INTRODUCTION:^(1,9-12)

Plant based medicines are used by a majority of the world’s population. Almost 25% of modern pharmacopoeias too contain drugs of plant origin. Many synthetic and herbal drugs suffer from the problem of low bioavailability. Bioavailability is the rate and extent to which a substance enters systemic circulation and becomes available atthe required site of action. 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 vailability of the drugs which are mixed with them and do not exhibit synergistic effect with the drug.

· Bioenhancers should have novel properties such as:

· Nontoxic to humans or animals,

· Should be effective at a very low concentration in a combination,

· Should be easy to formulate, and

· Most importantly, enhance uptake/absorption and activity of the drug molecules.

Following the use of bioenhancers, 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.^(1-5)

Drug absorption barriers: ^(5,7)

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. There are many structures in the intestinal epithelium which serve as barriers 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. 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 trans membrane 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.

Methods in use for enhancement of absorption of orally administered drugs:

There have been many approaches in use to enhance the intestinal absorption of poorly absorbed drugs. These approaches are as follows:

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. 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 EGTA and EDTA enhance absorption by reducing the extracellular calcium concentration, leading to the disruption of cell-cell contacts. ^[18]

Prodrugs:

To enhance the drug absorption and bioavailability chemical modification of drugs to produce prodrugs and more permeable analogues has been widely studied as a useful approach. 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. Ampicillin due to its hydrophilic nature is only 30 - 40% absorbed from the gastrointestinal tract. By esterification of carboxyl group of ampicillin the prodrugs of ampicillin such as pivampicilline, bacampicilln and talampicillin were synthesized .These prodrugs were more lipophilic than the parent compound following oral administration and they showed higher bioavailability in comparison with ampicillin.

Dosage Form Other Pharmaceutical Approaches:

Utilization of permeability-enhancing dosage forms is one of the most practical approaches to improve the intestinal absorption of poorly absorbed drugs. 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.

P-glycoprotein Inhibitors:

The application of P-gp inhibitors in improving peroral drug delivery has gained special interest. Several studies to enhance oral bioavailability have demonstrated the possible use of P-gp inhibitors that reverse P-gp-mediated efflux in an attempt to improve the efficiency of drug transport across the epithelia. P-gp inhibitors influence metabolism, absorption, distribution, and elimination of P-gp substrates in the process of modulating pharmacokinetics.

Need for bioenhancers:

Lipid solubility and molecular size are the major limiting factors for the molecules to pass the biological membrane and to be absorbed systematically following oral and topical administration. Several plant extracts and phytoconstituents, despite having excellent bioactivity in vitro demonstrate less or no in vivo action due to their poor lipid solubility or molecular size or both, resulting poor absorption and poor bioavailability. It is often found that, when individual constituents are isolated from plant extract there is specific loss of bioactivity. Sometimes some constituents of multi-constituent plant extract are destroyed in gastric environment when taken orally. They reduce the dose, shorten the treatment period and thus reduce drug resistance problem.

Mechanisms of Action of Bioenhancers:^(1,4-6)

There are several mechanisms of action by which bioenhancers act. Different bioenhancers may have same or different mechanism of action. Nutritional bioenhancers enhance absorption by acting on gastrointestinal tract. Antimicrobial bioenhancers mostly act on drug metabolism process. Among the various mechanisms of action postulated for herbal bioenhancers some are as follows:

(a) Reduction in hydrochloric acid secretion and increase in gastrointestinal blood supply

(b) Inhibition of gastrointestinal transit, gastric emptying time and intestinal motility

(d) Cholagogous effect

(e) Bioenergetics and thermogenic properties

(f) Suppression of first pass metabolism and inhibition of drug metabolizing enzymes and stimulation of gamma glutamyl transpeptidase (GGT) activity which enhances uptake of amino acids.

Classification of Bioenhancers:⁽⁴⁾

Bioenhancers can be classified based on origin and mechanism of action.

Based on origin

Plant origin

Animal origin

Cuminum cyminum

Carum carvi

Stevia

Lysergol

Glycyrrhizin

Ginger

Allicin

Aloe vera

Simomenine

Curcumin

Gallic acid

Ellagic acid

Cow urine

Based on mechanism of action:^{(3, 4)}

Inhibition of P-gp efflux pump and other efflux pumps:

Examples: Carum carvi (Caraway), Genistein, Sinomenine, Cuminum cyminum (Black cumin), Naringin, Quercetin

Suppressors of CYP-450 enzyme and its isozymes:

Examples: Naringin, Gallic acid and its esters, Quercetin

Regulators of GIT function to facilitate better absorption:

Examples: Aloevera (Aloe), Niaziridin (Drumstickpods), Zingiber officinale (Ginger), Glycyrrhiza (Liquorice)

Bioenhancers:

Piperine:^(1,4,9)

Piperine (1-piperoyl piperidine) is an amide alkaloid found inplants of Piperaceae family like Piper longum (long pepper), Pipernigrum (black pepper). The bioenhancing property of piperine was first utilized in the treatment of tuberculosis in human. Piperine was found to increase the bioavailability of rifampicin by about 60%and hence reduce the dose from 450 to 200mg. In human medicine piperine is approved to be combined with anti-tubercular drugs. Piperine also showed enhanced bioavailability when combined with Nevirapine; a potent non-nucleoside inhibitor ofHIV-1 reverse transcriptase which is used in combination with other antiretroviral agents for the treatment of HIV-1 infection. Piperine also increases the bioavailability of curcumin, the active principle of Curcuma longa (turmeric). A 20 mg dose of piperine can increase the bioavailability of curcumin by 20 fold in humans. Several animal studies on piperine have shown promising results in bioenhancing capacity of piperine for various drugs.

Fig: Piperine

Turmeric:^(1,3,4)

Turmeric (Curcuma longa) is a common household item used as remedy for various ailments. Curcumin, a flavonoid from turmeric suppresses drug metabolizing enzymes like CYP3A4 in liver and is also capable of inducing change in drug transporter P-gp and thus increased the bioavailability of celiprolol and midazolam in rats. The bioenhancer nature of curcumin is similar to piperine. Curcumin suppresses UDP-glucuronyl transferase level in intestine and hepatic tissues. It also modifies the physiological activity inthe gastrointestinal tract leading to better absorption of drugs.

Fig: Turmeric

Allicin:^(1,4)

It is an allyl sulphur compound obtained from garlic (Allium sativum).Allicin enhances the fungicidal activity of Amphotericin B against pathogenic fungi such as Candida albicans, Aspergillus fumigates and yeast Saccharomyces cerevisiae. Amphotericin B when given along with Allicin exhibited enhanced antifungal activity against S. cerevisiae.

Fig: Allicin

Ginger:^(1,4)

It contains Gingerol which facilitates better absorption by regulating GI tract function. The effective dose of the bioenhancer extract is in the range of 10-30 mg/kg body weight.It enhances the bioavailability of rifampicin by 65% and ethionamide by 56%. It also enhances the bioavailability of antibiotics (Azithromycin – 78%), anti-fungal (Ketoconazole –125%), anti-viral (Zidovudine – 105%) and anti-cancer (5-fluorouracil – 110%) drugs.

Fig: Ginger:^(1,4)

Stevia (Honey leaf):

Stevia is anti-hypertensive agent and also promotes insulin secretion. The bioenhancing chemical constituent present in Stevia is stevioside. Though the mechanism of action is not known, it enhances the bioavailability of anti-tubercular, anti-leprotic, anti-cancer, antifungal and anti-viral drugs. The effective dose of the bioenhancer extract is in the range of 0.01-50 mg/kg body weight.

Fig: Stevia (Honey leaf)

Peppermint oil:^(1,4)

Peppermint oil significantly improves the oral bioavailability of cyclosporine. Co-administration of 100 mg/kg peppermint oil almost tripled the Cmax and AUC of cyclosporine. It exerts its mechanism of action probably by CYP3A inhibition.

Fig: Peppermint oil

Aloe Vera:^(1,4)

Aloe is an important source of phytochemicals and increases the absorption of vitamins C and E.

Fig: Aloe vera

Gallic acid:^(1,4)

Gallic acid exerts a synergistic effect when administered with piperine and provides a more pronounced therapeutic potential in reducing beryllium-induced hepatorenal dysfunction and oxidative stress consequences. Gallic acid esters like propyl gallate, octyl gallate, aluryl gallate etc. have been found to enhance bioavailability of several drugs like nifedipine.

Capsaicin:^(1,4)

It is an active component of Capsicum annum and other chilli species. It enhances the bioavailability of theophylline.

Fig: Capsaicin

Liquorice:^(1,4)

Liquorice consists of dried, peeled or unpeeled, root and stolon of Glycyrrhiza glabra and exhibits anti-hepatotoxic, anti-fertility, anti-inflammatory, expectorant and anti-oxidant activity. It contains glyzirrhizin which enhances the bioavailability of rifampicin by 6.5 fold at the concentration of 1µg/ml. It also enhances the bioavailability of taxol by 5 fold at the concentration of 1 µg/ml.

Fig: Liquorice

Morning glory plant:^(1,4)

It is a source of lysergol that enhances the bioavailability of rifampicin by 4.5-6 folds at 0.2 µg/ml concentration. It also enhances the bioavailability of antibiotics in the range of 2-12 folds. It’s mechanism of bioenhancer action is not yet clearly known.

Fig: Morning glory plant

Drumstick pods:^(1,4)

It contains niaziridin, a nitrile glycoside which is a powerful bioenhancer. It regulates GIT functions to facilitate better absorption. It enhances the bioavailability of rifampicin by 38.8 folds at 1.0 µg/ml. It also enhances the bioavailability of Clotimazole by 5-6 folds. An in-vitro study of active fraction of M. oleifera pod sagainst Mycobacterium tuberculosis (H37Ra) exhibited no antituberculosis activity at the concentration at which it enhanced the anti tubercular activity of rifampicin. Khanuja et al. performed a pre-clinical study to evaluate the influence of M. oleifera (MoAF) on pharmacokinetic disposition of rifampicin using HPLC-PDA method.26 They orally administered to Swiss albino mice a dose of 20 mg/kg body weight of rifampicin along with a dose of 0.1 mg/kg body weight of the active fraction of M. oleifera (viz. Niaziridin). They observed the bioavailability pattern shown in the following figure thereby proving the success of Niaziridin as an effective bioenhancer for rifampicin.

Fig: Drumstick pods

Cumin/Caraway:^(1,4)

Cumin seeds have carminative, mild stomachic, aromatic and diuretic actions. The effective dose for the Carum carvi bioactive fraction as bioenhancer is in the range of 1-55 mg/kg body weight. It has been reported to enhance bioavailability of antibiotics, antifungal, antiviral and anticancerous drug. It is also found to be more effective as bioenhancers when used in combination with bioenhancer from Zingiber officinale (10-150 mg/kg body weight) and piperine (3-15 mg/kg body weight).

Fig: Cumin

Black cumin:^(1,4)

It is an effective gastric stimulant, carminative and anthelmintic. The doses of its fractions responsible for the bioavailability enhancement activity ranged from 0.5 to 25 mg/kg body weight. Bioactive fraction of Cuminum cyminum enhanced bioavailability of Erythromycin (105%), Cephalexin (75%), Amoxycillin (111%), Fluconazole (126%), Ketoconazole (156%), Zidovudine (270%) and 5-Fluorouracil (290%).

Fig: Black cumin

Quercetin:^{(1, 4)}

Quercetin is a flavonoid; an aglycone form of a number of other flavonoid glycosides found in citrus fruits. It exhibits anti-oxidant, radical scavenging, anti-inflammatory, anti-atherosclerotic activities. It works by inhibiting CYP3A4 and P-gp efflux pump. Quercetin has been shown to increase bioavailability, blood levels and efficacy of a number of drugs including diltiazem, digoxin, verapamil, etoposide, and paclitaxel.

Fig: Citrus fruits containing Quercetin

Sinomenium acutum:⁽⁴⁾

Sinomenine is an alkaloid extracted from Sinomenium acutum. It is found to increase the bioavailability of paeoniflorin by inhibition of P-gp efflux pumps. Paeoniflorin is used in the treatment of inflammation and arthritic conditions but has a poor absorption rate and thus a very low bioavailability (3–4%) when administered orally.

Fig: Sinomeniumacutum

Cow urine distillate:^(4,8)

Cow urine distillate is more effective as a bioenhancer than cow urine. It enhances the transport of antibiotics like rifampicin, tetracycline and ampicillin across the gut wall by 2-7 folds. It also enhances the potency of taxol against MCF-7 cell lines. It enhances the bioavailability of rifampicin by 80 fold in 0.05 µg/ml concentration, ampicillin by 11.6 fold in 0.05 µg/ml concentration also has antitoxic activity against the cadmium chloride toxicity and it can be used as a bioenhancer of zinc. The bioenhancing ability is by facilitating absorption of drugs across the cell membrane.

Recent Advances:^(1,13-21)

Kheradmandnia et al. evaluated the preparation and characterization of ketoprofen-loaded solid lipid nanoparticles (SLNs) made from beeswax and carnauba wax and found that the the mean particle size of drug loaded SLNs decreased upon mixing with Tween 80 and egg lecithin as well as upon increasing total surfactant concentration. High drug entrapment efficiency of 97% revealed the ability of SLNs to incorporate a poorly water-soluble drug such as ketoprofen. Differential scanning calorimetry thermograms and high-performance liquid chromatographic analysis indicated the stability of nanoparticles with negligible drug leakage after 45 days of storage. It was also found that nanoparticles with more beeswax content in their core exhibited faster drug release as compared with those containing more carnauba wax in their structure.

Martins et al. carried out the development and validation of a simple reversed-phase HPLC method for the determination of camptothecin in animal organs following administration in SLNs and concluded that the method developed is reliable, precise and accurate and can be used in the determination of CPT amount in rat organ samples after i.v., administration of camptothecin in suspension, in physical mixture with SLN and incorporated in SLN [103].

Tiyaboonchai et al. carried out formulation and characterization of curcuminoids loaded SLNs and found that at optimized process conditions, lyophilized curcuminoids loaded SLNs showed spherical particles with a mean particle size of 450 nm and a polydispersity index of 0.4, up to 70% (w/w). The results revealed that after storage in the absence of sunlight for 6 months, the percentages of the remaining curcumin, bisdemethoxy curcumin and demethoxycurcumin were 91, 96 and 88, respectively.

Wang et al. evaluated the preparation, characterization and antitumor activity studies on emodin loaded solid lipid nanoparticles (E-SLNs). The physicochemical properties of the E-SLNs were investigated by particle size analysis, zeta potential measurement, drug entrapment efficiency (EE), stability and in vitro drug release behavior. The E-SLNs showed stable particle size at (28.6±3.1) nm, ideal drug EE and relative long-term physical stability after being stored for 4 months. The drug release of E-SLNs could last 72 h and exhibited a sustained profile, which made it a promising vehicle for oral drug delivery. Moreover, these results suggested that the delivery of emodin as lipid nanoparticles maybe a promising approach for cancer therapy.

Kwon et al. prepared silk fibroin coated SLNs by an emulsification and solidification method using sodium lauryl sulfate (an anionic surfactant) as a stabilizer and then, the SLN was coated with silk fibroin under an acidic condition by an electrostatic interaction. The silk fibroin coat of nanoparticles was positively charged, so it would strongly interact with negatively charged skins, enhancing the skin permeability.

Kuchler et al. proposed 3D wound healing model and the influence of morphine with SLNs and the results has concluded the acceleration of wound closure, low cytotoxicity irritation and possible prolonged morphine release make SLN an interesting approach for innovative wound management.

Yuan et al. investigated the cellular uptake of SLNs and cytotoxicity of encapsulated paclitaxel in A549 cancer cells. The order of cellular uptake ability was glycerol tristearate SLN > monostearin SLN > stearic acid SLN> compritol 888 ATO SLN (ATO888 SLN). Furthermore, the cellular cytotoxicities of paclitaxel were highly enhanced by the encapsulation of lipid matrix. The PEG and folate modified SLN could enhance the cellular uptake of SLN and the cellular cytotoxicity of drug by the membrane disturb ability of PEG chains on the SLN surface and the improved endocytosis mediated by folate receptor.

Chen et al. evaluated the SLNs as the topical carrier for epidermal targeting of podophyllotoxin (P-SLN). The results had showed the penetration of P-SLN with low particle size into stratum corneum along the skin surface furrow and the consequent controlled release of podophyllotoxin might lead to the epidermal targeting. Furthermore, P-SLN provides a good epidermal targetting effect and may be a promising carrier for topical delivery of podophyllotoxin.

Jenning et al. evaluated the potential use of solid lipid nanoparticles in dermatology and cosmetics, glycerylbehenate SLN loaded with vitamin A (retinol and retinyl palmitate) and incorporated in a hydrogel and o/w-cream were tested with respect to their influence on drug penetration into porcine skin. The results had showed that the transepidermal water loss and the influence of drug free SLN on retinyl palmitate uptake exclude pronounced occlusive effects. Therefore enhanced retinyl palmitate uptake should derive from specific SLN effects and is not due to non-specific occlusive properties.

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 arylhydrocarbon hydroxylase and UDP glucuronyltransferase activities when orally administered to rats. The results of the experiment demonstrated that piperine is a potent inhibitor of drug metabolism.

Singh et al. 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 mg/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 mg/mL. The binding ability of rifampicin to RNA polymerase is enhanced by piperine.

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, alongwithhaemotological count and other necessary parameters.

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.

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 6th hour. Traces of piperine were detected in the spleen, kidney and serum from 0.5 hour to 24 hour.

Singh et al. studied the alteration of pharmacokinetics of oxytetracycline following oral administration of P. 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.

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.

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.

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.

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.

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.

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.

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 days. 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.

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 weeks. 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.

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 inhibition of glucuronidation and gastrointestinal transit.

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 21 days produces a statistically different approximately 30% greater, area under the plasma curve.

Vladimir et al. 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.

Kumari et al. encapsulated the plant isolated antioxidant quercitrin on poly-d, l-lactide (PLA) nanoparticles by solvent evaporation method to improve the solubility, permeability and stability of this molecule. The size of quercitrin-PLA nanoparticles is (250±68) nm. The encapsulation efficiency of nanoencapsulated quercitrin evaluated by HPLC and antioxidant assay is 40%. The in vitro release kinetics of quercitrin under physiological condition reveals initial burst release followed by sustained release. These properties of quercitrinnano medicine provide a new potential for the use of such less useful highly active antioxidant molecule towards the development of better therapeutic for intestinal anti-inflammatory effect and nutraceutical compounds.

Niraimathi et al. used the aqueous extract of Alternanthera sessilis L. (A. sessilis) (Amaranthaceae) in producing silver nano particles (AgNPs) from silver nitrate. The AgNPs obtained was characterized by UV-Visible spectroscopy, FT-IR spectroscopy, SEM, Zeta sizerand TG-DSC. SEM images which revealed the presence of various shapes and sizes. FT-IR spectrum showed the AgNPs having a coating of proteins indicating a dual role of bio-molecules responsible for capping and efficient stabilization of the silver nanoparticles. Presence of impurities and melting point profile were screened by TG-DSC analyzer. AgNPs were synthesized from the silver nitrate through the reducing power of ascorbic acid present in A. sessilis leaves.

Sahni et al. provided a concise incursion on the current pharmacotherapies for Alzhimer's disease besides reviewing and discussing the literature on the different drug molecules that have been successfully encapsulated in nanoparticles. Some of them have been shown to cross the blood brain barrier (BBB) and have been tested either for diagnosis or treatment of Alzhimer's disease. Finally, the route of nanoparticles administration and the future prospects had also been discussed.

Aromal et al. developed a new synthesis method for monodispersed gold nanocrystals using cheap and nontoxic chemicals, environmentally benign solvents and renewable materials. The nanoparticles have been characterized by UV-Visible spectroscopy, transmission electron microscopy (TEM), X-ray diffraction (XRD) and FTIR analysis. The high crystallinity of nanoparticles is evident from bright circular spots in the SAED pattern and peaks in the XRD pattern. The synthesized gold nanoparticles show good catalytic activity for the reduction of 4-nitrophenol to 4-aminophenol by excess NaBH4 and found to exhibit size dependent catalytic property, the smaller nanoparticles showing faster activity.

Khalil et al. conducted the biological synthesis of gold nanoparticles (AuNPs) of various shapes (triangle, hexagonal, and spherical) using hot water olive leaf extracts as reducing agent. The size and the shape of gold nanoparticles are modulated by varying the ratio of metal salt and extract in the reaction medium. The nanoparticles obtained are characterized by UV-Vis spectroscopy, photoluminescence, TEM, XRD, FTIR spectroscopy and thermogravimetric analysis. The TEM images showed that a mixture of shapes (triangular, hexagonal and spherical) structures was formed at lower leaf broth concentration and high pH, while smaller spherical shapes were obtained at higher leaf broth concentration and low pH.

Jeevitha et al. aimed to engineer a biodegradable [chitosan (CS) and poly (lactic acid) (PLA)] as anthraquinone carrier with nanometer dimensions and to evaluate the anticancer potency of the prepared CS/PLA-AQ nanoparticles in human carcinoma (HepG2) cells. The in vitro release study showed that these nanoparticles provided a continuous release of the entrapped anthraquinone for 10 days, and the release behavior was influenced by the pH value of the medium thereby making feasible to develop CS-PLA for enhanced and sustained release of anthraquinone. The results also suggested that upon CS/PLA-AQ nanoparticles exposure the cell viability decreased due to apoptosis, as demonstrated by the formation of apoptotic bodies, sub-G1 hypodiploid cells, and DNA fragmentation. Henceforth, CS/PLA-AQ nanoparticles demonstrated a strong antitumor activity in vitro by reducing cell viability, inducing cell necrosis, decreasing the negative surface charge and mitochondrial membrane potential, and fragmenting DNA.

Parhi et al. reported that nanotechnology-based combination drug delivery to tumor tissues has emerged as an effective strategy by overcoming many biological, biophysical and biomedical barriers that the body stages against successful delivery of anticancer drugs. The sustained, controlled and targeted delivery of chemotherapeutic drugs in a combination approach enhanced therapeutic anticancer effects with reduced drug associated side effects. In this article, we have reviewed the scope of various nanotechnology-based combination drug delivery approaches and also summarized the current perspective and challenges facing the successful treatment of cancer.

Rajendran et al. loaded the ethanolic extract of Ocimum sanctum inside the sodium alginate chitosan nanoparticles by cation induced controlled gellification method and finished on cotton fabric by pad dry cure method. The average particle size of the nanoparticles was calculated using dynamic light scattering technique. The antimicrobial activity of the fabrics was assessed by using the standard AATCC technique (AATCC 100). The quantitative tests proved that cotton fabrics finished with the methanol extract of Ocimum sanctum loaded nanoparticles possessed remarkable antibacterial activities with excellent wash durability. The study revealed that the herb encapsulated nanoparticle could act as a biocontrol agent against bacteria in fabrics.

Yallapu et al. focused on the design and development of nanoparticles, self-assemblies, nanogels, liposomes and complex fabrication for sustained and efficient curcumin delivery as it has proven to be a modulator of intracellular signaling pathways that control cancer cell growth, inflammation, invasion and apoptosis, revealing its anticancer potential. The anticancer applications and clinical benefits of nanocurcumin formulations was also discussed. Only a few novel multifunctional and composite nanosystem strategies offer simultaneous therapy as well as imaging characteristics. We also summarize the challenges to developing curcumin delivery platforms and up-to-date solutions for improving curcumin bioavailability and anticancer potential for therapy.

Chaudhary et al. provided a consise review on an account of the main issues emanating from applications of nanotechnologies in food and related sectors with a particular reference to developing countries.

Li et al. reviewed that nanoparticle therapeutics, comprising of drugs, nucleic acids or proteins in association with a carrier, have emerged as safe and efficient systems in the treatment of the respective liver diseases and described the targeting strategies employed in relation to liver anatomy and disease etiologies, summarized recent advances in the field and discussed the challenges and future perspectives for the effective treatment of liver diseases using polymer- and lipid-based nanoparticle therapeutics.

Jain et al. studied the advances in understanding the aetiology, epidemiology and microbiology of periodontal pocket flora in revolutionising the therapeutic strategies for the management of periodontal disease progression and summarised the recent developments in the field of intra-pocket drug delivery systems and identifies areas where further research may lead to a clinically effective intra-pocket delivery system.

Suryawanshi et al. reviewed that the bioavailability can be improved by phytosomal drug delivery system, which can enhance the rate and the extent of drug absorption across the lipoid biomembrane, which have been found promising for better and effective delivery of drug and providing much appropriate systematic drug delivery.

Priprem et al. compared and evaluated oral quercetin (300 mg/kg body weight/day) was compared with oral and intranasal quercetin liposomes (20 µg/day). Anxiolytic and cognitive-enhancing effects of quercetin, conventional and liposomal, were subjected to elevated plus maze and Morris water maze tests, respectively. Both conventional and quercetin liposomes showed anxiolytic and cognitive-enhancing effects. A lower dose and a faster rate were observed with intranasal quercetin liposomes when compared with oral quercetin, conventional and liposomal and the intranasal quercetin liposomes are effective in the delivery of quercetin to the central nervous system.

Yilmaz et al. synthesized silver nanoparticles employing a shadow-dried Stevia rebaudiana leaf extract in AgNO3 solution. TEM and XRD inspections indicate that nanoparticles are spherical and polydispersed with diameters ranging between 2 and 50 nm with a maximum at 15 nm. Ultraviolet-visible spectra recorded against the reaction time confirms the reduction of silver nanoparticles indicating that the formation and the aggregation of nanoparticles take place shortly after the mixing, as they persist concurrently with characteristic times of 48.5 min and 454.5 min, respectively. Proton nuclear magnetic resonance spectrum of the silver nanoparticles reveals the existence of aliphatic, alcoholic and olefinic CH2 and CH3 groups, as well as some aromatic compounds but no sign of aldehydes or carboxylic acids. Infrared absorption of the silver nanoparticles suggests that the capping reagents of silver and gold nanoparticles reduced in plant extracts/broths are of the same chemical composition of different ratios.

Philippi et al. reviewed the concept of telomerase and telomerase inhibition in cancer therapy and also aimed to provide an overview of the different currently known telomerase inhibitors. Finally, the biopharmaceutical limitations of these molecules are discussed as well as the possibilities to overcome those limits by novel drug carrier systems and formulation approaches.

CONCLUSION:

Bioenhancers constitute an innovative concept the discovery of which was based on a traditional system of Indian medicine. They will lead to reductions in drug cost, toxicity, and other adverse effects, and have a beneficial influence on the national economy. It is safe, effective, economical, easily procured, non-addictive, and has a widely-based effect on several classes of drug. A synthetic process for its commercial production has been developed for industrial use.

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Received on 27.09.2015 Modified on 16.10.2015

Res. J. Pharm. Dosage Form. and Tech. 7(4): Oct.-Dec., 2015; Page 274-284

DOI: 10.5958/0975-4377.2015.00039.7