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.

Keywords: buprenorphine; first-pass metabolism; lymphatic transport; opioid analgesics; oral bioavailability; prodrug; triglyceride mimetic.

FIGURE 1

Panel (A) Structure of BUP, TG prodrugs and MG forms of the prodrugs (i.e., the lipolysis products after the removal of the fatty acids in the sn-1 and sn-3 positions from the prodrugs). Panel (B) General schematic to show the proposed mechanisms of release of drug from prodrug in plasma for both SI and non-SI containing prodrugs. The dashed lines and arrows indicate the expected mechanisms for BUP release from the MG or acid forms of the prodrugs and the numbers indicate the expected order of transition. Panel (C) Structures of the acid forms of the prodrugs (i.e., the intermediate products after cleavage from the MG in plasma and before breakdown of the acid form to generate BUP).

FIGURE 2

The main metabolism pathway and metabolites of BUP, including norbuprenorphine, norbuprenorphine glucuronide, and buprenorphine glucuronide.

FIGURE 3

GI stability profiles of BUP prodrugs. Data are shown as % mass change (Mean ± SEM, n = 3) for MG-like forms and parent BUP, or as arbitrary peak area for BUP-linker acid forms, upon in vitro incubation of BUP-C4-TG (A), BUP-CE-C4-TG-TG (B), BUP-TML-C4-TG (C), BUP-TML-C5bMe-TG (D), and BUP-C5bMe-TG (E), with simulated intestinal fluid (SIF) containing porcine pancreatin.

FIGURE 4

Cumulative lymphatic transport of total BUP related derivatives (% of administered dose) versus time in anaesthetised, mesenteric lymph duct cannulated rats following intraduodenal infusion of formulations from 0 to 2 h. Formulations contained 50 µg of BUP or prodrugs, dispersed in 40 mg oleic acid, 25 mg Tween 80 and 5.6 ml PBS. Data are presented as Mean ± SEM when n = 3 or 4 (as labelled for individual groups) or as Mean ± Range in the case of BUP-C5bMe-TG when n = 2. * indicates statistically significantly higher lymphatic transport of BUP-C5bMe-TG and BUP-TML-C5bMe-TG compared to parent BUP (p < 0.01).

FIGURE 5

In vitro prodrug conversion profile. Data (Mean ± SEM, n = 3) are shown as % mass change of MG-like forms and parent BUP, or as peak area for BUP-linker-acid forms, upon in vitro incubation of BUP-C4-TG (A), BUP-CE-C4-TG-TG (B), BUP-TML-C4-TG (C), BUP-TML-C5bMe-TG (D), and BUP-C5bMe-TG (E) with rat plasma supplemented with lipoprotein lipase (LPL).

FIGURE 6

Dose-normalised BUP plasma concentrations following oral gavage (A) or intravenous infusion over 5 min (B) of formulations to conscious, carotid artery cannulated rats (the data for oral BUP and oral BUP-TML-C5bMe-TG are replicated in Panel B for comparison to IV dosing). Oral formulations contained 20 µg of BUP or 50 µg of BUP prodrugs dispersed in 40 mg oleic acid, 25 mg Tween 80 and 2 ml PBS. The IV formulation contained 10 µg of BUP dissolved in 0.5 ml PBS. Doses are normalized to a 0.06 mg/kg equivalent dose of BUP. Data are presented as Mean ± SEM (n = 3–6, as labelled for individual groups). The embedded bar chart in (A) shows the plasma AUC values (AUC_0-inf for IV BUP, and AUC_0–6h for other groups), and * indicates the value is statistically significantly higher than oral BUP group (p < 0.05).

FIGURE 7

Comparison of lymphatic transport and GI lumen stability of BUP prodrugs, where GI lumen stability of the MG intermediates is categorized as low (apparent half-life < 10 min) and high (apparent half-life > 1 h). GI stability ranking, rather than exact half-lives are used for x-axis because the rapid degradation of BUP-C4-MG and BUP-CE-C4-MG prevents accurate calculation of half-lives.

FIGURE 8

Comparison between oral bioavailability and lymphatic transport of the BUP prodrugs.