The pharmaceutical market is dominated by oral solid and intravenous dosage forms. For some therapeutic compounds, however, conventional delivery is not possible due to drug degradation in the GI tract, drug instability, the inability to get the drug to the target site at the required concentration (bioavailability), or systemic side effects. For these drug substances, topical delivery may provide an attractive alternative to overcome these challenges in a rapidly growing marketplace.
With topical formulations, it may be possible to deliver the active ingredient to a specific site and avoid first-pass metabolism, changing drug concentrations in the bloodstream and patient-specific differences. In addition, topical products can be applied by the patient and often lead to increased medication adherence. “There can be substantial benefits to delivering a drug topically, even if the intended domain of action is systemic,” notes John M. Newsam, CEO of Tioga Research. “Topical formulations continue to be of substantial appeal to populations of patients affected by many different conditions. Where compliance and patient preference have been assessed, a topical or transdermal mode of administration is often preferred over all others.”
In addition to more traditional, passive, or molecular means of modulating the skin barrier using topical delivery formats such as emulsions, ointments, creams, sticks, gels, foams, sprays, and patches, active or physical methods compromising the skin barrier to enable delivery are being researched, including microneedles, iontophoresis, and electrophoresis, among others.
Complex formulations and many challenges
A topical or transdermal drug formulation suitable for development must satisfy, simultaneously, several different criteria, according to Newsam. The formulation must provide an appropriate level of delivery and/or permeation (in some cases, deposition), no irritation or sensitization of the skin, physical and chemical stability and compatibility with the container-closure system, suitable esthetics characteristics, and regulatory compliance.
“The ultimate objective of any formulator is to produce effective and patient-friendly formulations, and with topical formulations this can be a complex journey,” says Charles Evans, vice-president of pharmaceutical development at MedPharm. One of the major challenges that general formulators face, he adds, is the limited understanding of the complexity of topical formulations, particularly from an industry used to working on more conventional dosage forms such as oral solids and injectables.
Key challenges for topical formulation relate to the properties of the APIs in development today and include stability, low drug solubility, and permeability, observes Benjamin Goodyear, global technical marketing manager for BASF’s Pharma Solutions group. These challenges must be overcome while creating formulations with the right sensory characteristics and that are not irritating to the skin.
Many different types of excipients are required to achieve the desired performance properties of topical formulations, which has led to additional challenges. Presently, there is no separate approval pathway for novel excipients, so formulators generally are only willing to use excipients that are already used in approved pharmaceutical products.
Most of these excipients were introduced many decades ago and often do not have the properties needed to satisfy the complex criteria required of topical drug products today, which has created a real need for novel materials. “Currently, discussions regarding possible routes of introduction for novel excipients that are separate from inclusion in a new drug application (NDA) submission have been gaining some interest, but as of yet there is no clear method outlined by the regulatory authorities,” Goodyear says.
Fighting COVID-19 with topical formulations
The COVID-19 pandemic has driven tremendous innovation within the pharmaceutical industry over the last year. Topical formulators were no exception, with many interested in developing effective solutions for fighting the SARS-CoV-2 virus. Tioga Research has beenhelping groups develop viricidal topical formulations for administration to one or more mucosal surfaces.
BASF developed a hand wash based on polyvinylpyrrolidone (PVP)-iodine, the active ingredient considered the gold standard in the medical community for sanitizing prior to surgical procedures. PVP-Iodine presented as a mouth gargle and topical spray may be potential candidates to combat viruses as well, and clinical data significant enough to validate its performance against SARS-CoV-2 are being developed, according to Benjamin Goodyear, global technical marketing manager for BASF’s Pharma Solutions group.
Tergus Pharma entered an agreement with Phenom Pharmaceuticals to develop a unique delivery solution for intranasal administration of a unique API with the potential to prevent viral infection. “In this partnership, we are leveraging our technology in topical pharmaceutical R&D and manufacturing,” says Vijendra Nalamothu, chairman and CEO of Tergus Pharma.
The lack of novel excipients is a particular issue for the formulation of topical products based on biologics. Investment in biologics is increasing, and in 2019 they accounted for 35% of all dermatological investments, with topical -focused biologics contributing approximately 5–10% of this total, according to Evans. “While they offer targeted treatments for a multitude of conditions, their physicochemical properties means that biologics are inherently difficult to deliver across the skin,” he explains.
For proteins, peptides, and nucleic acids, Newsam notes that in addition to the huge delivery challenge, maintaining the stability of the active(s) in the formulation, avoiding degradation in contact with skin, and realizing analytical methods with sufficient sensitivity are all potential issues. Even with complex small molecules, susceptibility to isomerization, hydrolysis, or reaction with classes of excipients can be a primary concern, he adds.
Formulators at small- to mid-sized pharmaceutical organizations, meanwhile, may be more inclined to use non-pharmaceutical grade materials during prototyping and scale up to cut development costs, not realizing that these materials do not always have the same performance as pharmaceutical-grade excipients, Goodyear observes.
In addition, introducing a safe and efficacious finished product into the global marketplace presents an overabundance of difficulties due to region-specific requirements mainly driven by the lack of harmonized testing protocols for complex semi-solid dosage forms, according to Goodyear.
There are further challenges for the development of topical generic formulations. To be approved as a generic drug, a topical formulation must perform equivalently to a reference listed drug (RLD) product, which can be realized by preparing a material that is termed Q1/Q2/Q3 equivalent. In addition to having the same API at the same strength, the formulation has the same excipients (Q1) in the same relative concentrations (Q2), and the same microstructure (Q3). Developing such a formulation, Newsam comments, requires the development team to first complete a formulation deconstruction operation using a variety of analytical tools.
Bioequivalence can, however, be achieved with a formulation comprising a different slate of excipients. “This approach opens the interesting possibility of gaining patent protection for a generic topical product,” Newsam observes.
Key considerations for topical formulation development
Formulating effective topical formulations attractive to patients requires consideration and prioritization of numerous variables. To address the challenges of solubility, permeability, and stability for topical formulations requires consideration of critical quality attributes. “A blend of solvents/co-solvents may be used to improve solubility, chemical penetration enhancers can be employed to improve permeability, and anti-oxidants, preservatives, pH buffers, etc., can be used to stabilize the API, according to Vijendra Nalamothu, chairman and CEO of Tergus Pharma.
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.
