Abstract
The main factors influencing the absorption of orally administered drugs are solubility and permeability, which are location-dependent and may vary along the gastrointestinal tract (GIT). The purpose of this work was to investigate segmental-dependent intestinal absorption and its role in controlled-release (CR) drug product development. The solubility/dissolution and permeability of carvedilol (vs. metoprolol) were thoroughly studied, in vitro/in vivo (Octanol-buffer distribution coefficients (Log D), parallel artificial membrane permeability assay (PAMPA), rat intestinal perfusion), focusing on location-dependent effects. Carvedilol exhibits changing solubility in different conditions throughout the GIT, attributable to its zwitterionic nature. A biorelevant pH-dilution dissolution study for carvedilol immediate release (IR) vs. CR scenario elucidates that while the IR dose (25 mg) may dissolve in the GIT luminal conditions, higher doses used in CR products would precipitate if administered at once, highlighting the advantage of CR from the solubility/dissolution point of view. Likewise, segmental-dependent permeability was evident, with higher permeability of carvedilol vs. the low/high Peff marker metoprolol throughout the GIT, confirming it as a biopharmaceutical classification system (BCS) class II drug. Theoretical analysis of relevant physicochemical properties confirmed these results as well. A CR product may shift the carvedilol’s solubility behavior from class II to I since only a small dose portion needs to be solubilized at a given time point. The permeability of carvedilol surpasses the threshold of metoprolol jejunal permeability throughout the entire GIT, including the colon, establishing it as a suitable candidate for CR product development. Altogether, this work may serve as an analysis model in the decision process of CR formulation development and may increase our biopharmaceutical understanding of a successful CR drug product.
Highlights
Oral drug absorption depends on various parameters: physicochemical (e.g., ionization, pKa, solubility, physicochemical stability, lipophilic nature, polar surface area (PSA), molecular weight,), physiological, and parameters associated with the dosage form [1,2,3]
Change in pH or presence of bile salts can modify drug solubility/dissolution in a given intestinal segment; for a drug to be considered as a high solubility compound as per the biopharmaceutical classification system (BCS), it needs to be dissolved in an aqueous media (250 mL or less) with the different pH values relevant to the gastrointestinal tract (GIT) lumen (1.0–6.8) [5,6,7]
This study offers a deeper understanding of the factors that could influence segmental-dependent permeability and solubility in a controlled-release setting, and their contribution to a successful controlled-release drug product
Summary
Oral drug absorption depends on various parameters: physicochemical (e.g., ionization, pKa, solubility, physicochemical stability, lipophilic nature, polar surface area (PSA), molecular weight,), physiological (e.g., gastrointestinal pH, surface area available for absorption, transit time, expression of certain transporters, enzymes), and parameters associated with the dosage form [1,2,3]. Keeping this complexity in mind, it was determined that the drug permeability and solubility/dissolution in the gastrointestinal aqueous milieu are the two essential variables that guide absorption in the gastrointestinal tract (GIT) [4]. Regional-dependent permeability factors need to be considered, for instance, expression of membrane transporters (influx/efflux) along the intestinal tract [11,14,15,16], luminal pH that influences the changes in the drug ionization [1,3,8,13], local water absorption [10], and others
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