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

Patent metadata

Field	Value
Publication number	US-10144740-B2
Application number	US-201715812730-A
Country	US
Kind code	B2
Filing date	Nov 14, 2017
Priority date	Nov 25, 2014
Publication date	Dec 4, 2018
Grant date	Dec 4, 2018

Abstract

The presently described technology provides compositions comprising aryl carboxylic acids and, for example NSAIDs, chemically conjugated to oxycodone (4,5-α-epoxy-14-hydroxy-17-methylmorphinan-6-one) to form novel prodrugs/compositions of oxycodone, including benzoates, salicylates, propionates, fenamates, and acetates, which have a decreased potential for abuse of oxycodone. 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 composition comprising an oxycodone conjugate wherein the oxycodone is conjugated to 4-hydroxy-benzoic acid, pharmaceutically acceptable salt thereof, or a combination thereof, wherein the oxycodone conjugate has the following structural formula

2. The composition of claim 1 , wherein the oxycodone conjugate exhibits an improved AUC and rate of release over time when compared to unconjugated oxycodone over the same time period; exhibits less variability in the oral PK profile when compared to unconjugated oxycodone; or has reduced side effects when compared with unconjugated oxycodone.

3. The composition of claim 2 , wherein the reduced side effects comprise reduced opioid induced constipation.

4. The composition of claim 1 , wherein the composition is formulated for oral administration.

5. The composition of claim 4 , wherein the composition formulated for oral administration is a tablet, capsule, caplet, pill, powder, troche, lozenge, slurry, liquid solution, suspension, emulsion, elixir or oral thin film (OTF).

6. The composition of claim 1 , wherein the composition in a solid form, a solution, a suspension, or a soft gel form.

7. The composition of claim 6 , wherein the solid form further comprises excipients, binders, derivatives thereof, or combinations thereof.

8. The composition of claim 7 , wherein the binder is povidone.

9. The composition of claim 1 , wherein the oxycodone conjugate is in an amount sufficient to provide a therapeutically equivalent AUC when compared to unconjugated oxycodone after oral administration.

10. The composition of claim 1 , wherein the oxycodone conjugate is in an amount sufficient to provide a therapeutically equivalent AUC and C max when compared to an equivalent molar amount of unconjugated oxycodone after oral administration.

11. The composition of claim 1 , wherein the oxycodone conjugate 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 oxycodone after oral administration.

12. The composition of claim 1 , wherein intranasal or intravenous administration of the oxycodone conjugate provides a lower AUC and/or C max when compared to an equivalent molar amount of unconjugated oxycodone.

13. The composition of claim 1 , wherein oral administration of the oxycodone conjugate provides a decreased overdose potential when compared to an equivalent molar amount of unconjugated oxycodone.

14. The composition of claim 1 , wherein the oxycodone conjugate provides an increased tamper resistance when compared to unconjugated oxycodone.

15. The composition of claim 1 , wherein the pharmaceutically acceptable salt of the oxycodone conjugate 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 (mucate), galacturonate, gallate, gentisate, glutamate, glutamate, glutarate, glycerophosphate, heptanoate (enanthate), 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, undecylenate, sodium, potassium, calcium, magnesium, zinc, aluminium, lithium, cholinate, lysinium, ammonium, tromethamine, and derivatives thereof.

16. The composition of claim 1 , wherein the oxycodone conjugate 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 oxycodone.

17. A compound having the following structure

or a pharmaceutically acceptable salt thereof.

Assignees

• Kempharm Inc
• Kempharm Inc

Inventors

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

Classifications

• A61K31/485

  Morphinan derivatives, e.g. morphine, codeine · CPC title

• C07D489/04 Primary

  Salts; Organic complexes · CPC title

• A61P25/36

  Opioid-abuse · CPC title

• A61K45/06

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

• A61K9/00 Primary

  Medicinal preparations characterised by special physical form {(nuclear magnetic resonance contrast preparations or magnetic resonance imaging contrast preparations A61K49/18; preparations containing radioactive substances A61K51/12)} · CPC title