Enhancing transdermal delivery of opioid antagonists and agonists using codrugs linked to bupropion or hydroxybupropion
View Patent ↗The present invention is directed to novel codrugs comprising bupropion or hydroxybupropion and an opioid antagonist or an opioid agonist joined together by chemical bonding. The codrugs provide a significant increase in the transdermal flux across human skin, as compared to the basic opioid antagonist or opioid agonist.
1. A codrug comprising:
(a) hydroxybupropion; and
(b) an opioid antagonist or an opioid agonist selected from the group consisting of Naltrexone, Buprenorphine, Butorphanol, Codeine, Dihydrocodeine, Dihydromorphine, Ethylmorphine, Hydromorphone, Levallorphan, Levorphanol, Nalbuphine, Nalmefene, Nalorphine, Naloxone, 6-β-Naltrexol, Phenazocine, Pholcodine, and 6-α-Naltrexol;
wherein hydroxybupropion is linked via a carbonate linker to the opioid antagonist or opioid agonist to form a single chemical entity.
2. The codrug of claim 1 , wherein said carbonate linker is cleavable.
3. The codrug of claim 2 , wherein said carbonate linker is cleavable via hydrolysis and/or enzymatic digestion.
4. The codrug of claim 1 , wherein said codrug comprises Naltrexone or 6-β-Naltrexol.
5. The codrug of claim 4 , wherein said codrug comprises 6-β-Naltrexol.
6. The codrug of claim 4 , wherein said codrug comprises Naltrexone.
7. A transdermal patch comprising a substrate and a layer of the codrug of claim 1 .
8. A codrug having the following structure:
9. A codrug having the following structure:
10. A codrug having the following structure:
11. A codrug having the following structure:
12. A codrug having the following structure:
13. A codrug having the following structure: