Topical dosage forms are difficult to develop and rely on differing drug physicochemical properties and are applied to complex biological membranes that have evolved to keep such xenobiotics out. The global topical market is around $95 billion USD and is forecast to increase by $70 billion USD over next 4-5 years (1), where the dermatology market is a significant segment. Currently, there are approximately 900 new products in development for dermatology, split between small molecules (65%) and biologics (35%) (2).
Here, Marc Brown, Jon Lenn and Charles Evans, from MedPharm, discuss the latest industry innovations, the benefits of automation and mitigating the risk of product failure in the development of topical products.
Innovation
Formulation in topical product development
The level of risk that a company takes largely affects their development strategy. This can vary between the development of prototype formulation (higher risk) or a full market-ready, commercially viable product (lower risk) to be used in initial preclinical/clinical evaluation. Different sizes of companies will base their own level of risk around commercially viability, their target markets, and corporate culture.
Typically, smaller biotech companies only have a single drug candidate and are often funded by external investment and therefore find the development of a prototype formulation more favourable. These small companies tend to be more risk tolerant too, addressing problems as they arise, so the drug candidate can be evaluated in a clinical Proof of Concept (PoC) study as quickly as possible.
However, this prototype formulation approach presents its own challenges. 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 turn resulting in the formulation development needing to be re-done to proceed to final Marketing Authorisation Application (MAA) or New Drug Application (NDA). Thus, the time and money initially saved in the early stages is often lost and/or exceeded later in the project.
It’s important to emphasise that a topical products’ ‘ease-of-use’, aesthetic and cosmetic properties are often as important as efficacy. The selection of such a formulation for topical application is influenced by the physicochemical properties of the drug and its potency, the disease to which it is utilised, and the patient who will receive it (Figure 1).
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Figure 1 - Common considerations for topical product development
Therefore, a Quality Target Product Profile (QTPP) should be created to define the key requirements around the quality, safety, and efficacy of the drug product. This should be updated as the project progresses where any Critical Quality Attributes influenced by Critical Material Attributes (CMA) and Critical Process Parameters (CPP) are identified, monitored, and controlled.
The pre-formulation stage of a new drug candidate is the most critical step for topical programs and is best performed using automated and robotic systems. The lowest risk approach to any submission is to try and keep to excipients, packaging, processes, and parameters with which the regulatory authority is familiar. A series of formulations can be developed based on the QTPP once the ‘formulatability’ of a drug is known. Ultimately, it is essential that the lead formulation is optimised and characterised not only to demonstrate that it will maintain its quality and performance during its entire shelf-life but also gives the formulation the best chance of success in the clinic.
Performance testing: Innovation, automation and high throughput screening
Performance testing tools and models can be divided into four main areas: 1) ex vivo pharmacodynamic or disease models 2) in vitro (drug) release testing (IVRT), 3) in vitro (drug) penetration and permeation (IVPT) and 4) product characterisation and stability testing. These models provide a way to evaluate new chemical entities (NCE) and drug products, drug delivery, product safety, efficacy, and quality of topical formulations to reduce their risk of clinical failure.
The development of pharmacological disease (PD) models using fresh human skin has experienced huge growth thanks to the increasing interest and understanding in the basic biology of inflammatory dermatosis. Skin research has a huge advantage thanks to its direct access to large sections of surgical tissue. Latest advances in tissue culture have allowed scientists to keep surgical skin alive in culture for much longer than previously, creating a living tissue explant. By combining an increased understanding of immunology, tissue culture, and pathway biology these ex vivo skin PD models have become critical in the development of NCEs and are helping bridge the gap for clinical translation along with de-risking the development process for topical products.
IVRT is routinely used throughout the development process from the early stages of formulation optimisation, through process development, and to scale-up. Additionally, regulatory bodies are increasingly requiring IVRT as a quality tool in release and stability specifications and for demonstrating generic bioequivalence. The majority of industry adopt an IVRT method based on an open chamber vertical diffusion cell (VDC) system (Figure 2a) fitted with a synthetic membrane as a support for semi-solid dosage forms in order to measure and optimise the drug release from the formulation over time (akin to tablet dissolution testing).
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Figure 2 – Static and flow through diffusion cell designs
However, a fully automated VDC system (MedStat-HT) (Figure 2b) differs from traditional manual VDCs by providing significant improvements in sample collection, data variation, operator repeatability, and study robustness.
Most of the industry uses similar manual VDCs for IVPT studies where the drug is applied to the skin, mounted in the VDC onto which formulation is applied and the absorption of the drug into and across the tissue is quantified. However, these systems are known for variability and are challenging for modern lipophilic drugs, making data interpretation problematic. MedFlux-HT®, a fully automated flow-through diffusion system for use in such IVPT studies dramatically reduces the variability and more closely mimics the clinical situation compared with the manual VDCs (4).
Using automated liquid handlers and robots reduces the risk of variability when compared to manual procedures. When assessing longer-term physical stability, automated instrumentation (LUMiSizer) provides a more accurate prediction of shelf-life compared to harsher centrifugation techniques. Assessment of product microstructure is quite often overlooked until much later in the clinical phases of development. However, it is not only key in the development of generic products to show uniformity, but also during early phase process development to show that the developed product is robust.
Final thought
Whether via the eye, skin, lungs, nail, or other mucosal membranes these alternative topical routes clearly offer key advantages despite presenting unique challenges. A formulation strategy that builds the formulation specific to the compound will generate a solid foundation that proactively focuses on a final product that will be physically and chemically stable and ready for the clinic. It will also de-risk potential product failure that may come from an inability to deliver the compound to the target site or elicit a biological response prior to the clinic.