Nanotechnology Applied To Pharmaceutical Technology 


               Nanotechnology Applied To Pharmaceutical Technology


Pharmaceutical technology is based on the use of different technologies for the preparation and development of pharmaceutical products. It is a branch of the pharmaceutical sciences constantly linked to the development and use of innovative technologies for the production and development of products with maximum effectiveness, adequate dosage, and stable formulations, aiming at different appli-cations in living beings.
Nanotechnology is a recent, highly interdisciplinary and versatile branch of science that allows to develop products with interesting and novel structural characteristics totally different from those obtained by the compounds in their conventional form, a fact that attributes differentiated properties and specific interaction mechanisms, which adds technological value to the newly developed products. Thus, the use of nanotechnology in the pharmaceutical science promotes the design and development of products known as nanopharmaceuticals, which are composed of nanoscale properties with slow drug release systems, as stabilizers of formulations, pharmaceutical activities, or systems for detection and evaluation. The possibility of obtaining different mechanisms of response provided by the nanotechnologically developed products allows varied combinations enriching the range of products to be developed from this technology.
In this context, the book seeks to integrate the pharmaceutical sciences with nanotechnology as a way to obtain innovative products and solutions applied to the pharmacy. It provides the reader with a broad vision where nanotechnology is employed with different perspectives and applications. This approach focuses on the application of nanotechnology in pharmaceutical technology and also represents an interdisciplinary nature that can be used by people interested in expanding their knowledge in applied nanotechnology. The present book is highly interdisciplinary and would be very useful for a diverse group of readers including pharmacologists, nanotechnologists, microbi-ologists, biotechnologists, clinicians, and those, who are interested in development of nanoproducts. The students should find this book useful and reader-friendly.

Bioinspired Metal Nanoparticles with Special Reference to Mechanism

Abstract The interest in metallic nanoparticles and their synthesis has greatly increased over the past decades. Several physical and chemical methods for syn-thesis of nanoparticles have been developed. However, involvement of toxic chemicals, high-energy consumption, and costly equipments are the drawbacks to their wide use. Therefore, “green” approach for the synthesis of metallic nanoparticles by using plants and their extracts, algae, fungi, and bacteria, including actinomycetes as well as viruses and biomolecules, is promising way, which is quick, low-cost, and eco-friendly. The mechanism of synthesis of metal nanopar-ticles by living organisms has not been fully explained, to date. However, the bioreduction process with involvement of NADP-dependent nitrate reductase is considered as a main step. The physical (e.g., morphology, zeta potential) and chemical (composition of capping agents) properties of nanoparticles, which effect on their activity, can be controlled during biosynthesis process. There are several factors such as temperature, time, pH, and concentration of reagents used, which influence the biological synthesis of metallic nanoparticles, mainly the size and yield of synthesized nanoparticles.
Introduction

Nanoparticles (NPs) are those particles, which have two or more than two dimensions and are in the size range of 1–100 nm (Alanazi et al. 2010). Due to the increased demand for various metallic and nonmetallic nanoparticles over the past two decades, a wide range of physical and chemical techniques have been devel-oped to produce nanoparticles of different sizes, shapes, and compositions. Nanoparticles can be synthesized and stabilized via physical, chemical, and bio-logical techniques. The physical approach includes techniques such as laser abla-tion, lithography, and high-energy irradiation (Joerger et al. 2001), while the chemical methods use chemical reduction, electrochemistry, and photochemical reduction (Rajput 2015). Physical and chemical methods for synthesis of metal nanoparticles are often extremely expensive and non-environmentally friendly due to the use of toxic, flammable, and hazardous chemicals, which may pose potential environmental and biological risk and high-energy requirement (Awwad et al. 2013). Additional drawbacks of chemical and physical approaches to nanoparticle synthesis are low production rate, structural particle deformation, and inhibition of particle growth (Keat et al. 2015). Thus, one of the primary goals of nanotech-nology is to develop an eco-friendly production method that can provide nanoparticles with low toxicity. Because physical and chemical methods use high radiation or highly concentrated reductants and stabilizing agents that are harmful to environment and to human health, the researchers have turned to biological systems for inspiration of synthesis of metal nanoparticles, as these methods are rapid, cost-effective, and eco-friendly. Biosynthesis of metal nanoparticles mediated by living organisms such as bacteria, fungi, algae, plants or viruses and plant products such as their enzymes, proteins, or carbohydrates becomes an important field of nanotechnology (Iravani 2011, 2014). The green methods employ biological sys-tems to fabricate nanostructures, which have the benefit of improving the bio-compatibility of the nanomaterial (Xie et al. 2007). Prokaryotic and eukaryotic organisms are considered as excellent candidates to be used to synthesize metallic nanostructures by a purely enzymatic process (Ahmad et al. 2002). The important advantage of using biological methods is that newly formed nanostructures are stabilized by proteins, which act as capping agents and are also assumed to be responsible for the bioreduction metal ions to metal nanoparticles (Ahmad et al. 2002; Xie et al. 2007; Mukherjee et al. 2008). Such stabilization protects nanoparticles from aggregation and affects on their physical and chemical proper-ties (Gole et al. 2001). It is known that any synthesis process, including synthesis of metallic nanoparticles, depends on many physical and chemical factors such as pH, reagent concentrations, temperature, and time (Joerger et al. 2001; Quester et al. 2016). The reaction conditions effect on nanoparticle morphology (Gericke and Pinches, 2006). Therefore, it is necessary to control reaction parameters resulting in desired nanoparticles (Sanghi and Verma, 2010; Quester et al. 2016).
Mechanisms of biological synthesis of metal nanoparticles have not been fully explained. It is claimed that NADH-dependent nitrate reductase enzyme is an important factor in biogenic synthesis of metal nanoparticles. The proposed mech-anism is that bioreduction of metal ions (e.g., Ag+) is initiated by electron transfer from NADH by NADH-dependent reductase as electron carrier. The metal ions which receive electrons are reduced to metal (e.g., Ag0) and then to metal nanoparticles (e.g., AgNPs) (Duran et al. 2011; Duran and Seabra 2012). However, other non-enzymatic mechanisms are suggested to be involved in biogenic synthesis of metal nanoparticles where proteins, amino acids, and sugars play a major role in the reduction of metal ions (Mukherjee et al. 2001, 2008; Duran and Seabra 2012).
There is a long list of organisms (plants or plant extracts, micro- and macroalgae, fungi, yeasts, bacteria, and actinomycetes) that have been used to synthesize various metal nanoparticles such as silver, gold, platinum, lead, iron, titanium, cadmium (Bhau et al. 2015; Zahir et al. 2015; Kumar and Kathireswari, 2016; Ali et al. 2016; de Aragao et al. 2016; Quester et al. 2016;Składanowski et al. 2016; Wypij et al. 2017). However, synthesis of silver and gold nanoparticles has been mostly reported to date.
In this chapter, the use of prokaryotic (bacteria and actinomycetes) and eukaryotic (algae, fungi, yeast, and plants) organisms as well as viruses and biomolecules to the biosynthesis of metal NPs with special reference to mechanisms is presented.

Nano-antimicrobials: A Viable Approach to Tackle Multidrug-Resistant Pathogens

Escalating resistance to almost every class of antibiotics is reducing the utility of currently available antimicrobial drugs. A part of this menace is attributed to poor pharmacokinetics and pharmacodynamics of the drug. Improvement in drug delivery is the most challenging task encountered by the pharmaceutical industries; however, nanotechnology can bring a revolution in drug design and delivery. Nano-antimicrobials have their own intrinsic antimicrobial activity (nanoparticles) or augment overall efficacy of enclosed antibiotics (nano-carriers), thus contribute in mitigating or reversing the resistance phenomenon. Nanoparticles (NP) having their own intrinsic antimicrobial activity kill microbes by mimicking natural course of killing by phagocytic cells, i.e., by producing large quantity of reactive oxygen species (ROS) and reactive nitrogen species (RNS). It is believed that NPs kill microbes by simultaneously acting on many essential life processes or metabolic routes of microbes; that as many genetic mutations to develop resistance against them seems to be impossible. Nano-carriers improve the pharmacokinetics of the enclosed drug. Moreover, one of the major techniques by which NAMs can overcome resistance is targeted drug delivery to the site of disease. In this chapter, a comprehensive detail about the mechanism of action of NAMs is presented in context to multidrug-resistance phenomenon.

2.1 Introduction
Antibiotics have brought a revolution to the history of modern medicine and have played a fundamental role in ensuring safe surgical procedures, organ transplants, and chemotherapy (Fabbretti et al. 2011). Due to antibiotics, both the mortality and morbidity rates have significantly declined as the infectious diseases were always considered as the principal cause of death. However, antibiotic’s meteoric rise proved to be short lived, because of rapid emergence of resistance to almost every class of antibiotics. World Health Organization (WHO) has already declared an-tibiotic resistance among the three paramount threats to health. The theme of World Health Day, on April 7, 2011, was “antimicrobial resistance: no action today and no cure tomorrow” (Piddock 2012).
Antimicrobial resistance (AMR) is the ability of a microorganism (like bacteria, viruses, and some parasites) to stop an antimicrobial (such as antibiotics, antivirals, and antimalarials) from working against it. As a result, standard treatments become ineffective, infections persist and may spread to others (http://www.who.int/antimicrobial-resistance/en/). Such multidrug-resistant (MDR) microbes make the treatment more difficult, expensive, and with more side effects. All those diseases that were under control are causing difficulty in their treatment after the advent of MDR bacteria (Alanis 2005; Hajipour et al. 2012; Al-Assil et al. 2013). Because now the higher dose and potent antibiotics are needed to cure them.
The situation continues to be more alarming due to meager efforts put into develop new drugs (Wright 2012). Since 2000, almost 22 new antibiotics had been developed to overcome MDR phenomenon (Butler et al. 2013). Yet, antibiotic resistance still persists. The major contributors to this menace are increased diffi-culty in isolating novel antibiotics, prolonged development time, immense clinical trials cost, “merger mania” in the industry, and most importantly the emergence of resistance against newly developed compounds.
WHO has placed three pathogens in the newly revised list (2017) of critical priority pathogens. It includes carbapenem-resistant pathogens, i.e., Acinetobacter baumannii, Pseudomonas aeruginosa, and all other enterobacteriaceae that display resistance against carbapenems. WHO has urged the need to develop new antibi-otics against these three pathogens on priority basis (http://www.who.int/mediacentre/news/releases/2017/bacteria-antibiotics-needed/en/).
Almost a decade back, it was the resistance in Gram-positive microbes that was posing the threat. Nonetheless, with the implementation of control policies and through the development of new medicines, it is considered to be under good control now (Kumarasamy et al. 2010). However, though the situation against Gram-positive microbes has improved the same against Gram-negative has exacerbated to an extent that clinical microbiologists reached to the consensus that multidrug-resistant Gram-negative bacteria are the existent threat to public health. There are many whys and wherefores that can be attributed to this menace (Jamil 2014).
Gram-negative bacilli (GNB) include large number of clinically significant pathogens: including both enterobacteriaceae and non-fermenting GNB(P. aeruginosa, A. baumannii, and Stenotrophomonas maltophilia) (Ruppé et al. 2015). Only the enterobacteriaceae comprises of more than 70 genera, it constitutes normal flora of GIT and is the principal causative agents of gastrointestinal (GI) infections. Clinically, significant pathogens belonging to this family are Escherichia coli (E. coli), Klebsiella species, Salmonella, shigella, and Enterobacter species (Pickering 2004; Paterson 2006; Lupo et al. 2013). Enterobacteriaceae spread easily by hand carriage besides contaminated food and water. It has genetic plasticity that reveals tendency to acquire genetic material through horizontal gene transfer, mediated mostly by plasmids and transposons. This combination is why emerging multidrug resistance in enterobacteriaceae is of the utmost importance for clinical therapy (Paterson 2006).
It was considered to be causative agent of easily curable ailments; however, past several decades have observed the spread of enterobacteriaceae with resistance to broad-spectrum antimicrobials. Especially, the emergence of carbapenem-resistant enterobacteriaceae (CRE) has invalidated almost all the available therapies. It has created the havoc that once easily treatable infections like diarrhea may become untreatable or very difficult to be managed. KPC (Klebsiella pneumoniae carbapen-emase) and NDM (New Delhi metallo-beta-lactamase) are the recently discovered types of CRE. KPC and NDM are the enzymes that break down carbapenems and make them ineffective (Talukdar et al. 2013; Bologa et al. 2013; Jamil 2014).
It is evident that enterobacteriaceae has developed resistance against Carbapenem, which is considered to be the drug of last resort. Second reason why resistance in enterobacteriaceae is considered to be more notorious is that the rate of spread of resistance; being very fast in Gram-negative than the same in Gram-positive bacteria, the resistance genes in enterobacteriaceae are found on mobile genetic elements that can readily disseminate resistance through horizontal gene transfer to unrelated bacterial populations (Wellington etal. 2013). Moreover, unprecedented human air travel is also considered to be a cause of dissemination of resistance between countries and continents. Thirdly, there is currently no new antibiotic in the developmental pipeline that can specifically target Gram-negative microbes though many against Gram-positive are in the way (Butler et al. 2013).
The aim of this chapter was to discuss the various resistance mechanisms in bacteria and how they can be addressed to prevent the development of further resistance enzymes and dissemination of resistance phenomenon.
2.2 Multidrug-Resistance Prevalence
Multidrug-resistant phenomenon is displaying an escalating trend and represents a great challenge to the health care system. The situation is particularly more drastic for “ESKAPE” pathogens including Enterococcus spp., Staphylococcus aureus, Klebsiella spp., A. baumannii, P. aeruginosa, and Enterobacter spp. A few of these pathogens like A. baumannii has already become pan-resistant (Lewis 2013). Exact data on MDR prevalence is not available from many countries, particularly from developing countries. Nonetheless, few studies have reported more than 80%prevalence of ESBL positive E. coli (Nahid et al. 2013; Shakya et al. 2017), whereas 32.5% prevalence of bla NDM-1 was observed in K. pneumoniae by Dadashi et al. (2017).




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