Triglyceride-Mimetic Prodrugs of Buprenorphine Enhance Oral Bioavailability via Promotion of Lymphatic Transport

Abstract

Buprenorphine (BUP) is a potent opioid analgesic that is widely used for severe pain management and opioid replacement therapy. The oral bioavailability of BUP, however, is significantly limited by first-pass metabolism. Previous studies have shown that triglyceride (TG) mimetic prodrugs of the steroid hormone testosterone circumvent first-pass metabolism by directing drug transport through the intestinal lymphatics, bypassing the liver. The current study expanded this prodrug strategy to BUP. Here different self-immolative (SI) linkers were evaluated to conjugate BUP to the 2 position of the TG backbone via the phenol group on BUP. The SI linkers were designed to promote drug release in plasma. Lipolysis of the prodrug in the intestinal tract was examined via incubation with simulated intestinal fluid (SIF), and potential for parent drug liberation in the systemic circulation was evaluated via incubation in rat plasma. Lymphatic transport and bioavailability studies were subsequently conducted in mesenteric lymph duct or carotid artery-cannulated rats, respectively. TG prodrug derivatives were efficiently transported into the lymphatics (up to 45% of the dose in anaesthetised rats, vs. less than 0.1% for BUP). Incorporation of the SI linkers facilitated BUP release from the prodrugs in the plasma and in concert with high lymphatic transport led to a marked enhancement in oral bioavailability (up to 22-fold) compared to BUP alone. These data suggest the potential to develop an orally bioavailable BUP product which may have advantages with respect to patient preference when compared to current sublingual, transdermal patch or parenteral formulations.

Nanotechnology-Enhanced Naloxone and Alternative Treatments for Opioid Addiction

“…This potential is particularly promising for lymphatic drug targeting, as these particulates accumulate more readily in tumor tissues or sites of inflammation than in healthy tissues, owing to the enhanced permeable vasculature and reduced lymphatic drainage. 50,51 The consumption of opioids or alcohol can adversely affect health including the lymphatic system. Disruption of the lymphatic system can impair its ability to remove toxins and pathogens, leading to the accumulation of harmful substances in the body.…”

“…Furthermore, the lymphatic system is gaining interest as a potential vehicle for drug delivery attributed to its ability to transport various substances such as colloids, lipids, polymeric nano- and microparticles, and prodrugs from the interstitial space. This potential is particularly promising for lymphatic drug targeting, as these particulates accumulate more readily in tumor tissues or sites of inflammation than in healthy tissues, owing to the enhanced permeable vasculature and reduced lymphatic drainage. , …”