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234 Herbal Pharmacopeia
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11

Nanoparticle Synthesis and Characterization for Herbal Drug Delivery

Kashmala Khalid
Department of Plant Sciences, Quaid- i- Azam University, Islamabad, Pakistan
Muhammad Abdullah Aziz
Institute of Soil and Environmental Sciences, Pir Mehr Ali Shah Arid Agriculture University, Rawalpindi, Pakistan
Sana Saleem
Department of Microbiology, Quaid- i- Azam University, Islamabad, Pakistan
Arshad Farid
Gomal Center of Biochemistry and Biotechnology, Gomal University, D.I. Khan, Pakistan
Fati Ullah Khan and Haza Sehrish Kiani
Department of Biochemistry, Quaid- i- Azam University, Islamabad, Pakistan

11.1 INTRODUCTIONS

Recently, there has been signicant focus on the construction of a novel drug delivery system (NDDS) specically designed for herbal medications. Traditional dosage forms, such as those with a prolonged release, are unable to meet the needs of the body for both retaining the drug component at a specic rate during the course of treatment and delivering the phytoconstituents to the intended target site for the best possible therapeutic effect (Aminu et al., 2020). Prior to reaching the bloodstream, numer­ous phytochemicals present in herbal medications undergo decomposition when they pass through the very acidic pH of the stomach and are acted upon by liver enzymes. Therefore, the optimal quantity of herbal medications may not reach the bloodstream. For the drug to have the desired effect, it must reach the affected region in the optimal amount necessary to produce a therapeutic impact. If it fails to do so, it will not be powerful enough (Jain, 2020). Nanoparticles employed in herbal medicines unequivocally possess the capability to transport an optimal quantity of the medication to the targeted area of effect, thereby bypassing obstacles such as, for instance, the acidic pH of the stomach, liver processing, and increased systemic drug circulation, which is due to their diminutive size (Devi et al.,
2010). Phytoformulation research focuses on creating small- sized forms of herbal drugs, such as poly­meric nanoparticles, liposomes, phytosomes, nanocapsules, solid lipid nanoparticles, nanoemulsions,
238
Nanoparticle Synthesis and Characterization for Herbal Drug Delivery 239
and many others. These various forms offer several benets, including the increased solubility and bioavailability of the drugs, improved pharmacological activity, protection against toxicity, enhanced stability, better distribution in body tissues, sustained release, and safeguarding against chemical as well as physical degradation (Amol & Pratibha, 2014). Therefore, these studies show that the nano- sized nanodelivery systems of herbal therapeutics possess promising prospects for augmenting the efcacy and surmounting challenges linked to plant- based medications (Devi et al., 2010).

11.2 BACKGROUND AND LITERATURE REVIEW

11.2.1 Historical overview and Present trends in Herbal Medicine

Treatment for human illness has always relied on natural resources like plants. The primary idea behind the evolution of contemporary medicine can be linked to conventional therapies and medicine. Since prehistoric times, plants have been utilized for medical purposes in several regions of the world, includ­ing Africa, ancient China, America, Egypt, and India, (Darji et al., 2022). Plants produce a diverse array of bioactive compounds from various components. These include, among others, latex, stems, leaves, bark, seeds, roots, and owers. These substances, which are known as secondary metabolites, play a crucial role in the defense mechanism of plants against bacteria, insects, and herbivores. Plants con­tain various bioactive substances, such as avonoids, terpenoids, saponins, steroids, alkaloids, cardiac glycosides, tannins, phenolic compounds, and others (Sendker & Sheridan, 2017). Even today, herbal remedies and natural products remain essential for treating various illnesses. Contrary to the commonly used allopathic method, herbal treatments contain several phytochemicals that act collectively in com­bating ailments (Afzal et al., 2022). The availability of chemical analysis emerged in the early 19th century, marking the commencement of the extraction and alteration of herbal extracts. Herbal medica­tions were formerly disregarded for creating new formulations because of insufcient scientic valida­tion and challenges in processing, extracting, standardizing, and identifying the different components of these complex mixtures (Darji et al., 2022). Due to their possible therapeutic efcacy and reduced side effects when compared to other medications, herbal medicines have gained recognition from both doctors and patients. In addition, they boost the medicine's bioavailability (Sendker & Sheridan, 2017).

11.2.2 overview of nanoParticles in drug delivery

Conventional drug dosage forms often struggle to deliver the intended dose to specic areas of the body due to the tendency of drugs to disperse throughout the body based on their biochemical as well as physicochemical properties (Jain, 2020). The novel drug delivery system (NDDS) for herbal medicines is designed to address this issue by focusing on targeted drug delivery, which can reduce the frequency of dosage and elimination while also improving solubility and absorption (Dongare et al., 2021). Among them, nanoparticles (NPs), that is, those with a diameter of 10–100nm, play an essential role in which they are recognized as the versatile nanoscale drug delivery system to modulate pharmacodynamic and pharmacokinetic properties for the distribution of both small molecules and large molecules (Hsu et al.,
2023). The initial observation of nanoparticles revealed that they were composed of non- biodegradable polymers (polymethyl- methacrylate, polyacrylamide, and polystyrene). These polymeric nanoparticles demonstrate the ability to load drugs and proteins, allowing bioactive substances to be incorporated within the polymer matrix through chemical or physical attachment to the particle surface (Idrees et al., 2020). Enzyme activity and nanoparticle solubilization in the blood vessels within the target tissue is proven to be helpful in raising the retention and stability of the drug. During nanoparticle design, it is essential to carefully consider surface properties and dimensions as well as release patterns in order to establish the accurate interaction, rate, and dosage with the specic locations in the body (Chenthamara et al., 2019).

11.2.3 advantages of nanoParticle- based drug delivery systeMs

Some of the benets associated with nanoparticles are their site- targeting properties, biodegrad­ability, and non- toxicity with a shelf life of at least one year (Afzal et al., 2022). Magnetic guidance
240 Herbal Pharmacopeia
or attachment of specic ligands on particle surfaces can help in targeting a medicine to some particular location within the body. A nano- sized delivery system was chosen based on its ability to target disease sites effectively. They are nano- sized, so they have a high loading efciency and, therefore, offer the advantage of delivering a high concentration of drugs at the targeted site. It pro­vides controllable drug release rates and customizable particle degradation behavior by selecting specic matrix components (Chakraborty et al., 2016). This is due to the ability of the nano- scaled drug delivery system to release drugs in a controlled manner and has a tendency of maintaining drug concentration at the disease sites for longer durations. They also manifest the EPR effect – increased permeation and retention –, meaning they can easily permeate barriers due to their small size and are retained in the body due to limited the drainage of lymphatic uid, especially in the case of cancer. Since the particle size and surface properties of the nanoparticles can be personalized, it can easily reach passive and active pharmaceutical sites after injection. This enables the introduction of drugs into the systems without any chemical reaction due to high loading of medication, which is essential in the safe operation of drugs. Moreover, nanoparticles are used for passive targeting of diseases, and there is no need to attach specic ligands to drugs and, therefore, causing less harm and requir­ing lower drug formulation concentrations (Afzal et al., 2022).
11.3 TYPES OF NANOPARTICLES EMPLOYED IN THE DELIVERY
OF HERBAL DRUGS

11.3.1 PolyMer nanoParticle

Polymer nanoparticles are solid colloidal particles that vary between 10 and 1000 nm in size. The most commonly physical systems of polymer nanoparticles are called nanospheres and nanocap­sules (Chakraborty et al., 2016). These can be made either directly from monomers through polym­erization or from preformed polymers (Afzal et al., 2022). A variety of techniques are employed, including dialysis, supercritical uid evaporation, solvent evaporation, salting out, and quick super­critical solution expansion. Several factors, such as, for instance, the type of polymeric system, the intended application area, and the desired size specications, determine the selection of the preparation method (Chakraborty et al., 2016). These techniques have proven successful in creating polymeric nanoparticles with demonstrated effective medicinal properties.

11.3.2 Metallic nanoParticles

Metal nanoparticles, which typically measure between 1 and 100 nm in length, width, and thick­ness, are commonly produced using liquid phase techniques – for instance, chemical reduction, reversed micelle methods as well as sol gel. These nanoparticles are prized for their large surface area, their unique electronic properties which bridge molecular and metallic states, and the presence of multiple low coordination sites. They have diverse applications, including magnetic separation for isolating labeled cells, along with other biological entities, gene and drug delivery, as well as in radio frequency techniques for hyperthermia- based tumor breakdown and as contrast enhancement agents in magnetic resonance imaging (Chakraborty et al., 2016).

11.3.3 Magnetic nanoParticles

Various compositions and phases of magnetic nanoparticles have been synthesized, for instance, pure metals such as iron, copper, and nickel as well as alloys of metals, such as iron platinum and copper platinum (Chakraborty et al., 2016). Magnetic nanoparticles can be utilized in producing particles as small as 3 nm in size. Magnetic nanoparticles (MNPs) have found a signicant application in bio­separation. By modifying MNPs with specic receptors and linking them to target biomolecules,
Nanoparticle Synthesis and Characterization for Herbal Drug Delivery 241
complexes are formed. The aforementioned complexes can be separated out from the original mix­ture via magnetic eld application. Thus, this approach proves to be an efcient one when compared with approaches such as ltration as well as centrifugation (Chakraborty et al., 2016).

11.3.4 liPosoMes

These are tiny sacs that are spherical in nature and have size ranges from 0.05 to 5.0 μm in diameter and they are observed to be formed when the polar lipids undergo self- organization and become hydrated in aqueous media (Nalla & Chinnala, 2017). Such colloidal particles have the ability to encapsulate a solvent portion and allow it to move freely in its central sac (Afzal et al., 2022). The absolute benets of liposomes include their chemical stability as they have ability to encapsulate various compounds, such as hydrophilic, amphiphilic, and lipophilic ones. It is also easy for them to be prepared and exhibit higher compatibility. In addition, it is easy to alter liposomes’ pharmacoki­netic properties through changing its chemical composition (Tiwari et al., 2020).

11.3.5 dendriMers

These kinds of nanomaterials are considered to be highly branched and exhibit unique features – for instance, small size, large surface area, high biocompatibility, lower side effects, and the ability to encapsulate a larger drug quantity in its core, as well as being non- toxic, allowing for sustained and controlled release and being biodegradable. Their functionalization can be enhanced when it is com­bined with targeting agents – for instance, antibodies or peptides – which could lead to increased specicity of dendrimers for specic regions in the body (Tiwari et al., 2020).

11.3.6 niosoMes

Multilamellar vesicles, also known as niosomes, are formed by the combination of cholesterol and nonionic surfactants from the alkyl or dialkylpolyglycerol ether class. Previous research suggests that niosomes, like liposomes, have the potential to act as effective drug carriers. Niosomes offer several advantages over liposomes, including their relatively low cost, chemically stable against oxidation and temperature, longer shelf life, better skin penetration, as well as higher encapsulation efciency, (Nalla & Chinnala, 2017).

11.3.7 ProniosoMes

The proniosome gel system represents a progression from niosomes and offers a versatile approach to delivering actives to specic locations. Proniosomal gels are formulations that, upon hydration with skin water, transform into niosomes. Proniosomes, which are carrier particles soluble in water and coated with surfactant, can be hydrated to form a niosomal dispersion before use by agitating them briey in hot water (Nalla & Chinnala, 2017) (Figure 11.1).

11.3.8 PHytosoMes

Flavonoids, the main bioactive components of phytomedicines, have low oral bioavailability. Phytosomes are molecular complexes formed from water- soluble phytoconstituent molecules, primarily polyphenols, and are lipid- compatible (Nalla & Chinnala, 2017). Due to their ability to navigate through lipid- rich biomembranes and reach their source, phytosomes have higher bioavail­ability compared to simple herbal extracts. These complexes are prepared by encapsulating phy­toconstituents in soy- derived phospholipids phosphatidyl choline to make them lipid- compatible (Tiwari et al., 2020).
242 Herbal Pharmacopeia
FIGURE 11.1 Types of nanoparticles employed in herbal drug delivery.

11.3.9 transfersoMes

Transfersomes can be described as vesicles of remarkable design capable of transformation of speed at breakneck speed, and within a relatively affordable process, when exposed to stress on the out­side. The advancement of efcient strategies like transfersomes has reasonably reduced problems found in transdermal drug delivery systems like the stratum corneum barrier, the transport of large molecules and the attributes of physical and chemical of drugs that hinder their transport through the skin. In addition to their suitability for larger molecules, these adjustable vesicles can pass through skin pores much smaller than the size of the vesicles. Transfersomes have the ability to penetrate the skin’s initial barrier, also known as the stratum corneum, to deliver nutrition that is vital in carrying out skin functions, thereby supporting skin health (Nalla & Chinnala, 2017).

11.3.10 MicrosPHeres

Microspheres are dened as small spherical beads which have a diameter of between 1μ and 50 μ. At the moment, there is an extensive uninterrupted study on these particles mainly regarding their ef­ciency in targeting a certain area in the body, and retaining the medication in that particular region without provoking adverse effects (Tiwari et al., 2020). Of the technologies relevant to this eld, microencapsulation is known to greatly prolong the effectiveness of the administered drugs and increase patient compliance with the prescribed medication. Currently, microspheres are being used to encapsulate various bioactive substances extracted from plants such as zedoary oil, camptothecin, tetrandrine, quericin, Cynara scolymus extract, and rutin (Nalla & Chinnala, 2017).
Nanoparticle Synthesis and Characterization for Herbal Drug Delivery 243

11.3.11 etHosoMes

Ethosomal patches are the most recent innovation in the eld of patches. These reagents are pre­pared from soya phosphatidylcholine, ethanol and water, and incorporate multilamellar vesicles that are capable of capturing particles with variable lipophilic properties. Ethosomes’ encapsulation efciency and deformability improve drug penetration into the skin because of their ability to get deeper into the skin layers. The ethosomes possess characteristics pertaining to physical and chemi­cal prole that enable enhanced diffusion across the skin layers and bloodstream; thus, ethosomes can play a key role in applications in transdermal delivery systems and for topical drug carriers (Tiwari et al., 2020). Ethosomes can accommodate hydrophilic as well lipophilic drugs and can deliver these drugs into the cells efciently. This property increases the percutaneous penetration of other enterprises such as matrine, which is an herbal anti- inammatory drug and also increases the penetration of antibacterial peptides into brocytes (Nalla & Chinnala, 2017).

11.4 NANOPARTICLE SYNTHESIS TECHNIQUES

The preparation techniques used have considerable inuence on the shape, size, architecture and efciency of the nanoparticles. Additionally, the electrical, optical physiochemical, and electro­chemical properties of the nanoparticles are also inuenced. In some cases, the aim of coating of nanoparticles is to maintain their properties while they form a sediment in the suspension solution. Two conventional methods exist for creating nanoparticles, namely the top- down and bottom- up approaches (Kumari et al., 2023).

11.4.1 toP-down aPProacH

The top- down approach is a technique that fragments big molecules into smaller pieces before turn­ing them into the appropriate nanoparticles. This technique has been used to create carbon, dichal­cogenides, iron oxide, and also cobalt (III) oxide nanoparticles. Some of the common methods used to achieve synthesis using a top- down strategy include thermal decomposition, mechanical milling, nanolithography, and laser ablation (Kumari et al., 2023). The production of nanoparticles can also be achieved by adopting other strategies as physical, chemical, or biological means.

11.4.2 bottoM-uP aPProacH

The process entails the systematic production of nanoparticles from basic raw materials. It is fea­sible, inexpensive, less toxic, and environmentally benecial. Examples of the bottom- up approach, according to this denition, include laser pyrolysis, sol- gel processing, chemical vapor deposition and so on (Kumari et al., 2023).
Typically, there are four major methods (chemical, physical, biological and mechanical) employed for synthesizing nanoparticles, which are discussed below:

11.4.3 cHeMical MetHods

The synthesis of nanoparticles often involves the use of various chemical techniques – for instance, the microemulsion technique, hydrothermal synthesis, the sol- gel method, polyol synthesis, chemi­cal vapor synthesis and also plasma- enhanced chemical vapor deposition (Dhand et al., 2015).
11.4.3.1 Sol- Gel Method
The sol- gel method is the most popular bottom- up method because it is easy to use and can make a variety of nanoparticles (Ealia & Saravanakumar, 2017). The precursor materials are uniformly mixed in a solvent to create a gel, which is then heated to generate the desired nanoparticles. Therst