There are a number of specific issues that need to be addressed to improve the delivery of peptide and biologic therapeutics, notably the fact that most of these drugs are BCS Class III compounds, i.e. they have good solubility properties but low membrane permeability. The current default option for delivery is by injection, but the inconvenient and possibly painful nature of such a procedure can lead to issues with patient compliance and thus treatment effectiveness. Drug delivery technology companies have, therefore, been active in looking for new delivery methods for these highly effective macromolecular drug compounds.
It became clear that the development of alternative non-invasive delivery technologies, in particular for macromolecular drugs, was a major unmet requirement within the medical sector
The Catalent Applied Drug Delivery Institute has succeeded in its initial goals of bringing together key innovators, organisations and academia to better apply drug delivery technology and improve patient treatment outcomes. In early discussions, it became clear that the development of alternative non-invasive delivery technologies, in particular for macromolecular drugs such as peptide and protein therapeutics, was a major unmet requirement within the medical sector. The increasing share of pharma pipelines filled by macromolecular therapies prompted the Institute to establish the Non-invasive Macromolecule Delivery Consortium (NMDC) with a view to finding new ways of improving the patients’ experience and avoiding injections. New delivery methods are being sought to minimise pain and inconvenience, simplify dosing regimens and drug administration, eliminate the dangers of glass and needles, and also obviate the need for refrigeration.
The NMDC was established by leading pharma and drug delivery technology companies, including Takeda Pharmaceuticals, Genentech/Roche, Allergan, Novartis, Catalent Pharma Solutions and 3M Drug Delivery Technologies. Academic institutions such as Helmholtz Institute and Brown, Rutgers, and Johns Hopkins Universities have been instrumental in introducing new technologies and the latest academic research.
The NMDC is organised globally, enabling experts and innovators to collaborate in bringing new technologies to the industry faster and allowing the safest, most efficacious therapeutics to continue to be developed and serve the best interests of patients. The consortium has set up working groups for four main types of drug delivery: oral; nasal and pulmonary; transdermal; and ocular. The oral delivery working group has identified three challenges that need to be met in the shorter term – a consensus definition of terms; communication of progress; and characterisation and stability of the oral products. In the longer term, predictive models, clear regulatory pathways and molecular targets have to be identified.
Oral products may be able to offer improved patient compliance, access to a larger market for drug substances delivered by this method, and localised product safety. The working group identified gastrointestinal delivery of tumour necrosis factor inhibitors, chronic and maintenance therapies, and delivery of vaccines as the most promising applications for oral delivery methods.
Nasal and pulmonary delivery may improve patient compliance
The nasal and pulmonary delivery working group has identified a number of short-term challenges in its area, including communication and education; preclinical modelling; identification of clinical endpoints and biomarkers; and the adaptation of biopharmaceutical business models. The group also noted the importance of the potential for self-administration through established routes, and for localised targeting for respiratory therapies and lung cancer treatments.
Vaccines and anti-infectives, gene and cell therapies, and aerosolised surfactants for neonatal use were also identified as products with potential for these forms of delivery, as was the life-cycle management of biologics nearing patent expiration.
Immediate challenges for transdermal delivery identified by the NMDC group working in that area include the technical difficulties associated with this form of delivery, as well as the perceived high risk of entering this market due to the lack of approved products and a clear regulatory pathway. The group has also recognised the need for more safety and pharmaco-kinetic/pharmacodynamic (PK/PD) data, as well as for improved co-operation between drug development and drug delivery professionals.
Immediate challenges for transdermal delivery include technical difficulties, as well as the perceived high risk of entering this market due to the lack of approved products and a clear regulatory pathway
Geriatric patients, and in particular gastrointestinal-compromised patients, have been identified as potential beneficiaries of this form of delivery, with modified or ‘depot’ release as a possible option. Local and targeted delivery, as well as patient compliance, are also potential benefits. Osteoporosis treatments, vaccines and human growth hormone are therapies that could benefit from transdermal delivery, and there is also the possibility of introducing non-prescription transdermal biologics.
Finally, several short-term challenges have been identified by the ocular delivery working group, including macromolecular stability and ease of manufacture of ocular formulations; tolerability and barriers to delivery; the kinetics of controlled release; and how to limit systemic exposure to drugs.
In the longer term, the challenges are how to include animal PK/PD models; ocular injectability; and the need for depots and controlled-release systems that act over four to six months. Localised ocular delivery is highly suited to the treatment of conditions such as macular degeneration, glaucoma and ocular inflammation, and the availability or future development of optimised treatments for such conditions make it worthwhile investing in ocular delivery technologies for these agents.
Adapting established technologies
There are, however, several well-established small-molecule drug delivery technologies that have been, or are currently being investigated, as suitable means of delivering macromolecular therapeutics. Lipid-based drug delivery systems (LBDDSs) and oral fast-dissolve technologies each offer the potential to deliver the macromolecular drugs of the future.
LBDDSs incorporated into softgel technology is well understood and has frequently been used to improve delivery of poorly-soluble BCS Class II and IV drugs. Currently, more than 50 NDAs have been approved for poorly-soluble drug compounds delivered by LBDDS. In addition to improving drug bioavailability by addressing solubility issues, the technology also enables the delivery of macromolecular drugs with low membrane permeability.
The enteric coating protects the macromolecular API from degradation in the harsh stomach environment
Research into the application of lipid based formulations for the non-invasive delivery of biologics has resulted in the development of softgel technologies that incorporate an enteric coating and permeation enhancers, increasing the bioavailability of macromolecular compounds. The technology addresses challenges such as poor stability, the high acidity of the gastrointestinal tract, and poor membrane permeability of the molecules. The enteric coating protects the macromolecular API from degradation in the harsh stomach environment, allowing the drug to reach the small intestine, where the softgel releases permeation enhancers along with the active ingredient, the drug thereby passing through the intestinal membrane, resulting in absorption to the bloodstream. The technology is applicable to several classes of macromolecules, including oligosaccharides as well as peptides and some proteins, and research continues into further expanding its application to the more complex delivery challenges associated with larger and less stable molecules.
Orally disintegrating tablets (ODTs), also known as fast-dissolve technology, have been in use for the delivery of small-molecule drug compounds for a number of years but have recently attracted attention as a highly efficient method for the delivery of macromolecules, and in particular for the delivery of vaccines. The vaccination of large populations in the developing world presents many problems for current injectable vaccines: cold-chain logistics, the need for sterile conditions for administration, local infrastructure and the number of trained doctors and nurses on the ground. These challenges can be overcome by administering a vaccine using fast-dissolve technology as the tablets would be stable above room temperature and dissolve in the mouth in seconds without the need for water. Transport problems are largely eliminated, the products remain stable for long periods, and they can be self-administered.
The vaccination of large populations in the developing world presents many problems for current injectable vaccines
ODT technology also provides benefits for the delivery of macromolecular drugs where swallowing could be problematic for patients: it provides a simple means of administration for patients with Parkinson’s disease or those who have suffered a stroke, as well as for those with psychiatric disorders, ensuring patient compliance. Drug products commonly delivered using ODT technology include analgesics, anti-anxiety products, treatments for nausea and diarrhoea, anti-psychotics and allergy treatments. A typical formulation comprises a freeze-dried tablet in which the drug substance is encapsulated in a water-soluble matrix with two components, a saccharide such as mannitol to impart crystallinity, and a polymer such as gelatin to impart strength. Added excipients may include flocculating agents to provide uniform dispersion of drug particles, and taste masking agents may also be used.
The development of new drug delivery technologies and formulation types is an ongoing process taking place hand-in-hand with the discovery and development of new actives. In addition to technologies and formulations that increase drug substance bioavailability, new, more targeted drug delivery systems, including polymeric systems, continue to be approved. Further modification of formulations with local or external triggering agents will enhance drug delivery based on these systems. Such systems have the potential to be highly beneficial in cancer treatment by eliminating some of the distinctly unpleasant side effects of many chemotherapies.
Thus, bioavailability and precise delivery of drug substance to where it is needed will continue to be major issues in drug development, and the search for newer and more effective routes of administration that improve drug delivery and the patient experience will remain a major priority.