Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of hydrocodone, prodrugs, methods of making and uses thereof

Patent metadata

Field	Value
Publication number	US-10358452-B2
Application number	US-201615376211-A
Country	US
Kind code	B2
Filing date	Dec 12, 2016
Priority date	Jul 2, 2009
Publication date	Jul 23, 2019
Grant date	Jul 23, 2019

Abstract

The presently described technology provides compositions comprising aryl carboxylic acids chemically conjugated to hydrocodone (morphinan-6-one, 4,5-alpha-epoxy-3-methoxy-17-methyl) to form novel prodrugs/compositions of hydrocodone, including benzoates and heteroaryl carboxylic acids, which have a decreased potential for abuse of hydrocodone. The present technology also provides methods of treating patients, pharmaceutical kits and methods of synthesizing conjugates of the present technology.

First claim

The invention claimed is:

1. A compound having the following structural formula:

or salt of said compound.

2. The compound of claim 1 , wherein the salt is a pharmaceutically acceptable salt.

3. A composition comprising the compound of claim 1 or the salt of said compound.

4. The composition of claim 3 , wherein the salt is a pharmaceutically acceptable salt.

5. The composition of claim 4 , wherein the compound is used to treat narcotic or opioid abuse; to reduce narcotic or opioid withdrawal; to treat moderate to severe pain; to reduce oral, intranasal or intravenous drug abuse; or to provide oral, intranasal or parenteral drug abuse resistance.

6. The composition of claim 4 , wherein the compound exhibits an improved AUC and rate of release over time when compared to unconjugated hydrocodone over the same time period; exhibits less variability in the oral PK profile when compared to unconjugated hydrocodone; or has reduced side effects when compared with unconjugated hydrocodone.

7. The composition of claim 6 , wherein the reduced side effects comprise reduced opioid induced constipation.

8. The composition of claim 4 , wherein the composition is formulated for oral, sublingual, transdermal, suppository, or intrathecal administration.

9. The composition of claim 8 , wherein the compound is in an amount sufficient to provide a therapeutically equivalent AUC when compared to unconjugated hydrocodone after oral administration.

10. The composition of claim 8 , wherein the compound is in an amount sufficient to provide a therapeutically equivalent AUC and C max when compared to an equivalent molar amount of unconjugated hydrocodone after oral administration.

11. The composition of claim 8 , wherein the compound is in an amount sufficient to provide a therapeutically equivalent AUC and a lower C max when compared to an equivalent molar amount of unconjugated hydrocodone after oral administration.

12. The composition of claim 8 , wherein intranasal or intravenous administration of the compound provides a lower AUC and/or C max when compared to an equivalent molar amount of unconjugated hydrocodone.

13. The composition of claim 8 , wherein oral administration of the compound provides a decreased overdose potential when compared to an equivalent molar amount of unconjugated hydrocodone.

14. The composition of claim 4 , wherein the compound provides an increased tamper resistance when compared to unconjugated hydrocodone.

15. A method for treating a patient having a disease, disorder or condition mediated by binding of at least one opioid to one or more opioid receptors of the patient, comprising orally administering to the patient a therapeutically effective amount of at least one compound of claim 1 .

16. The composition of claim 4 , wherein the salt of the compound is selected from the group consisting of an 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, L-tartrate, D,L-tartrate, meso-tartrate, benzoate, gluceptate, D-glucuronate, hybenzate, isethionate, malonate, methylsufate, 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, methanesufonate, 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, and undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, tromethamine, a mixture thereof or a combination thereof.

17. The composition of claim 4 , wherein the compound is present in an amount per unit dose of between about 1 mg and about 200 mg per unit dose wherein the amount per unit dose is based on the content of hydrocodone.

18. The composition of claim 17 , wherein the compound is present in an amount per unit dose of between about 1 mg and about 100 mg per unit dose wherein the amount per unit dose is based on the content of hydrocodone.

19. The composition of claim 8 , wherein the composition is in a form selected from the group consisting of a solid form, a tablet, a capsule, a caplet, a pill, a soft gel, a suppository, a troche, a lozenge, a powder, a solution, an oral film, a thin strip, a slurry, a liquid, an emulsion, an elixer and a suspension.

20. The composition of claim 19 , wherein the solid form further comprises excipients, anti-adherents, binders, coatings, disintegrants, fillers, flavors, dyes, colors, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, or combinations thereof.

21. The composition of claim 20 , wherein the binder is selected from the group consisting of hydroxypropylmethylcellulose, ethyl cellulose, povidone, acrylic and methacrylic acid co-polymers, pharmaceutical glaze, and gums.

22. The compound of claim 1 , wherein the compound is used to treat narcotic or opioid abuse; to reduce narcotic or opioid withdrawal; to treat moderate to severe pain; to reduce oral, intranasal or intravenous drug abuse; or to provide oral, intranasal or parenteral drug abuse resistance.

23. The compound of claim 1 , wherein the compound or salt of said compound is a conjugate of hydrocodone.

24. The salt of the compound of claim 1 prepared by a process comprising the steps of:
(a) reacting 2-MOM-salicylic acid ester of hydrocodone in the presence of methanol with HCL to produce a residue;
(b) isolating and dissolving the resulting residue in the presence of methanol followed by ethyl acetate to produce a mixture;
(c) isolating the resulting mixture to produce a solid; wherein the solid is the salt of the compound of claim 1 .

Assignees

• Kempharm Inc

Inventors

• Mickle Travis
• Guenther Sven
• Mickle Christal
• Chi Guochen
• Kanski Jaroslaw
• Martin Andrea K
• Bera Bindu

Classifications

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K31/167 Primary

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title

• A61K47/55

  the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title