Benzoic acid, benzoic acid derivatives and heteroaryl carboxylic acid conjugates of oxymorphone, prodrugs, methods of making and use thereof

Patent metadata

Field	Value
Publication number	US-9682076-B2
Application number	US-201514956642-A
Country	US
Kind code	B2
Filing date	Dec 2, 2015
Priority date	Dec 2, 2014
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

The presently described technology provides compositions comprising aryl carboxylic acids and, for example NSAIDs, chemically conjugated to oxymorphone (4,5-α-epoxy-3,14-dihydroxy-17-methylmorphinan-6-one) to form novel prodrugs/compositions of oxymorphone, including benzoates, salicylates, propionates, fenamates, and acetates, which have a decreased potential for abuse of oxymorphone. 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 structure:

or a salt of said compound.

2. A composition comprising a conjugate, wherein the conjugate is the compound of claim 1 or a pharmaceutical acceptable salt thereof.

3. The composition of claim 2 , wherein the composition is in a dosage form selected from the group consisting of: a tablet, a capsule, a caplet, a soft gel, a suppository, a troche, a lozenge, an oral powder, a solution, an oral film, a thin strip, a slurry, and a suspension.

4. The composition of claim 2 , wherein the composition has reduced side effects when compared with unconjugated oxymorphone.

5. The composition of claim 4 , wherein the reduced side effects comprise reduced opioid induced constipation.

6. The composition of claim 2 , wherein the composition is in an amount sufficient to provide a therapeutically equivalent AUC when compared to unconjugated oxymorphone when administered orally.

7. The composition of claim 2 , wherein the composition is in an amount sufficient to provide a therapeutically equivalent AUC and C max when compared to an equivalent molar amount of unconjugated oxymorphone when administered orally.

8. The composition of claim 2 , wherein the composition 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 oxymorphone when administered orally.

9. The composition of claim 2 , wherein intranasal or intravenous administration of the at least one conjugate provides a lower AUC and/or C max when compared to an equivalent molar amount of unconjugated oxymorphone.

10. The composition of claim 2 , wherein oral administration of the at least one conjugate provides a decreased overdose potential when compared to an equivalent molar amount of unconjugated oxymorphone.

11. The composition of claim 2 , wherein the at least one conjugate provides an increased tamper resistance when compared to unconjugated oxymorphone.

12. The composition of claim 2 , wherein the conjugate is a pharmaceutically acceptable anionic or cationic salt form or salt mixture thereof.

13. The composition of claim 12 , wherein the anionic salt form 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 or a mixture thereof.

14. The composition of claim 12 , wherein the cationic salt form is selected from the group consisting of sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, tromethamine, or derivatives thereof.

15. The composition of claim 2 , wherein the conjugate of oxymorphone 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 oxymorphone.

16. The composition of claim 2 , wherein the composition is formulated for oral, suppository, powder for injection, or intrathecal administration.

17. The composition of claim 16 , wherein the composition formulated for oral administration is a tablet, a capsule, a soft gel, a caplet, a pill, an oral powder, a troche, a lozenge, a slurry, a solution, a suspension, an emulsion, an elixir or an oral thin film (OTF).

18. The composition of claim 17 , wherein the composition is formulated in a tablet form, a solution, a suspension, or a soft gel form.

19. The composition of claim 18 , wherein the tablet form further comprises one or more excipients, wherein the excipients are selected from the group consisting of anti-adherents, binders, coatings, disintegrants, fillers, flavors, dyes, colors, glidants, lubricants, preservatives, sorbents, sweeteners, derivatives thereof, and combinations thereof.

20. The composition of claim 19 , wherein the binder is selected from the group consisting of hydroxypropylmethylcellulose, ethyl cellulose, povidone, acrylic and methacrylic acid co-polymers, pharmaceutical glaze, gums, and milk derivatives.

21. The composition of claim 2 , wherein the composition exhibits an improved AUC and rate of release over time when compared to unconjugated oxymorphone over the same time period when administered orally.

22. The composition of claim 2 , wherein the composition exhibits less variability in the oral PK profile when compared to unconjugated oxymorphone.

Assignees

• Kempharm Inc

Inventors

• Mickle Travis
• Guenther Sven
• Bera Sanjib
• Kanski Jaroslaw
• Martin Andrea

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D221/28 Primary

  Morphinans · CPC title