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

• US 8,816,083 B2
• Filed: 10/25/2012
• Issued: 08/26/2014
• Est. Priority Date: 10/26/2011
• Status: Active Grant

• Current Assignee: Zevra Therapeutics, Inc.
• Original Assignee: KemPharm, Inc.
• Inventors: Mickle, Travis, Guenther, Sven, Chi, Guochen, Kanski, Jaroslaw, Martin, Andrea K., Bera, Bindu
• Primary Examiner(s): Carter, Kendra D
• Assistant Examiner(s): Deck, Jason A
• Application Number:
  US13/660,112
• Publication Number:
  US 20130150395A1
• Time in Patent Office: 670 Days
• Field of Search: 514/282, 546/45, 546/44
• US Class Current: 546/44
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/616 by carboxylic acids, e.g. acetylsalicylic acid
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/55 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 11/14 Antitussive agents
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

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.

Claims

1. A prodrug composition comprising at least one conjugate, wherein the at least one conjugate is 3,6-di-aspirin-hydromorphone.

2. The prodrug composition of claim 1, wherein the at least one conjugate 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.

3. The prodrug composition of claim 1, wherein oral administration of the at least one conjugate results in an improved AUC and rate of release over time when compared to unconjugated hydromorphone over the same time period.

4. The prodrug composition of claim 1, wherein oral administration of the at least one conjugate results in less variability in the oral PK profile when compared to unconjugated hydromorphone.

5. The prodrug composition of claim 1, wherein oral administration of the at least one conjugate results in reduced side effects when compared with unconjugated hydromorphone.

6. The prodrug composition of claim 5, wherein the reduced side effect is reduced opioid induced constipation.

7. The prodrug composition of claim 1, wherein at least one conjugate is provided in a dosage form selected from the group consisting of a tablet, a capsule, a caplet, a suppository, a troche, a lozenge, an oral powder, a solution, an oral film, a thin strip, a slurry, and a suspension.

8. The prodrug composition of claim 1, wherein oral administration of the at least one conjugate provides a therapeutically bioequivalent AUC and/or a bioequivalent or lower C_max when compared to an equivalent molar amount of unconjugated hydromorphone.

9. The prodrug composition of claim 1, 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 hydromorphone.

10. The prodrug composition of claim 1, wherein oral administration of the at least one conjugate provides a decreased overdose potential when compared to an equivalent molar amount of unconjugated hydromorphone.

11. The prodrug composition of claim 1, wherein the at least one conjugate provides an increased tamper resistance when compared to unconjugated hydromorphone.