Received date: June 03, 2016; Accepted date: June 17, 2016; Published date: June 22, 2016
Citation: Gopi S, Amalraj A, Haponiuk JT, Thomas S (2016) Introduction of Nanotechnology in Herbal Drugs and Nutraceutical: A Review. J Nanomedine Biotherapeutic Discov 6:143. doi:10.4172/2155-983X.1000143
Copyright: © 2016 Gopi S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Nanotechnology is an opening up for new perspectives in all scientific and technological fields. Among these applications, herbal drugs and nutraceuticals are the fast growing fields in nanoresearch. A variety of new herbal formulations and nutraceuticals like polymeric nanoparticles, nanocapsules, nanoemulsions, transferosomes and ethosomes has been reported using bioactive, plant extracts and food materials. New herbal drugs and nutraceuticals are reported to have remarkable advantages over conventional formulations of plant actives and extracts which include enhancement of solubility, bioavailability, expansion of stability, sustained delivery, improved tissue macrophages distribution, protection from toxicity, enhancement of pharmacological activity and protection from physical and chemical degradation. This review provides an overview of the introduction of nanotechnology in the field of herbal drugs and nutraceuticals.
Nanotechnology; Herbal drugs; Nutraceuticals; Phytomedicine
Phytomedicines have been serving as a crucial source of drugs sinceancient times, their usage has been increased due to their therapeutic activity and less side effects rather than the other medicines. Both developing and developed countries are focusing on the popularity of herbal drugs mainly due to their natural origin and low side effects. Fast-growing nanotechnologies have provided strong support for developing innovative novel herbal drugs. Nutraceuticals are foods and food constituents that provide health benefits beyond basic nutrition, but many nutraceuticals show poor bioavailability. Applications of nanotechnology have granted to overcome the challenges and technical barriers related to the solubility, bioavailability, stability and delivery of bioactives from foods. The rapid growth of nutraceutical nanotechnology carries great promise to provide new and effective functional foods as a tool for preventing and possible even bringing a cure to some non-communicable diseases. Numerous studies are already reported in different types of preparative methods of nanomaterials in the field of nanotechnology for herbal drug delivery and nutraceuticals (Figure 1) [1-5]. The current review focuses on the introduction of nanotechnology in herbal drugs and nutraceuticals for nanomedicine and functional foods. It is also highlights important and rapid developments in biomedical and food technology.
Nanotechnology in herbal drugs
Nanotechnology can be used to enhance delivery of poorly water soluble herbal drugs, targeted delivery in a cell or tissue, also a cross tight epithelial and endothelial barriers, release of large herbal molecules, co-delivery to two or more drugs and observation of sites of drug delivery by incorporating herbal drugs with imaging modalities [6-8]. Applications of nanotechnology formulated herbal drugs are schematically represented in Figure 2. Table 1 summarizes the various nanostructured herbal formulations, their different applications and biological activities.
|Formulations||Active ingredients||Biological activity||Method of preparation||Applications of the formulations||References|
|Diclofenacdiethylamine and curcuminnanocarrier transdermal gel||Curcumin||Anti-inflammatory activity||Encapsulation with sonication||Enriched biological activity
|Chaudhary et al. |
|Nanotransfersomes of diclofenacdiethylamine and curcumin||Curcumin||Anti-inflammatory activity||Encapsulation with sonication||High bioavailability
|Chaudhary et al.|
|pH sensitive NPs loaded curcumin-celecoxib combination||Curcumin||Anti-inflammatory and antioxidant activity||Solvent emulsion evaporation||Enhanced efficacy for mitigating ulcerative colitis||Gugulothu et al.|
|Curcumin-lipid NPs with Gelucire 39/01, Gelucire 50/13, percirol, compritol and polozamer 407||Curcumin||Anti-microbiological activity||Hot homogenization||Promising alternative for the manipulation of curcumin to overcome the clinical applications||Hazzahet al.|
|Curcumin loaded NPs of HPMC and PVP||Curcumin||Anti-malarial activity||Solvent emulsion – evaporation technique||Beneficial for the prolonged utilization of the formulation as an adjuvant anti-malarial therapy to prevent the recrudescence and reduce the dose of the standard anti-malarial drugs||Dandekar et al.|
|AgNPs of Mukiascabrella||Cysteine residues in protein||Anti-microbial activity||Nanosuspension||Antibacterial activity against MDR-GNB nosocomial pathogens||Prabaka ret al. |
|AgNPs of Bauhinia tomentosa Linn||Amines, carboxylic acids, aldehydes and ketone||Anticancer and antioxidant activity||Nanosuspension||Potential agent for cancer therapy||Mukundan et al.|
|Fluorescent AgNPs of Artemisia annua||Amides and phenolics||Anticytotoxicity
and antibacterial activity
|Nanosuspension||Fluorescent properties can be exploited in biomedical applications
Biocompatible cytotoxicity against human erythrocytes
|Khatoon et al. |
|AuNPs of Pistaciaintegerrima gall extract||Amines, amides, phenolic and alcoholic||Antifungal activity||Nanosuspension||Significant attenuation of pain and muscle relaxant effect||Islam et al.|
|NiNPs of Aeglemarmeloscorrea||Amines, amides, phenolic and alcoholic||Anti-inflammatory and mosquito larvicidal activity||Nanosuspension||Excellent anti-inflammatory agent
Acts as a drug carrier for the control of Cx. quinquefasciatas
|Angajala et al.|
|Curcumin and temozolomide loaded magnetic NPs||Curcumin and temozolomide||Anticancer and antitumor activity||Nanosuspension with sonication||Dual drug delivery system (Cur + Temo) is provoking greater anticancer activity by stimulating cell death pathways||Dilnawaz et al. |
|Polymeric NP formulation of Syzygiumcumini||Gallic, chlorogeniccaffeic and ellagic acids, catechin, epicatechinquarcetinetc||Antifungal activity||Emulsification/evaporative solvent technique||Significant attenuation against the chronic complications of diabetes mellitus||Bitencourt et al. |
|Witepsol SLNPs and Carnauba SLNPs||Thujone, pinene, camphor||Antioxidant activity||Hot melt ultrasonication||Suitable vehicle for herbal extracts with high stability during digestion
A significant release percentage of phenolic compounds at the small intestine
|Campos et al.|
|SNEDDS formulation of Persimmon (Diospyros kaki) leaf extract||Flavonoids (Quercetin and Kaempferol)||Antioxidant activity||Self nanoemulsion||Promising method for poorly aqueous soluble drugs including the extract of herbal medicine to achieve a significant improvement in bioavailability||Li et al. |
|SNEDDS formulation of quercetin||Quercetin||Anti-liver toxicity||Self nanoemulsion||Protective effect against paracetamol induced hepatotoxicity
Enhance the activity of antioxidant
|Ahmed et al.|
|SNEDDS formulation of Zedoary turmeric oil||Essential oil||Oral bioavailability||Self nanoemulsion||Increase drug loading
Decrease the inert oil requirement
|Zhao et al. |
|MUDDS with four units||Realgar, frankincense and myrrh oil, musk, and bezoar||Antitumor activity||Ball milling followed by solvent evaporation||High antitumor activity
|Shi et al. |
|Incorporation of four prenylatedflavanones from leaves of Eysenhardtiaplatycarpa||5,7-Dihydroxy-6-methyl-8- prenylflavanone; 5,7-dihydroxy-6-methyl-8-prenyl-4_-methoxy-flavanone; 5,7-dihydroxy-6-prenylflavanone; and 5-hydroxy-7-methoxy-6- prenylflavanone||Anti-inflammation activity||Oil, solvent and surfactant-cosurfactant mixture||Acts as potential topical anti-inflammatory agent||Domínguez-Villegas et al. |
|Oleanolic acid loaded PEGylated PLA and PLGA NPs||Oleanolic acid||Anti cytotoxicity against cancer cells||Ring opening polymerization followed by nanoprecipitation method||High potentials to develop into an effective anticancer delivery platform for cancer chemotherapy||Man et al. |
|Polycaprolactone/polyvinyl pyrrolidonenanofiber mat with bark extract of Tecomella undulate||Alcoholic, phenolic compounds carboxylic acids||Antibacterial activity||Nanofiber fabrication through electro spinning||Great potential in drug delivery, wound healing and treating against surface pathogenic microorganisms||Suganya et al. |
|Electrospun gelatin nanofibres containing Centellaasiatica extract||Alcoholic, phenolic compounds carboxylic acids||Anticytotoxicity and antibacterial activity||Electrospinning||Promising and potential material for use as wound dressing materials||Yao et al. |
Table 1: Nanostructured herbal formulations.
Herbal and nanomedicine researchers have discovered that therapeutic nanoparticles (NPs) can provide as more effective drug delivery system than conventional forms of drugs. Nanocarriers transdermal gel (NCTG) was formulated from optimized nanotransfersomes of diclofenac diethylamine (DDEA) and curcumin (CRM) for providing a sustained and targeted effect. Due to nanoparticulate size of NCTG achieving higher absorption of the drug plus co-administration of lecithin; providing hydration gradient to the vesicles, increase permeability, decreased degradation and clearance by surfactant than that from marketed gel and plain curcumin gel was reported . Formulated and optimized nanotransfersomes of DDEA and CRM provided a large surface area with high penetration potential and achieved high bioavailability . pH-sensitive nanoparticles of curcumin-celecoxib combination were formulated as a potential therapy for uncreative colitis . Curcumin solid lipid nanoparticles (CRM-SLN) were prepared with a high-loading capacity and chemical stability for the treatment of oral mucosal infection . Curcuminloaded hydrogel nanoparticles of hydroxyl propyl methyl cellulose (HPMC) and polyvinyl pyrrolidone (PVP) were successfully formulated and exhibited a significant improvement in anti-malarial action .
Biosynthesis of silver nanoparticles (AgNPs) were demonstrated by leaf extract of Mukiascabrella, it exhibited significant antimicrobial activity against MDR-GNB nosocomial pathogens . AgNPs have been synthesized by Mukundanet al.  using an aqueous leaves extract of Bauhinia tomentosa Linnand their in vitroanticancer activity has also been studied.Fluorescent AgNPs were synthesized using Artemisia annualeaf extract and these AgNPs were biocompatible, which was confirmed by checking the cytotoxicity against human erythrocytes and they showed significant fluorescence and antibacterial activity .
Gold nanoparticles (AuNPs) were synthesized by using a gall extract of Pistaciaintegerrima and they have potential for various biomedical and pharmaceutical applications particularly with significant antifungal and antinociceptive activity . Phytofabrication of nickel nanoparticles (NiNPs) from Aeglemarmelos Correa (AMC) aqueous leaf extract was investigated NiNPs can be used as excellent anti-inflammatory agents and drug carriers . Magnetic nanoparticles (MNPs) based drug delivery approach for co-delivering of curcumin and temozolomide has been implemented and this system has been well efficient in provoking greater anti-cancerous activity .
In vitroefficacy against the complications of diabetes mellitus (DM) and the in vivotoxicity was evaluated by using an aqueous extract from Syzygiumcuminiseed (ASc) and of polymeric nanoparticles containing ASc (NPASc). NPASc demonstrated a high inhibitory activity against ox-LDL particles and showed high in vitro activity . Solid lipid nanoparticles (SLNPs) can be used as vehicles for phenolic compounds rich extracts. Witepsol and carnauba were tested for the production of solid lipid nanoparticles (WSLNPs ad CSLNPs) loaded with medicinal herbs, sage and savory extracts. WSLNPs showed to be a more suitable vehicle for herbal extracts, with high stability during digestion and a significant release percentage of phenolic compounds in the small intestine .
The persimmon leaf extract was successfully formulated as a stable self-nanoemulsifying drug delivery system (SNEDDS) formulation that had significant improvement in solubility, in vitro release and bioavailability compared with Naoxinqing tablets . SNEDDS formulation of the optimized quercetin (QT) formulae offered superior protective effect against liver damage, compared with QT against paracetamol-induced hepatotoxicity. Sefsol and linoleic-acid-optimized SNEDDS formulation showed no symptoms associated with toxicity and offered a protective effect against paracetamol-induced hepatotoxicity . Potential utility of SNEDDS for formulating Zedoary turmeric oil (ZTO) extracted from rhizome of Curcuma zedoaria was demonstrated by improved aqueous dispersion activities, stability and oral bioavailability. The formulated ZTO-SNEDDS could serve as a partial lipid phase with double advantages of increasing drug loading as well as minimizing the amount of requirement of the inert oils . Shi et al. were prepared a multi-unit drug delivery system (MUDDS) for a Chinese medicine NiuhuangXingxiao Wan (NXW) to enhance the bioavailability and efficacy. NXW was formulated into four units, such as realgar, frankincense and myrrh oil (FMO), musk, and bezoar. The assay of in vivo antitumor activity shown that the efficacy of NXW-MUDDS was significantly higher than the NXW .
Incorporation of four prenylatedflavanones isolated from Eysenhardtiaplatycarpa leaves into nanoemulsion and poly lactic-co-glycolic acid (PLGA) NPs as anti-inflammatory agents for topical administration was investigated. Among four prenylatedflavanones, 5-hydroxy-7-methoxy-6-prenyl flavanone loaded nanoemulsion and polymeric nanoparticles could be proposed as potential topical anti-inflammatory formulations with the best properties for the treatment of inflammatory disorders . Oleanolic acid (OA) was efficiently encapsulated in methoxypoly(ethylenglycol) (mPEG) with poly (lactic acid) [mPEG-PLA] and mPEG-poly(lactic-co-glycolic acid) (PLGA) NPs as nanoformulations for cancer therapy. All OA-loaded NPs system produced significant cytotoxic effects through apoptosis on cancer cell lines . Polycaprolactone (PCL)/polyvinylpyrrolidone (PVP) nanofiber mat containing crude bark extract of Tecomella undulate were prepared and evaluated for their antibacterial properties. Extract loaded PCL/PVP nanofiber mat had inhibited the growth of bacterial strains which indicated that it could act in the treatment of wound healing or dermal bacterial infections . Centellaasiatica (CA) extract was successfully incorporated into electrospun membranes to improve wound healing in a rat model. The wound areas that were covered with electrospun gelatin membranes containing CA (EGC) membranes exhibited more collagen deposition and a higher number of capillaries than the wound areas to which the other treatments were applied. Hence EGC membranes can be used as a potential material for wound dressings .
Nanotechnology in nutraceuticals
Nanotechnology platforms are widely being used to create delivery systems for nutraceuticals and bioactive natural products with poor water solubility. Some of the extensively studied nutraceuticalnanomaterials are discussed here. Figure 2 depicts the potential applications of nanotechnology in nutraceuticals. Table 2 summarizes the potential applications of nutraceuticals formulated as nanomaterials.
|Functional food components||Delivery system/ Experimental model/Route||Major activities / Applications||Reference|
|Hydrophobins (Hyd)- Vitamin D3||Nanoencapsulation||Hyd found to be promising nanovehicle of hydrophobic nutraceutical for food beverage enrichment
Hyd provide excellent protection vitamin D3 against degradation
|Israeli-Lev et al. |
|Folic acid with whey protein and commercial resistant starch||Nanoencapsulation||Greater encapsulation efficiency
Improved folic acid stability
Increase bioactive stabilization
|Pérez-Masiá et al. |
|Pluronic-127 and poly-?-caprolacotne envelop nanocapsule through emulsification-diffusion method (EDM)||EDM is a promising method to prepare nanoparticle for food materials||Zambrano-Zaragoza et al. |
|Vitamin D3 entrapped with whey protein NPs with different calcium concentration||Encapsulation||Great stability of Vitamin D3
Can be used in clear and non-clear beverage as an enriching agent
|Abbasi et al. |
|Folic acid and calcium||Duel nutraceutical nanomaterial||To provide high content of essential nutrient in human health||Kim and Oh |
|β-carotene, folic acid, curcumin and ergocalciferol||Protein-polysaccharide soluble nanocomplex||To increase the antioxidant activity||Hosseini et al. |
|Carotenoids||Lipid nanocarriers||Great potential for clinical applications
New delivery system for lipophilic plant extracts
|Lacatusu et al. |
|CoQ10||Lipid free nanoformulation||Effective vehicle for improving oral bioavailability of CoQ10||Zhou et al. |
|Long chain fatty acids and CoQ10||Nanoemulsion||Nanoemulsion based delivery systems that increased oral bioavailability of lipophilic nutraceuticals||Cho et al. |
|Omega-3-fatty acids and oil soluble vitamins||Biopolymericnanogels||Encapsulate and protect bioactives
Used only food grade ingredient
Fabricated system improves the quality of food and beverages
|Matalanis et al.|
|Curcumin||Organogel based nanoemulsion||Digestion of nanoemulsion significantly fast and complete
Oral bioavailability of curcumin increased
Can be used in functional foods, dietary supplements and pharmaceutical industries
|Yu et al. |
|α-tocopherol||Supercritical assisted nanosuspension||Increases the dissolution rate
Increases the bioavailability
Increases the stability
|Campardelli et al. |
|(-)-epigalocatechin-3-gallate||Protein-polyphenol coassemblies:Lactoferrinbased NPs||LF-EGCG-nano and submicrometer particles can be used as protective vehicles for EGCG for control release of other bioactive materials
LF-EGCG have potential for the development of food formulation based on LF as a carrier of bioactive compounds
|Yang et al. |
|Clove oil and Eugenol||Oil titration–precipitation of COM and EM||Formulation in microemulsion provides a delivery system for oral administration of clove oil in homogenous, water based and thermodynamically stable dose||Al-Okbi et al. |
|Dextran and isoflavonegenistein||Enzymatic assisted inclusion complexation method||DMSO-water inclusion protocol has been found to be more suitable for the inclusion of genistein in the enzymatically dextran
Increased the yield of inclusion of nutraceuticals by 11 to 141 folds due to formation of new H-bonds and Vander walls interaction
|Semyonove et al. |
Table 2: List of nutraceuticals formulated as nanomaterials and their characteristics.
Hydrophobins (Hyd) used for nanoencapsulation of nutraceuticals for food enrichment is very much interesting they bid to hydrophobic materials like vitamin D3 (VD3). Hyd provided excellent protection to VD3 against degradation. Moreover, Hyd were found to be promising nanovehicles of hydrophobic nutraceuticals for food and beverages enrichment . Folic acid was encapsulated with two different matrices (whey protein concentrate (WPC) and a commercial resistant starch) and two different encapsulation techniques (spray drying and electro-spraying). Greater encapsulation efficiency was observed using WPC as encapsulating matrix. Electrospraying is a promising method in the food industry for encapsulation applications . Emulsification-diffusion method (EDM) is an excellent alternative to prepare nanocapsules from food constituents. Formation of nanocapsules with DL-α-tocopheryl acetate and β-carotene has confirmed the versatility and reproducibility of the EDM when batches with different materials are prepared under optimal conditions .
VD3 was entrapped in whey protein isolate (WPI) nanoparticles prepared with different calcium concentration. Composition of nanoparticles with calcium can perform a compact structure providing reduction of VD3 degradation during storage time. WPI nanoparticles containing VD3 can be used for enriching of clear or non clear drinks such as herbal beverages, fruit drinks or low fat food . Dual nutraceuticalnanohybrids consisting of folic acid (FA) and calcium were prepared based on layered double hydroxide (LDH) structure through exfoliation-reassembly hybridization method FA/LDH nanohybrids showed higher contents of essential nutrients in human health and they could be considered as dual nutraceuticalnanomaterials . Hosseiniet al.  were explored the potential application of the protein-polysaccharide soluble nanocomplexes as delivery systems for nutraceuticals in liquid foods. The complexation between β-lactoglobulin (BLG) and four nutraceutical models including β-carotene, folic acid, curcumin and ergocalciferol was investigated under different conditions and the low water soluble nutraceuticals were successfully entrapped within electrostatically stable nanocomplexes . Nanocarriers made with hempseed oil or a blend of amaranth and hempseed oils were investigated for a concomitant encapsulation and release of the carotenoids enriched plant extract. The nanocarriers have a great potential for clinical applications as a new delivery system for other lipophilic plant extracts enriched in bioactive compounds . A novel lipid-free nano-CoQ10 system formulated and stabilized by various surfactants and the bioavailability of CoQ10 was evaluated by oral administration of CoQ10 formulation in Sprague-Dawley rats. The formulation can be an effective vehicle for improving oral bioavailability of CoQ10, it was confirmed by the observation of significant increase in the maximum plasma concentration and the area under the plasma concentration time curve . The bioavailability of heptadecanoic acid and CoQ10 was investigated for the influence of droplet size and oil digestibility by a rat feeding study. The developed nanoemulsion based delivery system has increased oral bioavailability of lipophilic nutraceuticals . Food grade biopolymers, proteins and polysaccharides can be used to create a diverse range of delivery systems suitable for encapsulating, protecting and delivering lipophilic functional components such as omega 3-fatty acids, conjugated linoleic acid, oil-soluble vitamins, flavors, colorants and nutraceuticals . Novel organogel-based nanoemulsions were developed for oral delivery of curcumin and improvement of its bioavailability. In vitro lipolysis profiles revealed that the digestion of nanoemulsion was significantly faster and more complete than the organol. Organogel based nanoemulsion can be used for oral delivery of poorly soluble nutraceuticals with high loading capacity, which has significant impact in functional foods, dietary supplements and pharmaceutical industries .
Supercritical assisted injection in the liquid antisolvent process has been used for the production of α-tocopherol nanoparticles suspensions and produced NPs can be used as supplementation and as an antioxidant in food, cosmetics and pharmaceutical industries . The potential of native and thermally modified lactoferrin (LF) to form co-assembled vehicles for the delivey of (-)-Epigallocatechin-3-gallate (EGCG) was investigated by Yang et al. LF-EGCG nano and submicrometer particles could act as protective vehicles for EGCG and a beneficial aid for the development of controlled release of other bioactive materials . The effect of clove essential oil (CO) and its major constituents, eugenol, formulated in water-based microemulsion was studied on fatty liver and dyslipidemia in high-fractose-fed rats. CO and eugenolmicroemulsion (EM) produced significant improvement in fatty liver and dyslipidemia with consequent protection from cardiovascular disease and other complications of fatty liver . Two nutraceutical induction methods, DMSO dilution in water and acidification were used for enzymatically synthesis of dextran NPs to entrap hydrophobic nutraceutical, the isoflavonegenistein. The DMSO method was found to be more suitable for inclusion of genistein in dextran, resulted in a high genistein load and high percentage of nanosized particles .
Nanotechnology in drug delivery has been manifested into nanoformulations that can have unique properties both in vivo and in vitro, especially in targeted delivery. A few clinical studies have done to great effect in small animal models, but the translation of the small animal results to clinical successes has been limited . Successful translation requires revisiting the meaning of nanotechnology in drug delivery, understanding the limitations of nanoparticles, identifying the myth persistent in the field, and facing inconvenient facts. For this approach to be successful, it may require fine-tuning of the procedure to maximize the usefulness of the nanoparticle to the drug delivery system. Nanoparticle researchers need to realize is that clinical application of any formulation requires approval by the Food and Drug Administration (FDA) or its overseas equivalent. The safety and efficacy of new formulations must be proven through controlled clinical studies. Doxil® is the first FDA approved nanodrug in 1995 based on the three unrelated principles (i) prolonged drug circulation time and avoidance of the reticuloendothelial system due to the use of polyethylene glycolatednanoliposomes, (ii) high and stable remote loading of doxorubicin driven by a transmembrane ammonium sulfate gradient, which also allows for drug release at the tumor and (iii) having liposome lipid bilayer in a “liquid ordered” phase composed of the high temperature (53 ?C) phosphatidylcholine and cholesterol . Even though, large reward, nearly two years after Doxil-related patents expired, there is still no FDA-approved generic “Doxil” available. The complexity of FDA approval of generic Doxil, the current situation is even more complex. Accordingly turning the potential of nanoformulations into clinically useful requires clear setting and reasonable goals. The challenges in drug delivery using nanoformulations can be overcome through understanding the limitations of nanoformulation approaches by FDA regulations and maximizing the existing capabilities of nanoformulations.
Overall, this review indicates that nanotechnology has great potential for delivering herbal drugs and nutraceuticals, and in light of the comprehensive health problems, its utilization for effective disease prevention and health promotion is necessary and to be anticipated. Even though nanotechnology offers promising approaches in herbal drug delivery and nutraceutical applications, additional innovative research is needed to address the cost effective and long-term safety of the nanomaterials.