Formulations, Advancements and Challenges in Nanotechnology for Pharmaceuticals

Introduction

The study of extremely small structures having dimensions ranging between 1 to 100nm (nano scale), and diﬀerent scientific as well as engineering processes associated with them is combinedly defined as nanotechnology(Yousaf & Salamat, 2011). In general, the processes in nanotechnology deals with treatment of individual atoms, molecules and compounds in order to develop structures that are further used for producing materials and devices with special properties(Chaudhary & Singh, 2017). The fabrication processes in nanotechnology primarily employ two approaches – top-down approach that involves reducing the size of large structures to smaller ones, and bottom-up approach that involves changing individual atoms and molecules into nanostructures, referred to as self-assembly. Most of the techniques in fabrication of nano materials have been borrowed from the field of microfabrication. Developments in the field of nanotechnology and its wide range of applications in diﬀerent areas, right from the basic sciences to the engineering products has revolutionized scientific progress. This paper attempts to briefly describe some of the advancements made in the domain of pharmaceuticals by leveraging nanotechnology, and limits the scope in giving an overview of diﬀerent types of pharmaceutical nanosystems that are products engineered at nano scale, which in their own rights or in combination with other systems bring about therapeutic benefits and medicinal value. These nanosystems have brought profound changes in drug delivery systems, therapy techniques, diagnostic techniques, anti-microbial techniques and cell repair finding their uses in the fields ranging from ophthamology, oncology, tissue engineering to gene therapy. Due to their unique properties and widespread usage, a separate section is dedicated to give a glimpse of some of the most popular nanosystems. A broader perspective of the applications of nanotechnology in pharmaceuticals is also presented, concluding the paper with some of the major challenges faced in this spectrum.

Pharmaceutical Nanosystems

Pharmaceutical nanosystems form the base for diﬀerent smart drug delivery, therapeutic, and diagnostic processes and techniques. The nanoparticles used in pharmaceuticals have unique properties that challenges conventional chemicals and methods, and makes them extremely suitable for achieving high precision in targeted treatments with the additional benefit of minimizing side eﬀects. Some of the characteristics of these nanosystems are resistant to settling, higher saturation solubility, rapid dissolution and enhanced adhesion to biological surfaces (Masareddy, Sutar, & Yellanki, 2011). These makes them the most suitable candidates for rendering rapid therapeutic action and increases their bioavailability. The main advantages that these nanosystems have over conventional systems in the domain of pharmaceuticals are

Get Help With Your Essay

If you need assistance with writing your essay, our professional essay writing service is here to help!

Essay Writing Service

- improved eﬃcacy, reduced toxicity, enhanced bio distribution and improved patient compliance. These nanosystems can be classified into two main categories of nanotools-nanomaterials and nanodevices. Nanomaterials can be further categorized on the basis of three basic parameters including structure, dimension, and phase composition(Mir et al., 2017), as shown in Figure 1, presenting a schematic diagram of various types of pharmaceutical nanosystems. The pharmaceutical industry is increasingly focusing on developing these nanosystems as developing new medicines and chemicals are more time consuming as well as expensive. The nanosystems can be used in conjunction with the currently available medicines for delivering them to their sites of action with additional advantages of overcoming the problems associated with the current mechanisms such as high toxicity, poor bioavailability, instability in biological environments and low therapeutic action at the site of action. Some of the popular nanosystems applied to drug delivery and therapy along with their properties and uses are discussed next.

Polymeric Nanoparticles

Polymeric nanoparticles are very small colloidal particles and exist in the form of nanosphere or nanocapsule. Polymer nanoparticles are formed by two strategies, top-up and bottom-up processes. Size of nanoparticles is about 10 to 500 nm (Semete,

Kalombo, Katata, & Swai, 2010) as shown in Figure 2. These nanoparticles are used in drug delivery systems because of their biocompatible and non-toxic nature, and have found wide usage in treatment of tumor and cancer(Van Vlerken & Amiji, 2006).

Liposomes

Liposomes are spherical vesicles that are 50 to 200nm in size and are composed of amphiphilic phospholipids and cholesterols shown in Figure 3. It is biocompatible and has good entrapment eﬃciency. These properties allow them to be used for long circulatory and active delivery of gene and peptides. It is the first nanomaterial, which was applied to drug delivery(Semete et al., 2010).

Dendrimers

Dendrimers are nanoparticles which has size less than 10 nm with tree like structure as shown in Figure 4. It consists of three diﬀerent units – closely packed surface, branching unit and core moiety. It has application in many fields like Photodynamic therapy, Boron neutron capture therapy, and potent anticancer agent(Gillies & Frechet, 2005; Menjoge, Kannan, & Tomalia, 2010).

Polymeric Micelles

It is formed by amphiphilic block copolymer of size less than 100 nm (Figure 5). Its amphiphilic nature, increases the drug solubility in water which leads to increase in the bioavailability of the drug in the human body.

Polymer Drug Conjugate

Polymer drug conjugates (Figure 6) are formed by covalent bond between water soluble polymers and bioactive molecules, which enhances the solubility and bioavailability of drugs. Polymer drug conjugate also protect drugs from premature degradation(Alley, Okeley, & Senter, 2010).

Carbon Nanotubes

These are hexagonal networks of carbon atoms as shown in Figure 5, having a length and diameter of 1nm and 1-100nm, respectively. Nanotubes are categorized into single walled nanotubes (SWNTS) and multi walled nanotubes (MWNTS). It has been used to enhance solubility of drug and target delivery system.

Quantum Dots

Quantum dots (QDs) have sparked great interest among medical scientists because of their unique advantages over traditional fluorescent dyes, such as broad excitation spectra, narrow and symmetric photoluminescence bands, large two-photon absorption cross-section, size-tunable absorption and photoluminescence spectra, exceptional photo stability, high quantum yield, and versatility in surface modification(Valizadeh et al., 2012).

In the next section, popular applications of nanotechnology in pharmaceuticals at a broader level is discussed

Application of Nanotechnology in Pharmaceuticals

Drug delivery

Currently, nanomedicine is influenced by drug delivery systems, accounting for more than 75 percent of the total sales(Wagner, Dullaart, Bock, & Zweck, 2006). As discussed in the earlier section, due to the unique properties of the nanoparticles they are widely used in the process of delivering drugs, heat, light and many other diﬀerent substances to targeted cells such as cancer cells in order to combat against diseases.

Apart from delivering the drug they have also increased a drug’s half-life by reducing immunogenicity, improved bioavailability, diminished drug metabolism and enabled a more controllable release of therapeutic compounds and the delivery of two or more drugs simultaneously for combination therapy(Sanvicens & Marco, 2008). They have been widely used in the fields of Ophthamology, Pulmonology and Oncology for delivering drugs related to chemotherapy, influenza, arterial clots and many more. They

have also found uses in delivering vaccines, delivering drugs to damaged brain tissues, releasing insulin and destroying virus molecules. The contributions of nanonparticle carriers in these areas are briefly discussed next.

• Ophthalmology – Many novel controlled drug delivery systems have emergedincluding hydrogels, muco-adhesive polymers, micro-emulsions, dendrimers, iontophoretic drug delivery, siRNA-based approaches, stem cells technology, non-viral gene therapy, and laser therapy with scleral plugs (Patel, Cholkar, Agrahari, & Mitra, 2013). Diﬀerent systems for drug delivery are costumed for the delivery of the drug through the ocular route. The chief goal of all the drug delivery systems is to improve the residence period, enhance the corneal permeability, and liberate the drug at the posterior chamber of the eye, leading to increased bioavailability and improved patient compliance (Puglia et al., 2015).

• Pulmonology -Previous reports have shown that chronic obstructive pulmonarydisease (COPD) and lung carcinoma are the primary diseases that are responsible for the majority of the deathMir et al. (2017). There has been an increase in use of nanoparticles in the therapy of these diseases(Weber, Zimmer, & Pardeike, 2014). Delivery of curative agents to the place of action for lung diseases may result in eﬀective treatment of chronic lung infections, lung cancers, tuberculosis, and other respiratory pathology(Yang, Peters, & Williams III, 2008). The nanocarriers used for this purpose include liposomes, lipid- or polymer based micelles, dendrimers, and polymeric NPs(Smola, Vandamme, & Sokolowski, 2008). Generally used nanocarriers in pulmonary drug delivery contain natural polymers such as gelatin, chitosan, and alginate and synthetic polymers like poloxamer, PLGA, and PEG(Sung, Pulliam, & Edwards, 2007).

• Oncology– Out of all the uses of nanoparticles in the area of drug delivery, it hasbeen most widely used in the treatment of cancer. Chemotherapeutic is a widely used treatment of cancer which prevents cancer cells from dividing and growing, however chemotherapy also kill normal cells and create toxic side eﬀect. To

overcome this side eﬀect, a huge interest has been shown in developing nanoscale

delivery carriers that can be targeted directly to the cancer cell, deliver the drug at

a controlled rate, and optimize the therapeutic eﬃcacy (Mishra, Patel, & Tiwari,

2010). Nanoparticles (NPs) can be conjugated with various smart therapeutic

carriers like polymeric nanoparticles(Cao, Deng, Su, & He, 2016), micelles(Xie et

al., 2016), liposomes(Eloy et al., 2016), solid lipid nanoparticles (SLNs)(ud Din et

al., 2017), protein nanoparticles(Lee et al., 2017), viral nanoparticles(Le, Lee,

Shukla, Commandeur, & Steinmetz, 2017), metallic nanoparticles(Volsi et al.,

2016), dendrimers(Wang et al., 2016), and monoclonal antibody (Gray et al.,

2016) to improve their eﬃcacy and decrease the systemic toxicity.

Tissue engineering

Tissue engineering is an emerging field and is also playing very important role in pharmaceutical and medicines, which is focusing on biological substitutes to restore, replace, maintain or enhance tissue and organ function(Khademhosseini, Vacanti, & Langer, 2009). Over the past few years, continued progress in this field has led to the creation of implantable tissues, some of which are already used in humans (e.g. skin and cartilage) or have entered clinical trials (e.g. bladder and blood vessels)(Kheirabadi et al., 2019). Nanotechnologies and microtechnologies can be merged with biomaterials to generate scaﬀolds for tissue engineering that can maintain and regulate cell behavior (Shi, Votruba, Farokhzad, & Langer, 2010). In the arena of tissue engineering nanotechnology has found its uses in tissue repair and replacement, implant coatings, tissue regeneration scaﬀolds, structural implant materials, bone repair, bioresorbable materials, implantable devices, surgical aids, operating tools, and smart instruments.

Gene therapy

Polymeric nanoparticles and liposomes of size less than 100 nm is playing important role in gene therapy. Polymeric nanoparticle could treat breast cancer using gene therapy. Kupﬀer cell of liver could easily be incorporated with liposomes treated with polyethylene glycol and galalctose. Therefore, enabling diﬀerent types of liver

disorder like Wilson’s disease and hereditary hemochromatosis to be treated with help of gene therapy using them(Faraji & Wipf, 2009).

Challenges

Nanotechnology has been widely applied in the field of pharmaceuticals, but with many drawbacks that has posed several challenges to the scientific community. Toxicity of nanoparticles has attracted the most vital criticism because of their peculiar characteristics such as size, size distribution, surface charge and properties, expanded surface area, self-assembly, and stability(Pourmand & Abdollahi, 2012). These exceptional properties influence the nanoparticles’ ADME(Koopaei & Abdollahi, 2016) (Adsorption, Distribution, Metabolism, and Excretion) properties like cellular uptake, distribution within the body fluids, and transport through biological barriers. For example, because of the small molecular size of the nanoparticles, they are able to cross

Future direction and conclusion

Applications of nanotechnology in pharmaceuticals are wide and oﬀers innovative tools, opportunities and scope that can impact areas such as drug delivery, diagnosis of diseases, and therapy. Despite its eﬀectiveness, the industry is facing many challenges in order to fully use the potential of nanoscale materials and systems as already discussed. But as the conventional techniques become outdated due to changing factors in the industry, nanotechnology will play the most crucial role in propelling the drug and pharmaceutical industry. Although, it has already started showing its impact, yet it is just in its infancy. There is a need to address the diﬀerent shortcomings of nanotechnology as pointed out in the challenges section. Some of the ways to do so would be to come up with better protocols for testing toxicity, monitoring the level of exposure, assessing the impact of these materials on the environment, and take steps to make them more and more bio-compatible. Diﬀerent measures to develop guidelines for safe use and manufacturing of these systems should be done in parallel to the great work that the scientists and engineers are already doing across the world. Apart from the direct applications, these nanoscale materials can also be used for understanding the

diﬀerences between normal and abnormal cells and study various phenomena of diseases occurring at the molecular level. Nanotechnology is certainly one of the most important tools that humanity has and we are well poised to bring more revolutions in the near future, by using it.

FIGURES

Figure 1 . Schematic diagram of various types of pharmaceutical nanosystems

Figure 8 . Polymeric nanoparticles

Figure 3 . Structure of Liposome

Figure 4 . Structure of Dendrimers

Figure 5 . Carbon nanotubes

Figure 6 . Quantum dots

Figure 7 . Polymeric Micelles

Figure 8 . Polymeric Drug Conjugate

References

Alley, S. C., Okeley, N. M., & Senter, P. D. (2010). Antibody–drug conjugates: targeted drug delivery for cancer. Current opinion in chemical biology, 14 (4), 529–537.

Cao, J., Deng, X., Su, T., & He, B. (2016). Fabrication of polymeric nanoparticles for cancer therapy and intracellular tracing. Nanomedicine: Nanotechnology, Biology, and Medicine, 2 (12), 459.

Chaudhary, A., & Singh, A. (2017). Synthesis, characterization, and evaluation of antimicrobial and antifertility eﬃcacy of heterobimetallic complexes of copper (ii). Journal of Chemistry, 2017 .

Eloy, J. O., Petrilli, R., Topan, J. F., Antonio, H. M. R., Barcellos, J. P. A., Chesca, D. L., . . . Marchetti, J. M. (2016). Co-loaded paclitaxel/rapamycin liposomes: development, characterization and in vitro and in vivo evaluation for breast cancer therapy. Colloids and Surfaces B: Biointerfaces, 141 , 74–82.

Faraji, A. H., & Wipf, P. (2009). Nanoparticles in cellular drug delivery. Bioorganic & medicinal chemistry, 17 (8), 2950–2962.

Gillies, E. R., & Frechet, J. M. (2005). Dendrimers and dendritic polymers in drug delivery. Drug discovery today, 10 (1), 35–43.

Gray, M. J., Gong, J., Nguyen, V., Schuler-Hatch, M., Hughes, C., Hutchins, J., & Freimark, B. (2016). Abstract b27: targeting of phosphatidylserine by monoclonal antibody ch1n11 enhances the antitumor activity of immune checkpoint inhibitor pd-1/pd-l1 therapy in orthotopic murine breast cancer models. AACR.

Khademhosseini, A., Vacanti, J. P., & Langer, R. (2009). Progress in tissue engineering. Scientific American, 300 (5), 64–71.

Kheirabadi, M., Samadi, M., Asadian, E., Zhou, Y., Dong, C., Zhang, J., & Moshfegh, Z. (2019). Well-designed ag/zno/3d graphene structure for dye removal: Adsorption, photocatalysis and physical separation capabilities. Journal of Colloid and Interface Science, 537 , 66 – 78. Retrieved fromhttp://www.sciencedirect.com/science/article/pii/S0021979718312992 doi: https://doi.org/10.1016/j.jcis.2018.10.102

Koopaei, N. N., & Abdollahi, M. (2016). Opportunities and obstacles to the development of nanopharmaceuticals for human use. BioMed Central.

Le, D. H., Lee, K. L., Shukla, S., Commandeur, U., & Steinmetz, N. F. (2017). Potato virus x, a filamentous plant viral nanoparticle for doxorubicin delivery in cancer therapy. Nanoscale, 9 (6), 2348–2357.

Lee, J.-j., Kang, J. A., Ryu, Y., Han, S.-S., Nam, Y. R., Rho, J. K., . . . Kim, H.-S. (2017). Genetically engineered and self-assembled oncolytic protein nanoparticles for targeted cancer therapy. Biomaterials, 120 , 22–31.

Masareddy, R., Sutar, R., & Yellanki, S. (2011). Nano drug delivery systems-a review. International Journal of Pharmaceutical Sciences and Research, 2 (2), 203.

Menjoge, A. R., Kannan, R. M., & Tomalia, D. A. (2010). Dendrimer-based drug and imaging conjugates: design considerations for nanomedical applications. Drug discovery today, 15 (5-6), 171–185.

Mir, M., Ishtiaq, S., Rabia, S., Khatoon, M., Zeb, A., Khan, G. M., . . . ud Din, F. (2017). Nanotechnology: from in vivo imaging system to controlled drug delivery. Nanoscale research letters, 12 (1), 500.

Mishra, B., Patel, B. B., & Tiwari, S. (2010). Colloidal nanocarriers: a review on formulation technology, types and applications toward targeted drug delivery. Nanomedicine: Nanotechnology, biology and medicine, 6 (1), 9–24.

Patel, A., Cholkar, K., Agrahari, V., & Mitra, A. K. (2013). Ocular drug delivery systems: an overview. World journal of pharmacology, 2 (2), 47.

Pourmand, A., & Abdollahi, M. (2012). Current opinion on nanotoxicology. BioMed Central.

Puglia, C., Oﬀerta, A., Carbone, C., Bonina, F., Pignatello, R., & Puglisi, G. (2015). Lipid nanocarriers (lnc) and their applications in ocular drug delivery. Current medicinal chemistry, 22 (13), 1589–1602.

Sanvicens, N., & Marco, M. P. (2008). Multifunctional nanoparticles–properties and prospects for their use in human medicine. Trends in biotechnology, 26 (8), 425–433.

Semete, B., Kalombo, L., Katata, L., & Swai, H. (2010). Nano-drug delivery systems: Advances in tb, hiv and malaria treatment. Smart Biomol. Med, 15–52.

Shi, J., Votruba, A. R., Farokhzad, O. C., & Langer, R. (2010). Nanotechnology in drug delivery and tissue engineering: from discovery to applications. Nano letters, 10 (9), 3223–3230.

Smola, M., Vandamme, T., & Sokolowski, A. (2008). Nanocarriers as pulmonary drug delivery systems to treat and to diagnose respiratory and non respiratory diseases. International journal of nanomedicine, 3 (1), 1.

Sung, J. C., Pulliam, B. L., & Edwards, D. A. (2007). Nanoparticles for drug delivery to the lungs. Trends in biotechnology, 25 (12), 563–570.

ud Din, F., Kim, D. W., Choi, J. Y., Thapa, R. K., Mustapha, O., Kim, D. S., . . .others (2017). Irinotecan-loaded double-reversible thermogel with improved antitumor eﬃcacy without initial burst eﬀect and toxicity for intramuscular administration. Acta biomaterialia, 54 , 239–248.

Valizadeh, A., Mikaeili, H., Samiei, M., Farkhani, S. M., Zarghami, N., Akbarzadeh, A, others (2012). Quantum dots: synthesis, bioapplications, and toxicity.

Nanoscale research letters, 7 (1), 480.

Van Vlerken, L. E., & Amiji, M. M. (2006). Multi-functional polymeric nanoparticles for tumour-targeted drug delivery. Expert opinion on drug delivery, 3 (2), 205–216.

Volsi, A. L., de Aberasturi, D. J., Henriksen-Lacey, M., Giammona, G., Licciardi, M., & Liz-Marzán, L. M. (2016). Inulin coated plasmonic gold nanoparticles as a tumor-selective tool for cancer therapy. Journal of Materials Chemistry B, 4 (6), 1150–1155.

Wagner, V., Dullaart, A., Bock, A.-K., & Zweck, A. (2006). The emerging nanomedicine landscape. Nature biotechnology, 24 (10), 1211.

Wang, X., Wang, H., Wang, Y., Yu, X., Zhang, S., Zhang, Q., & Cheng, Y. (2016). A facile strategy to prepare dendrimer-stabilized gold nanorods with sub-10-nm size for eﬃcient photothermal cancer therapy. Scientific reports, 6 , 22764.

Weber, S., Zimmer, A., & Pardeike, J. (2014). Solid lipid nanoparticles (sln) and

nanostructured lipid carriers (nlc) for pulmonary application: a review of the state of the art. European Journal of Pharmaceutics and Biopharmaceutics, 86 (1), 7–22.

Xie, J., Zhang, X., Teng, M., Yu, B., Yang, S., Lee, R. J., & Teng, L. (2016). Synthesis, characterization, and evaluation of mpeg–sn38 and mpeg–pla–sn38 micelles for cancer therapy. International journal of nanomedicine, 11 , 1677.

Yang, W., Peters, J. I., & Williams III, R. O. (2008). Inhaled nanoparticles—a current review. International journal of pharmaceutics, 356 (1-2), 239–247.

Yousaf, S., & Salamat, A. (2011). Eﬀect of heating environment on fluorine doped tin oxide (f: Sno/sub 2/) thin films for solar cell applications. In Proceedings of the international conference on power generation systems technologies.

Figure 2 . Polymeric Nanoparticles