Patent Application
20240315965
The “Rule of Five” states that the logarithm base-10 of the octanol-water partition coefficient of a druglike molecule is generally no greater than 5. A generally-applicable strategy to overcome this feature of the Rule of Five is desirable.
An octanol-water partition coefficient with a logarithm base-10 greater than 5 limits solubility in bodily fluids, which limits bioavailability. Many classes of hydrophobic bioactive molecules can be converted into anions that display improved octanol-water partition coefficients using simple acid/base chemistry. Such anions convert back into their parent bioactive molecules upon administration to a subject. Various aspects of this patent document relate to the discovery that the anionic form of a bioactive agent can overcome the octanol-water partition coefficient limitation set forth in the Rule of Five.
Various aspects of this patent document relate to a composition, comprising a solvent, a Brønsted base, a cation, an anion, and a molecule, wherein the solvent has the chemical formula CxHyOz; each carbon atom of the solvent is an unsaturated carbon atom; x is an integer of at least 2 and no greater than 7; either the solvent has the chemical formula C6H12O6, or y equals 2× plus 2; the solvent comprises z hydroxyl group(s); each hydroxyl group of the solvent is covalently bound to a different carbon atom of the solvent; z is an integer of at least 1 and no greater than x; the Brønsted base is a conjugate base of the solvent; the Brønsted base has the chemical formula CxHwOz1−; the Brønsted base comprises 1 oxide group; the Brønsted base comprises z minus 1 hydroxyl group(s); w equals y minus 1; the cation is either a metal cation or an ammonium cation; the anion is a conjugate base of the molecule; the molecule has an acid dissociation constant in water of at least 50 femtomolar and no greater than 50 nanomolar for conversion of the molecule into the anion; the solvent has a solubility in water of at least 100 grams per liter; the liquid phase has a molar concentration of the solvent, which is at least 5 molar and no greater than 17 molar; the Brønsted base, the cation, the anion, and the molecule are solutes that are dissolved in the liquid phase; the liquid phase has a molar concentration of the Brønsted base that is dissolved in the liquid phase, which is at least 1 nanomolar and no greater than 1 molar; the molar concentration of the solvent in the liquid phase is at least 10 times greater than the molar concentration of the Brønsted base that is dissolved in the liquid phase; the liquid phase has a molar concentration of the cation that is dissolved in the liquid phase, which is at least 10 nanomolar and no greater than 1 molar; the liquid phase has a molar concentration of the anion that is dissolved in the liquid phase, which is at least 10 nanomolar and no greater than 1 molar; and the liquid phase has a molar concentration of the molecule that is dissolved in the liquid phase, which is less than the molar concentration of the anion that is dissolved in the liquid phase.
“Comprise” refers to an open set; a composition that comprises a solvent, a Brønsted base, a cation, an anion, and a molecule, for example, can also comprise the anionic form of a bioactive agent.
“Dissolved” refers to a chemical species that is solvated in a liquid phase, for example, by a solvent; a chemical species that is present within a phase that is dispersed within a liquid phase, such as the dispersed phase of an emulsion, is not dissolved in the liquid phase; a chemical species that is non-covalently bound to any chemical species that is a solid in the absence of a solvent, such as a cyclodextrin, is not dissolved.
“Ammonium cation” refers to either ammonium (“NH4+”) or an aminium cation.
In some specific embodiments, the solvent has the chemical formula C2H6O, C3H8O, C3H8O2, C3H8O3, C4H10O, C4H10O2, C4H10O3, C4H10O4, C5H12O, C5H12O2, C5H12O3, C5H12O4, C5H12O5, C6H12O6, C6H14O, C6H14O2, C6H14O3, C6H14O4, C6H14O5, C6H14O6, C7H16O, C7H16O2, C7H16O3, C7H16O4, C7H16O5, C7H16O6, or C7H16O7. In some very specific embodiments, the solvent has the chemical formula C2H6O, C3H8O2, C3H8O3, C4H10O2, C4H10O4, C5H12O5, C6H12O6, C6H14O6, or C7H16O7.
In some very specific embodiments, the solvent is 1,2-propanediol; 1,3-propanediol; 1,2,3-propanetriol; 1,3-butanediol; 1,4-butanediol; 2,3-butanediol; butane-1,2,3,4-tetrol; pentane-1,2,3,4,5-pentol; cyclohexane-1,2,3,4,5,6-hexol; hexane-1,2,3,4,5,6-hexol; or heptane-1,2,3,4,5,6,7-heptol.
In some specific embodiments, the liquid phase has a molar concentration of the solvent, which is at least 5 molar and no greater than 14 molar.
In some specific embodiments, the Brønsted base has the chemical formula C2H5O1−, C3H7O1−, C3H7O21, C3H7O31−, C4H9O1−, C4H9O21−, C4H9O31−, C4H9O41−, C5H11O1−, C5H11O21−, C5H11O31−, C5H11O41−, C5H11O51−, C6H11O61−, C6H13O1−, C6H13O21−, C6H13O31−, C6H13O41−, C6H13O51−, C6H13O61−, C7H15O1−, C7H15O21−, C7H15O31−, C7H15O41−, C7H15O51−, C7H15O61−, or C7H15O71−. In some very specific embodiments, the Brønsted base has the chemical formula C2H501−, C3H7O21−, C3H7O31−, C4H9O21−, C4H9O41−, C5H11O51−, C6H11O61−, C6H13O61−, or C7H15O71−.
In some embodiments, the Brønsted base is ethoxide; propane-1-oxide; 1-hydroxypropane-2-oxide; 2-hydroxypropane-1-oxide; 3-hydroxypropane-1-oxide; 1,3-dihydroxypropane-2-oxide; 2,3-dihydroxypropane-1-oxide; butane-1-oxide; butane-2-oxide; 1-hydroxybutane-2-oxide; 2-hydroxybutane-1-oxide; 3-hydroxybutane-1-oxide; 3-hydroxybutane-2-oxide; 4-hydroxybutane-1-oxide; 4-hydroxybutane-2-oxide; 1,3,4-trihydroxybutane-2-oxide; 2,3,4-trihydroxybutane-1-oxide; pentane-1-oxide; pentane-2-oxide; pentane-3-oxide; 1,2,4,5-tetrahydroxypentane-3-oxide; 1,3,4,5-tetrahydroxypentane-2-oxide; 2,3,4,5-tetrahydroxypentane-1-oxide; 1,2,4,5,6-pentahydroxyhexane-3-oxide; 1,3,4,5,6-pentahydroxyhexane-2-oxide; 2,3,4,5,6-pentahydroxyhexane-1-oxide; 2,3,4,5,6-pentahydroxycyclohexane-1-oxide; 1,2,3,5,6,7-hexahydroxyheptane-4-oxide; 1,2,4,5,6,7-hexahydroxyheptane-3-oxide; 1,3,4,5,6,7-hexahydroxyheptane-2-oxide; or 2,3,4,5,6,7-hexahydroxyheptane-1-oxide. In some specific embodiments, the Brønsted base is ethoxide; 1-hydroxypropane-2-oxide; 2-hydroxypropane-1-oxide; 3-hydroxypropane-1-oxide; 1,3-dihydroxypropane-2-oxide; 2,3-dihydroxypropane-1-oxide; 1,3,4-trihydroxybutane-2-oxide; 2,3,4-trihydroxybutane-1-oxide; 1,2,4,5-tetrahydroxypentane-3-oxide; 1,3,4,5-tetrahydroxypentane-2-oxide; 2,3,4,5-tetrahydroxypentane-1-oxide; 1,2,4,5,6-pentahydroxyhexane-3-oxide; 1,3,4,5,6-pentahydroxyhexane-2-oxide; 2,3,4,5,6-pentahydroxyhexane-1-oxide; 2,3,4,5,6-pentahydroxycyclohexane-1-oxide; 1,2,3,5,6,7-hexahydroxyheptane-4-oxide; 1,2,4,5,6,7-hexahydroxyheptane-3-oxide; 1,3,4,5,6,7-hexahydroxyheptane-2-oxide; or 2,3,4,5,6,7-hexahydroxyheptane-1-oxide. In some very specific embodiments, the Brønsted base is 1-hydroxypropane-2-oxide; 2-hydroxypropane-1-oxide; 3-hydroxypropane-1-oxide; 1,3-dihydroxypropane-2-oxide; or 2,3-dihydroxypropane-1-oxide.
In some specific embodiments, the molar concentration of the Brønsted base that is dissolved in the liquid phase is at least 10 nanomolar and no greater than 100 millimolar.
In some specific embodiments, the molar concentration of the solvent in the liquid phase is at least 100 times greater than the molar concentration of the Brønsted base that is dissolved in the liquid phase.
In some embodiments, the composition comprises water and hydroxide; the hydroxide is a solute that is dissolved in the liquid phase; the liquid phase has a molar concentration of the hydroxide that is dissolved in the liquid phase; and the liquid phase has a molar concentration of water, which is at least 10 times and no more than 1 billion times greater than the molar concentration of the hydroxide that is a dissolved in the liquid phase. In some specific embodiments, the liquid phase has a molar concentration of water, which is at least 100 times and no more than 100 million times greater than the molar concentration of the hydroxide that is a dissolved in the liquid phase. In some very specific embodiments, the liquid phase has a molar concentration of water, which is at least 1000 times and no more than 10 million times greater than the molar concentration of the hydroxide that is a dissolved in the liquid phase.
In some embodiments, the composition comprises ethoxide.
Various aspects of this patent document relate to a composition for use as a medicament, wherein the composition comprises a salt; the salt comprises an anion and a cation; the anion is a conjugate base of a molecule; and the molecule has an acid dissociation constant in water of at least 50 femtomolar and no greater than 50 nanomolar for conversion of the molecule into the anion.
In some specific embodiments, the cation in is a metal cation. In some very specific embodiments, the cation is a metal cation, and the metal cation is lithium cation (“Li+”); sodium cation (“Na+”); potassium cation (“K+”); magnesium cation (“Mg++”); calcium cation (“Ca++”); zinc cation (“Zn++”); manganese cation (“Mn++”); iron (II) cation (“Fe++”); iron (III) cation (“Fe+++”); copper (I) cation (“Cu+”); or copper (II) cation (“Cu++”).
In some specific embodiments, the cation is a metal cation, and the metal cation is potassium cation or sodium cation. In some very specific embodiments, the cation is a metal cation, and the metal cation is potassium cation. In some very specific embodiments, the cation is a metal cation, and the metal cation is sodium cation.
In some specific embodiments, the cation is an ammonium cation. In some very specific embodiments, the cation is an ammonium cation, and the ammonium cation is ammonium; protonated ethanolamine; choline; protonated lysine; protonated arginine; or protonated sphingosine.
In some specific embodiments, the molar concentration of the cation that is dissolved in the liquid phase is at least 100 nanomolar and no greater than 100 millimolar.
In some embodiments, the molecule has the chemical formula C(MC)H(MH)X(MX)N(MN)O(MO)S(MS); the anion has the chemical formula C(AC)H(AH)X(AX)N(AN)O(AO)S(AS)1−; MC is an integer from 6 to 32; MH is an integer from 6 to 50; MH is both at least half MC and no more than 1.75 times greater than MC; X is a halogen selected from F, Cl, Br, and I; MX is either 0, 1, or 2; MN is either 0, 1, or 2; MO is an integer from 1 to 12; MC is at least 2 times greater than MO; MS is either 0 or 1; AC equals MC; AH equals MH minus 1; AX equals MX; AN equals MN; AO equals MO; and AS equals MS. In some specific embodiments, the molecule has the chemical formula C(MC)H(MH)N(MN)O(MO); and the anion has the chemical formula C(AC)H(AH)N(AN)O(AO)1−. In some specific embodiments, the molecule has the chemical formula C(MC)H(MH)O(MO)S(MS); and the anion has the chemical formula C(AC)H(AH)O(AO)S(AS)1−. In some specific embodiments, the molecule has the chemical formula C(MC)H(MH)X(MX)O(MO); and the anion has the chemical formula C(AC)H(AH)X(AX)O(AO)1−. In some very specific embodiments, the molecule has the chemical formula C(MC)H(MH)O(MO); and the anion has the chemical formula C(AC)H(AH)O(AO)1−.
The nature of the molecule and the anion is not particularly limiting so long as the molecule has an acid dissociation constant in water of at least 50 femtomolar and no greater than 50 nanomolar for conversion of the molecule into the anion. A molecule that comprises a hydroxyl group that is bound to an unsaturated carbon atom typically has an acid dissociation constant in water of at least 50 femtomolar and no greater than 50 nanomolar for conversion of the molecule into the anion provided that the hydroxyl group is the most acidic functional group of the molecule. Examples of such molecules include numerous natural products such as eugenol, thymol, and carvacrol.
In some embodiments, the molecule is selected from acacetin; actiphenol; albofungin; alizarin; alizarin 1-methyl ether; alizarin 2-methyl ether; alkannin; aloe emodin; alpha-estradiol; alpha-kosin; alpha-naphtholphthalein; alpha-peltatin; alpha-thujaplicin; alpha-tocopherol; alpha-tocotrienol; alpha-zearalenol; ampelopsin; anthragallol; anthralin; anthranol; anthrapurpurin; anthrarobin; anthrarufin; apigenin; apocynin; arbutamine; aspidinol; atovaquone; atranorin; aza-[6]-gingerol; baicalein; baptigenin; benzarone; benzbromarone; benzestrol; benziodarone; benzophenone-6; benzoresorcinol; beta-kosin; beta-mangostin; beta-peltatin; beta-resorcylaldehyde; beta-thujaplicin; beta-tocopherol; beta-tocotrienol; bifluranol; biochanin A; bisphenol A; bisphenol B; brazilin; brodifacoum; bromadiolone; bromosalicylchloranilide; bromosaligenin; buparvaquone; butopyronoxyl; butylated hydroxyanisole; butylated hydroxytoluene; butylparaben; cabenegrin A-I; cabenegrin A-II; cannabidiol; cannabidiphorol; cannabidivarin; cannabinol; capsaicin; carvacrol; catechin; cavicularin; chavicol; chlorindanol; chrysarobin; chrysin; clofoctol; clorophene; collinomycin; combretastatin; combretastatin A-1; combretastatin A-4; combretastatin B-1; coniferyl alcohol; cotoin; coumafuryl; coumestrol; curcumin; curvularin; cyclovalone; daidzein; danthron; daphnetin; datiscetin; DBMC; deferiprone; dehydroequol; delta8-tetrahydrocannabinol; delta-tocopherol; dexanabinol; dichlorophen; dicoumarol; dienestrol; diethylstilbestrol; diethylstilbestrol monobenzyl ether; difenacoum; dihydrocapsaicin; dihydrokaempferide; dihydrokaempferol; dihydroresveratrol; dimethylheptyl cannabidiol; dimethylstilbestrol; dioxybenzone; dobutamine; embelin; emodin; enterolactone; epicocconone; epigallocatechin gallate; equilenin; equilin; equol; ergoflavin; eriodictyol; esculetin; estradiol; estradiol 170-cyclopentanepropanoate; estradiol enanthate; estradiol undecylate; estradiol valerate; estriol; estrone; eta-tocopherol; ethinyl estradiol; ethyl biscoumacetate; ethyl maltol; ethyl vanillin; ethylidene dicoumarol; ethylparaben; eugenol; euparin; eupatorin; fenoterol; fenretinide; fisetin; flavopurpurin; flocoumafen; flopropione; fluorescein; formestane; formononetin; fraxetin; fulvestrant; fumigatin; fusarubin; fuscin; fustin; galangin; gallein; gallocatechin; gamma-mangostin; gamma-thujaplicin; gamma-tocopherol; gardenin A; gardenin B; gardenin C; gardenin D; gardenin E; genistein; gentisin; gentisyl alcohol; geranylhydroquinone; gossypol; guaiacol; hematein; hematoxylin; heminordihydroguaiaretic acid; herqueinone; hesperetin; hexestrol; homocapsaicin I; homocapsaicin II; homodihydrocapsaicin; homoeriodictyol; homosalate; homovanillyl alcohol; honokiol; hydrocarbostyril; hydroxytyrosol; hymecromone; ilimaquinone; irigenin; irisolone; isoestradiol; isoeugenol; isomaltol; isosilybin A; ivacaftor; javanicin; juglone; kaempferol; lapachol; lawsone; leucocyanidin; licochalcone A; licochalcone B; licochalcone C; licochalcone D; licochalcone E; licochalcone F; linomide; luteolin; magnolol; maltol; mangostin; medicagol; medicarpin; menadiol; mestilbol; meta-cresol; methestrol; methylchrysin; methylparaben; mexenone; monobenzone; morin; morphenol; moxestrol; myricetin; nabilone; naphthoresorcinol; naringenin; nimbiol; nonivamide; nordihydrocapsaicin; nordihydroguaiaretic acid; octabenzone; oleocanthal; oroxylin A; ortho-benzylphenol; orthocaine; ortho-cresol; oryzanol A; oryzanol C; osajin; osalmid; ostruthin; ourateacatechin; oxabolone; oxabolone 17-cyclopentanepropionate; oxybenzone; oxymesterone; oxymetholone; oxyphenbutazone; para-anol; para-benzylphenol; para-cresol; para-tert-pentylphenol; para-vinylguaiacol; parietin; paroxypropione; parvaquone; pectolinarigenin; perezone; phaseolin; phenolphthalol; phenprocoumon; phloretin; phthiocol; pinosylvin; pinosylvin monomethyl ether; plumbagin; pratensein; probucol; procerin; propofol; propyl gallate; propylparaben; protiofate; protocatechualdehyde; prunetin; pseudobaptigenin; psiguadial A; psiguadial B; psiguadial C; psiguadial D; psoralidin; purpurin; purpurin 1-methyl ether; purpurin 2,4-dimethyl ether; purpurin 2-methyl ether; purpurogallin; quercetagetin; quercetin; quinalizarin; raspberry ketone; resacetophenone; resveratrol; rhamnetin; rottlerin; rottlerin 5,7-dimethyl ether; rubiadin; salicyl alcohol; salicylaldehyde; salicylanilide; scopoletin; scutellarein; siccanin; silybin A; sparassol; stilbestrol; strobilurin F; sulfuretin; sumatrol; synhexyl; syringaldehyde; taxodione; tectorigenin; tetrahydrocannabinol; tetrahydrocannabinol-C4; tetrahydrocannabiorcol; tetrahydrocannabiphorol; tetrahydrocannabivarin; tetrahydrorottlerin; thymol; tioclomarol; tolcapone; trilostane; tyrosol; uliginosin A; uliginosin B; umbelliferone; vanillin; vanillyl alcohol; violacein; viridicatin; xanthoxylin; xibornol; zearalenone; zeranol; zeta2-tocopherol; zingerone; [1]-gingerol; [10]-gingerol; [12]-gingerol; [14]-gingerol; [16]-gingerol; [2]-gingerol; [3]-gingerol; [4]-gingerol; [5]-gingerol; [6]-gingerol; [7]-gingerol; [8]-gingerol; [9]-gingerol; 16-epiestriol; 17alpha-dihydroequilin; 2,5-di-tert-pentylhydroquinone; 2′,7′-dichlorofluorescein; 2-naphthol; 3,6-dimethylmangostin; 3-methoxy-4-hydroxyphenylglycol; 4′,5′-dichlorofluorescein; 4′,5′-diiodofluorescein; 4′-fluorocannabidiol; 4-hexylresorcinol; 4-O-methylhonokiol; 4′-O-methylkaempferol; 5-ethoxy-10-gingerol; 5-O-methyl-9-gingerol; 6-deoxy-gamma mangostin; 8-isoestrone; 9-hydroxy-[6]-gingerol; abediterol; abnormal cannabidiol; acerosin; acetosyringone; adipostatin A; afzelechin; aleuritin; alnetin; alternariol; AM-087; AM-1714; AM-2389; AM-4030; AM404; AM-411; AM-855; AM-905; AM-919; AM-938; amentoflavone; AMG-1; AMG-36; AMG-41; amylmetacresol; apiforol; arctigenin; artocarpetin; artocarpin; ascofuranone; aureusidin; axillarin; azaleatin; bakuchiol; balanophonin; benzophenone-2; bilobol; bisdemethoxycurcumin; bisphenol F; blumeatin; butin; caflanone; calphostin A; calphostin B; calphostin C; calphostin D; calycosin; campesteryl ferulate; canbisol; cannabichromene; cannabicyclohexanol; cannabicyclol; cannabicyclovarin; cannabigerol; cannabigerovarin; cannflavin A; cannflavin B; cannflavin C; canolol; chaetochromin A; chaetochromin C; chaetochromin D; chavibetol; chrysoeriol; cirsilineol; cirsiliol; cirsimaritin; corymbosin; coumatetralyl; CP 55,244; CP 55,940; damnacanthal; DB-2073; debromomarinone; delta-tocotrienol; demethoxycurcumin; derrubone; dianol; dihydrokanakugiol; dihydromorin; dimethylheptylpyran; diosmetin; DOPAL; DOPEG; drupanol; durantin A; echioidinin; enterodiol; epicatechin gallate; ermanin; estetrol; eupatilin; euxanthone; ferruginol; ferujol; fisetinidol; gamma-tocotrienol; garbanzol; genkwanin; geraldone; geranin A; glabrene; glabridin; glyceollin I; glyceollin II; glyceollin III; glyceollin IV; glycinol; glycitein; glycyrrhizol A; gossypetin; guibourtinidol; heptylparaben; hispidulin; HU-210; HU-243; HU-331; hydroxymatairesinol; hymenoxin; hypolaetin; iodoresiniferatoxin; irilone; isojacareubin; isoliquiritigenin; isorhamnetin; isosakuranetin; isoscutellarein; isosilychristin; isoxanthohumol; jaceosidin; kanakugiol; KM-233; kuwanon G; lariciresinol; laricitrin; leptosidin; leptosphaerin A; leucofisetinidin; leucopelargonidin; leucopeonidin; liquiritigenin; luteoforol; luteone; macelignan; matairesinol; mearnsetin; meciadanol; melacacidin; mequinol; mesquitol; mikanin; mutisianthol; myricanone; naphthazarin; negletein; nepetin; nevadensin; nigrosporin B; nodifloretin; norartocarpetin; norwogonin; O-1602; O-1656; O-1660; O-1871; O-806; obovatol; olivetol; onopordin; oritin; orobol; ortho-phenylphenol; oxyanthrarufin; oxychrysazin; pachypodol; patuletin; pedalitin; perrottetinene; phenylacetylrinvanil; phylloquinol; piceatannol; pilloin; pinobanksin; pinocembrin; pinoresinol; pinostrobin; plicadin; pomiferin; poriol; pratol; primetin; primuletin; PSB-SB-487; pseudoisoeugenol; psi-tectorigenin; pterostilbene; purpuroxanthin; quinizarin; resiniferatoxin; retusin; rhamnazin; robinetinidol; sakuranetin; sappanol; scaposin; scillavone A; scillavone B; secoisolariciresinol; selligueain A; serpyllin; sesamol; shogaol; silychristin; silydianin; sinapyl alcohol; sitostanyl ferulate; sitosteryl ferulate; sophoradin; sophoraflavanone G; sorbifolin; spinacetin; spinochrome B; sterubin; stigmasteryl ferulate; stigmatellin; sudachitin; syringaresinol; syringetin; syringol; taxifolin; taxodone; techtochrysin; thunberginol F; thunberginol G; tinabinol; tinyatoxin; tithonine; tricetin; tricin; ubiquinol; urolithin A; urolithin B; velutin; verrulactone A; verrulactone B; verrulactone E; wedelolactone; wighteone; wightin; wogonin; xanthohumol; xanthomicrol; xylindein; zapotinin; (C6)-CP 47,497; (C7)-CP 47,497; (C9)-CP 47,497; [10]-dehydroshogaol; [10]-shogaol; [12]-shogaol; [4]-shogaol; [8]-dehydroshogaol; [8]-shogaol; 1,6-dihydroxyanthraquinone; 1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one; 11-hydroxytetrahydrocannabinol; 11-hydroxyyangonin; 11-methoxy-12-hydroxydehydrokavain; 11-nor-9beta-hydroxyhexahydrocannabinol; 3′,5′-di-tert-butyl-4′,7-dihydroxyflavone; 3,5,7-trihydroxy-8-isoprenyl-2-(4-methoxyphenyl)-4H-chromen-4-one; 3-hydroxychrysazin; 4′,7-dihydroxyflavone; 4-hydroxycoumarin; 4-hydroxyphenylacetaldehyde; 5-chloro-2-hydroxybenzophenone; 5-hydroxykavain; 5-O-methylgenistein; 6-hydroxyflavone; 6-hydroxyluteolin; 7,8-dihydroxyflavone; 7-O-methylisoxanthohumol; 7-O-n-pentylisoxanthohumol; 9-hydroxychrysarobin; sesaminol; omeprazole; and psilocin.
In some specific embodiments, the molecule has an acid dissociation constant in water of at least 100 femtomolar and no greater than 10 nanomolar for conversion of the molecule into the anion. In some very specific embodiments, the molecule has an acid dissociation constant in water of at least 5 picomolar and no greater than 5 nanomolar for conversion of the molecule into the anion.
In all embodiments, the molecule and anion buffer the pH of the liquid phase such that the bioactive agent exists primarily in an anionic form. In some very specific preferred embodiments, the molecule is the molecular form of the bioactive agent and the anion is the anionic form of the bioactive agent, for example, such that the anionic and molecular forms of the bioactive agent act as their own buffer. In such embodiments, the anionic form of the bioactive agent is typically present at a therapeutically effective concentration, and the molecular form of the bioactive agent is typically present at a concentration that is less than any known therapeutically effective concentrations for the molecular form.
In some specific embodiments, the molar concentration of the anion that is dissolved in the liquid phase is at least 100 nanomolar and no greater than 100 millimolar.
Various aspects of this patent document relate to a composition described anywhere in this patent document for use as a medicament.
In some embodiments, the composition is formulated for administration to a human; and the composition is formulated to convert the anion into the molecule ex vivo prior to the administration.
In some embodiments, the composition is formulated for administration to a human; and the composition is formulated to convert the anion into the molecule in situ subsequent to the administration.
Various aspects of this patent document relate to a method to administer a bioactive agent to a subject, comprising providing a composition described anywhere in this patent document, and administering the composition to the subject.
In some embodiments, the administering is oral, sublingual, sublabial, buccal, rectal, intranasal, inhalational, transmucosal, topical, transdermal, intravenous, intramuscular, subcutaneous, intradermal, intraocular, parenteral, intrathecal, intralesional, or intratumoral administering. In some specific embodiments, the administering is oral, sublingual, or buccal administering. In some specific embodiments, the administering is topical or transdermal administering.
In some specific embodiments, the composition is formulated to allow the conversion of an anionic form of the bioactive agent into a molecular form of the bioactive agent. In some very specific embodiments, the composition is formulated to allow the conversion of the anionic form of the bioactive agent into the molecular form of the bioactive agent ex vivo prior to administering the composition to the subject. In some very specific embodiments, the composition is formulated to allow the conversion of the anionic form of the bioactive agent into the molecular form of the bioactive agent in situ subsequent to administering the composition to the subject.
In some specific embodiments, administering comprises topical administration. In some very specific embodiments, the composition is formulated for topical administration, and topical administration results in conversion of an anionic form of the bioactive agent into a molecular form of the bioactive agent.
In some specific embodiments, administering comprises oral administration. In some very specific preferred embodiments, the composition is formulated for oral administration, and the composition is formulated to allow the conversion of an anionic form of the bioactive agent into a molecular form of the bioactive agent before the bioactive agent reaches the stomach of the subject to allow absorption of the bioactive agent by the epithelial lining of the gastrointestinal tract between the lips and the stomach, excluding the stomach and the outer surfaces of the lips, and including the esophagus and the inner surfaces of the lips.
In some specific embodiments, the subject is a rodent, lagomorph, feline, canine, porcine, ovine, caprine, lama, vicugna, bovine, equine, or primate. In some very specific embodiments, the subject is human.
This patent application claims priority to U.S. Provisional Patent Application No. 63/154,512, filed Feb. 26, 2021; U.S. Provisional Patent Application No. 63/154,545, filed Feb. 26, 2021; U.S. Provisional Patent Application No. 63/191,817, filed May 21, 2021; U.S. Provisional Patent Application No. 63/191,834, filed May 21, 2021; U.S. Provisional Patent Application No. 63/191,848, filed May 21, 2021; U.S. Provisional Patent Application No. 63/191,879, filed May 21, 2021; U.S. Provisional Patent Application No. 63/194,814, filed May 28, 2021; U.S. Provisional Patent Application No. 63/254,434, filed Oct. 11, 2021; U.S. Provisional Patent Application No. 63/256,456, filed Oct. 15, 2021; and U.S. Provisional Patent Application No. 63/282,126, filed Nov. 22, 2021, each of which is incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/016001 | 2/10/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63154512 | Feb 2021 | US | |
| 63154545 | Feb 2021 | US | |
| 63191817 | May 2021 | US | |
| 63191834 | May 2021 | US | |
| 63191848 | May 2021 | US | |
| 63191879 | May 2021 | US | |
| 63194814 | May 2021 | US | |
| 63254434 | Oct 2021 | US | |
| 63256456 | Oct 2021 | US |
