Numerous skin diseases and disorders that affect different layers of the skin can be treated with topical dermal drug delivery (TDDD) systems. Topical delivery is advantageous over systemic administration due to its ability to provide targeted treatment and avoid first-pass metabolism. Successful topical formulations deliver the API to the proper layer of the skin at an appropriate rate so as to maintain the necessary concentration over a period of time; in other words, they provide appropriate permeation kinetics. There are many factors that determine the delivery kinetics of TDDD systems, not the least of which is the need to overcome the protective barrier function of the skin. Thoughtful formulation development is essential to developing optimal topical drug products.
A look at topical delivery mechanisms
Over the years, the skin has become an accessible and practical site for the delivery of medicines, according to Gayathri Krishnan, associate director of in vitro sciences with Tergus Pharma. Many different dosage forms enable delivery of actives to the skin, such as creams, ointments,
lotions, liquids, suspensions, gels, hydrogels, pastes, foams, suppositories, and nail lacquers.
Drugs in topical formulations can exhibit activity on the superficial layers of tissues, or via penetration and permeation into deeper layers, or through systemic distribution depending on the physiochemical qualities, targeted site of action, and formulation procedures, Krishnan observes. She adds that there are three main delivery mechanisms: transcellular, intercellular, and trans-appendageal.
In the trans-appendageal pathway, or the shunt route, the API is delivered through appendages such as hair follicles and sweat ducts, which provide entry through the protective stratum corneum. APIs delivered via the transcellular route leverage phospholipid membranes and the cytoplasm in the dead keratinocytes that make up the stratum corneum to directly cross the skin. This is the fastest route, but APIs must be able to pass through each cell’s lipophilic membrane, hydrophilic keratin-containing interior, and phospholipid bilayer membrane, repeating this process multiple times to cross the entire thickness of the stratum corneum. APIs that can do so effectively are rare, according to Krishnan.
The intercellular pathway comprises narrow crevices between skin cells that APIs can traverse. Despite therelative thinness (approximately 20 μm) of the stratum corneum, most APIs following this pathway must travel
another 400 μm or more as they diffuse this top skin layer.
Indication and delivery mode determine ideal delivery kinetics
In addition to these different delivery mechanisms, there are several possible modes of action of topical formulations, according to John M. Newsam, CEO of Tioga Research. Some are designed for the API to be active on the exterior of the skin, and thus operate via a superficial mode. Most are intended for the API to be active in the epidermis or dermis, which requires penetration into the skin. Some are designed for the API to be delivered through the skin but remain locally concentrated in an area adjacent to the site of application, such as a knee joint. Finally, transdermal formulations are engineered for the API to pass through the skin into the vasculature or lymphatic system to achieve systemic delivery.
The kinetics of delivery depend on which of these four modes is being emphasized, Newsam says. For instance, transdermal delivery has an initial lag time as the API diffuses through the layers of the skin and then achieves relatively uniform provision of the active into systemic circulation over a period of time. “The ideal product will have a short lag time, moving to steady state delivery as quickly as possible and then enable sustained delivery for an extended period of time,” he notes. Ideally, a topical formulation will deliver the APIs to the right site at the correct therapeutic level over a few hours.
Delivery kinetics also depend on the type of skin and the area of the body to which the product is applied. Some topical drugs are, for instance, applied to areas of the skin that are compromised. These drugs are designed to not only treat the problem, but provide relief as quickly as possible, according to Newsam. In other cases, the API could be beneficial in treating a skin disorder but potentially give rise to systemic toxicity. Delivery to the epidermis or dermis with minimal API reaching the vasculature or use of an API with a short half-life so that it is rapidly cleared from the bloodstream would be important.
The nature of the topical formulation should also be designed to deliver the active to the appropriate part of the skin. Treatments of conditions involving the skin surface and very top layers should be designed to remain on the surface. Treatments targeting the epidermis should ideally deliver the active in a sustained-release fashion, while deeper delivery through the epidermis to the dermis is needed to treat inflammatory skin conditions.Options include film-formers for surface treatments and transdermal patches for deeper delivery.
Patient-related factors important
Topical formulations targeting different indications and different patient populations must be designed to address the specific needs of those patients, according to Newsam. The condition of the skin and the location of application are two primary factors to consider. Others may include the age and skin color/pigmentation of the patients receiving the treatment. Blood supply to the skin along with skin moisture, pH, and temperature are also important, says Krishnan.
Patients with eczema or psoriasis might have cracked skin and, therefore, a reduced protective barrier. This reduced barrier could allow an increased rate of API delivery. Unlike the hands and feet where the barrier layer is thickest, barrier function is lowest in the eyelids and scrotum. Skin also tends to be more permeable for the very young and the very old.
The presence of structures such as hair follicles and sweat and apocrine glands can provide areas of ingress; a topical formulation applied to the scalp would likely exhibit different delivery attributes than the same formulation applied to the upper torso or thigh. Sebum, which is a thin, buttery film exuded from sebum glands located on the scalp, face, and underarms, has its own barrier characteristics that differ from those of the skin itself, leading to different delivery requirements.
The rate and degree of drug absorption can also be affected by a variety of illness conditions, with hepatic, cardiovascular, and gastrointestinal disorders having the greatest impact on API bioavailability, according to Krishnan. She adds that the area of absorptive surface, the level of vascularity, and the degree of skin hydration can impact delivery as well. For instance, stress reduces blood flow to the gastrointestinal tract, leading to less absorption. “As a result, patient-related factors have a significant impact on how well medications can be absorbed via the skin and thus on the ultimate efficacy of topical formulations,” she contends.
It is also important to consider the cosmetics and aesthetics of topical products, because they have a direct impact on patient compliance. People with acne want quick-drying products while those with psoriasis prefer soothing creams or ointments, for instance.
API properties are crucial
Transdermal absorption is influenced by an API’s physicochemical characteristics, such as charge, polarizability, hydrogen bonding, shape, and molecular weight. For delivery into the skin, the molecular shape of an API can, in fact, be a key determiner of bioavailability, according to Krishnan. “The skin acts as a physical barrier against particles on a macroscopic level, hence the physical state of the API has a significant impact on its permeation,” she says.
Most traditional drug substances chosen as transdermal delivery candidates fall within a relatively small molecular-weight range of 100–500 Dalton, Krishnan notes. “Due to its simplicity, molecular weight is typically used to approximate molecular volume with the implicit presumption that the majority of molecules are essentially spherical,” she explains.In that constrained range, the impact of molecular weight on drug flux seems to be rather small, Krishnan adds. For larger molecules, factors such as pH and particle size come into play as well.
A second important characteristic of APIs that determines their skin permeability is their lipophilicity/hydrophilicity. That is because the API most likely enters the stratum corneum through the lipid bilayers in between desiccated cells, and this initial partitioning occurs according to the API’s partition coefficient.
In practical terms, Newsam indicates that optimal skin permeability is realized for APIs that have logP (octanol-water coefficient) values between 2 and 3. “Lipophilic molecules such as cannabidiol get stuck in the lipid layers in the stratum corneum and don’t diffuse much further. Very water-soluble molecules with negative logP values also have intrinsically low skin permeability because they are typically charged or highly polar, which also prevents diffusion through the skin,” he explains.
It is also important to optimize the concentration or ‘strength’ of API in a topical formulation as the concentration gradient drives API diffusion from the formulation into the skin. If the API is poorly-soluble in the formulation, then the driving force for delivery into the skin will be low with only modest extents of delivery. Ideal formulations have the API concentration approaching, but no more than approximately 85% of the saturation limit, according to Newsam.
The potential for APIs to bind to proteins in different layers of the skin must also be considered because it can contribute to reduced activity. The increasing potency of APIs is also important, as the percentage of drug candidates in the pipeline that are highly potent is increasing, and higher potency may allow for topic formulations containing molecules with properties outside the typically acceptable ranges.
APIs must also be stable in topical formulations and in the skin. That means, comments Newsam, they must be resistant to isomerization, oxidation, or hydrolysis in the formulation itself and also to degradation by esterases, proteases, and other enzymes present in the skin. Finally, they should not be injurious to the skin, and therefore not be irritants or sensitizers, both as is and when exposed to photo-irradiation.
Excipients play a role
It is important to remember that in topical formulations, excipients comprise the bulk of the drug product. “Excipients affect the physicochemical properties of the API and the drug product, the sensory properties of the formulation, and the quality features of topical products,” agrees Krishnan.
The selection of the vehicle is influenced by the physiochemical properties of the drug, the disease, and the target patient population. The other excipients perform a variety of functional roles, including improving solubility to allow incorporation of the drug at the target concentration, controlling or improving API release and permeation, creating the desired aesthetics, enhancing API and formulation stability, and preventing microbial growth.
By looking at an API’s physicochemical characteristics—molecular weight, logP, polar surface area, number of hydrogen-bonding donors and acceptors, melting and boiling points, etc.—Newsam indicates it is possible to estimate how readily it will diffuse into the skin. But once an API is put into a real formulation, “all bets are usually off”. As a result, excipients play a very important role in topical formulations.
Excipients that affect the permeability of the skin include molecular penetration enhancers such as alcohols, fatty acids, and fatty esters. However, Newsam cautions that because of cross interactions between different diffusion pathways, the effect of these excipients is rarely simply additive or subtractive, making it difficult to predict formulation performance.
Other excipients are used to create the desired appearance and texture of topical formulations depending on the dosage form. Emulsifiers or surfactants are needed to stabilize lotions and creams, which typically comprise two immiscible phases, while rheology modifiers are needed to achieve the desired viscosity for products that must flow. Bioadhesives make it possible for patches to adhere to the skin even when wet, but still allow them to be removed without causing too much pain. Antioxidants and antimicrobials protect formulations in storage and in use.
Permeability and solubility enhancers must be compatible with not only the API, but all of these other excipients and the carrier, Krishnan comments. They must adhere to pharmacopeial quality requirements, and not irritate, sensitize, or irreversibly perturb the stratum corneum barrier. “Often extensive screening is required to identify the right combination of excipients for a given API that affords the optimum solution with respect to permeability, applicability, and appearance,” states Newsam.
Formulation success requires more than achieving the right level of permeation
Topical formulations are highly complex medicines intended to interact with the skin, which is designed to serve as a protective barrier and therefore by its nature limits the delivery of APIs into and through it.
“Achieving the appropriate level of delivery or permeation is usually the greatest challenge in topical drug formulation,” says Newsam. “The number of approved drugs that actually deliver API through the skin is few, because even fairly small molecules can have low skin permeability, and that permeability tails off exponentially as molecular weight increases above about 500 Da,” he says. APIs in transdermal products on the market today were, Newsam adds, initially approved for another mode of administration and developed as topical formulation in a next-generation approach.
Even with the challenge of achieving appropriate levels of delivery and permeation, the failure of many topical drug candidates that make it into clinical development can be attributed not to efficacy or safety, but actually to chemistry, manufacturing, and controls (CMC) issues, according to Newsam. “To achieve the desired level of permeability, topical formulations are often complex, which can complicate their preparation in a robust, reproducible, and uniform fashion,” he explains.
In addition, the API must be intrinsically stable in the formulation and not react with water or other excipients at the formulation pH or undergo a structural conversion such as isomerization. It could also degrade when coming in contact with the skin, and the degradants might be irritating to the skin. “As a consequence, while delivery and permeation are often the governing concern, there are many other factors that must be addressed when developing topical formulations,” Newsam concludes.
Topicals have received a lot of attention recently and are becoming a greater focus in the pharma industry, but often, says Krishnan, issues arise because drug developers do not apply formulation principles correctly and safely. “These problems most likely arise due to a lack of comprehension of the concepts relating to skin permeation mechanisms and kinetics and the complex requirements for successful topical formulations. Effective development of safe, efficacious, patient-acceptable, and manufacturable topical products cannot be realized unless these concepts are applied and formulators understand the full range of characteristics and qualities that impact topical drug delivery and patient acceptance,” she concludes.
Several potential strategies for optimizing topical drug delivery
Topical drug formulation development is a multistep process, according to Newsam. The first step should be to understand the physicochemical characteristics of the API using in silico computational methods to identify the various challenges that must be overcome. Analytical method development should come next so that API quantitation is possible. Determination of solubility and compatibility properties follows. With this information it is possible to narrow down the potential tactics for achieving required levels of delivery.
Quality by design for topical product development with an emphasis on determination of the quality target product profile, critical process parameters, critical quality attributes, and critical material attributes is essential, Krishman underscores. “Product development at Tergus focuses on quality and compliance in topical formulation development, analysis, in vitro release and permeation testing, and all the way through clinical supply manufacturing,” she says
Tioga Research uses a three-pronged approach. First, the company has a set of established formulation systems designed and built for particular classes of molecules, such as with logP values in a particular range. A new API is introduced into the appropriate starting formulation, potentially with other compatible excipients, and the extent of delivery and permeation measured. Second, Tioga’s formulation scientists mine the company’s databases for results with similar molecules over their 20 years of experience in topical drug development to be guided towards optimum formulation systems.
If these two methods do not yield an optimal formulation, Tioga leverages its high-throughput experimentation platforms and proprietary Cascading Screening methodology to evaluate large numbers of different formulations. An added benefit of Cascading Screening, particularly for 505(b)(2) products, Newsam points out, is the potential to establish a solid basis for composition of matter patentability for the best formulations. “Screening the entire useful formulation space means that it is unlikely that there are other formulations that will perform as well, which makes it difficult for competitors to circumvent such a patent,” he explains.
Overall, Newsam stresses that topical formulation development strategies should be geared toward the desired dosage form, and formulation innovation should focus on the key requirements of the specific product as quickly in the development process as possible, whether that is a transdermal patch, a film-forming matrix, a foam, a spray, a gel or a cream. “At Tioga, we might run some initial screens using simple solutions, but as quickly as possible we progress to preparing libraries of prototype formulations and measuring the performance of each, because, for instance, results with simple solutions may be poorly predictive of behavior in a practicable patch formulation,” he observes.
About the author
Cynthia A. Challener, PhD, is a contributing editor to Pharmaceutical Technology.
Article details
Pharmaceutical Technology
Volume 46, Number 9
September 2022
Pages: 22–27
Citation
When referring to this article, please cite it as C. Challener, “Delivery Kinetics for Topical Drugs,” Pharmaceutical Technology 46 (9) (2022).
Download Issue: Pharmaceutical Technology, September 2022
