Why transdermal formulations will be high on everyone’s agenda in 2018
Topical formulations have traditionally been a niche area that Big Pharma has focused on from time to time between looking for blockbuster solid oral and IV products. Recent discoveries in inflammatory dermatosis and regulatory changes are now causing development groups across the industry to re-evaluate this route of delivery.
The challenge in topical dermal formulation design has always been the skin itself, which by its very nature is a significant barrier to entry for any drug. Traditional thinking has previously suggested that drugs with a molecular weight of more than 500 Daltons will not permeate across the skin and hence cannot be applied topically for the treatment of dermatological diseases. New research, published in the Journal of Investigative Dermatology, now challenges current theories on the permeation and penetration of large molecular weight molecules across and into human skin. The aptamer used in this recent research was an RNA-based 62 unit nucleotide with a molecular weight of more than 20,000 Daltons. This aptamer and others have significant potential in the treatment of a range of skin diseases such as psoriasis and atopic dermatitis.
Using ex vivo skin, the authors showed that the aptamer not only passed across the stratum corneum, but could also be detected at therapeutic levels in the epidermal and dermal layers. The research showed that the aptamer remained in its biologically active conformation and was capable of binding to endogenous IL-23, a well described target in important inflammation pathways.
As co-authors of the study with the University of Reading and GSK, MedPharm scientists believe it could have significant implications for the discovery of a new treatment paradigm for dermatological products for major diseases such as psoriasis. With the explosion in knowledge and understanding of new biological pathways and mechanisms, macromolecules such as peptides and nucleotides are being increasingly identified as potentially important drugs.
In another important recent development, regulators on both sides of the Atlantic have recognised that the previous requirement to demonstrate therapeutic equivalence between a qualitatively, quantitatively and microstructurally similar generic product and its originator (RLD) in clinical trials has created a significant barrier to generic introduction. This is a key governmental concern because it has meant that authorities have seen little impact on post-patent pricing for many topical products. The costs and risks of doing the required clinical trial as part of any generic submission have just been far too prohibitive.
The EMEA has been leading the way with the first generic approvals, which demonstrated in vitro bioequivalence without any therapeutic clinical trial data. At the end of 2017, the FDA, using its typical product by product approach, started the introduction of numerous guidance notes stating that for exact generic copies of certain products, in vitro release testing (IVRT) and in vitro penetration testing (IVPT) can be submitted in lieu of clinical therapeutic equivalence data. Thus, all indications suggest that FDA and European agencies will be open to submissions for topical dermal generics using in vitro models to demonstrate bioequivalence — provided they are based on sufficient scientific rigour and validation. Indeed, both agencies have expressed a desire for dialogue and an openness to discuss these approaches at presubmission meetings.
By significantly reducing the costs and risks of demonstrating bioequivalence, these changes in strategy by regulatory authorities are opening up new market opportunities for generic products. Increased understanding of basic biology and immunology is also impacting all aspects of pharmaceutics and none more so than topical delivery. One important area is in the development of disease activity models. These models allow product performance to be accessed in the laboratory using culture conditions that allow human skin from elective surgeries to be kept in a viable healthy state for up to 10 days.
Key pathways associated with major diseases such as psoriasis or atopic dermatitis can be induced in the skin so that the models assess both the delivery of the drug into the different skin layers, and also demonstrate the drug remains bioavailable, active and engages the target. These models can be used to establish a pharmokinetic/pharmacodynamic (PK/PD) assessment from a topical application to the skin and are increasingly playing a key role in derisking decisions by investors to move forward with expensive clinical trials. They are also making an important contribution to drug candidate selection and formulation screening and optimisation.
These new developments in the pharmaceutical landscape are already generating a great deal of excitement because of the opportunities they offer both to existing players and new entrants. However, to take advantage of these changes, pharmaceutical development groups, whether focused on new actives or generics, need to move quickly. Here, the role of contract development organisations such as MedPharm is more important to clients than ever before.