Compositions comprising methylphenidate-prodrugs, processes of making and using the same

10954,212

16/588914

September 30, 2019

The present technology is directed to d-threo-methylphenidate conjugates and a composition comprising d-threomethylphenidate conjugated to nicotinoyl-L-serine, or salt thereof. The present technology also relates to a composition comprising at least one conjugate of d-methylphenidate having at least two or more chiral centers. The composition is optically active. The present technology additionally relates to oral formulations and pharmaceutical kits comprising at least one d-threo-methylphenidate conjugate. The pharmaceutical kit may comprise a specified amount of individual doses in a package. Each individual dose in the package may contain a pharmaceutically effective amount of a conjugate of d-threo methylphenidate.

KemPharm, Inc. (Celebration, FL, US)

KemPharm, Inc. (Celebration, FL, US)

1. A method of extending the release of d-methylphenidate in a human or animal subject as compared to the release of d-methylphenidate of an equivalent molar amount of immediate release unconjugated d-methylphenidate, the method comprising orally administering to the human or animal subject a pharmaceutically or therapeutically effective amount of a composition comprising a compound, wherein the compound is a conjugate of d-methylphenidate, having the following chemical formula: [chemical expression included] or salt of said compound, wherein oral administration of said pharmaceutically or therapeutically effective amount of the composition is effective to produce an extended release of d-methylphenidate in the subject as compared to the release of d-methylphenidate upon oral administration of an equivalent molar amount of immediate release unconjugated d-methylphenidate.

2. The method of claim 1 , wherein the salt of the compound is a pharmaceutically acceptable salt selected from the group consisting of acetate, l-aspartate, besylate, bicarbonate, carbonate, d-camsylate, l-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide/bromide, hydrochloride/chloride, d-lactate, l-lactate, d,l-lactate, d,l-malate, l-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 method of claim 2 , wherein the pharmaceutically acceptable salt of the compound has the following structure: [chemical expression included]

4. A method for producing both an immediate release and extended release of d-methylphenidate in a human or animal subject as compared to the release of d-methylphenidate of an equivalent molar amount of unconjugated d-methylphenidate, the method comprising orally administering to the human or animal subject a pharmaceutically or therapeutically effective amount of a composition comprising a compound, wherein the compound is a conjugate of d-methylphenidate, having the following chemical formula: [chemical expression included] or salt of said compound wherein oral administration of said pharmaceutically or therapeutically effective amount the composition is effective to produce both an immediate release and extended release of d-methylphenidate in the human or animal subject as compared to the release of d-methylphenidate upon oral administration of an equivalent molar amount of unconjugated d-methylphenidate.

5. The method of claim 4 , wherein the pharmaceutically acceptable salt of the compound has the following structure: [chemical expression included]

6. The method of claim 1 , wherein the pharmaceutically acceptable salt of the compound has the following structure: [chemical expression included] and the subject is human.

7. The method of claim 4 , wherein the pharmaceutically acceptable salt of the compound has the following structure: [chemical expression included] and the subject is human.

5908850 June 1999 Zeitlin et al.
6210705 April 2001 Mantelle et al.
8101782 January 2012 Rupniak et al.
8632750 January 2014 Suffin et al.
8969337 March 2015 Blumberg et al.
9079928 July 2015 Guenther et al.
9453037 September 2016 Buenther et al.
2002/0103162 August 2002 Epstein et al.
2002/0132793 September 2002 Epstein et al.
2004/0063628 April 2004 Piccariello et al.
2006/0100243 May 2006 Froimowitz et al.
2007/0042955 February 2007 Mickle et al.
2007/0123468 May 2007 Jenkins
2008/0139653 June 2008 Mickle
2009/0137486 May 2009 Mickle et al.
2010/0145057 June 2010 Thennati et al.
2010/0249242 September 2010 Poulsen et al.
2011/0021564 January 2011 Sanfilippo
2011/0213034 September 2011 Mickle
1999036403 July 1999
2004080959 September 2004
PCT/US2004/017204 January 2005
2008097546 August 2008
2008147518 December 2008
2009035473 March 2009
2013016668 January 2013
2018107131 June 2018
2018107132 June 2018

Destevens, G.: “Investigations in Heterocycles. XV. Methylphenidate : A Versatile Intermediate in the Synthesis of Bicyclic Heterocycles with Bridged Nitrogen Atom,” J. Med. Chem., pp. 146-149, 1964. cited by applicant
Dias, Luiz C., et al.: “Short Synthesis of Methylphenidate and its p-Methoxy Derivative,” Synthetic Communications, vol. 30, No. 7, p. 1313, 2000. cited by applicant
Misra M., et al., “Quantitative structure-activity relationship studies of threo-methylphenidate analogs,” Bioorganic & Medicinal Chemistry, Pergamon, GB, vol. 18, No. 20, pp. 7221-7238, 2010. cited by applicant
Pilli et al., “The Stereochemistry of the Addition of Chlorotitanium Enolates of N-Acyl Oxazolidin-2-ones to 5- and 6-Membered N-Acyliminium Ions.” J. Braz. Chem. Soc., vol. 12, No. 5, pp. 634-651, 2001. cited by applicant
EESR for International Patent Application No. PCT/US2012/048641 mailed Jan. 23, 2015. cited by applicant
Notice of Allowance for U.S. Appl. No. 14/234,440 dated Dec. 4, 2014. cited by applicant
Notice of Allowance for U.S. Appl. No. 14/234,440 dated Mar. 16, 2015. cited by applicant
Japanese Office Action for JP Appl No. 014-523083, dated Mar. 30, 2016. cited by applicant
Alexander et al., “(Acyloxy)alkyl Carbamates as Novel Bioreversible Prodrugs for Amines: Increased Permeation through biological Membranes,” J. Med. Chem, 1988, pp. 318-322. cited by applicant
Ribeiro et al., “Aminocarbonyloxymethyl Ester Prodrugs of Flufenamic Acid and Diclofenac: Suppressing the Rearrangement Pathway in Aqueous Media,” Arch. Pharm. Chem Life Sci., 2007, pp. 32-40. cited by applicant
Canadian Examiner's Report for Application No. 2,837,732, dated Dec. 12, 2016. cited by applicant
Restriction Requirement for U.S. Appl. No. 15/249,088, dated Jan. 30, 2017. cited by applicant
Extended European Search Report for Appl No. 17157635.8, dated May 4, 2017. cited by applicant
Office Action for U.S. Appl. No. 14/727,498, dated Feb. 11, 2016. cited by applicant
Notice of Allowance for U.S. Appl. No. 14/727,498, dated Jun. 23, 2016. cited by applicant
Notice of Allowance for Japan Patent Application No. 2016-139995, dated Dec. 5, 2017, 4 pages. cited by applicant
Final Rejection for Korea Patent Application No. 10-2016-7010571, dated Jan. 10, 2018, 6 pages. cited by applicant
Examination Report for India Patent Application No. 11264/DELNP/2013, dated Jan. 23, 2018, 7 pages. cited by applicant
Notice of Allowance of Korea Patent Application No. 10-2016-7010571, dated Mar. 14, 2018, 6 pages. cited by applicant
International Search Report for PCT Application No. PCT/US17/65482, dated Feb. 1, 2018, 4 pages. cited by applicant
IPRP for International Application No. PCT/US2017/065482 mailed Jun. 20, 2019, 9 pages. cited by applicant
Rochdi, M., et al.: “Dose-proportional pharmacokinetics of a methylphenidate extended-release capsule,” Int. J. Pharmacol. Ther., 42(5)285-92, May 2004. cited by applicant
Tuerck, D., et al.: “Dose-proportional pharmacokinetics of d-threo-methylphenidate after a repeated-action release dosage form,” J. Clin. Pharmacol., 47(1):64-69, Jan. 2007. cited by applicant
Mickle, Travice C., et al.: “Pharmacokinetics and Abuse Potential of Benzhydrocodone, A Novel Prodrug of Hydrocodone, After Intranasal Administration in Recreational Drug Users,” Pain Med., 19(12):2438-2449, Dec. 2018. cited by applicant
International Search Report regarding PCT Application No. PCT/US2019/035803, dated Aug. 19, 2019, 11 pgs. cited by applicant
Extended International Search Report regarding PCT Application No. PCT/US2004/017204, dated Jun. 23, 2020, 9 pgs. cited by applicant
Ermer, James C., et al., Lisdexamfetamine Dimesylate: Prodrug Delivery, Amphetamine Exposure and Duration of Efficacy, published online: Mar. 28, 2016, 16 pgs. cited by applicant
Israeli Patent Office, Office Action regarding Application No. 267172, dated Oct. 25, 2020, 19 pages. cited by applicant

edspgr.10954212