Approaching strategy to increase the oral bioavailability of berberine, a quaternary ammonium isoquinoline alkaloid: part 2. development of oral dosage formulations

ABSTRACTIntroduction Berberine (BBR) possesses a wide variety of pharmacological activities. However, the oral bioavailability of BBR is low due to extensive intestinal first-pass metabolism by cytochrome P450s (CYPs), insufficient absorption due to low solubility and P-glycoprotein (P-gp)-mediated efflux transport, and hepatic first-pass metabolism in rats.Areas covered Various dosage formulations were developed to increase the oral bioavailability of BBR by overcoming the reducing factors. This article provides the developing strategy of oral dosage formulations of BBR based on the physicochemical (low solubility, formation of salts/ion-pair complex) and pharmacokinetic properties (substrate of P-gp/CYPs, extensive intestinal first-pass metabolism). Literature was searched using PubMed.Expert opinion Here, formulations increasing the dissolution rates/solubility; formulations containing a P-gp inhibitor; formulations containing solubilizer exhibiting P-gp and/or CYPs inhibitors; formulations containing absorption enhancers; gastro/duodenal retentive formulations; lipid-based formulations; formulations targeting lymphatic transport; and physicochemical modifications increasing lipophilicity were reviewed. Among these formulations, formulations that can reduce intestinal first-pass metabolisms such as formulations containing CYPs inhibitor(s) and formulations containing absorption enhancer(s) significantly increased the oral bioavailability of BBR. Further studies on other dosing routes that can avoid first-pass metabolism such as the rectal route would also be important to increase the bioavailability of BBR.KEYWORDS: BerberinebioavailabilityP-glycoproteinCypsoral dosage formulations Article highlights The oral bioavailability of berberine (BBR) in humans is quite low. To increase the oral bioavailability of BBR, a variety of dosage formulations were developed to overcome absorption barriers (low solubility, P-glycoprotein (P-gp)-mediated efflux transport, and plural CYPs-mediate metabolism).Solubility increase can be achieved through size reduction, use of co-solvents or surfactant solution, formation of salt/ion-pair complex, cyclodextrin (CD) inclusion complex, or phospholipid complex.There are some surfactants and CDs that possess P-gp and/or CYPs inhibition. They can solubilize, and inhibit P-gp-mediated efflux transport, and CYPs-mediated intestinal-first-pass metabolism.Most of P-gp substrate drugs including BBR are preferentially absorbed from the proximal small intestine, where there is lower expression of P-gp. To deliver BBR to the proximal small intestine, gastro/duodenal retentive formulations were developed.Formulations containing absorption enhancers such as sodium caprate (C10) and deoxycholate (DCA) facilitate paracellular transport, which can avoid CYPs-mediated first-pass metabolism in cells.Formulations targeting lymphatic transport can avoid first-pass metabolism in the liver.Alternate administration routes are also proposed as some routes can escape intestinal/hepatic first-pass metabolism such as rectal routes.Declaration of interestThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresPeer reviewers on this manuscript have no relevant financial or other relationships to disclose.Additional informationFundingThis paper was not funded.