Targeting Optimal DRUG DELIVERY
In recent years, several innovations have emerged around long-acting formulations and medical device development to improve patient compliance. Consequently, the growing need for controlled drug release coupled with technological advancements in pharmacology is promoting the adoption of novel drug delivery systems (NDDS). It is now crucial for Asia Pacific (APAC) drug formulators to learn and act upon these advances in therapeutic modalities that address long-standing bioavailability, dosage, and ingestion challenges of drug components to remain competitive in the global market. Simultaneously, it’s essential to optimise the therapeutic efficacy and safety profiles of a drug by regulating dosage parameters, while DDS plays an important role in administering drugs, vaccines, and therapeutic agents. Optimising these techniques enhance the performance efficacy ratio of medications by economically managing therapeutics assets. Let’s examine recent advancements in drug delivery modalities that are greatly encouraging stakeholders’ collaboration among innovators, manufacturers, investors, and contract development and manufacturing companies (CDMOs) who are capitalising on competitive advantages.
In recent years, several innovations have emerged around long-acting formulations and medical device development to improve patient compliance. Consequently, the growing need for controlled drug release coupled with technological advancements in pharmacology is promoting the adoption of novel drug delivery systems (NDDS). It is now crucial for Asia Pacific (APAC) drug formulators to learn and act upon these advances in therapeutic modalities that address long-standing bioavailability, dosage, and ingestion challenges of drug components to remain competitive in the global market. Simultaneously, it’s essential to optimise the therapeutic efficacy and safety profiles of a drug by regulating dosage parameters, while DDS plays an important role in administering drugs, vaccines, and therapeutic agents. Optimising these techniques enhance the performance efficacy ratio of medications by economically managing therapeutics assets. Let’s examine recent advancements in drug delivery modalities that are greatly encouraging stakeholders’ collaboration among innovators, manufacturers, investors, and contract development and manufacturing companies (CDMOs) who are capitalising on competitive advantages.
Advancements in the drug delivery systems (DDS) are gradually offering solutions to the rising prevalence of chronic conditions. It is now more crucial than ever before to improve patient compliance while lowering the cost of treatment. As drug manufacturers strive to overcome patient compliance concerns, both small molecules and large molecule active pharmaceutical ingredients (APIs) need to be efficiently managed to achieve the desired therapeutic effect in moderate dosage.
According to experts a significant proportion of APIs or drugs on the whole, exhibit low solubility, low bioavailability, and/or low inconsistent dissolution rate. For biopharmaceutical pipelines to advance, it is essential to address these concerns effectively by identifying, resolving, and reinventing drug delivery channels. Maximising solubility and absorption eliminate the need for reformulation and, hence, promotes the market reach of a drug candidate. Utilising complementary drug delivery technologies can achieve a full range of absorption profiles by modulating pharmacokinetics. As a result, CDMOs are developing a portfolio of bioavailability enhancement technologies and services.
Recent developments in DDS
Advanced drug delivery technologies are enabling and enhancing the next generation of specialised parenteral medicines. Over the last decade, NDDS are evolving as smart, safe, and efficient modes of a therapeutic regimen in a pulsatile, sustained or controlled manner to enhance precision therapeutic regimens. The objective of control and/or sustained drug release is to reduce dose frequency and increase drug moiety efficacy compared to conventional delivery. The industry is also being propelled by the rapidly growing pediatric and geriatric population,
owing to the high incidence of non-adherence to prescription drugs in these age groups. NDDS modes also prevent doses from being missed or taken incorrectly by patients requiring thirdparty assistance. Further, they simplify the challenge of patient compliance and facilitate precision in dosage including reduced treatment cost, guards against overdosing, and reduced side effects. On the other side, the traditional dosage form offers spontaneous drug liberation that leads to drug concentration variation in the circulatory system.
Advanced Drug Delivery Systems (ADDS) are essential for delivering medicine in a regulated or modulated manner within cells or tissues (organ, cellular, and subcellular level of specific tissue) in order to ensure steady levels of medication in the blood. An ideal drug delivery system performs multiple functions such as reducing/ eliminating adverse effects and improving the stability and solubility of the drug while being non-toxic to the biological system on itself. While developing advanced drug delivery systems, various factors, such as pharmacodynamics, drug toxicity, immunogenicity, biocompatibility, pharmacokinetics, and drug efficacy, are considered.
Many therapies require frequent dosing to maintain drug concentrations at therapeutic levels. By using controlled release formulations to extend the half-life of medicines inside the body, dosing frequency can be minimised and make treatments easier and more convenient for patients. By maintaining drug levels within the therapeutic window, active drug ingredients or a biologically active molecule will be regulated by time, period, and release rate through systemic circulation while treating chronic diseases.
Competitive landscape
The growing trend towards self-injection devices and the rapidly growing pipeline of biologics/biosimilars and auto-injectors could be one of the reasons for market growth. According to the market research analytics at ‘Research and Markets, the global advanced drug delivery market was valued at $44,029 million in 2020 and is estimated to reach $1,95,132 million by 2030, growing at a CAGR of 16 per cent from 2021 to 2030. North America currently dominates the global DDS market. The Asia Pacific DDS market is witnessing an expansion due to increased collaboration among stakeholders from the industry and academia through R&D and M&A activities.
An integrated portfolio of drug delivery systems, and formulations, is attracting manufacturers and CDMOs alike to explore commercial opportunities by leveraging small molecules, peptides, proteins, nucleic acids (DNA/ mRNA), vaccines, and other drug substances or combination products. The market segment is
expected to continue to grow as the popularity of personalised and gene-based drugs with precision therapeutic targets is burgeoning. Further, an increase in R&D spending, stakeholders’ interest in nanomedicine across all disciplines of medicine like oncology, cardiology, immunology, and pain management, and a surge in healthcare expenditure in developing APAC economies are progressing DDS commercial-stage development and manufacturing capabilities.
Following advancements in formulation technologies, multi-drug combination models, recent investments, and strategic acquisitions across core technology areas, CDMOs are uniquely positioned and investing in a major expansion of R&D and CGMP manufacturing capabilities. Though garnering attention as a promising candidate for treatment for some of the refractory diseases unmet up to this point, certain DDS products have to pass through hurdles, stringent regulations, and complex regulatory approval.
“One of pharma’s main needs today, in the development of new injectable DDDs, is to accelerate time to market with integrated endto-end technology platforms from formulation development to small- and large-volume fill and finish, including complementary services such as regulatory testing protocols to know exactly how to customise platforms to customers’ drugs and improve device efficiency,” says Chetan N Patel, CEO, SMC Ltd, a global CDMO.
An increasingly diverse multifaceted market
The market for DDS is diverse reflecting different types of systems and routes of administration. Leading CDMO markets are producing amenable DDS systems offering a wide variety of matrices and formulation approaches in increasing kinetics and delivery strategies. A variety of ‘micro molecular vehicles’ in the form of nano-sized vesicular carriers (liposomes, niosomes, dendrimers, micelles, polymeric or lipid-based nanoparticles) or carrierbased systems (nanoparticles, nanospheres, nanocapsules, nanoemulsions), and other drugloaded nano-devices/implants are designed to carry medicine or new genes particles in capsule format.
CDMOs across APAC are catering to integrated portfolios to meet the widespread adoption of these nanoparticles. In vivo devices, transdermal devices, and reservoir implantation devices are structured as capsules, robotics, or microfabrication systems to deliver drugs/ therapeutics at a particular location in response to a stimulus within the body or externally controlled microprocessors as per the predetermined schedule and protocol. Among established ADDS formulations, a few diverse and distinctive drugloaded implant models are described here.
Lipid NanoParticles
For complex parenteral drug products including vaccines, nucleic acids (mRNA, DNA, siRNA), and ligand-targeted formulations, microencapsulation has been the most preferred choice in the biopharma industry.
Lipid-based formulations encapsulate API ingredients in PEG-lipids, liposomes, or Lipid NanoParticles (LNP) formulations to protect them from degradation on their path acidic and alkaline body fluids. There has been a resurgence of interest in LNPs given their well-established record, multiple faceted therapeutics usage while achieving prolonged circulation regimens.
“We believe oral versions of biologics have the potential to take significant market share”
TALAT IMRAM
CEO, Rani Therapeutics T
Global CDMO, Evonik’s Strategic Marketing, and Business Development expert opines “Lipid-based drug delivery systems have been traditionally used for highly potent molecules such as anti-cancer agents, antibiotics or antifungals and oligonucleotides that require intravenous administration. While the market for nucleic acid-based vaccines and therapies is yet to reach critical mass, there are hundreds of personalised medicines in development that are expected to utilise these technologies moving forward.”
“One of the main advantages of LNP-based technologies is that they can reliably encapsulate high payloads for both hydrophilic and lipophilic drugs. That is a key reason why they are now the de facto standard to deliver nucleic acidbased vaccinations and other therapies, where the payload must be protected until such time as it can be delivered to the site to silence targeted genes or express therapeutic proteins. They can also be designed to exhibit specific physicochemical properties such as particle size, surface charge, and surface function to satisfy a variety of performance requirements,” explains Evonik’s LNPs Business Development expert.
The largest single application of LNPs in drug delivery is in cancer treatment, because of the improved bioavailability and selectivity of LNP-encapsulated antitumor agents over the free drugs. Lipid-based nanocarriers reduce the toxicity of anticancer drugs to normal tissues, increase the water solubilities of hydrophobic drugs, extend the drug residence time, and improve control over drug release. The second
How do you define the impact of Robo-pill technology on patients and pharmaceutical companies in APAC?
The RaniPill technology is poised to transform the market for biologics in APAC, both for patients and for pharma companies. Patient adherence is an issue with biologics, as with all injectables, and up to a third of patients on chronic injections frequently skip prescribed doses. This can have major implications for the clinical progression of medical conditions such as osteoporosis, which is notoriously overrepresented and undertreated in Asia. In Korea, for example, the prevalence of osteoporosis in women over the age of 50 is about 38 per cent. A rapidly growing population of elderly people throughout the continent is set to exacerbate the problem (as with a host of other chronic age-related conditions), and by some estimates, hip fractures due to osteoporosis in Asia will more than double in the next few decades.
Rani is conducting a Phase 1 clinical trial of RT-102, an oral formulation of parathyroid hormone (PTH). Injectable PTH is an effective way of treating osteoporosis, and its use is on the rise in Korea. We expect patient preference to strongly sway towards an oral option over
injectables. An oral PTH could reach more patients earlier in the care continuum, and potentially improve the clinical outcomes for millions of patients in APAC. And osteoporosis is just one example.
Oral versions of biologics also provide inherent differentiation, which is especially valuable for APAC pharma companies that have historically focused on “fast follower” products. Given higher reimbursement rates outside of the region, the RaniPill offers an attractive development opportunity for companies that have had limited access to markets outside Asia.
How do you summarise the performance of Robo-pills in achieving high bioavailability and precise delivery of drugs?
The enteric coating of the RaniPill capsule allows it to pass through the acidic stomach environment, only dissolving once it has entered the small intestine. There, it injects the payload directly into the intestinal wall, which is highly vascularised but has no sharp pain receptors. This approach achieves bioavailability similar to that of a subcutaneous injection, and enables the delivery of a dose that is close to or equivalent to a subcutaneous dose.
By contrast, most previous efforts to make oral versions of biologics have been based on chemistry reformulations, but even the successful attempts have achieved bioavailability no greater than low single digits. That requires a massive (up to a hundred times larger) dose increase to achieve therapeutic effect, which also leads to high dosing variability.
How is Rani Therapeutics leveraging its investments in manufacturing and automation of novel drug delivery systems? As a venture capitalist, how do you map the growth and opportunities for Robo-pill in the APAC region?
We’re investing in manufacturing process-step automation to increase throughput. We take a progressive approach, starting with semi-automation and ultimately culminating in fully integrated automation.
The Robo-pill technology can transform the current product portfolios of APAC pharma companies. Overwhelming patient preference for oral over injectable therapeutics will be a game-changer, once oral alternatives of biologics become available on the market. Additionally, there tends to be a larger disparity in paying power in APAC markets. Oral versions of injectable biologics will allow payers and pharma companies the ability to stratify reimbursement based on product presentation.
What is your prediction on APAC market dynamics for Robo-pills? How do you foresee the future of Robo-pill in replacing subcutaneous injection in modern-day therapeutics?
Our mission is to replace most chronically dosed subcutaneous injections with a daily oral RaniPill dose. These types of injections are used across almost all therapeutic areas, including inflammatory disease, endocrinology, rare disease, oncology, and more. Given the price competition in the market for biosimilars and the strong patient preference for oral medications, we believe that oral versions of biologics have the potential to take significant market share around the world, especially in APAC.
Would you like to add a note on the scalability of Robo-pill’s design?
We’re laser-focused on improving our manufacturing automation: first, to enable the production of RaniPill capsules to support a larger Phase 2/3 trial, and then at commercial scale. We designed the RaniPill capsule with high-scale, lowCOGS manufacturability in mind.
largest group of liposomal drugs comprises fungicides. Nucleic acid therapeutics are an emerging class of LNP drugs showing potential for treating viral infections like COVID-19,
Zika and more. The nucleic acid drug Patisiran (ONPATTRO), a siRNA formulated in LNPs to reduce transthyretin protein formation in the liver (hereditary transthyretin-mediated amyloidosis) is the earliest FDA approved LNPformulated siRNA nucleic acid drug, marking an important milestone in nucleic acid therapeutics development.
LNP formulations are gaining global awareness, notably after being instrumental in boosting the immune system in mRNA vaccine mode against the SARS-CoV-2 virus. By advancing the existing classical LNP model, researchers at Moderna developed the mRNA COVID-19 vaccine from lipid libraries. FDA Emergency Use Authorisation (EUA) of LNP encapsulated mRNA vaccines from Moderna ‘mRNA-1273’ and BioNTech/Pfizer ‘BNT162b2’ has revamped LNP in the drug delivery sector.
Scientists are developing advanced polymers with the aim of improving the biocompatibility of polymeric nanoparticles hoping polymer nanoparticles might offer a significant advantage over LNPs for pulmonary administration and in regard to overall RNA loading. The invention of LNPs has been promising to date in tackling SARS-CoV-2 variants and has prepared the healthcare system with an efficacious vaccine delivery model to tackle future pandemics. The formulations that have been successful in the current pandemic, can be customised for future outbreaks.
Drug-Loaded Implants
Microelectromechanical system (MEMS) & Nano Electromechanical Systems (NEMS) devices offer minimally invasive and controlled drug delivery. These MEMS devices filled with prescribed drugs as micro reservoirs substrate are implanted in the body or ingested as pills through oral administration. Certain self-administering device reservoirs offer the provision to load multiple drugs in one pill as per the treatment regimen.
Describing the major trends in the DDD industry, Riccardo Butta, Senior Vice President at Singapore’s Flex Health
Solutions, says, “Major trend
“Using nanoparticles to deliver promising drug candidates to their site of action has the potential to help us improve the therapeutic index of small molecules and new modalities. By targeting delivery of a medicine precisely to the tissue where it is needed, we want to achieve a therapeutic concentration while minimising the potential for unwanted off-target activity at other sites that could cause side effects and prevent patients staying on the treatment they need.” - Marianne Ashford, Senior Principal Scientist, Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca “Developing polymer nanoparticles and nanocomplexes for RNA delivery regards biocompatibility as a bottleneck in RNA delivery. Indeed, polymer nanoparticles involve the use of positively-charged polymers to pre-condense the nucleic acid, which makes approval by the regulatory bodies difficult. For this reason, using LNPs has been advantageous for the fast development of vaccines”. - Dr Olivia M Merkel, Professor of Drug Delivery, Ludwig-Maximilians-University, Germany
involves the wave of biologics coming to market and the need for different delivery mechanisms for their higher-viscosity, larger-volume. and therapy-specific requirements. This sustained the idea to combine these large-molecule formulations with electromechanical devices, allowing pharma companies to offer improved user interface, sensing capabilities, programmable delivery profiles (e.g., dosage, delivery rate), and connected solutions to their patients”.
“Rapid expansion of digital health, not only with sensing and connectivity features inside the device, but to include end-to-end solutions to capture, transfer, store, and manage data to improve clinical outcomes. This fuels the need for the integration of connected devices, cloud infrastructure, data analytics, and mobile applications, all within a regulated and fully compliant ecosystem” explains Butta, while describing the digital DDD space on a survey by AliraHealth.
One such device is the RaniPill capsule, a smart Robo-pill from Korea’s Rani Therapeutics, which navigates through the stomach and enters the small intestine to inject the drug painlessly into the intestinal wall.
Transdermal Devices
As opposed to In vivo devices, transdermal devices deliver one or more drug molecules through the skin potentially offering a painless smart patch method for drug delivery. The needles on these patches are fabricated with microchannels through which the drug pumps into the body. Innovations in transdermal include skin ablation and microneedles with iontophoresis, bringing transdermal drug-delivery devices into the digital health space.
“The Asia Pacific transdermal drug delivery system market, based on type, is segmented into the transdermal patch and transdermal semisolids. The transdermal patch segment is further sub-segmented into drug-in-adhesive patches, matrix patches, reservoir membrane patches, and microneedle patches”, explains Research and Markets, an analytics group. In Asia, China is the largest market for transdermal drug delivery systems owing to the increased adaptation of transdermal patches for pain management in the region.
Alternatives like Hollow Microneedles (for higher doses) and Intelligent Iontophoresis (biofeedback patch that is self-powered and microprocessor-controlled with SmartPower LED)
“Each disease has a peptide sequence which is recognised as the key antigen. If we are able to determine the most appropriate administration method for the vaccine carrying that specific sequence, and if we can elucidate on the transmission mechanism of the antigen information after its administration, we could apply this not only to this novel Coronavirus but also to other new infectious diseases as well.” - Dr Yoshiro Tahara, Associate Professor, Doshisha University, Japan “We focus on the potential use of mRNA to produce therapies directly in the cell, turning the cell into ‘biological factories’ that produce the therapeutic proteins, antigens and/ or antibodies to treat diseased organs and tissues. RNA therapeutics offer potential to specifically modulate cellular pathways in ways not previously possible. We are investigating lipid nanoparticles (LNPs) as a promising vehicle for intracellular delivery of mRNA for production of protein therapeutics in cells”. - Lennart Lindfors, Adjunct Professor, Principal Scientist, Advanced Drug Delivery, Pharmaceutical Sciences, R&D, AstraZeneca
and many contemporary models are adding to the transdermal drug delivery market. Alternatively, Dissolvable microneedles will overcome risks of reuse and needle-stick injuries as they will dissolve in the skin leaving no marks.
A group of scientists at the Georgia Institute of Technology (USA) has demonstrated that intradermal vaccination leads to a much better immune response than the classical intramuscular vaccination. Vaccine dose delivered intradermally by a microneedle patch can be equally immunogenic. As a result of reduced doses, immunisation programmes could make more vaccine supplies available to a larger number of people, potentially reducing the costs of vaccines and associated distribution. Additionally, logistical advantages have motivated the development of microneedle patches for vaccination campaigns in remote locations. Delivering vaccines by microneedle patches is easy and does not require the expertise of a healthcare professional in giving it as an injection, could be transported without/reduced refrigeration, and does not generate sharp medical waste. This, in turn, can enable quick and massive immunisation, beneficial in pandemic situations.
Perspectives for the future
Advanced drug delivery technologies hold a major part of the drug delivery market and will play a major role in shaping the future of the drug delivery domain and also in finding the cure for unmet diseases. The key benefit of ADD is its flexibility and potential to increase drug bioavailability, improve therapy, and avoid drug degradation by enhancing drug stability.
The pharmaceutical industry’s focus is on accelerating innovation in delivery devices. Advances in therapeutic modalities and an increase in molecular complexity have led to the need for an evolution in multidisciplinary drug delivery approaches over the years. Several key developments are set to shape and transform the advanced drug delivery arena in the coming years with the evolution of novel carriers for drug delivery. Understanding and acting on them now is crucial for Asia-Pacific drug formulators to continue to thrive in a competitive global market.