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

• US 8,759,368 B2
• Filed: 07/01/2010
• Issued: 06/24/2014
• Est. Priority Date: 07/02/2009
• Status: Active Grant

• Current Assignee: Zevra Therapeutics, Inc.
• Original Assignee: Kempharma Incorporated
• Inventors: Mickle, Travis, Guenther, Sven, Mickle, Christal, Chi, Guochen, Kanski, Jaroslaw, Martin, Andrea K., Bera, Bindu
• Primary Examiner(s): Aulakh, Charanjit
• Application Number:
  US13/378,800
• Publication Number:
  US 20120142719A1
• Time in Patent Office: 1,454 Days
• Field of Search: 514/282
• US Class Current: 514/282
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/545 Heterocyclic compounds A61K47/558 takes precedence
• 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 47/556 enzyme catalyzed therapeutic agent [ECTA]
• 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 9/20 Pills, tablets, discs, rods A61K9/0004, A61K9/0007, A61K9/0056, A61K9/0065 take precedence; for reconstitution of a drink A61K9/0095
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: C07D 489/02 with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
• CPC Class Codes: C07D 489/04 Salts; Organic complexes
• CPC Class Codes: C07D 491/08 Bridged systems

Abstract

The presently described technology provides compositions comprising aryl carboxylic acids chemically conjugated to hydrocodone (morphinan-6-one, 4,5-alpha-epoxy-3-methoxy-17-methyl) to form novel prodrugs/compositions of hydrocodone, including benzoates and heteroaryl carboxylic acids, which have a decreased potential for abuse of hydrocodone. The present technology also provides methods of treating patients, pharmaceutical kits and methods of synthesizing conjugates of the present technology.

Claims

1. A method for treating pain in an individual comprising the step of orally administering a pharmaceutically effective amount of a composition comprising a conjugate, wherein the conjugate is benzoate-hydrocodone (Bz-HC) having the following structure:

2. The method of claim 1 wherein the conjugate exhibits an improved AUC and rate of release over time when compared to unconjugated hydrocodone over the same time period;

exhibits less variability in the oral PK profile when compared to unconjugated hydrocodone;

or has reduced side effects when compared with unconjugated hydrocodone.

3. The method of claim 1 wherein the composition 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.

4. The method of claim 1 wherein the conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC when compared to unconjugated hydrocodone.

5. The method of claim 1 wherein the conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and C_max when compared to an equivalent molar amount of unconjugated hydrocodone.

6. The method of claim 1 wherein the conjugate is provided in an amount sufficient to provide a therapeutically bioequivalent AUC and a lower C_max when compared to an equivalent molar amount of unconjugated hydrocodone.

7. The method of claim 1 wherein the composition is used for treating pain mediated by binding of an opioid primarily to μ

opioid receptors of the patient.

8. The method of claim 7, wherein the conjugate binds reversibly to the μ

opioid receptors of the patient.

9. The method of claim 7, wherein the conjugate binds reversibly to the μ

opioid receptors of the patient without a CNS depressive effect.

10. The method of claim 1 wherein the composition also reduces narcotic or opioid abuse.

11. The method of claim 1 wherein the composition also reduces narcotic or opioid withdrawal.

12. The method of claim 1 wherein the composition also reduces oral, intranasal or intravenous narcotic or opioid abuse.

13. The method of claim 1 wherein the composition also provides oral, intranasal or parenteral narcotic or opioid abuse resistance.