In the quest of delivering therapeutic agents with improved efficacy and minimum side effect, novel drug delivery system (NDDS) has created paradigm shift in pharmaceutical market. The thrust behind development of NDDS has increased owing to its manifold advantages such as safety, high efficacy, improved pharmacokinetics, decreased dosing frequency, minimization side effect on account of targeting capability to specific site, patient compliance and its economical aspect; the most important perspective for pharmaceutical companies.
NDDS based generic products can be developed only in three to four years with an investment of $20-50 million with high rate of market return in contrast to $800 million for development of new drug molecule by investing huge time period of 10-12 years and still having higher probability of failure in clinical trials.
The burgeoning interest in NDDS has increased due to advancement and availability of variety of technology to deliver conventional drug in novel dosage form. The novel drug delivery system includes various nanocarriers based drug delivery system such as liposome, niosome, micelles, nanoemulsions, nanoparticles, dendrimers etc. and administration technologies resulting in site specific delivery. These delivery systems make it possible to administer drugs through routes which were not explored earlier such as spray systems for nose-to-brain delivery, microneedles for transdermal drug and vaccine delivery, depot systems for intramuscular administration, aerosolized systems for pulmonary delivery and so on.
Moreover, these novel nanoparticulate based systems have capability to deliver therapeutics RNA/DNA based by acting as nonviral transfection systems and to deliver therapeutics at target site by conjugating antibodies/peptide to their surface and thereby reducing off-target effects. These systems also have great potential in delivery of biologics by protecting them from rapid elimination, enzymatic degradation and releasing them in controlled manner and hence overcome problems of conventional painful continuous multiple infusions. Several such novel delivery systems are in market and many are on their way to market.
Global market of NDDS
It is estimated that NDDS products contribute to 17 per cent of the world's pharma market, amounting to $104 billion and India is also following a similar trend.
According to BCC research, the global market for this advanced drug delivery systems was valued at nearly $176.7 billion in 2012 and is expected to increase to nearly $212.8 billion by 2018, with a five-year compound annual growth rate of 3.2 per cent from 2013 to 2018. In a study, it is forecast that the global market for nanotechnologies will grow from US$ one billion in 2010 to US$ 136 billion in 2021 in the ratio of 60:40 for nanocarriers which include gold nanoparticles and liposome to nanorystal based nanomedicine. In a comprehensive survey of the worldwide status of investigational and approved nanomedicine products as of January 2012 has identified 67 commercialized nanodevices and 33 marketed nanomedicine. In the study, total of 789 clinical trials were found for 25 devices and 122 nanomedicine currently in development of which majority are targeted for treatment of cancer followed by infectious disease and CNS disorders. Various marketed nanoformulations are described in the Table 1.
To promote research on nanomedicine, to improve communication between academia and industry and to translate nanomedicine based research from benchside to bedsidevarious programmes such as European Technology Platform Nanomedicine (ETP Nanomedicine), European Foundation for Clinical Nanomedicine (CLINAM), Alliance for Nanohealth, American Society for Nanomedicine (ASNM) have been established by several governments. With the bird’s eye view, the most innovative companies’ are focusing on NDDS of new molecule entities (NME) to take advantages of market exclusivity and protection from generic competition due to complexities involved in its manufacturing. While small companies are focusing on development of NDDS of existing drug molecule to improve their bioavailability, safety and other problem with their conventional dosage form.
Kaleidoscopic scenario of R&D in NDDS in India
Today, Indian pharmaceutical industry is recognized as a global leader in pharmaceutical market with the production of high quality generic drugs and is ranked third in terms of manufacturing pharmaceutical products by volume and fourteenth in terms of value. With change in regulatory requirement and introduction of product patent in 2005, Indian pharmaceutical industry is shifting from imitative R&D to innovative R&D. The current market for NDDS in India stands at almost four to six per cent of the total pharmaceutical market which is expected to upsurge in recent years.
Developing NDDS for existing drugs has been a priority area of research for most leading firms in India owing to establish roots in the field which ease their development with less investment. The thrust of R &D in NDDS majorly focuses towards delivery of protein/peptide drugs, development of formulations to circumvent invasive administration, to minimize toxicity and so on. Despite high risk and cost, trend towards product R & D has increased nowadays. The leading pharmaceutical companies have established many platform technologies for NDDS to trap the domestic market and are now expanding towards global market.
It started with Ranbaxy when it launched ciprofloxacin once a day tablet, India’s first NDDS based on conventional dosage form. Since that time, Indian pharmaceutical increased their focusing towards development of NDDS based product. Today many Indian companies have launched their NDDS products in domestic market. Alembic Pharma’s antiepileptic drug Keppra, and Dabur Pharma’s Nanoxel are few success stories of NDDS products in India. Recently, SUN pharma has also received approval of its paclitaxel injection concentrate for nanodispersion (PICN) using its proprietary “Nanotecton” platform technology for use in metastatic breast cancer in India. The company has also established other NDDS based platform technologies which include swollen microemulsion technology and gel free reservoir technology for ophthalmic drugs, wrap matrix technology, and GRID (Gastroretentive innovative delivery) technology for oral control release of drugs.
Not only big pharmaceutical companies, but medium pharmaceutical companies are also jumping into emerging market of NDDS. Intas Pharma’s recently launched Doceaqualip, the world’s first Nanosomal Docetaxel Lipid Suspension (NDLS), Psorosome gel byLlifecare Pvt. Ltd., Trypofol, propofol nanoemulsion manufactured using parenteral nanoemulsion technology by Troikaa Pharma are few example of it. Indian pharmaceutical companies are also leading in development of generic of NDDS based innovative formulation which reflects in first generic approval of liposomal doxorubicin (DOXIL) to Sun Pharma by USFDA.
Challenges and opportunities
Although Indian firms have made significant progress in R&D sector, it is very less in comparison to other multinational companies’ investment. The eye stretching reality is that combined R&D investment of India’s top 10 pharma R&D investors during the last 10 years was almost 40 per cent of Pfizer’s investment in just one year as of 2008. This accounts for monetary, regulatory and patenting challenges associated with research in India.
The pronounced expectations and future market potential suggest that the path toward market introduction of NDDS is clear. NDDS have claimed for reduction of undesirable side effects of drugs in comparison to conventional DDS, but to date very limited clinical data is available to actually support these claims. The lack of specific methodologies for testing effects of nanoparticles in body remains questionable till date and establishing safety profile of NDDS based product is challenge for regulatory approval of product. However, nonexistence of specific regulatory guidelines for NDDS products has given an opportunity to pharmaceutical company for market approval of product by convincing regulatory authority based on scientific concepts. At the same time, such an underdeveloped regulatory body-DCGI has allowed several NDDS products without appropriate clinical testing and strong scientific backing and thus diluting the research in NDDS field.
Further, patent defending for new drug delivery systems will also be difficult due to already existing patents of colloidal system and other patent issues like patent land grab and overlapping patents. These challenges can be addressed by development of specific regulatory guidelines, devising specific methodologies to evaluate nanoparticulate systems, multidisciplinary research to resolve associated safety issue, establishment of uniform discussion platform for scientists to learn from failure of research on this novel system and combine effort of academia, industries, physician, patients and economist for data gathering about performance of marketed NDDS in comparison to conventional systems.
Despite several challenges, positive regulators such as low cost scientific man power, significantly low production cost, low cost of clinical trials has in one way boosted R&D in NDDS in Indian pharmaceutical firms. Government has also participated through Pharmaceutical Research and Development Committee which recommended setting up of Drug Development Promotion Foundation (DDPF) and a Pharmaceutical Research and Development Support Fund (PRDSF) for promoting research in new drug discovery as well as in development of new drug delivery systems. Additionally, many firms have entered into collaborative research with academic institutes and with foreign companies which has allowed innovation in the field and also overcoming the problem of lack of funding through risk sharing.
Future of NDDS
From concept of magic bullet to marketed nanoformulations, future of NDDS appears very bright. As more and more industrial and academic research endeavor is focused towards these advance delivery systems, it will not be surprising if in recent future, conventional dosage form seemed replaced by novel delivery system. The main goal of medicine, targeted drug delivery system will be addressed by these novel delivey systems by conjugating peptides/antbodies to surface of nanoparticulate system. The Indian industry needs to focus in field of bionanoengineering for administration of various proteins, peptides, cytokines, hormones, siRNA, microRNA, plasmids using novel delivery system. Administration of these molecules will be major breakthrough in NDDS sector in future and will help industries to establish themselves in global competitive market and to capture the regulated market by filing more ANDA and NDA.
Indian industries also need to increase their total R&D investment in NDDS to compete at global level. With these forecasted promises of NDDS, various critical issues need to be addresses collectively by public and private sector such as scale up, technology transfer, efficient manufacturing, their regulation, commercial value and patient and physician counseling for efficient utility of these novel medicines. Now, this is the time to put in place combined efforts by academia, industry and government to integrate solution for these challenges and to develop various strategies for advance understanding of this emerging field by developing facilities in our pharmaceutical industries with the help of collaborations, research and innovation to go one step ahead in arena of nanomedicine.
(The author is Dean, Faculty of Technology & Engineering, The Maharaja Sayajirao University of Baroda, Vadodara )