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Editor of Pharmaceutical Technology Europe
Rapid growth in biologics and increasing complexity of new compounds are some of the factors driving development of innovative delivery solutions.
Rapid growth in biopharmaceuticals, an increasingly complex drug landscape, and rising expectations for administration convenience by the consumers, are all contributing factors that are driving demand for new delivery solutions across the bio/pharma industry. “The market continues to shift towards the development of complex oral and complex parenteral drug products that require advanced drug delivery technologies and functional excipients to improve targeting, enhance performance, or eliminate the need for boosters in vaccine applications,” explains Maaike Everts, strategic marketing leader for parenteral drug delivery at Evonik.
“The past couple of decades have seen a rapid growth in both biologics and biosimilars as treatments for a variety of conditions,” asserts George I’ons, head of product strategy and insights, Pharmaceutical Services, Owen Mumford. As a result of the composition of biologics, drug delivery is typically limited to intravenous injections, which is considered to be less convenient for the patient. Therefore, work is being done on the development of more convenient routes of administration, such as subcutaneous (SC) injections rather than intravenous (IV).
Behzad Mahdavi, vice-president open innovation biologics, cell & gene therapy, Catalent, agrees that changing the route of delivery, to either SC injections or oral delivery, is a key driver in the field of biologics. “The technologies and approaches therefore vary in this category from having to formulate the drug at a high concentration in a smaller volume by simple viscosity reduction, to the use of more complex systems that integrate several mechanisms of actions to counter different barriers in the gastrointestinal tract,” he says.
“The second driver [for biologics] is targeted delivery, to assure that the drug reaches its target and delivers its therapeutic efficiently,” Mahdavi continues. “In contrast to small molecules, where formulators are able to optimize therapies to suit a certain patient group, biologics are personalized right from the start during therapy design.”
In concurrence, Arul Balasundaram, formulation manager at Recipharm’s Queensborough facility (United Kingdom) emphasizes the need for development of delivery solutions that can achieve more effective, targeted, and controlled release within target parts of the anatomy. “Large-molecule drug substances are becoming more complex, presenting both manufacturing and formulation challenges—particularly both the inherent difficulties in ensuring the drug’s stability until it reaches the target organ and administration convenience,” he says.
When considering small-molecule therapies that are already available and approved, there are numerous drivers for the development of novel delivery solutions, such as variation in the therapeutic need of the formulation for new target patient groups (i.e., geriatrics or pediatrics), notes Andrew Parker, director Open Innovation, Small Molecules, Oral and Specialty Drug Delivery, Catalent. “In addition to dosing requirements, other drivers include the need for a different delivery profile (for example extended release) to enable a better area-under-curve for therapeutic effect; adjacent therapy target requiring modification of the delivery platform (e.g., different in-vivo target such as the lymphatic system); alternative delivery platforms to enable a faster onset (e.g., inhaled versus oral administration); second-generation formulation to improve on any relative weaknesses in the initially marketed products; and intellectual property drivers such as evergreening a delivery portfolio based on a specific API,” he says.
The well-documented rise in poorly water-soluble drugs entering the development pipeline over the past few decades has led to advancements in ways that APIs in an improved ‘bioavailability-enhanced state’ are delivered, Parker notes. “These [advances] include building on well-known delivery technologies such as spray drying, hot-melt extrusion, and the use of lipidic systems, with excipient manufacturers developing improved polymers that are tailored to improve processing and/or solubility, enhance stability, or improve performance in vivo for APIs with solubility challenges,” he says. “Additionally, new ways to process materials such as supercritical fluid processing are also possible under CGMP [current good manufacturing practice] conditions in the pharmaceutical industry that can impart desired attributes based on particle size, shape and morphology, to further aid with delivery of poorly water-soluble molecules.”
For Lynn Allen, vice-president Business Development, MedPharm, de-risking the development process has been important in helping to speed up timescales and enabling faster patient access to critical treatments. Although in-vitro performance testing models have been used for some time in the industry to screen new actives and optimize formulations, MedPharm has been applying the models to de-risking clinical trials for products targeting skin, eye, and mucosal membrane diseases, Allen states. “These models allow developers to screen with significant throughput for the activity and potential side effects of drug products against key pathways as well as understand their pharmacokinetics early in the development program,” she says. “Crucially, they provide this information using viable human tissue thereby greatly reducing the need for expensive animal and human safety/efficacy studies.”
Many new technologies are being explored for drug delivery and approaches are being assessed for new skin, buccal, and nasal membrane delivery methods, adds Ralph Landau, head of development, Drug Product, Cambrex. “Controlled drug delivery has long been pursued in the industry, but this still has challenges to overcome from dose-dumping, erratic dissolution, and food effects. Today, modified-release coating ingredients can now be modulated to enable greater precision for dosing the drug substance in targeted areas of the gastrointestinal tract,” he says. “Further development of modified-release dosage forms will enable the delivery of these molecules to a specific site of treatment. This [targeted delivery] will ensure that the therapy is introduced and actively initiated at the right time and place to disrupt the disease with precision and minimal impact to the patient.”
“The new delivery advances to target drug delivery to specific organs and tissues has helped the formulators in improving therapeutic response and bioavailability with site-specificity,” Satish Shetty, director of Product Development, Cambrex adds. “The availability of biodegradable polymers enables development of new dosage forms that overcomes physiological hurdles.”
Ophthalmic drug delivery is a specific area where advancements are providing significant opportunities, according to Everts. “Recent advances in formulation, process, and manufacturing technologies are enabling significant opportunities to better maintain effective therapeutic concentrations over time and reduce the total number of injections,” she states. “Enhancements in polymers and other biomaterials are also encouraging the formulation of hydrophobic and hydrophilic drugs that can precisely match the desired release profile, allowing the incorporation of drugs with high potency by reducing systemic side effects.”
Additionally, Everts underlines the use of lipid nanoparticle (LNP) technologies as a particular highlight of 2020. “For parenteral drugs, one of the highlights of 2020 was the use of LNP technologies to enable the rapid development and emergency use authorization of the first mRNA vaccines for COVID-19,” she says.
The momentum that has been seen in the area of LNPs is expected to continue in the future for the delivery of nucleic acids, gene and cell therapies, and other nanomedicines, Everts notes. “However, to maximize this opportunity for LNPs, challenges relating to stability, shipping, storage, and one-time administration need to be addressed,” she continues. “So, we expect to see many industry innovations focused on formulations that can be stored either at normal refrigeration or room temperature, and then remain stable for several months or more.”
The recent use of mRNA technology in the treatment of COVID-19 has paved the way for formulators to target other infectious diseases, according to Balasundaram. “Advancement in nanotechnologies has enabled the formulators to use drug carriers, such as nanoparticles, liposomes, dendrimers, nanowafer, and hydrogels to deliver proteins via non-invasive drug delivery routes,” he says.
“Biologics are increasingly being developed with the aim of reducing the frequency of administration in order to improve patient acceptance and also in turn increase adherence,” stresses I’ons. “To achieve this, the formulations often require either higher volumes (typically over 1 mL) and/or higher concentrations, and hence increased viscosities.”
To overcome the issues associated with increased viscosities, drug delivery devices have been developed that can accommodate a primary container with larger fill volumes and effectively deliver high viscosity formulations, I’ons states. “Newer designs in autoinjectors and prefilled safety devices that satisfy these requirements, and allow delivery of these more complex formulations, are emerging on the market,” he says.
Also, alternative devices to conventional spring-based auto-injectors have been developed to facilitate the delivery of highly viscous parenteral formulations, confirms Balasundaram. “There is also a lot of work going on to help formulators who need to deliver high dose formulations as one dose, for example the development of electronically enabled delivery devices such as patch-pumps to deliver several mL over minutes,” he adds.
Mahdavi adds that there are some macromolecules that can now be delivered orally, overcoming the permeability and stability challenges in a more easily administered form than injections. “The use of surfactant-based permeation enhancers may improve the permeability of large-molecule APIs, and when combined with enteric coating, prevent degradation of the encapsulated formulation in the stomach,” he says. “In turn, this benefits the patient through reduced dosing complexity, improved safety, and better adherence.”
Having the ability to target a drug to a specific site within the body or for it to be released at a certain time provides many advantages. “Targeted delivery of drugs not only means less API is needed to be delivered to generate a desired therapeutic effect, but also a lower risk of off-target toxicity issues being observed in a patient,” Parker reveals. “Additionally, targeted delivery may facilitate lower dosing regimens and a corresponding reduction in a patient’s burden of compliance.”
“Multiple approaches are available for the targeted delivery of drugs, with varying degrees of precision, from highly-targeted approaches such as antibody-drug conjugates (ADCs), to LNPs that offer degrees of affinity,” emphasizes Mahdavi. “There are also novel targeting approaches being researched or undergoing early preclinical testing, including natural nanoparticles such as extracellular vesicles. It is important to note that in order to get high efficacy, other aspects such as stability and efficient release of the drug payload before and after reaching the target are key considerations.”
Some of the techniques and solutions that are currently available to formulators for targeted drug delivery include microencapsulation, microsponges, nanotechnology, immunoconjugates, and viruses, reports Shetty. These targeted delivery approaches are important in pharmaceutical research to overcome solubility issues, protect the drug from the environment and pH changes, prevent dose dumping by controlling the release profile, control targeting at the site of action, and improve patient compliance, he says.
Employing a disease or route of delivery specific performance model can help formulators target specific objectives, states Allen. “If we focus on nasal delivery, historically the industry has been reliant on models of nasal drug performance that are limited in their ability to present a more complete picture of nasal drug delivery. Although the passive barrier remains intact within these models (e.g., simple cell monolayers), active components such as cilia, tight junctions, mucus production, and other cellular activities do not,” she notes. “Reconstituted nasal epithelial (RNE) models present an improved version of this model system. To more closely mimic the in-vivo physiology, cell signaling, and architecture, primary human nasal epithelial cells are regrown on permeable inserts and stimulated to develop into a well-differentiated nasal epithelium cell.”
Through the continuous development of models, such as RNE, formulators are being afforded the opportunities to expand the techniques and possibilities available for targeted drug delivery, Allen stresses.
Balasundaram believes that there will be a greater number of products designed for a local effect in the near future. “Different dosage forms for local effect are very useful when it comes to achieving a high drug concentration in the target organ,” he says. “For instance, inhalation products are very useful not only when treating respiratory diseases, but also central nervous system diseases.”
A targeted delivery approach that has proven to be successful in the eye of Everts is local drug delivery, whereby sustained-release formulations are applied onto specific anatomical areas, such as the knee, eye, and sinus. “With this approach, efficacious drug concentrations are maintained at the site of administration for weeks and months,” she says.
“Another successful approach is passive targeting,” Everts adds, “for example, targeting the liver by achieving liver uptake of drug-loaded nanoparticles following intravenous administration.”
In addition, active targeting is a useful approach to deliver a drug to specific cells or cellular compartments such as tumor cells, immune cells that can be stimulated for immunotherapy, or to deliver gene therapy drugs to the nucleus versus the cytoplasm of a cell, Everts states. “Achieving active targeting is a challenge and requires the development of complex parenteral formulations that will continue to rely upon existing and novel functional excipients, understanding, and overcoming biological barriers, optimizing new emerging drugs, such as nucleic acids, and developing manufacturing processes that can be scaled up for commercial success,” she says.
The biologics market is becoming more saturated, and it is expected that there will be many more large molecules in development in the near future. As a result of this market saturation, developers will be seeking more ways to deliver these complex drugs. “When considering oral delivery as a possible administration method for future biopharma treatments to avoid parenteral delivery, avoiding degradation in the harsh gastrointestinal environment, as well as transporting large and hydrophilic biologic molecules into the bloodstream remain major barriers to development,” stresses Balasundaram.
Research has been undertaken by MedPharm experts (1), demonstrating the ability for some aptamers to penetrate the skin irrespective of their large molecular weight, Allen reveals. “This research offers hope for the discovery of new treatments of difficult-to-treat dermatological diseases,” she says. “There is a tremendous amount of effort to prove these diseases can be treated with targeted topical delivery.”
Additionally, research into nasal or inhaled delivery of biologics is ongoing and has the potential to lead to a new generation of inhalation biopharma therapies, confirms Balasundaram. “Possible examples include the delivery of gene therapy to the lungs, as well as inhaled insulin,” he says.
However, the oral route of administration remains the most preferred, due to convenience, cost-effectiveness, fewest sterility constraints, relative flexibility in the design of the dosage form, and ease of production, states Mahdavi. Innovative approaches that can overcome the three main obstacles to administering biologics orally—digestive enzymes in the gut that can destabilize the molecules, the physical barrier of the thin mucus in the gut, and the tight junctions of the gut cell wall lining that prevent transportation of proteins—would be game-changing in drug delivery of large-molecule products. “A combinational integrated technology containing enteric coating, protease inhibition and absorption enhancement will continue to have an enormous impact on oral delivery of biologics,” he notes.
Thanks to recent improvements in the understanding of the human genome, in addition to advanced diagnostic and analytical tools, the biologics market is positioned for explosive growth over the coming decade, Everts declares. Even though the majority of biologics entering the market are using parenteral routes of administration, limiting therapeutic applications to areas where no oral standard of care is available, efforts are underway to facilitate the oral delivery of peptides, antibodies, and nucleic acids, with most platforms in early, pre-clinical stages, she confirms.
“However, there are some encouraging developments using either polymeric or lipid-based excipients that will protect the biologic from acid and enzymatic degradation, increase contact time with epithelium to enhance absorption and increase mucosal permeability,” Everts says. “The coming years will provide greater clarity as to which platform technologies will provide the right balance between safety and efficacy.”
Felicity Thomas is the European editor for Pharmaceutical Technology Group.
Vol. 45, No. 2
When referring to this article, please cite it as F. Thomas, “Developments Driving Drug Delivery,” Pharmaceutical Technology 45 (2) 2021.