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-10544153-B2
Application number	US-201816165194-A
Country	US
Kind code	B2
Filing date	Oct 19, 2018
Priority date	Nov 25, 2014
Publication date	Jan 28, 2020
Grant date	Jan 28, 2020

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 compound having the following structural formula

or salt thereof.

2. A composition comprising a compound of claim 1 , a salt thereof, or a combination thereof.

3. The composition of claim 2 , wherein the salt is a pharmaceutically acceptable salt.

4. The composition of claim 3 , wherein the pharmaceutically acceptable salt 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, and a mixture thereof.

5. The composition of claim 3 , wherein the compound 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.

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

7. The composition of claim 3 , wherein the composition is formulated for oral, sublingual, transdermal, suppository, intranasal, intravenous, or intrathecal administration.

8. The composition of claim 7 , wherein the composition is in a dosage form selected from the group consisting of a solid form, 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, an emulsion, an elixir, and a suspension.

9. The composition of claim 8 , wherein the solid form further comprises excipients selected from anti-adherents, binders, coatings, disintegrants, fillers, flavors, dyes, colors, glidants, lubricants, preservatives, sorbents, sweeteners, or combinations thereof.

10. The composition of claim 9 , 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.

11. The composition of claim 3 , wherein the compound is in an amount sufficient to provide a therapeutically equivalent AUC when compared to unconjugated oxycodone after oral, sublingual, transdermal, suppository, intranasal, intravenous, or intrathecal administration.

12. The composition of claim 3 , 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 oxycodone after oral administration.

13. The composition of claim 3 , 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 oxycodone after oral administration.

14. The composition of claim 3 , 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 oxycodone.

15. The composition of claim 3 , wherein oral administration of the compound provides a decreased overdose potential when compared to an equivalent molar amount of unconjugated oxycodone.

16. The composition of claim 3 , wherein the compound provides an increased tamper resistance when compared to unconjugated oxycodone.

17. The composition of claim 3 , 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 oxycodone.

18. A kit comprising individual doses of a therapeutically effective amount of a composition comprising a compound of claim 1 , a salt thereof, or a combination thereof.

19. The kit of claim 18 , further comprising instructions directing use of the compound in a dosage range of between about 1 mg to about 200 mg per dose.

Assignees

• Kempharm Inc

Inventors

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

Classifications

• A61P25/36

  Opioid-abuse · 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

• C07D498/08 Primary

  Bridged systems · CPC title

• C07D489/04 Primary

  Salts; Organic complexes · CPC title

• A61K31/485

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