Drug Discovery, Development & Delivery
Multifactorial Disease Models: Their Role in De-risking Topical Formulation Development The global topical pharmaceutical market is valued at around $95 billion USD and is forecast to grow by $70 billion USD over the next 4–5 years1. Currently, there are approximately 900 new products in development for dermatology, split between small molecules (65%) and biologics (35%)2 with a considerable focus on topicals for the treatment of conditions such as psoriasis, atopic dermatitis, and acne vulgaris. A company’s attitude towards risk fundamentally affects their product development strategy, which can vary between the development of a simple or prototype formulation (higher risk) or a fully market-ready, commercially viable product (lower risk) to be used in initial preclinical/ clinical evaluation. Large pharma, with many potential drug candidates to prioritise, tends to be more risk-averse and so generally focuses on entering clinical evaluation with a market-ready formulation that has been developed with risk mitigation considered throughout the development process. For these large companies, an early failure is much less expensive than a failure in the clinic. Conversely, small biotech companies that may only have a single drug candidate and are typically funded by external investment often favour the development of a prototype formulation. These small companies tend to be more risk-tolerant and prefer to address problems as they arise, so they can evaluate the drug candidate in a clinical proof of concept (PoC) study as quickly as possible. The challenge with this prototype formulation approach is that if the PoC study achieves a positive outcome then further reformulation work would be required to achieve a more patient-friendly and usable product leading to extensive bridging safety studies. In the worstcase scenario, the formulation development may have to restart to proceed to final marketing authorisation application (MAA) or new drug application (NDA). Therefore, the time and money initially saved in the early stages is often lost and/or exceeded later in the project. 22 INTERNATIONAL PHARMACEUTICAL INDUSTRY
Perhaps the optimal route to success sits somewhere between these two approaches where experienced formulators can leverage their extensive technical and regulatory expertise, and utilise innovative models, to mitigate the risks described above as much as possible. Different Types of Performance Testing Performance testing is an integral part of any formulation development programme and can be used strategically throughout the development process to mitigate development risks and failures. The method that has historically been used for assessing a drug’s thermodynamic activity is in vitro drug release testing (IVRT), where a nonrate limiting synthetic membrane is used to support the semi-solid topical formulation and the drug’s release rate is measured in a receptor solution beneath the membrane. Regulatory bodies are increasingly requiring IVRT use as a quality tool in release and stability specifications and for demonstrating generic bioequivalence. Nevertheless, IVRT methodologies can only be used to assess and compare the diffusion and release of a drug from a formulation. They provide no insight on the ability of a drug to partition in and permeate across the Stratum corneum and subsequent skin layers or any mechanistic understanding of how a formulation will affect the barrier properties of the skin. Given the difficulties, costs and time associated with in vivo experimentation, most topical formulators will attempt to use ex vivo/in vitro methodology to optimise and compare their formulations in this regard. In vitro permeation testing (IVPT) is an established methodology recognised by regulators to assess the skin permeation (and commonly penetration) of a drug from topical formulation. It is used to understand the influence of formulation on drug absorption across and into the skin whilst also being used to optimise and compare different formulations during the early stages of development and through product development to post-marketing studies and competitor analysis. The major limitation of any permeation and penetration model is that it shows how
the drug is moving into the biological tissue but does not give any indication of how the formulation affects the skin and whether the drug is bioavailable, engages the target and can act on the desired pathway(s). Traditionally IVPT models have utilised human cadaver skin or ex vivo surgically excised healthy skin, but for many topical products these skin samples do not reflect the condition of the skin to which they will ultimately be applied. Human and Animal Studies Clearly topical and transdermal formulations are for the treatment of patients in situ, therefore the “gold standard” in the experimental design for formulation development would be to employ human volunteers and monitor drug delivery in vivo. Practically, this is extremely difficult for most drugs (e.g., NCEs/NMEs) and would be unethical and cost-prohibitive for formulation development. Performing pharmacokinetic (PK) studies in humans for transdermal formulations, where the intent is to deliver the drug systemically with drugs of known safety, is well established. Additionally, for topical steroid formulations in vivo studies have been performed, typically using vasoactive agents with measurements of pharmacological activity, such as blanching, used to assess drug delivery. Such vasoconstrictor studies have been useful for researching dose dependencies, or the influence of thermodynamic activity on drug delivery, but are necessarily limited and do not transpose to allow predictions for delivery of other therapeutic agents. Other in vivo techniques include skin stripping using adhesive tapes or cyanoacrylate glue, punch biopsies, suction blister techniques, various forms of microdialysis and non-invasive determinations such as confocal laser scanning microscopy, confocal Raman spectroscopy or ART-FTIR. Animals are obviously a potential alternative to human testing. The testing of cosmetic and pharmaceutical excipients and active ingredients for possible irritation effects has remained relatively unchanged since its inception in the early 1900s. In 1944, the first U.S. Food and Drug AdministrationSummer 2021 Volume 13 Issue 2
