BR102017003561B1 - STRONTIUM-BASED COMPOSITIONS AND FORMULATIONS FOR PAIN, ITCHING AND INFLAMMATION - Google Patents

Abstract

STRONTIUM-BASED COMPOSITIONS AND FORMULATIONS FOR PAIN, ITCHING, AND INFLAMMATION Therapeutically active compositions and formulations for treating pain, itching, irritation, inflammation, and tissue damage due to irritation and inflammation, and therapeutically active compositions and formulations for wound management, including wounds that are at high risk of infection. Compositions based on strontium and beta hydroxybutyrate and formulations that can be topically applied.

Description

INCORPORATION BY REFERENCE TO RELATED ORDERS

[0001] Any and all priority claims identified in the Application Data Sheet, or any corrections thereto, are incorporated herein by reference under 37 CFR 1.57. This application is a continuation in part of US Serial No. 15/239,171, filed August 17, 2016, which claims the benefit of US Serial No. 62/208,249, filed August 21, 2015. Each of the above applications mentioned is incorporated herein by reference in its entirety, and each of them is hereby expressly made a part of this specification.

TECHNICAL FIELD

[0002] The present disclosure relates to therapeutically active compositions and formulations for treating pain, itching, irritation, inflammation and tissue damage due to irritation and inflammation. The disclosure herein also relates to therapeutically active compositions and formulations for administration to wounds, including wounds that are at high risk of infection. In one embodiment, the disclosure relates to compositions and formulations based on strontium and beta-hydroxybutyrate that can be applied topically. In another embodiment, the disclosure relates to compositions and formulations based on strontium and iodine or strontium and silver that can be applied topically.

FUNDAMENTALS

[0003] Topically applied strontium, in divalent ionic form, has the ability to rapidly suppress acute sensory irritation (e.g., burning, burning, pain and/or itching) and associated inflammation due to chemical irritants, electromagnetic radiation, allergies and diseases. Although not connected to or limited by any particular biochemical mechanism, it was theorized that strontium's anti-irritant activity was due to strontium's ability to selectively suppress the activation of Type C Nociceptors (TCN), the only sensory nerves that produce and transmit Burning, pain, itching sensation and the neurogenic inflammatory response that can accompany TCN activation.

[0004] When compared to existing topical drugs capable of suppressing sensory irritation such as lidocaine or NOVOCAIN®, the local anesthetic typically used by dentists during dental procedures, strontium has a unique property - it is highly selective only for TCN and not significantly affect the many other sensory nerves that provide normal tactile sensations and "cutaneous awareness." Since lidocaine and other topical local anesthetics lack this specificity for TCN, they can cause numbness and loss of function.

SUMMARY

[0005] The following simplified summary provides a basic understanding of some aspects of the claimed subject matter. This summary is not a comprehensive overview and is not intended to identify key/critical elements or to outline the scope of the subject matter claimed. Its purpose is to present some concepts in a simplified way as a prelude to the more detailed description that is presented below.

[0006] In one embodiment, the description referred to herein refers to compositions and formulations comprising a component containing strontium and beta-hydroxybutyrate. In another embodiment, the description herein refers to compositions and formulations comprising a component containing strontium and iodine. In another embodiment, the description herein refers to compositions and formulations comprising a component containing strontium and silver. For any of the strontium-based compositions and formulations described herein, the strontium-containing component may be strontium chloride, strontium sulfate, strontium carbonate, strontium nitrate, strontium hydroxide, strontium hydrosulfide, strontium oxide, strontium acetate , strontium glutamate, strontium aspartate, strontium malonate, strontium citrate, strontium threonate, strontium lactate, strontium pyruvate, strontium ascorbate, strontium alpha-ketoglutarate or strontium succinate, strontium carbonate, strontium bicarbonate , strontium hydroxide, strontium phosphate or strontium citrate.

[0007] In another embodiment, any of the compositions and formulations described above further includes at least one polyhydroxyphenol. The polyhydroxyphenol may be gallic acid, caffeic acid, tannic acid, epicatechin, epigallocatechin gallate, epigallocatechin, epicatechin gallate, ellagic acid, myricetin, luteolin, naringen, genistein, apaginin, nordihydroguaiaretic acid, or a combination of two or more of these agents .

[0008] In another embodiment, any of the compositions and formulations described above further includes at least one cysteine-based antioxidant. The cysteine-based antioxidant can be cysteine, cystine, acetylcysteine, diacetylcysteine, their esters, or a combination of two or more of these agents.

[0009] In another embodiment, any of the compositions and formulations described above further includes at least one beneficial agent. The beneficial agent may be aluminum acetate, aspartame, colloidal oatmeal, a corticosteroid, a coal tar, an antidepressant, an antihistamine, a plant extract, a local anesthetic, a vitamin, a ceramide, a moisturizer , a polymer or a combination of two or more of these agents. When the beneficial agent is a corticosteroid, it is often selected from alclomethasone dipropionate, aminonide, betamethasone dipropionate, clobetasol propionate, desonide, deoxymethasone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasone propionate, halcinonide, halobetasol propionate, halomethasone, hydrocortisone, hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, prednisone, triamcinolone acetonide, or a combination of two or more of these agents.

[00010] When the beneficial agent is an antidepressant, then it is often selected from amitriptyline, paroxetine, doxepin, hydroxyzine, mirtazapine, or a combination of two or more of these agents. When the beneficial agent is an antihistamine, it is often selected from acrivastine, azelastine, bilastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine, chlorpromazine, cyclizine, chlorpheniramine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetindene, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, hydroxyzine, levocetirizine, loratadine, meclozine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, quetiapine, rupatadine, tripelennamine, triprolidine or a combination of two or more Of these agents. When the beneficial agent is a plant extract, it is often selected from jewelweed, black current seed oil, ginger, tea tree oil, mint, thyme, menthol, camphor, chamomile, comfrey (allotonin), lavender, aloe, (Boerhavia diffusa), calendula (Calendula officinalis), licorice, white willow bark, honey, green tea, frankincense, witch hazel, clove, Arnica montana, basil, or a combination of two or more of these agents. When the beneficial agent is a local anesthetic, it is often selected from benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine, pramoxine, proparacaine, proximethacaine or tetracaine, or a combination of two or more of these agents.

[00011] When the beneficial agent is a vitamin, it is often selected from vitamin B, vitamin B3 (niacin), vitamin C, vitamin D, vitamin E, vitamin K, tocopherol, ascorbic acid or a combination of two or more of these agents . When the beneficial agent is a moisturizer, it is often selected from lipids, fats, oils, waxes, shea butter, lanolin, humectants, glycerol, honey, hyaluronic acid, allantoin, dimethicone or ceramides, or a combination of two or more of these agents. When the beneficial agent is a polymer, it is often selected from polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), cyclodextrins, carrageenans, iota carrageenan, alginic acid, xanthan gum, guar gum, sulfated polysaccharides such as carrageenan, dextran sulfate, polysulfate. pentosan, chondroitin sulfate, heparin sulfate, or a combination of two or more of these agents.

[00012] In another embodiment, the beneficial agent is corticosteroid. In another embodiment, the beneficial agent is an antidepressant. In another embodiment, the beneficial agent is an antihistamine. In another embodiment, the beneficial agent is a plant extract. In another embodiment, the beneficial agent is a local anesthetic. In another embodiment, the beneficial agent is a vitamin. In another embodiment, the beneficial agent is a moisturizer. In one embodiment, the beneficial agent is aspartame. In another embodiment, the beneficial agent is colloidal oatmeal. In another embodiment, the beneficial agent is coal tar. In another embodiment, the beneficial agent is ceramide. In another embodiment, the beneficial agent is aluminum acetate. In another embodiment, the beneficial agent is hyaluronic acid. In another embodiment, the beneficial agent is dimethicone. In another embodiment, the beneficial agent is a polymer.

[00013] In another embodiment, the beneficial agent is a combination of at least two of the aforementioned beneficial agents. In another embodiment, the beneficial agent is a combination of at least three of the aforementioned beneficial agents. In another embodiment, the beneficial agent is a combination of at least four of the aforementioned beneficial agents.

[00014] In another embodiment, the composition or formulation comprises a component containing strontium, beta-hydroxybutyrate and acetylcysteine in a pharmaceutical carrier. In another embodiment, the composition or formulation comprises a component containing strontium, beta-hydroxybutyrate and iodine in a pharmaceutical carrier. In another embodiment, the composition or formulation comprises a component containing strontium, beta-hydroxybutyrate and silver in a pharmaceutical carrier.

[00015] In another embodiment, the compositions and formulations described above further include a skin penetration enhancer. Often, the skin penetration enhancer is a sulfoxide, a dimethyl sulfoxide, an azone, an azone derivative, a pyrrolidone, a fatty acid, an essential oil, a terpene, a terpenoid, an oxazolidinone, a urea, a of urea, an alcohol, glycol, an enzyme, a surfactant, a monoolein, an iminosulfuran or a phospholipid.

[00016] In another embodiment, the compositions and formulations described above further include an excipient such as those used to increase stability, increase the disintegration of solid tablets or increase customer appeal. Often, the excipient is a preservative, a binder, a bulking agent, a diluent, a sweetener, a fragrance, a flavoring, a lubricant or a colorant.

[00017] In another embodiment, the compositions and formulations described above are designed to be applied topically to epithelial tissue such as skin or mucous membranes. In another embodiment, the above-described compositions and formulations may be designed to have a pH of less than 5. Alternatively, the pH may be less than 4. Alternatively, the pH may be less than 3. In certain embodiments, the above-described Compositions and formulations are designed to have an osmolarity that is greater than 300 mOsm. Alternatively, the osmolarity is often greater than 350 mOsm.

[00018] In certain embodiments, the osmolarity is greater than 400 mOsm. In certain embodiments, the osmolarity is greater than 500 mOsm. In certain embodiments, the osmolarity is greater than 600 mOsm. In certain embodiments, the osmolarity is greater than 700 mOsm. In certain embodiments, the osmolarity is greater than 800 mOsm. In certain embodiments, the osmolarity is greater than 900 mOsm. In certain embodiments, the osmolarity is greater than 1000 mOsm.

[00019] In another embodiment, the composition or formulations described herein are formulated for delivery to various epithelial tissues. In some cases, the compositions and formulations are formulated as a topical that is applied to keratinized skin or mucous membranes of the eyes or genitourinary tract. Non-limiting examples include powders, drops, vapors, mists, sprays, foams, gels, emulsions, lotions, creams, ointments, pastes, liquid, semi-solid and solid powders.

[00020] In another embodiment, the compositions and formulations described above are used to treat itching, pain or acute inflammation in a subject in need thereof, by administering the compositions or formulations to the subject. In some cases, acute itching, pain, or inflammation is due to or associated with allergies, insect bites, exposure to venom, poison ivy, atopic dermatitis, psoriasis, thermal burns, ionizing radiation, chemical exposure, trauma, surgery, nerve Compression, oral or throat ulcers, bacterial infections or viral infections.

[00021] In another embodiment, the compositions and formulations described above are used to treat chronic itching, pain or inflammation in a subject in need thereof, by administering the compositions or formulations to the subject. In some cases, chronic itching, pain or inflammation is due to or associated with atopic dermatitis, psoriasis, viral infections, nerve compression, back pain, amputation or trauma.

[00022] In another embodiment, the compositions and formulations described above are used to treat itching, pain or neuropathic inflammation in a subject in need thereof, by administering the compositions or formulations to the subject. In some cases, neuropathic itching, pain, or inflammation is due to or associated with postherpetic neuralgia, back pain, nerve entrapment, viral infections, multiple sclerosis, Parkinson's disease, diabetes, trauma, amputation, or drug use.

[00023] In another embodiment, the compositions and formulations described above are used to treat the prevention or reversal of a neuropathic condition in a subject in need thereof by administering the compositions or formulations to the subject. In some cases, the neuropathic condition is due to nerve compression, nerve oversensitization, stump pain, post herpetic neuralgia, shingles, diabetic neuropathy, arthritis, bacterial infections, viral infections or drug use.

[00024] In another embodiment, the compositions and formulations described above are used to treat an epithelial wound in an individual in need by administering the compositions or formulations to the subject. In some cases, the epithelial wound is skin plaques, dermatoses, scales, ulcers, rashes, burns, acne, wounds, hives, canker sores, blisters, shingles, warts or boils. In some cases, the sore is due to psoriasis, atopic dermatitis, eczema, bacteria, viruses, delayed-type hypersensitivity or allergies.

[00025] In another embodiment, the compositions and formulations described above are used to treat the prevention or reduction of damage to epithelial tissue in a subject in need thereof by administering the compositions or formulations to the subject. In some cases, the damage presents as a blister, a wart, a rash, or a hive. In some cases, the damage is due to a virus, a burn, an allergen, an insect bite, or a critter bite.

[00026] In another embodiment, a topical formulation including, at a minimum, strontium and a vehicle is used to treat postherpetic neuralgia in a subject in need thereof. In another embodiment, a topical formulation including at least strontium and a carrier is used to treat, reduce, or prevent pain, itching, or inflammation associated with posthepatic neuralgia in an individual in need thereof. In another embodiment, the compositions and formulations described above are used to treat postherpetic neuralgia in a subject in need thereof. In another embodiment, the compositions and formulations described above are used to treat, reduce or prevent pain, itching or inflammation associated with postherpetic neuralgia in a subject in need thereof.

[00027] In another embodiment, a topical formulation including at least strontium and a vehicle is used to treat psoriasis in a subject in need thereof. In another embodiment, a topical formulation including at least strontium and a carrier is used to treat, reduce, or prevent pain, itching, or inflammation associated with psoriasis in a subject in need thereof. In another embodiment, the compositions and formulations described above are used to treat psoriasis in a subject in need thereof. In another embodiment, the compositions and formulations described above are used to treat, reduce or prevent pain, itching or inflammation associated with psoriasis in a subject in need thereof.

[00028] In another embodiment, a topical formulation including at least strontium and a vehicle is used to treat diabetic neuropathy in a subject in need thereof. In another embodiment, a topical formulation including at least strontium and a carrier is used to treat, reduce, or prevent pain, itching, or inflammation associated with diabetic neuropathy in a subject in need thereof. In another embodiment, the compositions and formulations described above are used to treat diabetic neuropathy in a subject in need thereof. In another embodiment, the compositions and formulations described above are used to treat, reduce or prevent pain, itching or inflammation associated with diabetic neuropathy in a subject in need thereof.

[00029] In another embodiment, a topical formulation including at least strontium and a vehicle is used to treat radiation dermatitis in a subject in need thereof. In another embodiment, a topical formulation including at least strontium and a carrier is used to treat, reduce, or prevent pain, itching, or inflammation associated with radiation dermatitis in a subject in need thereof. In another embodiment, the compositions and formulations described above are used to treat radiation dermatitis in a subject in need thereof. In another embodiment, the compositions and formulations described above are used to treat, reduce or prevent pain, itching or inflammation associated with radiation dermatitis in a subject in need thereof.

[00030] In another embodiment, a topical formulation including at least strontium and a vehicle is used to treat atopic dermatitis in a subject in need thereof. In another embodiment, a topical formulation including at least strontium and a carrier is used to treat, reduce or prevent pain, itching or inflammation associated with atopic dermatitis in a subject in need thereof. In another embodiment, the compositions and formulations described above are used to treat atopic dermatitis in a subject in need thereof. In another embodiment, the compositions and formulations described above are used to treat, reduce or prevent pain, itching or inflammation associated with atopic dermatitis in a subject in need thereof.

[00031] In another embodiment, a topical formulation including at least strontium and a carrier is used to treat restless legs syndrome in a subject in need thereof. In another embodiment, a topical formulation including at least strontium and a carrier is used to treat, reduce, or prevent restless legs syndrome associated with pain, itching, or irritation in an individual in need thereof. In another embodiment, the compositions and formulations described above are used to treat restless legs syndrome in a subject in need thereof. In another embodiment, the compositions and formulations described above are used to treat, reduce or prevent pain, itching or irritation associated with restless legs syndrome in a subject in need thereof.

[00032] In another embodiment, a topical formulation including at least strontium and a carrier is used to treat joint pain in a subject in need thereof. In another embodiment, a topical formulation including at least strontium and a carrier is used to treat, reduce, or prevent joint pain associated with pain, itching, or inflammation in an individual in need thereof. In another embodiment, the compositions and formulations described above are used to treat joint pain in an individual in need thereof. In another embodiment, the compositions and formulations described above are used to treat, reduce or prevent pain, itching or inflammation associated with joint pain in a subject in need thereof. In one embodiment, the joint pain is in the fingers, wrists, elbows, shoulders, neck, knee, ankle, or toes.

[00033] In another embodiment, the compositions and formulations described above are used to treat a thermal, radiation or chemical burn in a subject in need. In another embodiment, the compositions and formulations described above are used to treat, reduce or prevent pain, itching or inflammation associated with a thermal, radiation or chemical burn in a subject in need thereof. In another embodiment, the burn is a secondary burn. In another embodiment, the burn is a main burn. In another embodiment, the compositions and formulations described above are part of a dressing used to cover thermal, radicular or chemical burns in a subject in need.

[00034] In another embodiment, the compositions and formulations described above are used to treat a surgically closed wound or an amputation stump in a subject in need thereof. In another embodiment, the compositions and formulations described above are used to treat, reduce or prevent pain, itching or inflammation associated with a surgically closed wound or amputation stump in a subject in need thereof. In another embodiment, the compositions and formulations described above are part of a dressing used to cover the surgically closed wound or amputation stump in a subject in need thereof.

[00035] In accordance with the teachings presented here, the present description generally refers to compositions of strontium-containing complexes in a suitable carrier vehicle. The complexes are bipartite or tripartite in nature in that they include at least one or two different components: divalent cationic strontium and at least one counterion, such as a beta hydroxybutyrate. In the form of a tripartite composition, the complexes include divalent cationic strontium, beta-hydroxybutyrate and at least one cysteine-based antioxidant.

[00036] The cysteine-based antioxidant can be selected from the group consisting of: cysteine, cystine, N-acetylcysteine (NAC), N-acetylcysteinate, N-acetylcysteine and N, S-diacetylcysteine, or mixtures thereof.

[00037] Bipartite or tripartite complexes can also be complexed with a polymer, such as a polyanionic polymer. This polymer may be selected from the group consisting of: polyvinylpyrrolidone (PVP), cyclodextrins, carrageenans, alginic acid, xanthan gum, sulfated polysaccharides, pentosan polysulfate, chondroitin sulfate, dextran sulfate and heparin sulfate.

[00038] The osmolarity of the compositions may beneficially have a high osmotic activity, such as having an osmolarity equal to or greater than 400 mOsm, or between 400 and 2000 mOsm.

[00039] In an alternative embodiment of a tripartite composition, the at least one cysteine-based antioxidant and an aliphatic hydroxy acid (e.g., 2-hydroxybutanoic acid, which produces a beta-hydroxybutyrate moiety) are conjugated together by a cleavable bond , such as a peptide bond, an ester bond, a thioester bond, an enzymatically cleavable bond, a disulfide bond, or a pH-dependent bond.

[00040] In an alternative embodiment of a bipartite composition, divalent cationic strontium is complexed with an aliphatic hydroxyacid (e.g., 2-hydroxybutanoic acid, which produces a beta-hydroxybutyrate moiety) and the complex is placed in a suitable carrier vehicle prior to administration.

[00041] Compositions containing bipartite complexes may also include other constituents, such as any of the aforementioned strontium counterions.

[00042] In another embodiment, a composition is provided comprising a complex of: a portion of divalent cationic strontium; a cysteine-based moiety selected from the group consisting of cystine, N-acetylcysteine, N-acetylcysteinate, N-acetylcysteine, N, S-diacetylcysteine and their esters; and a beta-hydroxybutyrate moiety; wherein the cysteine-based antioxidant and an aliphatic hydroxyacid moiety (e.g., beta hydroxybutyrate) are conjugated together by a cleavable bond. The cysteine-based anti-oxidant moiety may be N-acetylcysteine or an ester thereof. The strontium portion may be a strontium salt selected from the group consisting of strontium chloride, strontium chloride hexahydrate, strontium sulfate, strontium carbonate, strontium nitrate, strontium hydroxide, strontium hydrosulfide, strontium oxide, strontium acetate, strontium glutamate, strontium aspartate, strontium malonate, strontium maleate, strontium citrate, strontium threonate, strontium lactate, strontium pyruvate, strontium ascorbate, strontium alpha-ketoglutarate and strontium succinate. The cleavable bond can be selected from the group consisting of a peptide bond, an ester bond, a thioester bond, an enzymatically cleavable bond, a disulfide bond, and a pH-dependent bond. The cleavable bond may be a thioester bond. The composition may further comprise a polymer. The polymer may be selected from the group consisting of polyvinylpyrrolidone, cyclodextrins, carrageenan, alginic acid, xanthan gum, sulfated polysaccharides, pentosan polysulfate, chondroitin sulfate, dextran sulfate and heparin sulfate. The composition may be a complex of divalent cationic strontium, N-acetylcysteine or an ester thereof and beta hydroxybutyrate, wherein the N-acetylcysteine or an ester thereof and beta hydroxybutyrate are conjugated together by a thioester bond formed by a sulfhydryl group of N Acetylcysteine or an ester thereof and a carboxyl group of the beta-hydroxybutyrate moiety.

[00043] In another embodiment, a formulation is provided comprising a complex and at least one pharmaceutically acceptable excipient, wherein the complex is a divalent cationic strontium moiety; A cysteine-based moiety selected from the group consisting of cystine, N-acetylcysteine, N-acetylcysteinate, N-acetylcysteine, N, S-diacetylcysteine and their esters; And a beta-hydroxybutyrate portion; Wherein the cysteine-based antioxidant and the beta-hydroxybutyrate moiety are conjugated together by a cleavable bond. The formulation can be configured for topical administration. The formulation can be configured for oral or systemic administration. The formulation can be configured for oral ingestion. The formulation may further comprise a polymer. The polymer can be a neutral or anionic polymer. The neutral polymer may be polyvinylpyrrolidone. Polyvinylpyrrolidone can be chemically modified by derivatization and/or cross-linking. The polymer can be configured for ionic association with the complex and facilitates the controlled release of the divalent cationic strontium. The polymer can be configured to minimize osmolarity. The formulation may further comprise at least one aromatic amino acid selected from the group consisting of histidine, tyrosine, phenylalanine and tryptophan. The at least one aromatic amino acid can be an L-isomer.

[00044] In another embodiment, a method of treating pain in a patient in need is provided, comprising topical administration to the patient of a composition comprising a complex of: a portion of divalent cationic strontium; a cysteine-based moiety selected from the group consisting of cystine, N-acetylcysteine, N-acetylcysteinate, N-acetylcysteine, N, S-diacetylcysteine and their esters; And an aliphatic hydroxy acid moiety such as beta-hydroxybutyrate or a similar moiety; wherein the cysteine-based antioxidant and the beta-hydroxybutyrate moiety are conjugated together by a cleavable bond.

[00045] In another embodiment, a method is provided for treating pruritus in a patient in need thereof, comprising topically administering to the patient a composition comprising a complex of: a portion of divalent cationic strontium; a cysteine-based moiety selected from the group consisting of cystine, N-acetylcysteine, N-acetylcysteinate, N-acetylcysteine, N, S-diacetylcysteine and their esters; And a beta-hydroxybutyrate portion; Wherein the cysteine-based antioxidant and an aliphatic hydroxyacid moiety (e.g., beta hydroxybutyrate) are conjugated together by a cleavable bond.

[00046] In another embodiment, the compositions and formulations described above are applied after the incident or after the development of the condition. In another embodiment, the compositions and formulations described above are used in a preventive manner. In another embodiment, the compositions and formulations described above are applied continuously.

[00047] For each of the treatments described above, the compositions or formulations are administered topically to the epithelial tissue. Epithelial tissue is keratinized skin or mucous membranes in the eyes, mouth, throat, esophagus, gastrointestinal tract, respiratory or genitourinary tract. In some embodiments, the compositions or formulations are administered using an applicator device. Often the device is a patch, roller, syringe, dropper, sprayer, mister or bandage.

DETAILED DESCRIPTION

[00048] The present description relates to therapeutically active compositions that combine strontium with a second compound that synergistically increases the overall therapeutic potency of the combination beyond the potency of any of the separate constituents. Specifically, the combinations described herein enhance the ability of strontium to (1) inhibit acute sensory itching, pain, redness, swelling and inflammation (collectively defined for purposes of this disclosure, "irritation"), (2) inhibit chronic irritation that may contribute to the development and maintenance of painful or pruritic neuropathic conditions, (3) inhibit neuropathic irritation that may contribute to increased nerve sensitivity or reactivity, (4) interrupt the neuropathic positive response cycle that contributes to neuropathic pain or itching, (5) promote healing in damaged epithelial tissue, and/or (6) minimize infection in a wound.

Definitions

[00049] In the following description, a number of terms are used extensively. The following non-limiting definitions provide a clear and consistent understanding of the specification and claims, including the exemplary scope to be given to such terms. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is normally understood by one skilled in the art to which this invention belongs.

[00050] The terms "invention" or "present invention", as used herein, are intended to be non-limiting and are not intended to refer to any single embodiment of the particular invention, but encompass all possible embodiments as described in the specification and in the claims.

[00051] As used herein, the term "and/or" may mean "and", may mean "or", may mean "exclusive-or", may mean "one", may mean "some, but not all". , can mean "no", and/or can mean "both".

[00052] The term "epithelial" or "epithelium" as used herein refers to the outer surfaces of the body in the broadest sense of the word, and consequently implicitly includes all keratinized tissue, as well as mucous membranes, for example, the mouth, throat, surfaces of the eye, respiratory tract, gastrointestinal tract and genitourinary tract, including the cervix and vagina.

[00053] The term "beneficial agent" as used herein refers to a chemical, compound or ingredient that helps reduce pain, itching, or inflammation and/or promotes epithelial tissue healing and/or improves fibrotic conditions. Beneficial agents may be chemicals or compounds that are either generally recognized as safe, approved by the United States Chemical and Drug Administration (or equivalent body in other countries), or recognized by those skilled in the art as being beneficial. Non-limiting examples of beneficial agents are described and listed herein, including analgesics, antihistamines, antibacterial agents, corticosteroids, moisturizers, vitamins, biologics, plant extracts, and polymers.

[00054] As used herein, "treatment" means any way in which the symptoms of a condition, disorder or disease are improved or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions described herein.

[00055] As used herein, "subject" refers to an animal, including, but not limited to, a primate (e.g., human). The terms "individual" and "patient" are used interchangeably herein.

[00056] As used herein, the term "strontium-containing component" refers to elemental strontium or a strontium salt. The terms "elementary strontium" and "strontium cation" are used interchangeably herein.

[00057] As used herein, the terms "moisturizer" and "skin protector" are used interchangeably unless otherwise indicated.

[00058] The term "complex" as used herein refers to a combination of the strontium cation and two other negatively charged or polar molecules (strontium counterions), through electrostatic forces (for example, due to the pin electrons in the phenolic ring structures), or association with a partial negative charge or other intermolecular charges. In addition to strontium and the two strontium counterions, the complex may also contain polymeric substances such as polyvinylpyrrolidones, polyacrylamides, polyanionic polymers such as alginic acid, carrageenans or carbohydrate polymers that have an inherent ability to reversibly bind to and complex with thiol-containing molecules such as aliphatic N hydroxy acids, such as beta-acetyl-L-cysteine hydroxy acid (NAC), or (e.g. beta-hydroxybutanoic acid or 3-hydroxybutanoic acid), polyhydroxyphenolic compounds such as gallic acid, a quercetin, luteolin, myricetin and other similar molecules.

[00059] The term "cysteine-based" antioxidant as used herein refers to cysteine, cysteine derivatives, small (less than four amino acids), cysteine-containing peptides and cysteine precursors.

[00060] The term "cleavable" means a covalent chemical bond that is capable of being broken. "Cleavable" which requires only a fraction of the chemical bonds are cleaved, that is, the chemical bonds are cleavable if a portion of the bonds are cleaved. In one case, the bond is cleavable in the skin after administration.

[00061] The term "conjugate" means a compound in which at least two of the components are joined together with a cleavable bond.

[00062] As used herein, abbreviations for any protecting groups, amino acids and other compounds, are, unless otherwise indicated, in accordance with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Nomenclature Biochemistry (see, Biochem. 11: 942-944 (1972)).

[00063] It is understood that in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may be, regardless of whether the R configuration or the S configuration or a mixture of the same. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture thereof. It is further understood that, in any compound described herein having one or more double bond(s) generating geometric isomers that may be defined as E or Z, each double bond may be E or Z independently, a mixture thereof.

[00064] Likewise, it is understood that, in any described compound, all tautomeric forms are also intended to be included. For example all tautomers of phosphate groups are intended to be included. Furthermore, all tautomers of heterocyclic bases known in the art are intended to be included, including purine tautomers, natural and non-natural bases, and pyrimidine bases.

[00065] Unless otherwise defined, all terms (including technical and scientific terms) are to be given their normal and customary meaning to a person of ordinary skill in the art, and are not to be limited to a special meaning or personalized, unless expressly set forth herein. It should be noted that the use of particular terminology when describing certain features or aspects of the description should not be taken to imply that the terminology being redefined herein is limited to including any specific features of the features or aspects of the description. with which this terminology is associated. Terms and phrases used in this application, and variations thereof, particularly in the appended claims, unless expressly stated otherwise, are to be construed as open-ended as opposed to limiting. As examples of the foregoing, the term "including" should be read to mean "including, without limitation, 'including but not limited to,' or the like; the term "comprising" as used herein is synonymous with "including", " containing", or "characterized by", and is inclusive of, or open to and does not exclude, additional unrecited elements or steps of the method; the term "have" shall be interpreted as "having at least"; the term "includes" should be interpreted as “includes, but is not limited to; ' the term "example" is used to provide exemplary cases of the item under discussion, and not an exhaustive list or limitation thereof; adjectives such as "known", "normal", "standard", and terms of similar meaning should not be construed as limiting the item described to a particular period of time or to a product available as of a given time, but in instead it should be read to cover known, or normal standard technologies that may be available or known now or at any time in the future; and the use of terms such as "preferred", 'preferred', 'desired', or 'desirable', and words of similar meaning should not be understood to mean that certain characteristics are fundamental, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. Likewise, a group of items related to the conjunction "and" should not be read as requiring that each and every such item be present in the grouping, but rather should be read as 'and/or' unless expressly stated otherwise. Likewise, a group of items related to the conjunction "or" does not should be read as requiring mutual exclusivity between that group, but should be read as 'and/or' unless expressly stated otherwise.

[00066] With regard to the use of substantially all of the plural and/or singular terms described herein, those skilled in the art may translate from the plural to the singular and/or from the singular to the plural, as is appropriate for the context and/or application. The various singular/plural permutations may be expressly provided for in this document for the sake of clarity. The indefinite article "one" or "an" does not exclude a plurality. A single processor or other unit may perform the functions of multiple items recited in the claims. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference marks in the claims should not be construed as limiting the scope.

[00067] When a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the scope of the embodiments.

[00068] It will be further understood by those within the art that if a specific number of an introduced claim recitation is intended, such intention will be expressly recited in the claim, and in the absence of such recitation such intention is present. For example, as an aid to understanding, the following appended claims may contain use of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles "a" or "an" limits any particular claim containing such introduced recitation claim to embodiments containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "a" (e.g., "a" and/or "a" should normally be interpreted as meaning "at least one" or "one or more"); the same goes for the use of definite articles used to introduce claim recitations. Furthermore, even if a specific number of an introduced claim recitation is expressly recited, those skilled in the art will recognize that the recitation should typically be interpreted as meaning at least the number recited (e.g., the bare recitation of "two recitations ," without other modifiers, typically means at least two recitations, or two or more recitations). Furthermore, in cases where a convention analogous to "at least one of A, B, and C, etc" is used generally as an intended construction, in the sense having one skilled in the art would understand the convention (e.g., "a system that has at least one of a, b, and c" may include, but not be limited to, systems that have a alone, b alone, c alone, a and b together, a and c together , B and C together, and/or A, B, and C together, etc.). In those cases where a convention analogous to "at least one of A, B, or C, etc." is used, in general such a construction is intended in the sense that one skilled in the art would understand the convention (e.g. , "a system that has at least one of A, B, or C" may include, but not be limited to, systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims or drawings, should be understood to contemplate the possibility of including one of the terms, any of the terms or both terms. For example, the phrase "A or B" will be understood as including the possibilities of "A" or "B" or "A and B."

[00069] All numbers expressing quantities of ingredients, reaction conditions, and so on used in the specification are to be understood as being modified in all cases by the term "about". Consequently, unless otherwise indicated, the numerical parameters set forth herein are approximations that may vary depending on the desired properties sought to be obtained.

[00070] At a minimum, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claim in any application claiming priority for the present application, each numerical parameter should be interpreted in light of the number of significant figures and approaches of common rounding.

[00071] It is understood that the compounds described herein can be isotopically labeled. Substitution with isotopes such as deuterium may provide certain therapeutic advantages resulting from greater in vivo metabolic stability, such as, for example, increased half-life or reduced dosage requirements. Each chemical element in a compound can be any isotope of said element. Thus, reference here to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[00072] It is understood that the methods and combinations described in the present invention include crystalline forms (also known as polymorphs, which include different crystalline packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates and hydrates. In some embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the crystallization process with pharmaceutically acceptable solvents such as water, ethanol or the like.

[00073] Hydrates form when the solvent is water, or alcoholates form when the solvent is an alcohol. Furthermore, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[00074] The term "salt" as used herein is a broad term, and includes, without limitation pharmaceutically acceptable salts, such as a salt of a compound that does not cause significant harm to an organism to which it is administered and that does not nullify the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, an organic acid, or a base. Suitable pharmaceutically acceptable salts include metallic salts, organic salts, salts of free acids and bases, inorganic salts and other salts that are currently in common pharmaceutical use and are listed in sources well known to those skilled in the art, such as, e.g. The Merck Index.

Pathways of Nociception and Inflammation

[00075] Nociception involves the neural processes of encoding and processing stimuli that have the potential to damage tissue. Nociceptors are specialized nerves located throughout the body that detect mechanical, thermal, or chemical changes. There are two classes of nociceptors, the first class is "A-delta" nerves, which respond to physical trauma by transmitting a sensation of pain with a sharp, stinging quality. The second class is "type C" nerves (TCN), which are chemical sensors that respond to irritants in our environment such as microbes, extreme temperatures and ionizing radiation and transmit diffuse sensations of burning, aching, stinging or itching pain. ("irritation"). When overstimulated, TCN can also release neuropeptides (e.g., substance P) that directly activate histamine-containing mast cells and attract and activate other immune system cells such as neutrophils that cause redness, swelling, and even local tissue damage. Upon activation by a stimulus, nociceptors synapse near the spinal cord into dorsal root ganglia (DRG) and release neurotransmitters that activate nerve pathways that transmit signals to the brain. The brain interprets the signals as various types of pain or itching.

A. Acute, chronic, and neuropathic pain and pruritus occur after nociceptor activation

[00076] Exposure to stimuli activates nociceptors. Depending on the stimuli, both types of nociceptors can be activated or in many cases, A-delta or TCN are preferentially activated. Since only TPNs that extend to the outermost portions of the body, such as the skin, mouth, nose, throat, eyes, etc. (herein referred to as "epithelium" or "epidermis") and can be activated by any process that virtually alters the biochemistry of local epidermis, TPNs which are preferentially activated in response to more irritating stimuli. Upon activation of the NPT in the skin, the NPT transmits a signal to the trigger cord and releases spinal neurotransmitters in the DRG that activate nerves in the spinal cord, which transmit pain and itch signals to the brain.

[00077] Acute activation of the TCNs that is caused by exposure to an irritating chemical, trauma or a sunburn generally causes painful or itchy sensations that last only a few days and is called "nociceptive pain". When the stimulus is prolonged or excessively severe, as may occur after a viral illness such as shingles or HIV, or the nerves are damaged by trauma to the nerves from physical pressure, thermal burns, diabetes, or extensive physical trauma to a limb, the sensations Painful or itchy sensations may continue for many years. Such chronic pain or itching brought on by excessive nociceptor activation or damage is termed "neuropathic" and is among one of the most difficult conditions to treat. Even the best oral or topical medications have only very limited therapeutic benefit and many have substantial side effects that limit their use.

B. Nociceptive signals are normally encoded as precisely time changes in intracellular calcium concentration that travel as "calcium waves" within nociceptors

[00078] No matter what causes the nociceptor to activate, the event is encoded in a universal code; a complex change in intracellular calcium concentration which, in turn, is transmitted along the nociceptor. Calcium thus acts as a universal "second messenger" and information transmitted by a nociceptor, including the intensity and quality of pain or itching is converted into a language consisting of rapidly changing concentrations of calcium. Since nerves in general and nociceptors in particular transmit their calcium code normally within about 1/1000 of a second, the timing and spatial distribution of calcium must be exquisitely regulated to accurately transmit the coded information. In virtually all nerves, including nociceptors, signal intensity (e.g., severity of pain or itching) is encoded as a frequency change of calcium waves that trigger neurotransmitters that are released into the synapse and activate postsynaptic nerves. that ultimately relay information to the brain. The higher the frequency, the more intense the sensation perceived. When a nociceptor is activated, the calcium signal is transmitted through multiple biochemical pathways, many of which operate in sequence such that the output of one pathway becomes the input of the next.

[00079] Activation of the nociceptor triggers the release of neurotransmitters, namely glutamic acid, substance P, and adenosine triphosphate (ATP). The frequency of nociceptor activation determines which neurotransmitter is released by the TCN. Under low frequency, only glutamic acid is released. Under high frequency, both glutamic acid and substance P are released and substance P has a synergistic effect to increase pain, itching and inflammation.

[00080] Glutamic acid is the most widely used excitatory neurotransmitter in the center and periphery of the nervous system and is an activator of pain and itching. Glutamic acid functions as a neurotransmitter in two distinct ways. The first is as a point-to-point transmitter and the second is through induced synaptic crosstalk between synapses. When synaptic crosstalk occurs, the combined amount of glutamic acid released from the neighboring synapse creates extrasiatic signaling/volume transmission. Glutamic acid is stored in vesicles near the synaptic junction. As mentioned above, activation of the nociceptor triggers the release of glutamic acid, where it acts on ionotropic and metabotropic receptors (coupled to G protein). After glutamic acid is released, several different glutamic acid transporters rapidly clear the glutamic acid from the extracellular space thus terminating synaptic transmission. The main transporters of glutamic acid are excitatory amino acid transporters (EAAT 1-5), vesicular glutamate transporters (VGLUT 1-3), and cystine-glutamate transporter (xCT). EAATs are dependent on the electrochemical gradients of ions such as sodium, potassium, or hydrogen whereas VGLUT and xCT are not. xCT is located in the plasma membrane of cells, while VGLUT is found in the membrane of glutamate-containing synaptic vesicles. VGLUTs repackages glutamic acid into vesicles using an acid (hydrogen ion) gradient. Vesicular ATPase use ATP to acidify the vesicle. The resulting pH gradient is then used to trigger a calcium hydrogen phosphate (Ca/H) antiporter, which transports glutamic acid into the vesicle.

[00081] Substance P is part of a family of neuropeptides commonly referred to as tachykinins or neurokinins. The release of substance P is a complex process involving several intracellular effectors, such as extracellular calcium influx, inositol 1,4,5-triphosphate-induced calcium release, activation of extracellular signal-regulated kinase (ERK), cyclooxygenases (COX), prostaglandins, and cyclic AMP-dependent protein kinase A (PKA). Substance P binds to neurokinin 1, 2, and 3 (NK) G protein-coupled receptors. Activation of NK receptors activated several messenger systems, including phospholipase C (PLC), cyclate cyclase, ERK1/2, p38, mitogen-activated protein (MAP) kinase, kappa factor B (NFKB), and nuclear protein kinase C (PKC). Activation of secondary messenger systems results in an increase in 1,4,5-inositol triphosphate, cyclic AMP, prostaglandin E2 and COX-2. Substance P also activated several cells of the immune system, including keratinocytes, neutrophils, B-cells, T-cells and others. Substance P also sensitized other cells to release and activate interleukin 8 (IL-8) and leukotriene B4, both of which activate neutrophils and initiate the neutrophil feedback loop as neutrophils also release leukotriene B4.

[00082] As mentioned above, substance P is only released under high-frequency nerve stimulation. The amount of substance P released is proportional to the intensity and frequency of stimulation. When released in high amounts, substance P has the ability to diffuse and bind to NK1 receptors on nearby neurons. Substance P is also secreted by inflammatory cells such as macrophages, eosinophils, lymphocytes and dendritic cells.

[00083] Following binding by substance P, the NK1 receptor undergoes clathrin-mediated endocytosis in which the bound receptor and other signaling molecules are docked into a lipid endosome. The resulting signaling endosome further activates other pathways, including mitogen-activated protein kinases (MAPK). Mitogen-activated protein kinases (MAPK) are involved in directing the cellular response to a diverse set of stimuli, such as mitogens, osmotic stress, heat shock and inflammation. The MAPK family consists of three main members: extracellular signal-regulated kinases 1 and 2 (ERK-1/2), p38-kinase, and c-Jun N-terminal kinase (JNK), each of which represents separate signaling pathways. . Accumulating evidence shows that all three MAPK pathways may contribute to pain following tissue sensitization and nerve injury through distinct molecular and cellular mechanisms. Activation of ERK-1/2, p38, and JNK leads to the synthesis of pro-inflammatory and/or pronociceptive mediators, which can result in intensified and prolonged pain.

[00084] MAPKs can be activated on any cell membrane or in the cytoplasm. Once activated, MAPKs can phosphorylate proteins in both the cytosol and nucleus. Thus, MAPKs can transmit extracellular stimuli from the plasma membrane to cellular targets distant from the membrane, such as transcription factors, initiating diverse cellular responses. In some pathways, activated MAPK is believed to undergo endocytosis to allow rapid transport to remote locations (e.g., nucleases) to facilitate propagation of cellular signals to remote locations.

[00085] ATP is a neurotransmitter in the peripheral nervous system. Similar to glutamic acid and substance P, which is also stored in vesicles. Often, ATP is also found co-stored in a single vesicle with other neurotransmitters, possibly serving as a neurotransmitter and/or an energy source upon vesicle exocytosis. Similar to glutamic acid, ATP is loaded into vesicles using a hydrogen ion gradient. Vesicular nucleotide transporter (VNUT) use the hydrogen ion gradient to move ATP into the vesicle. Also similar to glutamic acid, the hydrogen ion gradient is created using a calcium/hydrogen antiporter.

C. Nociceptive signals and the biochemical pathways that encode signals have an output that is logarithmically related to the input

[00086] The various nociceptor pathways, as well as the release of neurotransmitters in general by a nociceptor, are typically logarithmically related to the intensity of the stimulus. For example, if the irritant caused the activation of the nociceptor to increase its frequency of activation, also called depolarization, by 10 to 50 per second, the frequency of resulting neurotransmitter release may only increase by a factor of 1.7 ( log 10 = 1.0; Log 50 = 1.7). This fact is particularly relevant as it indicates that a relatively small amount of inhibition of nociceptor activation can cause a large reduction in the perceived severity of the painful or pruritic stimulus. Since there are many separate pathways in nociceptors that act in sequence to encode and transmit an irritant stimulus, inhibiting each of the sequential pathways at one or more of the steps in a pathway has the potential to produce a very large cumulative reduction in painful sensation. or itchy.

D. The development and maintenance of neuropathic pain or pruritus requires excessive and continuous nociceptor activation

[00087] In order for a neuropathic condition to develop, nociceptors must be continually activated by a potent stimulus. The duration of activation required can vary substantially depending on the specific nerve injury or stimulant. When such activation occurs, the peripheral nociceptors innervating the skin and mucous membranes may become sensitized within hours and may continue to increase their sensitivity to irritants and may even be activated by stimuli that are not normally irritating. Infections such as the HIV or herpes virus or chronic colonization by bacteria such as Staphylococcus aureus, which is present in excessive levels on the skin of patients with atopic dermatitis, patients with burns, and patients suffering from radiation or traumatic ionizing damage to a nerve are especially potent nociceptor sensitizers. Release of various inflammatory mediators that accompany any trauma or inflammation are also important contributors to sensitization.

[00088] In order to establish a neuropathic state, the sensory nerves in the DRG that receive sensory information from the TCN must also become sensitized ("central sensitization"). As for the peripheral TCN, the central neurons require sustained, high-intensity activation over a prolonged period of time that may be as short as several days or much longer. The presence of inflammation, infectious agents, or trauma can accelerate the sensitized, neuropathic state. Due to neuronal "crosstalk", it is common for an initially small painful part of sensitized tissue, for example as occurs in postherpetic neuralgia, to expand into adjacent tissue via previously uninjured nociceptors, including A-delta nociceptors. Sensitized neuropathic tissue can also generate painful stimuli in response to mechanical pressure, for example coughing or swallowing, or changes in temperature, a condition known as allodynia.

[00089] The sensitized state in both peripheral nociceptors and their central counterparts is a form of activity-dependent plasticity that is very similar to that of neurons in the CNS that form memories. In the case of neuropathic pain or itching, the nociceptive response produces a "pain or itching memory." The molecules and pathways that produce long-lasting neuronal sensitization are reasonably well defined. In particular, the activation of intracellular kinases. Of particular importance are protein kinases A and C (PKA and PKC, respectively), each of which exists in several different forms, and the mitogen-activated protein kinases (MAPK) which include p38 MAPK, ERK-1/2 and MAPK and JNK MAPK. These kinases are activated by a wide range of environmental "danger signals" and cytokine and internal growth factor exposures including ionizing radiation, reactive oxygen species (ROS) that always accompany infection and trauma. When activated, these kinases are activated in multiple pathways and give rise to sequential cascades that result in the regulation and activation of genes that regulate well over 100 different molecules that activate immune cells, produce inflammation and molecules that influence ion channels and sensors. molecular molecules that cause peripheral and central nociceptor sensitization that causes neuropathic pain and itching. Among these inflammation and immune responses of the activating gene system, the most important one is called nuclear factor, the immunoglobulin light chain Kappa, B-cell enhancer, abbreviated NF-kappa B, called the "master gene regulator of inflammation". Furthermore, some of these kinases such as PKC can directly sensitize and activate nociceptors that cause calcium influx and interfere with the ability of strontium to alter calcium dynamics that occur in neuropathic states.

[00090] There are many causes of neuropathies, some of which are very common. For example, common neuropathies include viral infection (e.g., HIV, the Herpes virus, varicella zoster (VZV) that causes chickenpox and in recent years, or secondary to immunosuppression, shingles, and for many, postherpetic neuralgia, a condition intensely painful that usually occurs in old age). Diabetes is the most common cause of typical burning pain due to glucose-induced nerve damage, severe burns, severe trauma or amputation and a number of drugs, especially some that are used to treat HIV. While there are orally available medications such as gabapentin (e.g. Neurontin®) and pregabalin (e.g. LYRICA®) that can provide significant relief from neuropathic symptoms, they all have potentially important side effects such as drowsiness, dizziness and changes in mentation in more than 25% of patients. Since many neuropathic patients are in their 70s or 80s and already have health limitations, these side effects can be particularly problematic and potentially dangerous. This often leads to reduced compliance with the required dosing schedule and thus reduced benefit to patients.

E. Stimuli that Oxidize Multiple Intracellular Glutathione Trigger Nociceptor Activation Pathways

[00091] Among the many conditions that can cause nociceptor activation, during the development of neuropathic conditions, the redox state of a nociceptor can produce some of the most potent acute and chronic nociceptor activating stimuli that exist. One of the most important regulatory signals that cause a cell to convert to a defensive state in which multiple immune activators and protective inflammatory cells are activated is the intracellular ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG). Glutathione is the most abundant intracellular thiol antioxidant, and is one of the most important generators of signals that trigger a cell to synthesize powerful inflammatory mediators and activate genes that, in turn, activate virtually all inflammatory cells in the immune system. The ratio of reduced glutathione, GSH, to the oxidized form, GSSG, is typically 9-1 or more. When cells are exposed to trauma, infection, inflammation or inflammatory mediators, ionizing radiation or general "cellular stress", the amount of reduced glutathione drops and directly triggers several gene activation cascades that ultimately lead to the synthesis of much more 100 inflammatory, pro-inflammatory mediators (e.g., TNF-alpha, IL-1, IL-6 and many others), and cytokines that attract and activate immune inflammatory cells, which activate and sensitize nociceptors that transmit pain signals and pruritic, and in turn amplify these inflammatory cascades through neurogenic inflammatory pathways. Many of the most important cellular regulators of inflammation and immune defense are highly sensitive to a reduction in a cell's GSH concentration, and are directly triggered by a low GSH/GSSG ratio indicating that a cell is in an oxidative redox state.

[00092] Perhaps the most important of these redox-sensitive regulatory pathways is NF-Kappa B. This molecule is responsible for directly or indirectly inducing the synthesis of the most important and powerful activators of inflammation, including TNF-alpha and many of the inflammatory interleukins and chemokines that attract inflammatory cells that secrete mediators that activate nociceptors directly and thus increase their long-term sensitization and conversion to a neuropathic state.

[00093] Since NF-kappa B acts as a "final common pathway" for the activation of multiple inflammatory pathways, substances that reduce or block NF-kappa B activation will have important and broad anti-inflammatory activity and will block many forms of immune system - mediated activation of inflammatory pathways. NF-kappa B is also one of many regulatory molecules that is directly activated by an intracellular oxidative environment - one in which the ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) is minimized. This oxidative environment directly activates NF-kappa B, which greatly increases the synthesis of nociceptor-activation mediators and cytokines.

[00094] Since both peripheral nociceptors with ends in the epithelium and central nociceptors in the DRG and spinal cord become sensitized after continuous activation, activation of NF-Kappa B is an important and critical stimulator of neuropathic sensitization.

F. Activation of restriction type receptors by microbes Activates Gene Transcription by NF-Kappa B which sensitizes activation of Nociceptors

[00095] Epidermal cells (e.g., keratinocytes), mucosal cells, and virtually all inflammatory immune system cells have many receptors that can cause nociceptor activation. Among the most important are restrictor-like molecules (TLRs), molecules that recognize conserved molecular structures of bacteria, fungi, and viruses. TLRs bind to molecular structures called pathogen-associated molecular patterns (PAMPs) that are present in bacteria, protozoa, fungi, and viruses. Upon activation, TLRs trigger multiple nociceptor activation and inflammatory pathways, which lead to NF-Kappa B activation.

[00096] The present invention is based on the belief that certain conditions exhibit increased levels of bacteria on the skin. For example, patients with atopic dermatitis or eczema have a 100 times higher level of Staphylococcus aureus in their skin compared to patients without atopic dermatitis. Similarly, diabetic patients also tend to experience overgrowth of skin bacteria. The high levels of skin bacteria activate TLR, which in turn activate several inflammatory pathways and nociceptors and results in the patient experiencing pain, itching and irritation.

G. Activation of Inflammation Pathways by Viruses

[00097] The present invention is also based on the belief that many viruses, including herpes simplex virus (HSV), HIV, hepatitis, Epstein slash, influenza, adenovirus and cytomegalovirus require the activation of NF-kappa B to infect host cells. Upon infection, some viruses also utilize the NF-kappa B pathway, either for its anti-apoptotic properties to evade host defense mechanisms or to trigger apoptosis as a mechanism for virus propagation. For example, HSV activates NF-kappa B, in two distinct phases; the initial phase is during viral uptake and the second phase is during de novo synthesis of viral proteins.

H. Activation of NF-Kappa B Produces chemokines that attract inflammatory cells

[00098] One of the most important consequences of NF-kappa B is to stimulate the production of chemokines, including IL-8, which attract and activate neutrophils, a blood-based white blood cell (WBC) that normally constitutes more than 50% of all white blood cells in the blood.

[00099] Neutrophils are the first to respond to any type of trauma, infection or inflammatory process and accumulate at the trigger site in massive quantities. Upon activation by IL-8 and other inflammatory mediators, neutrophils produce massive levels of powerful oxidants, reactive oxygen species (ROS, e.g. superoxide, hydrogen peroxide, nitric oxide and hypochlorous acid) that rapidly destroy GSH from cells, including nociceptors, thereby promoting oxidative activation of NF-Kappa B and the activation of many kinases, including protein kinase A, protein kinase C, and mitogen-activated protein kinases that act to amplify virtually all inflammatory pathways that directly activate nociceptors.

[000100] The activation of these multiple independent inflammatory pathways and inflammatory cells results in intense activation of nociceptors that contribute to the development of neuropathic sensitization and neuropathic pain and pruritus.

[000101] Such activation of nociceptors also causes the release of substance P, which directly triggers the activation of mast cells and release of histamine, TNF-alpha, IL-1, IL-6, IL-8 and many more inflammatory substances which activate even more nociceptors. Due to the simultaneous activation of multiple inflammatory pathways and nociceptor activation, there is a net amplification of nociceptor activation that is known to directly lead to neuropathic pain and pruritus.

Strontium affects nociception and inflammation pathways

[000102] Strontium's unique therapeutic properties are due to its chemical similarity to calcium, the most important and universal "second messenger" in nerves and all other cells that regulate virtually all cellular functions. The calcium ion always has two positive charges and its ionic radius is 0.99 angstroms, approximately the size of a hydrogen atom. Of all the elements, strontium most closely resembles calcium, as it also exists only as a positively charged divalent ion and has an ionic radius of 1.13 angstroms. For this reason, strontium normally binds to calcium binding sites and calcium mimic activity. Most often a strontium-induced response is less potent and can be as low as about 1/1000 as active as calcium, but for certain calcium-dependent activities, strontium has an activity that is about the same as calcium. or in the range of 1/10 to 1/30° as active as calcium. In other calcium-dependent activities, strontium may be more active than calcium. It is the calcium-strontium mimetic activity that allows strontium to produce its many and varied activities. Since calcium is essential for many cellular functions, if it were strongly inhibited the effects would be toxic to a cell. In contrast, since strontium can typically replace calcium, albeit with lower activity, the activity of the calcium-dependent pathway will not be turned off. Instead, lane activity will be reduced, similar to turning down the volume control on a radio. Since strontium, in a metaphorical sense, merely turns down the volume control of calcium-dependent pathways rather than turning off such pathways, the chances of significant adverse reactions or toxicity are greatly reduced compared to a drug that completely blocks the via.

A. strontium alters the dynamics and spatial distribution of calcium waves

[000103] When chemical irritants, disease, trauma or other hazards activate receptors on the surface of TPN that encode the intensity of its response as rapid changes in intracellular calcium concentration, these changes can occur in less than 1/1000 of a second and produce highly complex "waves" of calcium concentration that propagate through the nerve and trigger most, if not all, of the pathways that cause acute, chronic and neuropathic irritation. In addition to the frequency of calcium waves, changes in the dynamics of calcium concentration alter the duration, amplitude, and exact shape of the calcium waveform which alters the coexisting electrostatic field that is an essential regulator of TPN activity. These changes independently activate the release of several inflammatory mediators, including prostaglandins (e.g., PGE2), leukotrienes (e.g., LTB4, C4, D4, and E4), and reactive oxygen species (ROS), including superoxide, hydrogen peroxide, hydroxyl radicals, hypochlorous acid and peroxynitrite.

[000104] Strontium thus significantly alters the sensations of pain and itching encoded within calcium waves present in painful and pruritic neuropathic conditions, and has the effect of distorting the signal and reducing its intensity perceived by the brain. Due to strontium's binding to multiple calcium-dependent signaling pathways, strontium significantly alters calcium-encoded signals by several independent mechanisms. Some of the calcium-dependent kinases are known to be essential for the development of neuropathic conditions, since their inhibition in animal models can prevent or reverse established neuropathic conditions.

[000105] Strontium is not able to bind effectively to binding proteins within the cytoplasm of nociceptors that normally remove calcium in less than a millisecond after the calcium enters the nociceptor, thus producing a transient increase in concentration of calcium that contributes to precisely timed calcium waves. Strontium is also much less effectively pumped into and released from the primary calcium storage site of a nociceptor, the endoplasmic reticulum (ER). When a nociceptor activation signal is received, strontium inhibits the calcium pathway - induced calcium release (CICR) pathway which amplifies the calcium signal, and strontium does not have the ability to regulate inositol triphosphate (IP3)-induced release of calcium, acting to inhibit the release of additional calcium if the concentration of calcium in the cytoplasm is too high.

[000106] Once calcium enters a nociceptor during its activation and depolarization, it activates the release of a large amount of calcium that is stored in the ER via the CICR pathway. This mechanism has the effect of greatly amplifying the amount of calcium that is available to form a wave and to regulate calcium-dependent pathways. Strontium is more than a hundred times less active than calcium in its ability to induce CICR and thus significantly alters the calcium concentration changes that normally occur in response to irritants. When in the ER, strontium also binds much less avidly to the ER proteins that act as buffers and sequester free calcium until it is released by CICR or other similar calcium-binding mechanisms. As a result, strontium reaches a concentration more than 150% higher than calcium and displaces calcium from performing its amplification function during CICR. Strontium is also much less active in calcium regulation, then a second important calcium amplification mechanism triggered by IP3, a ubiquitous substance that also activates calcium release from the ER by an IP3-specific receptor. In the case of low calcium concentrations, IP3 acts as a potent stimulator of calcium release that acts to amplify the calcium influx during the much smaller depolarization. When the calcium concentration is sufficiently high, calcium acts to inhibit the release of calcium, thus maintaining the calcium concentration within a limited concentration range. When strontium is present, it can mimic calcium in its ability to activate IP3 - induced calcium release, but strontium is unable to inhibit excessive calcium release causing calcium and strontium to reach higher concentrations over a prolonged time. . Strontium's ability to substantially inhibit calcium release induced due to IP3 is particularly important, since IP3-induced calcium release is known to be responsible for the generation of calcium waves. These types of strontium effects significantly alter calcium dynamics and calcium waveforms associated with neuropathic conditions and thus contribute to strontium's suppressive effects on pain and itching.

B. Strontium Inhibits Calcium-Dependent Neurotransmitter Release

[000107] While strontium also affects additional pathways that control calcium dynamics within nociceptors, there is a strontium-induced crosstalk with calcium-dependent transmission of pain and itch-encoded calcium waves that is critically important for the suppression of acute , chronic, and neuropathic conditions. That is, the ability of strontium to bind and inactivate synaptotagmin-1, a molecule that is primarily responsible for the release of neurotransmitters in the DRG. Other members of the synaptotagmin molecular superfamily and related calcium-regulated molecules regulate the release of inflammatory neuropeptides including substance P from the peripheral portion of a TCN in the epithelium. Substance P is known to be the most important inflammatory neuropeptide released from TPN that activates virtually all immune inflammatory "leukocytes" (WBC), including cells containing histamine and more than 50 different inflammatory substances, including tumor necrosis factor-alpha. (TNF - alpha), interleukin 1 alpha and beta (IL-1 alpha and beta) and IL-6. These three pro-inflammatory cytokines are believed to be "first aid" agents that directly activate TCNs to cause pain and/or itching and are thought to contribute significantly to the development and maintenance of neuropathic conditions as well as most skin diseases. which are associated with inflammation, pain or itching.

[000108] Synaptotagmin-1 is a protein present on the surface of vesicles that contain and ultimately release neurotransmitters that bind to postsynaptic neurons in the DRG and peripheral TCN endings in the epithelium that transmit pain and coded signals. itching to the brain. Normally, the frequency of presynaptic neurotransmitter release from nociceptors is precisely matched so that the intensity, timing, and other properties of the original pain or itch signal encoded in the calcium wave are accurately transmitted to the brain. . The delay between the arrival of the calcium wave, neurotransmitter release and postsynaptic activation is generally about 1/1000 of a second and the amount released is related to the strength of the original TCN signal. This type of neurotransmission is called "synchronous release", since the moment the calcium wave arrives is well synchronized with the release of neurotransmitters that triggers the postsynaptic activation of the DRG nerve. Without this precise coupling, the frequency-encoded pain or itch signal becomes distorted.

[000109] When strontium is substituted for calcium, the amplitude of synchronous neurotransmitter release in response to TCN activation is typically reduced by more than 90%. Strontium has an additional signal distortion effect that significantly distorts the timing of neurotransmitter release called "asynchronous release." In contrast to synchronous release which is closely linked to the stimulating signal, asynchronous release can extend to several hundred milliseconds. With strontium, the total amount of neurotransmitter that is released may be the same as with calcium, however, the strength of the synchronous release that contains the encoded pain or itch intensity information is strongly reduced, and the critical timing information is essentially destroyed. This strontium mechanism not only reduces the perceived severity of a pain or itch signal, but also suppresses the release of substance P at the proximal end of the TCN in the epithelium at the original site of TCN activation. Strontium's ability to inhibit the release of TNF-alpha, IL-alpha, and IL-6 is likely due to a similar crosstalk of synaptotagmin or related calcium release mechanisms, since it is the secretion mechanism utilized by virtually all cells. . Suppression of synchronous neurotransmitter release also has an important therapeutic benefit for neuropathic pain or pruritus treatment.

[000110] Thus, in one embodiment, consequently, it is desirable to further alter the calcium dynamics of nociceptors by further suppressing calcium release or by interfering with critical calcium-dependent pathways that are partially inhibited by strontium.

C. Strontium Binds to a Calcium Sensing Receptor on Nociceptors That Suppresses Nociceptor Activation

[000111] Most, if not all, cells have a recently identified surface receptor (CaSR) that detects extracellular calcium concentration. Strontium also binds and activates the CaSR receptor as efficiently as calcium, but triggers additional activities. In view of this, a simple strontium salt has been commercially developed, strontium ranelate, which is an orally administered prescription medication for the treatment of osteoporosis in more than 100 countries. Due to strontium's unique ability to mimic the ability of calcium to activate the CaSR and, additionally, to activate additional pathways linked to the CaSR, strontium ranelate is the only known osteoporosis medication that has two independent osteoporosis therapeutic mechanisms - strontium inhibits Loss of bone mass by inhibiting bone resorption by osteoclasts and simultaneously stimulating osteoblasts, which produce new bone.

[000112] Nociceptors also have a CaSR that inhibits nociceptor activation when the extracellular calcium concentration is elevated above normal, or if a similar concentration of strontium is administered. Although it is not intended to be limited by any particular theory of operation, this mechanism is believed to contribute to the ability of strontium to inhibit rapid TCN activation by, for example, highly acidic chemical peels such as 70% glycolic acid, pH 0.6, which causes burning pain within seconds of application. When strontium is mixed with acid, burning and stinging is suppressed by 80% or more, so that any remaining sensory irritation is not bothersome.

[000113] Activation of the CaSR also causes the activation of several pathways that are known to increase both acute, chronic and neuropathic pain and itching and inflammation. Since in real-world use, strontium typically inhibits pain and itching, it is likely that the amelioration of the pain and itching effect caused by CaSR activation by strontium is, in effect, negated by other anti-irritant mechanisms of strontium. However, even a low level, “subclinical” pain and itch intensifying effect reduces the ability of strontium to effectively treat, prevent, or reverse neuropathic conditions in which any excess TCN activation is known to promote the neuropathic condition.

[000114] Of particular concern is the reported ability of strontium to bind to the CaSR and rapidly activate two of the MAPK molecules, p38 and ERK-1/2, which are known to be among the major contributors to peripheral nociceptor sensitization and central. Strontium binding to the CaSR is also reported to activate an important enzyme, phospholipase C, which produces two important regulatory molecules, the aforementioned IP3, and diacylglycerol (DAG), both of which contribute to nociceptor activation and sensitization and inflammation. IP3 is one of the most important and potent calcium releasing molecules that directly trigger the release of calcium from ER stores. Many of the pain and itch-producing chemicals that are produced during inflammation, infection, or trauma utilize the IP3 pathway to activate nociceptors and produce the calcium waves that transmit pain and itch sensations. DAG is the principle activator of protein kinase C (PKC), a family of molecules that directly activate nociceptors and many of the pathways that produce pain and itch and inflammatory mediators. PKC is also known to be an important nociceptor sensitizer, since PKC inhibition can prevent or reverse neuropathic pain in animal models. PKC also activates NF-kappa B, one of the most important stimulatory molecules that triggers pain, itching and inflammation and is thought to be capable of directly causing neuropathic sensitization. It should be emphasized that the recognition that strontium produces its therapeutic benefits for osteoporosis through binding to the CaSR is very recent and additional strontium-sensitive pathways are likely to be identified. The fact that human nociceptors have the CaSR that regulate nociceptor activation suggests that topically applied CaSR activation of strontium may be working at a reduced level due to the ability of strontium to inhibit important pain and itch pathways while simultaneously activating pathways through the CaSR which are known to cause pain and itching. Most importantly, since activation of these CASR pathways is known to contribute to the development of neuropathic conditions, strontium's therapeutic potential may be substantially compromised.

[000115] Thus, in one embodiment, it is therefore desirable to create strontium-based formulations, for example, salts or complexes, which have molecular components that specifically inhibit CaSR pathways known to improve neuropathic pain, pruritus and inflammation.

[000116] It is an object of the present invention to inhibit multiple nociceptor pathways by combining strontium with other molecules that specifically target strontium-regulated pathways and produce an overall reduction in pain or itching or other benefits to a patient, such as preventing or reversing neuropathic pain or pruritic conditions. It is another object of the present disclosure for strontium to combine with other molecules that also cause inhibition or stimulation of strontium-regulated pathways, but a different step than those that are regulated by strontium. It is important to note that some nociceptor pathways are inherently inhibitory and if inhibited, the overall result may be nociceptor stimulation. For this reason, the term "strontium-regulated pathway" will be used to denote the fact that the overall effect of strontium or the molecules that are to be combined with strontium can stimulate or inhibit a particular nociceptor pathway. It is another object of the present disclosure to combine strontium and additional molecules in a chemical manner that causes the strontium and the molecules to chemically combine as a "salt" or "complex", e.g., a high molecular weight polymer, such as such as polyanionic polymers such as alginic acid, carrageenan or other polymers that can form a matrix with strontium and additional strontium regulatory molecules. By creating complexes of strontium or salts, the osmolarity of a formulation will be reduced compared to having one strontium and two inactive counterions to balance two positive charges of strontium.

D. Strontium Inhibits NF-kappa B

[000117] As mentioned above, bacteria and viruses on the skin activate various inflammatory pathways such as TLRs. Ultimately, activating NF-kappa B. By turning off NF-kappa B TLR, strontium can prevent immune system activation

E. Strontium Block Packaging and Vesicle Endocytosis

[000118] Without wishing to be limited by any theory, it is believed that strontium affects the packaging and formation of endocytosis vesicles, blocking or reducing the activity of at least two distinct mechanisms. The first mechanism is VGLUT-2, which is used to pack glutamic acid into vesicles and the second mechanism is dynamin, which is used to squeeze out the endocytic vesicle from the membrane. Each mechanism is discussed briefly below.

[000119] As mentioned above, glutamic acid and ATP are packaged and stored in vesicles.

[000120] VGLUT and VNUT pump glutamic acid and ATP, respectively, into the vesicle, utilizing the hydrogen gradient created by a calcium/hydrogen antiporter. Strontium's ability to mimic calcium allows it to bind in place of calcium in the calcium/hydrogen antiporter. Strontium binding reduces the effectiveness of the antiporter, thereby reducing the amount of glutamic acid that can be loaded into a vesicle. As noted above, the amount of glutamic acid released correlates with the level of perceived pain/itchiness on a log basis scale. Thus, small changes in the amount released translate into large changes in the perception of pain/itching. Reducing the amount of glutamic acid packaged into vesicles translates into a decrease in the amount of glutamic acid released, which translates into a reduced perception of pain/itching.

[000121] As mentioned above, the binding of substance P to the NK 1 receptor induces endocytosis of the bound receptor together with other signaling molecules. Final vesicle formation involves dynamin, which spirals around the neck of the endocytic vesicle and squeezes until the vesicle is released from the membrane. Dynamin is a phosphoprotein and GTPase enzyme. The calcium influx that occurs following TCN activation results in the dephosphorylation of dynamin and its movement from the cytosol to the membrane. Dephosphorylation of dynamin can occur through the calcium-dependent phosphatase, calcineurin. GTPase activity generates the energy needed to drive the clamping mechanism. Strontium's ability to mimic calcium allows it to bind in place of calcium, blocking or reducing the effectiveness of a dynamin.

[000122] As mentioned above, mitogen-activated protein kinases (MAPK) are involved in directing the cellular response to a diverse set of stimuli, such as mitogens, osmotic stress, heat shock and inflammation. The MAPK family consists of three main members: extracellular signal-regulated kinases 1 and 2 (ERK-1/2), p38, and c-Jun N-terminal kinase (JNK), which represent three separate signaling pathways. Accumulating evidence shows that all three MAPK pathways may contribute to pain following tissue sensitization and nerve injury through distinct molecular and cellular mechanisms. Activation of ERK-1/2, p38, and JNK leads to the synthesis of pro-inflammatory and/or pronociceptive mediators, which can result in intensified and prolonged pain. MAPKs can be activated either at the cell membrane or in the cytosol. Once activated, MAPKs can phosphorylate proteins in both the cytosol and nucleus. Thus, MAPKs can transmit extracellular stimuli from the plasma membrane to cellular targets distant from the membrane, such as transcription factors, initiating diverse cellular responses. In some pathways, activated MAPK is believed to undergo endocytosis to allow rapid transport to remote locations (e.g., nucleases) to facilitate propagation of cellular signals to remote locations. Consequently, strontium's ability to block endocytosis may prevent MAPK from activating downstream targets.

F. Exocytosis of Substance P Strontium Blocks of Dense Core Granules

[000123] Two main neurotransmitters involved in TCN transmission are glutamic acid and substance P. Glutamic acid and substance P are packaged in vesicles and are released from presynaptic vesicles by exocytosis. As mentioned above, glutamic acid is released with low-frequency nerve activation while substance P is only released with high-frequency nerve activation.

[000124] Neurotransmitters are stored in vesicles at the end of a neuron and are held in place by calcium-sensitive vesicle membrane proteins (vampires). The influx of calcium into the neuron's terminal triggers the release of neurotransmitters from the vesicle. Once released, the vesicle travels to the presynaptic membrane. Vesicle fusion is dependent on a second wave of calcium ions, which bind to synaptotagmin. Synaptotagime works with the soluble NSF binding protein receptor (SNARE) to affect vesicle exocytosis and neurotransmitter release. Strontium reduces or blocks exocytosis of neurotransmitter vesicles by binding to the calcium receptor on synaptotagmin.

G. Limitations of Strontium on Nociception and Inflammatory Pathways

[000125] It has surprisingly been discovered that the reason that strontium is often unable to completely block pain, itching or inflammation is due to two factors: (1) the limited amount of strontium that can be topically applied, after which the hyperosmotic effects of the strontium salts begin to cause pain, itching or inflammation; and (2) the ability of strontium to stimulate pathways that may act to nullify the inherent anti-irritant activities of strontium, thereby reducing the overall therapeutic benefit.

[000126] With regard to the first element, that is, due to the fact that strontium has a relatively low activity in its ability to suppress pain, itching and inflammation compared to many other medicines with similar therapeutic objectives (e.g. , non-steroidal anti-inflammatory drugs). It is this low potency of strontium that prevents it from blocking pain when it is taken orally in the form of the prescription medication, strontium ranelate, which is approved for the treatment of osteoporosis in more than 100 countries. Regarding the second element, the degree to which strontium will negate its anti-irritant benefits depends on many factors related to the type of nerve damage that caused the neuropathic condition to develop (e.g., viral infection, physical trauma such as amputation or nerve compression, metabolic nerve damage as occurs in diabetes, coexisting inflammation and other factors.

Beta Hydroxybutyrate Affects Nociception and Inflammation Pathways

[000127] Beta hydroxybutyrate, (also known as beta-hydroxybutyric acid, beta-hydroxybutanoic acid, 3-hydroxybutyrate, 3-hydroxybutyric acid, 3-hydroxybutanoic acid, D-3-hydroxybutyrate, R(3-hydroxybutyric acid), D, R( racemic mixture of D and D), and naturally and collectively referred to as "BHB") is a beta hydroxy acid. BHB acts at different stages on the same inflammatory pathways inhibited by strontium, and thus in effect expand the basic anti-irritant and anti-pain and nociceptor-protective activities of strontium. The effects of some of the BHBs on nociception and key inflammatory pathways are discussed below.

A. G Protein Coupled to the A Receptor

[000128] G protein-coupled receptor 109A (GPR109A) is a receptor for nicotinic acid, also known as niacin or vitamin B3 (collectively referred to as "niacin"). High doses of niacin are commonly used to treat high cholesterol levels in humans. An unpleasant side effect of high doses of niacin is deflating/flushing, which is a redness of the skin due to vascular dilation, often accompanied by an itching or burning sensation. Flushing/flushing occurs due to activation of GRP109A upon binding of niacin. Activation of GPR109A increases cyclic AMP (cAMP) levels and releases arachidonic acid from cell membranes. Arachidonic acid is metabolized to produce prostaglandins (including D2 and E2), prostacyclin, and thromboxane. Activation of prostaglandin D2 and E2, EP4 and IP receptors can lead to vasodilation of blood vessels, resulting in flushing/redness of the skin.

[000129] BHB also binds to GPR109A. The present disclosure includes the unexpected discovery that BHB does not activate the flush/blush response like niacin.

B. BHB Inhibits Presynaptic Vesicle Loading

[000130] Similar to strontium, BHB also affects vesicular filling of glutamic acid (VGLUT2) and ATP (VNUT). However, BHB utilizes a different mechanism than strontium. As discussed above, vesicle loading utilizes a hydrogen gradient that is created by a calcium/hydrogen antiporter. The calcium/hydrogen antiporter has a unique regulatory system that requires the presence of chloride in order to function. BHB blocks the chloride binding site, thus reducing the effectiveness or even turning off the calcium/hydrogen antiporter.

C. Mast cell degranulation

[000131] Mast cells are part of the immune system and contain granules packed with histamine, heparin, proteoglycans, and serotonin proteases. Cell can be activated by several different mechanisms. Once activated, mast cells rapidly degranulate to release granule contents, which activate several inflammatory pathways.

Polyhydroxyphenols affect nociception and inflammation pathways

[000132] Polyhydroxyphenols are phenolic compounds that have at least two hydroxyl groups. In one embodiment, the polyhydroxyphenols also exhibit one or more carboxyl groups. Also contemplated by the present invention are polymeric phenolic compounds that have two or more aromatic rings, which normally, but not necessarily, have the same structure.

[000133] Polyhydroxyphenols act at different stages on the same inflammatory pathways inhibited by strontium, and thus, in effect, expand the anti-irritant and anti-pain activities and basic protective nociceptors of strontium. The effects of some of the polyhydroxyphenols on nociception and key inflammatory pathways are discussed below.

A. Polyhydroxyphenols Inhibit Multiple Inflammatory Pathways That Activate Nociceptors

[000134] Polyhydroxyphenols are powerful antioxidants that bind directly to NF-Kappa B components and cause direct inhibition of activation. They also directly inactivate superoxide, hydrogen peroxide, hydroxyl radicals and hypochlorous acid by displacing them, preventing the intracellular GSH concentration from being reduced, which activates other redox activated molecules and NF-Kappa molecules that directly activate nociceptors. B. Polyhydroxyphenols also inhibit the expression of several cell adhesion molecules such as ICAM-1, VCAM-1 and members of the selectin adhesion molecules that allow neutrophils and monocytes to extravasate from blood vessels and accumulate at sites of inflammation, contributing thus for the activation of the nociceptor.

[000135] Polyhydroxyphenols are also inhibitors of protein kinase C (PKC) isozymes, and in particular, PKC epsilon. (See, for example, Cancer Res 70 (6): 2415-2423 (2010); and Biochem Pharmacol. 38: 1627-1634 (1989), both incorporated herein by reference). Furthermore, as described and demonstrated by both of these articles, methods for determining the degree of PKC inhibition by compounds are known in the pharmaceutical arts. This is particularly useful since strontium can mimic the effects of calcium as a cofactor for PKC. As used herein, polyhydroxyphenol will be considered a PKC inhibitor if it suppresses 10% or more of PKC activity.

[000136] Polyhydroxyphenols are also known calmodulin inhibitors. More in particular, they inhibit phosphodiesterase activity promoted by calmodulin. See, for example, Plant and Cell Physiol. 26 (1) 201-209 (1985), which describes the inhibition of phosphodiesterase-calmodulin activity promoted by flavonoids such as catechin, epicatechin, quercetin, caffeic acid and naringenin. As used here, polyhydroxyphenol will be considered to be a calmodulin inhibitor if it suppresses 10% or more of calmodulin activity.

[000137] Polyhydroxyphenols are also known as adenosine triphosphate (ATP) analogs.

[000138] ATP is a molecule that binds to the active sites of kinases such as protein kinase C and other regulatory kinases that are part of the multi-pathway signal transduction pathways that activate NF-Kappa B and directly activate nociceptors. These kinases are also known to be necessary for the development of neuropathic nociceptor sensitization and neuropathic pain and pruritus. Polyhydroxyphenols that have hydroxyl groups adjacent to each other on the phenolic moiety at the meta positions and to mimic the three-dimensional structure of ATP and compete with ATP for the ATP binding site of protein kinase. The binding of polyhydroxyphenol to the ATP binding site prevents protein kinase from being active. Studies on the activities of various ATP analogues, such as flavonoids, are known in the literature. (See, for example, Phytochemistry Reviews 1:325-332 (2002), in which the effect of flavonols on ATP-dependent activities was studied, incorporated herein by reference)

[000139] Polyhydroxyphenols also possess an ability to inhibit the Fenton reaction whereby low concentrations of ferrous iron (Fe2++) and copper (Cu++) catalytically produce the highly toxic and inflammatory hydroxyl radical which is a powerful activator of inflammation .

[000140] Polyhydroxyphenols are additionally potent inhibitors of prostaglandins and leukotrienes, particularly PGE2 and LTB4. PGE2 is one of the most important nociceptor sensitizers that is synthesized in virtually all inflammatory conditions. LTB4 is one of the most important attractors and activators of neutrophils, which are the first cell to accumulate in large numbers at sites of trauma, irritation, inflammation and infection and are among the most important triggers of nociceptor activation.

[000141] Polyhydroxyphenols also have potent inhibitory activities on one of the most important inflammatory molecules, mast cells. Mast cells are present in the dermis and submucosal tissue throughout the body and are among the most important sources of preformed inflammatory mediators such as histamine, TNF-alpha, IL-1 and IL-6. Nociceptors are activated, either directly or indirectly, by TNF-alpha, IL-1, IL-6 and others. Nociceptor activation is also an important stimulator of substance P release from TCN that directly activates mast cells, neutrophils and any other type of inflammatory white blood cell.

[000142] Furthermore, polyhydroxyphenols also have a critical ability to inhibit various inflammatory and nociceptor activation pathways that are stimulated by strontium. In particular, the ability of strontium to activate the calcium-sensing receptor (CaSR) in cells including nociceptors is known to activate protein kinase A, protein kinase C and NF-kappa B. Activation of each of these molecules is known to contribute to nociceptor activation and development of neuropathy. Combining strontium with polyhydroxyphenols would limit this activation, thus negating the undesirable activities of strontium.

[000143] Polyhydroxyphenols also have the ability to alter intracellular calcium dynamics. Specifically, they reduce the increase in intracellular calcium in response to extracellular stimuli triggering pain and inflammation.

[000144] The combination of strontium with polyhydroxyphenols as described herein results in complexes that are more effective inhibitors of many of the same nociceptor activation pathways that are inhibited by strontium alone by having several, overlapping and distinct mechanisms. Furthermore, polyhydroxyphenols also inhibit strontium-activated pathways that contribute to pain, itching and the development of neuropathic diseases.

B. Binding of Polyhydroxyphenols to Conserved Hydrophobic Sites

[000145] Polyhydroxyphenols are known to bind to hydrophobic amino acids such as phenylalanine, tyrosine and tryptophan via pi-pi bond stacking. Hydroxy groups are also important as they can hydrogen bond with the amide and carbonyl groups of a peptide backbone in a protein and to select amino acid side chains. Among the amino acids to which gallic acid and other polyhydroxyphenols bind, proline and other aromatic amino acids are among the most important.

Cysteine-based antioxidants affect nociception and inflammation pathways

[000146] Cysteine is abbreviated by the three-letter amino acid code, Cys. Cysteine is a naturally occurring amino acid that is present in many foods and proteins. Cysteine has a thiol side chain, which is easily oxidized. Due to its high reactivity, the thiol group of cysteine has numerous biological functions. In a broad sense, cysteine possesses the following major pharmacological activities: (1) antioxidant activity, (2) direct regulation of oxidation-reduction sensitive regulatory molecules, and (3) inhibition of intracellular calcium levels that trigger pain and inflammation, each of which is discussed below.

A. cysteine, cystine and glutathione

[000147] Cystine is composed of amino acids made up of two cysteine molecules linked by a single disulfide bond. In the extracellular environment, cystine is the predominant form and is the only form transported into cells by a specific amino acid exchange molecule, the System Xc- antiporter. This protein exchanges extracellular cystine for intracellular glutamic acid using the relative concentration gradient between the two as the energy source for transport. Within cells, the cystine disulfide bond is reduced to form two cysteine molecules, each possessing a free sulfhydryl group. Free cysteine is then incorporated into the tripeptide, glutathione, Glu-Cys-Gly band. Glutathione is the most prevalent and important intracellular thiol antioxidant in all cells and acts as a "redox" reduction/oxidation switch that directly or indirectly controls the expression of hundreds of regulatory molecules, many of which are potent inducers of pain and inflammation. Free cysteine can also directly inactivate reactive oxygen species (ROS) which can inactivate regulatory proteins and, oxidize lipids and directly cause mutations in DNA that can lead to abnormal cell growth and cancer.

[000148] Cysteine is the rate-limiting amino acid that controls the synthesis of reduced glutathione (GSH). Consequently, administration of a cysteine-based anti-oxidant increases the concentration of GSH and reduces the intracellular concentration of oxidized glutathione (GSSG), thus normalizing a redox state of the nociceptor. This has the immediate effect of inhibiting the activation of NF-Kappa B and the activation of many other redox-sensitive inflammatory pathways, thus reducing nociceptor activation by both direct and indirect pathways. Cysteine based antioxidants also have unique antioxidant activity due to their ability to suppress nitric oxide (SH groups) to covalently bind and activate inflammatory kinases that are known to directly contribute to neuropathic thiol conditions. Cysteine-based antioxidants also directly inactivate other oxidants that activate inflammatory pathways and, more importantly, they inhibit nociceptor activation.

B. Cysteine-based antioxidants inhibit strontium-regulated inflammatory pathways that activate nociceptors

[000149] Due to their thiol group, cysteine-based antioxidants also have the ability to directly bind to the thiol groups of cysteine residues within molecules that are part of inflammatory pathways that contribute to nociceptor activation. Since there are many thiol-sensitive regulatory molecules, cysteine-based antioxidants have the ability to block the oxidation of critical cysteines in such molecules and thus block activation, which leads to increased inflammation and nociceptor activation. For many redox-sensitive cysteine-regulated pathways, the calcium concentration within nociceptors is increased and, as for many other nociceptor activators, the resulting calcium-concentration encoded pain, itching and activation signals contribute to the formation and maintenance of long-term neuropathic conditions.

[000150] A particularly thiol-sensitive inflammation and pain-inducing molecule present in nociceptors and inflammatory cells is transient receptor potential ankyrin, subtype 1 (TRPA1) which is highly sensitive to the oxidation of its free cysteine amino acids that cause pain, itching and inflammatory responses. TRPA1 is unique among known oxidation-sensitive ion channels in its sensitivity to a wide variety of chemical irritants found in the environment, inflammatory chemicals released in inflammatory reactions such as hydrogen peroxide and prostaglandin metabolites, and chemicals in spicy, pungent foods. It is considered to be one of the most important “chemical sensors” present in nociceptive neurons, immune cells and epithelial cells. Simple thiol antioxidants, such as those of the present disclosure, can prevent reverse cysteine oxidation in TRPA1 and can thus prevent its activation and the production of pain and inflammatory responses due to chemical irritants in the stomach contents and inflammatory reactions in the esophageal mucosa.

[000151] Cysteine-based antioxidants also have the ability to alter intracellular calcium dynamics. Specifically, they reduce oxidized regulatory proteins that regulate intracellular calcium levels. When cells are exposed to inflammatory mediators, reactive oxygen species oxidize molecules in the endoplasmic reticulum that store calcium and release it into the cytoplasm in response to an initial calcium-mediated signal. These oxidized molecules increase the sensitivity of the calcium release mechanism and increase the magnitude of the signal, thus potentially increasing pain and inflammatory responses.

C. Limitations of Cysteine-based Antioxidants in Nociception and Inflammatory Pathways

[000152] In certain situations cysteine-based antioxidants can cause more harm than good. It is believed that in situations of low pH (e.g., acidic conditions) and high osmolarity (e.g., high concentration of cysteine-based antioxidant), the presence of cysteine-based antioxidants will increase tissue damage, rather than to decrease. Each of these is discussed briefly below.

[000153] Acidic conditions can provoke pain through the activation of acid-sensitive ion channels, the most notable being acid-sensing ion channels (ASICs) and the transient receptor potential vanilloid 1 (TRPV1). ASICs are a family of voltage-insensitive cation channels that are activated in the presence of excess hydrogen ions (i.e., acidic environments). All ASICs are present in the peripheral nervous system with ASIC3 specifically expressed in nociceptors.

[000154] Activation of ASICs leads to the perception of pain. TRPV1, also known as the capsaicin receptor and the vanilde 1 receptor, can be activated by a wide variety of exogenous and endogenous physical and chemical stimuli, such as elevated temperatures, acidic conditions, capsaicin, and allyl isothiocyanate. TRPV1 is a central integrator of pain, itch and inflammation. The activation of TRPV1 directly sensitizes other molecules, such as the opening of calcium ion channels and the release of substance P, which results in a painful burning sensation.

[000155] It is believed that some reducing agents (e.g., antioxidants, cysteine-based antioxidants) can also activate ASIC. Furthermore, cysteine-based antioxidants can also activate calcium ion channels and therefore act synergistically with ASIC1a and TRPV1 to intensify the perception of pain, itching and inflammation.

[000156] It is believed that molecules with free thiol groups (-SH) can activate and open ion channels in nociceptors, resulting in the transmission of pain, itching and inflammation signals. Furthermore, this activation occurs at low millimolar to micromolar concentrations. Furthermore, the release of cysteine from the cytoplasm triggers nociceptor activation. Based on the above, compositions and formulations containing high concentrations of cysteine-based antioxidants can (1) activate nociceptors and (2) mimic high levels of extracellular cysteine that also activate nociception.

[000157] Unexpectedly, it was found that by combining cysteine-based antioxidants with strontium, even at low pH or high concentration of cysteine-based antioxidant actually reduces pain, itching and inflammation. Without wishing to be bound by any theory, it is believed that the opening of ion channels, in the presence of strontium, allows higher levels of strontium to enter the nociceptor and terminate or decrease its activity. This is due to (1) strontium having a greater affinity than calcium to flow into the ion channels and (2) the excessive amount of strontium ions present compared to the physiological levels of calcium present. Furthermore, cysteine-based antioxidants and strontium target different mechanisms to block nociception. The combination results in a synergistic feeling,

[000158] which provides a surprising level of pain, itching, inflammation and relief compared to the individual compounds.

Psoriasis

[000159] Psoriasis is an immune-mediated skin disease characterized by lesions. There are five main types of psoriasis, plaque, guttate, inverse, pustular and erythrodermic, of which plaque is the most common. The skin lesions associated with psoriasis are usually due to the abnormally rapid and excessive growth of skin cells, resulting in thick build-up and patches referred to as plaques. Skin cells are replaced every 3-5 days instead of the usual 28-30 days. Rapid skin growth is maintained through a vicious cycle of the inflammatory system causing cell growth, which in turn triggers the inflammatory system.

[000160] The psoriatic cycle is believed to begin with a triggering event such as trauma, infection, or stress that causes keratinocytes to bulge and activate dendritic cells. Dendritic cells release IL-12 and IL-23, which in turn stimulate Th1 and Th17 cells respectively. Th17 releases TNF-alpha interferon, which stimulates inflammation. Likewise, Th1 cells release IL-17, which stimulates inflammation. Th1 cells also stimulate the division of keratinocytes, leading to the formation of plaques. Activation of immune cells releases cytokines that also activate keratinocytes. The interaction between the immune system and the activation of keratinocytes becomes a self-feeding cycle.

[000161] Preliminary investigations indicate that strontium can disrupt the inflammatory/keratinocyte cycle of psoriasis, specifically by blocking TNF-alpha and IL-17. By targeting and blocking the two main pathways that activated dendritic cells use to trigger a psoriatic episode, strontium has immense potential as a therapeutic for psoriasis.

Atopic dermatitis

[000162] Atopic dermatitis, also referred to as eczema is a condition presenting as dry, itchy, inflamed skin. The condition can also manifest as raised lesions that crumble, crack, swell, and scab. The lesions present an increased risk of bacterial, fungal, or viral infections. While the cause of atopic dermatitis is unknown, it is believed that many factors contribute to the conditions, including, but not limited to, genetics, microbes and environmental.

[000163] People with atopic dermatitis are believed to have higher levels of Staphylococcus aureus on their skin. Higher levels of bacteria trigger an immune response through Toll-like receptors, in particular Toll-like receptor 4 (TLR-4). It is also believed that continuous activation of TLR-4 contributes to the chronicity of atopic dermatitis.

[000164] Other molecular pathways that activate in atopic dermatitis include matrix metalloproteinases (MMP). MMPs are a family of enzymes capable of breaking down extracellular matrix proteins, including connective tissues.

[000165] Preliminary data indicates that strontium can block the activity of TLR-4 and MMP.

Herpesviridae, herpes zoster and postherpetic neuralgia

[000166] Herpesviridae is a large family of viruses that cause disease in people and animals. The family includes herpes simplex viruses 1 and 2 (HSV1, HSV2), varicella zoster, Epstein-Barr virus, cytomegalovirus, Roseolovirus, and Kaposi's sarcoma-associated herpes virus. After resolution of the initial infection, many of the herpes viruses remain latent in the nerve cell bodies. The virus can reactivate days, months, years or even decades later. Upon activation, the virus travels along nerve axons to cause viral skin infection (e.g., vesicular rash) in the nerve region.

[000167] Herpes simplex causes several distinct medical disorders based on the site of infection. Common sites of infection include the face/mouth (orofacial herpes), anogenital (genital herpes), hands (herpetic whitlow), eyes (herpes keratitis), and the central nervous system (herpes encephalitis). HSV1 and 2 usually present as painful and/or itchy small red bumps that develop into fluid-filled blisters. The blisters rupture, leaving behind an ulcer that crusts over and eventually heals. Treatments range from painkillers to antivirals to dietary supplements.

[000168] Varicella zoster virus (VZV) initially presents as chickenpox in children. Once the initial infection has resolved, the virus can remain dormant for decades. Activation of the virus results in a condition commonly referred to as shingles or shingles. Shingles initially presents with flu-like symptoms such as headache, fever and malaise followed by burning pain and itching sensations. A rash usually develops one to two days after the first symptoms but can be as long as three weeks later. The rash presents as red, fluid-filled blisters that break open and fold over. The rash usually appears on one side of the body in a belt-like pattern. The rash usually heals within two to four weeks. In older adults, the rash may be more severe and last longer.

[000169] Postherpetic neuralgia (PHN) is a condition in which the patient experiences continuous pain for months or years after the rash has resolved. PHN occurs in about 2-20% of patients with shingles. The pain usually occurs in the same area affected by shingles, may be constant or intermittent, and may mimic the broad spectrum of pain sensations associated with shingles. PHN can result in increased skin sensitivity, a condition referred to as alidynia. The true cause of PHN is unknown; however, it is believed to be due to inflammation or damage to the affected nerve. Post-herpetic neuralgia is extremely difficult to treat and treatments range from analgesics and antivirals to antidepressants and anticonvulsants.

[000170] Preliminary investigations indicate that strontium can reduce and or eliminate the formation of pain, itching, and rash/blister associated with HSV1. Without wishing to be bound by any theory, it is believed that strontium's ability to block NF-kappa B contributes to minimizing symptoms associated with an active infection. As mentioned above, HSV 1 and 2 require NF-Kappa B activation for de novo virus synthesis. By blocking NF-kappa B, strontium essentially stops the infection at an early stage.

[000171] Preliminary investigations indicate that strontium may reduce or block pain associated with PHN.

Wound care

[000172] The skin provides a protective barrier against microbial infection. Damage to the skin presents opportunities for microbial infection. Consequently, controlling infection is an important aspect of wound care. In most cases, for example small cuts, infection is a secondary consideration. However, when damage occurs to large areas of skin (e.g. burns) or with prolonged open wounds (e.g. ulcers) infection control becomes crucial. Controlling infection usually occurs through the use of antimicrobial agents, such as antibiotics and antifungals. However, prolonged use of antibiotics can lead to bacterial resistance. To date, only two antibiotics, iodine and silver, have never shown bacterial resistance. That being said, neither iodine nor silver can be used to treat a systemic infection.

A. Burns

[000173] Burns can be caused by heat, electricity, chemicals, friction or radiotherapy. Burns are classified based on the depth of damage to the skin and underlying tissue. First degree or superficial burns only affect the outer layer of skin i.e. epidermis. Second degree or partial thickness burns- penetrate the underlying layers of the skin, i.e. upper layers of the dermis. Third degree or full thickness burns extend through all layers of the skin. Fourth degree burns involve deeper tissue, such as muscle or bone. Chemical burns can be caused by any of the corrosive substances, such as acids, bases, oxidants, solvents, reducing or alkylating agents. Chemical burns are uncommon in that the damage may not be immediately noticeable (e.g. under the skin). One notable source of chemical burns is from chemicals that are used as weapons. Non-limiting examples include choking irritants, vesicants/blistering agents, blood agents, nerve agents, vomiting agents, riot control agents, incapacitating agents, toxins, and allergens.

[000174] Treatment of burns depends on the severity. Small burns, i.e. first-degree and second-degree burns that are less than 2-3 inches in diameter, can usually be self-treated by keeping the area clean and taking over-the-counter pain medications. Severe burns, meaning second-degree burns greater than 3 inches in diameter and all third- and fourth-degree burns, require medical treatment. Treatment of severe burns often involves the use of dressings to (1) absorb exudate, (2) maintain high humidity at the wound site to encourage healing, and (3) reduce the risk of infection. A variety of different dressings are available, non-limiting examples include hydrocolloids, polyurethane film, hydrogel, silicone-coated nylon, biosynthetic skin substitute, antimicrobial (e.g., silver and iodine), fiber, and dressing pads. Some of the dressings available use polymers to absorb exudate and create a gel-like barrier to help keep the wound moist. Others contain antimicrobial agents such as silver or iodine.

[000175] The strontium-based compositions and formulations described herein could be beneficial for use in burn management. Preliminary clinical evidence indicates that topically applied strontium-based compositions and formulations can provide relief from pain and itching associated with minor burns, such as scalds or minor thermal burns. Preliminary clinical evidence also indicates that, when applied shortly after the incident, topically applied strontium-based compositions and formulations can reduce or eliminate blistering or peeling of the skin. For large burns, topically applied strontium-based compositions and formulations could also be used to help control pain, itching, and inflammation associated with severe burns. For example, strontium-based compositions and formulations can be applied to the burn area prior to dressing application. Alternatively, strontium-based compositions and formulations can be integrated into or part of the wound dressing. Furthermore, the use of strontium-based compositions and formulations described herein may reduce or prevent the development of neuropathic pain or itching due to burns. Lastly, the strontium-based compositions and formulations described herein could prevent or reduce scar formation.

B. Surgery and Trauma

[000176] Prevention of infection is also critical during and after surgery and after traumatic incidents that result in skin breakdown. When it comes to surgery, medical personnel typically use iodine solutions to clean their hands and the surgical site. Post-surgery, the incision is usually coated with antibacterial and kept covered with a bandage. The strontium-based compositions and formulations disclosed herein may be useful in the treatment of post-surgical wounds and amputation stumps. Furthermore, the strontium-based compositions and formulations disclosed herein may be useful in treating pain, itching, or irritation associated with post-surgical wounds and amputation stumps. Lastly, the strontium-based compositions and formulations described herein could prevent or reduce scar formation.

C. Compositions and Formulations based on Strontium

[000177] In one embodiment, strontium-based compositions and formulations for use in treating wounds further include iodine or silver to provide additional antimicrobial support.

[000178] A non-limiting example uses strontium iodide salts. Strontium iodide provides another unexpected benefit in that the color is much lighter than standard iodine. One of the disadvantages of iodine is that the color looks like dried blood. Thus, having a lighter strontium iodine composition/formulation would help medical professionals assess the status of the wound. In another embodiment, the strontium iodine or silver strontium compositions and formulations may further include BHB. As noted above, BHB acts on the same or different inflammatory pathways and nociception in strontium. Consequently, its inclusion can synergistically enhance the effects of strontium iodine or strontium silver salts. In another embodiment, the BHB is in polymer form. The breakdown of BHB polymer results into individual BHB molecules. Consequently, the BHB polymer can provide sustained release of BHB. In another embodiment, the strontium-based compositions and formulations disclosed herein can be integrated into or part of the wound dressing.

[000179] In one embodiment, two separate formulations are used in combination. The first formulation is strontium iodine or strontium silver. The second formulation is strontium and at least one beneficial agent (discussed below) such as polyhydroxyphenol, cysteine based antioxidant, or BHB. The first formulation is used when the risk of infection is high, for example early phase of burn management. The second formulation is used when the risk of infection is not as high, for example, after a layer of epithelial tissue is covering most of the wound. The dual/tandem formulation would allow the use of oxidizing agents (e.g. iodine) and antioxidants/reducing agents (e.g. cysteine and base antioxidant polyhydroxyphenol) during the key phase of wound healing.

D. Application and Treatment

[000180] Burns, surgical incisions, and amputations tend to cause nerve damage and therefore result in neuropathic pain. One way to minimize the potential development of neuropathic pain is the immediate and/or continuous application of strontium-based compositions and formulations described herein. This can be achieved through routine application of extended release formulas or the use of a device that continuously releases strontium-based compositions and formulations. In one embodiment, treatment is continuous for the first few days or weeks. As the wound heals, treatment may be more intermittent based on the patient's pain, itching, or level of irritation. Ultimately, the patient's perception of pain, itching, or irritation determines the frequency of application.

restless leg syndrome

[000181] Restless legs syndrome (RLS), also known as Willis-Ekbom disease or Wittmaack-Ekbom syndrome, is a neurological disorder that causes uncomfortable "itchy", "pins and needles", or "crawling" sensations in the legs and arms (sometime or other parts of the body). Moving the affected body part may provide temporary relief. Causes of RLS include genetic predisposition, iron imbalance (too low or too high), and certain medications.

[000182] Unexpectedly, it was found that topically applied strontium-based compositions can reduce or eliminate symptoms associated with restless legs syndrome.

Joint pain

[000183] Common pain has many causes, including but not limited to arthritis, injuries and repetitive movements. When it comes to arthritis, there are over 100 different causes of arthritis, which are divided into two main categories. The first category is arthritis caused by wear and tear of the cartilage and the second category is arthritis associated with inflammation, usually associated with an overactive immune system. The most common causes of arthritis are osteoarthritis, rheumatoid arthritis and psoriatic arthritis. As for damage, the injury can be a sprain, strain, or sprain that leads to damage and/or inflammation of the tendons, ligaments, or cartilage. In relation to repetitive strain injuries, the term is used to cover a range of conditions associated with repetitive tasks, vigorous exertion, vibrations, mechanical compression, or awkward holding/positions. Non-limiting examples of repetitive strain injuries include carpal tunnel syndrome, cubital tunnel syndrome, golfers elbow, tennis elbow, De Quervain syndrome, thoracic outlet syndrome, crossover syndrome, stenosing tenosynovitis, radial tunnel syndrome, and focal dystonia.

[000184] The present invention includes the unexpected discovery that the strontium-based compounds described herein can provide relief from joint pain when applied topically.

[000185] Early theories in managing joint pain and inflammation believed that the analgesic/anti-inflammatory needed to be at the source of the pain/inflammation, for example deep within the joint. Without wishing to be bound by any theory, it is believed that disruption of nerve signaling at nerve endings also disrupts nerve signals deeper into the tissue based on the following concepts. First, a single physiological nerve reaches from the spinal cord to just below the surface of the skin. Second, nerve signal propagation is based on the flow of calcium along the nerve in a wave-like fashion. And thirdly, the signal strength correlates with the frequency of the calcium wave. Based on these three concepts, disturbance of the calcium wave at the end of the nerve can affect signal propagation further along the length of the nerve. Interruption in signal propagation can lead to a reduction or elimination in the perception of pain or itching.

Hyperosmotic formulations

[000186] Recent research has demonstrated that high osmolarity formulations activate specific osmotic sensors present on nociceptors, keratinocytes and immune or inflammatory cells. An example of this is the "salt in the wound" effect that causes you to suffer side effects if a concentrated solution of a simple salt is poured into a wound. In addition to causing discomfort, high osmolarity solutions can directly activate inflammatory cells and cause them to release chemicals that cause nociceptor activation.

A. Hyperosmotic Formulations Can Also Physically Damage Tissue and Cause Pain and Inflammation

[000187] Topical formulations with high osmotic activity (more than 400 mOsm, e.g. between 400 and 2000 mOsm) can also damage delicate tissues and can cause pain, especially in non-keratinized skin that has a mucous membrane or tissue that has a damaged 'barrier function', due to physical trauma, infection or inflammation. Such hyperosmotic-induced damage is popularly known as "the salt-in-the-wound effect" and occurs when osmotic forces cause water to flow out of cells and tissues in hyperosmotic formulations. It is also believed that the application of hyperosmotic formulations can directly activate certain molecules that function as sensors and osmolarity, when activated, activate pain detection nerves and immune and non-immune cells that can produce inflammation and cellular damage. This recent understanding has potential critical importance for the goal of preventing the development of chronic or neuropathic pain.

[000188] The potential importance of this observation is of critical importance for the treatment or prevention of the development of neuropathic pain since chronic nociceptor activation is known to be necessary for neuropathic painful conditions to develop. The recent discovery that there are several ion channels and related hyperosmotic molecular sensors that trigger nociceptor activation following exposure to hyperosmotic topical formulations suggests that their chronic use may predispose to the development of neuropathic pain conditions if there is severe or chronic coexisting damage. to nociceptors. In this scenario, long-term application of a hyperosmotic formulation to the skin, and especially to delicate mucous membranes, e.g., the vaginal or cervical mucosa, may cause low-level but long-term activation of nociceptors, thus contributing to their awareness. It is believed that the progression from a transient, acute pain state to a chronic, long-lasting, 'neuropathic state' is due to continued excessive nociceptor activation that results in increased expression of genes that reduce the magnitude of irritant stimuli, also called 'threshold' of nociceptor activation or irritant and thus provoke an increase in nociceptor activation and an increase in the perception of pain and/or itching. Furthermore, these genes can also increase the synthesis of inflammation-producing molecules that further irritate nociceptors, thus producing what is commonly termed 'a vicious circle' of increasing irritation and sensory inflammation.

B. Hyperosmotic Formulations May Also Increase Herpes and HIV Infection

[000189] In addition to causing painful or itchy sensations and even low-level inflammation, chronic exposure to nociceptor-activating irritants can predispose to infection by a multitude of pathogenic microbes than herpes simplex viruses 1 and 2 (HSV) and The Human Immunodeficiency Virus (HIV) poses the greatest threat to public health. While a detailed explanation of the many and varied reasons why nociceptor activation and coexisting inflammation facilitates HSV and HIV infection is not discussed in detail here, in essence, the release by Type C nociceptors of inflammatory neuropeptides such as substance P is known to damage the anatomical 'barriers' of both skin and keratinized mucous membranes that block viral infection. The resulting inflammation is also known to activate inflammatory immune cells which, ironically, contribute to the ability of both HSV and HIV to cause acute infection and in the case of HSV, the reactivation of an existing latent infection.

[000190] The application of topical hyperosmotic formulations of, for example, lubricants or microbicides, to the mucous membranes of male or female genital organs or to vaginal, cervical and anal tissues can greatly increase the possibility of transferring one of these viruses or other microbes Pathogens that cause disease from an infected person are sexually transmitted to a healthy person. It is therefore advantageous to create strontium-containing formulations with high concentrations of strontium that are intended to minimize osmotic shock.

C. Strontium Suppresses Damage Due to Hyperosmotic Formulations

[000191] Initially, the "salt in the wound" effect was considered non-specific, that is, the release of water per cell was due to the presence of a salt. Without wishing to be bound by any theory, it is believed that osmotic sensors trigger nociception and inflammation in response to changes in the extracellular environment. Osmotic receptors are G protein-coupled receptors with calcium as their endogenous ligand. Consequently, calcium acts as one of the primary regulators of osmotic stress. Intracellular calcium levels rise during hypo-osmotic and hyper-osmotic stresses. Strontium can reduce osmotic shock by binding to calcium receptors on osmotic sensors and thus preventing them from triggering nociception and inflammation pathways.

PH

[000192] Human skin is protected with a layer of sebum and sweat, often referred to as the "acid mantle." The acid mantle helps protect the skin by inhibiting the growth of bacteria and fungi and reducing exposure to environmental elements such as sunlight, pollution, or chemicals. Due to the acid mantle, the average pH of human skin is about 5.5 and can range from 4 to 7. A high skin pH tends to make the skin dry, whereas low skin pH tends to make it dry. with oily skin.

[000193] Many skin diseases arise when the pH of the skin is too high or too low. A high skin pH allows for increased bacterial growth, which can lead to infections and inflammation. Low skin pH can result in irritation and redness. Various skin conditions such as eczema and rosacea tend to be associated with skin pH that is outside the normal range, that is, either very acidic or alkaline.

[000194] Most skin products are "pH balanced" to help maintain healthy skin pH. Unexpectedly, it was found that compositions and formulations containing strontium work best at a low pH, for example lower than 4, or even lower than 3. While not wishing to be bound by any theory, it is believed that the application of a Low pH formulation of human skin activates acid-sensitive ion channels such as ASIC and TRPV1 resulting in the opening of ion channels on the nociceptor. The opening of ion channels in the presence of strontium allows higher levels of strontium to enter the nociceptor and terminate or decrease activity. This is due to (1) strontium having a greater affinity than calcium to flow into the ion channels and (2) the excessive amount of strontium ions present compared to the physiological levels of calcium present.

Compositions

[000195] The compositions and formulations of the present invention have been formulated to perform one or more of the following functions: (1) inhibit acute sensory irritation (e.g., itching and pain), redness, swelling and inflammation (collectively defined for the purposes of the present description, "irritation"), (2) inhibit chronic irritation that is characteristic of, and contributes to the development and maintenance of painful or pruritic neuropathic conditions, (3) inhibit neuropathic irritation that may contribute to increased nerve sensitivity or reactivity, (4) break the neuropathic positive feedback loop that contributes to neuropathic pain or itching, (5) prevent the development of neuropathic conditions, (6) reduce the risk of tissue infection, and/or (7) promote the healing of damaged epithelial tissue. At a minimum, the compositions and formulations of the present invention contain strontium. In some embodiments, strontium containing compositions and formulations also contain at least one of the beneficial agents described below. In some embodiments, combinations of strontium and at least one beneficial agent described herein achieve the above objectives through the interaction of multiple different molecular pathways, thereby creating a synergistic effect that greatly surpasses the actions of each component alone. In other embodiments, the strontium-based compositions and formulations of the present invention achieve the aforementioned objectives through continuous exposure to/from the application of the strontium-based compositions and formulations. In still other embodiments, the compositions and formulations are tailored to a specific disease or condition to maximize therapeutic benefit. Examples of compositions and formulations are formulated, for example, using the various components discussed below. These examples include tripartite complexes containing at least three components, one component of which is strontium, as well as bipartite complexes containing at least two components, one component of which is strontium. The components of the tripartite and bipartite complexes are discussed below.

A. strontium

[000196] Strontium is present as a divalent cation. Strontium is designated by its commonly used atomic symbol, "Sr" and is described below.

[000197] Strontium mimics the ability of calcium to pass through voltage-dependent calcium channels and once inside cells, it competes with calcium for binding to calcium-dependent receptors. Calcium is thought to play a role in the pain process by regulating the release of neurotransmitters, and thus the analgesic effect of strontium may be in preventing calcium from binding to nerve cells.

[000198] Strontium is available as an inorganic or organic salt that is soluble in water at room temperature, in the range of 1 to 100 g/l. Inorganic salts include, for example, strontium chloride, strontium sulfate, strontium carbonate, strontium nitrate, strontium hydroxide, strontium hydrogen sulfide, strontium oxide, strontium acetate, etc. Organic salts include, for example, negatively charged organic acid, such as a mono-, di-, tri- or tetra-carboxylic acid, or an amino carboxylic acid which may have a branched carbon chain of from 2 to 30 carbon atoms. carbon and one or more amino groups attached to it or linear. Amino carboxylic acid can be a natural or synthetic amino acid. Examples of organic strontium salts include, for example strontium glutamate, strontium aspartate, strontium malonate, strontium maleate, strontium citrate, strontium threonate, strontium lactate, strontium pyruvate, strontium ascorbate, strontium alpha-ketoglutarate or strontium succinate. Other examples of strontium salts, and methods for their preparation, can be found, for example, in US Patent Application Pub. No. 2010/0048697.

B. Beta hydroxybutyrate (BHB)

[000199] The aliphatic hydroxy acid beta-hydroxybutyric acid (also known as beta-hydroxybutanoic acid, 3-hydroxybutyric acid and 3-hydroxybutanoic acid, as well as the conjugate base form 3-hydroxybutyrate and beta-hydroxybutyrate, are collectively referred to herein as " BHB") is a beta hydroxy acid. It is synthesized by the liver during fasting states in humans and is often used as an indicator for diabetic ketoacidosis.

[000200] BHB can be a salt form or polymer form.

C. Polyhydroxyphenols

[000201] Polyhydroxyphenols are phenolic compounds that have at least two hydroxyl groups, preferably in the ortho and para positions. An exemplary compound is 3,4,5-tri benzoic acid, also called gallic acid. The term "polyhydroxyphenol" does not include carboxylic acids such as ranelate. Non-limiting examples of polyhydroxyphenols include: gallic acid, caffeic acid, tannic acid, epicatechin, epigallocatechin gallate, epigallocatechin, epicatechin gallate, ellagic acid, myricetin, luteolin, Naringen, genistein, apagenin, nordihydroguaiaretic acid, and their esters.

[000202] Polyhydroxyphenol can be added to the compositions described herein in essentially purified form, or they can be added in the form of plant extracts containing polyhydroxyphenol, such as green tea and soy extracts.

[000203] Flavonoids are phenolic compounds that have 15 carbon atoms; two six-carbon benzyl rings that are typically joined by three saturated, linear carbon chains.

[000204] Other flavonoids may consist of two benzyl rings joined together by a third ring structure of 5 or 6 carbons. Flavonoids constitute one of the most characteristic classes of compounds in higher plants. Many flavonoids are easily recognized as pigments in flowering plants.

[000205] Monomeric phenolic compounds, for example, gallic acid and caffeic acid, have a carboxylic acid group, which can be esterified with a sugar moiety, such as glucose. In the case of gallic acid, for example esterification produces glucogalin. Other organic esters may also be effective, such as the ethyl ester of gallic acid, ethyl gallate, or the propyl ester of gallic acid, propyl gallate.

[000206] Also contemplated by the present invention are polymeric phenolic compounds that have two or more aromatic rings, which normally, but do not necessarily have the same structure. An example is reservatrol. Another is glucose pentagallyol, which consists of five gallic acid residues that are esterified to a glucose molecule. This molecule will be cleaved in vivo by non-specific esterases, which release individual gallic acid residues. The use of such forms of polyhydroxyphenolic compounds has the additional advantage of lowering osmotic activity, since one pentagallyol glucose molecule produces one unit of osmotic activity, compared to five units of osmotic activity produced by the use of five separate acid molecules. Gallic.

[000207] Tannic acid is another example of a high molecular weight polymer of gallic acid in which one or more more esterified gallic acid residues are esterified to a central glucose molecule.

[000208] Ellagic acid is an example of a dimer gallic acid. Although this molecule does not possess the phenolic structure like gallic acid, it maintains many of the same bioactivities of gallic acid and is therefore useful in the practice of the present disclosure.

[000209] Compounds that have a flavone skeleton include, for example, quercetin and epicatechin (EC) and their derivatives, such as epigallocatechin gallate (EGCG found in green tea), epigallocatechin (EGC) and epicatechin gallate (ECG).

[000210] Other polyhydroxyphenolic compounds include, for example, myricetin, luteolin, Naringen, genistein and nordihydroguaiaretic acid (NDGA).

[000211] In a particular embodiment, useful polyhydroxyphenols also exhibit one or more carboxyl groups, such as gallic acid. The carboxyl group can serve as an additional counterion, and also aids in matrix formation with an optional polyanionic polymer.

[000212] Also contemplated is a composition that incorporates a combination of strontium with a mixture of polyhydroxyphenols, for example one or more, or two or more, of the polyhydroxyphenols known or discussed herein above. The use of more than one polyhydroxyphenol has a synergistic effect due to the differential activities of each polyhydroxyphenol. This synergistic effect is considered to have improved efficacy in the treatment of sensory irritation which includes, but is not limited to, pain, itching, and the development of neuropathic diseases. In one embodiment, the mixture includes monophenolic and polyphenolic polyhydroxyphenols. In one embodiment, the mixture includes monophenolic and biphenolic polyhydroxyphenols. In another embodiment, the mixture includes monophenolic and triphenolic polyhydroxyphenols. In another embodiment, the mixture includes biphenolic and triphenolic polyhydroxyphenols. In another embodiment, the mixture includes monophenolic, biphenolic and triphenolic polyhydroxyphenols. In another embodiment, the mixture includes an ATP analogue with monophenolic, biphenolic or triphenolic polyhydroxyphenols. In yet another embodiment, the mixture of polyhydroxyphenols is gallic acid and caffeic acid. In another embodiment, the mixture of polyhydroxyphenols is caffeic acid and myricetin. In another embodiment, the mixture of polyhydroxyphenols is gallic acid and myricetin. In another embodiment, the mixture of polyhydroxyphenols is myricetin, gallic acid, and caffeic acid.

D. Cysteine-Based Antioxidant

[000213] The term "cysteine-based" includes cysteine and cystine. Alternatively, the cysteine-based compound is acetylated at the amino group of cysteine to produce N-acetyl-cysteine, commonly abbreviated acetylcysteine or NAC. Examples of non-limiting cysteine-based antioxidants include: cysteine, cystine, acetylcysteine, diacetylcysteine, and their esters.

[000214] Cysteine exists in two enantiomeric forms, designated "L-cysteine" and "D-cysteine”, of which the L form is used in living organisms, while the D form is not. Although both the L and D forms are contemplated in the present description, the L form of acetylcysteine is most preferred, i.e., NAC. If the D form of NAC is intended, it will be referred to as D-NAC. Furthermore, both L-Cys and D-Cys can form disulfide bonds between the two thiol groups to form a "dimer," literally a pair of Cys molecules. Such disulfide bonds occur in many proteins and play a critical regulatory role in biochemical pathways due to the ease of their reversible formation by oxidative processes and dissolution by reductive processes. By convention, a dimer linked by cysteine disulfide is called cystine. Thus, one molecule of cysteine, under appropriate reducing conditions, or enzymatic processing will produce two molecules of cysteine. Cystine can be formed from of any of two L-Cys molecules, two D-Cys molecules, or one L-Cys and one D-Cys. Another exemplary cysteine-based compound is N,S-diacetylcysteine. All of these variants are incorporated within the present disclosure.

E. silver and/or iodine

[000215] Silver and iodine are known antimicrobial agents for which antibiotic resistance has never developed. Non-limiting silver compounds include silver salts (e.g., silver nitrate, silver sulfadiazine), silver zeolite, and silver nanoparticles, colloidal silver.

F. Cleavable Bonds

[000216] In one embodiment, the complexes of the present invention use a cleavable bond to join the beta hydroxybutyrate and the cysteine-based compound together into tripartite complexes. Complexes that utilize a cleavable bond to join the beta hydroxybutyrate and cysteine-based compounds together into tripartite complexes will be referred to as the "conjugate" form of the compounds.

[000217] As defined above, a breakable bond is a chemical bond joining two molecules together, which can subsequently be broken, thus releasing the two molecules from each other. The present disclosure contemplates the use of cleavable bonds that are known in the art, examples of which include, but are not limited to, peptide bonds, thioester bonds, enzymatically cleavable bonds, disulfide bonds, pH-dependent bonds, and other covalent bonds.

[000218] The use of cleavable bonds in the present disclosure can create a less active form of the compound that can be converted to an active form. The benefits of using a less active form are known in the art. For example, the less active form can be used to increase the stability of a compound that allows for an increased shelf life or a wider range of storage temperatures. The less active form can also be used to ensure that the compound reaches its target destination before becoming active.

[000219] The use of cleavable bonds in the present disclosure offers other advantages that can improve the performance of the complex. For example, the conjugate form can be used to reduce the osmolarity of a chemical compound, which in the present specification is useful since the human body has sensors that recognize molecular changes in osmolarity and trigger pain and itch pathways. The conjugated form can also be used to alter the solubility of a compound, for example, making the compound more lipophilic to allow better absorption into cells.

[000220] As described elsewhere here, limiting the osmolarity of the composition of the present invention is described here may be beneficial. Therefore, conjugating beta hydroxybutyrate to the cysteine-based antioxidant reduces osmolarity by about a third, thus increasing efficacy. The addition of a neutral or anionic polymer reduces osmolarity further, allowing multiple tripartite complexes to bind to one polymer.

[000221] In one embodiment, the conjugate-cleavable bond of the compound is cleaved after application of the compound to the skin. An example of this modality is the use of thioester to join beta hydroxybutyrate to NAC. When this compound is applied to human skin, non-specific esterases on the surface of the skin cells cleave the thioester bond.

[000222] In another embodiment, only a small percentage of the cleavable bonds of the conjugated form of the compound are cleaved after application of the compound to the skin or from there the majority of the conjugated form of the compound is taken into the cell, where the Cleavable bonds are cleaved. Absorption of the conjugated form of the compound allows a higher concentration of strontium to be present within a cell than applying a strontium salt to the skin orally or ingesting strontium.

[000223] In another embodiment, the cleavable bond is cleaved after application of a second compound containing a cleavage agent. A cleaving agent is an agent that cleaves specific chemical bonds. The second compound can be applied to the skin immediately after application of the conjugated form of the compound or, alternatively, the two compounds can be mixed together immediately before application to the skin. Examples of cleaving agents include, but are not limited to, enzymes, oxidizing agents, reducing agents, light, and chemicals that induce pH changes.

[000224] In one embodiment, the complexes of the present invention are derived from: 1) a strontium atom; 2) a portion of beta-hydroxybutyrate; and 3) a molecule of N-acetyl-L-cysteine, (NAC) or 1) a strontium atom; 2) two halves of beta-hydroxybutyrate; and 3) two molecules of N-acetyl-L-cysteine (NAC). In another embodiment, beta-hydroxybutyrate and NAC are joined by a thioester and complexed with beta-hydroxybutyrate.

G. Beneficial Additional Agents

[000225] Beneficial agents synergistically enhance the effects of strontium by targeting distinct molecular pathways and/or targeting different points along the same molecular pathways. Beneficial agents can also target microorganisms that cause or contribute to conditions that result in pain, itching, or irritation. Lastly, beneficial agents can also increase strontium through unique formulations that allow for greater delivery or prolonged release. Any of the beneficial agents listed below can be used alone or in combination with each other.

1. Aluminum Acetate

[000226] Aluminum acetate is recognized for treating minor skin irritation due to poison ivy/oak, contact dermatitis, athlete's foot, etc. It is the active component in Toca's solution.

2. Aspartame

[000227] Aspartame is an artificial sweetener. It is a methyl ester of dipeptide and phenylalanine aspartic acid. Aspartame can be used topically to treat skin irritation.

3. Colloidal Oatmeal

[000228] Colloidal oatmeal is finely ground powder from shell oat seeds from the Avena sativa plant. Colloidal oatmeal has many compounds that are beneficial for the skin. Beneficial properties of colloidal oatmeal include anti-itching, anti-inflammatory, moisture retention, and antioxidant capabilities.

4. Corticosteroids

[000229] Corticosteroids are a class of molecules that are produced in the adrenal cortex. They are involved in a wide variety of physiological processes including the stress response, the immune response and inflammation. Topical forms of corticosteroids have anti-inflammatory properties and are typically used to treat rashes, eczema, dermatitis, psoriasis, and other skin conditions. Topical corticosteroids are generally used for short periods of time as long-term use can lead to secondary bacterial or fungal infection, skin atrophy, telangiectasia, bruising, and skin fragility. Non-limiting examples of topical corticosteroids include alclomethasone dipropionate, amcinonide, betamethasone dipropionate, clobetasol propionate, desonide, desoximethasone, diflorasone diacetate, fluocinolone acetonide, fluocinonide, flurandrenolide, fluticasone propionate, halcinonide, halobetasol propionate, halomethasone, hydrocort isone , hydrocortisone butyrate, hydrocortisone valerate, mometasone furoate, prednisone, and triamcinolone acetonide.

5. Mineral Tar

[000230] Mineral tar (also known as liquor carbonis detergens) is a mixture of organic compounds, including phenols, heterocyclic oxygens, hydrocarbons, sulfides and nitrogen. Mineral tar may have anti-proliferative and anti-inflammatory effects on the skin.

6. Antidepressants

[000231] Some antidepressants may have antihistamine effects and can be used to treat pruritus. Non-limiting examples include amitriptyline, paroxetine, doxepin, hydroxyzine, and mirtazapine. Doxepin is a tricyclic antidepressant and anxiolytic (anti-anxiety) drug that reduces the reuptake of norepinephrine and serotonin (neurotransmitters) to bring their levels back to normal. Doxepin is an anticholinergic, a drug that blocks parasympathetic nerves, and a sedative. It is the only tricyclic antidepressant to relieve itching as well as various types of pain. Mirtazapine is a noradrenergic and specific serotonergic antidepressant. It is also a histamine H1 receptor antagonist.

7. Antimicrobials

[000232] In many cases, the presence of bacteria, fungi or viruses cause or worsen symptoms associated with a skin disease. For examples, high levels of Staphylococcus aureus are said to contribute to atopic dermatitis. Additionally, several species of Candida worsen rashes due to excessive wet skin in children and infants. Lastly, several herpes viruses cause painful vesicular rashes. Antimicrobials act synergistically with strontium to provide relief from pain and itching and decrease healing time. Non-limiting examples of antimicrobial agents include antibacterials, antifungals, or antivirals. Non-limiting examples of antibacterial agents include: silver, iodine, bacitracin, polymyxin B, neomycin, gentamicin, mupirocin, sulfacetamide, erythromycin, neomycin and honey. Non-limiting examples of antifungals include: benzoic acid, undecylenic alkanolamide, cyclopiroxolamine polyenes, nystatin, imidazoles, bifonazole, clotrimazole, econazole, ketoconazole, miconazole, tioconazole, allylamine, terbinafine, thiocarbamates, tolcyclate, tolnaftate, azoles, sulconazole, efinaconazole, luliconazole, naftifine, benzoxaborole, tavaborole and other drugs in the same class as those listed. Non-limiting examples of antiviral agents include acyclovir famciclovir penciclovir valacyclovir, docosanol and lysine.

8. Plant Extracts

[000233] Many plants, herbs and spices have anti-inflammatory, antiseptic, healing and/or calming properties. Non-limiting examples include jewelweed, black current seed oil, ginger, tea tree oil, spearmint, thyme, menthol, camphor, chamomile, comfrey (allotonin), lavender, aloe, feverfew, soybean, red cannabraz (Boerhavia diffusa) , calendula (Calendula officinalis), licorice, white willow bark, honey, green tea, frankincense, witch hazel, cloves, Arnica montana, and basil.

9. Antihistamine

[000234] Antihistamines are drugs that are used to prevent the symptoms of an allergic reaction. They work by blocking histamine receptors. There are four histamine receptors, H1, H2, H3 and H4. Activation of H1 receptors causes vasodilation and increased cell permeability. Activation of H2 receptors stimulates the secretion of gastric acid. H3 receptors function as presynaptic autoreceptors on histamine-containing neurons. H4 receptors regulate the release of neutrophils into the bone marrow and are involved in mast cell chemotaxis. Common over-the-counter H1 antihistamines include diphenhydramine (Benadril), fexofenadine (Allegra), and loratadine (Claritin). Common H2 antihistamines include cimetidine (Tagamento), famotidine (Pepcid), and ranitidine (Zantac). Non-limiting examples of H1 antihistamines include acrivastine, azelastine, bilastine, brompheniramine, buclizine, bromodiphenhydramine, carbinoxamine, cetirizine, chlorpromazine, cyclizine, chlorpheniramine, chlorodiphenhydramine, clemastine, cyproheptadine, desloratadine, dexbrompheniramine, dexchlorpheniramine, dimenhydrinate, dimetide no, diphenhydramine, doxylamine, ebastine, embramine, fexofenadine, hydroxyzine, levocetirizine, loratadine, meclozine, mirtazapine, olopatadine, orphenadrine, phenindamine, pheniramine, phenyltoloxamine, promethazine, pyrilamine, quetiapine, rupatadine, tripelenamine and triprolidine. Non-limiting examples of H2 antihistamines include cimetidine, famotidine, lafutidine, nizatidine, ranitidine, Roxatidine and thiotidine.

10. Local Anesthetics

[000235] Topical anesthetics are agents that reduce sensation in the area to which they are applied. Non-limiting examples include benzocaine, butesin, dibucaine, lidocaine, oxybuprocaine, pramoxine, proparacaine, proximethacaine and tetracaine.

11. Vitamins

[000236] Vitamins applied topically have shown some promise in treating pain and itching.

[000237] Non-limiting examples include vitamin B, vitamin B12, vitamin B3, vitamin C, vitamin D, vitamin D3, vitamin E, vitamin K and other compounds that have vitamin activity, such as tocopherol and ascorbic acid.

12. Moisturizers/skin protectors

[000238] Moisturizers/skin protectants (often referred to as moisturizers) can be used to help maintain the integrity of the epidermal barrier and promote its protective function against dehydration, irritants, allergens, and infectious pathogens, all of which can cause itching and/or pain. Non-limiting examples include lipids, oils, fats, waxes, wetting agents, glycerol, honey, shea butter, lanolin, hyaluronic acid, silicone-based, allantoin, dimethicone and ceramides.

[000239] Ceramides are a family of wax-like lipid molecules that are found in high concentrations within the cell membrane of cells.

13. About Counter Active Ingredients, Diet Supplements, and Homeopathic Ingredients

[000240] Also contemplated are several over the counter ingredients that are beneficial to epithelial surfaces (e.g., skin or mucous membranes), as recognized by the FDA or as used by the general public. Also contemplated are different over the counter ingredients that are protective for epithelial surfaces, as recognized by the FDA or as used by the general public. Also covered are several homeopathic ingredients that are beneficial to epithelial surfaces. Also covered are several dietary supplements that are beneficial to epithelial surfaces. Non-limiting examples of the aforementioned categories include sun protection (non-limiting examples include zinc oxide, titanium dioxide, p-aminobenzoic acid, padimate O, phenylbenzimidazole sulfonic acid, cinoxate, dioxybenzone, oxybenzone, avobenzone, homosalate, menthyl anthranilate, octorylene, octyl methoxycinnamate, octyl salicylate, sulisobenzone, trolamine salicylate, and ecamsul), insect repellent (non-limiting examples include N,N-diethyl-m-toluamide, citronella oil, p-menthane-3, 8- diol, icaridin, neem oil, dimethyl carbate, (3-[N-butyl-N-acetyl]-aminopropionic acid, ethyl ester), dimethyl phthalate, and SS220), urea, lysine, hydroxy acids, alum, essential oils, olive oil, almond oil, coconut oil, and honey.

14. Biologicals

[000241] The strontium-based compositions described herein may also include biological products.

[000242] Biologicals are complex mixtures that are not easily identified or characterized. They may be composed of sugars, proteins, nucleic acids, or combinations of the aforementioned entities or still living (e.g., cells, tissues, microorganisms). Biologics can be purified from natural sources or produced using recombinant DNA technology. Non-limiting examples include thymus polypeptides, cholazine, peptides, and tissue extracts.

15. Polymers

[000243] The strontium-based compositions disclosed herein may also include polymers. Strontium and other compounds may be capable of ionic association with the polymer, thus forming a matrix. Matrix formation can improve the bioavailability of the complexes and therefore prolongs the therapeutic effect of the composition (e.g., sustained release). The use of polymers can also minimize osmolarity. As mentioned previously, high osmolarity can lead to unstable formulations and physically damage tissues and cause pain, especially in non-keratinized skin that has a damaged mucous membrane or "barrier function" due to physical trauma, infection or inflammation. Non-limiting examples of polymers include polyvinylpyrrolidone (PVP), dextrins, cyclodextrins, carrageenans, iota carrageenan, alginic acid, xanthan gum, guar gum, sulfated polysaccharides such as carrageenan, dextran sulfate, pentosan polysulfate, chondroitin sulfate, aqueous polymers , fatty acids, heparin sulfate and polyethylene glycol (PEG).

The. Alginic Acid

[000244] Alginic acid is a naturally occurring polysaccharide obtained from brown algae.

[000245] Structurally, it is a linear copolymer of polyanionic (1-4)-linked beta-D-mannuronic acid and L-alpha-glucuronic acid. Due to its repeated carboxyl groups, alginic acid electrostatically binds to positively charged atoms such as strontium and calcium when the pH of the carrier is above the pKa of the carboxyl groups (approximately 4/3) causing them to be charged. negatively and capable of binding strontium and calcium. As the pH decreases and approaches empty stomach pH (1 or less), hydrogen ions will compete with strontium and calcium and will displace free strontium and calcium. Alginic acid thus acts as a typical ion exchange column matrix. By utilizing various naturally occurring polymer blends of alginic acid, the release rate of calcium and strontium as a function of the pH and ionic strength of the carrier can be adjusted to achieve release over a long period of time.

[000246] Alginic acid and its salts are widely used in foods, cosmetics and medical devices. The FDA has declared alginic acid GRAS (Generally Recognized as Safe). A similar security classification exists in the European Union and other countries.

B. Polyvinylpyrrolidone (PVP)

[000247] Polyvinylpyrrolidone (PVP) is commonly used as an inert vehicle for therapeutically active molecules. Due to the varying polar structure of PVP polymer, it features multiple repeating sites where atoms and molecules can bind through ionic forces. Upon subsequent exposure to ionic media, such as water, the bound substance may be released into the medium over a prolonged period of time. Thus, facilitating the gradual release of the substance as a function of pH and other adjustable conditions such as temperature, etc. As such, PVP acts as a "molecular reservoir" to provide sustained release of therapeutic substances. The PVP polymer can be in its native form, or can be chemically modified by derivatization and/or cross-linking to adjust the "releasing" properties of the polymer. In one embodiment, PVP is used as a carrier for gallic acid, related to molecules containing gallic acid or other polyhydroxyphenolic molecules.

[000248] PVP is used in foods, cosmetics and medical devices. It is used as an FDA-approved excipient in oral medications as a tablet binder.

[000249] In one embodiment, the compositions of the present invention include a strontium complex and a polymer capable of ionic association with the complex, in which case the polymer complex forms a matrix. Such matrix formation increases the bioavailability of the complexes and therefore prolongs the therapeutic effect of such complexes. In particular, when the strontium complex includes a polyhydroxyphenol, such compounds have a high affinity for polymers such as polyvinylpyrrolidone (PVP).

[000250] For example, PVP is typically used as an inert carrier of therapeutically active molecules. Due to the varying polar structure of PVP polymer, it features multiple repeating sites where atoms and molecules can bind through ionic forces. Upon subsequent exposure to ionic media, such as water, the bound substance may be released into the medium over a prolonged period of time. Thus, facilitating the gradual release of the substance as a function of pH and other adjustable conditions such as temperature, etc. As such, PVP acts as a "molecular reservoir" to provide sustained release of therapeutic substances.

[000251] The PVP polymer can be in its native form, or it can be chemically modified by derivatization and/or cross-linking to adjust the "release" properties of the polymer.

[000252] Polyhydroxylated phenols, such as gallic acid, have a high affinity for PVP. As such, the combination of PVP, gallic acid, and cationic divalent strontium forms an ionic complex matrix that facilitates the release of strontium following controlled administration.

[000253] Such polymer-based compositions also minimize osmolarity, which can lead to unstable formulations and physically damage tissues and cause pain. For example, topical formulations with high osmotic activity can damage delicate tissues, especially non-keratinized skin that has a damaged mucous membrane or "barrier function" due to physical trauma, infection or inflammation.

C. Polyethylene glycol (PEG)

[000254] Polyethylene glycol, polyethylene oxide, and polyethylene are polymers of ethylene oxide. As used herein, "PEG" will refer to all ethylene oxide polymers. The molecular weight of PEG varies between 300 g/mol to 10,000,000 g/mol. Furthermore, PEG can have several different geometries, such as linear, branched, star and comb. Chain lengths and geometries can affect the physical properties of PEG.

16. Skin Penetration Enhancers

[000255] Experiments indicate that simple solutions of strontium and water can be effective in reducing pain and irritation when applied topically to the skin. This indicates that strontium is able to pass through the outer layers of the skin without the inclusion of skin penetration enhancers. Without wishing to be bound by any theory, it is believed that one of the ways in which strontium passes through the outer layers of the skin is through the use of the pilosebaceous unit. The pilosebaceous unit is composed of a hair follicle, hair shaft, and the sebaceous gland. The follicle is about 1-4 micrometers in diameter. The epidermis wraps around to form the interior of the follicle. However, the tough outermost layer of the epidermis, i.e. the stratum corneum, is much thinner and/or non-existent within the follicle. Consequently, compounds that are small enough to pass through the hair follicle can penetrate through the skin better than larger compounds. Strontium's ability to penetrate the skin through hair follicle use reduces the need to add skin penetration enhancers to the formulation. While skin penetration enhancers are not necessary, in some cases, in certain embodiments, it is advantageous to include a skin penetration enhancer to the formulations of the present disclosure. Non-limiting examples of skin penetration enhancers include lactic acid, sulfoxides, dimethyl sulfoxide, Azone and derivatives, pyrrolidones, fatty acids, essential oils, terpenes, terpenoids, oxazolidinones, urea and its derivatives, alcohols, glycols, enzymes, surfactants, monooleins , iminosulfurans, phospholipids, etc.

17. Extended-release agents

[000256] Various chemicals that can prolong the release of strontium or strontium and combinations of beneficial agents are also contemplated. Such agents include, but are not limited to, polymers, liposomes, microparticles, nanoparticles, film-forming agents, and the like.

18. Other Pharmaceutical Excipients

[000257] The compounds of the present disclosure may also be formulated with additional ingredients known in the pharmaceutical art to increase stability, increase the disintegration of solid tablets, or increase customer appeal. Non-limiting examples include possible excipients, preservatives, binders, bulking agents, diluents, sweeteners, flavors, lubricants and colorants.

Formulation and Administration

[000258] In general, it is desirable to administer the compositions of the modalities in a topical manner; however, other routes of administration are also contemplated. Routes of administration include, but are not limited to oral, parenteral and subcutaneous. The compositions may be formulated into liquid preparations for, for example, oral administration, when the tissue to be so treated comprises a membrane of the gastrointestinal tract or orally. Such suitable forms include suspensions, syrups, elixirs and the like. Unit dosage forms configured for a single administration can be prepared; however, in certain embodiments, it may be desirable to configure the form for administration twice per day, or more.

[000259] In one embodiment, the compositions and formulations described herein can be formulated for topical application to epithelial cells/tissues including but not limited to keratinized cells/tissues, gastrointestinal tract, respiratory tract, reproductive tract, eyes and ears. Non-limiting examples for application to keratinized tissues include powders, drops, vapors, mists, aerosols, patches, foams, films, gels, emulsions, lotions, creams, ointments, pastes and solids. Non-limiting examples for application to the gastrointestinal tract include liquids, gels, sprays, powders, suppositories and tablets. Non-limiting examples for application to the upper and lower respiratory tract include aerosols, powders, gels and sprays. Non-limiting examples for application to the reproductive tract include sprays, gels, suppositories, tablets, creams, ointments and foams. Non-limiting examples of eye and ear application include drops, sprays, creams and ointments.

[000260] The viscosity of topical compositions can be maintained at the selected level using a pharmaceutically acceptable thickening agent. Methylcellulose can be used as an easily and economically available excipient. Other suitable thickening agents include, for example, xanthan gum, carboxymethyl cellulose, hydroxypropyl cellulose, carbomer and the like. The concentration of the thickening agent will depend on the thickening agent chosen. An amount is typically used that will achieve the selected viscosity. Viscous compositions are normally prepared from solutions by adding such thickening agents. In certain embodiments, no thickening agent is employed.

[000261] For oral administration, pharmaceutical compositions can be provided as a tablet, an aqueous or oil suspension, dispersible powder or granule, emulsion, hard or soft capsule, syrup or elixir. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and may include one or more of the following agents: sweeteners, flavoring agents, coloring agents and preservatives. Aqueous suspensions may contain the active ingredient in admixture with excipients suitable for the manufacture of aqueous suspensions.

[000262] When administered orally in liquid form, a liquid carrier such as water, petroleum, oils of animal or vegetable origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils can be added to the active ingredient(s). Physiological saline, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol are also suitable liquid carriers. The pharmaceutical compositions may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil such as olive oil or peanut oil, a mineral oil such as liquid paraffin, or a mixture thereof. Suitable emulsifying agents include gums such as naturally occurring gum acacia and gum tragacanth, naturally occurring phosphatides such as soy lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and partial condensation products of these esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. Emulsions may also contain sweetening agents and flavoring agents.

[000263] Formulations for oral use can also be provided in the form of hard gelatin capsules, in which the active ingredient(s) are mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules. In soft capsules, the active compounds can be dissolved or suspended in suitable liquids, such as water or an oily medium, such as peanut oil, olive oil, fatty oils, liquid paraffin, or liquid polyethylene glycols. Stabilizers and microspheres formulated for oral administration can also be used. Capsules may include snap-on capsules made of gelatin, as well as sealed, soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Snap-on capsules may contain the active ingredient in admixture with fillers such as lactose, binders such as starches and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In cases where it is desirable to maintain the components of compositions in a reduced form, it may be desirable to include a reducing agent in the capsule or other dosage form.

[000264] Tablets can be uncoated or coated using known methods to delay disintegration and absorption in the gastrointestinal tract and thus provide sustained action over a longer period of time. For example, a retardation material such as glyceryl monostearate can be used. When administered in solid form, such as tablet form, the solid form typically comprises from about 0.001 by weight. % Or less up to about 50 by weight. % or more of active ingredient(s), preferably about 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0 .09, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, or 1 part by weight. % To about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, or 45% by weight.

[000265] Tablets may contain the active ingredients in mixture with pharmaceutically acceptable non-toxic excipients, including inert materials. For example, a tablet may be prepared by compression or molding, optionally, with one or more additional ingredients. Pressed tablets can be prepared by compressing in a suitable machine the active ingredients into a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, active surface or dispersing agent. Molded tablets can be made by molding, in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent.

[000266] Preferably, each tablet or capsule contains from about 10 mg or less to about 1,000 mg or more of a compound of various embodiments, more preferably between about 20, 30, 40, 50, 60, 70, 80 , 90, or 100 mg to about 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650,

[000267] 700, 750, 800, or 900 mg. More preferably, the tablets or capsules are provided in a range of dosages to allow divided dosages to be administered. An appropriate dosage for the patient and the number of doses to be administered daily can thus be conveniently selected. In certain embodiments, it may be desired to incorporate two or more of the therapeutic agents to be administered into a single tablet or other dosage form (e.g., in a combination therapy); however, in other embodiments it may be desirable to provide therapeutic agents in separate dosage forms.

[000268] Suitable inert materials include diluents, such as carbohydrates, mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, starch, and the like, or inorganic salts thereof, such as calcium triphosphate, calcium phosphate, sodium phosphate, calcium carbonate, sodium carbonate, magnesium carbonate, and sodium chloride. Disintegrants or granulating agents may be included in the formulation, for example, starches such as corn starch, alginic acid, sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite, insoluble cation exchange resins, powdered gums such as agar, karaya or tragacanth, or alginic acid or its salts.

[000269] Binders can be used to form a hard tablet. Binders include natural product materials such as acacia, tragacanth, starch and gelatin, methylcellulose, ethylcellulose, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose and the like.

[000270] Lubricants, such as stearic acid or its corresponding magnesium or calcium salts, polytetrafluoroethylene, liquid paraffin, vegetable oils and waxes, sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol, starch, talc , fumed silica, hydrated silicoaluminate, and the like, can be included in tablet formulations.

[000271] Surface-active agents can also be used, for example, anionic detergents, such as sodium lauryl sulfate, sodium dioctyl sulfosuccinate and sodium dioctyl sulfonate, cationic ones, such as benzalkonium chloride or benzethonium chloride, or non-ionic detergents such as polyoxyethylene-hydrogenated castor oil, glycerol monostearate, polysorbates, sucrose fatty acid esters, methyl cellulose, or carboxymethyl cellulose.

[000272] Controlled-release formulations can be employed, in which strontium, BHB, and/or therapeutic compounds are incorporated into an inert matrix that allows release either by diffusion or by leaching mechanisms. Slow degeneration matrices can also be incorporated into the formulation. Other delivery systems may include timed release, delayed release, or sustained release delivery systems.

[000273] Coatings can be used, for example, non-enteric materials, such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose , providone and polyethylene glycols, or enteric materials such as phthalic acid esters. Dyes or pigments can be added for identification or to characterize different dose combinations of active compound.

[000274] When a compound of various embodiments is administered by intravenous, parenteral, or other injection, it is preferably in the form of a pyrogen-free, parenterally acceptable aqueous solution or oleaginous suspension. Suspensions may be formulated according to methods well known in the art using suitable dispersing or wetting agents and suspending agents. The preparation of acceptable aqueous solutions with suitable pH, isotonicity, stability and the like is within the skill of the art. A pharmaceutical composition for injection may contain an isotonic vehicle such as 1,3-butanediol, water, isotonic sodium chloride solution, Ringer's solution, dextrose solution, dextrose and sodium chloride solution, lactated Ringer's solution, or other vehicles as are known in the art. Furthermore, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. Furthermore, fatty acids such as oleic acid can also be used in the formation of injectable preparations. The pharmaceutical compositions may also contain stabilizers, preservatives, buffers, antioxidants or other additives known to those skilled in the art.

[000275] The duration of the injection can be adjusted depending on various factors, and can comprise a single injection administered over the course of a few seconds or less, at 0.5, 0.1, 0.25, 0.5, 0 .75, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours or more of continuous intravenous administration.

[000276] Compositions according to various embodiments can, in certain cases, be formulated to be isotonic with a recipient's bodily fluid. The isotonicity of the compositions can be achieved using sodium tartrate, propylene glycol or other inorganic or organic solutes. Sodium chloride may be used, as may buffer agents such as acetic acid and salts, citric acid and salts thereof, boric acid and salts thereof, and phosphoric acid and salts. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, Ringer's lactate, or fixed oils

[000277] The compositions may be in admixture with a suitable carrier, diluent, or excipient, such as sterile water, physiological saline solution, glucose, or the like, and may contain auxiliary substances such as wetting or emulsifying agents, pH buffering agents, gelling or viscosity-increasing additives, preservatives, flavoring agents, colors, and the like, depending on the route of administration and the intended preparation. See, for example, "Remington: The Science and Practice of Pharmacy", Lippincott Williams &Wilkins; 20th edition (June 1, 2003) and "Pharmaceutical Sciences by Remington," Mack Pub. co.; 18 and 19 editions (December 1985 and June 1990, respectively). Such preparations may contain complexing agents, metal ions, polymeric compounds such as polyacetic acid, polyglycolic acid, hydrogels, dextran, and the like, liposomes, microemulsions, micelles, unilamellar or multilamellar vesicles, erythrocyte ghosts or spheroblasts. Suitable lipids for the liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. The presence of such additional components can influence the physical state, solubility, stability, penetration rate and clearance rate, and are thus chosen according to the intended application, so that the characteristics of the carrier are adapted to the selected route of administration.

[000278] Compositions of various modalities may further employ adjunctive components conventionally found in pharmaceutical compositions in their established form and at their levels established in the art. Thus, for example, the compositions may contain additional compatible pharmaceutically active materials for combination therapy (e.g., additional antimicrobial agents, astringents, local anesthetics, anti-inflammatory agents, reducing agents, and the like), or may contain materials useful in physically formulating various dosage forms of various embodiments, such as excipients, colorants, thickening agents, stabilizers, preservatives or antioxidants.

A. Osmolarity

[000279] Strontium's anti-irritant activity is due to the divalent ion of strontium. Pure strontium is highly reactive with oxygen and water. Thus, formulations containing strontium use strontium salts as the strontium source. Due to its double positive charges, two anionic counterions are needed to balance the electrostatic charge and thus create a strontium salt. With most commercially available strontium salts, negatively charged counterions such as nitrate (NO3) or chloride (Cl-) contribute to the ionic strength and osmolarity of the formulation, but not to the overall anti-irritant benefits. . Additionally, clinical studies have demonstrated that higher strontium concentrations produce increased clinical benefits.

[000280] Consequently, it is clinically and commercially advantageous to create commercially acceptable and stable formulations with high concentrations of strontium.

[000281] While high concentration strontium formulations would be clinically beneficial, they can also cause osmotic shock, resulting in tissue damage and pain, especially in non-keratinized epithelium such as mucous membranes or in keratinized epithelium, which has reduced barrier capabilities due to to physical trauma, infection or inflammation.

[000282] Various methods can be used to reduce osmotic shock. For example, using strontium base salts where the counterions also have therapeutic benefits. This would reduce the number of solutes when compared to formulations using standard strontium salts. In one embodiment, a strontium salt and a polyhydroxyphenol is used. In another embodiment, a strontium salt and a cysteine-based antioxidant is used. In another embodiment, a strontium salt, a polyhydroxyphenol, and a cysteine-based antioxidant is used. Using the aforementioned strontium base salts would decrease the total solutes compared to formulations that combined strontium nitrate or strontium chloride with the polyhydroxyphenol or cysteine based antioxidants.

[000283] Another method that has been discovered to reduce osmotic shock is to combine the strontium cation with a carrier, which does not affect osmolarity. For example, using polymers capable of binding strontium cations. Non-limiting examples of polymers include polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyacrylic acid, polyacrylamide, N-(2-hydroxypropyl) methacrylamide, divinyl ether-maleic anhydride, polyoxazoline, polyphosphates, polyphosphazene, xanthan gum, pectins, chitosan derivatives, dextran , carrageenan, iota carrageenan, guar gum, cellulose ethers, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, hyaluronic acid, starch, and starch base derivatives.

[000284] Osmolarity can impact many formulations such as lotions, creams, and hydrogels depend on a delicate balance of factors that produce stable emulsions or hydrogels. Formulations with high ionic strengths can prevent the formation of a stable emulsion. For example, emulsions in which more than about 6-7% strontium nitrate or strontium chloride hexahydrate (equivalent to about 2% elemental strontium) are incorporated tend to be unstable and separate. Likewise, hydrogels that contain more than about 12% to 13% (equivalent to about 4% elemental strontium) of these salts also tend to be unstable.

B. pH

[000285] The pH of topical application formulations tends to equal the pH of the surface to be applied. For example, the pH of the skin ranges from 4 to 7, accordingly, most skin formulations (e.g. lotions, soaps, shampoos, etc.) are formulated with a pH between 4 and 7. Contrary to convention, it has been verified Surprisingly, topical strontium-based formulations work best at a pH that is lower than the pH of the skin. In one embodiment, the pH of a topical formulation of the present invention is less than 4, or less than 3. In another embodiment, the pH is from about 2 to about 3.

C. Extended release

[000286] The strontium-based compounds described here can be formulated for prolonged release. It is believed that long-term exposure to strontium or strontium and combinations of beneficial agents are useful in treating certain conditions, such as neuropathic pain, itching or irritation. Sustained release can be achieved by a variety of methods; Non-limiting examples include microencapsulation, specialized polymers, films, nanoparticles and the like.

D. Formulation Aids

[000287] The strontium-based compounds described here can be formulated in a variety of forms. The form, e.g. lotion, emulsion, hydrogel, tablet, inhalants, etc., will dictate the additional ingredients/materials needed to make the final product. Additionally, ingredients to improve commercial attraction can be included. Non-limiting examples include thickeners, flavors, perfumes, dyes, lubricants, solvents, emulsifying agents, wetting agents, and drying agents.

E. Preservatives

[000288] A pharmaceutically acceptable preservative can be employed to increase the shelf life of the compositions. Benzyl alcohol may be suitable, although a variety of preservatives including, for example, parabens, thimerosal, chlorobutanol, or benzalkonium chloride may also be employed. A suitable concentration of the preservative is typically about 0.02% to about 2% based on the total weight of the composition, although greater or lesser amounts may be employed depending on the agent selected. Reducing agents can advantageously be used to maintain the acceptable shelf life of the formulations.

Kits

[000289] Compounds of various embodiments can be provided to an attending physician or other health care professional, or for self-administration by the patient, in the form of a kit. The kit is a package that houses a container that contains the compositions in appropriate packaging, and instructions for administering the composition. The kit may optionally also contain one or more additional therapeutic agents. For example, a kit containing one or more topical compositions in combination with one or more additional anesthetic, antibacterial, and/or anti-inflammatory agents may be provided. The kit may also contain separate doses for serial or sequential administration. The kit may optionally contain one or more diagnostic tools and instructions for use. The kit may contain suitable delivery devices, for example, syringes, wipes, or the like, together with instructions for administering the compositions, as well as any other agent. The kit may optionally contain instructions for storage, reconstitution (if applicable), and administration of any or all of the included compositions. Kits may include a plurality of containers that reflect the number of administrations to be given to an individual.

Applicator devices

[000290] The strontium-based compounds described here can be applied using a variety of applicator devices. Non-limiting examples include wraps, bandages, films, patches, rollers, syringes, sprays, droppers, nebulizers, nebulizers, and inhalers.

Methods of Use/Treatment

[000291] Strontium-based compositions described herein are used to treat pain, itching, inflammation, irritation due to a variety of factors and conditions (e.g., medical conditions). Non-limiting examples include allergies, hymenopteran insect bites (e.g., fleas, bed bugs, spiders, ants, ticks, etc.), stinging bugs (e.g., jellyfish, scorpions, caterpillars, etc.), delayed hypersensitivity, urticaria, exposure to poison, poison ivy, atopic dermatitis, eczema, herpes, shingles, acne, psoriasis, rosacea, ichthyosis vulgaris, dermatomyositis, thermal burns, ionizing radiation, exposure to chemicals, trauma, surgery, nerve compression, back pain, amputation, trauma, oral or throat ulcers, post-herpetic neuralgia, multiple sclerosis, Parkinson's disease, lupus, diabetes, diabetic neuropathy, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, idiopathic arthritis, bacterial infections, viral infections and drug use .

[000292] Strontium-based compounds described here are intended to be applied topically. Topical application in its broadest sense means application to epithelial surfaces such as skin or mucous membranes, including eyes, mouth, throat, esophagus, gastrointestinal tract, respiratory tract, and genitourinary tract.

[000293] In one embodiment, the strontium-based compounds described here are intended to be applied in powders or incident to the development of the condition. For example, strontium base compounds are applied after exposure to poison ivy, after receiving an insect bite, after developing sunburn, or after psoriatic plaque develops, etc. In another embodiment, strontium base compounds are regularly applied at the initial appearance of symptoms or during the early stages of a condition to reduce or minimize symptoms or skin damage associated with a condition. For example, applying strontium-based compounds to a cold sore area when the skin begins to itch, early stage psoriatic plaque, immediately after burn, etc. In another embodiment, strontium-based compounds are applied in a preventative manner to reduce symptoms or minimize skin damage that typically occurs with a certain condition. For example, applying strontium-based compounds to shingles rash area before the rash develops, etc. In another embodiment, strontium base compounds are applied on a regular basis as part of a normal daily routine. For example, using a strontium + sunscreen or strontium + insect repellent or strontium + moisturizing composition as part of a normal daily routine. In another embodiment, strontium-based compounds are continuously applied to an affected area using sustained-release technology to desensitize hypersensitive or overactive nerves.

[000294] In another embodiment, the strontium-based compounds described here are intended for use immediately after a traumatic event that is known to result in a neuropathic condition. Non-limiting examples of traumatic events include surgical incisions, amputation, burns, compound or open bone fractures, and shingles. In many of these situations (e.g. burns, surgery) controlling the infection is crucial to the patient's recovery. For these situations, strontium-based formulations often include an antibacterial agent or antimicrobial agent, such as iodine or silver.

Acute conditions

[000295] In one embodiment, the strontium-based compounds described here are used to treat acute pain, itching, inflammation or irritation. Acute pain, inflammation or irritation usually lasts less than a month, or even less than two weeks, or even less than a week. Not limiting examples of acute conditions include allergies, atopic dermatitis, eczema, stinging bugs, insect bites, delayed hypersensitivity, hives, poison exposure, poison ivy, herpes, herpes, psoriasis, acne, rosacea, thermal burns, back pain, radiation ionizing, chemical exposure, trauma, surgery, nerve compression, amputation, bacterial infection and viral infection.

Chronic conditions

[000296] In another embodiment, the strontium-based compounds described here are used to treat chronic pain, itching, irritation or inflammation. Chronic pain, inflammation or irritation usually lasts more than two weeks, or even more than a month, or even more than 3 months, or even more than 6 months, or even more than 9 months, or even more than a year . Non-limiting chronic conditions include trauma, surgery, eczema, atopic dermatitis, psoriasis, rosacea, back pain, amputation, nerve entrapment, postherpetic neuralgia, multiple sclerosis, Parkinson's disease, lupus, diabetes, diabetic neuropathy, arthritis rheumatoid, psoriatic arthritis, and drug use.

A. Neuropathic conditions

[000297] In another embodiment, the strontium-based compounds described here are used for the treatment of neuropathic pain, itching, inflammation or irritation. Neuropathic pain, itching, inflammation or irritation can be acute or chronic. Non-limiting examples of acute neuropathic conditions include trauma, surgical incisions, shingles, amputations, postherpetic neuralgia, and deep tissue burns (or thermal radiation). Non-limiting examples of chronic neuropathic conditions include nerve entrapment, postherpetic neuralgia, amputation, trauma, diabetic neuropathy, and drug use.

[000298] Strontium-based compositions described here are also used to prevent or reverse neuropathic conditions. Non-limiting examples of neuropathic conditions include nerve entrapment, nerve oversensitization, amputation/stump pain, post-herpetic neuralgia, shingles, diabetic neuropathy, arthritis, bacterial infections, viral infections, and drug use.

[000299] In some embodiments, neuropathic conditions are treated using a prolonged release of the strontium-based formulation. In other embodiments, acute neuropathic conditions are treated immediately after the neuropathic condition begins or occurs.

B. Prevention of the development of neuropathic conditions

[000300] In another embodiment, the strontium-based compounds described here are used to prevent the development of neuropathic conditions, as well as mild pain and itching. In situations where an event occurs that is known to cause neuropathic pain or itching, early use of the compounds described herein may reduce or prevent the development of neuropathic pain or itching. Non-limiting case examples include trauma, burns, surgery, amputation, and shingles/shingles.

C. Prevention and/or repair of damaged epithelial tissue

[000301] The strontium-based compounds described here are also used to promote healing in damaged epithelial cells/tissue. Non-limiting examples include skin plaques, dermatoses, scale, ulcers, rashes, burns (heat, ionizing radiation, etc.), acne, herpes, hives, canker sores, blisters, herpes, warts, and boils. The conditions noted above may be due to a variety of causes, such as (but not limited to) psoriasis, atopic dermatitis, bacteria, viruses, delayed-type hypersensitivity, sun damage, excessive heat, radiation therapy, and allergies.

[000302] Strontium-based compounds described here are also used to prevent or reduce damage to epithelial tissue. Non-limiting examples include rashes, blisters, warts, burns (heat, ionizing radiation, etc.), and hives. Non-limiting examples of causes include herpes, viruses, burns, sun damage, excessive heat, radiation therapy, exposure to allergens, insect bites and stinging bugs.

D. Joint pain

[000303] The strontium-based compounds described here can also be used to treat joint pain. Joint pain can be in the neck, back, knee, ankle, foot, shoulder, elbow, wrist or fingers. Non-limiting examples of causes of joint pain include injury, arthritis, and repetitive motion.

E. Specific Conditions

[000304] In one embodiment, the strontium-based compounds described herein are used to treat pain, itching, inflammation and irritation associated with herpes simplex infections. In another embodiment, the strontium-based compounds described herein are used to reduce the intensity and duration of a herpes simplex infection.

[000305] In another embodiment, the strontium-based compounds described here are used to treat pain, itching, inflammation and irritation associated with post-herpetic neuralgia.

[000306] In another embodiment, the strontium-based compounds described here are used to treat pain, itching, inflammation and irritation associated with diabetic neuropathy.

[000307] In another embodiment, the strontium-based compounds described here are used to treat pain, itching, inflammation and irritation associated with radiation dermatitis.

[000308] In another embodiment, the strontium-based compounds described here are used for pain, itching, inflammation and irritation associated with mimo atopic dermatitis. In another embodiment, the strontium-based compounds described herein are used to treat atopic dermatitis by breaking the inflammation/itch cycle.

[000309] In another embodiment, the strontium-based compounds described here are used to treat pain, itching, inflammation and irritation associated with psoriasis. In another embodiment, the strontium-based compounds described herein are used for the treatment of psoriasis by breaking the inflammation/keratinocyte cycle.

[000310] In another embodiment, the strontium-based compounds described here are used to treat pain, itching, inflammation and irritation associated with restless legs syndrome. In another embodiment, the strontium-based compounds described herein are used to treat restless legs syndrome.

[000311] In another embodiment, the strontium-based compounds described here are used to treat pain, itching, inflammation and irritation associated with joint pain. In another embodiment, the strontium-based compounds described herein are used to treat joint pain.

EXAMPLES Exemplary formulation

[000312] Strontium and BHB are combined. Additionally, excipients are added to make a topical formulation.

Exemplary formulation

[000313] Strontium, BHB and colloidal oatmeal are combined. Additionally, excipients are added to make a topical formulation.

Exemplary formulation

[000314] Strontium, BHB and acetylcystine are combined. Additionally, excipients are added to make a topical formulation.

Exemplary formulation

[000315] Strontium, BHB, and cystine are combined. Additionally, excipients are added to make a topical formulation.

Exemplary formulation

[000316] Strontium and iodine are combined. Additionally, excipients are added to make a topical formulation.

Exemplary formulation

[000317] Strontium, BHB and iodine are combined. Additionally, excipients are added to make a topical formulation.

Exemplary formulation

[000318] Strontium and silver are combined. Additionally, excipients are added to make a topical formulation.

Exemplary formulation

[000319] Strontium, BHB, and silver are combined. Additionally, excipients are added to make a topical formulation.

Exemplary formulation

[000320] Strontium, silver, and iodine are combined. Additionally, excipients are added to make a topical formulation.

Exemplary formulation

[000321] Strontium, BHB, silver and iodine are combined. Additionally, excipients are added to make a topical formulation.

Exemplary synthesis Synthesis of thioester linked to beta-hydroxybutyric acid and NAC

[000322] Synthesis 1: The hydroxyl group of beta-hydroxybutyric acid was selectively protected as tert-butyl-dimethyl silyl ether (TBS), using tert-butyl-dimethyl-silyl chloride and triethylamine in acetonitrile at 40-50 °C. The solvent was partially removed and the protected hydroxy compound (Compound A) was precipitated with water. The product was washed with water and dried under vacuum.

[000323] Synthesis of 2: Compound A was treated with N-hydroxysuccinimide in the presence of (3-dimethylaminopropyl) carbodiimide (EDC), 1-ethyl-3- in acetonitrile to prepare the activated ester of TBS protected beta-hydroxybutyric acid. The product was isolated and dried under vacuum (Compound B).

[000324] Synthesis 3: Compound B (beta-hydroxybutyric acid protected TBS NHS ester) was treated with N-acetyl cysteine in the water/1,4-dioxane mixture. The product was extracted with ethyl acetate and washed with water and brine (Compound C). The crude product was precipitated from ethyl acetate/hexanes and dried under vacuum.

[000325] Synthesis of 4: Compound C (TBS protected BHB: NAC) was dissolved in dichloromethane and treated with TFA to remove the TBS group. The reaction mixture was concentrated to dryness and washed with tert-butyl methyl ether (Compound D).

[000326] Synthesis of 5: Compound D (BHB: NAC thioester) was treated with strontium acetate in water and the resulting strontium salt was precipitated by triturating the mixture with acetone.

[000327] The final compound, tripartite strontium with thioester linkage (SR: BHB: NAC), was isolated and dried under vacuum to produce a white crystalline solid (92%).

Exemplary reaction Linked thioester cleavage using human enzymes

[000328] The strontium compound with tripartite thioester bond synthesized as described above was subjected to enzymatic cleavage with three different enzymes, human carboxylesterase I (CES1), human carboxylesterase II (CES2), and liver microsome enzyme S9.

[000329] For each of the three enzymes evaluated, SR:BHB:NAC was added to four sample tubes, A, B, C, and D. Enzyme was added to tubes A and B and 3-hydroxybutanoic acid was added to the tube D. Samples were tested by monitoring the UV count at 5, 60, 180, 360, 540, 1380 minute time points by HPLC using a C18 column.

[000330] The results demonstrated that all three enzymes cleaved the thioester bond to release NAC and beta hydroxybutyrate.

Clinical observation

[000331] BHB acts on the same pathway that causes flushing in individuals taking high doses of niacin. A topical formulation containing BHB was evaluated to see if it induced pruritus and erythema. The BHB formulation was compared to a topical niacin formulation.

[000332] A 1% BHB in water solution was made and a 1% niacin in water solution was made. Unknown to the subject, the BHB formula was applied in a 4 x 2 inch patch on the inside left forearm and the niacin formula was applied in a 4 x 2 patch on the inside right forearm. The skin was evaluated over a period of time. Within minutes the right forearm, where the niacin was applied, began to redden and itch. Throughout the entire evaluation period, the left forearm with the BHB did not redden or become itchy.

[000333] While the disclosure has been illustrated and described in detail in the drawings and the foregoing description, the illustration and description should be considered illustrative or exemplary and not restrictive. Disclosure is not limited to the disclosed modalities. Variations to the described embodiments can be understood and effected by those skilled in the art in practical realization of the claimed disclosure, from a study of the drawings, the disclosure and the attached claims.

[000334] All references cited herein are incorporated herein by reference in their entirety. For extension publications and patents or patent applications incorporated by reference in contradiction with the disclosure contained in the specification, this is intended to replace and/or take precedence over any contradictory material.

[000335] Unless otherwise defined, all terms (including technical and scientific terms) are to be given their normal and customary meaning to a person of ordinary skill in the art, and are not to be limited to a special meaning or personalized, unless expressly set forth herein. It should be noted that the use of particular terminology when describing certain features or aspects of the description should not be taken to imply that the terminology is being redefined herein and is limited to include any specific features of the features or aspects of the description with which this terminology is associated with. Terms and phrases used in this application, and variations thereof, particularly in the appended claims, unless expressly stated otherwise, are to be construed as open-ended as opposed to limiting. As examples of the foregoing, the term "including" should be read to mean "including, without limitation", "including but not limited to", or the like; the term "comprising" as used herein is synonymous with "including", " containing", or "characterized by", and is inclusive of, or open to and does not exclude, additional unrecited elements or steps of the method; the term "have" shall be interpreted as "having at least"; the term "includes" should be interpreted as “includes, but is not limited to; ' the term "example" is used to provide exemplary cases of the item under discussion, and not an exhaustive list or limitation thereof; adjectives such as "known", "normal", "standard", and terms of similar meaning should not be construed as limiting the item described to a particular period of time or to a product available as of a given time, but in instead it should be read to cover known, or normal standard technologies that may be available or known now or at any time in the future; and the use of terms such as "preferred", "preferred", "desired", or "desirable", and words of similar meaning should not be understood to mean that certain characteristics are fundamental, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. Likewise, a group of items related to the conjunction "and" should not be read as requiring that each and every such item be present in the grouping, but rather should be read as 'and/or' unless expressly stated otherwise. Likewise, a group of items related to the conjunction "or" does not should be read as requiring mutual exclusivity between that group, but should be read as 'and/or' unless expressly stated otherwise.

[000336] As used in the claims below and throughout this description, by the expression "consisting essentially of" is meant to include elements listed after the expression, and limited to other elements that do not interfere with or contribute to the activity or action specified in the disclosure of the listed elements. Thus, the expression "consisting essentially of" indicates that the listed elements are necessary or mandatory, but that other elements are optional and may or may not be present, depending on whether or not they affect the activity or action of the listed elements.

[000337] When a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the scope of the embodiments.

[000338] With regard to the use of substantially all of the plural and/or singular terms described herein, those skilled in the art may translate from the plural to the singular and/or from the singular to the plural, as is appropriate for the context and/or application. The various singular/plural permutations may be expressly provided for in this document for the sake of clarity. The indefinite article "one" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference marks in the claims should not be construed as limiting the scope.

[000339] It will further be understood by those within the art that if a specific number of a claim recitation introduced is intended, such intention will be expressly recited in the claim, and in the absence of such recitation such intention is present. For example, as an aid to understanding, the following appended claims may contain use of the introductory phrases "at least one" and "one or more" to introduce claim recitations. However, the use of such phrases should not be construed to imply that the introduction of a claim recitation by the indefinite articles "a" or "an" limits any particular claim containing such introduced recitation claim to embodiments containing only one such recitation, even when the same claim includes the introductory phrases "one or more" or "at least one" and indefinite articles such as "a" or "a" (e.g., "a" and/or "a" should normally be interpreted as meaning "at least one" or "one or more"); the same goes for the use of definite articles used to introduce claim recitations. Furthermore, even if a specific number of an introduced claim recitation is expressly recited, those skilled in the art will recognize that the recitation should typically be interpreted as meaning at least the number recited (e.g., the bare recitation of "two recitations, " without other modifiers, typically means at least two recitations, or two or more recitations). Furthermore, in cases where a convention analogous to "at least one of A, B, and C, etc" is used generally as an intended construction, in the sense having one skilled in the art would understand the convention (e.g., "a system that has at least one of a, b, and c" may include, but not be limited to, systems that have a alone, b alone, c alone, a and b together, a and c together , B and C together, and/or A, B, and C together, etc.). In those cases where a convention analogous to "at least one of A, B, or C, etc." is used, in general such a construction is intended in the sense that one skilled in the art would understand the convention (e.g., "a system that has at least one of A, B, or C" may include, but not be limited to systems that have A alone, B alone, C alone, A and B together, A and C together, B and C together, and/or A, B, and C together, etc.). It will be further understood by those within the art that virtually any disjunctive word and/or phrase presenting two or more alternative terms, whether in the description, claims or drawings, should be understood to contemplate the possibility of including one of the terms, any of the terms or both terms. For example, the phrase "A or B" will be understood to include the possibilities of "A" or "B" or "A and B" unless the context indicates otherwise.

[000340] All numbers expressing quantities of ingredients, reaction conditions, and so on used in the specification are to be understood as being modified in all cases by the term "about". Consequently, unless otherwise indicated, the numerical parameters set forth herein are approximations that may vary depending on the desired properties sought to be obtained. At a minimum, and not as an attempt to limit the application of the doctrine of equivalents to the scope of any claim in any application claiming priority for the present application, each numerical parameter should be interpreted in light of the number of significant figures and common rounding approaches.

[000341] Furthermore, although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it is apparent to those skilled in the art that certain changes and modifications may be practiced. Therefore, the description and examples should not be interpreted as limiting the scope of the invention to the specific embodiments and examples described herein, but rather to cover all modifications and alternatives that are the true scope and spirit of the invention.

Claims (23)

1. Composition characterized by the fact that it comprises a complex of: a bivalent cationic strontium component; a cysteine-based moiety selected from the group consisting of cysteine, N-acetyl cysteine, N-acetyl cysteineate, N-acetyl cystine, N,S-diacetylcysteine and esters thereof; and a beta hydroxybutyrate; wherein the cysteine-based antioxidant and the beta hydroxybutyrate moiety are conjugated together by a cleavable bond. 2. Composition according to claim 1, characterized by the fact that the cysteine-based antioxidant moiety is N-acetyl cysteine or an ester thereof. 3. Composition according to claim 1 or 2, characterized by the fact that the bivalent cationic strontium component is a strontium salt selected from the group consisting of strontium chloride, strontium chloride hexahydrate, strontium sulfate, strontium carbonate, strontium nitrate, strontium hydroxide, strontium hydrosulfide, strontium oxide, strontium acetate, strontium glutamate, strontium aspartate, strontium malonate, strontium maleate, strontium citrate, strontium threonate, strontium lactate strontium, strontium pyruvate, strontium ascorbate, strontium alpha-ketoglutarate and strontium succinate. 4. Composition according to any one of claims 1 to 3, characterized in that the cleavable bond is selected from the group consisting of a peptide bond, a steric bond, a thioesteric bond, an enzymatically cleavable bond, a disulfide bond and a pH-dependent bond. 5. Composition according to claim 4, characterized by the fact that the cleavable bond is a thioesteric bond. 6. Composition according to any one of claims 1 to 5, characterized in that it additionally comprises a polymer. 7. Composition according to claim 6, characterized in that the polymer is selected from the group consisting of polyvinylpyrrolidone, cyclodextrin, carrageenan, alginic acid, xanthan gum, sulfated polysaccharides, pentosan polysulfate, chondroitin sulfate, dextran sulfate and heparin sulfate. 8. Composition according to claim 1, characterized in that it comprises a complex of bivalent cationic strontium, N-acetylcysteine or an ester thereof and beta hydroxybutyrate, wherein the N-acetylcysteine or an ester thereof and beta hydroxybutyrate are conjugated together by a thioesteric bond formed by a sulfhydryl group of N-acetylcysteine or an ester thereof and a carboxyl group of beta hydroxybutyrate. 9. Formulation characterized by the fact that it comprises the composition, as defined in any one of claims 1 to 8, and at least one pharmaceutically acceptable excipient. 10. Formulation according to claim 9, characterized by the fact that the formulation is configured for topical administration. 11. Formulation according to claim 9, characterized by the fact that the formulation is configured for oral or systemic administration. 12. Formulation according to claim 9, characterized by the fact that the formulation is configured for oral ingestion. 13. Formulation according to claim 9, characterized in that it additionally comprises a polymer. 14. Formulation according to claim 13, characterized by the fact that the polymer is a neutral or anionic polymer. 15. Formulation according to claim 14, characterized in that the neutral polymer is polyvinylpyrrolidone. 16. Formulation according to claim 15, characterized in that the polyvinylpyrrolidone is chemically modified by derivatization or crosslinking. 17. Formulation according to any one of claims 13 to 16, characterized by the fact that the polymer is configured for ionic association with the complex and facilitates the controlled release of the bivalent cationic strontium. 18. Formulation according to any one of claims 13 to 17, characterized by the fact that the polymer is configured to minimize osmolarity. 19. Formulation according to claim 9, characterized in that it additionally comprises at least one aromatic amino acid selected from the group consisting of histidine, tyrosine, phenylalanine and tryptophan. 20. Formulation according to claim 19, characterized by the fact that at least one aromatic amino acid is an L-isomer. 21. Use of the composition, as defined in any one of claims 1 to 8, or of the formulation, as defined in any one of claims 9 to 20, characterized by the fact that it is to prepare a medicine to treat pain. 22. Use of the composition, as defined in any one of claims 1 to 8, or of the formulation, as defined in any one of claims 9 to 20, characterized by the fact that it is to prepare a medicament for treating pruritus. 23. Composition according to any one of claims 1 to 8, characterized by the fact that the bivalent cationic strontium component is strontium hydroxide and the cysteine-based antioxidant is N-acetyl-L-cysteine.