NZ785776A - Compositions and methods for the treatment of chronic pain - Google Patents

Abstract

The invention relates to the compounds or its pharmaceutical acceptable polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV and formula XV and the methods for the treatment of chronic pain may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, lozenge, spray, intravenous, oral solution, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treatment of chronic pain.

Description

COMPOSITIONS AND METHODS FOR THE TREATMENT OF C PAIN PRIORITY The present application claims the benefit of Indian Provisional Patent Application No. 201641044329 filed on ember-2016, the entire disclosure of which is relied on for all purposes and is incorporated into this application by reference.

FIELD OF THE INVENTION This disclosure generally s to compounds and compositions for the treatment of c pain. More particularly, this invention relates to treating subjects with a ceutically acceptable dose of compounds, crystals, solvates, enantiomer, stereoisomer, esters, hydrates, or es thereof.

BACKGROUND OF THE ION Chronic pain is a common medical condition afflicting up to 35% of the adult population (40% are female). Patients with co-existing chronic pain are prone to exacerbation of their underlying pain condition following surgery. Both pre-existing pain and elevated analgesic requirements continue to be significant predictors of severe postoperative pain development.

Specific approaches toward perioperative management of patients with co-existing chronic pain are not adequately described in the scope of current chronic and acute pain management guidelines ide Epidural analgesia provides significant acute pain benefits in the early perioperative period, especially for major nal and thoracic surgery, and several large studies have demonstrated these benefits. However, the ability to prevent progression to chronicity has been less effective, with mixed results across several studies.

Good perioperative analgesia and minimization of surgical tissue injury will remain important goals for both anesthesiologist and surgeon in the perioperative period. The broader and more consistent use of multimodal analgesic techniques remain the simplest current method by which anesthesiologists could have a major impact on the development of c post surgical pain.

The mechanisms of postoperative chronic pain are x and not fully understood.

Different mechanisms are responsible for different pain syndromes, even in one type of surgery.

The surgical us and tissue trauma that results from incision cause postoperative inflammatory reaction which only terminates with the final healing process; thus, tating the process of neuroplasticity and consequent changes in neuronal membrane excitability.

Furthermore, there is a possible reduction of the central inhibitory mechanisms and increased excitatory synaptic efficacy. lasticity can be divided into two interconnected types: peripheral and central. Peripheral neuroplasticity occurs from the e of inflammatory mediators (cytokines, prostaglandins, bradykinin, histamine, serotonin, H+ ions) by damaged tissues or inflammatory cells, with tion of intracellular cascades that culminate in reducing the excitatory threshold and may cause pain perception with a reduced us (allodynia) or sed response to aggressive stimulus (hyperalgesia).

Persistent postoperative chronic pain is a complex entity whose etiology is not fully elucidated, which affects the quality of life of individuals. Neuropathic pain resulting from surgical trauma is still the most common expression of this entity. For its prevention, appropriate perioperative sia is essential and techniques that avoid nerve damage are recommended and should be used whenever possible.

Managing acute ogy of often relies on the addressing underlying pathology and symptoms of the disease. There is currently a need in the art for new compositions to treatment or delay of the onset of chronic pain and its associated complications progression.

WO 22626 SUMMARY OF THE INVENTION The present invention provides compounds, compositions containing these compounds and methods for using the same to treat, prevent and/or ameliorate the s of the ions such as chronic pain.

The invention herein provides compositions comprising of formula I or pharmaceutical acceptable hydrates or solvates thereof. The invention also provides pharmaceutical compositions comprising one or more compounds of formula I or ediates thereof and one or more of pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in the ent of chronic pain and its associated complications.

Formula I and pharmaceutically acceptable hydrates, solvates, omers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, osalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, sulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, ic acid, glycerophosphoric acid, ic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, lic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, nic acid, menthol, ic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, l, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 erol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, otriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, iamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, nol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or wherein, within the proviso R, R2, R3 independently represents WO 22626 PCT/1B2017/052247 0 0 0H HH / 0 The compositions are typically compounds in the forms of hydrates or solvates of cinchocaine/dibucaine and an acidic moiety [RH] containing compound selected [RH] in which the cinchocaine/dibucaine is protonated and the acid moiety [RH] of the ceutically acceptable salt is at least in partially ionic form. In some instances, however, for example depending on the pH of the environment, the composition may be in the form of a mixture of cinchocaine/dibucaine and acid components [RH]. The invention also provides pharmaceutical compositions comprising compositions of formula I and pharmaceutically acceptable excipients.

In certain embodiments, the compounds of formula II are described: N YN H S Formula II and ceutically acceptable hydrates, es, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, ric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, ophosphoric acid, glycolic acid, hippuric acid, romic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, alene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, ic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, lic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, anic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, ic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, l, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene -carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, otachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, oquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, xal ate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or Rj-O----R3 n, within the proviso R, R2, R3 independently represents 0 o O OH WO 22626 PCT/1B2017/052247 0 0 0 OH0 : Nss0-0 OH 0 00 0 0 9 0 0 The compositions are typically compounds in the forms of hydrates or solvates of articaine and an acidic moiety [RH] ning compound ed [RH] in which the articaine is protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is at least in partially ionic form. In some instances, however, for example depending on the pH of the environment, the composition may be in the form of a mixture of articaine and acid components [RH]. The invention also provides pharmaceutical compositions comprising itions of formula II and pharmaceutically acceptable excipients.

In certain embodiments, the nds of formula III are described: Formula III and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, oxyethanesulfonic acid, lutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, ic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, eptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, ic acid, romic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, lenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, nic acid, menthol, retinoic acid, vitamin A, l, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene l, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, henic acid, thenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, sanol or O--R2 Rj-OO-R3 wherein, within the proviso R, R2, R3 independently represents O 1 O OH O OH O WO 22626 PCT/1B2017/052247 0 000 N 0H0 0 0 NH20 H 0 0 The compositions are typically compounds in the forms of hydrates or solvates of etidocaine and an acidic moiety [RH] ning compound selected [RH] in which the etidocaine is protonated and the acid moiety [RH] of the pharmaceutically able salt is at least in lly ionic form. In some instances, however, for example depending on the pH of the environment, the composition may be in the form of a mixture of etidocaine and acid components [RH]. The invention also provides pharmaceutical compositions comprising compositions of formula III and pharmaceutically acceptable excipients.

In certain ments, the compounds of formula IV are described: 0 NH Formula IV and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, aric acid, ic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, ophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, utamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, esulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, olipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, l, laidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, drocholesterol, cholecalciferol, 25-hydroxycholecalciferol, riol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, avin, niacin, nicotinamide, pantothenic acid, dexpanthenol, hine, pyridoxine, pyridoxal ate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or O--R2 wherein, within the proviso R, R2, R3 independently represents O O O O OH WO 22626 PCT/1B2017/052247 0 0 0 OH0 0 0 0 0 ) -17 0 0 The compositions are typically compounds in the forms of hydrates or solvates of levobupivacaine and an acidic moiety [RH] ning compound ed [RH] in which the levobupivacaine is protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is at least in partially ionic form. In some instances, however, for example depending on the pH of the environment, the composition may be in the form of a mixture of levobupivacaine and acid components [RH]. The invention also es pharmaceutical compositions comprising compositions of formula IV and pharmaceutically acceptable excipients.

In certain embodiments, the compounds of formula V are described: and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; RH independently represents olipids, phosphatidylcholine, menthol, retinoic acid, vitamin A, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7 dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25 dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, xamine, pyritinol, biotin, folic acid, ofolic acid, c acid, levomefolic acid, adenosylcobalamin, obalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or wherein, within the proviso R, R2, R3 ndently represents 0 0 N 0 0 0O 0 OH O O O OH0 20 WO 22626 PCT/1B2017/052247 0 ~Js0 0 0 The compositions are typically compounds in the forms of es or solvates of ine and an acidic moiety [RH] containing compound selected [RH] in which the lidocaine is protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is at least in partially ionic form. In some instances, however, for example depending on the pH of the environment, the ition may be in the form of a mixture of lidocaine and acid components [RH]. The invention also provides pharmaceutical compositions comprising compositions of a V and pharmaceutically acceptable excipients.

In certain embodiments, the nds of formula VI are described: Formula VI and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently ents phospholipids, phosphatidylcholine, menthol, retinoic acid, n A, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7 dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25 dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, quinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, avin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, c acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or Rj-O----R3 n, within the proviso R, R2, R3 independently represents O OH O 0 0 O OH O N 0 O OH O 0 0 NH 2 , NH2 WO 22626 0 ~ss0 The compositions are typically compounds in the forms of hydrates or solvates of bupivacaine and an acidic moiety [RH] containing compound ed [RH] in which the bupivacaine is protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is at least in partially ionic form. In some instances, r, for example depending on the pH of the environment, the composition may be in the form of a mixture of bupivacaine and acid ents [RH]. The invention also provides pharmaceutical compositions comprising compositions of formula VI and pharmaceutically acceptable excipients.

In certain ments, the nds of formula VII are described: Formula VII and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, ic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, -1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, ic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, onic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, lenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, olipids, phosphatidylcholine, oleic acid, c acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, l, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, l, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, erol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, namide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, ofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, ocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, , 1-docosanol or Rj-O----R3 wherein, within the o R, R2, R3 independently represents O H 0 0 O OHH 0OH O N 0 NH2 O / 0 The compositions are typically compounds in the forms of hydrates or solvates of mepivacaine and an acidic moiety [RH] containing compound selected [RH] in which the caine is protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is at least in partially ionic form. In some instances, r, for example depending on the pH of the environment, the composition may be in the form of a mixture of mepivacaine and acid components [RH]. The invention also provides pharmaceutical compositions comprising compositions of formula VII and pharmaceutically able excipients.

In the Formula VII, mepivacaine might consists of R(-)-mepivacaine and S(+) caine in equal proportions and one of the enantiomer could be selected for the salt preparation process or the c mixture containing equal propositions of R and S enantiomers can be selected for the salt preparation process.

In certain embodiments, the compounds of formula VIII are described: a VIII and ceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, osalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, ic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, oric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, anic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), e, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, ic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, donic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, in, tretinoin, u-carotene j-carotene retinol, d2 erol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, quinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, iamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, xal ate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, folic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, , 1-docosanol or Rj-O----R3 wherein, within the proviso R, R2, R3 independently represents WO 22626 PCT/1B2017/052247 0 0 0H HH / 0 The compositions are typically compounds in the forms of es or solvates of ropivacaine and an acidic moiety [RH] containing compound selected [RH] in which the ropivacaine is protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is at least in partially ionic form. In some instances, however, for example depending on the pH of the nment, the composition may be in the form of a mixture of ropivacaine and acid components [RH]. The invention also provides pharmaceutical compositions comprising compositions of formula VIII and pharmaceutically acceptable excipients.

In certain embodiments, the compounds of a IX are described: and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH ndently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor fonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, lsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, c acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, c acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, c acid, succinic acid, sulfuric acid, ic acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, l, retinal, isotretinoin, curcumin, tretinoin, u-carotene tene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, lcidol, dihydrotachysterol, otriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, quinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, , nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ic acid, dehydroascorbic acid, 1-docosanol or Rj-O----R3 wherein, within the proviso R, R2, R3 independently represents 0 0 O OH WO 22626 PCT/1B2017/052247 0 0 0 OH0 0 0 0 0 ) -35 0 0 The compositions are typically compounds in the forms of hydrates or solvates of aine and an acidic moiety [RH] containing compound selected [RH] in which the tetracaine is protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is at least in partially ionic form. In some instances, however, for example ing on the pH of the environment, the composition may be in the form of a mixture of tetracaine and acid components [RH]. The invention also provides pharmaceutical compositions comprising compositions of a IX and pharmaceutically acceptable excipients.

In certain ments, the compounds of a X are described: H2N CI Formula X and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, lutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), ic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, aric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, onic acid, pyroglutamic acid, lic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, tene j-carotene retinol, d2 erol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, lcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), inones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, amine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, xamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or O--R2 Rj-O-O-R3 wherein, within the proviso R, R2, R3 ndently represents O 3 O OH O O O OH , 0 WO 22626 PCT/1B2017/052247 0 000 N 0H0 0 0 NH20 H 0 0 The compositions are typically compounds in the forms of hydrates or solvates of chloroprocaine and an acidic moiety [RH] containing compound ed [RH] in which the chloroprocaine is protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is at least in partially ionic form. In some instances, however, for example depending on the pH of the environment, the composition may be in the form of a mixture of chloroprocaine and acid components [RH]. The invention also provides ceutical compositions comprising compositions of formula X and pharmaceutically able excipients.

In certain embodiments, the compounds of formula XI are described: and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and isomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, lsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, ic acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, c acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl ne (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, ic acid, myristic acid, myristoleic acid, ic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene tene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, riol (1,25-dihydroxycholecalciferol), roic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, iamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, c acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, e, ascorbic acid, dehydroascorbic acid, 1-docosanol or wherein, within the proviso R, R2, R3 independently represents O O O OH O O O OH , 0 WO 22626 PCT/1B2017/052247 0 000 N 0H0 0 0 NH20 H 0 0 The compositions are typically compounds in the forms of hydrates or solvates of procaine and an acidic moiety [RH] containing compound selected [RH] in which the procaine is protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is at least in lly ionic form. In some instances, however, for example depending on the pH of the environment, the composition may be in the form of a mixture of ne and acid ents [RH]. The invention also es pharmaceutical compositions comprising compositions of formula XI and pharmaceutically acceptable excipients.

In certain embodiments, the compounds of formula XII are described: H2N ON a XII and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, oxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), c acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, lsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, ic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, lic acid, sebacic acid, c acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, yl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, WO 22626 linoleic acid, nic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, l, retinoic acid, vitamin a, retinol, retinal, isotretinoin, in, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, itol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), one (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or Rj-O----R3 wherein, within the proviso R, R2, R3 ndently represents O O O OH O O O OH , 0 WO 22626 PCT/1B2017/052247 0 000 N 0H0 0 0 NH20 H 0 0 The compositions are typically compounds in the forms of hydrates or solvates of proparacaine and an acidic moiety [RH] containing compound selected [RH] in which the acaine is protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is at least in partially ionic form. In some instances, however, for example depending on the pH of the environment, the composition may be in the form of a mixture of proparacaine and acid ents [RH]. The invention also provides ceutical compositions sing compositions of formula XII and pharmaceutically acceptable excipients.

In certain embodiments, the compounds of formula XIII are described: Formula XIII and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; RH independently ents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, lutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, -1,2-disulfonic acid, sulfonic acid, formic acid, fumaric acid, galactaric acid, ic acid, eptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, ic acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, ic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, l, retinal, isotretinoin, curcumin, tretinoin, tene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, roxycholecalciferol, riol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, iamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, hine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or Rj-O----R3 wherein, within the proviso R, R2, R3 independently represents O O O OH O O O OH , 0 WO 22626 PCT/1B2017/052247 0 000 N 0H0 0 0 NH20 H The compositions are typically compounds in the forms of hydrates or solvates of pramocaine and an acidic moiety [RH] ning compound selected [RH] in which the pramocaine is protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is at least in partially ionic form. In some instances, however, for example depending on the pH of the environment, the composition may be in the form of a mixture of pramocaine and acid components [RH]. The ion also provides pharmaceutical compositions sing compositions of formula XIII and pharmaceutically acceptable ents.

In certain embodiments, the compounds of formula XIV are described: RH R 1-O -- R3 Formula XIV and pharmaceutically able hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, R', R2, R3 independently represents 0 0 0 0 OH H o o NH2 O 0530 20 WO 22626 PCT/1B2017/052247 RH independently represents oxytetracycline, tetracycline, amphenicol, chloramphenicol, neomycin, icin, amikacin, nadifloxacin, virginiamycin, rifaximin, fusidic acid, acin, tyrothricin, mupirocin, sulfonamides, silver, sulfadiazine, sulfathiazole, mafenide, sulfamethizole, sulfanilamide, sulfamerazine, aciclovir, penciclovir, idoxuridine, edoxudine, mod, resiquimod, podophyllotoxin, docosanol, tromantadine, inosine, lysozyme, ibacitabine, lysine, ingenol mebutate, metronidazole, acyclovir, phenol, valaciclovir, valacyclovir, famciclovir, silver, zinc, iodine, benzalkonium, benzethonium, cetylpyridinium, clioquinol, triclosan, chlorhexidine, chloramphenicol, menthol, neomycin, gentamicin, in, ne, esketamine, arketamine, ceftriaxone or cefepime.

The compositions are typically compounds in the forms of hydrates or solvates of glycerol fatty acid ate and a moiety ented by [RH] containing compound selected [RH] in which the glycerol fatty acid conjugate is an acid moiety ionic d and the base moiety represented by [RH] in a ceutically acceptable salt form. In some instances, however, for example depending on the pH of the environment, the composition may be in the form of a mixture of glycerol fatty acid conjugate and base components [RH]. The invention also provides pharmaceutical itions comprising compositions of formula XIV and pharmaceutically acceptable excipients.

In certain embodiments, the compounds of formula XV are described: Formula XV and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, esulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, ic acid, citric acid, cyclamic acid, dodecylsulfuric acid, -1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, ic acid , onic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, ic acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, lenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), e, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, olipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, laidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, ic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, lcitol, tocopherol, naphthoquinone, phylloquinone (kl), inones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or O--R2 Rj-OO-R3 n, within the o R, R2, R3 independently represents O 0 O OH O OH O WO 22626 PCT/1B2017/052247 0 000 N 0H0 0 0 NH20 H The compositions are typically compounds in the forms of hydrates or solvates of ketamine and an acidic moiety [RH] containing compound ed [RH] in which the ketamine is protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is at least in partially ionic form. In some instances, however, for example depending on the pH of the environment, the ition may be in the form of a mixture of ketamine and acid components [RH]. The invention also provides pharmaceutical compositions comprising itions of formula XV and pharmaceutically acceptable excipients.

In the Formula XV, ketamine can exist in R enantiomer and S enantiomer or in equal proportions and one of the enantiomer could be ed for the salt preparation process or the racemic mixture containing equal propositions of R and S enantiomers can be selected for the WO 22626 salt preparation process. R- enantiomer is also referred as arketamine and S- enantiomer is also referred as esketamine.

Herein the application also provides a kit comprising any of the pharmaceutical itions disclosed herein. The kit may comprise instructions for use in the treatment of chronic pain or its related complications.

The application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the compositions herein. In some aspects, the pharmaceutical composition is formulated for oral solution, oral g solution, oral antiseptic solution, systemic administration, oral administration, sustained release, parenteral administration, injection, mal administration, or transdermal administration.

Herein, the application additionally provides kits sing the pharmaceutical compositions described herein. The kits may r comprise instructions for use in the treatment of chronic pain or its related complications.

The compositions described herein have several uses. The present ation provides, for example, s of treating a patient suffering from chronic pain or its related complications manifested from metabolic or genetic conditions or disorders, metabolic diseases, chronic diseases or disorders; neurodegenerative ers, lic condition, Hepatology, Cancer, Respiratory, logical, Orthopedic, Cardiovascular, Renal, Skin, Vascular or Ocular complications.

DETAILED DESCRIPTION OF THE INVENTION Definitions As used herein, the following terms and phrases shall have the meanings set forth below.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art.

Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers." Isomers that differ in the arrangement of their atoms in space are termed oisomers." Diastereomers are stereoisomers with opposite configuration at one or more chiral centers which are not enantiomers. Stereoisomers bearing one or more tric centers that are non superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric , for example, if a carbon atom is bonded to four different , a pair of enantiomers is possible. An enantiomer can be terized by the absolute configuration of its tric center or centers and is described by the R- and S-sequencing rules of Cahn, Ingold and , or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".

As used herein, the term "metabolic condition" refers to an Inborn errors of metabolism (or genetic metabolic conditions) are genetic disorders that result from a defect in one or more metabolic pathways; specifically, the function of an enzyme is ed and is either deficient or completely absent.

The term "polymorph" as used herein is art-recognized and refers to one crystal structure of a given compound.

The phrases "parenteral administration" and "administered parenterally" as used herein refer to modes of administration other than enteral and topical administration, such as injections, and include without limitation intravenous, intramuscular, intrapleural, intravascular, intrapericardial, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradennal, intraperitoneal, racheal, subcutaneous, subcuticular, articular, sular, subarachnoid, intraspinal and intrastemal injection and infusion.

A "patient," "subject," or "host" to be treated by the subject method may mean either a human or non-human animal, such as primates, mammals, and vertebrates.

The phrase "pharmaceutically acceptable" is art-recognized. In certain embodiments, the term includes compositions, polymers and other materials and/or dosage forms which are, within the scope of sound l judgment, suitable for use in contact with the tissues of mammals, human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically able carrier" is art-recognized, and includes, for example, pharmaceutically acceptable materials, itions or vehicles, such as a liquid or solid filler, diluent, solvent or encapsulating material involved in carrying or transporting any t composition, from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of a subject composition and not ous to the patient. In certain embodiments, a pharmaceutically acceptable carrier is non-pyrogenic. Some examples of materials which may serve as pharmaceutically acceptable carriers include: (1) sugars, such as e, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and ose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, ol, mannitol and hylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and um hydroxide; (15) alginic acid; (16) n free water; (17) isotonic saline; (18) 's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

The term "prodrug" is intended to encompass compounds that, under physiological conditions, are converted into the therapeutically active agents of the present invention. A common method for making a prodrug is to include selected es that are yzed under physiological conditions to reveal the desired molecule. In other embodiments, the g is converted by an enzymatic activity of the host animal.

The term "prophylactic or therapeutic" treatment is cognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the ent is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the ent is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

The term "predicting" as used herein refers to assessing the probability d diseases patient will suffer from abnormalities or complication and/or terminal platelet aggregation or e and/or death (i.e. mortality) within a defined time window (predictive window) in the future. The mortality may be caused by the central nervous system or cation. The predictive window is an al in which the subject will develop one or more of the said complications according to the predicted probability. The predictive window may be the entire remaining lifespan of the subject upon analysis by the method of the present invention.

The term "treating" is art -recognized and includes preventing a disease, disorder or condition from occurring in an animal which may be predisposed to the disease, disorder and/or ion but has not yet been diagnosed as having it; inhibiting the disease, disorder or condition, e.g., impeding its progress; and relieving the e, disorder, or condition, e.g., causing sion of the disease, disorder and/or condition. Treating the e or condition includes ameliorating at least one symptom of the particular e or condition, even if the underlying hysiology is not affected, such as treating chronic pain , surgery pain, wound pain, ulcer pain, neuropathic pain, central and peripheral nerve damage pain and other related diseases or any other medical condition, is well understood in the art, and includes stration of a composition which reduces the frequency of, or delays the onset of, symptoms of a medical condition in a subject relative to a subject which does not receive the composition.

The phrase "therapeutically effective amount" is an art-recognized term. In certain embodiments, the term refers to an amount of a solvate or hydrate or composition disclosed herein that produces some desired effect at a able benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary ing on such factors as the disease or condition being treated, the particular targeted constructs being administered, the size of the subject, or the ty of the disease or condition. One of ordinary skill in the art may empirically determine the effective amount of a particular composition without necessitating undue experimentation.

In certain embodiments, the pharmaceutical itions described herein are formulated in a manner such that said compositions will be delivered to a patient in a therapeutically effective amount, as part of a prophylactic or therapeutic treatment. The desired amount of the composition to be administered to a patient will depend on absorption, vation, and excretion rates of the drug as well as the delivery rate of the es or solvates and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be ated. It is to be further understood that for any particular subject, ic dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions. Typically, dosing will be ined using techniques known to one d in the art.

Additionally, the optimal concentration and/or quantities or amounts of any particular solvate or hydrate or composition may be adjusted to accommodate variations in the treatment parameters. Such treatment parameters e the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the e or condition.

In certain embodiments, the dosage of the subject compositions provided herein may be determined by reference to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used.

WO 22626 2017/052247 When used with respect to a pharmaceutical composition or other material, the term "sustained release" is art-recognized. For example, a subject composition which releases a substance over time may t sustained release characteristics, in contrast to a bolus type administration in which the entire amount of the substance is made biologically available at one time. For e, in particular embodiments, upon contact with body fluids including blood, spinal fluid, mucus secretions, lymph or the like, one or more of the pharmaceutically acceptable excipients may undergo gradual or delayed degradation (e.g., through hydrolysis) with concomitant release of any material incorporated therein, e.g., an therapeutic and/or biologically active solvate or hydrate and/or composition, for a sustained or extended period (as compared to the release from a bolus). This release may result in prolonged delivery of therapeutically ive amounts of any of the therapeutic agents disclosed herein.

The phrases "systemic administration," "administered systemically," "peripheral administration" and "administered peripherally" are art-recognized, and include the administration of a subject ition, therapeutic or other material at a site remote from the disease being treated. Administration of an agent for the disease being treated, even if the agent is subsequently distributed ically, may be termed "local" or "topical" or "regional" administration, other than directly into the central nervous system, e.g., by subcutaneous administration, such that it enters the patient's system and, thus, is subject to metabolism and other like processes.

The phrase "therapeutically effective amount" is an art-recognized term. In certain ments, the term refers to an amount of a solvate or hydrate or composition disclosed herein that es some desired effect at a reasonable benefit/risk ratio applicable to any medical treatment. In certain embodiments, the term refers to that amount necessary or sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount may vary depending on such factors as the disease or condition being treated, the ular targeted constructs being stered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art may empirically determine the ive amount of a ular composition without necessitating undue experimentation.

The t disclosure also contemplates gs of the compositions disclosed herein, as well as pharmaceutically acceptable hydrates or solvates of said prodrugs.

This application also discloses a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the ition of a compound of Formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, a XI, formula XII, formula XIII, formula XIV or formula XV may be formulated for systemic or topical or oral administration. The pharmaceutical composition may be also formulated for oral administration, oral solution, injection, mal stration, or transdermal administration. The ceutical composition may further comprise at least one of a pharmaceutically acceptable stabilizer, diluent, surfactant, filler, binder, and lubricant.

In many embodiments, the pharmaceutical compositions described herein will incorporate the sed compounds and itions (Formula I, formula II, formula III, formula IV, formula V, formula VI, a VII, formula VIII, formula IX, formula X, formula XI, a XII, formula XIII, formula XIV or formula XV) to be delivered in an amount sufficient to deliver to a patient a therapeutically effective amount of a compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, a XIV or formula XV or composition as part of a prophylactic or therapeutic ent. The desired concentration of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV or formula XV or its pharmaceutical acceptable es or solvates will depend on absorption, inactivation, and excretion rates of the drug as well as the delivery rate of the hydrates or solvates and compositions from the subject compositions. It is to be noted that dosage values may also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time ing to the individual need and the professional nt of the person administering or supervising the administration of the compositions. Typically, dosing will be determined using techniques known to one skilled in the art.

Additionally, the optimal concentration and/or quantities or amounts of any particular compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, a VIII, formula IX, formula X, formula XI, formula XII, formula XIII, a XIV or formula XV may be adjusted to accommodate ions in the treatment parameters. Such treatment parameters include the clinical use to which the preparation is put, e.g., the site treated, the type of patient, e.g., human or non-human, adult or child, and the nature of the disease or condition.

The concentration and/or amount of any compound of formula I, formula II, formulaIII, formula IV, formula V, formula VI, formula VII, a VIII, formula IX, a X, formula XI, a XII, formula XIII, formula XIV or formula XV may be readily identified by e screening in animals, e.g., rats, by screening a range of concentration and/or amounts of the material in question using appropriate assays. Known methods are also available to assay local tissue concentrations, diffusion rates of the hydrates or solvates or compositions, and local blood flow before and after administration of therapeutic ations disclosed herein. One such method is microdialysis, as reviewed by T. E. Robinson et al., 1991, microdialysis in the ciences, Techniques, volume 7, Chapter 1. The methods reviewed by Robinson may be applied, in brief, as follows. A microdialysis loop is placed in situ in a test animal. Dialysis fluid is pumped through the loop. When compounds with a I, formula II, formula III, formula IV, formula V, formula VI, formula VII, a VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV or formula XV such as those disclosed herein are injected adjacent to the loop, released drugs are collected in the dialysate in proportion to their local tissue concentrations. The ss of diffusion of the hydrates or es or compositions may be determined thereby with suitable calibration procedures using known concentrations of hydrates or solvates or compositions.

In certain embodiments, the dosage of the subject compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV or formula XV provided herein may be determined by nce to the plasma concentrations of the therapeutic composition or other encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to infinity may be used. lly, in carrying out the methods detailed in this application, an effective dosage for the compounds of Formula I, formula II, formula III, formula IV , formula V, formula VI, formula VII, formula VIII, formula IX, a X, formula XI, formula XII, formula XIII, formula XIV or a XV is in the range of about 0.01 mg/kg/day to about 100 day in single or divided doses, for instance 0.01 mg/kg/day to about 50 mg/kg/day in single or divided doses. The compounds of Formulas I may be administered at a dose of, for example, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0 mg/kg/day, 5 day, 10 mg/kg/day, 20 mg/kg/day, 30 day, or 40 mg/kg/day. Compounds of Formula I, formula II, a III, formula IV, a V, formula VI, formula VII, formula VIII, a IX, formula X, formula XI, formula XII, formula XIII, a XIV or formula XV may also be administered to a human patient at a dose of, for example, between 0.1 mg and 1000 mg, between 5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400, 500, 800, 1000, 2000, 5000 mg per day. In certain embodiments, the compositions herein are administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% of the compound of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, a IX, formula X, formula XI, formula XII, formula XIII, formula XIV or formula XV required for the same therapeutic benefit.

An effective amount of the compounds of formula I, formula II, formula III, formula IV, a V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV or formula XV described herein refers to the amount of one of said es or solvates or compositions which is capable of inhibiting or preventing a disease.

An effective amount may be sufficient to prohibit, treat, alleviate, ameliorate, halt, restrain, slow or reverse the ssion, or reduce the severity of a complication resulting from nerve damage or demyelization and/or elevated reactive oxidative-nitrosative species and/or abnormalities in neurotransmitter homeostasis's, in patients who are at risk for such complications. As such, these methods include both medical therapeutic (acute) and/or prophylactic (prevention) administration as appropriate. The amount and timing of compositions administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician. Thus, because of patient-to-patient variability, the dosages given above are a guideline and the physician may titrate doses of the drug to achieve the treatment that the physician considers appropriate for the t. In considering the degree of treatment desired, the physician must balance a variety of factors such as age of the patient, presence of preexisting disease, as well as presence of other diseases.

The compositions provided by this application may be administered to a subject in need of treatment by a variety of tional routes of administration, including orally, topically, parenterally, e.g., intravenously, aneously or intramedullary. Further, the compositions may be administered intranasally, as a rectal suppository, or using a "flash" formulation, i.e., allowing the medication to dissolve in the mouth without the need to use water. Furthermore, the itions may be administered to a subject in need of treatment by lled release dosage forms, site specific drug delivery, transdermal drug ry, patch (active/passive) mediated drug delivery, by stereotactic injection, or in nanoparticles.

The compositions may be administered alone or in combination with pharmaceutically acceptable carriers, vehicles or ts, in either single or multiple doses. Suitable pharmaceutical carriers, es and diluents include inert solid diluents or fillers, sterile s solutions and various organic solvents. The pharmaceutical compositions formed by ing the compositions and the pharmaceutically acceptable carriers, vehicles or diluents are then readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, ents and the like. Thus, for purposes of oral administration, tablets containing various ents such as nine, sodium citrate, calcium carbonate and calcium phosphate may be employed along with s disintegrates such as starch, alginic acid and n complex silicates, er with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl e and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and high molecular weight polyethylene s. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various ning or flavoring , coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene , glycerin and combinations thereof. The compounds of a I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, a IX, formula X, formula XI, formula XII, formula XIII, a XIV or formula XV may also comprise enterically coated comprising of various excipients, as is well known in the pharmaceutical art.

For parenteral administration, solutions of the compositions may be prepared in (for example) sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solutions may be employed. Such aqueous solutions should be suitably ed if necessary and the liquid diluent first rendered isotonic with ient saline or glucose. These ular aqueous solutions are especially suitable for intravenous, uscular, subcutaneous and intraperitoneal administration. In this connection, the sterile s media employed are all readily available by standard techniques known to those d in the art.

The formulations, for instance tablets, may contain e.g. 10 to 100, 50 to 250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300, 500, 700, 800 mg of the nds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV or formula XV disclosed herein, for instance, compounds of formula I, formula II, a III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV or formula XV or pharmaceutical acceptable hydrates or solvates of a compounds of Formula I.

Generally, a composition as described herein may be administered orally, or parenterally (e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may also be indicated, for example, where the patient is suffering from intestinal disorder that prevent oral administration, or whenever the medication is best applied to the surface of a tissue or organ as determined by the attending ian. zed administration may also be indicated, for example, when a high dose is desired at the target tissue or organ. For buccal administration the active composition may take the form of tablets or lozenges formulated in a conventional manner.

The dosage administered will be dependent upon the identity of the neurological disease; the type of host involved, including its age, health and weight; the kind of concurrent ent, if any; the frequency of treatment and therapeutic ratio.

Illustratively, dosage levels of the administered active ients are: intravenous, 0.1 to about 200 mg/kg; intramuscular, 1 to about 500 mg/kg; orally, 5 to about 1000 mg/kg; intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of host body weight.

Expressed in terms of concentration, an active ingredient can be present in the itions of the present invention for localized use about the cutis, intranasally, pharyngolaryngeally, bronchially, intravaginally, rectally, or ocularly in a concentration of from about 0.01 to about 50% w/w of the composition; preferably about 1 to about 20% w/w of the composition; and for parenteral use in a concentration of from about 0.05 to about 50% w/v of the composition and preferably from about 5 to about 20% w/v.

The compositions of the present invention are preferably presented for administration to humans and animals in unit dosage forms, such as tablets, es, pills, powders, granules, suppositories, sterile parenteral solutions or suspensions, sterile non-parenteral solutions of suspensions, and oral solutions or suspensions and the like, containing suitable ties of an active ingredient. For oral administration either solid or fluid unit dosage forms can be As discussed above, the tablet core contains one or more hydrophilic polymers. Suitable hydrophilic polymers include, but are not d to, water swellable cellulose derivatives, polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays, gelling starches, swelling cross-linked rs, and mixtures thereof. Examples of suitable water swellable cellulose derivatives e, but are not limited to, sodium carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose, hydroxyphenylcellulose, hydroxyethylcellulose (HEC), hydroxypentylcellulose, hydroxypropylethylcellulose, hydroxypropylbutylcellulose, and hydroxypropylethylcellulose, and mixtures f. Examples of suitable polyalkylene glycols include, but are not limited to, polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides include, but are not limited to, poly(ethylene oxide). Examples of suitable acrylic polymers include, but are not limited to, potassium methacrylatedivinylbenzene copolymer, thylmethacrylate, high molecular weight crosslinked acrylic acid homopolymers and copolymers such as those commercially available from Noveon als under the tradename OLTM.

Examples of suitable olloids include, but are not limited to, alginates, agar, guar gum, locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, anth, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan, methylan, , cyclodextrin, chitosan, and mixtures thereof. Examples of suitable clays include, but are not limited to, smectites such as bentonite, , and laponite; magnesium icate; magnesium aluminum silicate; and mixtures thereof. Examples of suitable gelling starches e, but are not limited to, acid hydrolyzed starches, swelling starches such as sodium starch glycolate and derivatives thereof, and mixtures thereof. Examples of suitable swelling cross-linked polymers include, but are not limited to, cross-linked polyvinyl pyrrolidone, cross-linked agar, and cross-linked carboxymethylcellulose sodium, and mixtures thereof.

The carrier may contain one or more suitable excipients for the ation of tablets.

Examples of suitable excipients e, but are not limited to, s, adsorbents, binders, disintegrants, lubricants, glidants, release-modifying excipients, superdisintegrants, antioxidants, and es thereof.

Suitable binders include, but are not limited to, dry s such as polyvinyl pyrrolidone and hydroxypropylmethylcellulose; wet binders such as soluble polymers, including olloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan, carboxymethylcellulose, tara, gum arabic, tragacanth, pectin, xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan, inulin, whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose, and starches; and mixtures thereof. Suitable disintegrants include, but are not limited to, sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked carboxymethylcellulose, es, microcrystalline cellulose, and mixtures thereof.

] Suitable lubricants e, but are not d to, long chain fatty acids and their es or solvates , such as magnesium stearate and stearic acid, talc, glycerides waxes, and es thereof. Suitable glidants include, but are not limited to, colloidal silicon dioxide.

Suitable release-modifying excipients include, but are not limited to, insoluble edible materials, pH-dependent polymers, and mixtures thereof.

Suitable insoluble edible materials for use as release-modifying excipients include, but are not limited to, water-insoluble polymers and low-melting hydrophobic materials, copolymers thereof, and mixtures f. Examples of suitable water-insoluble rs e, but are not limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose e and its derivatives, acrylates, methacrylates, acrylic acid mers, mers thereof, and mixtures thereof. Suitable low-melting hydrophobic materials include, but are not limited to, fats, fatty acid esters, phospholipids, waxes, and mixtures thereof. es of suitable fats include, but are not limited to, enated vegetable oils such as for example cocoa butter, enated palm kernel oil, hydrogenated cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids and their hydrates or solvates , and mixtures thereof. Examples of suitable fatty acid esters include, but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate, yl tristearate, glyceryl trilaurylate, glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, stearoyl macrogol-32 glycerides, and mixtures thereof. Examples of suitable phospholipids include phosphotidyl choline, phosphotidyl , phosphotidyl ol, phosphotidic acid, and mixtures thereof.

Examples of suitable waxes include, but are not limited to, carnauba wax, spermaceti wax, beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing mixtures such as chocolate, and mixtures thereof. Examples of super disintegrants include, but are not limited to, croscarmellose , sodium starch glycolate and cross-linked povidone ovidone). In one embodiment the tablet core contains up to about 5 percent by weight of such super disintegrant.

] Examples of antioxidants include, but are not limited to, tocopherols, ascorbic acid, sodium pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate hydrates or solvates , and es thereof. Examples of preservatives include, but are not limited to, citric acid, tartaric acid, lactic acid, malic acid, acetic acid, c acid, and sorbic acid, and mixtures thereof.

] In one embodiment, the immediate release coating has an e thickness of at least 50 s, such as from about 50 microns to about 2500 microns; e.g., from about 250 microns to about 1000 microns. In embodiment, the immediate release coating is typically compressed at a density of more than about 0.9 g/cc, as measured by the weight and volume of that specific layer.

In one embodiment, the immediate release coating contains a first portion and a second portion, wherein at least one of the ns contains the second pharmaceutically active agent. In one embodiment, the portions contact each other at a center axis of the tablet. In one embodiment, the first portion es the first pharmaceutically active agent and the second portion includes the second pharmaceutically active agent.

In one embodiment, the first portion contains the first pharmaceutically active agent and the second portion contains the second pharmaceutically active agent. In one embodiment, one of the portions contains a third pharmaceutically active agent. In one embodiment one of the portions contains a second immediate release portion of the same pharmaceutically active agent as that contained in the tablet core.

] In one embodiment, the outer coating portion is prepared as a dry blend of materials prior to addition to the coated tablet core. In another embodiment the outer g portion is included of a dried granulation including the pharmaceutically active agent.

Formulations with different drug release mechanisms described above could be combined in a final dosage form containing single or multiple units. Examples of multiple units e multilayer tablets, capsules containing tablets, beads, or granules in a solid or liquid form. l, immediate release formulations include compressed tablets, gels, films, coatings, liquids and particles that can be encapsulated, for example, in a gelatin e. Many methods for preparing coatings, ng or incorporating drugs, are known in the art.

The ate release dosage, unit of the dosage form, i.e., a tablet, a plurality of drug-containing beads, granules or particles, or an outer layer of a coated core dosage form, contains a eutically effective quantity of the active agent with tional ceutical excipients. The ate release dosage unit may or may not be coated, and may or may not be admixed with the delayed release dosage unit or units (as in an encapsulated mixture of immediate release drug-containing granules, particles or beads and delayed release drug-containing granules or beads).

Extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in gton-The Science and Practice of cy", 20th. Ed., Lippincott Williams & Wilkins, Baltimore, Md., 2000). A diffusion system typically consists of one of two types of devices, reservoir and matrix, which are wellknown and bed in die art.

The matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form.

An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core; using coating or compression processes or in a multiple unit system such as a capsule containing extended and immediate release beads.

Delayed release dosage formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, but soluble in the neutral environment of small intestines. The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected g material.

The drug-containing composition may be a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, les or es, for incorporation into either a tablet or capsule.

A pulsed release dosage form is one that mimics a multiple dosing profile t repeated dosing and typically allows at least a twofold reduction in dosing frequency as compared to the drug ted as a conventional dosage form (e.g., as a solution or prompt drug-releasing, conventional solid dosage form). A pulsed release profile is characterized by a time period of no release (lag time) or reduced release ed by rapid drug release.

Each dosage form contains a therapeutically effective amount of active agent. In one embodiment of dosage forms that mimic a twice daily dosing profile, approximately 30 wt. %to 70 wt. %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage form is released in the initial pulse, and, correspondingly approximately 70 wt. % to 3.0 wt. %, preferably 60 wt. % to 40 wt. %, of the total amount of active agent in the dosage form is ed in the second pulse. For dosage forms mimicking the twice daily dosing profile, the second pulse is preferably released approximately 3 hours to less than 14 hours, and more preferably approximately 5 hours to 12 hours, ing administration.

Another dosage form contains a compressed tablet or a capsule having a drug containing ate release dosage unit, a d release dosage unit and an optional second delayed release dosage unit. In this dosage form, the immediate release dosage unit contains a plurality of beads, es particles that release drug substantially immediately ing oral administration to provide an initial dose. The delayed release dosage unit contains a plurality of coated beads or granules, which release drug approximately 3 hours to 14 hours following oral administration to provide a second dose.

WO 22626 For purposes of transdermal (e.g., topical) administration, dilute sterile, aqueous or partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the above parenteral solutions, may be prepared.

Methods of preparing s pharmaceutical compositions with a certain amount of one or more nds of formula I, formula II, formula III, a IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV or formula XV or other active agents are known, or will be apparent in light of this disclosure, to those skilled in this art. For examples of methods of preparing pharmaceutical compositions, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 19th Edition (1995).

In addition, in certain embodiments, subject compositions of the present application maybe lyophilized or subjected to r appropriate drying technique such as spray drying.

The t itions may be administered once, or may be divided into a number of r doses to be administered at varying intervals of time, depending in part on the release rate of the compositions and the desired .

Formulations useful in the methods provided herein include those le for oral, nasal, l (including buccal and sublingual), rectal, l, aerosol and/or parenteral administration. The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of a subject composition which may be combined with a carrier material to produce a single dose may vary depending upon the subject being treated, and the particular mode of administration.

Methods of preparing these formulations or compositions include the step of bringing into association subject itions with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a subject composition with liquid carriers, or finely divided solid carriers, or both, and then, if ary, shaping the product.

The compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII, formula VIII, formula IX, formula X, formula XI, formula XII, formula XIII, formula XIV or formula XV described herein may be administered in inhalant or aerosol formulations. The inhalant or aerosol ations may comprise one or more agents, such as adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalation therapy.

The final aerosol formulation may for example contain 0.005-90% w/w, for instance 0.005 50%, 0.005-5% w/w, or 0.01-1.0% w/w, of medicament relative to the total weight of the formulation.

In solid dosage forms for oral administration les, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically able carriers and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, ymethylcellulose, alginates, gelatin, nyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as ol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or a starch, c acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol earate; (8) absorbents, such as kaolin and bentonite clay; (9) ants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and es thereof; and (10) coloring agents. In the case of capsules, s and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.

Liquid dosage forms for oral administration include pharmaceutically able emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the t compositions, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, corn, peanut, sunflower, soybean, olive, , and sesame oils), ol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Suspensions, in on to the subject itions, may contain suspending agents such as, for example, ethoxylated aryl alcohols, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, um metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations for rectal or vaginal stration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non irritating carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax, or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the appropriate body cavity and e the encapsulated compound(s) and composition(s). Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, , foams, or spray formulations ning such carriers as are known in the art to be appropriate.

Dosage forms for transdermal administration include powders, sprays, ointments, , creams, lotions, gels, solutions, patches, and inhalants. A subject composition may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required. For transdermal administration, the complexes may include lipophilic and hydrophilic groups to achieve the desired water solubility and transport properties.

The ointments, , creams and gels may contain, in addition to subject compositions, other carriers, such as animal and vegetable fats, oils, waxes, ins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or es thereof. Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, um hydroxide, calcium silicates and polyamide powder, or mixtures of such substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Methods of delivering a ition or compositions via a transdermal patch are known in the art. Exemplary patches and methods of patch delivery are described in US Patent Nos. 6,974,588, 6,564,093, 6,312,716, 6,440,454, 6,267,983, 6,239,180, and 6,103,275.

In another embodiment, a transdermal patch may comprise: a substrate sheet comprising a composite film formed of a resin composition comprising 100 parts by weight of a polyvinyl chloride-polyurethane ite and 2-10 parts by weight of a styrene-ethylene butylene-styrene copolymer, a first adhesive layer on the one side of the composite film, and a polyalkylene terephthalate film d to the one side of the composite film by means of the first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on the surface of the kylene terephthalate film; and a second adhesive layer comprising a e-diene-styrene block copolymer containing a pharmaceutical agent layered on the primer layer. A method for the manufacture of the above-mentioned substrate sheet ses preparing the above resin composition molding the resin composition into a composite film by a ar process, and then adhering a polyalkylene thalate film on one side of the composite film by means of an adhesive layer thereby forming the substrate sheet, and forming a primer layer comprising a saturated polyester resin on the outer surface of the polyalkylene terephthalate film.

Another type of patch comprises incorporating the drug ly in a pharmaceutically acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing member, e.g. a polyester backing membrane. The drug should be present at a concentration which will not affect the adhesive properties, and at the same time deliver the required clinical dose.

Transdermal patches may be passive or active. Passive transdermal drug delivery systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver small-molecule drugs. Many of the newly developed proteins and peptide drugs are too large to be delivered through passive transdermal patches and may be delivered using technology such as electrical assist (iontophoresis) for large-molecule drugs. ontophoresis is a que employed for enhancing the flux of ionized substances through membranes by application of electric current. One example of an iontophoretic membrane is given in U.S. Pat. No. 5,080,646 to Theeuwes. The principal mechanisms by which iontophoresis enhances lar transport across the skin are (a) repelling a d ion from an electrode of the same charge, (b) electroosmosis, the convective movement of solvent that occurs through a d pore in response the preferential passage of counter-ions when an electric field is applied or (c) increase skin permeability due to application of electrical current.

Methods and compositions for the treatment of inflammation. Among other things, herein is ed a method of treating inflammation and its ated pain, comprising stering to a patient in need f a therapeutically effective amount of compound of Formula I: O NH and pharmaceutically acceptable es, solvates, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, chloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, amidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid oic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, ic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, ic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, alene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, c acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, nic acid, menthol, ic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, tene -carotene l, d2 erol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, otachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, folic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or O--R2 wherein, within the proviso R, R2, R3 independently represents O O O O N 0 WO 22626 PCT/1B2017/052247 Methods and compositions for the treatment of inflammation. Among other things, herein is provided a method of treating inflammation and its ated pain, comprising administering to a patient in need thereof a eutically effective amount of compound of Formula II: N N H S Formula II and pharmaceutically acceptable hydrates, solvates, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, lutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor fonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, -1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, ic acid, sulfuric acid, tartaric acid, thiocyanic acid, esulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl e, aminocaproic acid, c acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, ic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, ic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, roxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, itol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, iamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, nol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, ylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, sanol or wherein, within the proviso R, R2, R3 independently represents WO 22626 PCT/1B2017/052247 0 0 0 H 0 0 OH / 0 s and compositions for the treatment of inflammation. Among other things, herein is provided a method of treating inflammation and its associated pain, comprising administering to a patient in need thereof a therapeutically effective amount of nd of Formula III: Formula III and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, lutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, eptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, utamic acid, salicylic acid, sebacic acid, c acid, succinic acid, ic acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, yl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, olipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, l, retinoic acid, vitamin A, retinol, linolelaidic acid, donic acid, phospholipids, atidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, tinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, lcitol, erol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, oascorbic acid, 1-docosanol or O--R2 Rj-OO-R3 wherein, within the proviso R, R2, R3 independently represents O 0 O OH O O O OH , 0 WO 22626 PCT/1B2017/052247 0 000 N 0H0 0 0 NH20 H or 0. s and compositions for the ent of inflammation. Among other things, herein is provided a method of treating inflammation and its associated pain, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula IV: 0 NH Formula IV WO 22626 and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, chloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, amidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor fonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, ic acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, onic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, ic acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, ic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, ic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene -carotene retinol, d2 ergosterol, ergocalciferol, drocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, lcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, tiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ic acid, oascorbic acid, 1-docosanol or --- R3 wherein, within the proviso R, R2, R3 independently represents O O O O o oa 0 OH O N 0 o o WO 22626 0 ~ss0 0 0 ] Methods and compositions for the treatment of inflammation. Among other things, herein is provided a method of ng inflammation and its associated pain, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula V: Formula V and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin A, retinol, retinal, isotretinoin, in, tretinoin, u-carotene j-carotene l, d2 ergosterol, ergocalciferol, 7 dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25 oxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, nol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, oascorbic acid, sanol or --- R3 wherein, within the proviso R, R2, R3 independently represents O OH O o a O O OH O 41y : N.' 0- O WO 22626 0 0 NH2 O NH2 Methods and compositions for the treatment of inflammation. Among other things, herein is ed a method of treating mation and its associated pain, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula VI: Formula VI and pharmaceutically acceptable hydrates, es, prodrugs, enantiomers, and stereoisomers thereof; ] Wherein, RH independently represents phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin A, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7 dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25 dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, quinone (kl), menaquinones (k2), one (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal ate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, sanol or O--R2 wherein, within the proviso R, R2, R3 independently represents o o Y O O~ O OH O WO 22626 PCT/1B2017/052247 0 000 N 0H0 0 0 NH20 H Methods and compositions for the treatment of mation. Among other things, herein is provided a method of treating inflammation and its associated pain, comprising administering to a patient in need thereof a therapeutically ive amount of compound of Formula VII: RI IM N Formula VII and pharmaceutically able hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, oxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, r -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 onic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, utamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, ic acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, c acid, linoleic acid, linolenic acid, l, retinoic acid, vitamin A, retinol, laidic acid, arachidonic acid, phospholipids, phosphatidylcholine, l, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene -carotene retinol, d2 ergosterol, ergocalciferol, drocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, xine, pyridoxal ate, xamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, ocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, , 1-docosanol or O--R2 wherein, within the proviso R, R2, R3 independently represents O OH 0 0 0 0 O OH O N 0- O H O 0 0 NH2 O NH2 WO 22626 PCT/1B2017/052247 Methods and compositions for the treatment of mation. Among other things, herein is provided a method of treating inflammation and its associated pain, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula VIII: Formula VIII and ceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, oxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor fonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), ic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, ic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 onic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, c acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, nic acid, menthol, ic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), roic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, itol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, tiamine, sulbutiamine, riboflavin, , nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, , sanol or wherein, within the proviso R, R2, R3 independently represents WO 22626 PCT/1B2017/052247 0 0 0H HH / 0 Methods and compositions for the treatment of inflammation. Among other things, herein is provided a method of treating inflammation and its associated pain, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula IX: Formula IX and pharmaceutically able hydrates, solvates, gs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, eptonic acid, gluconic acid , onic acid, glutamic acid, glutaric acid, glycerophosphoric acid, ic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nic acid, nitric acid, oleic acid, oxalic acid, ic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, olipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, oin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 oergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), ne, tiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, , nicotinamide, pantothenic acid, dexpanthenol, hine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, cobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or Rl---R3 wherein, within the proviso R, R2, R3 independently represents o o O OH WO 22626 PCT/1B2017/052247 0 0 0 OH0 0 0 0 / 0 Methods and compositions for the treatment of inflammation. Among other , herein is provided a method of treating inflammation and its associated pain, sing administering to a patient in need thereof a therapeutically effective amount of compound of Formula X: and pharmaceutically acceptable hydrates, es, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, ric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, ic acid, ic acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, ic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, lenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), e, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, olipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, drocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, otriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, avin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, obalamin, hydroxocobalamin, methylcobalamin, choline, ic acid, oascorbic acid, 1-docosanol or O--R2 Rj-OO-R3 wherein, within the proviso R, R2, R3 independently represents O 1 O OH O OH O WO 22626 PCT/1B2017/052247 0 000 N 0H0 0 0 NH20 H Methods and compositions for the treatment of inflammation. Among other things, herein is provided a method of treating inflammation and its associated pain, comprising administering to a t in need thereof a therapeutically effective amount of compound of a XI: Formula XI and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, amidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, ic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, eptonic acid, ic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, nic acid, menthol, retinoic acid, vitamin A, l, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, l, retinal, isotretinoin, curcumin, tretinoin, u-carotene -carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, roxycholecalciferol, calcitriol dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, otachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, quinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, avin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ic acid, dehydroascorbic acid, 1-docosanol or --- R3 wherein, within the proviso R, R2, R3 independently represents O O O O o oa 0 O o o NH2, ONH, WO 22626 PCT/1B2017/052247 0 ~ss0 ] Methods and compositions for the treatment of inflammation. Among other things, herein is provided a method of treating inflammation and its associated pain, comprising administering to a patient in need f a therapeutically effective amount of compound of Formula XII: H2N ON Formula XII and pharmaceutically acceptable es, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, -1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, ic acid, glutaric acid, ophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, c acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, ic acid, palmitoleic acid, olipids, phosphatidylcholine, oleic acid, elaidic acid, ic acid, linolenic acid, menthol, ic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, l, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, tiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, xal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or wherein, within the proviso R, R2, R3 independently represents WO 22626 PCT/1B2017/052247 0 0 0H HH OH123 / 0 s and compositions for the treatment of inflammation. Among other things, herein is provided a method of treating inflammation and its associated pain, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula XIII: Formula XIII and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and isomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, ic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, yric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, ic acid, methanesulfonic acid, alene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, lic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, lenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl e, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, ic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, atidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, tinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, hine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, c acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, cobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or Rl---R3 wherein, within the proviso R, R2, R3 independently represents o o O OH O O O OH , 0 WO 22626 PCT/1B2017/052247 0 000 N 0H0 0 0 NH20 H s and compositions for the treatment of inflammation. Among other things, herein is provided a method of treating inflammation and its ated pain, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula XIV: RH R 1-O Formula XIV and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; R', R2, R3 independently represents O O -0 H N 0 WO 22626 PCT/1B2017/052247 RH independently represents oxytetracycline, tetracycline, icol, chloramphenicol, neomycin, gentamicin, amikacin, nadifloxacin, virginiamycin, rifaximin, fusidic acid, bacitracin, tyrothricin, mupirocin, sulfonamides, silver, sulfadiazine, sulfathiazole, de, sulfamethizole, sulfanilamide, sulfamerazine, vir, penciclovir, idoxuridine, edoxudine, imiquimod, resiquimod, podophyllotoxin, docosanol, tromantadine, inosine, lysozyme, ibacitabine, lysine, ingenol mebutate, metronidazole, acyclovir, phenol, valaciclovir, clovir, lovir, silver, zinc, iodine, benzalkonium, benzethonium, cetylpyridinium, clioquinol, san, chlorhexidine, chloramphenicol, menthol, in, gentamicin, amikacin, ketamine, esketamine, arketamine, ceftriaxone or cefepime.

Methods and compositions for the treatment of inflammation. Among other things, herein is provided a method of treating inflammation and its associated pain, comprising administering to a patient in need thereof a therapeutically effective amount of compound of Formula XV: NH N RH Formula XV and pharmaceutically acceptable hydrates, es, prodrugs, omers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, oxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, amidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor -sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, ic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, c acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl e, ethyl e, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene -carotene l, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, riol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, quinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, WO 22626 acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, cobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or --- R3 wherein, within the proviso R, R2, R3 independently represents O O O O o oa 0 O o o NH2 , 0 NH2 WO 22626 PCT/1B2017/052247 0 ~ss0 WO 22626 METHODS OF MAKING Examples of synthetic pathways useful for making compounds of formulas are set forth in example below: Example 1: 0 00 0 0 CI NaCNBH4, AcOH, 0 o HO ,J OH 2 0 THF,0°Ctort,16h 5H DCM, Pyridine, DMAP 0 71% OH TEA, CHCl3, 0 1 t1hStep-2 73% 0 120C,72% 3h 000q0 Step-1 0 Step-3 6 OH Synthesis of 2-oxopropane-1,3-diyl dioctanoate (3): To an ice cold solution of 1,3 dihydroxypropanone (1, 25.0 g, 0.277 mol) in dichloromethane (500 mL) was added 4 dimethylaminopyridine (10.17 g, 0.083 mol) and pyridine (49.2 mL, 0.610 mol) and d for next 5 min. To the above mixture octanoyl chloride (2, 105.4 mL, 0.610 mol) was added dropwise at 0 °C and the reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was filtered; the solid was washed with dichloromethane (100 mL), filtrate was washed with brine (200 mL), saturated on of sodium bicarbonate (200 mL) and 0.1 N HC solution (100 mL). c layer was separated and dried over anhydrous sodium sulfate and solvent was removed under d pressure to get crude. The crude was purified by silica gel (100-200 mesh) column chromatography eluting with 10% ethyl acetate in hexanes to afford the desired product as white solid. Yield: 70.0 g, 73%; MS (ESI) m/z 343.19[M+1]+; 'H NMR (400 MHz, DMSO-d6); 6 4.84 (s, 4H), 2.37 (t, J= 7.2 Hz, 4H), 1.45-1.62 (m, 4H), 1.15-1.35 (m, 16H), 0.78-0.92 (m, 6H). sis of oxypropane-1,3-diyl dioctanoate (4): To an ice cold solution of 2 oxopropane-1,3-diyl dioctanoate (3, 70.0 g, 0.204 mol) in THF (1000 mL) was added drop wise acetic acid (15 mL) followed by the portion wise addition of sodium orohydride (15.43 g, 0.245 mol). The reaction mixture was stirred at room temperature for 16h. After completion, reaction mixture was diluted with water (400 mL) and extracted with ethyl acetate (3 x 200 mL). The c layer was separated, dried over anhydrous sodium sulfate and t was removed under reduced pressure. The crude thus obtained was purified by silica gel (100-200 mesh) column tography eluting with 12 to 15% ethyl acetate in hexanes to afford the desired product 4 as yellow liquid. Yield: 50.0 g, 71%; MS (ESI) m/z 345.29[M+1]*; 1H NMR (400 MHz, DMSO-d6); 6 5.25 (d, J= 5.2 Hz, 1H), 3.92-4.03 (m, 4H), 3.81-3.90 (m, 1H), 2.29 (t, J= 7.6 Hz, 4H), 1.45-1.59 (m, 4H), 1.12-1.35 (m, 16H), 0.85 (t, J= 6.8 Hz, 6H).

Synthesis of 4-((1,3-bis(octanoyloxy)propanyl)oxy)oxobutanoic acid (6): To a solution of 2-hydroxypropane-1,3-diyl noate (4, 50.0 g, 0.145 mol) in chloroform (200 mL), dihydrofuran-2,5-dione (5, 17.44 g, 0.174 mol) and triethylamine (30.0 mL, 0.218 mol) were added at room temperature. The reaction mixture was stirred at 120°C for 3h. After tion, reaction mixture was diluted with water (200 mL) and extracted with 1,2 dichloromethane (3 x 200 mL). The organic layer was separated, dried over anhydrous sodium sulfate and concentrated under d pressure. The crude thus obtained was purified by silica gel (100 200 mesh) column chromatography eluting with 10 to 15% ethyl acetate in hexanes to affored the desired product 6 as white solid. Yield: 47.0g, 72%; MS (ESI) m/z 443.2[M-1]; 'H NMR (400 MHz, DMSO-d6); 6 12.22 (s, 1H), 5.12-5.22 (m, 1H), 4.18-4.25 (m, 2H), 4.09 4.17 (m, 2H), 2.42-2.50 (m, 4H), 2.29 (t, J= 7.24 Hz, 4H), 1.44-1.55 (m, 4H), .31 (m, 16H), 0.79-0.90 (m, 6H).

Example 2: Synthesis of 1-butyl((2,6-dimethylphenyl)carbamoyl)piperidinium 4-((1,3 bis(octanoyloxy)propanyl)oxy)oxobutanoate 8 (CLX-SYN-G161-CO1): 0 0 NH 0 0 O 0 0 oa ACN, 50-C, 6h o 01 CLX-SYN-G161-C0 Procedure: To a solution of 4-((1,3-bis(octanoyloxy)propanyl)oxy)oxobutanoic acid (6, 7.0 g, 3 mol) in acetonitrile (150 mL) was added 1-butyl-N-(2,6 dimethylphenyl)piperidinecarboxamide (7, 4.60 g, 0.01583 mol) at ambient temperature. The resulting reaction mixture was heated up to 50°C for next 6h followed by the ation of solvent under reduced pressure to get the d product 1-butyl((2,6 dimethylphenyl)carbamoyl)piperidinium4-((1,3-bis(octanoyloxy)propanyl)oxy)-4 oxobutanoate 8 (CLX-SYN-G161-C1) as off-white semi solid (hygroscopic). Yield: 11.60 g, quant.

Example 3: Synthesis of 2-((2,6-dimethylphenyl)amino)-N,N-diethyloxoethanaminium 3 bis(octanoyloxy)propanyl) oxy)oxobutanoate 10 YN-G161-C02): ON O , O1 gH | N* 9 NHH O ACN, 50°C, 6h 00 o V 4 Z - - O OH CLX-SYN-G161-C02 ure: To a solution of 3-bis(octanoyloxy)propanyl)oxy)oxobutanoic acid (6, 7.86 g, 0.01768 mol) in acetonitrile (150 mL) was added 2-(diethylamino)-N-(2,6 dimethylphenyl)acetamide (9, 4.14 g, 0.01768 mol) at ambient temperature. The resulting reaction mixture was heated up to 50°C for next 6h followed by the evaporation of solvent under reduced pressure to get the desired product 2-((2,6-dimethylphenyl)amino)-N,N-diethyl 2-oxoethanaminium 4-((1,3-bis(octanoyloxy)propanyl)oxy)oxobutanoate 10 (CLX SYN-G161-C02) as yellow liquid. Yield: 12.0 g, quant.

Example 3: Synthesis of [(2S)butylpiperidinecarbonyl]-(2,6-dimethylphenyl)ammonium; dodecanoate 10 (CLX-SYN-G161-C03): NH0 HHO12 HN 0 ACN, 50°C, 6h 1 06 13 11 CLX-SYN-G161-C03 Procedure: To a solution of (S)butyl-N-(2,6-dimethylphenyl)piperidinecarboxamide (11, 6.79 g, 0.02353 mol) in acetonitrile (150 mL) was added dodecanoic acid (12, 4.71 g, 0.02353 mol) at ambient temperature. The resulting reaction mixture was heated up to 50°C for next 6h followed by the evaporation of solvent under reduced pressure to get the desired product [(2S) 1-butylpiperidinecarbonyl]-(2,6-dimethylphenyl)ammonium;dodecanoate 13 (CLX-SYN G161-C03) as off white semi solid. Yield: 11.50 g (quantitative).

ANTI-MICROBIAL PROPERTIES OF FATTY ACIDS: The antibacterial mode of action of Free Fatty Acids (FFA) is still poorly understood, the prime target of FFA action is the cell membrane, where FFAs disrupt the electron transport chain and oxidative phosphorylation; also it can interfere with cellular energy production, generation of peroxidation and auto-oxidation degradation ts or direct lysis of bacterial cells. Medium-chain saturated fatty acids that lack a kinked structure can be packed more tightly and can reduce membrane fluidity and disrupt electron transport perhaps by restricting the movement of carriers within the membrane. The antibacterial effect of long chain unsaturated fatty acids were due to their inhibition of fatty acid biosynthesis.

Anti-microbial property of Linoleic acid: Linoleic acid is GRAS listed long chain fatty acid. Among the hain fatty acids, donic acid, linoleic acid, leic acid, palmitoleic acid, and palmitic acid had the greatest antimicrobial ty. Linoleic acid was bactericidal at a concentration of 25 pg/ml; the mean % inhibition was between 80 to 100% for S. mutans; A. actinomycetemcomitans; P. gingivalis; S. gordonii; S. sanguis. Its activity against C. albicans was <40%, MIC for linoleic acid against the Candida Species was 0.45 pmoles/ml (which corresponds to 130 ng/ml). The minimum inhibitory concentration for ic acid against Porphyromonas gingivalis was 9 to 78 mcg/ml.

In vitro studies have suggested that gamma ic acid (GLA) has icant anti microbial activity against the various oral pathogenic microorganisms.

] The n-6 fatty acids GLA were icidal at a concentration of 25 pg/mL. These fatty acid and their esters also showed crobial activity t the periodontopathogens, A. actinomycetemcomitans, and P. gingivalis, gh they were generally most active t the oral streptococci. GLA and their methyl and ethyl esters were found to have antimicrobial activities against various oral microorganisms, including S. mutans, A. actinomycetemcomitans, C. albicans, P. gingivalis, F. nucleatum, and S. gordonii.

EQUIVALENTS The present disclosure provides among other things compositions and methods for treating neurological diseases and their cations. While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive.

Many variations of the systems and methods herein will become apparent to those skilled in the art upon review of this specification. The full scope of the d systems and methods should be determined by nce to the claims, along with their full scope of equivalents, and the specification, along with such variations.

ORATION BY REFERENCE All ations and patents mentioned herein, including those items listed above, are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

Claims (4)

1. A compound of Formula I: O RH Formula I and pharmaceutically acceptable hydrates, solvates, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, chloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor 10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, ic acid, glucoheptonic acid, gluconic acid , onic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, romic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, c acid, stearic acid, ic acid, sulfuric acid, tartaric acid, anic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), e, methyl e, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, ic acid, myristic acid, myristoleic acid, palmitic acid, oleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, tiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, xal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, sanol or n, within the proviso R, R2, R3 independently represents o o O OH WO 22626 PCT/1B2017/052247 0 0 0 OH0 0 0 0 0 ) 143 or 5 2. A compound of a II: RH 0 N N H S Formula II and pharmaceutically acceptable hydrates, solvates, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, c acid, camphoric acid, camphor 10-sulfonic acid, capric acid oic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, romic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 onic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, ic acid, pamoic acid, phosphoric acid, proprionic acid, utamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, ic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, atidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, n a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene -carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), ne, acefurtiamine, allithiamine, benfotiamine, tiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, hine, pyridoxine, pyridoxal ate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, WO 22626 folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or O--R2 wherein, within the proviso R, R2, R3 independently represents O O O O o oa .. O 0 0 O o OH O O NH2 O NH2 WO 22626 0 0 3. A compound of Formula III: Formula III and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ic acid, aspartic acid, benzenesulfonic acid, c acid, camphoric acid, camphor 10-sulfonic acid, capric acid oic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, WO 22626 gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, yric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, ic acid, tartaric acid, anic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, c acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, n a, l, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, riol (1,25-dihydroxycholecalciferol), roic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, avin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, oascorbic acid, 1-docosanol or n, within the proviso R, R2, R3 independently represents WO 22626 PCT/1B2017/052247 0 0 0H HH OH150 or 0 4. A compound of Formula IV: 0 NH Formula IV and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor 10-sulfonic acid, capric acid oic acid), caproic acid (hexanoic acid), ic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, ophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, c acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, WO 22626 toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, yl ne (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, ic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, lciferol, drocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, , nicotinamide, pantothenic acid, dexpanthenol, pantethine, xine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, sanol or O--R2 wherein, within the proviso R, R2, R3 independently represents O O15 O OH WO 22626 PCT/1B2017/052247 0 0 0 OH0 : Nss0-0 OH 0 0 0 0 0 5. A compound of a V: Formula V and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin A, l, l, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7 dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, riol (1,25 dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, erol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, tiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, c acid, folic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, oascorbic acid, 1-docosanol or Rl---R3 wherein, within the proviso R, R2, R3 independently represents o 0 0 OH O O O OH O WO 22626 PCT/1B2017/052247 0 000 N 0H0 0 0 NH20 H 0 0 6. A compound of Formula VI: Formula VI and pharmaceutically acceptable hydrates, solvates, prodrugs, omers, and stereoisomers thereof; ] Wherein, RH independently represents olipids, phosphatidylcholine, menthol, retinoic acid, n A, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7 dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25 dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, quinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, tiamine, sulbutiamine, riboflavin, niacin, nicotinamide, henic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, folic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or O--R2 Rj-OO-R3 wherein, within the proviso R, R2, R3 independently represents WO 22626 PCT/1B2017/052247 0 0 0H HH OH160 WO 22626 0 0 7. A compound of Formula VII: Formula VII and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor 10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, aric acid, gentisic acid, eptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, ic acid, sulfuric acid, ic acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), e, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, oleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, n A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, tene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, alciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, lcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, ylcobalamin, obalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, , 1-docosanol or O--R2 Rj-O-O-R3 wherein, within the proviso R, R2, R3 independently represents O OH O O o a WO 22626 PCT/1B2017/052247 0 0 NH20 H 0 0 8. A compound of Formula VIII: Formula VIII and pharmaceutically acceptable hydrates, es, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, chloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor 10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, sulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , onic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, romic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, onic acid, pyroglutamic acid, salicylic acid, c acid, stearic acid, succinic acid, ic acid, tartaric acid, thiocyanic acid, esulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, ic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, u-carotene -carotene retinol, d2 ergosterol, ergocalciferol, drocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, oquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, hine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, oascorbic acid, , 1-docosanol or wherein, within the proviso R, R2, R3 ndently represents 0 0 O OHH 0OH O O ON 0 WO 22626 PCT/1B2017/052247 0 ~Js0 0 0 9. A compound of a IX: Formula IX and ceutically acceptable es, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently ents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor 10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nic acid, nitric acid, oleic acid, oxalic acid, ic acid, pamoic acid, phosphoric acid, onic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), e, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, in, tretinoin, u-carotene tene l, d2 erol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, iamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, thenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, , folic acid, dihydrofolic acid, folinic acid, folic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or O--R2 Rj-OO-R3 wherein, within the proviso R, R2, R3 independently represents 0 o O OH O O O OH , 0 WO 22626 PCT/1B2017/052247 0 000 N 0H0 0 0 NH20 H O 0 10. A compound of Formula X: H2N CI Formula X and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, camphor 10-sulfonic acid, capric acid (decanoic acid), caproic acid oic acid), ic acid, ic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, romic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, ic acid, pamoic acid, oric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, esulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, ic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, tretinoin, tene -carotene retinol, d2 erol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, erol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, henic acid, dexpanthenol, pantethine, xine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, e, ascorbic acid, dehydroascorbic acid, 1-docosanol or O--R2 wherein, within the proviso R, R2, R3 independently represents O OH 0 0 0 0 O OH O N 0- O H O 0 0 NH2 O NH2 WO 22626 PCT/1B2017/052247 11. A nd of Formula XI: Formula XI and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, oxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, esulfonic acid, benzoic acid, camphoric acid, camphor 10-sulfonic acid, capric acid oic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, glutaric acid, ophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 onic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, ic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, c acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, ic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, l, retinal, isotretinoin, curcumin, tretinoin, u-carotene -carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, itol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), ol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, , nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, nol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, cobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or Rj-O----R3 wherein, within the proviso R, R2, R3 independently represents 0 o O OH WO 22626 PCT/1B2017/052247 0 0 0 OH0 0 0 0 0 ) 178 / 0 12. A compound of a XII: H2N ON Formula XII and pharmaceutically acceptable hydrates, solvates, prodrugs, omers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, osalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, r 10-sulfonic acid, capric acid (decanoic acid), caproic acid oic acid), carbonic acid, ic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, ic acid , glucuronic acid, glutamic acid, ic acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, alene-1,5 disulfonic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, yl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, oleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, l, isotretinoin, curcumin, tretinoin, u-carotene -carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, iamine, fursultiamine, amine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, xamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or --- R3 wherein, within the proviso R, R2, R3 independently represents O O O O o oa 0 O o o NH2, ONH, WO 22626 PCT/1B2017/052247 0 ~ss0 0 0 13. A compound of Formula XIII: Formula XIII and pharmaceutically acceptable hydrates, es, prodrugs, enantiomers, and stereoisomers thereof; Wherein, RH independently ents caprylic acid, 1-hydroxynaphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, esulfonic acid, benzoic acid, camphoric acid, camphor 10-sulfonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, eptonic acid, gluconic acid , glucuronic acid, ic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, romic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, naphthalenesulfonic acid, nic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, thiocyanic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), e, methyl e, ethyl furoate, aminocaproic acid, caproic acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, atidylcholine, oleic acid, elaidic acid, ic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, tinoin, curcumin, tretinoin, u-carotene j-carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, riol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 oergocalciferol, lcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, erol, naphthoquinone, phylloquinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, pyridoxamine, pyritinol, biotin, folic acid, dihydrofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or Rj-O----R3 wherein, within the proviso R, R2, R3 independently represents WO 22626 PCT/1B2017/052247 0 0 0H HH OH185 WO 22626 0 0 14. A compound of Formula XIV: O- R2 RH R1-0 O R Formula XIV and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers Wherein, R', R2, R3 independently represents O OH 0 0 0OH O N 0 o o WO 22626 PCT/1B2017/052247 0 ~ss0 WO 22626 RH independently represents oxytetracycline, tetracycline, amphenicol, chloramphenicol, neomycin, icin, amikacin, oxacin, virginiamycin, min, fusidic acid, bacitracin, tyrothricin, mupirocin, sulfonamides, silver, sulfadiazine, sulfathiazole, mafenide, sulfamethizole, sulfanilamide, sulfamerazine, aciclovir, penciclovir, idoxuridine, edoxudine, imiquimod, resiquimod, podophyllotoxin, docosanol, tromantadine, inosine, lysozyme, ibacitabine, lysine, ingenol mebutate, metronidazole, acyclovir, phenol, valaciclovir, valacyclovir, famciclovir, silver, zinc, iodine, benzalkonium, benzethonium, yridinium, clioquinol, triclosan, chlorhexidine, chloramphenicol, menthol, neomycin, gentamicin, in, ketamine, esketamine, arketamine, ceftriaxone or cefepime. 15. A compound of Formula XV: Formula XV and ceutically acceptable hydrates, solvates, prodrugs, omers, and stereoisomers thereof; Wherein, RH independently represents caprylic acid, 1-hydroxynaphthoic acid, chloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, camphoric acid, r fonic acid, capric acid (decanoic acid), caproic acid (hexanoic acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid , glucuronic acid, glutamic acid, ic acid, glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, naphthalene-1,5 disulfonic acid, alenesulfonic acid, nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid, pyroglutamic acid, salicylic acid, sebacic acid, stearic acid, ic acid, sulfuric acid, tartaric acid, anic acid, toluenesulfonic acid, undecylenic acid, omega 3 fatty acids, omega 6 fatty acids, n-acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate, aminocaproic acid, c acid, caprilic acid, capric acid, lauric acid, alpha lipoic acid, R-lipoic acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, phospholipids, phosphatidylcholine, oleic acid, elaidic acid, linoleic acid, linolenic acid, menthol, retinoic acid, vitamin A, retinol, linolelaidic acid, arachidonic acid, phospholipids, phosphatidylcholine, menthol, retinoic acid, vitamin a, retinol, retinal, isotretinoin, curcumin, oin, u-carotene -carotene retinol, d2 ergosterol, ergocalciferol, 7-dehydrocholesterol, cholecalciferol, 25-hydroxycholecalciferol, calcitriol (1,25-dihydroxycholecalciferol), calcitroic acid, d4 dihydroergocalciferol, alfacalcidol, dihydrotachysterol, calcipotriol, tacalcitol, paricalcitol, tocopherol, naphthoquinone, quinone (kl), menaquinones (k2), menadione (k3), menadiol (k4), thiamine, acefurtiamine, allithiamine, benfotiamine, fursultiamine, octotiamine, prosultiamine, sulbutiamine, riboflavin, niacin, nicotinamide, pantothenic acid, dexpanthenol, pantethine, pyridoxine, pyridoxal phosphate, xamine, nol, biotin, folic acid, ofolic acid, folinic acid, levomefolic acid, adenosylcobalamin, cyanocobalamin, hydroxocobalamin, methylcobalamin, choline, ascorbic acid, dehydroascorbic acid, 1-docosanol or --- R3 wherein, within the proviso R, R2, R3 independently represents O O O O o oa 0 O o o NH2, ONH, WO 22626 PCT/1B2017/052247 0 ~ss0 0 0 16. A Pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically able carrier. 17. A Pharmaceutical composition comprising a compound of claim 2 and a pharmaceutically acceptable carrier. 18. A Pharmaceutical ition comprising a compound of claim 3 and a pharmaceutically acceptable carrier. 19. A Pharmaceutical ition comprising a compound of claim 4 and a pharmaceutically acceptable carrier. 20. A Pharmaceutical composition sing a nd of claim 5 and a pharmaceutically acceptable r. 21. A Pharmaceutical composition comprising a compound of claim 6 and a pharmaceutically acceptable carrier. 22. A Pharmaceutical composition comprising a compound of claim 7 and a pharmaceutically acceptable carrier. 23. A Pharmaceutical composition comprising a compound of claim 8 and a pharmaceutically acceptable carrier. 24. A Pharmaceutical composition sing a compound of claim 9 and a pharmaceutically acceptable carrier. 25. A Pharmaceutical composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier. 26. A Pharmaceutical composition comprising a compound of claim 11 and a pharmaceutically acceptable carrier. 27. A Pharmaceutical composition comprising a compound of claim 12 and a pharmaceutically acceptable carrier. 28. A Pharmaceutical composition comprising a compound of claim 13 and a pharmaceutically acceptable carrier. 29. A Pharmaceutical composition comprising a compound of claim 14 and a pharmaceutically acceptable carrier. 30. A Pharmaceutical composition comprising a compound of claim 15 and a pharmaceutically acceptable carrier. 31. The pharmaceutical composition of claim 16, which is formulated to treat the ying etiology with an effective amount administering the patient in need by oral administration, d release or ned release, ucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration. 32. The pharmaceutical ition of claim 17, which is formulated to treat the underlying etiology with an effective amount administering the t in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration. 33. The pharmaceutical composition of claim 18, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed e or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration. 34. The pharmaceutical composition of claim 19, which is formulated to treat the underlying gy with an effective amount administering the patient in need by oral administration, delayed release or sustained release, ucosal, syrup, topical, parenteral administration, injection, subdermal, oral on, rectal stration, buccal administration or transdermal administration. 35. The pharmaceutical composition of claim 20, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal stration or transdermal administration. 36. The pharmaceutical composition of claim 21, which is formulated to treat the ying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal stration or transdermal administration. 37. The pharmaceutical composition of claim 22, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained e, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration. 38. The pharmaceutical composition of claim 23, which is formulated to treat the underlying etiology with an effective amount administering the t in need by oral stration, delayed release or sustained e, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration. 39. The pharmaceutical composition of claim 24, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral stration, d release or ned release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration. 40. The pharmaceutical composition of claim 25, which is formulated to treat the underlying etiology with an effective amount administering the t in need by oral administration, delayed release or ned release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration. 41. The pharmaceutical composition of claim 26, which is ated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, ucosal, syrup, topical, parenteral stration, ion, subdermal, oral solution, rectal administration, buccal administration or ermal administration. 42. The pharmaceutical composition of claim 27, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration. 43. The pharmaceutical composition of claim 28, which is formulated to treat the underlying gy with an effective amount administering the patient in need by oral administration, delayed release or sustained release, transmucosal, syrup, l, eral administration, injection, subdermal, oral solution, rectal administration, buccal administration or transdermal administration. 44. The pharmaceutical composition of claim 29, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral stration, delayed release or sustained release, transmucosal, syrup, topical, parenteral administration, ion, subdermal, oral solution, rectal administration, buccal administration or transdermal administration. 45. The pharmaceutical composition of claim 30, which is formulated to treat the underlying etiology with an effective amount administering the patient in need by oral administration, d release or sustained release, transmucosal, syrup, topical, eral administration, injection, subdermal, oral solution, rectal administration, buccal administration or ermal administration. 46. Compounds and compositions of claim 31 are formulated for the treatment of chronic pain, surgery pain, wound pain, ulcer pain, neuropathic pain, central and peripheral nerve damage pain. 47. Compounds and compositions of claim 32 are formulated for the treatment of chronic pain, y pain, wound pain, ulcer pain, neuropathic pain, central and peripheral nerve damage pain. 48. nds and compositions of claim 33 are formulated for the treatment of chronic pain, surgery pain, wound pain, ulcer pain, neuropathic pain, central and peripheral nerve damage pain. 49. Compounds and compositions of claim 34 are formulated for the treatment of chronic pain, surgery pain, wound pain, ulcer pain, athic pain, central and peripheral nerve damage pain. 50. Compounds and compositions of claim 35 are formulated for the ent of chronic pain, surgery pain, wound pain, ulcer pain, neuropathic pain, central and peripheral nerve damage pain. 51. Compounds and compositions of claim 36 are formulated for the treatment of c pain, surgery pain, wound pain, ulcer pain, athic pain, central and peripheral nerve damage pain. 52. Compounds and compositions of claim 37 are ated for the treatment of chronic pain, surgery pain, wound pain, ulcer pain, neuropathic pain, central and peripheral nerve damage pain. 53. Compounds and compositions of claim 38 are formulated for the treatment of chronic pain, surgery pain, wound pain, ulcer pain, athic pain, central and peripheral nerve damage pain. 54. Compounds and compositions of claim 39 are formulated for the treatment of chronic pain, surgery pain, wound pain, ulcer pain, neuropathic pain, central and peripheral nerve damage pain. 55. Compounds and compositions of claim 40 are formulated for the ent of chronic pain, y pain, wound pain, ulcer pain, neuropathic pain, central and peripheral nerve damage pain. 56. Compounds and compositions of claim 41 are formulated for the treatment of c pain, surgery pain, wound pain, ulcer pain, athic pain, central and peripheral nerve damage pain. 57. Compounds and compositions of claim 42 are formulated for the treatment of chronic pain, surgery pain, wound pain, ulcer pain, neuropathic pain, central and peripheral nerve damage pain. 58. Compounds and compositions of claim 43 are formulated for the treatment of chronic pain, surgery pain, wound pain, ulcer pain, neuropathic pain, central and peripheral nerve damage pain. 59. Compounds and compositions of claim 44 are formulated for the treatment of c pain, surgery pain, wound pain, ulcer pain, neuropathic pain, central and peripheral nerve damage pain. 60. Compounds and compositions of claim 45 are formulated for the treatment of chronic pain, surgery pain, wound pain, ulcer pain, neuropathic pain, central and peripheral nerve damage pain. 61. A compound of claim 4, comprising of formula IV: HN 0 62. A compound of claim 6, comprising of formula VI: 0 NH 0 63. A compound of claim 5, sing of formula V: H 0 64. 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