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-10758528-B2
Application number	US-201916573313-A
Country	US
Kind code	B2
Filing date	Sep 17, 2019
Priority date	Dec 2, 2014
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

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 a structure selected from the group consisting of:

or a salt of said compound.

2. A composition comprising at least one compound of claim 1 , a salt of said compound, or a combination 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 is in an amount sufficient to provide a therapeutically equivalent AUC when compared to unconjugated oxymorphone when administered orally.

5. 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.

6. 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.

7. The composition of claim 2 , wherein intranasal or intravenous administration of the compound provides a lower AUC and/or Cmax when compared to an equivalent molar amount of unconjugated oxymorphone.

8. The composition of claim 2 , wherein oral administration of the compound provides a decreased overdose potential when compared to an equivalent molar amount of unconjugated oxymorphone.

9. The composition of claim 2 , wherein the compound provides an increased tamper resistance when compared to unconjugated oxymorphone.

10. A method for treating pain in a patient, said method comprising the step of selecting a patient in need thereof and orally administering to the patient a therapeutically effective amount of at least one composition of claim 2 .

11. The method of claim 10 , wherein the pain is selected from the group consisting of acute pain, chronic pain, moderate pain, severe pain, and moderately severe pain.

12. The method of claim 10 , wherein the patient is human or animal.

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

14. The composition of claim 13 , wherein the reduced side effects comprise gastrointestinal dysfunction, wherein the gastrointestinal dysfunction comprises constipation, decreased hydrochloric acid secretion in the stomach, decreased gastric motility, esophageal reflux, or combinations thereof.

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

16. The composition of claim 15 , 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 mixtures thereof.

17. The composition of claim 15 , wherein the cationic salt form is selected from the group consisting of sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, tromethamine, or mixtures thereof.

18. The composition of claim 2 , wherein the at least one 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 oxymorphone.

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

20. The composition of claim 19 , wherein the composition formulated for oral administration is a tablet, a granule, 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).

21. The composition of claim 20 , wherein the composition is formulated in a tablet form, a solution, a suspension, or a soft gel form.

22. The composition of claim 21 , 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.

23. The composition of claim 22 , 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.

24. 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.

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

26. 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 non orally.

Assignees

• Kempharm Inc

Inventors

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

Classifications

• A61K31/485 Primary

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

• C07D221/28 Primary

  Morphinans · 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

• C07D489/08

  Oxygen atom · CPC title

• A61K47/545

  Heterocyclic compounds (A61K47/558 takes precedence) · CPC title