Herbal Drug Nanoparticles: Advancements in Herbal Treatment

 

Rinku Y. Patil^1*, Shubhangi A. Patil², Niranjan D. Chivate³, Yogesh N. Patil⁴

 

ABSTRACT:

Herbal medicines have been used all over the world from last many years. Especially in India, there is wide market for herbals. Herbal medicines have less adverse effects as compared with modern medicines. The delivery of plant/herbal therapeutic molecules as drugs is problematic due to poor solubility, poor permeability, low bioavailability, instability in biological milieu and extensive first pass metabolism. These limitations of herbal drugs can be overcome by attaching or encapsulating them with suitable nanomaterials. Over the past decade, major advances have been made on development of novel drug delivery systems (NDDS) from plant actives and extracts. By developing new formulation as nano herbal medicines like nanoparticles, dendrimers, Nano crystals, Quantum dots, Nanosperes, Nanocapsules, herbal market get good feedback. The new approach in herbals as nanotechnology have a sound future which has a scientific approach to deliver the component in sustained manner which increase the patient compliance and avoid repeated administration. So many conditions like bacterial infection, hepatotoxicity, inflammation, oxidation and chronic diseases like cancer, wound healing can be cured by nano herbals more effectively as compared to allopathic medicines. The next most important step for herbal formulations is their standardization which establishes consistent biological activity, consistent chemical profile or simply a quality assurance program. This review will provide information of the use of nanotechnology for herbal drugs, nanoparticles, formulation techniques of nanoparticles and their standardization.

 

 

 

INTRODUCTION:

From last many years, herbal remedies and natural products are being used to cure the diseases. Unlike widely used allopathic system, the herbal remedies have thousands of constituents that all work simultaneously against the diseases. The activity of herbal medicines depends on overall function of a variety of active components, as all the constituents provide synergistic action and thus enhance the therapeutic value. Each active constituent plays an important role and they are all related to each other.¹

 

Incorporation of herbal drugs in the delivery system also helps to increase in solubility, enhanced stability, protection from toxicity, enhanced pharmacological activity, improved tissue macrophage distribution, sustained delivery and protection from physical and chemical degradation.²

 

Most of the herbal actives are poorly water soluble because of their hydrophobic nature. This property results decreased bioavailability and increased systemic clearance thus necessitating repeated administration or increased dose, and thus limits the clinical use of herbal medicines. Therefore, nanoparticles can be utilized to increase the herbal drug solubility and help to localize the drug in a specific site thus resulting in better efficacy and improved patient compliance.³

 

Due to some limitations of herbal extracts/plant actives like instability in highly acidic pH, liver metabolism etc. leads to drug levels below therapeutic concentration in the blood resulting in less or no therapeutic effect.⁴ Among the novel drug delivery systems, nanoparticles are considered to be an important one. Nanoparticle can be used to reach the herbal drug to individual organ which improves the selectivity, drug delivery, effectiveness and safety and thereby reduces dose and increases patient compliance. The requirement of an ideal nanoparticulate system is that it should be capable of circulating in blood stream and should be small enough to reach target cells and tissues. Herbal medicines can be targeted to various organs such as brain, lung, liver, kidney, gastrointestinal tract, etc.⁵

 

The world market for product using nanotechnology is estimated to reach US$ 1trillion by 2015. In 2006 India and Australian government contributes to start Australia-India Science Research Funding Program. The market value of the worldwide Nanomedicine industry was $63.8 billion and $72.8 billion in 2010-2011 respectively. The market is estimated to grow up to $130.9 billion by fiscal year 2016.⁶

 

Evaluation of herbal preparation is a fundamental requirement of industry and other organization dealing with ayurvedic and herbal products. Standardization is an important step for the establishment of a consistent biological activity, a consistent chemical profile, or simply a quality assurance program for production and manufacturing of an herbal drug⁷

 

Nanotechnology for Herbal drugs:

 

Figure 1: Herbal Nanoparticle

 

Before reaching to the blood, many constituents of the herbal drugs will be smashed in the highly acidic pH of the stomach and other constituents are metabolized by the liver. It results; the optimum quantity of the herbal drugs may not reach the blood. If the drug does not reach in the optimum amount to the infected region at “minimum effective level,” then there will be no means to show the therapeutic effect of the drug. Nanocarriers applying to herbal remedies will carry optimum amount of the drug to their site of action bypassing all the barriers such as acidic pH of stomach, liver metabolism and increase the prolonged circulation of the drug into the blood due to their small size.⁸

 

Herbal remedies were selected for delivery through a nano delivery system because of the following properties:

 

1.       Effective chloroform, petrol, acetone, and methanolic extracts are available which may not be suitable for delivery as such.

2.       These are the bulk drugs so dose reduction is intended.

3.       Currently marketed formulations lack target specificity for various chronic diseases.

4.       Some other side effects are associated with currently marketed formulations.

5.       Patient non-compliance due to large doses and less effectiveness with the available formulations.⁹

 

Advantages of herbal nanoparticle delivery system

1.       Shows EPR (enhanced permeation and retention) effect i.e. enhanced permeation through the barriers because of the small size and retention due to poor lymphatic drainage such in tumor.⁹

2.       Exhibits passive targeting to the disease site of action without the addition of any particular ligand moiety. ⁹

3.       Decrease in the side effects.⁹ 

4.       Decrease in the dose of the drug formulation.⁹

5.       Nanoparticulate system delivers the herbal formulation directly to the site of action. ¹⁰

6.       Increased efficacy and therapeutic index. ¹⁰

7.        Increased stability via encapsulation. ¹⁰

8.       Improved pharmacokinetic effect. ¹⁰

 

Types of nano pharmaceuticals

·         Polymeric nanoparticles.¹

·         Solid lipid nanoparticles.¹

·         Magnetic nanoparticles.¹

^·          Metal and inorganic nanoparticles.¹

·         Polymeric micelles.¹

·         Phospholipids micelles.¹

·         Colloidal nano-liposomes.¹

·         Dendrimers.¹

^·          Nano crystals.¹

·      Quantum dots.⁸

·         Nanospere.¹¹

·         Nanocapsule.¹¹

 

 

Techniques which are used for the preparation of above nanopharmaceuticals:

1.       Complex coacervation method:

This is a spontaneous phase separation process of two liquid phases in colloidal systems, which results due to the interaction of two oppositely charged polyelectrolytes upon mixing in an aqueous solution. It mainly includes three steps-

1      Formation of three immiscible chemical phases.

2      Depositing the liquid polymer coating upon the core material.

3      Rigidizing the coating.^{8, 12, 13}

 

2.       Co-precipitation method:

This method is a modification of the complex coacervation method for the preparation of nano scale core-shell particles. This method has been reported to provide good dispersion stability to poorly water-soluble drugs.^{8, 12, 14}

 

 

Figure 1: Co-precipitation method

 

3.       Salting-out method:

This method is based on the solubility of a non-electrolyte in water is decreased upon addition of an electrolyte. Acetone is selected as water miscible solvent because of its solublizing properties and its well known separation from aqueous solution by salting out method with electrolytes. The diffusion of acetone from the droplets is the most imp step. This diffusion which takes place on dilution with excess water, can generate interfacial turbulence leading to polymer aggregation in the form of nanoparticles.^{8, 12, 14}

 

4      Nanoprecipitation method or solvent displacement method:

As biodegradable nanoparticles meet with increasing interest for drug delivery applications, a series of investigations were carried out to understand the mechanism of the formation of drug loaded nanoparticles using the solvent displacement method. This method is based on interfacial deposition of a polymer after displacement of a semipolar solvent miscible with water from a lipophilic solution, thereby resulting in a decrease in the interfacial tension between the two phases, which increases the surface area with a subsequent formation of small droplets of organic solvent even without any mechanical stirring.^{8, 12, 15}

 

5.       Solvent emulsification–diffusion method:

The method involves preparation of an o/w emulsion using oil phase containing polymer like PLGA and oil in an organic solvent which is emulsified with the aqueous phase containing stabilizer in high shear mixer followed by addition of water to induce the diffusion of organic solvent, thus resulting in formation of nanoparticles.^{8, 12,16}

 

Figure 2: solvent emulsification solvent diffusion method

 

6.       Supercritical fluid methods:

A supercritical fluid (SCFs) can either be a liquid or gas and used above its thermodynamic critical point of temperature and pressure. The most commonly used SCFs are carbon dioxide. Particles that have the smooth surfaces, small particle size and distribution and free flowing can be obtained with particular SCF techniques. Rapid Expansion of Supercritical Solutions (RESS), Supercritical Anti Solvent (SAS) and Particles from Gas Saturated Solutions (PGSS) are three groups of processes which lead to the production of fine and monodisperse powder.^{8, 12, 17}

 

7.       High-pressure homogenization method:

In this method, the lipid is pushed with high pressure (100 to 2000 bar) through a very high shear stress, which results in disruption of particles down to the submicrometer or nanometer range. High-pressure homogenization method is a very reliable and powerful technique for the large scale production of nano structured lipid carriers, lipid drug conjugate, SLNs, and parenteral emulsions.^{8, 12}

 

8.       Self-assembly methods:

Self-assembly is the physical process wherein pre-existing disordered components, atoms, or molecules organize themselves into regulated nanoscale structures by physical or chemical reactions without any contribution from any external source.^8,12

 

9.       Emulsion-Solvent Evaporation Method:

Emulsification-solvent evaporation involves two steps. The first step requires emulsification of the polymer solution into an aqueous phase. During the second step polymer solvent is evaporated, inducing polymer precipitation as nanospheres. The nano particles are collected by ultracentrifugation and washed with distilled water to remove stabilizer residue or any free drug and lyophilized for storage. Modification of this method is known as high pressure emulsification and solvent evaporation method. This method involves preparation of a emulsion which is then subjected to homogenization under high pressure followed by overall stirring to remove organic solvent. The size can be controlled by adjusting the stirring rate, type and amount of dispersing agent, viscosity of organic and aqueous phases and temperature. However this method can be applied to liposoluble drugs and limitation are imposed by the scale up issue. Polymers used in this method are PLA, PLGA, Poly (caprolactone)\ (PCL), Poly (β- hydroxybutyrate) (PHB) . ¹⁸

 

10.    Double Emulsion and Evaporation Method:

The emulsion and evaporation method have limitation of poor entrapment of hydrophilic drugs .Therefore to encapsulate hydrophilic drug the double emulsion technique is employed, which involves the addition of aqueous drug solutions to organic polymer solution under vigorous stirring to form w/o emulsions. This w/o emulsion is added into second aqueous phase with continuous stirring to form the w/o/w emulsion. The emulsion then subjected to solvent removal by evaporation and nano particles can be isolated by centrifugation at high speed. The formed nanoparticles must be thoroughly washed before lyophilisation (Vandervoort et al., 2002).In this method the amount of hydrophilic drug to be incorporated, the concentration of stabilizer used, the polymer concentration, the volume of aqueous phase are the variables that affect the characterization of nano particles (Ubrich et al., 2004).¹⁸

 

Advanced techniques for identification and characterization of nano herbal medicine:

1. High performance Liquid chromatography (HPLC):

Preparative and analytical HPLC are widely used in pharmaceutical industry for isolating and purification of herbal compounds.^{19, 20} Vasicine, the major bioactive alkaloid of Adhatoda vasica, was estimated by HPLC in two polyherbal drug formulations - Shereeshadi Kashaya and Yastyadivati, and its content was found to be 18.1 mg/100 g in Shereeshadi Kashaya and 0.7 mg/100g in Yastyadivati.²¹ Standardization of the Triphala (an antioxidant-rich herbal formulation) mixture of Emblica officinalis, Terminalia chebula and Terminalia belerica in equal proportions has been reported by HPLC method by using the RP18 column with an acidic mobile phase.²²The combination of HPLC and LC/MS is currently the most powerful technique for the quality control of herbal medicine like licorice.²³

 

2. High performance thin layer chromatography (HPTLC):

HPTLC is used for qualitative and quantitative phytochemical analysis of herbal drugs and formulations. Also with the help of HPTLC several samples can be analysed simultaneously using a small quantity of mobile phase. Gallic acid, rutin and quercetin these are important active constituents of Terminalia chebula were estimated by HPTLC method.²⁴  HPTLC technique was used for simultaneous determination of two  biomarkers  present  in Ashwagandha like Withaferin A and β sitosterol d-glucoside.²⁵ Glycoside (Jamboline), Tannin, Ellagic Acid and Gallic Acid are present in mother tincture of Syzygium Jambolanum was quantitatively evaluated in terms of stability, repeatability, accuracy and calibration by HPTLC.²⁶

 

The HPTLC method gives accurate, faster and cost effective quantitative control for the analysis of diosgenin .²⁷

 

3. UPLC:

Ultra performance liquid chromatography (UPLC) was used to evaluate decocting-induced chemical transformations and chemical consistency between traditional and dispensing granule decoctions.^{28, 29}

 

4. Liquid chromatography-Mass spectroscopy (LC-MS):

LC-MS has become method of choice in many stages of drug development.³⁰

LC-MS analysis of Amino glycosides showed that these drugs are highly soluble in water, exhibited low plasma protein binding, and were more than 90% excreted through the kidney. Further this technique helps in analysis of amino glycosides in plasma samples with ion pairing chromatography.³¹The pharmacokinetic studies of Chinese medicinal herbs using LC-MS.

 

5. Gas chromatography - mass spectroscopy (GC-MS):

It is the system used for identification of large number of components present in natural and biological systems.³² The identification and quantification of chemical constituents present in polyherbal oil formulation (Megni) consisting of nine ingredients, mainly Myristica fragrans, Eucalyptus globulus, Gaultheria procumbens and Mentha piperita was analyzed by GC-MS method.³³ Thirty-five volatile compounds were separated and identified.³⁴

6. Capillary Electrophoresis:

The methodology of CE was established to evaluate one herbal drug in terms of specificity, sensitivity and precision.³⁵ Several CE studies dealing with herbal medicines have been reported and two kinds of medicinal compounds i.e. alkaloids ³⁶ and flavonoids ³⁷ have been studied extensively. Furthermore, the analysis time of the CE method was two times shorter than that in HPLC and solvent consumption was more than 100 fold less.³⁸ The hyphenated CE instruments, such as CE-diode array detection, CE-MS and CE-NMR, have been utilized.³⁹ Some Herbal Drug Nanoparticles with their method of preparation and application presented in Table1.

 

 

Table 1: herbal drug nanoparticles

Sr. No.	Formulations	Active ingredients	Biological activity	Method of preparation	Benefit of formulation	References
1.	Berberine-loaded nanoparticles	Berberine	Anti-neoplastic activity	Ionic gelation method.	H.pylori growth inhibition	2,40
2.	Curcuminoids solid lipid nanoparticles	Curcuminoids	Antitumor, antioxidant, antiamylodin, antiplatelet aggregation and anti-inflammatory, antimalarial.	Micro-emulsion technique.	-increase in activity -Enhanced stability of curcuminoids	40,
3.	Artemisinin nanocapsules	Artemisinin	Anticancer	Self assembly procedure.	- achieving prolonged drug release through self-assembly of polyelectroytes on natural drug crystals. - controlled release	9,40,
4.	Nanoparticles of cuscuta chinensis	Flavonoids and lignans	-Hepatoprotective and antioxidant effects -Used to improve sexual function, prevent senescence and regulate the immune system. Some studies showed anticancer, antiageing and immune-stimulatory effects.46-50	Nanosuspension method.	Enhanced solubility	41
5.	Quercetin Nanoparticles-	Quercetin	antioxidant, anti-proliferative, antitumor, antibacterial	nano participation technique	- improve the bioavailability	42

 

Standardization of nano herbal medicine:

 

 

CONCLUSION:

India can emerge as the major country and play the lead role in production of standardized, therapeutically effective ayurvedic formulation. Preparation of standardized ayurvedic medicine can be achieved only if the herbal products are evaluated and analyzed using sophisticated modern techniques of standardization such as TLC, HPLC, HPTLC, LC-MS, GC-MS, Capillary Electrophoresis and other methods. The advancement of analytical techniques will serve as a rapid and specific tool in the herbal research; it helps manufacturers to set quality standards and specifications and it results increase therapeutic efficacy, safety and shelf- life of herbal drugs. Moreover, all herbal products manufacturers must follow WHO guidelines for quality control.

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Received on 04.08.2017            Modified on 24.08.2017

Accepted on 13.09.2017         © RJPT All right reserved