more active agents (e.g., an antimicrobial or antifungal agent).

[0123] 2.16. Hydrogel 2.15, wherein the hydrogel further comprises (c) a linear PEG / PPG triblock copolymer and a polypropylene glycol (PPG)-SMDI copolymer.

[0124] 2.17. Hydrogel 2.16, wherein (c) the linear PEG / PPG triblock copolymer and the PPG-SMDI copolymer consist of a linear PEG / PPG triblock copolymer portion, a PPG portion and an SMDI portion (e.g., a poloxamer 338 or 407 portion, a PPG-12 portion and an SMDI portion).

[0125] 2.18. Hydrogel 2.17, wherein component (c) is a mixture of a copolymer of PPG and SMDI and a linear PEG / PPG triblock copolymer.

[0126] 2.19. Hydrogel 2.17, wherein component (c) is a linear PEG / PPG triblock copolymer covalently linked to a copolymer of PPG and SMDI (e.g., poloxamer 338 or 407 covalently linked to a PPG-12 / SMDI copolymer).

[0127] 2.20. Hydrogel 2.17, wherein component (c) is a linear PEG / PPG triblock copolymer crosslinked with a copolymer of PPG and SMDI (e.g., poloxamer 338 or 407 crosslinked with a PPG-12 / SMDI copolymer).

[0128] 2.21. Hydrogel 2.17, wherein PPG (e.g., PPG-12) is condensed with SMDI.

[0129] 2.22. Hydrogel 2.17, wherein a linear PEG / PPG triblock copolymer is condensed with SMDI (e.g., poloxamer 338 or 407 condensed with SMDI).

[0130] 2.23. Hydrogel 2.17, wherein both the linear PEG / PPG triblock copolymer and PPG are condensed with SMDI (e.g., wherein the condensation occurs between the hydroxyl ends of SMDI and the PEG / PPG triblock copolymer, such as poloxamer 338 or poloxamer 407, and / or PPG, such as PPG-12).

[0131] 2.24. Hydrogels of any one of 2.17 to 2.23, wherein the average n value of PPG (the average number of moles of propylene oxide in the polymer) is 3 to 70.

[0132] 2.25. Hydrogel 2.24, wherein the average n value of PPG is 3 to 30, or 3 to 20, or 7 to 16, or 9 to 15, or about 12 (e.g., PPG-12).

[0133] 2.26. Hydrogels of any one of 2.17 to 2.25, wherein component (c) is a linear PEG / PPG triblock copolymer having the structure HO-[CH2CH2O]. a [-CH(CH3)CH2O-] b [CH2CH2O] a -H, where a is an integer from 100 to 200 and b is an integer from 30 to 80.

[0134] 2.27. Hydrogel 2.26, wherein component (c) is a linear PEG / PPG triblock copolymer having the structure described above, wherein a is an integer from 125 to 175 and b is an integer from 30 to 70, or wherein a is an integer from 135 to 165 and b is an integer from 40 to 60, or wherein a is an integer from 140 to 150 and b is an integer from 40 to 50, or wherein a is about 141 and b is about 44.

[0135] 2.28. Hydrogel 2.26 or 2.27, wherein the PPG core molecular weight of the linear PEG / PPG triblock copolymer of component (c) is about 2000 Da to 5000 Da, or about 2500 Da to 4000 Da, or about 3000 Da to 3500 Da, or about 3300 Da.

[0136] 2.29. Hydrogels of any one of 2.26 to 2.28, wherein the polyethylene oxide content of the linear PEG / PPG triblock copolymer of component (c) is from about 70% to 90% by weight, for example about 80% by weight.

[0137] 2.30. Hydrogels 2.26 to 2.29, wherein component (c) is a linear PEG / PPG triblock copolymer of poloxamer 338.

[0138] 2.31. Hydrogels of any one of 2.17 to 2.25, wherein component (c) is a linear PEG / PPG triblock copolymer having the structure HO-[CH2CH2O]. a [-CH(CH3)CH2O-] b [CH2CH2O] a -H, where a is an integer from 50 to 130 and b is an integer from 30 to 80.

[0139] 2.32. Hydrogel 2.31, wherein component (c) is a linear PEG / PPG triblock copolymer having the structure described above, wherein a is an integer from 75 to 125 and b is an integer from 50 to 70, or wherein a is an integer from 85 to 115 and b is an integer from 55 to 65, or wherein a is an integer from 90 to 110 and b is an integer from 55 to 60, or wherein a is an integer from 95 to 105 and b is an integer from 55 to 60, or wherein a is an integer from 98 to 101 and b is about 56.

[0140] 2.33. Hydrogel 2.31 or 2.32, wherein the PPG core molecular weight of component (c) linear PEG / PPG triblock copolymer is about 2500 Da to 5000 Da, or about 3000 Da to 4500 Da, or about 3500 Da to 4100 Da, or about 3500 Da to 3700 Da, or about 3700 Da to 4100 Da, or about 3600 Da, or about 4000 Da.

[0141] 2.34. Hydrogels of any one of 2.31 to 2.33, wherein the polyethylene oxide content of the linear PEG / PPG triblock copolymer of component (c) is about 60% to 80% by weight, for example about 70% by weight.

[0142] 2.35. Hydrogels of any one of 2.31 to 2.34, wherein the linear PEG / PPG triblock copolymer of component (c) has a molecular weight of 5,000 Da to 25,000 Da, or about 7,000 Da to 20,000 Da, or about 8,000 Da to 16,000 Da, or about 9,000 Da to 15,000 Da, or about 9,840 Da to 14,600 Da.

[0143] 2.36. Hydrogels 2.31 to 2.35, wherein the HLB (hydrophilic-lipophilic balance) value of component (c) PEG / PPG triblock copolymer is 18 to 22.

[0144] 2.37. Hydrogels of any one of 2.31 to 2.36, wherein component (c) is a linear PEG / PPG triblock copolymer of poloxamer 407.

[0145] 2.38. Hydrogels of any one of 2.16 to 2.37, wherein component (c) is ExpertGel 412 (e.g., a poloxamer 407 / PPG-12 / SMDI copolymer).

[0146] 2.39. Hydrogels of any one of 2.16 to 2.38, wherein component (c) is ExpertGel 312 (e.g., a poloxamer 338 / PPG-12 / SMDI copolymer).

[0147] 2.40. Hydrogels 2.16 to 2.39, wherein the hydrogel contains component (c) (e.g., ExpertGel 312 or ExpertGel 412) in an amount of 1% to 20% by weight, such as 5% to 15% by weight, or 5% to 10% by weight, or 8% to 12% by weight, or about 10% by weight.

[0148] 2.41. Hydrogel 2.15 to 2.40, wherein the hydrogel further comprises a polyethylene glycol (PEG) polymer.

[0149] 2.42. Hydrogel 2.41, wherein the average molecular weight of the PEG polymer is 400 to 20,000 (i.e., PEG-400 to PEG-20,000).

[0150] 2.43. Hydrogel 2.42, wherein the average molecular weight of the PEG polymer is 2,000 to 12,000 (i.e., PEG-2000 to PEG-12000).

[0151] 2.44. Hydrogel 2.42 or 2.43, wherein the average molecular weight of the PEG polymer is 6,000 Da to 10,000 Da (i.e., PEG-6000 to PEG-10000).

[0152] 2.45. Hydrogel 2.42 to 2.44, wherein the hydrogel comprises PEG-6000, PEG-8000, PEG-10000, or a combination thereof.

[0153] 2.46. Hydrogel 2.42 to 2.45, wherein the hydrogel contains PEG polymer in an amount of 0.1 wt% to 3 wt%, for example 0.1 wt% to 2 wt%, or 0.1 wt% to 1 wt%, or 0.1 wt% to 0.5 wt%, or 0.5 wt% to 1 wt%.

[0154] 2.47. Hydrogel 2, or any one of 2.15 to 2.46, wherein the hydrogel further comprises a polyacrylic acid or polyacrylate polymer (e.g., an acrylic homopolymer), such as carbomer homopolymer type A.

[0155] 2.48. Hydrogel 2.47, wherein the polyacrylic acid or polyacrylate polymer is a crosslinked polymer, for example, crosslinked with allyl sucrose or allyl pentaerythritol.

[0156] 2.49. Hydrogel 2.48, wherein the polyacrylic acid or polyacrylate polymer is a highly crosslinked polymer, for example having a viscosity of 29,000 mPa-s to 40,000 mPa-s, such as carbomer 974 PNF.

[0157] 2.50. Hydrogel 2.48, wherein the polyacrylic acid or polyacrylate polymer is a lightly crosslinked polymer, for example having a viscosity of 4,000 mPa-s to 11,000 mPa-s, such as carbomer 971 PNF.

[0158] 2.51. Hydrogel 2.47 to 2.50, wherein the hydrogel contains a polyacrylic acid or polyacrylate polymer in an amount of 0.05% to 5% by weight, for example 0.1% to 2% by weight, or 0.1% to 1% by weight, or 0.1% to 0.5% by weight, or about 0.3% by weight.

[0159] 2.52. Hydrogels 2.15 to 2.51, wherein the hydrogel further comprises high molecular weight hyaluronic acid or alkali metal hyaluronic acid polymers (>100,000 Da).

[0160] 2.53. Hydrogel 2.52, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronic acid salt polymer is from 200,000 Da to 1,500,000 Da, for example 300,000 Da to 1,200,000 Da, or 300,000 Da to 700,000 Da, or 700,000 Da to 1,100,000 Da, or 300,000 Da to 450,000 Da, or 350,000 Da. Up to 600,000 Da, or 900,000 Da to 1,100,000 Da, or 250,000 Da to 700,000 Da, or 250,000 Da to 500,000 Da, or 250,000 Da to 350,000 Da, or about 290,000 Da, or about 315,000 Da, or about 370,000 Da, or about 480,000 Da, or about 1,000,000 Da.

[0161] 2.54. Hydrogel 2.52 or 2.53, wherein the hyaluronic acid or alkali metal hyaluronic acid salt polymer is a sodium hyaluronate polymer.

[0162] 2.55. Hydrogels of any one of 2.52 to 2.54, wherein the hydrogel contains hyaluronic acid or an alkali metal hyaluronic acid polymer in an amount of 0.05% to 5% by weight, for example 0.1% to 2% by weight, or 0.1% to 1% by weight, or 0.3% to 0.5% by weight, or about 0.4% by weight; and optionally, wherein the weight ratio of the linear PEG / PPG triblock copolymer (e.g., Pluronic F-127) to the hyaluronic acid or alkali metal hyaluronic acid polymer is 10:1 to 30:1, for example 10:1 to 25:1, or 10:1 to 20:1, or 10:1 to 15:1, or about 12.5:1.

[0163] 2.56. Hydrogel 2, or any one of 2.1 to 2.55, wherein the hydrogel further comprises one or more active agents (e.g., antimicrobial agents or antifungal agents).

[0164] 2.57. Hydrogel 2.56, wherein the active agent is selected from zinc salts, stannous salts, quaternary ammonium compounds, guanidines, amino acids, amino acid complexes, fluoride ion sources, tetrahydrocurcumin, vitamins, antibacterial agents, antifungal agents, antisensitizing agents, anti-inflammatory agents, anesthetics (e.g., local anesthetics), essential oils, and combinations thereof.

[0165] 2.58. Hydrogel 2.57, wherein the active agent is selected from zinc oxide, zinc citrate, zinc sulfate, zinc chloride, zinc phosphate, zinc lactate, zinc pyrophosphate, zinc salicylate, zinc pyridinecarboxylate, stannous chloride, stannous fluoride, stannous pyrophosphate, and hexadecylpyridine chloride. Ammonium benzoyl chloride, chlorhexidine (e.g., chlorhexidine gluconate), arginine (e.g., arginine carbonate, arginine bicarbonate, arginine hydrochloride), lysine, histidine, zinc-dilysine-chloride complex, zinc-diarginine-chloride complex, sodium fluoride, sodium monofluorophosphate, fluorinated amine, tetrahydrocurcumin, eugenol, nicotinamide, riboflavin, sodium nitrate, potassium nitrate, strontium nitrate, eucalyptol, thymol, menthol, hydrogen peroxide, doxycycline, minocycline, ketoconazole, or combinations thereof.

[0166] 2.59. Hydrogel 2.58, wherein the active agents are zinc oxide and hexadecylpyridine chloride. Chlorhexidine gluconate, eugenol, or a combination thereof.

[0167] 2.60. Hydrogels 2.56 to 2.59, wherein each active agent is present in an amount of 0.01% to 5% by weight, for example 0.05% to 2.5% by weight, or 0.1% to 1% by weight, or 0.05% to 0.5% by weight.

[0168] 2.61. Hydrogel 2.59, wherein the hydrogel contains 0.1% to 1% by weight, for example, about 0.5% by weight of zinc oxide; and / or 0.01% to 0.2% by weight, for example, about 0.015% by weight or about 0.075% by weight of hexadecylpyridine chloride. And / or in amounts of 0.1% to 5%, such as about 2.5% or about 5% chlorhexidine gluconate; and / or in amounts of 0.1% to 0.5%, such as about 0.3% eugenol.

[0169] 2.62. Hydrogel 2, or any one of 2.1 to 2.61, wherein the hydrogel further comprises one or more thickeners (e.g., cellulose derivatives, silica, arginine, or carbonates).

[0170] 2.63. Hydrogel 2.62, wherein one or more thickeners are selected from carboxymethyl cellulose (e.g., sodium CMC), silica, calcium carbonate, sodium carbonate and arginine carbonate).

[0171] 2.64. Hydrogels 2.62 or 2.63, wherein the hydrogels contain one or more thickeners in amounts of: 0.5% to 50% by weight, for example 0.5% to 10% by weight, or 0.5% to 5% by weight, or 0.5% to 3% by weight, or 5% to 50% by weight, or 5% to 30% by weight, or 5% to 20% by weight, or 5% to 15% by weight, or 15% to 40% by weight, or 15% to 30% by weight.

[0172] 2.65. Hydrogel 2.63 or 2.64, wherein the hydrogel contains carboxymethyl cellulose in an amount of 0.5% to 10% by weight, such as 0.5% to 5% by weight, or 0.5% to 3% by weight, or about 0.5% by weight, 1.0% by weight or 1.5% by weight.

[0173] 2.66. Hydrogel 2.63 to 2.65, wherein the hydrogel contains one or more types of silica in a net amount of 5% to 50% by weight, for example 8% to 35% by weight, or 10% to 30% by weight, or 10% to 20% by weight.

[0174] 2.67. Hydrogels 2.63 to 2.66, wherein the hydrogel contains calcium carbonate in an amount of 5% to 50% by weight, for example 10% to 40% by weight, or 25% to 35% by weight, or 10% to 20% by weight.

[0175] 2.68. Hydrogels 2.62 to 2.67, wherein the hydrogel contains arginine.

[0176] 2.69. Hydrogel 2.68, wherein the hydrogel contains arginine in an amount of 1% to 30% by weight, for example 1% to 20% by weight, or 10% to 20% by weight, or 1% to 10% by weight.

[0177] 2.70. Hydrogel 2, or any one of 2.1 to 2.69, further comprising one or more preservatives (e.g., benzyl alcohol), colorants, flavoring agents (e.g., eugenol), sweeteners, buffers (e.g., acids or bases), or other oral care ingredients, for example, in amounts less than 0.5% by weight, or less than 0.3% by weight, or less than 0.1% by weight, or less than 0.05% by weight.

[0178] 2.71. Hydrogel 2, or any one of 2.1 to 2.70, wherein the pH of the hydrogel is 5.5 to 6.5 (e.g., 5.5 to 6.0).

[0179] 2.72. Hydrogel 2, or any one of 2.1 to 2.71, wherein the hydrogel is an amorphous solid or semi-solid but absorbs water to form a viscous gel in the oral cavity (e.g., in the periodontal cavity).

[0180] 2.73. Hydrogel 2.72, wherein the hydrogel is a dry, non-hygroscopic solid or semi-solid at temperatures below 30°C (e.g., at 20°C to 30°C or at about 25°C) and does not absorb a significant amount of water from the air.

[0181] 2.74. Hydrogel 2.73, wherein the hydrogel rapidly hydrates and forms a viscous gel at a temperature above 30°C and below 40°C, for example at a temperature of 35°C to 39°C, or at a temperature of 36°C to 38°C (e.g., at about 37°C) and / or at a pH of 6.5 or greater (e.g., 7.0 or greater).

[0182] 2.75. Hydrogel 2.74, wherein the viscosity of the resulting viscous gel is at least 100,000 mPa-s, for example 100,000 mPa-s to 5,000,000 mPa-s, or 200,000 mPa-s to 2,000,000 mPa-s, or 600,000 mPa-s to 1,400,000 mPa-s, or 800,000 mPa-s to 1,200,000 mPa-s, or about 1,000,000 mPa-s.

[0183] 2.76. Hydrogel 2.72 to 2.75, wherein the resulting viscous gel adheres to the mucous lining of the oral cavity (e.g., periodontal cavity or oral mucosa).

[0184] 2.77. Hydrogels 2.72 to 2.76, wherein the resulting viscous gel interacts with mucin to enhance adhesion to mucosal surfaces of the oral cavity (e.g., periodontal cavity or oral mucosa), for example due to rheological synergy with mucin.

[0185] 2.78. Hydrogels of any one of 2.72 to 2.77, wherein the resulting viscous gel slowly releases any surfactant and / or any hyaluronic acid or alkali metal hyaluronic acid salt in a continuous manner (e.g., at a rate of 1% to 20% of the surfactant content per day for at least 1 day, for example, 1 to 30 days).

[0186] In another embodiment, this disclosure provides hydrogel 1, or any one of 1.1 to 1.84, or hydrogel 1A, or hydrogel 2, or any one of 2.1 to 2.78, wherein the hydrogel is a local barrier gel or an injectable periodontal gel.

[0187] In a third aspect, this disclosure provides methods for treating or preventing oral diseases, the methods comprising applying hydrogel 1, or any of 1.1 to 1.84, or hydrogel 1A, or hydrogel 2, or any of 2.1 to 2.78, to the oral cavity. This disclosure also provides the use of hydrogel 1, or any of 1.1 to 1.84, or hydrogel 1A, or hydrogel 2, or any of 2.1 to 2.78, for the treatment or prevention of oral diseases. This disclosure further provides hydrogel 1, or any of 1.1 to 1.84, or hydrogel 1A, or hydrogel 2, or any of 2.1 to 2.78, for use in the treatment or prevention of oral diseases. In some embodiments of the foregoing aspects, the oral diseases are periodontal diseases (including gingivitis and periodontitis), dental caries, tooth hypersensitivity, halitosis, and oral infections (e.g., fungal or bacterial infections of the oral mucosa). In some implementations, the hydrogel is applied by injection into the oral cavity, for example by using a syringe (e.g., with a narrow-hole needle), such as into the periodontal cavity, periodontal pocket, or gingival pocket.

[0188] In some embodiments, the hydrogel is configured for delivery as an oral spray. In some embodiments, the aforementioned kit contains a hydrogel packaged in a container having a fingertip-actuated spray device, optionally with a long tip for accurately delivering the spray into small spaces within the oral cavity. In some embodiments, the hydrogel is formulated for injection, for example, into periodontal pockets. In some embodiments, hydrogen is packaged in a container or kit (e.g., metal or plastic) with a syringe and needle suitable for injecting the hydrogel into periodontal pockets. In some embodiments, the hydrogel is packaged in a tube (e.g., a squeeze tube) or in a single-use dressing for application, for example, using an applicator (e.g., a plastic applicator or cotton swab) or fingertip (e.g., a patient's finger or a dentist's or dental hygienist's finger) to teeth (e.g., to damaged teeth) or gums, or to the oral mucosa, or to the alveolar bone (e.g., after tooth extraction).

[0189] In further embodiments of the foregoing methods and uses, hydrogel 1 or any of 1.1 to 1.84, or hydrogel 1A, or hydrogel 2 or any of 2.1 to 2.78, is used in, or is effective for:

[0190] (i) Forming a barrier within the oral cavity, for example, on the damaged surface of a tooth or on the damaged portion of the gingiva or oral mucosa, or in or above the dental pocket (e.g., after tooth extraction).

[0191] (ii) Carrying, dissolving, suspending, and / or delivering a drug (e.g., an active agent) to the oral cavity, such as to the damaged surface of a tooth or a damaged portion of the gingiva or oral mucosa, or in or above a dental pocket (e.g., after tooth extraction).

[0192] (iii) Adhesion to oral surfaces, such as adhering to damaged surfaces of teeth or damaged portions of the gums or oral mucosa, or in or above dental pockets (e.g., after tooth extraction), to provide a barrier against infection or to deliver medications (e.g., active agents) to oral tissues.

[0193] (iv) Reduce or inhibit the formation of tooth decay.

[0194] (v) Reduce, repair, or inhibit precarious enamel lesions, such as those detected by quantitative light-induced fluorescence (QLF) or electrocary measurement (ECM).

[0195] (vi) Reduce or inhibit demineralization and promote tooth remineralization.

[0196] (vii) Reduce tooth hypersensitivity.

[0197] (viii) Reduce or suppress gingivitis

[0198] (ix) Promotes the healing of mouth ulcers or wounds.

[0199] (x) Reduce the level of bacteria that produce acid and / or produce foul odors.

[0200] (xi) Increase the relative level of bacteria that break down arginine in the mouth.

[0201] (xii) Inhibits the formation of oral microbial biofilms.

[0202] (xiii) Following the sugar challenge, raise and / or maintain the pH of the plaque at a level of at least pH 5.5.

[0203] (xiv) Reduce plaque buildup, and / or

[0204] (xv) To treat, relieve or reduce dry mouth.

[0205] In another aspect, this disclosure provides kits comprising hydrogel 1 or any of 1.1 to 1.84, or hydrogel 1A, or hydrogel 2 or any of 2.1 to 2.78, and an oral administration device, such as a syringe and / or needle. Preferably, the syringe is a disposable plastic syringe (e.g., polyethylene and / or polypropylene) optionally packaged with a long-tipped needle of size 21 (21G) or narrower (e.g., 21G to 34G, 23G to 32G, 25G to 28G). In some embodiments, the kit contains 0.5 mL to 1.5 mL (e.g., 0.7 mL to 1.2 mL) of hydrogel. In some embodiments, the kit contains hydrogel pre-filled into the syringe. Preferably, the needle is a blunt-tipped needle (i.e., not a hypodermic needle). Alternatively, the administration device may be a medicator.

[0206] The inventors have discovered that hydrogel compositions as described herein (e.g., hydrogel 1, or any of 1.1 and below, etc.) have low viscosity at ambient temperature, but undergo a sol-gel phase transition upon heating to normal oral temperatures and / or exposure to oral pH levels, resulting in the formation of a viscous gel. Specifically, the hydrogels can be formulated as free-flowing liquids at ambient temperature with a pH greater than 7.0 (e.g., 8.0 to 9.0 or 8.5 to 9.0). However, upon exposure to temperatures of about 37°C (e.g., 35°C to 40°C) or upon exposure to mucins, or any combination thereof, the hydrogels undergo a rapid sol-gel transition to form a high-viscosity gel. Without being bound by theory, it is considered that the temperature-dependent aspect of the transition is primarily generated by the behavior of the poloxamer polymers in the composition, while the pH-dependent aspect is primarily generated by the polyacrylate polymers in the composition. This transition is facilitated by the acid-base neutralization of the polyacrylate polymers, which leads to the swelling of the cross-linked gel network.

[0207] It was also discovered that the hydrogel according to this disclosure unexpectedly interacts with mucin polymers present in secretions covering the oral mucosa of normal individuals. Unbound by theory, it is believed that the polyacid chains provided by the polyacrylate polymers and / or hyaluronic acid polymers in the composition induce entanglement with the mucins, leading to modulation of the mucin nanostructure and pores. It is thought that the carboxyl and hydroxyl groups of the polymers form intermolecular hydrogen bonds and / or ionic bonds with the glycosyl groups on the mucin polymers, further promoted by the flexible conformation of high molecular weight hyaluronic acid. The resulting reduced pore size can facilitate the removal of pathogenic organisms from the mucosal surface.

[0208] The gel can then be used as a carrier to directly and controlledly release therapeutic agents, such as antibacterial agents, antifungal agents, anticariogenic agents, and antihypersensitizing agents, into oral tissues over a prolonged period of time without interference from dilution by saliva. In some embodiments, such a composition can be applied to periodontal pockets, completely or partially filling the pockets, whereby the liquid transforms into an adhesive gel that adheres to and remains within the inflamed pocket, releasing the therapeutic agent in a sustained manner to treat underlying periodontal disease.

[0209] The terms “periodontal pocket,” “periodontal gap,” “gingival pocket,” “gingival gap,” and “tooth pocket” that are used interchangeably in this article refer to an abnormal space between the enamel at the neck of a tooth and the overlying unattached gingiva, created by a chronic inflammatory response associated with untreated gingivitis or periodontitis, which leads to the destruction and fracture of the bone and tissues supporting the tooth.

[0210] The terms “sustained release,” “extended release,” and “controlled release,” which are used interchangeably herein, refer to the release of an active agent from a composition containing it at predetermined intervals or gradually, such that the contained active agent is available over an extended period of time, such as hours (e.g., up to 6, 12, 18, 24, 36, or 48 hours), days (e.g., 1 to 30 days), or weeks (e.g., 1 to 4 weeks). Upon gelation, the release characteristics of the active agent from the compositions of this disclosure depend on several parameters, such as the specific polymer used and its amount in the composition; and the ratio (by weight) between the various polymers.

[0211] The term "poloxam" or "poloxam copolymer" refers to a polyethoxy / polypropoxy block copolymer, which is a nonionic triblock copolymer consisting of a central polyoxypropylene unit (also known as a poly(propylene oxide) unit) with a hydrophobic chain and two hydrophilic polyoxyethylene units (e.g., poly(ethylene oxide) units) attached to its sides. Poloxamer has the following chemical structure:

[0212] HO-[CH2CH2O] a [-CH(CH3)CH2O-]b[CH2CH2O] a -H,

[0213] Where a and b are integers, each typically ranging from 10 to 200. Poloxamers are named according to common convention based on their molecular weight and ethoxy content, and include poloxamer 407, poloxamer 338, poloxamer 237, poloxamer 188, and poloxamer 124. Pluronic is the name of a series of poloxamer polymers manufactured by BASF. For example, Pluronic F-127 is poloxamer 407. Poloxamers differ from other polyethylene glycol / polypropylene glycol copolymers (PEG / PPG copolymers or EO / PO copolymers) that have structures other than a triblock structure (e.g., random copolymer structures). Such copolymers that differ from poloxamers include PEG / PPG copolymers marketed by BASF as polymers in the Pluracare and Pluraflow series.

[0214] Carbomer is a general term for polyacrylic polymers, such as the Carbopol brand polymer sold by Lubrizol.

[0215] ExpertGel 312 and ExpertGel 412 are proprietary composite polymers marketed by PolymerExpert. ExpertGel 312 is a copolymer of poloxamer 338 and PPG-12 / SMDI. ExpertGel 412 is a copolymer of poloxamer 407 and PPG-12 / SMDI. SMDI is a saturated methylene diphenyl diisocyanate or a saturated methylene dicyclohexyl diisocyanate, also known as 1,1-methylenebis[4-isocyanophenyl] or 1,1'-methylenebis[4-isocyanocyclohexane]. SMDI has two isocyanate functional groups that can condense with the free hydroxyl groups of PEG polymers, PPG polymers, or PEG / PPG copolymers (including poloxamer) to form urea (carbamate) linking groups. ExpertGel polymers are also described, for example, in US 7,339,013, the contents of which are incorporated herein by reference in their entirety.

[0216] Hyaluronic acid is an anionic, non-sulfated glycosaminoglycan (GAG) widely distributed in the connective tissues of vertebrates, and is the most abundant high-molecular-weight glycosaminoglycan in the extracellular matrix of soft periodontal tissues. Hyaluronic acid can exist as a free acid or as a salt (e.g., alkali metal salt). It possesses important hygroscopic, rheological, and viscoelastic properties, which fluctuate with changes in temperature, pH, ionic environment, and binding partner. However, these properties are also highly dependent on chain length. In terms of molecular weight, hyaluronic acid can reach over 10⁻⁶. 7 However, it also exists in several smaller forms (called low molecular weight hyaluronic acid or oligomeric hyaluronic acid).

[0217] Hyaluronic acid has been found to be effective in treating inflammation in medical fields such as orthodontics, dermatology, and ophthalmology, and has also been found to have anti-inflammatory and antibacterial properties in the treatment of gingivitis and periodontitis. Due to its tissue-healing properties, it has been suggested for use as an adjunct to mechanical therapy in the treatment of periodontitis. Hyaluronic acid affects endothelial cell proliferation and monolayer integrity, and also has an effect on angiogenesis.

[0218] As used herein, the term "activator" refers to any agent that may be beneficial in treating or preventing oral diseases such as periodontal disease, such as antimicrobial agents, antibacterial agents, antifungal agents, anti-inflammatory agents (e.g., nonsteroidal anti-inflammatory drugs), desensitizing agents, anesthetics, tartar control agents, and fluoride agents.

[0219] Examples of antifungal agents include, but are not limited to, fluconazole, itraconazole, amphotericin B, voriconazole, nystatin, clotrimazole, econazole nitrate, miconazole, terbinafine, ketoconazole, enconazole, boric acid, and miconazole.

[0220] As used herein, the term “nonsteroidal anti-inflammatory drug” (NSAID) refers to any nonsteroidal anti-inflammatory drug / pharmaceutical / analgesic / medication, and includes both selective inhibitors of cyclooxygenase (COX)-2 (such as celecoxib, rofecoxib, vardicoxib, parecoxib, etorcoxib, and rumicoxib) and non-selective inhibitors of COX-2 (such as etodoxacin, aspirin, naproxen, ibuprofen, indomethacin, piroxicam, and nabumetone).

[0221] Examples of anesthetics include, but are not limited to, local anesthetics such as lidocaine, benzocaine, debulacaine, tetracaine, and promecaine. Additionally, eugenol has local anesthetic properties.

[0222] Examples of antibacterial agents include zinc salts, such as zinc oxide, zinc citrate, zinc lactate, zinc phosphate, zinc pyrophosphate, zinc chloride, zinc nitrate, zinc acetate, zinc gluconate, and zinc sulfate; stannous salts, such as stannous chloride, stannous fluoride, stannous pyrophosphate, stannous nitrate, and stannous sulfate; and quaternary ammonium compounds or their pharmaceutically acceptable salts, such as benzyl ammonium chloride or hexadecylpyridine chloride. Guanidine compounds or their pharmaceutically acceptable salts, such as chlorhexidine (e.g., chlorhexidine gluconate), alexiconidine, or polyhexamethylene biguanide (PHMB); hexoctidine; eucalyptol; menthol; methyl salicylate; thymol; peppermint oil; bispyridineamine octinidine (1,1,4,4'-tetrahydro-N,N'-dioctyl-1,1'-decamethylenedi-(4-pyridinidine)) or their pharmaceutically acceptable salts, such as octinidine dihydrochloride.

[0223] Examples of tartar control agents include phosphates and polyphosphates (e.g., pyrophosphates and tripolyphosphates), polyaminopropanesulfonic acid (AMPS), hexameric metaphosphates, polyolefin sulfonates, polyolefin phosphates, and diphosphates. In certain embodiments, these salts are alkali metal phosphates, such as salts of alkali metal hydroxides or alkaline earth metal hydroxides, such as sodium, potassium, or calcium salts. As used herein, "phosphate" encompasses oral-acceptable monophosphates and polyphosphates, such as P... 1-6 Phosphates, such as monophosphates like monobasic phosphates, dibasic phosphates, or tribasic phosphates; and dipolyphosphates such as pyrophosphates; and polyphosphates such as tripolyphosphates, tetraphosphates, hexaphosphates, and hexapolymetaphosphates (e.g., sodium hexapolymetaphosphate). In specific instances, the selected phosphates are chosen from alkali metal dibasic phosphates and alkali metal pyrophosphates, such as disodium hydrogen phosphate, dipotassium hydrogen phosphate, dicalcium phosphate dihydrate, calcium pyrophosphate, tetrasodium pyrophosphate, tetrapotassium pyrophosphate, sodium tripolyphosphate, and mixtures of any two or more of these.

[0224] Examples of fluoride reagents include stannous fluoride, sodium fluoride, potassium fluoride, sodium monofluorophosphate, sodium fluorosilicate, ammonium fluorosilicate, amine fluoride, ammonium fluoride, and combinations thereof.

[0225] In some embodiments, the hydrogel composition may contain small amounts of additional polymers (e.g., 0.1% to 10% by weight, or 0.1% to 5% by weight, or 0.1% to 3% by weight, or 0.1% to 1% by weight, each being in total) to further adjust the viscosity of the formulation or enhance the solubility or stability of the activator or other components. Such additional polymers include polyethylene glycol, polypropylene glycol, polysaccharides (e.g., cellulose derivatives such as carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, microcrystalline cellulose; or polysaccharide gums such as xanthan gum, guar gum, or carrageenan gum, arabic gum); polyvinylpyrrolidone (PVP), such as crosslinked PVP; synthetic anionic polymer polycarboxylate, such as maleic anhydride or a copolymer of maleic acid with another polymerizable olefinically unsaturated monomer (preferably methyl vinyl ether) (e.g., a copolymer of maleic anhydride / maleic acid to methyl vinyl ether in a ratio of 1:4 to 4:1). Acidic polymers (such as polyacrylate gels) can be provided in the form of their free acid or partially or completely neutralized water-soluble alkali metals (such as potassium and sodium) or ammonium salts. In one embodiment, the oral care composition may contain PVP. PVP generally refers to a polymer containing vinylpyrrolidone (also known as N-vinylpyrrolidone, N-vinyl-2-pyrrolidone, and N-vinyl-2-pyrrolidone) as a monomer unit. The monomer unit consists of a polar imide group, four nonpolar methylene groups, and a nonpolar methane group.

[0226] As used herein, the term "object" refers to any mammal, such as humans, non-human primates, horses, ferrets, dogs, cats, cattle, and goats. In a preferred embodiment, the term "object" refers to a person, i.e., an individual.

[0227] The liquid hydrogel solution disclosed herein (i.e., hydrogel 1 or any of 1.1 to 1.84) can be packaged in a suitable sealed syringe equipped with a suitable blunt-tipped needle, wherein the amount of said liquid composition in the syringe is sufficient to treat different numbers of gingival pockets (e.g., about 0.7 ml to about 1.2 ml). Such a syringe can be equipped with a 25G needle or tip for optimal injection; however, smaller or larger sizes can also be used. The syringe is preferably operated at or below ambient temperature, where the viscosity is low enough to allow for precise and controlled delivery without applying excessive pressure. At this temperature, the dentist can deliver an appropriate amount of the liquid composition directly into the oral cavity, for example to the bottom of the gingival pocket, where the liquid composition will gel, and the gel will adhere and remain in situ. After gelation, the highly viscous structure controls the release of hyaluronic acid or salts and / or any other active agents present in a sustained manner, i.e., for hours and up to days.

[0228] In some embodiments, the hydrogels of this disclosure can be characterized by one or more rheological parameters. Basic parameters include shear stress (tau, τ), shear rate (gamma point, ... ) and shear viscosity (eta, η), which are obtained through, for example The viscosity is related to Newton's laws. However, viscosity, shear stress, and shear rate are not constant for all substances and can vary based on conditions (e.g., temperature, shear rate). Therefore, the flow behavior varies. For Newtonian compositions, viscosity is independent of shear rate; thus, the shear stress versus shear rate graph will produce a straight line with a slope equal to the shear viscosity. Many substances exhibit non-Newtonian flow behavior. Non-Newtonian flow behavior includes shear-thinning behavior, characterized by a decrease in viscosity with increasing shear rate, and shear-thickening behavior, characterized by an increase in viscosity with increasing shear rate. Another class of compositions exhibits mixed viscous and elastic behavior in response to shear; these are called viscoelastic compositions.

[0229] Viscoelastic behavior is typically described using parameters G, G', and G”. G is the shear modulus, which is equal to the shear stress (τ) divided by the shear strain (γ). The shear modulus can be decomposed into two components: the storage modulus G' and the loss modulus G”. These two parameters describe the elastic portion (solid behavior) and the viscous portion (liquid behavior) of the shear modulus, respectively. Viscoelastic solids have a higher G' than G” (i.e., a G' / G” ratio > 1), while viscoelastic liquids have a higher G” than G' (i.e., a G' / G” ratio < 1). Compositions according to this disclosure that exhibit heat-sensitive or mucosal-sensitive gelling behavior preferably have a G' / G” ratio < 1 in the liquid state and a G' / G” ratio > 1 in the gelling state.

[0230] Unless otherwise stated, all figures representing quantities of components, etc., used in this specification and claims should be understood to be modified by the term "about" in all cases. Therefore, unless otherwise indicated, the numerical parameters set forth in this specification and appended claims are approximations and can vary up to plus or minus 10% depending on the desired characteristics sought to be obtained by the invention.

[0231] Unless otherwise stated, all percentages and quantities expressed herein and elsewhere in this specification should be understood as weight percentages of the whole composition. The quantities given are based on the effective weight of the material.

[0232] As used throughout, "range" is used as a shorthand to describe the individual values ​​within a range and each value. Any value within the range can be chosen as the endpoint of the range. Furthermore, all references cited herein are incorporated herein by reference in their entirety. In the event of any conflict between definitions in this disclosure and definitions in the cited references, the definitions in this disclosure shall prevail.

[0233] The invention will now be illustrated by way of the following non-limiting embodiments.

[0234] Example

[0235] Example 1: Exemplary Aqueous Hydrogel Composition

[0236] The following exemplary aqueous hydrogel compositions were prepared according to this disclosure (all values ​​are in weight percent):

[0237]

[0238]

[0239] The hydrogel was prepared using a cold method. Formulated amounts of carbomer followed by hyaluronic acid were dissolved in deionized water via homogenization. Zinc oxide was then dispersed in the solution, and the resulting suspension was transferred to an ice bath for cooling. Formulated amounts of poloxamer 407 and ExpertGel 312 were added, and the mixture was stirred until complete dissolution. CPC was then added, and the suspension was mixed in an ice bath for at least 60 minutes. The pH was then adjusted to approximately 9 using a 50% sodium hydroxide aqueous solution.

[0240] Example 2: Exemplary Aqueous / Polyol Hydrogel Composition

[0241] The following exemplary aqueous hydrogel compositions comprising polyol moisturizers were prepared according to this disclosure (all values ​​are in weight percent):

[0242]

[0243]

[0244] All of the above formulations contain an appropriate amount (67% to 86%) of water, and small amounts of sweeteners, flavorings and / or colorings (<0.25% net weight).

[0245] The rheological behavior (viscosity measurement) of the selected hydrogel formulation as a function of temperature was performed.

[0246] formula Brinell viscosity, 25℃ (cP) Brinell viscosity, 37℃ (cP) ratio 2-6 48 2730 57 2-7 131 7880 60 2-8 183 5640 31 2-9 4960 12800 3 2-10 4600 6400 1 2-1 785 331,000 422 2-2 452 289,000 639 2-3 1,220 470,000 385 2-4 6,450 1,080,000 167 2-5 13,960 1,560,000 112

[0247] Brookfield viscosity was measured using a V74 blade rotor on a Brookfield HA-DV2 viscometer. The viscometer applies a user-controlled angular velocity to the rotor (typically measured in revolutions per second (RPM)) and reports the torque on the rotor shaft. The Brookfield viscosity was then calculated from the RPM and torque values ​​using two conversion parameters (shear rate constant, 0.2723; and rotor factor constant, 290) according to the instrument's operating instructions. Tests were performed at both 25°C and 37°C. Reported Brookfield viscosity readings were obtained at 1 RPM.

[0248] The results showed that the carbomer concentration must be fine-tuned in the formulation to avoid losing the desired thermosensitive properties. Preferably, the carbomer level in these formulations should be in the range of 0.2% to 0.5%. Including glycerol and formulating at high levels of gelling agents did not alter this trend. In these systems, an increase in the ratio of hydrogel viscosity at 37°C to hydrogel viscosity at room temperature was observed in carbomer concentrations of 0.2% to 0.5%.

[0249] As shown in formulations 2-25 and 2-26, the addition of low levels of hyaluronic acid (0.2%, 1 MDa) and zinc oxide (0.5%) did not alter the thermosensitivity of the hydrogel formulation.

[0250] formula Brinell viscosity, 25℃ (cP) Brinell viscosity, 37℃ (cP) ratio 2-25 5,580 1,020,000 183 2-26 173 55,200 318

[0251] Example 3: Rheological synergy with mucin

[0252] Charged mucosal adhesion polymers are thought to interact with mucins through a process called "rheological synergy." This means that the viscosity of the solution containing the mucin is greater than the sum of the viscosities of the polymer and the mucin solution. This experiment aims to evaluate whether the hydrogel composition of the present invention interacts synergistically with mucins in this manner.

[0253] Rheological synergies associated with mucosal adhesion can be measured in vitro by rheological analysis of materials in the presence and absence of mucins.

[0254] ΔG′=G 混合物 -(G′ f +G′ m )

[0255] Among them G' f G' m and G' 混合物 It is the elastic modulus of polymer formulations, mucin solutions, and mixtures of polymer formulations and mucin. If the viscoelastic properties of a blend of hydrogel and mucin are greater than the sum of the properties of the gel and mucin alone, the polymer material has mucosal adhesion properties.

[0256] Typically, a portion of the hydrogel is combined with mucin (10%), and temperature scans are performed to compare it with a matched control that does not contain mucin, and rheological characteristics are quantified. The elastic modulus (G') at 37°C of samples containing and without mucin is compared according to the above equation to determine mucosal adhesion under similar rheological conditions. An increase in ΔG' indicates rheological synergy and mucosal adhesion potential.

[0257] Three test formulations were prepared according to the table below. All values ​​are by weight percentage. EG312 is ExpertGel 312. CPC is hexadecylpyridine chloride. CHX stands for chlorhexidine.

[0258]

[0259] A mucin solution was prepared by dispersing mucin in water to a final concentration of 10% by weight. 10 g of hydrogel test sample was combined with 1.11 g of mucin solution, and the mixture was blended to form a slurry. Rheological parameters were determined using a TA Instruments AR1000 rheometer with a 40 mm diameter parallel-plate geometry, where the temperature of the lower plate was controlled by thermoelectric heating / cooling (Peltier effect).

[0260] The results of two experiments, both conducted using a TA Instruments AR1000 rheometer, are reported here. Both experiments were performed on samples stored at 4°C. In the first experiment, the sample was placed in a 1 mm gap between two plates, and the temperature was scanned upward from 4°C to 37°C at a heating rate of 0.0435 degrees per second. Once the target temperature of 37°C was reached, the viscoelastic modulus G' and G" were measured. In the second experiment, the sample was placed in a 0.5 mm gap between two plates, and the temperature was set to change abruptly from 4°C to 37°C. The rheometer read the actual temperature reaching 30°C in 30 seconds and 37°C in 60 seconds. After 300 seconds, a shear stress ramp test was performed. In this test, the shear stress increased at a rate of 10 Pa per second. The viscosity was measured when the viscosity reached its maximum value, which is reported below as the maximum instantaneous viscosity (ViscMax). The stress at which this maximum value was reached is reported as the yield stress (YS). The above parameters were determined for individual mucin dispersions, for each individual test composition, and for each test composition in a 10% weight / weight dilution in the mucin dispersion. The following results were obtained (all values ​​are at 37°C):

[0261] sample Yield stress (Pa) ViscMax(Pa-s) G'(Pa) mucin dispersion 0 <1 0.15 Formula 3-A 35 25 18 Formula 3-A+ mucin 55 163 243 Formula 3-B 35 111 165 Formula 3-B+ mucin 45 170 240 Formula 3-C 35 80 103 Formula 3-C+ mucin 45 170 217

[0262] These results indicate a synergistic increase in viscosity and elastic modulus of the tested mucin / hydrogel assemblies. The effect of adding hyaluronic acid (370 kDa, 0.20 wt%) was also determined for composition 3-A. The results are shown below (all values ​​are at 37°C):

[0263] sample Yield stress (Pa) ViscMax(Pa-s) G'(Pa) mucin dispersion 0 <1 0.15 Formula 3-A 35 25 18 Formula 3-A+ mucin 55 163 243 Formula 3-A+HA 25 47 55 Formula 3-A + Mucin + HA 45 139 276

[0264] These results indicate that the addition of hyaluronic acid increases the viscosity of the sample, but does not suppress the synergistic increase in viscosity and elastic modulus observed in the addition of mucin.

[0265] The temperature dependence of the elastic modulus G' was examined in the range of 5°C to 40°C (temperature scan experiment). It was found that for the individual mucin dispersions, G' steadily decreased with increasing temperature. In contrast, each of compositions 3-A, 3-B, and 3-C showed a steady decrease in G' from 5°C to approximately 25-30°C, followed by a sharp increase in G' from 25°C to 30°C to 37°C. This sharp transition was most pronounced for formulation 3-A. The combination of the compositions with mucin unexpectedly pushed the G' inflection point to a lower temperature, approximately 15°C for each combination, and exhibited a higher G' value at the highest temperature compared to the individual compositions alone. It was also found that the combination of formulation 3-A with hyaluronic acid had only a moderate effect on the G' trace, producing a slightly lower G' consistently from 5°C to 25°C, with similar behavior at higher temperatures. In contrast, the combination of formulation 3-A, mucin, and hyaluronic acid showed a slightly higher G' consistently throughout the temperature scan. These results indicate that the hydrogel according to this disclosure interacts synergistically with mucin to promote gelation at all relevant temperatures, with more viscous gels forming at higher temperatures (above ambient temperature). The results also show that the synergistic reaction with mucin promotes stronger gelation at lower temperatures compared to the absence of mucin.

[0266] The above experiments were repeated using additional gel samples 3-D, 3-E, and 3-F. These four samples had the same composition as shown below, but were prepared in different batches at different times:

[0267]

[0268] The results are shown in the table below (all values ​​are at 37°C):

[0269]

[0270] Example 4: Sustained release of the drug

[0271] Prepare the hydrogel formulation according to the following formula as described above:

[0272] Formula 4-A Formula 4-B Formula 4-C Poloxamer 407 (%) 20 5.75 Expert Gel 312 (%) 10 5.90 Expert Gel 412 (%) 10 5.25 PEG 8K (%) 0.7 0.5 water(%) 79 78.3 81.6 FD&C Blue 1 (%) 1 1 1

[0273] The test formulation was ice-cooled and then loaded with FD&C blue dye via dispersion using a rapid mixing device (FlackTek, Inc.). The samples were stored overnight at 4°C. Aliquots (250 μL) of each chilled gel were then placed in the wells of a chilled 24-well plate. The plate was heated at 37°C for 30 minutes to allow the system to gel. Aliquots (1 mL) of artificial saliva or DI water (both heated to 37°C) were added to each well, and the plate was incubated on a track shaker at 90 rpm. At specified time points (5 min, 20 min, 40 min, 60 min, 90 min, 120 min, 180 min, and 360 min), aliquots (3 μL) were removed from each well and diluted in DI water (270 μL). The amount of FD&C blue dye removed from the gel was quantified at 288 nm and 630 nm using a UV-Vis spectrophotometer. The results were compared with standard curves for FD&C Blue 1 (0.005 mg / ml to 0.5 mg / ml) in deionized water and diluted (1:100) artificial saliva. Controlled release of the dye was observed over a 6-hour period, exhibiting different characteristics in artificial saliva and deionized water. The results are summarized in the table below (showing the cumulative μg of gel released by mass):

[0274]

[0275]

[0276] These results indicate that the trapped FD&C Blue 1 dye is gradually released from the gel, with a significantly lower release rate in artificial saliva compared to water. In a similar set of experiments, zinc salicylate at concentrations ranging from 2% wt% to 10% wt% entrained in the gel also experienced similar stable release over a 6-hour period.

[0277] Example 5: Controlled degradation of hydrogels in saliva

[0278] Controlled degradation of the hydrogel was demonstrated in vitro under conditions representative of the oral environment. Samples of 2–25 (0.5 mL) of gel were placed in 3 μm transwells cell culture inserts and then in 1.5 mL of clear artificial saliva at 37 °C. The amount of zinc infiltrated into the saliva medium was quantified over a 50-day period (1 mL was collected for analysis at each time point). As measured by ICP-AES, gel degradation was associated with the release of zinc into the saliva medium. The results are shown in the table below and are reported as the average of nine replicates:

[0279]

[0280]

[0281] Example 6: Barrier layer protection against pathogens:

[0282] The ability of the polymer hydrogel according to the invention to provide a barrier protection against bacteria was tested in a modified bacterial challenge assay. Sterile hydroxyapatite discs and porcine oral mucosa were exposed to 2 mL of sterile filtered whole saliva collected from two healthy volunteers for approximately 2 hours. Half of the substrate was then treated with hydrogel formulations 1-9 (2 mL, 2 min), while the other half was treated as a control at room temperature with only phosphate-buffered saline (PBS, 1X) (2 mL, 2 min). The samples were washed by immersing the substrate in PBS (2 mL) at 37°C ten times. The treated substrate samples were then inoculated with saliva inoculum (1.5 mL / well, 2 mL whole saliva diluted in 40 mL McBain medium containing 80 μL ferric ammonium chloride, 1.6 μL vitamin K, and 400 μL sucrose) and incubated at 37°C for 24 hours. The samples were washed three times in cold, sterile 0.25x TSB, and the resistance to bacterial growth on each substrate was analyzed by bacterial colony count and decrease in ATP activity.

[0283] Visual examination clearly showed that the barrier formed by the oral hydrogel on the mucosal tissue reduced bacterial recolonization by more than 95% (in 10...). -4 (At dilution). The reduced ATP-based activity of the saliva-inoculated substrate pretreated with the experimental hydrogel compared to the PBS control also demonstrates the protective effect of the bacterial barrier. The results are shown in the table below as the percentage reduction for each sample relative to the PBS control:

[0284]

[0285] Example 7: Resistance to bacterial invasion

[0286] To assess bacterial resistance at different stages of gel degradation, samples for evaluation were prepared using the same degradation steps detailed above in the saliva gel degradation experiment (Example 6). 75 μL of an overnight bacterial culture consisting of *Actinomyces viscosus* (ATCC#43146) and *Streptococcus oralis* (ATCC#35037) was placed on top of the cured oral gel sample and incubated on a tracked shaker at 37°C for 1 hour, subject to surface viability via ATP. After incubation, analysis was performed using the BacTiter-Glo Microbial Cell Viability Assay Kit (Promega Ref#G8231), with reagents added according to the manufacturer's instructions. Analysis was performed using ATP bioluminescence readings.

[0287] Three samples were tested: (1) formulations 1-9 above, with 0.075% CPC; (2) formulations 1-9 modified to have 0.04% CPC; and (3) a control with formulations 1-9 but with 0% CPC and 0% hyaluronic acid. The results are shown below as the percentage reduction in ATP bioluminescence relative to the negative control (untreated).

[0288]

[0289] For viability via SIKT, overnight cultures of *Actinomyces viscosus* (ATCC#43146) and *Streptococcus oralis* (ATCC#35037) were treated using the same gel degradation procedure as described above. Cultures were treated with 100 μl of degrading oral gel for 30 seconds, after which the killing process was stopped. Samples were then processed, and results were expressed as the percentage of surviving cells relative to the control sample treated with PBS only (negative control).

[0290]

[0291] Example 8: Inhibition of the pro-inflammatory mediator PGE2 after LPS induction

[0292] Hyaluronic acid has been shown to attenuate the release of the pro-inflammatory cytokine IL-8 in cultured HEK-hTLR4 cells stimulated with bacterial lipopolysaccharide (LPS) in a dose-dependent manner. This experiment was conducted to determine whether a hydrogel containing high molecular weight hyaluronic acid could similarly inhibit the release of the pro-inflammatory mediator PGE2 after cell stimulation with LPS.

[0293] Mattek gingival tissue (n=3 per treatment group) was treated with 100 μL of oral gel formulation 1-9 for 2.5 h at 37 °C (with 5% CO2) in medium containing 1 μg / mL P. gigivalis LPS (lipopolysaccharide). After 2.5 h, the tissues were washed with PBS (phosphate-buffered saline), returned to the stimulated medium, and incubated overnight. After overnight incubation, the tissue supernatant was collected and the PGE2 concentration was analyzed. The results are shown in the table below:

[0294] PGE2 (pg / mL) The percentage reduction compared to culture medium + PgLPS Culture medium + PgLPS 1561.6 Placebo + PgLPS 1257.3 19.5％ Formula + PgLPS 1096.5 29.7％

[0295] Example 9: Maintenance of Gingival Tissue Viability

[0296] Tissue viability was tested using the MTT assay for tissues treated with formulated hydrogels. Mattek gingival tissues (n=3 per treatment group) were treated in culture medium at 37°C (with 5% CO2) with 100 μL of oral gel formulation 1–9 (2-fold dilution) for 2.5 h. After 2.5 h, the tissues were washed with PBS. Unstimulated tissues were incubated with 600 μL of 1 mg / mL MTT solution (3-(4,5-dimethylthiazolyl-2-yl)-2,5-diphenyltetrazolium bromide, or MTT) for 3 h, followed by immersion in 1 mL of extraction solution (0.04 N HCl in isopropanol) on a shaker in the dark for 2 h to release MTT for viability measurement. The optical density of the extracted samples was measured at 570 nm, and the percentage of viability relative to the negative control was calculated.

[0297]

[0298] Example 10: Formula Optimization

[0299] Experimental designs were conducted using the following variables: pH 6 to 9; CPC concentration 0% to 0.075%; and hyaluronic acid concentration 0% to 0.8% (370 kDa). Rheological characteristics as a function of temperature, formulation anti-settling stability, healing (scratching test), cytotoxicity, and microrobustness were determined for selected test formulations to further optimize properties for maximum therapeutic potential.

[0300] For the scratch test, use 5×10 4 HaCaT(P4) cells were seeded in 48-well plates. Cells were cultured at 37°C and 5% CO2 for 1 to 2 days. Serial dilutions of formulations 12-1 to 12-13 were prepared in DMEM complete medium. Scratches were made on the cell centers and images were acquired (T0). Cells were added to medium containing the formulations and the cultures were incubated at 37°C and 5% CO2 for 7 hours, after which images were repeated (T7). The percentage of cell migration from T0 to T7 was calculated using ImageJ software.

[0301] For cytotoxicity assays, 0.5 × 10⁻⁶ 4 HaCaT(P4) cells were seeded in 96-well plates. Cells were cultured overnight at 37°C and 5% CO2. Formulas 12-1 to 12-13 were pre-cooled at 4°C for 2 hours. Serial dilutions of the formulas were prepared in DMEM complete medium. The cells were added to the medium containing the formulas (two copies per treatment). Cells were cultured at 37°C and 5% CO2 for 24 hours. Alamar blue assay was performed to determine viability.

[0302] For microrobustness assays, a microrobustness index (MRI) value is calculated. MRI compares the microrobustness of a new formulation to established class standards. This provides an assessment of the formulation's ability to withstand incidental microbial contamination during manufacturing and consumer use. Raw data points, known as area under the curve (AUC) values, are generated using a microrobustness test (MRT). MRT measures the kill rate against a specified amount of microbial inoculum—the less microbial growth observed, the higher the sample's resistance to microbial contamination.

[0303] Standard industry procedures are used for MRT. In short, a mixed bacterial culture containing common oral species is grown, then the culture is inoculated onto samples of each test material, briefly incubated (0 to 2 hours), and then each mixture is diluted at multiple dilutions (10T). -1 Up to 10 4 The sample was spread onto sterile agar plates. The plates were incubated for 48 hours, followed by colony counting. At each time point, the logarithmic decrease in CFU (colony-forming units) relative to the inoculation pool was calculated, and the AUC was calculated based on this data. The MRI was then calculated as the ratio of the test formulation's AUC to the reference standard's AUC. Optionally, or additionally, a normalized (NAUC) value could be calculated, which is the ratio of the test formulation's AUC to the standard AUC multiplied by one hundred.

[0304] The following formulations were tested (all values ​​are in weight %; F127 is Pluronic F-127; 971P is Carbopol 971P; EG312 is ExpertGel 312; all formulations contain adequate water, approximately 85% by weight):

[0305]

[0306]

[0307] The experimental results of all studies are summarized below. NAUC and MRI are two different methods used to determine microbial stability. MIC20 is an indicator of cytotoxicity. The scratch test is used to determine healing. Lumisizer AUC is an indicator of sedimentation. G' was measured at 25°C and 37°C, and the ratio between them indicates the thermal response of the gel:

[0308]

[0309] The data show a complex interaction between the amount and type of poloxamer (linear, cross-linked), hyaluronic acid, and carbomer used, which allows for optimization of the thermosensitive aspects of the formulation (flowing liquid at room temperature, but elastic gel at oral temperature) while maximizing the potential benefits of the formulated system components (including mucosal adhesion, anti-inflammatory activity, and promoting healing).

[0310] Example 11: Development of poloxamer / polyethylene glycol hydrogel

[0311] Rheological characteristics (gelation properties) as a function of temperature were assessed on various hydrogel prototypes, demonstrating the need for unique combinations of different polymers to achieve the desired viscoelastic and thermosensitive properties (flowable, low-viscosity at 25°C, and elastic gel at 37°C). This formulation is unique among other systems because it includes both linear and cross-linked poloxamer as the carrier, resulting in enhanced gel strength; carbomer for mucosal adhesion; and high molecular weight hyaluronic acid (400 kDa to 1 MDa) for mucosal adhesion, anti-inflammatory, and healing benefits.

[0312] Thirty-three test compositions were prepared, each incorporating varying amounts of poloxamer 407, ExpertGel 312, and polyethylene glycol with average molecular weights of 6000 Da, 8000 Da, and 10000 Da. Gel morphology was observed at 25 °C and 37 °C. Viscosity, gelation time, and dissolution time in artificial saliva were evaluated.

[0313] It was found that at least 14% by weight of gelling agent is typically required to provide gel formation at 37°C. The inclusion of ExpertGel 312 and ExpertGel 412 indicates that they positively drive the yield stress of the formulation (an important property for the gel to maintain its structure at 37°C). Unexpectedly, ExpertGel 312 was found to promote the thermosensitive properties of poloxamer 407 in the mixed formulation (e.g., a viscous but flowable liquid at 25°C gelling at 37°C in the case of >19% gel). Poloxamer 407 was found to have a positive effect on the elasticity (G' / G”) of the final formulated gel.

[0314] The rheological parameters evaluated were yield stress, IVM, and elastic and viscous moduli. Yield stress (YS) characterizes the extent to which the gel retains its shape at 37°C after gelation. Instantaneous maximum viscosity (IVM) is another characteristic of this same property. Elastic modulus (G') and viscous modulus (G”) and their ratio (G' / G”) were also evaluated at 37°C.

[0315] The gelation of the test compositions was then evaluated using two different methods. An approximate determination of gelation was performed by inverting the material droplets at 45-degree and 90-degree angles after incubation at 37°C. Sample gelation was quantified by the amount of time it took for the fluid to gel and remain adhered to the slide at these locations. Samples were then classified into grades 1 to 4 (with grade 4 corresponding to the sample with the shortest gelation time). Gelation time was also determined by heating the liquid sample from 4°C to 37°C as quickly as possible on a rheometer. In practice, this heating took an average of 20 seconds, so samples that gelled before reaching 37°C were recorded as having a gelation time of 0 seconds. Three compositions (compositions 7, 24, and 23) were found to have the most favorable gelation times.

[0316] Dissolution rates were assessed using 0.7 g of gel suspended in artificial saliva at 37°C under constant oscillation. Sample observations were obtained every 30 minutes for the first seven hours, during which time samples still exhibiting visible gel were allowed to react overnight. Dissolution was defined as the complete absence of any solids or gel (complete dispersion in the saliva diluent). Samples that did not form a gel at 37°C were not tested. Dissolution times ranged from 1 hour to 20 hours. For the applications described throughout this document, longer dissolution times are preferred to provide sustained release of the active ingredient entrained in the gel. Six compositions were found to have the most favorable dissolution times (compositions 15, 28, 12, 29, 21, and 16).

[0317] The tested compositions are shown in the table below (all values ​​are in weight percent):

[0318]

[0319]

[0320] Based on the evaluation of all the above variables, the two main parameters of the test composition, gelation and dissolution, as well as the rheological parameters (IVM, G', and G” measured at 37°C), can be graded as shown in the table below. In columns two and three, gelation time (Gel.) and dissolution time (Diss.) are evaluated on a scale of 1 to 4, with higher numbers being more favorable (faster gelation and slower dissolution). In columns nine and ten, the actual gelation and dissolution times for some samples are reported.

[0321]

[0322]

[0323]

[0324] The results showed that the most preferred compositions in this set of experiments were formulations 12, 15, 16, 28, and 29. The results further support the following conclusions: (1) Favorable viscosity properties are mainly determined by the presence and amount of ExpertGel polymers (EG412 is more favorable than EG312), with less influence from Pluronic F-127; (2) Favorable gelling properties are mainly determined by the presence and amount of Pluronic F-127, with less and equal influence from EG312 or EG412; (3) Favorable solubility properties are mainly determined by the presence and amount of ExpertGel polymers (EG312 is more favorable than EG412), with less influence from Pluronic F-127.

[0325] Example 12: Hydrogel-based oral spray

[0326] An oral spray based on the aforementioned hydrogel technology is provided. While this spray shares characteristics (texture, rheology) with normal saliva, it provides continuous intraoral lubrication and salivary stimulation. The following polymer composition is formulated to transform from a liquid spray into a viscous gel with saliva-like properties at body temperature:

[0327]

[0328] The carbopol polymer constituting the formulation promotes gel adhesion to the oral mucosa. This mucosal adhesion is expected to provide sustained lubrication and a smooth sensation to oral tissues. Other active ingredients and excipients (arginine, xylitol, glycerin, zinc, etc.) can be readily added to tailor the consumer's sensory experience or desired basic benefits (e.g., breath neutralization, caries prevention).

[0329] Example 13: Low-water and non-aqueous hydrogel systems

[0330] While the hydrogel compositions according to this disclosure are primarily water and water / polyol-based liquids, there is a need to formulate the hydrogels in a manner that allows for the protection and stabilization of water-sensitive active substances. Therefore, it is of interest to provide non-aqueous, preferably solid or semi-solid, hydrogel compositions that, upon exposure to oral saliva, rehydrate to form a liquid hydrogel, which then undergoes the sol-gel transition as described above. Several methods for achieving this objective have been investigated.

[0331] freeze-dried hydrogels

[0332] To increase the stability of water-sensitive active substances, freeze-dried hydrogel compositions were prepared. The freeze-drying process removes water via sublimation, stabilizing the active substance in the polymer matrix to produce a precursor or concentrate. Reconstitution in room temperature or cold water (<15°C) dissolves the concentrate, producing a diluted solution of the active substance. Hydration with a minimal amount of warm water, saliva, or artificial saliva (e.g., at 37°C) produces a gel for topical application. The freeze-dried concentrate can be directly placed in the oral cavity without requiring an exogenous water source. Liquid hydrogel compositions were prepared according to the following formulation (amounts shown are by weight percentage):

[0333]

[0334] Freeze-drying removes all water except trace amounts, resulting in a product with a consistency similar to chewing gum, and approximately spherical or elliptical in shape.

[0335] Low-water toothpaste tablets

[0336] The table below details compositions for thermogel toothpaste tablets with rapid melting capabilities. These compositions differ from other tablet compositions in that poloxamer 407 is the main ingredient, unlike other inorganic substances and fillers such as calcium carbonate salts. Thin tablets are produced by freeze-drying an initial gel formulation to create a porous tablet structure. This composition and manufacturing process allows the delivery system to rapidly dissolve and gel in aqueous media (water, saliva, mouthwash) at body temperature. Furthermore, water-sensitive or oil-based active ingredients can be encapsulated in the dry polymer matrix of the thin tablets to enhance their stability. These include, but are not limited to, hydrogen peroxide, natural extracts, flavoring agents and oils, as well as easily oxidized metals. Solid tablet hydrogel compositions are prepared according to the following formulations (amounts shown are by weight percentage):

[0337]

[0338]

[0339] In testing, these single-dose toothpaste tablets were found to rehydrate in the presence of a few drops of water to form a gel suitable for application to teeth as standard toothpaste. Dissolution typically occurred within approximately 6 seconds with gentle stirring. As shown, these formulations can be successfully prepared using common toothpaste ingredients including sodium fluoride, silica abrasives, and arginine.

[0340] Anhydrous hydrogel paste

[0341] To enhance the stability of water-sensitive active substances, an anhydrous hydrogel precursor was produced. The precursor composition can consist of poloxamer 407 suspended in a non-aqueous, water-miscible solvent such as glycerol. Poloxamer can be prepared as a 25% solution in ethanol, blended with glycerol and sorbitol, and modulated at 37°C to remove the ethanol. Upon immersion in warm artificial saliva, the opaque paste transforms into a transparent hydrogel. When water is exchanged with glycerol and poloxamer 407 and sorbitol are dissolved, the hydration of the polymer system outpaces its dissolution, producing a substantial volume of heat-sensitive, clear gel within one minute. This system has the potential to deliver sensitive active substances such as, but not limited to, hydrogen peroxide, natural extracts / oils, and easily oxidized metals.

[0342] Several semi-solid (paste-like) hydrogel compositions were prepared for evaluation. Several combinations of polymers (including poloxamer 407, EG312, carrageenan, and sodium alginate) and polyol carriers (glycerol, sorbitol, and propylene glycol) were investigated. Pastes containing poloxamer 407 in glycerol or a glycerol / ethanol carrier were found to be the most preferred because they provided the most stable gel, while propylene glycol-based gels were also suitable but dissolved more quickly after gelation. Using ethanol as a co-carrier helped dissolve some components, and optionally, most of the ethanol could evaporate after the paste formed. Exemplary compositions of anhydrous pastes are as follows:

[0343] formula# Polosham 407 glycerin Sorbitol ethanol 13-33 1 1 0 3 13-34 1 1 0.22 3

[0344] Example 14: Hydrogel containing low-solubility active substances

[0345] Tetrahydrocurcumin is a highly poorly soluble drug. Its water solubility is approximately 6 μg / mL, which severely limits attempts to assess its in vitro or in vivo efficacy as a drug, because it is difficult to formulate compositions that can effectively deliver tetrahydrocurcumin to body tissues. Therefore, tetrahydrocurcumin is a useful reference for compositions designed to deliver poorly soluble active agents.

[0346] A series of hydrogel formulations were prepared in cold (4°C) deionized water. Each cold formulation was liquid-loaded with tetrahydrocurcumin (0.3 mg / mL gel) by dispersion using a rapid mixing apparatus (FlackTek, Inc.). The samples were allowed to interact at 4°C for 48 hours. The formulations were centrifuged at 10,000 rpm for 60 seconds to separate undissolved active material. The saturation of the active material was determined by UV absorbance at 280 nm. In the hydrogel compositions studied, the solubility of tetrahydrocurcumin increased to up to 35 times its saturation point in water.

[0347] Liquid hydrogel compositions formulated according to the following (amounts shown are by weight percentage) were prepared to evaluate the solubility of tetrahydrocurcumin:

[0348]

[0349] Tetrahydrocurcumin was found to be soluble in the above test gels at the following saturation concentrations:

[0350]

[0351]

[0352] Unexpectedly, the solubility of tetrahydrocurcumin was found to increase significantly compared to water after loading into the hydrogel formulation. The solubility of tetrahydrocurcumin in the test gels ranged from 85 μg / mL to 236 μg / mL. The poloxamer-based components F-127, EG312, and EG412 were identified as the main drivers of tetrahydrocurcumin solubility.

[0353] Example 15: Further Formulation Development

[0354] Based on the previous formulation 1-1, the following additional formulations 15-1, 15-2, and 15-3 are prepared.

[0355]

[0356] The hyaluronic acid used in these formulations has a molecular weight of approximately 250 kDa to 350 kDa. As described in Example 3 above, viscosity-related measurements were performed at 25°C and 37°C. The following results were obtained:

[0357]

[0358] The results showed that each of formulations 15-1, 15-2, and 15-3 was a fluid at room temperature (G' / G” ratio less than 1), but after mixing with mucin at room temperature or warming to body temperature, the three compositions transformed into gels (G' / G” ratio > 1). Similar results were obtained for formulations 15-4, 15-5, and 15-6 at 37°C, and similar results were expected at room temperature.

[0359] It is believed that cocamidopropyl betaine acts as a stabilizer to improve the effect of hexadecylpyridine chloride. The availability and efficacy of the antimicrobial agent (CPC) were investigated. Therefore, formulation 15-1 was compared with the same formulation without cocamidopropyl betaine (but with an additional 1.5% by weight water). Under accelerated aging conditions, it was found that for the CAPB-stabilized formulation, the CPC concentration remained at 100%, while in the absence of CAPB, the CPC recovery decreased to 97%.

[0360] Example 16: Physical stability of chlorhexidine preparations

[0361] Compositions 15-4, 15-5, 15-6, and 15-7 containing chlorhexidine were observed to be opaque white. This is believed to be due to the formation of an insoluble chlorhexidine complex within the hydrogel polymer matrix. Because the polymer matrix contains a high molecular weight anionic polymer, the precipitated chlorhexidine complex is supported within the gel matrix and does not settle under gravity. The gravitational stability of this opacity was confirmed by subjecting samples of formulations 15-4 and 15-5 to a gravity test at 2300 rcf (relative centrifugal force) for 36 hours. In summary, samples were loaded into cuvettes on a Lumisizer dispersion analyzer at 25°C. They were aged at 2300 rcf for 24 hours at 25°C, followed by another 12 hours at 10°C. Settlement was evaluated by the light transmittance through the sample as an integral of the sample length. The results are shown in the table below:

[0362]

[0363]

[0364] The results showed that both formulations tested remained opaque throughout the experiment. This supports evidence of the formulations' physical stability against excessive precipitation, which could adversely affect the delivery of the active ingredient and thus efficacy. Since CHX remained uniformly distributed, this was not a problem.

[0365] Example 17: Chemical stability of chlorhexidine preparations

[0366] Chlorhexidine is known to undergo degradation to form p-chloroaniline (PCA), and it is difficult to formulate chlorhexidine compositions to maximize chemical stability during storage or aging. Formulations of this disclosure were evaluated under accelerated aging conditions 15-4, 15-5, and 15-6 to determine whether the formulations of this disclosure stabilize chlorhexidine and prevent degradation. Samples were kept at 4°C or 40°C for 13 weeks, and samples were taken for analysis at 4 and 13 weeks. The results are shown in the table below, expressed as ppm PCA / % chlorhexidine:

[0367]

[0368] In some of the formulations studied (e.g., formulations 15-6), chlorhexidine underwent negligible degradation during storage (PCA levels remained essentially unchanged compared to the initial formulation).

Claims

1. A liquid thermosensitive hydrogel, comprising: (a) 0.1% to 20% by weight of a linear polyethylene glycol (PEG) / polypropylene glycol (PPG) triblock copolymer, wherein the linear PEG / PPG triblock copolymer is poloxamer 407; (b) 1% to 20% by weight of a linear PEG / PPG triblock copolymer and a polypropylene glycol (PPG)-SMDI copolymer, wherein the linear PEG / PPG triblock copolymer and the PPG-SMDI copolymer are ExpertGel 312. (c) 0.05% to 5% by weight of a polyacrylic acid or polyacrylate polymer, and (d) Aqueous or non-aqueous polyol carriers, The weight ratio of poloxamer 407 to ExpertGel 312 is 1:1.5 to 1:2.

5. All weight percentages are based on the total weight of the liquid thermosensitive hydrogel.

2. The hydrogel of claim 1, wherein the weight ratio of poloxamer 407 to ExpertGel 312 is approximately 1:

2.

3. The hydrogel according to claim 1, wherein the amount of the linear PEG / PPG triblock copolymer is from 1% to 10% by weight.

4. The hydrogel according to claim 1, wherein the amount of the linear PEG / PPG triblock copolymer is from 2% to 8% by weight.

5. The hydrogel according to claim 1, wherein the amount of the linear PEG / PPG triblock copolymer is from 3% to 7% by weight.

6. The hydrogel of claim 1, wherein the amount of the linear PEG / PPG triblock copolymer is from 4% to 6% by weight.

7. The hydrogel of claim 1, wherein the amount of the linear PEG / PPG triblock copolymer is about 5% by weight.

8. The hydrogel of claim 1, wherein the amount of the linear PEG / PPG triblock copolymer and the PPG-SMDI copolymer is from 5% to 15% by weight.

9. The hydrogel of claim 1, wherein the amount of the linear PEG / PPG triblock copolymer and the PPG-SMDI copolymer is 5% to 10% by weight.

10. The hydrogel of claim 1, wherein the amount of the linear PEG / PPG triblock copolymer and the PPG-SMDI copolymer is from 8% to 12% by weight.

11. The hydrogel of claim 1, wherein the amount of the linear PEG / PPG triblock copolymer and the PPG-SMDI copolymer is about 10% by weight.

12. The hydrogel according to any one of claims 1 to 11, wherein component (b) is a linear PEG / PPG triblock copolymer crosslinked with a copolymer of PPG and SMDI.

13. The hydrogel according to any one of claims 1 to 11, wherein the carrier comprises water, ethanol, glycerol, propylene glycol, sorbitol and xylitol, or mixtures thereof.

14. The hydrogel according to any one of claims 1 to 11, wherein the carrier comprises water, ethanol, glycerol, propylene glycol, or a mixture thereof.

15. The hydrogel of claim 13, wherein the carrier is water.

16. The hydrogel according to any one of claims 1 to 11 or claim 15, wherein the hydrogel further comprises one or more of the following: (e) a polyethylene glycol (PEG) polymer, (f) a high molecular weight hyaluronic acid or alkali metal hyaluronic acid polymer with a molecular weight >100,000 Da, and (g) one or more surfactants.

17. The hydrogel according to any one of claims 1 to 11 or claim 15, wherein the polyacrylic acid or polyacrylate polymer is an acrylic homopolymer.

18. The hydrogel according to claim 16, wherein the active agent is an antibacterial agent.

19. The hydrogel of claim 17, wherein the acrylic homopolymer is a carbomer homopolymer type A.

20. The hydrogel according to any one of claims 1 to 11 or claim 15, wherein the polyacrylic acid or polyacrylate polymer is a highly crosslinked polymer having a viscosity of 29,000 mPa-s to 40,000 mPa-s; or a lightly crosslinked polymer having a viscosity of 4,000 mPa-s to 11,000 mPa-s.

21. The hydrogel of claim 20, wherein the polyacrylic acid or polyacrylate polymer is carbomer 974P NF; or carbomer 971P NF.

22. The hydrogel according to any one of claims 1 to 11 or claim 15, wherein the hydrogel comprises the polyacrylic acid or polyacrylate polymer in an amount of 0.2% to 0.5% by weight.

23. The hydrogel according to any one of claims 1 to 11 or claim 15, wherein the hydrogel comprises the polyacrylic acid or polyacrylate polymer in an amount of 0.1% to 2% by weight.

24. The hydrogel of claim 23, wherein the hydrogel comprises the polyacrylic acid or polyacrylate polymer in an amount of 0.1% to 1% by weight.

25. The hydrogel of claim 23, wherein the hydrogel comprises the polyacrylic acid or polyacrylate polymer in an amount of 0.1% to 0.5% by weight.

26. The hydrogel of claim 23, wherein the hydrogel comprises the polyacrylic acid or polyacrylate polymer in an amount of about 0.3% by weight.

27. The hydrogel of claim 16, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronic acid polymer is from 200,000 Da to 1,500,000 Da.

28. The hydrogel of claim 27, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronic acid polymer is from 300,000 Da to 1,200,000 Da.

29. The hydrogel of claim 27, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronic acid polymer is from 300,000 Da to 700,000 Da.

30. The hydrogel of claim 27, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronic acid polymer is from 700,000 Da to 1,100,000 Da.

31. The hydrogel of claim 27, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronic acid polymer is 300,000 to 450,000 Da.

32. The hydrogel of claim 27, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronic acid polymer is from 350,000 Da to 600,000 Da.

33. The hydrogel of claim 27, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronic acid polymer is from 900,000 Da to 1,100,000 Da.

34. The hydrogel of claim 27, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronic acid polymer is from 250,000 Da to 700,000 Da.

35. The hydrogel of claim 27, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronic acid polymer is from 250,000 Da to 500,000 Da.

36. The hydrogel of claim 27, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronic acid polymer is from 250,000 Da to 350,000 Da.

37. The hydrogel of claim 27, wherein the average molecular weight of the hyaluronic acid or alkali metal hyaluronic acid polymer is about 290,000 Da, about 315,000 Da, about 370,000 Da, about 480,000 Da, or about 1,000,000 Da.

38. The hydrogel according to any one of claims 27 to 37, wherein the hydrogel comprises the hyaluronic acid or alkali metal hyaluronic acid polymer in an amount of 0.01% to 10% by weight.

39. The hydrogel of claim 38, wherein the hydrogel comprises the hyaluronic acid or alkali metal hyaluronic acid polymer in an amount of 0.01% to 5% by weight.

40. The hydrogel of claim 38, wherein the hydrogel comprises the hyaluronic acid or alkali metal hyaluronic acid polymer in an amount of 0.05% to 5% by weight.

41. The hydrogel of claim 38, wherein the hydrogel comprises the hyaluronic acid or alkali metal hyaluronic acid polymer in an amount of 0.1% to 2% by weight.

42. The hydrogel of claim 38, wherein the hydrogel comprises the hyaluronic acid or alkali metal hyaluronic acid polymer in an amount of 0.1% to 1% by weight.

43. The hydrogel of claim 38, wherein the hydrogel comprises the hyaluronic acid or alkali metal hyaluronic acid polymer in an amount of 0.3% to 0.5% by weight.

44. The hydrogel of claim 38, wherein the hydrogel comprises the hyaluronic acid or alkali metal hyaluronic acid polymer in an amount of about 0.4% by weight.

45. The hydrogel of claim 16, wherein the one or more surfactants comprise zinc oxide, hexadecylpyridine chloride, etc. Chlorhexidine gluconate, eugenol, or combinations thereof.

46. ​​The hydrogel of claim 1, wherein the hydrogel further comprises (f) a high molecular weight hyaluronic acid or alkali metal hyaluronic acid polymer with a molecular weight >100,000 Da, wherein the hydrogel does not contain a polyethylene glycol polymer.

47. A kit comprising the hydrogel of claim 1 and an oral application device.

48. The kit of claim 47, wherein the oral administration device is a syringe and / or a needle.

49. Use of the hydrogel of claim 1 in the preparation of products for the treatment or prevention of oral diseases, wherein the oral diseases are selected from periodontal disease, dental caries, tooth hypersensitivity, halitosis, and oral infections involving fungal or bacterial infections of the oral mucosa.

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