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Volume 6, Issue 1, February Issue - 2018, Pages:87-107

Authors: Sonu Ambwani*, Roopali Tandon, Tanuj Kumar Ambwani, Yashpal S. Malik
Abstract: Herbal remedies have been extensively used since times immemorial throughout the world. These have wide acceptability due to their time-tested therapeutic values and minimal side effects in contrast to modern allopathic medicines. Commonly, the herbal medicines are available in the form of crude extracts prepared in different solvent systems which might not only need large dose administration but also could be less effective in the form of conventional formulations. Moreover, available phyto-formulations do not have the ability for specific tissue target delivery in case of different chronic diseases. Oral administration of these herbal formulations is subjected to adverse pH, enzymatic degradation and ultimately poor gut absorption and bioavailability. With the advancements in biotechnology, genomics, and combinatorial chemistry, new, more potent and specific drug delivery systems have been envisaged during the last few decades. Constraints associated with conventional phytopharmaceuticals have been improved by designing and using “Nano Delivery Systems” (NDS). The foremost aim of NDS is to provide sustained drug release, site-specific action, and improved patient’s compliance. Nano herbal medicines can be used to target them to the specific site in the body which improves their selectivity, solubility, delivery, safety, effectiveness and thus reduces the need for administration of frequent large doses. Nanocarriers loaded with herbal drugs can carry the optimal amount of the drug to their site of action avoiding different obstructions such as low pH in the stomach, metabolism by liver so that the drug can circulate into the blood for a longer period of time. Phytopharmaceuticals with NDS thus would be helpful in enhancing the efficacy of herbal drugs.
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Full Text: 1 Introduction From last decade there has been a wide acceptance and public interest in natural remedies both in developing and developed countries. As per World Health Organization (WHO) “herbal medicines as finished, labeled medicinal products that contain active ingredients, aerial or underground parts of the plant or other plant material or combinations”. According to WHO reports, 80% of the populations from developing countries exploit herbal medicines for their primary health care needs (Yadav et al., 2014). Herbal ‘renaissance’ is happening all over the world due to rising concern over the safety of modern allopathic medicines. Various modern medicines are causing side effects and not able to effectively treat many of the common health conditions with increased incidences of drug resistance. Even the genesis of modern medicine is from traditional therapeutic systems (Patwardhan et al., 2004). Plants and natural products have been used since long for curative/ healing purposes in different cultures like China, Egypt, Africa, America and India. Herbal medicine, also known as “herbalism” or “botanical medicine” is a medical system based on the use of plants or plant extracts that may be taken orally or applied to the skin (Griggs, 1982). In spite of criticisms regarding certain features of herbal medicine, many pharmacologists today, recognize the potential scientific rationale of biological effects produced by these phytomedicines (Sharma et al., 2011). Though herbal medicines are considered as dependable and affordable therapeutics, however, some problems are associated with them viz. rapid release of the herbal drug, unknown toxicity, low solubility, poor bioavailability and oral absorption, etc. (Thillaivanan & Samraj, 2014). Besides the general notion that “the herbal drugs are safe”, many pharmaco-vigilance studies have suggested that these natural drugs have frequently unknown active ingredients and thus their standardization and quality control are not an easy task (Ekor, 2013; Mathur, 2016). Delivery of herbal medicines also requires an improved delivery system for their sustained release and targeted delivery for enhanced patient compliance (Goyal et al., 2011). NDS is a new concept of drug delivery that can be helpful in surmounting the shortcomings of the traditional drug delivery systems. NDS, when employed for herbal medicine, may be helpful in enhancing the efficacy and lowering their side effects (Ansari et al., 2012).  In novel phytoformulations, various nano delivery vehicles, viz., liposomes, polymeric nanoparticles, nanoemulsion, nanospheres, solid lipid nanoparticles (SLNs), are used in which phytoconstituents can be incorporated and these nanosized herbal formulations not only help in sustained release of the drug but can also eliminate the inadequacies of conventional herbal formulations (Elmowafy et al., 2013; Priprem et al., 2015). Present communication deliberates upon various nano delivery systems that could be exploited to eliminate shortcomings of conventional herbal formulations and thus can be helpful in improvement of therapeutic efficacy of phytomedicines. 2 Advantages of herbal drugs Herbal medicine based therapeutic system is the ancient form of health care system known to human civilization. Phyto-formulations may contribute immensely to the health of an individual (Mathur, 2016). An exponential increase in human population, insufficient availability of costly allopathic drugs, associated side effects and problems like multidrug resistance amongst infectious pathogens have led to the development of alternative plant-based natural medicines for a broad range of diseases (Greenwell & Rahman, 2015). Phytomedicine or phytopharmaceutical, is a complex mixture derived from plant sources that is used as a medicine or drug. Approximately 50% of the functional drugs are prepared from natural resources (Kingston, 2011). Herbal formulations are cost effective and made up from natural ingredients that are readily metabolized in the body. Herbal preparations have been recognized for their potential curative and low side effects in comparison to other drugs (Mahima et al., 2012). Herbal drugs are reputed for treating diverse disease conditions associated with various systems like endocrine, skeletal, digestive, physiological, nervous, reproductive, respiratory and immune systems. These biological properties of herbal drugs are attributed to the biological activities of various secondary metabolites like phenolics, terpenoids (sapogenin), alkaloids, steroids etc., present in them (Mathur, 2016). Herbal products can also be used to increase the bioavailability of the medicine (Kesarwani & Gupta, 2013). 3 Constraints of herbal drugs Many herbal formulations are crude preparations with hydrophobic phytoconstituents and thus exhibit low solubility. Several other tribulations such as low solubility, bioavailability, and oral absorption lead to reduced efficacy which can limit the use of herbal medicines (Jantarat, 2013). Till recently, phytopharmaceuticals were not preferred for development of novel formulations due to their crude combinations that lack scientific rationalization and processing difficulties (Ekor, 2013; Thillaivanan & Samraj, 2014). Most of the herbal ingredients are extracted in different solvents that may exert toxic effects. When traditional herbal formulations are administered, only a low amount of dose reaches to the site and rest of the drugs get wasted as it is distributed throughout the body depending on physicochemical and biochemical properties resulting in low therapeutic value. Another constraint of oral herbal formulations is that many ingredients of the herbal drugs may get deteriorated in the acidic pH of the stomach while some others may be metabolized in the liver so that inadequate amount of the phytopharmaceuticals may reach the blood (Yadav et al., 2011; Ansari et al., 2012). There would be either slow or no therapeutic effect if drug is not administered in the optimum quantity/ dose (minimum effective dose level). Some of the phytoconstituents derived from the natural origin have poor solubility and low bioavailability resulting in a narrow therapeutic index, thus scientists are working on drug targeting and controlled release of phytoconstituents to provide better therapeutic effect and increased patient compliance (Park, 2014). The route of administration of the drug has a considerable impact on its effectiveness. A drug molecule needs to be given in an optimal concentration (dose) to achieve its therapeutic potential. If it is given in a smaller amount than optimal concentration, no therapeutic benefit is derived and at higher concentration, it could exhibit toxic effects (Charman et al., 1999). Due to the above-mentioned constraints and poor efficacy of the treatment of relentless diseases, multidisciplinary approaches are envisaged for tissue-specific delivery of herbal therapeutics to enhance their pharmacokinetics, pharmacodynamics, bio-recognition, and efficacy. These novel delivery methods are based on interdisciplinary inputs of polymer chemistry, pharmacology, nanotechnology, bioconjugate chemistry, etc (Charman et al., 1999). 4 Nano Delivery Systems for herbal drugs From past two decades, nanotechnology is exploited for efficacious drug delivery and tissue-specific targeting of drug (Kumar et al., 2015). Improved drug delivery techniques help in minimizing toxic effects and achieving enhanced effectiveness which is beneficial for the patients. Important attributes pertaining to herbal remedies could be improved component solubility, enhanced bioavailability, increased absorbency, reduced herbal doses, achieving steady-state therapeutic levels of drugs and overall better compliance (Ansari et al., 2012). Some of the strategies of drug delivery are employed to cross physical barriers, viz. blood-brain barrier (BBB) or on finding alternative suitable routes for drug delivery other than the oral delivery where drug constituents can be degraded (Kumar et al., 2015). At present “Novel Drug Delivery Systems” (NDDS) are exploited mainly for allopathic medicines. However, recent emphasis has been given to employing NDDS for safe, effective and time-tested ‘ayurvedic’ herbal drug formulation that could prove to be an attractive choice in the present scenario. Delivery of pharmaceutical molecules is a process of administering it to the patient through suitable route to achieve a specific therapeutic effect. Common routes of drug delivery are per-oral (through the mouth), topical (skin), transmucosal (nasal, buccal, sublingual, vaginal, ocular and rectal) and inhalation routes. Modern phytopharmaceutical investigations can be exploited for development of NDDS based herbal drugs (Bhokare et al., 2016).  NDDS includes various strategies for transporting a pharmaceutical molecule in the body to safely attain its desired curative effects which may either require its specific targeting or it might require systemic pharmacokinetics. In nutshell, NDDS are advance delivery approaches to enhance drug effectiveness by targeting the drug to the desired site, by controlling drug release to provide sustained curative effect and offer better safety (Nagavarma et al., 2012). NDDS includes carrier based drug delivery system (liposomes, niosomes, microspheres, resealed erythrocytes as drug carriers), trans-dermal Delivery Systems (sonophoresis), mucoadhesive delivery systems, supramolecular delivery systems and variable release delivery systems (osmotic pump, nanoencapsulation), etc. Due to the presence of diverse ingredients development of NDDS for herbal formulations is a challenging task (Nagavarma et al., 2012). Nano herbal formulations can be employed for site-specific targeting of herbal medicines to enhance their selectivity, solubility, delivery, safety, and effectiveness. The nanosized drug increases their surface area thereby allowing quicker distribution in the blood and reduced toxicity while maintaining the therapeutic effects. The enhanced permeation and retention of nanoparticles (NPs) can also help to cross BBB (Kumar et al., 2015; Ganesan et al., 2017). Phyto-pharmaceuticals require a methodical strategy for efficient and sustained delivery to enhance patient acceptability and to prevent frequent drug administration. “Nano Delivery Systems” for herbal formulations can be employed for this purpose and combat limitations of herbal drugs. NDS help in enhancing therapeutic value and bioavailability and also decreasing frequent administration of herbal drugs (Govindarajan et al., 2017). Therefore, amalgamation of NDS in the traditional remedies is of vital importance for treatment of many chronic ailments like asthma, cancer, etc. (Aqil et al., 2013; Bonifácio et al., 2014; Sharma & Singh, 2014; Gunasekaran et al., 2014; Mathur, 2016). Flavonoids have shown to exhibit poor stability, bioavailability, and bioefficacy if administered through oral route (Manach et al., 2005). Due to this constraint, various bioactivities attained in vitro conditions reveal either poor or no in vivo activities. Bilia et al. (2014b) reviewed the role of NDS like nanospheres, nanocapsules, micro- and nanoemulsions, micelles, solid lipid nanoparticles and nanostructured lipid capsules, for resolving shortcomings associated with the oral delivery of flavonoids. Flavonoids displayed improved stability and absorption when administered through NDS (Dube et al., 2010; Manjili et al., 2016). It is further reported that nano-based flavonoids possess enhanced surface area, better stability and bioavailability due to receptor-mediated phagocytosis and endocytosis by specific cells (Tan et al., 2012). NDS also mediate controlled discharge of encapsulated flavonoids. Bilia et al. (2014b) concluded in their review that nanocarriers made of approved molecules referred to as “Generally Recognized as Safe” (GRAS) may be used for development of efficacious preparations of herbal functional foods, dietary supplements, and therapeutics. Different types of nanosized herbal formulations can be prepared to achieve the enhanced therapeutic potential of   Table 1 Examples of different types of nanosized phytopharmaceuticals
S. No. Plant/ phytopharmaceuticals Type of nano preparation References   Artemissia annua Atrimisinin nanoparticles Chen et al. (2009)   Berberine Berberine-loaded nano-particles Lin et al. (2007)   Centella asiatica Nano-encapsulation Kwon et al. (2012)   Curcuma longa (Curcumin) Micro-emulsion Bist et al. (2007)   Cuscuta chinensis Nano-suspension Yen et al. (2008)   Lippia sidoides Chitosan polymericnanoparticles Bilia et al. (2014a)   Origanum vulgare chitosan polymeric nanoparticles Hosseini et al. (2013)   Picrohiza kurrooa pluronic-F-68 copolymer based biodegradeable PLA nanoparticles  Jia et al. (2015)   Sophora japonica Nanprecipitation Wu et al. (2008)   Silibinin Solid lipid nanoparticles Zhang et al. (2007)   Curcuma longa Curcumin phytosome Maiti et al. (2007)   Echinacea angustifolia Phytosome Kareparamban et al. (2012)   Sophor a flavescens Oxymatrine Liposome Yue et al. (2010)   Allium sativum Garlicin liposome Khan et al. (2007)   Capsicum annua Capsaicin liposome Mahajan et al. (2010)   Curcuma longa Curcumin Liposome Dhule et al. (2012)   Hibiscus dabdariffa (Flowers) Liposome Gibis et al. (2014)   Magnolia officinalis Magnolol Liposome

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