NOVEL DRUG DELIVERY SYSTEMS

Conventional dosage forms and delivery systems present several challenges in treatment of diseases like poor bioavailability, high dose, frequent administration, systemic adverse effects, etc. Also, increasing prevalence of chronic diseases, high demand for non-invasive administration of drugs, need for high bioavailability and targeted delivery of drugs for lesser side effects have paved the way for innovation in drug delivery systems. Therefore, pharmaceutical companies are focused on designing novel drug delivery systems to overcome the limitations of using conventional dosage forms. For this reason, novel drug delivery systems might be among the fastest expanding segments in the drug industry.

Use of nanotechnology has further enhanced the importance of continuous improvisation and introduction of new delivery systems for administering active agents. Novel Drug Delivery Systems (NDDS) have played a crucial role in establishing nanomedicine over the conventional dosage forms. Therapies of several terminal diseases like cancer and immunodeficiency diseases where controlled and targeted therapy is required with minimum side effects. For these, smart nanocarrier-based systems have been used for better therapeutic action at the target site. Increased cost and timelines for developing new molecules has shifted the interests of the researchers to modify the routes of administration and drug delivering devices of existing molecules for better pharmacokinetic and therapeutic parameters. Industries are working majorly on advancements in administering drugs through patient friendly techniques including programmable, implanted devices, smartphone based solutions, lab-on-a-chip or microofluidic technology. All these techniques have increased the market share so much so that for the transdermal delivery systems alone, the market value is projected to have a Compound Annual Growth Rate (CAGR) of 4.3 per cent during 2020-2027. Presently amid the COVID-19 crisis, the global market for NDDS is projected to reach a market value of US$27.2 Billion by 2027 from US$7.7 Billion in the year 2020, growing at a CAGR of 19.7 per cent over the period 2020-2027. The industry for preparing nanoparticles, the key in the delivery systems, is projected to record 19 per cent CAGR and reach US$23.2 Billion in the coming years. This review focuses on the important NDDS that are extensively worked upon and account for a major share in the market today.

Nanocarriers

Nanocarriers have been actively used in developing drug delivery systems to overcome the limitations of conventional systems. These are designed and programmed to acquire unique physical properties and functions to protect the drug from degradation inside the body, to selectively deliver it to the target area and to minimise systemic exposure and metabolism. These consist of an inert carrier, drug molecule and the conjugated targeting moiety. The controlled release of entrapped drug molecules allows maximum and accurate cellular uptake thereby having minimum side effects that is a prerequisite in the therapy of several diseases like cancer. Nanocarriers generally comprise lipid systems (liposomes, micelles), Carbon Nanotubes (CNTs), metallic nanocarriers (iron oxide/gold nanoparticles), polymeric nanoparticles and dendrimers. Apart from the pharmaceutical industry, food technology including nutraceuticals and cosmetic industry are the major market holders for the nanocarrier based NDDS. Table comprises the various industrial applications of nanocarriers.

Microfluidics mediated NDDS

Microfluidics technology has gained enormous popularity by manipulating liquids in the microscale channels. Attributed to its precise drug delivery with flow control along with the use of minute quantities of samples, microfluidic systems have made targeted and controlled delivery possible in difficult areas like eye and brain. Drug delivery systems mediated through microfluidics are proving to be next generation delivery devices that could be designed to achieve maximum results using minimum active ingredients. They have been used in a wide range of applications like point-of-care testing, isolation, detection and analysis of biomolecules, etc.

The ability of microfluidics to undertake almost all the functions of the conventional methods is resulting in its expansion in the healthcare industry. In addition to this, technological advancements, increasing focus on data precision & accuracy, fast returns on investment, and faster testing & improved portability through microfluidic chip miniaturisation are contributing to the growth of the microfluidics industry. The global microfluidics market is growing at a CAGR of 22.9 per cent and its worth is projected to reach three times in the next five years. Several factors are responsible for the rising demand of microfluidics in the healthcare sector like technological advancements, increasing point-of-care testing, increasing portability through miniature lab-on-a-chip technology, emergence of microfluidics based organ-on-a chip, 3D cell culture and increasing focus on precise data collection. These systems can simulate the microenvironments and are used as drug delivery systems with desired physicochemical characteristics. The drug molecule can be immobilised to the microfluidic chip to reach the target site. Also a microfluidic system can be utilised to encapsulate multiple drugs in the same droplet. Khan et al. encapsulated ketoprofen and ranitidine HCl into a core-shell microparticle. Xi et al. developed another simple and economical method for encapsulation of two anticancer drugs using the fuidic nanoprecipitation system and PLGA polymer. Extensive research work is going in the field of production and targeting of nanoparticles to different organs of the body like transdermal, brain, ocular, etc. through microfluidic technology.

Martins et al. loaded efavirenz to a transferrin functionalised Poly (lacticco- glycolic) Acid (PLGA) nanoparticle complex, for targeting the BBB and treating HIV neuropathology. The use of microfluidics produced smaller particles, higher drug loading and association efficiency. Samaridou et al. designed RNA-loaded cationic nanocomplexes for nasal delivery to the brain. Modifying the microfluidic conditions enabled the rapid development of a scalable nanosystem with a uniform size and high association efficiency. Wang et al has presented a microfluidic system for transdermal delivery of very minute nanolitres volumes of drug solution in brief time pulses for neurological studies. Similarly, several studies have been done which use the microfluidic devices for drug delivery by forming nanoscale droplets or particles of the polymer and drug solution. They allow high throughput screening by using microwell arrays and multiplexed systems which is an important aspect for industrial application as industries encounter large numbers of parallel assays and samples. Microfluidics industry is flourishing as it uses minimum samples and has a wide range of applications in the bioengineering sector.

NDDS for gene therapy

The global market for gene therapy is estimated to grow to US$13.0 billion by 2024 from US$3.8 billion in 2019, at a CAGR of 27.8 per cent. This much growth is majorly driven by the high number of cancer and other target diseases, and the increasing funding for gene therapy research. Currently, microRNA (miRNA) and synthetic small interfering RNA (siRNA) loaded NPs have been greatly used in advancing target reach and therapeutic efficacy in several incurable diseases. They have shown a high therapeutic potential for gene therapy for a range of diseases, including genetic disorders, cancer, viral infections and autoimmune diseases. Attributed to the technological advancements in genebased therapeutics, an increasing number of approved gene therapies as well as an expanding pipeline is expected. In this process, miRNA or siRNA can target any gene in the cell and then silences the targeted gene¹. Various types of conjugated systems of drug and siRNA are employed to efficiently target the desired cellular structure. The gene delivery systems use viral or non-viral type vectors that show the desired cell specificity and are able to deliver an optimised amount of transgene expression to obtain the therapeutic effect. Sava et al loaded siRNA to chitosan nanoparticles to tone down the gene expression in Huntington’s disease through nasal administration. This system was designed to efficiently enter the brain and protect from degradation. Xia et al. conjugated selenium nanoparticles with siRNA for better therapeutic efficacy in hepatocellular carcinoma. Higher transfection efficiency, increased cytotoxicity to carcinoma cells and greater gene silencing ability was achieved. Mu et al developed the lipid-polymer hybrid nanoparticles for siRNA delivery to perform gene silencing in target cells. Extensive studies have been reported for siRNA delivery majorly for cancer treatment. Gene therapy is looked upon as a hope to combat the most difficult diseases like cancer, Alzhiemer, HIV, etc. and has the potential to be developed as a novel method and system for desired gene silencing.

¹https://pubs.rsc.org/en/content/articlelanding/2016/tb/c6tb01462c#!divAbstract

Guided delivery systems

Development of less-invasive or noninvasive routes for the systemic delivery of drugs, including subcutaneous, buccal, oral, inhalational, transdermal and nasal routes have always been a field of research and development. Global Non-Invasive Drug Delivery Devices Market is projected to a significant CAGR of 23.13 per cent during the period 2019-2025. Along with these conventional modes, different techniques have been innovated for targeted deliveries of the drug molecules through some guided medium. Diagnostic imaging agents including radio, ultra-sound and conventional magnetic contrast agents are engineered to deliver drugs as well as capture images of diseased organs. Novel therapeutic methods have emerged that use the guidance from outside to concentrate the drug molecules to the target tissues alongwith the real time imaging. This approach has been extensively studied to treat deadly diseases like tumours. These types of guided systems have better reach to the target site and can efficiently deliver the drug moiety even through the barriers. Therapeutics crossing the blood brain barrier has always been a focus of research in studying neuropathological ailments. Various approaches have been studied for non-invasive guided delivery to the brain. Nose to brain delivery is one such approach in which the nanocarriers are programmed to enter the brain via nasal administration.

Hasan et al have used weak electric currents to guide the liposomes through skin surface to improve the penetration of the encapsulated drug which otherwise had limited penetration due to the skin barrier.Nanoparticles conjugated with the ligands that could be detected in real time using fluorescent moieties can give the idea of the distribution of the drug. Nagaraju et al studied ligandbased drug delivery using nanoparticles in gastric cancer treatment. Another interesting NDDS guided externally is the Ultrasound (US)-triggered drug release. Major challenge in cancer chemotherapy is to enhance the amount of chemotherapeutic agents in the target tissues. Patrucco et al. used the US to stimulate the release of liposomal nanomedicine that is further monitored by using Magnetic Resonance Imaging (MRI). This type of technique generally needs co-administration of microbubbles  with the ultrasound and resonates with the US frequency to pave the way for the drug release at the target site through formation of cavities. Tomitaka et al. have explored a new area of guided delivery. They engineered nanoparticles having iron oxide cores and plasmonic  shells with gold branches. Strong magnetic and near-infrared stimulated nanocomplex systems gave image-guided drug delivery with a controllable drug release capacity.

Conclusion

Novel drug delivery systems have always been the area of research interests. With new technological advancements, research-industry collaborations, introduction of new therapeutic platforms and emergence of diseases, it becomes inevitable to upgrade the commercial scale up ability. Therefore, the market is expanding and would account for a major share in the healthcare sector in the coming years. Nanotechnology has given a breakthrough in efficiently delivering the drug at the target site. Several types of nanocarrier systems for drug delivery have been explored that possess desired physicochemical properties and have been used for the treatment of several ailments. Apart from protecting the drug from the inside environment and degradation after administration, they are developed for controlled release at the target site. Microfluidics mediated NDDS have a major role to play in increasing high throughput screening in research and using minute volumes of samples hence, are majorly used in industrial scale. Challenges of using this technology are its complexity and high cost of development. For better reach to difficult targets like crossing blood brain barriers, external stimuli guided NDDS has made its niche in the industry. Also, treating the diseases right from their emergence i.e. the genes that control them has opened the way to use gene therapy extensively. There is still much research to perform in all these areas to overcome their limitations and establish the aims of NDDS i.e. maximum therapeutic effect with minimum toxicity.

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