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Ashley Rein, Global Market Manager for Topical Drug Delivery at Lubrizol Life Science Health (LLS Health), explains how by using mucoadhesive drug delivery, developers can bring novel drugs to market and maximise the efficacy of pre-existing APIs.
Drug discovery and development is a time-consuming and costly endeavour. The journey from novel API to final approval can take up to 15 years or more, and the average cost of developing a new clinically approved therapeutic often exceeds $1 billion1. This journey is far from straightforward. At each stage, there is a continued process of attrition that ultimately limits the number of new APIs making it to the clinical phases, and approximately 90% of new drug candidates advancing to clinical trials fail to achieve final drug approval2,3.
As such, the pharmaceutical industry is increasingly focused on improving the intersection of drug discovery, formulation, and clinical research. To this end, R&D teams are investigating innovative drug delivery systems that can not only maximise the chances of successfully bringing a new API to market, but also improve the efficacy of APIs that have already been used in approved drug products4.
Of the systems being investigated by R&D teams, mucoadhesive drug delivery has attracted attention as a particularly versatile tool to meet real-world demands and enable commercially successful products. These formulations work by interacting with the mucus layer that covers the mucosal epithelial surface. This makes them highly versatile, as they can be applied to any tissue site with a mucosal layer to facilitate local or systemic drug delivery; nasal, ocular, buccal, vaginal, rectal, and more drug delivery routes can all be accessed. Mucoadhesive properties can be added to a formulation through the addition of excipients, which include carbomers, such as Carbopol polymers, hydroxypropyl cellulose (HPC), and many others, with each excipient type providing unique features and impact on the mucoadhesive profile of the finished product5. In addition, mucoadhesive excipients can benefit drug delivery when reformulating mucosal drug products or reformulating new drugs for mucosal drug products.
Though mucoadhesive delivery systems are well-recognised as an effective drug delivery route with an array of benefits, they are still not widely utilised. So, the question is this: how can the pharmaceutical industry make the most of mucoadhesion and successfully send more of these formulations to market? In this article we’ll discuss three key considerations that medicinal chemists, formulators, and drug developers can use to unlock the potential of mucoadhesive drug delivery and translate this into clinical and market success.
Consider drug delivery systems early on
Transitioning from early-stage drug discovery to the development phases can be a point of difficulty. This is due to the traditional siloed approach, where medicinal chemists focus on discovering candidate molecules based on selectivity and potency. In the search for the best candidate possible, considerations around development, delivery route, and patient appeal can often be overlooked. Additionally, once the candidate is identified, formulators must then focus on a multitude of factors, including administration route, dose, dosage form, and release profile. This can lead to further challenges, as each route has its individual considerations. When looking to develop therapeutics delivered through, to maximise success, formulators may want to move beyond the classic framework of pharmaceutical R&D, to a more holistic, open and multidisciplinary approach, such as considering excipients and the delivery systems they can enable from the get-go.
As previously mentioned, a key benefit of mucoadhesive drug delivery is its versatility. This refers both to its ability to administer drugs to various mucosal membranes, and its ability to be utilised in various dosage forms including, semisolids, oral tablets6 and liquids, lozenges, sprays, and more. The flexibility of mucoadhesive drug delivery provides formulators with a malleable tool to address complex challenges throughout the development process.
Though several polymers are widely used across the pharmaceutical industry for mucoadhesion, carbomers are well known for their ability to be utilised in different dosage forms and solvent systems, which can provide formulators with a powerful formulation tool. Formulations containing Carbopol polymers have been shown to provide improved retention at the target mucosal site compared with those containing alternative polymers7. Ultimately, by securing API-excipient combinations early in the discovery and development process, negative impacts on cost and time can be avoided.
Understand testing challenges
Preclinical studies can often be hampered by a lack of standard testing apparatus or procedures, and there are often difficulties with translating preclinicalresults to clinical and real-world success. So, to minimise failure of potential mucoadhesive drug formulations and enable the development of products with patient needs and market success in mind, our second key tip is to utilise appropriate testing systems. This is particularly important when it comes to delivering drugs via mucosa, as this route of delivery comes with some unique challenges. As these drug formulations are applied directly to tissues, maintaining a relatively long retention time at the target site is crucial for the effective delivery of the therapeutic. However, mechanical stresses, such as the blinking of the eye or saliva wash-off in the mouth, can limit contact time and potentially impact drug effectiveness.
Therefore, any testing systems employed should accurately mimic real-world conditions and facilitate mucoadhesion evaluation of drug formulations. For example, leveraging an adapted in-vitro oesophageal retention (IVOR) model would provide a testing system that allows mucoadhesion to be evaluated in a dynamic environment — the dosage form is subjected to continuous fluid flow during testing, and can be used to effectively simulate oral, vaginal, or peroral conditions.
Contemplate regulatory requirements at the start
The boundary between preclinical development and clinical trials is defined by the filing of an Investigational New Drug (IND) application, which is required prior to the initiation of clinical trials. The success of an IND program can depend on having a good understanding of the human therapeutic target, likely treatment schedule, disease indication, and clinical trial design to correctly identify the safety assessment studies needed to support first-in-human trials. Although it’s easy to view IND applications as clinical considerations, it can take up to 18 months of groundwork before starting an IND program. This means that preparation for regulatory filing must start as soon as possible, which will help drug developers avoid unexpected delays.
When it comes to mucoadhesive drug delivery, the regulatory framework can sometimes be less established than other, more traditional routes, and there may be additional steps that need to be carried out before filing.
By being aware of this, and by preparing as soon as possible for regulatory filing, formulators can ensure on-time development while remaining within budget. To further streamline this process, drug developers should utilise high-quality excipients that are already present in many marketed, mucoadhesive drug products.
As the pharmaceutical industry continues to move towards more personalised, patient-centric care, with a host of innovative and exciting therapeutics coming through the development pipeline, there is an opportunity to leverage this potential and translate it into clinical and market success. By utilising mucoadhesive drug delivery, developers can bring novel drugs to market and maximise the efficacy of pre- existing APIs, all while creating more accessible dosage forms that will enhance the patient experience.
To realise the full potential of mucoadhesive drug delivery, it will be vital to take account all the considerations discussed. By implementing a holistic approach, conducting thorough and appropriate testing, and preparing for regulatory filing as soon as possible, drug developers can get started on the right foot. Finally, excipient choice affects all stages of the development process, so using high-quality, high-performance excipients forms a crucial part of any mucoadhesive drug delivery strategy.
Volume 23 – Issue 4, Fall 2022
1. https://www.sciencedirect. com/science/article/pii/ S2211383522000521
2. https://www.frontiersin.org/ articles/10.3389/fphar.2020.00770/ full#B26
3. Dowden, H. & Munro, J. Trends in clinical success rates and therapeutic focus. Nature Reviews Drug Discovery 18, 495-496 (2019).
4. https://www.sciencedirect. com/science/article/pii/ S0168365911000332?via%3Dihub
5. https://www.lubrizol.com/ Health/Blog/2021/07/4-Ways- Mucoadhesion-Can-Benefit-Drug- Products
6. https://www.sciencedirect.com/science/article/ pii/S0378517314003901?via%3Dihub#bib0030
7. https://www.lubrizol.com/-/media/ Lubrizol/Health/Documents/ Mucoadhesion-Guide.pdf
About the author
Ashley Rein is Global Market Manager for Topical Drug Delivery at Lubrizol Life Science Health (LLS Health). Her work focuses on supporting formulators with pharmaceutical excipients for both innovative and generic topical, ophthalmic, and mucosal applications. Rein received her degree in Biomedical Engineering from Case Western Reserve University and holds several publications in this field.