Green Solutions for Better Medicine: Natural Bioavailability Enhancers in Drug Formulation

In the pursuit of sustainable and effective drug delivery strategies, the pharmaceutical industry is increasingly turning towards natural bioavailability enhancers as green alternatives [1]. Bioavailability, a critical parameter in drug formulation, refers to the fraction of an administered dose of drug that reaches systemic circulation [2].  Challenges such as poor solubility, low permeability, and degradation in the gastrointestinal tract often limit the bioavailability of orally administered drugs [3]. Traditional approaches to enhance bioavailability involve chemical modifications or formulation techniques that may carry environmental implications [4]. However, natural compounds derived from plants, herbs, and essential oils offer promising solutions with minimal ecological footprint. Drug facilitators known as "bioavailability enhancers" are molecules that, when taken together, increase the activity of drug molecules in a variety of ways. These include increasing the drug's bioavailability across membranes, potentiating the drug molecule through conformational interactions, acting as drug molecules' receptors, and increasing target cells' receptivity to drugs. When a medicine is coupled with another, an agent known as a "bioenhancer" might increase the drug's bioavailability and bioefficacy without having any usual pharmacological activity of its own at the dose being used. These functional excipients, which are added to formulations to increase the absorption of pharmacologically active drugs, are also known as "absorption enhancers." This poster presentation aims to explore the potential of natural bioavailability enhancers in drug formulation, emphasizing their role in promoting sustainability within the pharmaceutical industry. By enhancing the solubility, permeability, and stability of drugs, these natural compounds contribute to improved drug delivery efficiency.  Through a comprehensive review of the literature, we will elucidate the mechanisms of action and therapeutic benefits of various natural bioavailability enhancers. Furthermore, we will discuss the ecological advantages of incorporating these green solutions into pharmaceutical formulations, highlighting their potential to minimize environmental impact.

Concept and History

The concept of ‘bioavailability enhancers’ is derived from the traditional age old system of Ayurveda (science of life). In Ayurveda, black pepper, long pepper and ginger are collectively known as “Trikatu”. In sanskrit “Trikatu” means three acrids. The action of bioenhancers was first documented by Bose (1929) who described the action of long pepper to Adhatoda vasika leaves increased the antiasthamatic properties of Adhatoda vasika leaves. ‘Bioavailability enhancers’ are drug facilitators, they are the molecules which by themselves do not show typical drug activity but when used in combination they enhance the activity of drug molecule in several ways including increasing bioavailability of the drug across the membrane, potentiating the drug molecule by conformational interaction, acting as receptors for drug molecule and making target cells more receptive to drugs.

The term ‘bioavailability enhancer’ was first coined by Indian scientists at the Regional Research Laboratory, Jammu (RRL, now known as Indian Institute of Integrative Medicine, Jammu), who discovered and scientifically validated piperine as the world’s first bioavailability enhancer in 1979[5].

Need for Bioavailability Enhancers

Lipid solubility and molecular size are the major limiting factors for molecules to pass the biological membrane and to be absorbed systematically following oral or topical administration. Several molecules, despite having excellent bioactivity in vitro demonstrate less or no in vivo actions due to their poor lipid solubility or improper molecular size or both, resulting poor absorption and poor bioavailability. Sometimes some drugs are destroyed in gastric environment when taken orally, Enhancers reduce the dose, shorten the treatment period and thus reduce drug resistance problems. Due to dose economy, they make treatment cost-effective, minimize drug toxicity and adverse reactions [6].

Methods for enhancement of bioavailability [10]

Absorption of Enhancers

Numerous substances, including bile salts, surfactants, fatty acids, chelating agents, salicylates, and polymers, are helpful at enhancing intestinal absorption. Trimethylated chitosan, in particular, causes the tight junctions to open and redistributes cytoskeletal F-actin, which improves medication absorption through the Para cellular pathway. Surfactants such as bile, bile salts, and fatty acids improve absorption by making hydrophobic medications more soluble in the aqueous layer or by making the apical and basolateral membranes more fluid. Calcium chelators that lower the concentration of extracellular calcium, including ethylene glycol tetraacetic acid and ethylene diamine tetraacetic acid (EDTA), improve absorption by breaking down cell-to-cell connections.

Prodrugs

One of the most well-known examples of raising an agent's lipophilicity to improve a polar drug's absorption through prodrug approach is various ampicillin derivatives.

Because it is hydrophilic, ampicillin barely absorbs 30–40% from the gastrointestinal tract (GIT). Ampicillin's carboxyl group was esterified to create pivampicilline, bacampicilline, and talampicillin, among other ampicillin derivatives.

Dosage form and other pharmaceutical approaches

Various dosage formulations such as liposomes and emulsions enhanced the intestinal absorption of insoluble drugs. Particle size reduction such as micronization, nanoparticular carriers, complexation and liquid crystalline phases also maximize drug absorption. [11]

P-glycoprotein inhibitors

P-glycoprotein inhibitors reverse P-glycoprotein-mediated efflux in an attempt to improve the efficiency of drug transport across the epithelial membrane. P-glycoprotein inhibitors influences metabolism, absorption, distribution, and elimination of P-glycoprotein substrates in the process of modulating pharmacokinetics. [12]

Mechanism of action of Bioavailability Enhancers

Drug Delivery Systems as Bioavailability enhancers

The available lipids for enhancing bioavailability are liposomes, microspheres, nanoparticles, transferosomes, ethosomes, nanoemulsions/microemulsions, lipid based systems, polymeric micelle formulation and other novel vesicular herbal formulation (Fig.2; Table 2) [7].

       
           
       
Figure 2: Novel Drug Delivery systems