Rational of bioavailability enhancement

"Biopotentiation or bioenhancement refers to the phenomena of enhancing the overall occurrence of any chemical substance in the biological fluid and systemic circulation, as well as secondary chemicals responsible for the increase in plasma drug concentration of the major component” [3].

Bioenhancers are utilised in a variety of methods to promote bioavailability. Absorption boosters, prodrugs, permeability boosters, micronisation, and formulations of prolonged and sustained release pharmaceutical formulations such as liposomes and emulsions, as well as P-glycoprotein inhibitors are all examples of specific strategies (P-GP) [4].

Bioenhancers with ideal properties [5, 6]

Bioenhancers have the following properties

It should be nontoxic in nature.

It should be simple to formulate.

At a very low concentration, it should show its effect when combined with the drug.

It should increase the absorption and activity of the drug.

Compliance is simple.

Because of the low cost, acceptance is simple.

Easily accessible.

It must be non-irritating and allergy-free.

It should be stable in its surroundings and quick to react.

Advantages of bioenhancer

When a bioenhancer is used in combination with a drug, the drug’s dosage is decreased, and the possibility of drug resistance is minimised.

Adverse drug responses or side effects, as well as drug toxicity, will be decreased as a result of the lower dose.

This is particularly true with anticancer medications such as Taxol.

Due to an improvement in bioavailability, the drug's efficacy has increased.

As drug bioavailability is increased, they can lower both inter-individual and intra-individual variability [7].

Disadvantages of bioenhancer

Despite the success of bioenhancers in drug delivery, there are still some challenges for new bioenhancers in development, such as

Increasing the features of drug formulations such as blood circulation, functional surface area, drug dissolution protection, passing biological barriers, with site-specific targeting.

Researching and developing bioenhancer for large-scale manufacturing is a challenge. Laboratory or pilot technologies must always be scaled up for ultimate commercialisation. Scaling-up problems include low nanoparticle concentrations, aggregation, and the chemical process; it is easier to modify nanoparticles in the laboratory.

Regulations regulating the physiochemical and pharmacokinetic features of newer bioenhancers are required [8].

What exactly are bioenhancers?

“Bioavailability is the rate and amount to which an active pharmacological ingredient enters into systemic circulation and then becomes accessible at the necessary site of action.” When compared to oral delivery, intravenous medicines have the highest bioavailability since oral administration delivers a lower percentage due to partial drug absorption [9].

Definition

Bioenhancers are compounds that, when combined with pharmacological substances, stimulate and enhance drug bioavailability without having a synergistic activity with the drug.

Bioavailability enhancers are chemicals that, on their own, do not have the same effect as a traditional medicament. But when combined, they enhance drug macromolecular activity in a number of ways, including boosting drug bioavailability all across membranes, enhancing the drug molecule using conformational interactions, serving as drugs molecule receptors, and enhancing drug sensitivity in target cells. “A ‘bioenhancer’ is a chemical that increases the bioavailability and effectiveness of a medication it is combined with without having its own pharmacological action at the dose used” [10].

There are various benefits of using natural bioenhancer and are given in Fig. 1 [7]

Fig. 1

Benefits of herbal bioenhancers

History of bioenhancer

The term “bioavailability enhancer” was created by C.K. Atal, the Chairman of the Regional Research Laboratory at Jammu, when Piperine was discovered and scientifically demonstrated to be the first bioavailability booster in the history of the world in 1979. Bioenhancers are substances that, when taken orally, do not have any pharmacological effects on their own but rather increase biological activity or the uptake of the active ingredient and increase bioavailability during combination therapy [11].

The word “bioavailability enhancer” is derived from Trikatu, an Ayurvedic combination containing black pepper, long pepper, and ginger, is where the name “bioavailability enhancer” originates. Sanskrit word trikatu translates to “three acrids.” In 1929, Bose discovered the bioavailability enhancer activity. Trikatu is a Sanskrit word that means “three acrids.” Bose initially found the bioavailability enhancer action in 1929, when he detailed the effect of long pepper on Adhatodavasaka leaves, which improved Vasaka activity [12, 13].

Bioenhancers is an ancient Ayurvedic term that refers to the drug’s increasing effect, as well as the Sanskrit term “Yogvahi,” which means “to rise in effect” [14].

Classification of bioenhancers

Based on their properties, bioenhancers are divided into two groups. Bioenhancers can be classified into the following types:

Bioenhancers based on origin

Based on their origin, bioenhancers are classified into the following classes [15, 16]

I.

Bioenhancers derived from plant sources These bioenhancers are made up of different plant parts. Secondary metabolites from a variety of medicinal and aromatic plants are thought to be a rich source of bioenhancers (Table 1).

II.

Bioenhancers derived from other than plant sources Bioenhancers originating from non-herbal sources are number two. Non-herbal and synthetic chemical compounds can be used to obtain and synthesis these bioenhancers.

III.

Bioenhancers from plant sources

IV.

Bioenhancer from other than plant sources

Table 1 Herbs, their origin, dosage as bioenhancements, and mechanismCapmul

Source Glycerolysis of specified fats and oils, as well as esterification of glycerin with specific fatty acids, is used to make capmul (mono-, di-, and triglyceride).

Mechanism of action Capmul functions as a very effective transporter and solubiliser of active chemicals due to its lipophilic nature. Due to its mono-diglyceride medium-chain esters, which are used to dissolve troublesome compounds like sterols, it also has bacteriostatic properties. [27]

Drugs Ceftriaxone 70 (Capmul’s lipophilic nature contributes in improving Ceftriaxone 70's solubility.)

Distillate of cow urine

Cow urine distillate is more effective as a bioenhancer as compared to cow urine. Its Rasayana helps to modulate the immune system and acts as a bioenhancer [28].

Bioenhancers based on mechanism of action [10]

Inhibitors of P-gp efflux pumps

Example: Cuminumcyminum (Black cumin), Carumcarvi (caraway), Genistein, Sinomenine, Naringin, Quercetin

Suppressors of CYP-450 enzyme and its isozymes

Example: Naringin, gallic acid, and its ester, quercetin

Regulators of GIT function to facilitate better absorption

Example: Niaziridin (drumstick pods), Zingiber Officinale (ginger), Aloe vera (Aloe), and glycyrrhizin (licorice)

Mechanism of action of bioenhancers

Herbal bioenhancers work through a variety of processes. Different bioenhancers may have the same or different mechanisms of action. Nutritional bioenhancers work on the gastrointestinal tract to improve absorption. Antimicrobial bioenhancers primarily influence drug metabolism. [6, 29]

The following are the main mechanisms by which different bioenhancers increase the bioavailability of the medicinal component [30]:

By enhancing the GIT tract’s blood supply, orally administered drugs are better absorbed.

Active transporters at diverse places, like glycoprotein (p-GP), the efflux pumps that pumps drugs out of the body and prevents them from reaching its target site, can be modified. Bioenhancer works in these situations by blocking the pop-up from opening.

Inhibiting drug metabolism enzymes such as CYP3A4, CYP1A1, CYP1B2, and CYP2E1 in the liver, stomach, lungs, and other sites. This will also help with the first-pass action of drugs.

Reducing passive tubular reabsorption and preventing glomerular filtration as well as active tubular secretion by inhibiting renal clearance. Inhibiting the UDP glucuronosyl transferase enzyme, that conjugates and inactivates the drug, may occasionally obstruct biliary passage.

Some of the other mechanisms of action of bioenhancers are shown in Figs. 2 and 3.

Fig. 2

Classification of bioenhancers

Fig. 3

Mechanism of different natural bioenhancers [28]

Marketed formulation

Significant information has been published in a number of national and international journals by the Regional Research Laboratory, Jammu (RRL), and patent applications were filed in India, USA, as well as the Europe. Ant tubercular formulations were created following the proposed step-by-step medication development methodology. The Drug Control General of India (DCGI) granted a licence for antitubercular formulations to be commercialised in India following the conclusion of Phase IIIb clinical studies.

November of 2009, the Medication Control General of India (DCGI) approved CandilaPharma’s commercial version of antitubercular drug Risorine, It contains 10 mg of piperine, 300 mg of isoniazid, and 200 mg of rifampicin. When Rifamicin was combined with Piperine, its bioavailability increased by 60%. As a result, Piperine reduced the rifampicin dose from 450 to 200 mg, lowering the drug’s cost, dosage, and toxicity [31].

Some of the recent formulations of natural bioenhancers are given in below table (Table 2—Liposomal formulation, Table 3—Nanoparticle Formulation, Table 4—Transferosome Formulation, Table 5—Microspheres Formulation).

Table 2 Liposomal formulation containing natural bioenhancerTable 3 Nanoparticle formulation containing natural bioenhancerTable 4 Transferosome formulation containing natural bioenhancerTable 5 Microspheres formulation containing natural bioenhancerFuture prospectus

In today's world, the concept of bioenhancers has proven to be quite revolutionary. The dose of bioenhancers is lowered, and the risk of drug resistance is reduced. Due to the lower dosage, the toxicity of the drugs is lower; this is especially true for cancer drugs such as Taxol.

There are also environmental benefits. The bark of the Pacific yew, one of the largest and slowest growing plants in the world, is used to produce Taxol, a drug used to treat prostate and ovarian cancer. Currently, six trees between 25 and 100 years old would have to be cut down to cure one patient. As a result of bioenhancers, fewer people will die.