Bioenhancer Herbs: Natural Agents for Optimizing Drug Efficacy and Bioavailability

Pratik Singh^{1,2 *}

¹Rungta College of pharmaceutical science and research Bhilai, Chhattisgarh

²Formulation Research & Development –Non-Orals, Sun Pharmaceutical Industries Ltd, Vadodara, 390020, Gujarat, India

 

GRAPHICAL ABSTRACT

ABSTRACT

This review article explores the role of herbal bioenhancers in improving drug bioavailability, a crucial factor for therapeutic efficacy. Drug bioavailability is often limited by poor solubility, low membrane permeability, and metabolic degradation. Traditional and modern approaches have developed various methods to address these barriers, including the use of herbal bioenhancers, which naturally augment the absorption and therapeutic effects of drugs without producing pharmacological effects themselves. Key bioenhancers include piperine, curcumin, and ginger, which act by inhibiting metabolic enzymes like cytochrome P450 and efflux proteins such as P-glycoprotein, thereby increasing drug concentration at target sites. This article reviews bioenhancer mechanisms, highlighting how specific herbal compounds like ginger, turmeric, and aloe vera can enhance the bioavailability of drugs used in treating chronic conditions like tuberculosis, cancer, and infections. The benefits of bioenhancers extend beyond enhanced efficacy to reduced dosages, minimized side effects, and lower costs, making them an attractive adjunct in therapeutic formulations. However, challenges remain in scaling up production and ensuring regulatory compliance, especially in the context of novel drug delivery systems like nanoparticles and liposomes. This review consolidates recent findings on bioenhancer efficacy and presents an outlook on future research and clinical application, emphasizing the promise of bioenhancers in optimizing pharmacotherapy.

Keywords:  Bioavailability, Herbal, Novel Drug Delivery System, Nanotechnology, Bioenhancer, Formulation

INTRODUCTION

Bioavailability of drugs is a complex issue because therapeutic efficacy of the drug depends on it. There are many reasons for low bioavailability of drugs like low aqueous solubility, poor intestinal membrane permeation, degradation of drug in gastric fluids, presystemic intestinal or hepatic metabolism. Various approaches have been used to increase the bioavailability of drugs like microinization, complexation, use of cosolvents/surfactants prodrug approach and microencapsulation (Thomas et al. 2006)(Schmid and Smith 2004). For a long time, efforts were focused on the processes occurring in the liver and intestine on increasing the solubility and permeability of drugs when addressing the issue of bioavailability. In series of various techniques and approaches, permeation enhancer is also used by various pharmaceutical companies to address this issue. Absorption enhancers are functional excipients included in formulations to improve the absorption of a pharmacologically active drug. The term absorption enhancer usually refers to an agent whose function is to increase absorption by enhancing membrane permeation, rather than increasing solubility, so such agents are sometimes more specifically termed permeation enhancers. Absorption enhancers have been investigated for at least two decades, particularly in efforts to develop non-injection formulations for peptides, proteins, and other pharmacologically active compounds that have poor membrane permeability (Wadhwa and Gupta 2022).

Many synthetic and herbal drugs suffer from the problem of low bioavailability. Low membrane permeability is the major cause, lower lipophilicity, ionic characteristics, poor water solubility or P-glycoprotein. Bioavailability is the rate and extent to which a substance enters systemic circulation and becomes available at the required site of action (Bioph’cutics & Ph’cokinetics - Vallabh Prakashan n.d.). Maximum bioavailability is attained by drugs administered via intravenous route, whereas drugs administered orally are poorly bioavailable as they readily undergo first pass metabolism and incomplete absorption. Such unutilized drug in the body may lead to adverse effects and also drug resistance. Thus, there is need of molecules which themselves have no same therapeutic activity but when combined with other drugs/molecules enhance their bioavailability. Many natural compounds from medicinal plants have capacity to augment the bioavailability when co-administered with another drug(Sa, Sa, and Hn n.d.). The addition of bioenhancers provides additional advantage of easy availability, economy, and lesser side effects. In the current scenario, herbal bioenhancers are used to improve the absorption and, ultimately, the bioavailability of various drugs activities used to treat the diseases and disorders associated with the central nervous system (CNS), gastrointestinal tract, and the cardiovascular system (CVS)(Peterson et al. 2019). Nutraceuticals such as vitamins are also a class facing the challenge of inadequate bioavailability and, hence, herbal bioenhancers have great demand for bioavailability enhancement of nutraceuticals(Dudhatra et al. 2012a).

1.1 CONCEPT OF BIOAVAILABILITY ENHANCERS

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 acids. The action of bioenhancers was first documented by Bose (1929) who described the action of long pepper to Adhatoda vasika leaves increased the antiaesthetic properties of Adhatoda vasika leaves (Kesarwani and Gupta 2013a).

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 (Vijayarani et al. 2020).  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 acids.” In 1929, Bose discovered the bioavailability enhancer activity. Trikatu is a Sanskrit word that means “three acids.” Bose initially found the bioavailability enhancer action in 1929, when he detailed the effect of long pepper on Adhatodavasaka leaves, which improved Vasaka activity (Shukla et al. 2016) 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”(Thorat, Gujar, and Karale 2023a).

Figure 1. Bioavailability enhancer

1.2 NEED OF A BIOAVAILABILITY ENHANCER

It is estimated that globally humans consume about 250 million doses of antibiotics annually and 20 -50% of that use is unnecessary depending on the class of antibiotics. Further, widespread use of antibiotics promotes spread of antibiotic resistance many a times leading to multiple drug resistance. The total amount of drug/antibiotic given for the treatment of any disease is much higher than what is actually required [Figure 1]. More ever many therapeutic treatments are also accompanied by loss of essential nutraceuticals in the course of therapy. This is so because all drug/antibiotic given to the patient in a therapy does not reach the target site. This may due to lower absorption, instability, restrictive uptake by microbes, or due to operation of efflux pump. Thus, large portion of drug we apply are wasted and only a miniscule percentage of drug reach at desired site. But even worse part is that the unutilized drug/antibiotic remains as a load in the body and environment. This is then act as a selection pressure, facilitating emergence of drug resistance in parasites which may lead to the failure of antibiotics against resistant infections. Additionally, such a situation leads to side effects, illness and reduction in life expectancy being more acute in older population. One of the ways that has been feasible to reduce drug doses is the occurrence of synergism between different therapeutics agents. However, even in such a situation if both the molecules have antibiotic property, the problem of continued selection pressure on microbes is still likely to continue. Therefore, there the need is for a molecule, which by themselves are not microbicidal but when present with a drug or active molecule, enhance its activity or bioavailability of the drug so the bioenhancer or paracellular permeability enhancer or better choice to reduce time and cost for new drug discovery. Following the use of bioavailability enhancers, the dose of the drug is reduced and risk of drug resistance is minimized. It also reduces the dose-dependent toxicity of the drug, especially of anticancer drugs (Randhawa, Kullar, and Rajkumar 2011)(Wadhwa and Gupta 2022).

1.3  VARIOUS METHODS FOR ENHANCEMENT OF BIOAVAILABILITY OF ORALLY ADMINISTERED DRUG

1.     Absorption enhancers.

2.     Prodrugs.

3.     Dosage form and other pharmaceutical approaches.

4.     P-glycoprotein inhibitors.

1.3.1 ABSORPTION ENHANCERS: - Many of the absorption enhancers are effective in improving the intestinal absorption, such as bile salts, surfactants, fatty acids, chelating agents, salicylates and polymers [13,14]. Chitosan, particularly trimethylated chitosan, increases the drug absorption via paracellular route by redistribution of the cytoskeletal F-actin, causing the opening of the tight junctions. Bile, bile salts and fatty acids are surfactants which act as absorption enhancers by increasing the solubility of hydrophobic drugs in the aqueous layer or by increasing the fluidity of the apical and basolateral membranes. Calcium chelators such as ethylene glycol tetra acetic acid and ethylene diamine tetra acetic acid (EDTA) enhance absorption by reducing the extracellular calcium concentration, leading to the disruption of cell-cell contacts (Schipper, Vårum, and Artursson 1996).

1.3.1.1 MAJOR ISSUES WITH ORAL PERMEATION ENHANCER

According to Swenson and Curatolo surfactants can act as permeability enhancers by partitioning into the epithelial cell membrane and disrupting the packing of membrane lipids, forming structural defects that reduce membrane integrity (Swenson, Milisen, and Curatolo 1994)

Ø  Concentration and Time-Dependent Effects.

Ø  Local Toxicity.

Ø  Change the permeability of cell.

Ø  pH dependent effect.

Figure 2 DRUG ABSORPTION BARRIERS

1.3.1.2 DRUG ABSORPTION BARRIERS

 

The drug must cross the epithelial barrier of the intestinal mucosa for it to be transported from the lumen of the gut into the systemic circulation and exert its biological actions. There are many anatomical and biological barriers for the oral drug delivery system to penetrate the epithelial membrane (Joo Kang et al. 2009a). There are many structures in the intestinal epithelium which serve as barriers [Figure 2] to the transfer of drugs from the gastrointestinal track to the systemic circulation. An aqueous stagnant layer due its hydrophilic nature is potential barrier to the absorption of drugs. The membranes around cells are lipid bilayers containing proteins such as receptors and carrier molecules. Drugs cross the lipid membrane by passive diffusion or carrier-mediated transport which involves the spending of energy. For the passage of small water-soluble molecules such as ethanol there are aqueous channels within the proteins. The drug molecules larger than about 0.4 nm face difficulty in passing through these aqueous channels (Sa, Sa, and Hn n.d.).  Recent work has shown that drug efflux pumps like Pgp possess very important role inhibiting efficient drug entry into the systemic circulation. P-gp is a type of ATPase and an energy dependent transmembrane drug efflux pump it belongs to members of ABC transporters. It has a molecular weight of -170 kDa and has 1280 amino acid residues.  Since P-gp is gaining importance in absorption enhancement much work has still been made about its modulation due to its substrate selectivity and distribution at the site of drug absorption (Sa, Sa, and Hn n.d.).

1.3.2 PRODRUGS

Various ampicillin derivatives are one of the well-known examples of increasing the lipophilicity of agents to enhance absorption of a polar drug by prodrug strategy (Buur and Bundgaard 1987). Ampicillin due to its hydrophilic nature is only 30%-40% absorbed from the gastrointestinal tract (GIT). By esterification of carboxyl group of ampicillins, the produgs of ampicillin such as pivampicilline, bacampicilln and talampicillin were synthesized (Kesarwani and Gupta 2013b).

1.3.3 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 (Kesarwani and Gupta 2013b).

1.3.4 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 (M. Varma 2003).

1.4 RATIONALE OF BIOPOTENTIATION OR BIOAVAILABILITY ENHANCING

“The phenomenon of increasing the total availability of any chemical entity (nutrient or drug molecule) in biological fluid or systemic circulation is called biopotentiation or bioenhancement and the secondary agents which are responsible for this augmentation of plasma concentration of principle ingredient are termed as Biopotentiers or Bioavailability enhancers”

  1.4.1 ADVANTAGE OF BIOENHANCEMENT

Ø  Bioavailability is directly proportional to the available plasma concentration so ultimately related therapeutic efficacy.

Ø  This can make the expensive drugs affordable by lowering the dose or dosing frequency. Shortening the treatment period also increase the acceptance of patients mainly in case of chemotherapy. It comforts the patient in terms of cost also.

Ø  Reduce the required dose ultimately reduce the toxic effects.

Ø  Therapeutic treatments which include heavy doses, accompanied by loss of metals and vitamins available in body. The bioenhancers improve the nutritional status of body while duration of course (Jhanwar and Gupta n.d.; Kesarwani and Gupta 2013a).

 

2. HERBAL BIOENHANCER – AN ALTERNATIVE

The term bioavailability enhancer was first coined by Indian scientists C.K. Atal, the Director of the Regional Research laboratory, Jammu, who discovered and scientifically validated Piperine as the world’s first bioavailability enhancer in 1979. Natural products especially from plant sources have played an important role in drug development for treatment of communicable diseases. Either the isolated plant biomolecules or its semi synthetic derivatives have provided useful clues in the production of medicines. According to WHO nearly 80% of the world’s population relies on herbal medicines as primary health care. Bioenhancers are molecules, which do not possess drug activity of their own at the dose used but promote and augment the biological activity or bioavailability or the uptake of drugs in combination therapy (Johri 2011).

2.1 CLASSIFICATION AND MECHANISM OF ACTION OF BIOENHANCER HER

Figure 3 Classification of herbal enhancer

Improvement in bioavailability is the ultimate purpose in the use of herbal bioenhancers. They are classified into three classes according to their mechanism of actions [Figure 3 ].Herbal bioenhancers improve the bioavailability of various drug molecules by inhibiting P-glycoprotein (P-gp) drug efflux, inhibition of cytochrome P-450 (CYP-450), and enhancement of permeation (Dudhatra et al. 2012a).

1.     Inhibition of P-Glycoprotein Drug Efflux

2.     Inhibition of Cytochrome P-450 (Cyp-450) Enzymes

3.     Absorption Enhancers

2.1.1 INHIBITION OF P-GLYCOPROTEIN DRUG EFFLUX

P-gp is the efflux membrane transporter that regulates the intracellular uptake and distribution of various xenobiotics and toxins. [Error! Reference source not found.] This P-gp limits the permeability and absorption of various drugs due to the efflux mechanism, which ultimately results in low bioavailability. For efficient delivery and optimum bioavailability of drug, it is important to inhibit the P-gp efflux. The inhibition of P-gp efflux can be achieved by the blocking of the drug binding site of P-gp, alteration of the integrity of lipids in the cell membrane, and by disturbing the hydrolysis of adenosine triphosphate (Amin 2013). Multiple bioenhancers, such as piperine, naringin, curcumin, etc. improve the bioavailability of drugs by inhibiting the P-gp drug efflux (Kumar-Sarangi et al. 2018).

2.1.2 INHIBITION OF CYTOCHROME P-450 (CYP-450) ENZYMES

The enzymes from CYP-450 family are largely responsible for the first-pass metabolism and elimination of multiple drugs. [Figure 4] To improve the bioavailability of such drug molecules, it is important to inhibit these enzymes and to prevent the first-pass metabolism. Several herbal bioenhancers, such as piperine, curcumin, etc. inhibit the multiple enzymes CYPA1, CYP1B1, CYP1B2, CYP3A4, and CYP2E1, prevent the first-pass elimination of various drug molecules, and improves their bioavailability (Bibi 2008)(Tatiraju et al. 2013).

Figure 4 INHIBITION OF CYTOCHROME P-450 (CYP-450) ENZYMES

2.1.3 ABSORPTION ENHANCERS

Membrane permeability is the limiting factor for multiple drugs from the Biopharmaceutical Classification System (BCS) class III and BCS class IV. The inadequate permeation of these drugs reduces their absorption as well as therapeutic efficiency (Aungst 2012). [Figure 5] Improvisation in permeability can trigger the absorption of these lesser permeating drugs. This permeability-enhancement mechanism is executed by multiple herbal bioenhancers, such as aloe vera, ginger, niaziridine, and Carum carvi. These bioenhancers increase the permeation of drug molecules through biological membranes, resulting in better absorption and improved bioavailability (SAXENA and SINGH 2020a).

Figure 5 ABSORPTION ENHANCERS

3. BIOENHANCER FROM HERBAL SOURCES

3.1  PIPERINE

                               Figure 6 PIPERINE   

 

Piperine (1-piperoyl piperidine) IUPAC name: (2E,4E)-5-(2H-1,3-Benzodioxol-5-yl)-1-(piperidin-1- yl)penta-2,4-dien-1-one, is a pioneer alkaloidal component of Piper nigrum Linn. or Piper longum Linn. Piperine, or mixtures containing piperine, increases the bioavailability, blood levels and efficacy of a number of drugs including ingredients of vasaka leaves, vasicine, sparteine, rifampicin, phenytoin, sulfadiazine and propranolol. It has proved to be a milestone in the field of biopotentiation. It is authorized as safe by FDA.  It contains a cyclic six-membered secondary amine in its structure as follows (Sa, Sa, and Hn n.d.).

3.1.1 THE USE OF PIPERINE IN DIFFERENT FORMULATIONS

Metabolic enzymes

Piperine has shown its effect on metabolic enzymes and degradation related enzymes both in vitro and in vivo. It has been proved as a non-specific inhibitor of drug metabolism in different studies. There are various series of enzymes inhibited by piperine, mainly associated with P-GP and cytochrome P 450 families (Bhardwaj et al. 2002). It also includes others such as:

Ø  Aryl hydrocarbon hydroxylase (of Microsomal enzyme system)

Ø  Ethyl morphine-N demethylase

Ø  7-Ethoxycoumarin-O-de-ethylase

Ø  Uridine diphosphate glucose dehydrogenase

Ø  Uridine diphosphate glucose dehydrogenase

Ø  Uridine diphosphate glucuronyltransferase

Ø  5-Lipoxegenase (h) Cyclo-oxygenase-I.

 

Antitubercular and antileprotic drugs

Bioenhancing property of piperine utilized first to treat tuberculosis in humans, for example, alongside Rifampin or Rifampicin (the medication of first-line therapy in tuberculosis and leprosy). It extend the bioavailability of rifampicin by about 60%, and subsequently reduced the dose from 450 to 200 mg. Rifampin works by acting on RNA polymerase and inhibits the transcription of the polymerase in human cells, which is being catalyzed by Mycobacterium smegmatis. Piperine enhances this activity of rifampin by several folds against RNA polymerase Piperine also stimulates the coupling capacity of rifampin to RNA polymerase even in resistant strains (SAXENA and SINGH 2020a; S. Varma n.d.)

Antibiotics

There has been a considerable increment in the consumption of antibiotics and antimicrobials at a very high rate, which has caused most of the cases such as immune system resistance or addiction. Patients require a high dose of such drugs due to reduced GIT absorption, uptake by pathogens, and cells that have decreased due to resisting efflux pumps. The large part of the target dose remains as waste in body fluids having no remedial use but causing drug resistance and side effects or toxicity with time. In the studies done on rabbits, fluoroquinolones and piperine have shown raised bioavailability as piperine inhibits the P-glycoprotein efflux pump (Kesarwani and Gupta 2013a).

Chemoprevention and immunomodulators

Piperine decreases cytotoxicity by reducing aflatoxins, which causes cytotoxicity by inhibiting CYP-P450-mediated biological activation of mycotoxins into harmful ones. It modifies the oxidative changes in cells by inhibiting the lipid peroxidation phenomena, resulting in free radicals scavenging activity. . This process diminishes the harm to DNA and DNA proteins. The antiapoptotic property of piperine is due to the induction of Heme-oxygenase-1. It contains the pentacyclic oxindole group in it, responsible for all these activities (Khan et al. 2006; SAXENA and SINGH 2020b).

Nutraceuticals

It likewise enhances bioavailability and retention of nutrients by acting on the alimentary canal, acting as a nutritional bio-enhancer. During double-blind cross over studies, the increase in the concentration of vitamins against placebo by 50–60% utilizing herbal supplementation was revealed. The outcome from various studies expresses that it is because of the nonspecific mechanism and thermogenic properties of piperine (Badmaev, Majeed, and Norkus 1999). Other upgraded bioavailability showed by it of medications like Nevirapine, a potent non-nucleoside inhibitor of HIV-1 reverse transcriptase, utilized in blend with other antiretroviral agents for the treatment of HIV-1 infection.

 

3.2 LIQUORICE (Glycyrrhiza glabra)

Figure 7  LIQUORICE

It is commonly known as Liquorice which contains Glycyrrhizin. It augments the inhibition of cell division with the core antineoplastics drug. Studies have revealed its effect on taxol bioenhancement; this combination is used against breast cancer. Inhibition of cell growth by taxol with glycyrrhizin was higher than the taxol alone. Studies also report its positive effects on hat glycyrrhizin transportation of antibiotics like rifampin, tetracycline, ampicillin and vitamins B1 and B12 across the gut membrane (R. D. Singh et al. 2009) Bioenhancing activity of liquorice is due to its active component Glycyrrhizin. It enhances cell division inhibitory activity of anticancerous drug `Taxol` by 5 folds against the growth and multiplication of breast cancer cell line. Inhibition of cancerous cell growth by Taxol in presence of glycyrrhizin was higher than treatment with taxol alone. It is reported that glycyrrhizin enchances the transport of antibiotics like rifampicin, tetracycline, nalidixic acid, ampicillin and vitamins B1 and B12 across the gut membrane. At the same concentration Glycyrrhizin shows a more potent absorption enhancing activity than caproic acid. Absorption enhancing activity obtained from the simultaneous treatment of sodium deoxycholate and dipotassium-glycyyrihizin was much greater than sodium deoxycholate alone in Caco-2 cell monolayers (R. Singh et al. 2009a)(Kesarwani and Gupta 2013c)(Kesarwani and Gupta 2013c).

 

3.3 GINGER (Zingiber Officinale)

Figure 8 GINGER

has a powerful effect on GIT mucous membrane. It regulates the intestinal function to facilitate absorption. Ginger is used in the range of 10-30 mg/kg body weight as bioenhancer. The bioavailability of different antibiotics like Azithromycin (85%), Erythromycin (105%), Cephalexin (85%), Cefadroxil (65%), Amoxycillin (90%) and Cloxacillin (90%) are increased by it (Thorat, Gujar, and Karale 2023a; Yewale et al. 2015).

 Figure 9 GARLIC

3.4 GARLIC (ALLIUM SATIVUM)

Allicin, the active bioenhancer phytomolecule in garlic enhances the fungicidal activity of Amphotericin B against pathogenic fungi such as Candida albicans, Aspergillus fumigatus and yeast Saccharomyces cerevisiae. Amphotericin B when given along with Allicin exhibited enhanced antifungal activity against S. cerevisiae (Ogita et al. 2006a). Allicin is the active bio-enhancer found in garlic. It enhances the fungicidal activity of amphotericin B against pathogenic fungi such as Candida albicans, Aspergillus fumigatus, and yeast (Saccharomyces cerevisiae). Allicin is an acyclic compound with a straight-chain having sulfur as its constituent.

 Figure 10 INDIAN ALOE

3.5 INDIAN ALOE (aloe vera)

The results of two different Aloe vera preparations i.e. whole leaf extract and inner filled gel indicate that the aloes improve the absorption of both the vitamin C and E. The absorption is slower and vitamins last longer in the plasma with aloes, this increases bioavailability of Vitamin C and E in human. Aloe vera is a very promising future nutritional herbal bioenhancer (Vinson, Al Kharrat, and Andreoli 2005a). Its dried juice collected by incision, from the bases of the leaves of various species of aloe, Aloe perryi, A. vera or Aloe barbadensis, and Aloe ferox, belonging to family Liliaceae. There are two different preparation of A. vera, that is, entire leaf extract and gel-filled inside, which showed the increased absorption of both the Vitamins C and E. Various studies concluded, A. vera as an exceptionally promising future nutritional herbal bio-enhancer (Vinson, Al Kharrat, and Andreoli 2005b).

 Figure 11 TURMERIC

3.6 TURMERIC

It is a spice used for centuries in Ayurveda for therapeutic purposes and also in Indian kitchens for adding color and flavor to the food. It is called as Haldi in Hindi. It is derived from dried as well as fresh rhizomes of the plant known as Curcuma Longa, belonging to family Zingiberaceae. Turmeric contains a flavonoid called curcumin, which suppresses metabolizing enzymes like CYP3A4 in the liver. It is also capable of initiating an adjusting drug transporter P-gp; consequently, increases the bioavailability of celiprolol and midazolam in rats. The bio-enhancing property of curcumin is analogous to piperine. Curcumin put down the UDP-glucuronyl transferase level in intestine and hepatic tissues. It likewise changes the physiological activity in the GIT promoting better absorption of drugs (Hatcher et al. 2008).

 3.7 COW URINE DISTILLATE

 Figure 12 COW URINE DISTILLATE

It is more effective as bio-enhancer than cow urine. The potency of antimicrobial, antifungal, and anti-cancer drugs is enhanced by it. The US Patents (No. 6896907 and 6410059) has been granted to cow urine for its medicinal properties, especially as a bio-enhancer with antibiotics, antifungal, and anti-cancer drugs. The potency of paclitaxel, observed to increase against MCF-7, a human breast cancer cell line, in in vitro assays (US Patent No. 6410059) [56,57]. The cow urine distillate enhanced the rifampicin action by about 5–7 times against Escherichia coli and 3–11 times against Gram-positive bacteria. It most likely acts by improving the transport of antibiotics across the digestive tract membrane. The improvement in transport is roughly 2–7 folds. The gonadotropin-releasing hormone conjugate deleteriously affects the reproductive hormones and estrous cycle of female mice, and distillate of cow urine acts as a bio-enhancer in immunization efficacy adjust these impacts (Randhawa 2010).

 

3.8 DRUMSTICK PODS (Moringa oleifera)

Figure 13 DRUMSTICK PODS

Niaziridin a nitrile glycoside is isolated from the pods of Moringa oleifera which enhances bioactivity of commonly used antibiotics against gram-positive bacteria like Myobacterium smegmatis, Bacillus subtilis and gram-negative bacteria like Escherichia coli. It enhances activity of rifampicin, ampicillin, nalidixic acid by 1.2 - 19 folds against the grampositive strains, also enhances the activity of azole antifungal drugs such as clotrimazole against Candida albicans by 5 - 6 folds. Increases the absorption of Vitamin B12 (Thorat, Gujar, and Karale 2023a).

3.9 GENISTEIN

 

Figure 14 GENISTEIN

 

Genistein is reported to be able to inhibit P-gp, BCRP and MRP-22 efflux function. When co-administered with Genistein the intestional absorption of paclitaxel, a substrate for efflux transports such as P-gp and MRP2 was dramatically increased (Sparreboom et al. 1997).

3.10 BLACK CUMIN (Cuminum cyminum)

Figure 15 BLACK CUMIN

Bioactive fraction of Cuminum cyminum enhances the bioavailability of Erythromycin, Cephalexin, Amoxycillin, Fluconazole, Ketoconazole, Zidovudine and 5-Fluorouracil (Jhanwar 2014). The doses responsible for the bioavailability enhancement activity ranged from 0.5 to 25 mg/kg body weight. It in itself is an effective gastric stimulant, carminative and anthelmintic. It has been used therapeutically as an anti-diarrheal, galactagogue, diuretic and also beneficial in hoarseness of voice (Kesarwani and Gupta 2013b). Bioavailability/bioefficacy activity of Cuminum cyminum was attributed to various volatile oils, luteolin and other flavonoids. Luteolin especially has been demonstrated to be a potent P-gp inhibitor in literature (Boumendjel et al. 2002).

Cumin/Caraway (Carum carvi) seeds enhance the bioavailability of antibiotics, antifungal, antiviral and anticancerous drugs. The effective dose for the Carum carvi bioactive fraction as bioenhancer is in the range of 1-55 mg/kg body weight. They have carminative, mild stomachic, aromatic and diuretic actions. It shows greater bioenhancing effect when used in combination with bioenhancer from Zingiber officinale and piperine(Vijayarani et al. 2020; Wadhwa and Gupta 2022).

 

3.11 CAPSICUM ANNUM

 Figure 16 CAPSICUM ANNUM

It is commonly known as Chili pepper which gives Capsaicin which enhances the bioavailability theophylline and ciprofloxacin. In an experiment on rabbits’ oral dose of theophylline with or without Capsaicin has given the second maintenance dose of bioenhancer after 11 hours raised the plasma levels of theophylline (Dudhatra et al. 2012b)(Dudhatra et al. 2012c)(Jhanwar 2014).

       Table 1 HERBS, ITS SOURCE, MECHANISM AND THEIR DOSE AS BIOENHANCES

S.NO	Drug	Biological source	Mechanism	Dose of drug	Drug
1	Piperine (1-piperoyl piperidine)	Piper longum	Methylenedioxyphenyl ring in piperine helps in the inhibition of the drug metabolizing enzymes including CYP 450 enzymes and UDP glucuronyl transferase. It also inhibits P-GP and then efflux of absorbed drug from enterocytes	15 mg/kg.	Piperine is used in combination with various drugs and increases the efficacy of these drugs
2	Curcumin	Dried and fresh rhizomes of Curcuma longa Linn. Family-Zingiberaceae	Curcumin suppresses drug metabolizing enzymes (CYP3A4) in the liver as well as inducing changes in the drug transporter P-glycoprotein, hence increase the Cmax and AUC of celiprolol and midazolam in rats	12g/day	Celiprolol and Midazolam
3	Ginger (Whole Part)	Rhizome of the perennial plant Zingiber officinale Roscoe, Family-Zingiberacea	Due to the presence of saponins, flavonoids, and alkaloids, Ginger acts powerfully on GIT mucous membrane. The role of ginger is to regulate intestinal function to facilitate absorption.	1-55mg /kg	Antibiotics, antifungal, antiviral and anticancerous drugs. Therapeutic activity of Anti-TB drugs like Rifampicin, Pyrazinamide and Isoniazid
4	Caraway (Seeds)	Dried ripe seeds of Carum carvi Linn., Family-Umbelliferaceae	Due to a novel flavonoid glycoside it enhances the peak concentration (Cmax) and area under the curve (AUC) of rifampicin	1-55mg/kg	Antibiotics, antifungal, antiviral and anticancerous drugs. Therapeutic activity of Anti-TB drugs like Rifampicin, Pyrazinamide and Isoniazid
5	Glycyrrhizin	Dried root and stolon of Glycyrrhiza glabra Linn, Family- Leguminosae.	It enhances cell division inhibitory activity of anticancerous drug. Inhibition of cell growth by taxol with glycyrrhizin was higher than the taxol alone. this combination is used against breast cancer. It also enhances (2 to 6 fold) transport of antibiotics	1 μg/ml	Taxol and antibiotics like Rifampicin, Tetracycline, Nalidixic acid, Ampicillin and Vitamins B1 and B12 as bioenhancer
6	Indian aloe (Leaves)	Dried juice of the leaves of Aloe barbadensis Mill., Family-Liliaceae	longer in the plasma and increases bioavailability of Vitamin C and E in human. It also capable of inhibiting the release of reactive oxygen free radicals from activated human neutrophils		Vitamin C and E
7	Quercetin	It is a flavonoid found in many fruits (apples, citrus fruits like red grapes, raspberries, and cranberries), green leafy vegetables and black and green tea	It inhibits the p-glycoprotein efflux pump and metabolizing enzyme, CYP 3A4 in the intestinal mucosa and restraint the metabolizing enzyme CYP3A4		Diltiazem, Digoxin, Epigallocatechin gallate
8	Allicin	Aromatic bulb of Allium sativum Linn. FamilyLiliaceae	Allicin enhances AmB-induced vacuole membrane damage by inhibiting ergosterol trafficking from the plasma membrane to the vacuole membrane	120μM allicin	Fungicidal activity of Amphotericin B
9	Naringin	t is a flavanone-7-Oglycoside occurs naturally in citrus fruits, especially in grapefruit	It inhibits the CYP3A1/2 enzymes and p-glycoprotein is modulated in rats	3.3 and 10 mg/kg	Paclitaxel, Verapamil, Diltiazem
10	Tea (Leaves and Buds)	Leaves and leaf buds of Thea sinensis Linn. Family- Theaceae	The thermogenic properties of tea extract shows a synergistic interaction between caffeine and catechin polyphenols that appears to prolong sympathetic stimulation of thermogenesis. Green tea also promotes fat oxidation and decreased the absorption rate of zinc while black tea		Both teas promote the absorption of manganese and copper as nutrients in the blood circulation.
11	Niaziridin	Niaziridin a nitrile glycoside is isolated from the pods of Moringa oleifera Lam., FamilyMoringaceae	Commonly act with antibiotics against gram-positive bacteria like Myobacterium smegmatis, Bacillus subtilis and gram-negative bacteria like E. coli to increase the absorption of it		Vitamin B12, rifampicin, ampicillin, nalidixic acid, azole antifungal drugs such as clotrimazole
12	Lysergol	It is isolated from higher plants like Rivea corymbosa Linn., Ipomoea violacea Linn. and Ipomoea muricata Linn.	It promotes the killing activities of different antibiotics on bacteria. lysergol enhances the transport of antibiotics across the intestinal gut and cell membrane.	10 μg/ml	Broad-spectrum antibiotics
13	Genistein	It is an isoflavone found in a number of dietary plants like soybean (Glycine max Linn.) and kudzu (Pueraria lobata Willd.).	Genistein is reported to be able to inhibit P-gp, BCRP and MRP-22 efflux functions	1.3 mg/kg or 10 mg/kg	Paclitaxel, Epigallocatechin gallate the
14	Sinomenin e	Root of the climbing plant Sinomenium acutumThunb. FamilyMenispermace	The mechanism underlying the increase in bioavailability of paeoniflorin is explained as sinomenine could decrease the efflux transport of paeoniflorin by P-gp in the small intestine. This combination can be useful in the treatment of inflammation and arthritic	90mg/kg	Paeoniflorin
15	5’ methoxy hydnocarpi n (5′-MHC)	Leaves of Barberis fremontii Torr., FamilyBerberidaceae.	5′-MHC has no antimicrobial activity but it inhibits the MDRdependent efflux of berberine from S. aureus cells and effectively disabled the bacterial resistance mechanism against the berberin antimicrobial action.	100 μg/ml	Berberin
16	Hydnocarp oic acid	Seeds of Hydnocarpus wightiana FamilyAchariaceae	It acts by blocking the synthesis and coenzymatic activity of biotin.	4 μg/ml	Biotin
17	Stevia	Leaves of Stevia rebaudiana Bertoni., Family- Asteraceae.	Components of stevia called Stevioside and steviol stimulates insulin secretion via a direct action on beta cells. Due to the activity for reducing vascular tension it is used for patients with hypertension.	30 mg/kg	Antibiotics, antiobese drugs, antidiabetic drugs, antifungal drugs, antiviral drugs, anticancer drugs, cardiovascular drugs, anti-inflammatory, antiarthritic agents,
18	Capsaicin	Fruit of Capsicum annum Linn., Family- Solanaceae	The absorption of capsicum increases AUC of the drugs		Theophylline
19	Cumin seeds	Dried seeds of Cuminum cyminum Linn., FamilyApiacea	Possible mechanisms may be the Aqueous extract of cumin seeds stimulate β-adrenoceptors and/or inhibit histamine H1 receptors. It also worked in the opening of potassium channels and inhibition of calcium channels.	0.5 to 25 mg/kg	Erythromycin, Cephalexin, Amoxycillin, Fluconazole, Ketoconazole,
20	Ammaniol	Methanolic extract of Ammannia multiflora Roxb., Family-Lythraceae	Ammaniol have the property to increase glucose uptake and shows potent antihyperglycemic activity.		Antimicrobial drugs like Nalidixic acid

 

4. RELATION OF BIOENHANCERS WITH AYURVEDA (Sarangi and Padhi 2018).

Present-day science is developing bio-enhancers as a new science for expanding the adequacy of medication, still this concept was started and was documented hundreds of years back and was utilized as a system of medicine. In Ayurveda, several herbs were used, such as P. longum, Z. officinale, and G. glabra having action as bio-enhancers and different strategies for bio-enhancing for centuries. There are various concepts and techniques in Ayurveda such as-

·       Yogavahi,

·       Anupana,

·       Bhaishajya Kala,

·       Bhavana (trituration),

·       Rasayana,

·       Yoga (formulations), and

·       Kalpanas (various dosage forms).

The different ideas of Purana Aushadhies (old drugs), the concept of activity increasing medications, and penetration enhancers had been used since ancient time in Ayurveda. Besides, Samshodhana (biopurification) can be considered for this idea. The definite investigation of these ideas clarifies the idea of bio-enhancers (S. Singh, Tripathi, and Rai 2016)

 Ideal property of bio-enhancers

The ideal bio-enhancers need to be (B. Ita 2015)

§  Nontoxic, non-allergenic, and non-irritating,

§  Produce own pharmacological effects,

§  Rapid-acting with predictable and reproducible activity,

§  Unidirectional in action,

§  Compatible with other active pharmaceutical ingredients,

§  Stable with time and environment,

§  Easily formulated into a various dosage form, and

§  Easily available and cost-effective

5. HURDLES WITH BIOENHANCERS

Although bio-enhancers in drug delivery have been successful, not all approaches have met with the same success. New bio-enhancers being developed come with challenges which have to be surmounted. One of the challenges is to improve on properties of drug formulations such as long circulation in the blood, increased functional surface area, protection of incorporated drug from degradation, crossing of biological barriers and sitespecific targeting. Another challenge of research and development of herbal bioenhancers is large scale production. There is always a need to scale up laboratory or pilot technologies for eventual commercialization. The challenges of scaling up include low concentration of nanomaterials, agglomeration and the chemistry process; it is easier to modify nanomaterials at laboratory scale for improved performance than at large scale. Advances in herbal bio-enhancers also provide new challenges for regulatory control. There is an increasing need to have regulations that would account for physicochemical and pharmacokinetic properties of nano drug products, which are different from conventional drug products (Kesarwani and Gupta 2013b)(Cho, Lee, and Choi 2004).

 

6. 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 fled 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 (Atal and Bedi 2010a)(Thorat, Gujar, and Karale 2023b).

Table 2 Herbal bioenhancers for bioavailability improvement of various drugs

ROA	HERBAL BIOENHANCER	DRUG CANDIDATE FOR BIOAVAILABILITY ENHANCEMENT	MECHANISM OF ACTION
Oral	Curcumin	Efflux transporter (P-gp) inhibition; metabolism (CYP3A) inhibition	Midazolam: benzodiazepine
Oral	Emodin (anthraquinone derivative)	Efflux transporter(P-gp) inhibition	Digoxin: digitalis glycoside
Oral	Genistein (flavonoid)	Efflux transporter(MRP) inhibition	Epigallocatechin-3-gallate (EGCG): phenolic antioxidant
Oral	Gallic acid ester (organic acid)	Metabolism(CYP3A) inhibition	Nifedipine: calcium channel blocker
Oral	Moringa oleifera pods (traditional herbal medicine)	Metabolism(CYP450) inhibition	Rifampicin: semisynthetic rifamycin derivative
Oral	Naringin (flavonoid glycoside)	Metabolism(CYP3A4) inhibition	Tamoxifen: selective estrogen receptor modulator (SERM)
Oral	Peppermint oil (herbal)	Metabolism(CYP3A) inhibition	Cyclosporine: immunosuppressant
Oral	Piperine (alkaloid)	Metabolism(CYP450) inhibition	·        Nimesulide: nonsteroidal anti-inflammatory ·        Carbamazepine: carboxamide
Oral	Quercetin (flavonoid)	Metabolism(CYP3A) inhibition	·        Verapamil:Calcium channel blocker   ·        Pioglitazone: thiazolidinedione
Buccal	Aloe vera (gel, whole leaf)	Intercellular modulation	Didanosine: antiviral reverse transcriptase inhibitor
Pulmonary	HPBCD, CRYSMEB (cyclodextrin derivatives)	Tight junction modulation	Mannitol: sugar alcohol

 

8. HERBAL ENHANCERS USED IN NOVEL DRUG DELIVERY AND NANOTECHNOLOGY

Active pharmaceutical agents often demonstrate strong in vitro activity but face challenges in vivo due to limited membrane permeability, rapid efflux by cell transporters (e.g., P-gp), and metabolism by cytochrome P-450 (Kulkarni et al. 2022)These factors limit drug absorption, bioavailability, and therapeutic efficacy. However, combining these agents with herbal enhancers can significantly improve their bioavailability and effectiveness across various drug classes, including anticancer, antiviral, and antihypertensive drugs. Nanotechnology-based drug formulations—such as liposomes, nanoparticles, and transdermal patches—further enhance this effect. Key herbal enhancers, such as piperine, quercetin, and glycyrrhizin, have proven effective in improving the absorption and therapeutic impact of poorly soluble drugs when integrated into advanced drug delivery systems (Ajazuddin et al. 2014)(Byeon et al. 2019).

Figure 17 HERBAL ENHANCERS USED IN NOVEL DRUG DELIVERY AND NANOTECHNOLOGY

1.     Liposomal Formulation

 

Formulation	Active ingregient	Application	Biological activity	Method of preparation	Percent entrapment effeciency	ROA	reference
Quercetin Liposome	Quercetin	Reduced dose, enhanced penetration in blood brain barrier	Anti-oxidant Anti-cancer	Reverse evaporation technique	60%	Intranasal	(Kesarwani and Gupta 2013b)
Garlicin Liposome	Garlicin	increase efficiency	Lungs	Reverse phase evaporation	90.77%	In-vitro	(Gavini et al. 2005)
Curcumin Liposome	Curcumin	Long circulation with high entrapment effeciency	Anti-cancer	Ethanol injection method	88.2%	In-vitro	(Preparation of curcumin-loaded long-circulating liposomes and its pharmacokinetics in rats 2014)

 

2.     Nanoparticles. 

Formulation	Active ingredient	Application	Biological activity	Method of preparation	Entrapment effeciency	Route of administration	References
Triptolide nanoparticles	Triptolide	Enhance the penetration of drug through stratum corneum by increased hydration	Anti-inflam-matory	Emulsi-fication ultrasound		Topical	(Mei 2003)
Nanoparticle of Cuscuta chinensis	Flavonoids and Lignans	Improve water solubility	Hepato-protective and anti-oxidant activity	Nano-suspension method	90%	Oral	(Mei 2003)
Triptolide nanoparticles	Triptolide	Enhance the penetration of drug through stratum corneum by increased hydration	Anti-inflam-matory	Emulsi-fication ultrasound		Topical	(Kesarwani and Gupta 2013b)

 

3.     Transferosomes

Formulation	Active ingredient	Application	Biological activity	Droplet Size	Route of administration	References
Capsaicin transferosomes	Capsaicin	Increase skin penetration	Analgesic	150.6 nm	Topical	(Amol and Pratibha n.d.)
Colchicine transferosomes	Colchicine	Increase skin penetration	Antigout		In-vitro	(H. P. Singh et al. 2009)
Vincristine transferosomes	Vincristine	Increase entrapment efficiency and skin penetration	Anticancer	120 nm	In-vitro	(Opatha, Titapiwatanakun, and Chutoprapat 2020)

 

9. RECENT PATENTS ON HERBAL CONTROLLED RELEASE FORMULATIONS(Kesarwani and Gupta 2013b)

Table 3  RECENT PATENTS

US PATENT NO.	Active ingredients	Novel system incorporates
US 5948414	Opioid analgesic and aloe	Nasal spray
US 6340478 B1	Ginsenosides	Microencapsulated and controlled release formulations
US 6890561 B1	Isoflavones	Microencapsulated formulation
US 6896898 B1	Alkaloids of aconitum species	Transdermal delivery system
US patent 2005/0142232 A	Oleaginous oil of Sesamum indicum and alcoholic extract of Centella asiatica	Brain tonic
US patent 2007/0042062 A1	Glycine max containing 7s globulin protein extract, curcumin, Zingiber officinalis	Herbal tablet dosage form
US patent 2007/0077284A1	Opioid analgesic (phenanthrene gp)	Transdermal patch
US patent 7569236132	Flavonoids (such as quercetin) and terpenes (ginkgolide A, B, C and J)	Microgranules

 

10. RECENT ADVANCEMENT IN BIOENHANCERS

Atal et al worked on biochemical basis of enhanced drug bioavailability by piperine. The study was aimed at understanding the interaction of piperine with enzymatic drug biotransforming reactions in hepatic tissue. They found that piperine shows little discrimination between different cytochrome P-450 forms and is a non-specific inhibitor of drug metabolism. Piperine strongly inhibited the hepatic AHH and UDP- glucuronyltransferase activities when orally administered to rats. The results of the experiment demonstrated that piperine is a potent inhibitor of drug metabolism (J. Singh, Reen, and Wiebel 1994).

Singh et al reviewed the Indian Herbal Bioenhancers . They found Piperine in both Long Pepper and Black Pepper as the potent bioenhancer. Rifampicin transcription activity is augmented several fold by piperine against Mycobacterium smegmatis. Even at higher concentration of 50 microgram/ml, piperine alone shows no inhibitory effect for the growth of M. smegmatis but increases the inhibitory potential of rifampicin when given with it in ratio of 24:1 at the lower concentration of 0.125-0.5 microgram/ml. The binding ability of rifampicin to RNA polymerase is enhanced by piperine (Murase et al. 2019)(R. Singh et al. 2009b)

Navin et al reviewed the concept of bioenhancers to reduce treatment costs by increasing the bioavailability of the drug. The Indian scientists discovered and scientifically validated Piperine as the world’s first bioavailability enhancer (Atal and Bedi 2010b). DNA receptor binding, modulation of cell signal transduction and inhibition of drug efflux pump are the different mechanisms proposed for the bioenhancer activity of piperine (Kumar et al. 2008). They found that Piperine is added in a dose of 10mg irrespective of the dose of active combination in all formulations. Their work concluded piperine as a novel bioenhancer because it is effective, safe, economical, non-addictive, easily procured, and has a widely based effect on several classes of drugs (Kumar et al. 2008)

Chanda et al carried the acute and sub-acute toxicity study and chemical characterization of trikatu in Charles Foster rats for safety profiling. Their studies showed that in acute toxicity experiment Trikatu was well tolerated by the animals under study and no significant changes were observed in morbidity, mortality, gross pathology, vital organ weight, gain in weight, haemotological count and other necessary parameters (Tatiraju et al. 2013).

Karan et al studied the effect of trikatu on the pharmacokinetic profile of indomethacin in rabbits. The results showed that TRIKATU enhanced the absorption of indomethacin which was supposed to be the result of an increase in the gastrointestinal blood flow and an increased rate of transport across gastrointestinal mucosa (Atal and Bedi 2010b).

Bhat et al carried studies on the metabolism of piperine. They observed that the highest concentration in the stomach and the small intestine was attained at 6hours. Traces of piperine were detected in the spleen, kidney and serum from ½ hour to 24 hour (Ganesh Bhat and Chandrasekhara 1986a).(Ganesh Bhat and Chandrasekhara 1986b)

Singh et al studied the alteration of pharmacokinetics of oxytetracycline following oral administration of Piper longum in hens. Their studies revealed that the prior administration of P.longum increases total duration of antimicrobial action and enhances the therapeutic efficacy of oxytetracycline in poultry birds. There was reduction in loading and maintenance dose and thus the subsequent side effects (0118JVS_jvs-6-197 (1) n.d.; Ganesh Bhat and Chandrasekhara 1986b).

Kang et al studied the bioavailability enhancing activities of natural compounds from medicinal plants. They found Trikatu as an essential ingredient of many ancient prescriptions and formulations and that it played an important role in increasing drug bioavailability when given orally. They concluded that co-administration of natural compounds is one of the promising approaches for increasing bioavailability of drugs (Joo Kang et al. 2009b).

Dama et al worked on the effect of Trikatu pretreatment on the pharmacokinetics of pefloxacin administered orally in mountain Gaddi goats. They found that the trikatu treated animals showed a better penetration of the drug and the trikatu administration enhanced the duration of antimicrobial action by about 22%. There was an enhanced bioavailability due to suppression of drug metabolizing activities and not because of increased absorption (M. Singh et al. 2005)

Pattanaik et al. evaluated the effect of simultaneous administration of piperine on plasma concentration of carbamazepine twice daily in epileptic patients undergoing carbamazepine monotherapy. They observed that Piperine could significantly enhance the oral bioavailability of carbamazepine. The mechanism of action was possibly by decreasing the elimination or by increasing its absorption. They concluded that piperine significantly increased the mean plasma Concentrations of carbamazepine in both dose groups (Pattanaik et al. 2009).

Bhutani et al. investigated antidepressant effect of curcumin with piperine. They concluded that the combination of piperine with curcumin showed quite significant potentiation of its anti-immobility, neurotransmitter enhancing (serotonin and dopamine) and monoamine oxidase inhibitory effects as compared to curcumin effect (Atal and Bedi 2010b; Bhutani, Bishnoi, and Kulkarni 2009).

Kulkarni et al. found that there was potentiation of antidepressant activities when piperine was administered simultaneously with curcumin. This approach was useful in the management of depression (Kulkarni et al. 2022)(Randhawa, Kullar, and Rajkumar 2011).

Nirala et al. Evaluated the effect of piperine individually and in combination with tiferron against beryllium induced biochemical alteration and oxidative stress. They found that the combination of tiferron with piperine could reverse all the variables significantly towards the control (Nirala et al. 2008).

Zhao et al. Studies concluded that gallic acid exerts a synergistic effect when administered with piperine . This provided a more pronounced therapeutic potential in reducing beryllium-induced hepatorenal dysfunction and oxidative stress consequences. They observed that individual administration of gallic acid and piperine moderately reversed the altered biochemical variables. On the other hand the combination of these was found to completely reverse the beryllium-induced biochemical alterations and oxidative stress consequences (Nirala et al. 2008).

Kasibhatta et al. studied the Influence of piperine on the pharmacokinetics of nevirapine under fasting conditions. The study was randomized, crossover and placebo controlled. They administered piperine or placebo to healthy adult males for 6 day. On day 7 piperine or placebo was administered with nevirapine. Blood samples were collected post-dose. The results of the study showed that there was an enhanced bioavailability of nevirapine when administered with piperine (Kasibhatta and Naidu 2007)

Durgaprasad et al. evaluated the effect of oral curcumin (500 mg) with piperine (5 mg) on the pain, and the markers of oxidative stress in patients with tropical pancreatitis for 6 wks. There was a significant reduction in the erythrocyte malonyldialdeyde levels following curcumin therapy in comparison to placebo administration , with a significant increase in glutathione levels(Volak et al. 2013)

Lambert et al reported that piperine coadministered with (-)-Epigallocatechin-3-gallate to male CF-1 mice increased the plasma C(max) and area under the curve by 1.3-fold compared to mice treated with Epigallocatechin-3-gallate only. The results appeared such due to inhibiting glucuronidation and gastrointestinal transit (Monfared et al. 2009)

Vladimir et al. Studied the relative bioavailability of different doses of coenzyme Q10 simultaneous administered with piperine or placebo in healthy adult male volunteers. The results were studied for single-dose experiment or in separate experiments for 14 and 21 days. When compared with coenzyme Q10 plus placebo the result of single and the 14th day dose study indicated smaller, but no significant increase in plasma concentration. Compared to coenzyme Q10 plus placebo supplementation of higher dose coenzyme Q10 with piperine for 21st days produces a statistically different approximately 30% greater, area under the plasma curve (Badmaev, Majeed, and Prakash 2000)

Vladimir et al., 1999 studied the effect of simultaneous administration of piperine on serum concentration of β-carotene in healthy volunteers for 14-days. The results of the study indicated a significant increase in serum β-carotene concentration when supplemented with piperine in comparison to β-carotene plus placebo, respectively. They found that there was 60% increase in area under curve of β-carotene plus piperine when compared with β -carotene plus placebo (A. Singh and Duggal 2009).

 

11. RECENT CASE STUDIES(Kesarwani and Gupta 2013b).

Various nano/microcarriers have been used for the bioavailability enhancement of poorly absorbed water-soluble herbal constituents, such as flavonoids, tannins, glycosides, etc. Due to the large molecular size and poor lipid solubility, their ability to transport across lipid-rich cell membrane will be severely limited. Use of nano/microcarrier results in enhanced therapeutic action of poorly soluble plant extract.

Recent case studies utilizing nano/microformulations for delivery of herbal bioenhancers/products.

 

Table 4  RECENT CASE STUDIES

Formulation	Herbal product	Method of preparation	Application	Route of administration
Phytosome	Bacopa	Bacopa-phytophospholipid complex	Activity enhancer	Oral
Phytosome	Rutin	Rutinphospholipid complex	Solubility enhancement	Oral
Phytosome	Quercetin, kaempferol and isorhamnetin	Ginkgo biloba extractphospholipid complexes	Bioavailability enhancement	Oral
Silybin Phytosome®	Silybin Flavonoids	Silybinphospholipid complexation	Absorption enhancer	Oral
Ginseng Phytosome®	Ginsenosides	Phospholipid complexation	Absorption enhancer	Oral

 

12. HURDLES WITH BIOENHANCERS

Although bio-enhancers in drug delivery have been successful, not all approaches have met with the same success. New bio-enhancers being developed come with challenges which have to be surmounted. One of the challenges is to improve on properties of drug formulations such as long circulation in the blood, increased functional surface area, protection of incorporated drug from degradation, crossing of biological barriers and sitespecific targeting. Another challenge of research and development of herbal bioenhancers is large scale production. There is always a need to scale up laboratory or pilot technologies for eventual commercialization. The challenges of scaling up include low concentration of nanomaterials, agglomeration and the chemistry process; it is easier to modify nanomaterials at laboratory scale for improved performance than at large scale. Advances in herbal bio-enhancers also provide new challenges for regulatory control. There is an increasing need to have regulations that would account for physicochemical and pharmacokinetic properties of nano drug products, which are different from conventional drug products (Kesarwani and Gupta 2013b).

FUTURE PERSPECTIVE

Advancements in drug delivery continue to be a critical area of research. The limitations in drug absorption and bioavailability hinder the application of various therapeutic compounds with substantial potential. This restricted use of drugs with low bioavailability ultimately increases the healthcare burden associated with the development of new drugs. However, the challenge of limited bioavailability offers researchers valuable opportunities to explore a range of enhancement mechanisms, particularly through the use of herbal bioenhancers. Naturally derived bioenhancers present distinct advantages, including ease of access, cost-effectiveness, minimal side effects, and enhanced efficacy. Currently, bioenhancers are incorporated through various novel delivery systems, including nanocarriers. As per insights from SLICE News, the herbal medicine market is projected to reach 50 billion USD by 2030, reflecting the global surge in demand for herbal medicines and their ingredients. This growth underscores the significance of natural resources, largely attributed to their accessibility. Natural-origin bioenhancers hold significant promise for revitalizing multiple drugs by improving their pharmacokinetic profiles, offering profound implications for therapeutic innovation.

CONCLUSION

In developing countries such as India, the cost of treatment remains a primary concern in modern medicine. Systematic and innovative approaches are essential to reduce these expenses. Modern pharmaceutical research is fundamentally focused on discovering new chemical entities with novel mechanisms of action. Additionally, advancements in drug development technologies increasingly prioritize the economic aspects of drug creation. Ayurveda has significantly contributed to the drug discovery process through reverse pharmacology, offering new approaches to identify active compounds and lower development costs. Current research aims to reduce drug dosages, thereby lowering treatment costs and expanding accessibility to broader segments of society, including those with limited financial resources.

 

Conflict of Interest: The authors declare that they have no Conflict of interests.

Availability of Data:  I have not used any personal data that require being available for the reader.

Funding source: None

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