Topical formulations are typically disease-specific, so often certain other properties must be achieved or avoided. For instance, Nalamothu notes that for an acne formulation, oily excipients and comedogenic materials (those with a propensity to clog pores) should be avoided. Similarly, a psoriasis or eczema formulation should not contain drying or stinging agents such as alcohols and glycols.
More recently, Newsam notes that topical drug formulators have also begun to take into account the constitution of the microbiome that populates various human internal and external body surfaces. As an example, he points to the connection seen between the character of the skin microbiome and the appearance of skin lesions in atopic eczema patients. He also observes that selective topical antimicrobials are sought that do not cause harm to beneficial microbes. San Diego-based Pagoda Genomics, for instance, has developed the topical protein formulation Avlo, which exhibits selective activity against norovirus, the bane of many travelers, especially those on cruise ships.
All of these aspects must be considered in light of relevant consumer acceptance criteria such as smell, color, and texture/aesthetic appeal, Nalamothu adds. “The excipients selected to ensure that a formulation treats the disease and appeals to the consumer cannot interfere with the stability and permeability of the API,” he states.
Developing improved formulations with better application, break, and/or finish but that contain the same therapeutic effect is often the goal for generic topical products, according to Goodyear. “Patients will be more likely to repurchase certain products that provide a better sensorial experience, especially when it comes to more aesthetically pleasing formulations,” he says.
Often in-vitro or ex-vivo models comprising fresh tissue such as eyes, skin, or cultured human epithelium have been shown to de-risk the development of the drug product for the patient, according to Evans. In combination with additional evidence, in-vitro permeation testing may be used to demonstrate bioequivalence of generic topical drug products by comparing the rate and the extent to which an active ingredient gets to the relevant site(s) of action, says Goodyear. “While clinical end-point studies can be utilized to evaluate bioequivalence, they are costly and the least sensitive method,” he adds.
In more recent FDA-funded investigations, Goodyear notes that in-vivo cutaneous pharmacokinetics have been monitored in humans via dermal open-flow microperfusion and in preclinical studies with dermal microdialysis. “These methods have the potential to monitor the APIs accurately, sensitively, and reproducibly from topically applied drug products and ultimately can help reduce cost to the patient and increase the speed with which patients have these tests available,” he observes.
Robust implementation of quality-by-design (QbD) and design-of-experiment (DoE) methodologies also serves as an effective strategy for de-risking formulation processing and development, according to Goodyear. Consideration of the scalability of the manufacturing process is crucial to success as well, Nalamothu asserts. “Formulators must consider the critical process parameters and develop robust critical quality attributes to make sure that the product developed in the lab has the same physicochemical properties as that of the product obtained from large-scale batches made in the manufacturing suite,” he says.
Best strategies leverage multi-faceted approaches
With so many factors to consider when developing a topical formulation, the key to overcoming them is a multifactorial approach. “By integrating preformulation and formulation development closely with drug product design, key final product characteristics can be incorporated from a very early stage in the development,” Evans asserts. Understanding elements such as route of delivery, site of action, potency, patient preferences, and even the target shelf life of a drug product ensures that development projects are cost and time-effective, he adds.
For Newsam, the preferred approach to topical drug development combines the use of various computational techniques to inform the formulation research program, utilization of high throughput experimentation (HTE) tools in formulation innovation and DoE methods in formulation optimization.
“Formulation innovation is more efficient if the focus is first on the property that is most taxing to match, which commonly is realizing the required level of skin delivery and permeation. As most molecules have low intrinsic skin permeability, we work to identify those particular combinations of excipients that are effective in permeabilizing the skin barrier, preferably in a manner that is more or less selective for the particular API,” Newsam explains.
While software tools can help, there are no robust and broad means of predicting the effects of such excipient combinations; they must be measured. Because the space of excipient combinations is vast, HTE technologies have proven to be valuable in this endeavor.
Tioga Research’s approach begins with analyzing the physicochemical characteristics of the API followed by mining databases of formulation performance that the company has accumulated over the past 19 years. Formulation composition spaces that have worked well for other molecules not dissimilar to the given API are identified as an initial platform for formulation fine-tuning. “This tailored formulation approach is quite suitable for new chemical entities where patentability is less critical,” Newsam says.
Tioga has also developed a complementary approach referred to as Cascaded Screening methodology, which leverages the company’s HTE platforms. With this methodology, the skin permeation of an API from each of large numbers of different formulations is screened systematically, with the details informed by the molecular characteristics of the API. This approach, according to Newsam, has a remarkable success rate in yielding high-performing formulations that also prove patentable as novel compositions of matter.
When seeking to develop a “supergeneric”—or bioequivalent generic topical formulation with more attractive properties from a patient perspective—the formulator must first extract the quality target product profile (QTPP) from the patient and dermatologist viewpoints. “Defining the most important attributes about a topical treatment may shed some additional light on how product developers are able to enhance patient treatment outcomes in clinical settings,” he explains. The bottom line, Goodyear stresses, is that most patients would rather use a soothing foam or cream formulation over a greasy ointment if given a choice.
Repositioning opportunities tempered by challenges
There is broad interest in drug repositioning or reformulation for a 505(b)(2) regulatory path, as it is considerably faster and less expensive than the 505(b)(1) for a new chemical entity. By reformulating a drug for the same or different indication, companies are offered a much quicker route to approval and these products do not require the same level of toxicological and clinical testing as new chemical entities. Safety and efficacy data from the literature or from studies by another organization can be used in support of the 505(b)(2) NDA. The risk of an unexpected safety issue arising is also substantially reduced, and this faster approach is approved and supported by regulatory agencies globally.
Reformulation as a topical product is often pursued if the existing molecule/dosage form is unable to meet patient needs due to less-than-optimized delivery kinetics and/or dosage strength, according to Nalamothu. Repurposing of an existing drug for a new indication is another reason for reformulating a drug substance as a topical product.
Developing a topical formulation with an existing API can be challenging, though. Staying within the pharmacokinetic profile of the old dosage form and any efficacy/safety constraints is a primary one, Nalamothu says. “In other words, the new dosage form has to meet the TPP of the unmet (clinical/commercial) need while providing or exceeding the efficacy and safety of the originator drug,” he explains. Tergus uses various tools such as in-vitro skin permeation and other in-vitro skin biology tests to conduct proof-of-concept studies and a QbD approach when developing these new formulations.
Another challenge relates to the patentability of these new topical formulations. There is, according to Newsam, therefore a huge value in establishing a robust basis for formulation composition of matter patentability. It is difficult, though, to realize this type of patentability value using conventional development techniques, he says. Tioga Research has found that using its proprietary HTE technologies and Cascaded Screening procedure typically yields formulation innovation and support for patentability.
“Historically, formulation composition-of-matter patents were not considered valuable because they could potentially be circumventable by minor changes in composition,” Newsam observes. “We have shown through the development of products such as PENNSAID 2% (US Patent 9,066,913), which was approved via a 505(b)(2) route, that it is possible to establish robust patent protection using this fresh approach to formulation innovation,” he asserts.
Balance of art and science
Formulators of topical drugs are faced with a number of technology, regulatory, and drug-compatibility limitations. Overcoming them requires access to a dynamic “ingredient tool box” and the knowledge and know-how to use these tools effectively, according to Goodyear. “Developing topical semi-solid formulations intended to elicit a pharmacological effect is a delicate balance between art and pharmaceutical science,” he states.
Both entry-level and experienced staff may gain additional knowledge by getting involved with other experts working in the topical pharmaceutical industry through participation in workshops and professional communities such as the American Association of Pharmaceutical Scientists Topical and Transdermal Community, Goodyear notes.
Considering product availability and patient access to be part of the treatment selection process during early development of new topical formulations may also yield more positive clinical outcomes and change the way we see skin treatments and clinical acceptance, Goodyear adds. He also notes that establishing best practices in-house that are aligned to FDA requirements will help reduce time to market while further enabling the development of formulations that patients will truly appreciate.
Newsam concludes by observing that the skin is an amazing barrier. “The outermost layer of the skin (the stratum corneum), which provides most of this barrier function, is some 15 microns thin. It is in a sense an extremely fragile medium for keeping potentially harmful agents outside the body and our molecular constituents maintained within.” He also comments that there is still much to learn about the skin and how it functions. “As we gain a greater understanding of this crucial organ, it is exciting to think about the broader spectrum of formulations that might be suitable for topical administration,” Newsam considers
About the author
Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology.
Article Details
Pharmaceutical Technology
Vol. 45, No. 4
April 2021
Pages: 20–25
Citation
When referring to this article, please cite it as C. Challener, “Balancing the Art and Science of Topical Drug Formulation,” Pharmaceutical Technology 45 (4) 2021.
