Claims for Patent: 10,584,113

Summary for Patent: 10,584,113

Title:	Methylphenidate-prodrugs, processes of making and using the same
Abstract:	The present technology is directed to compositions comprising d-threo-methylphenidate conjugates and unconjugated methylphenidate. The present technology also relates to compositions and oral formulations comprising d-threo-methylphenidate conjugated to nicotinoyl-L-serine, and/or a pharmaceutically acceptable salt thereof, and unconjugated methylphenidate and/or a pharmaceutically acceptable salt thereof. The present technology additionally relates to a pharmaceutical kit containing the composition comprising d-threo-methylphenidate conjugated to nicotinoyl-L-serine, and/or a pharmaceutically acceptable salt thereof, and unconjugated methylphenidate and/or a pharmaceutically acceptable salt thereof.
Inventor(s):	Mickle; Travis (Kissimmee, FL), Guenther; Sven (Coralville, IA), Chi; Guochen (Coralville, IA)
Assignee:	KemPharm, Inc. (Celebration, FL)
Application Number:	16/431,422
Patent Claims:	1. A composition comprising unconjugated methylphenidate, wherein the unconjugated methylphenidate is d-threo-methylphenidate, at least one pharmaceutically acceptable salt thereof, or mixtures thereof, and a compound, wherein the compound is a conjugate of d-methylphenidate having the following chemical formula: ##STR00008## at least one pharmaceutically acceptable salt thereof, or mixtures thereof. 2. The composition of claim 1, wherein the at least one pharmaceutically acceptable salt of the unconjugated methylphenidate and/or compound is independently selected from the group consisting of acetate, 1-aspartate, besylate, bicarbonate, carbonate, d-camsylate, 1-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, d-lactate, 1-lactate, d,l-lactate, d,l-malate, 1-malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, d-tartrate, martrate, d,l-tartrate, meso-tartrate, benzoate, gluceptate, d-glucuronate, hybenzate, isethionate, malonate, methylsulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate, lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate, valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, undecylenate, and combinations thereof. 3. The composition of claim 2, wherein the at least one pharmaceutically acceptable salt of the unconjugated methylphenidate and/or the compound is independently selected the group consisting of chloride, hydrogen carbonate (bicarbonate), iodide, bromide, citrate, acetate, formate, salicylate, hydrogen sulfate (bisulfate), hydroxide, nitrate, hydrogen sulfite (bisulfite), propionate, benzene sulfonate, hypophosphite, phosphate, bromate, iodate, chlorate, fluoride, nitrite, and combinations thereof. 4. The composition of claim 3, wherein the pharmaceutically acceptable salt of the unconjugated methylphenidate is d-threo-methylphenidate hydrochloride. 5. The composition of claim 3 wherein the pharmaceutically acceptable salt of the compound has the following structure: ##STR00009## 6. The composition of claim 5, further comprising a pharmaceutically acceptable salt of the unconjugated methylphenidate, wherein the pharmaceutically acceptable salt is d-threo-methylphenidate hydrochloride. 7. The composition of claim 1, wherein the composition is in a dosage form selected from a group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), an oral strip, a rectal film, a syrup, a suspension, and a suppository. 8. The composition of claim 1, wherein the composition provides a dose amount that is the molar equivalent to a dose from about 0.1 mg to about 500 mg d-methylphenidate hydrochloride per dose. 9. The composition of claim 8, wherein the composition provides a dose amount that is the molar equivalent to a dose from about 1 mg to about 400 mg d-methylphenidate hydrochloride per dose. 10. The composition of claim 8, wherein the composition provides a dose amount that is the molar equivalent to a dose from about 1 mg to about 300 mg d-methylphenidate hydrochloride per dose. 11. The composition of claim 8, wherein the composition provides a dose amount that is the molar equivalent to a dose from about 1 mg to about 250 mg d-methylphenidate hydrochloride per dose. 12. The composition of claim 8, wherein the composition provides a dose amount that is the molar equivalent to a dose from about 2 mg to about 200 mg d-methylphenidate hydrochloride per dose. 13. The composition of claim 8, wherein the composition provides a dose amount that is the molar equivalent to a dose from about 5 mg to about 150 mg d-methylphenidate hydrochloride per dose. 14. The composition of claim 8, wherein the composition provides a dose amount that is the molar equivalent to a dose from about 10 mg to about 100 mg d-methylphenidate hydrochloride per dose. 15. The composition of claim 8, wherein the composition provides a dose amount that is the molar equivalent to a dose from about 20 mg to about 80 mg d-methylphenidate hydrochloride per dose. 16. The composition of claim 1, wherein the composition is provided in a unit dose form, blister pack, roll, or bulk bottle. 17. The composition of claim 16, wherein the unit dose form provides an amount of d-methylphenidate that is molar equivalent to from about 0.5 mg to about 500 mg d-methylphenidate hydrochloride. 18. The composition of claim 1, wherein the composition comprises a combined therapeutically effective dose of: a) a pharmaceutically acceptable salt of the unconjugated methylphenidate, wherein the pharmaceutically acceptable salt is d-threo-methylphenidate hydrochloride; and b) a pharmaceutically acceptable salt of the compound, wherein the pharmaceutically acceptable salt has the following structure: ##STR00010## 19. The composition of claim 1, wherein the unconjugated methylphenidate contributes an amount of d-threo-methylphenidate active in the range of about 5% to about 95% by weight, based on the total weight of the d-methylphenidate active in the composition, and the compound contributes an amount of d-threo-methylphenidate active in the range of about 95% to about 5% by weight, based on the total weight of the d-methylphenidate active in the composition. 20. The composition of claim 19, wherein the unconjugated methylphenidate contributes an amount of d-threo-methylphenidate active in the range of about 10% by weight, based on the total weight of the d-methylphenidate active in the composition, and the compound contributes an amount of d-threo-methylphenidate active in the range of about 90% by weight, based on the total weight of the d-methylphenidate active in the composition. 21. The composition of claim 19, wherein the unconjugated methylphenidate contributes an amount of d-threo-methylphenidate active in the range of about 30% by weight, based on the total weight of the d-methylphenidate active in the composition, and the compound contributes an amount of d-threo-methylphenidate active in the range of about 70% by weight, based on the total weight of the d-methylphenidate active in the composition. 22. The composition of claim 19, wherein the unconjugated methylphenidate contributes a molar equivalent amount of d-threo-methylphenidate active of about 1.3 mg, or about 2 mg, or about 2.6 mg, or about 3 mg, or about 3.5 mg, or about 3.9 mg, or about 4 mg, or about 5 mg, or about 5.2 mg, or about 6 mg, or about 6.5 mg, or about 7 mg, or about 7.8 mg, or about 9.1 mg, or about 10.4 mg, or about 11.7 mg, or about 13.0 mg, or about 14.3 mg, or about 15.6 mg, or about 16.9 mg, or about 18.2 mg, or about 19.5 mg, or about 20.8 mg; and the compound contributes a molar equivalent amount of d-threo-methylphenidate of about 6.5 mg, or about 13.1 mg, or about 19.6 mg, or about 26.1 mg, or about 32.7 mg, or about 39.2 mg, or about 40 mg, or about 45.8 mg, or about 52.3 mg, or about 58.8 mg, or about 60 mg, or about 65.4 mg, or about 70 mg, or about 71.9 mg, or about 78.4 mg, or about 80 mg, or about 85.0 mg, or about 91.5 mg, or about 98.1 mg, or about 100 mg, or about 102.7 mg, or about 120 mg, or about 130 mg, or about 140 mg. 23. The composition of claim 1, wherein the composition further comprises one or more excipients or one or more additional pharmaceutically active ingredients. 24. The composition of claim 23, wherein the excipients are selected from the group consisting of anti-adherents, binders, coatings, disintegrants, gel forming agents, fillers, flavors, colorants, glidants, lubricants, preservatives, sorbents and sweeteners.