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

Patent metadata

Field	Value
Publication number	US-10258696-B2
Application number	US-201816054575-A
Country	US
Kind code	B2
Filing date	Aug 3, 2018
Priority date	Oct 26, 2011
Publication date	Apr 16, 2019
Grant date	Apr 16, 2019

Abstract

The presently described technology provides compositions comprising aryl carboxylic acids chemically conjugated to hydromorphone (4,5-α-epoxy-3-hydroxy-17-methyl morphinan-6-one) to form novel prodrugs/compositions of hydromorphone. The hydromorphone prodrugs of the present technology have decreased side effects and decreased potential for abuse compared to unconjugated hydromorphone. 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 a hydromorphone conjugate wherein the hydromorphone conjugate is 3-cinnamate-hydromorphone, a pharmaceutically acceptable salt thereof, or a combination thereof.

2. The composition of claim 1 , where in the hydromorphone conjugate has the following structural formula

3. The composition of claim 1 , wherein the hydromorphone conjugate and/or at least one pharmaceutically acceptable salt thereof is used to treat narcotic or opioid abuse; to prevent narcotic or opioid withdrawal; to treat moderate to severe pain; to reduce or prevent oral, intranasal or intravenous drug abuse; or to provide oral, intranasal, or parenteral drug abuse resistance.

4. The composition of claim 1 , wherein the hydromorphone conjugate and/or at least one pharmaceutically acceptable salt thereof is provided in a dosage form selected from the group consisting of a tablet, a capsule, a caplet, a suppository, a troche, a lozenge, a powder, a solution, a film, a thin strip, a slurry, a suspension, a gel, a strip, a rectal film, a transdermal patch, a syrup, and an inhalation compound.

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

6. The composition of claim 5 , wherein oral administration of the hydromorphone conjugate and/or at least one pharmaceutically acceptable salt thereof results in an improved rate of release over time when compared to unconjugated hydromorphone over the same time period.

7. The composition of claim 5 , wherein oral administration of the hydromorphone conjugate and/or at least one pharmaceutically acceptable salt thereof results in less variability in the oral PK profile when compared to unconjugated hydromorphone.

8. The composition of claim 5 , wherein oral administration of the hydromorphone conjugate and/or at least one pharmaceutically acceptable salt thereof results in reduced side effects when compared with unconjugated hydromorphone.

9. The composition of claim 8 , wherein the reduced side effect is reduced opioid induced constipation.

10. The composition of claim 5 , wherein oral administration of the hydromorphone conjugate and/or at least one pharmaceutically acceptable salt thereof provides a therapeutically bioequivalent AUC and/or a bioequivalent when compared to an equivalent molar amount of unconjugated hydromorphone.

11. The composition of claim 5 , wherein oral administration of the hydromorphone conjugate and/or at least one pharmaceutically acceptable salt thereof provides a decreased overdose potential when compared to an equivalent molar amount of unconjugated hydromorphone.

12. The composition of claim 1 , wherein the composition is formulated for intranasal or intravenous administration.

13. The composition of claim 12 , wherein intranasal or intravenous administration of the at least one hydromorphone conjugate and/or at least one pharmaceutically acceptable salt thereof provides a lower AUC and/or Cmax when compared to an equivalent molar amount of unconjugated hydromorphone.

14. The composition of claim 1 , wherein the hydromorphone conjugate and/or at least one pharmaceutically acceptable salt thereof provides an increased tamper resistance when compared to unconjugated hydromorphone.

15. The composition of claim 1 , wherein the hydromorphone conjugate and/or pharmaceutically acceptable salt thereof is a prodrug.

16. The composition of claim 1 , wherein the pharmaceutically acceptable salt of the hydromorphone conjugate is an anionic salt form, amphoteric salt form, zwitterionic salt form, cationic salt form, or salt form mixtures thereof.

17. The composition of claim 16 , wherein the anionic salt form is selected from the group consisting of 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, d-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, 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, and mixtures thereof.

18. The composition of claim 16 , wherein the cationic salt form is selected from the group consisting of sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, cholinate, lysinium, ammonium, tromethamine, and mixtures thereof.

19. A compound having the following structure

or a pharmaceutically acceptable salt thereof.

Assignees

• Kempharm Inc

Inventors

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

Classifications

• A61P29/00

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

• A61P25/36

  Opioid-abuse · CPC title

• A61P25/04

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

• A61P11/14

  Antitussive agents · CPC title

• A61K31/616

  by carboxylic acids, e.g. acetylsalicylic acid · CPC title