Improving active bioavailability is key to improving the efficacy of skin care formulations. When products are clinically tested, subjects can normally be grouped into low, medium and high responders. By decreasing the number of low responders and increasing high responders, clinical efficacy can be dramatically improved.
I believe that much of the subject variability can be attributed to poor bioavailability of low responders. For example, benzophenone skin penetration has a subject variability of 6 ug/cm2 to 40 ug/cm2 penetrating in 48 hours on the same skin site. Best in class skin repair actives can reduce wrinkle depth in high responders by up to 60%, but only approximately 30% when averaged with low and medium responders. This suggests that improving bioavailability of an existing active by increasing the number of high responders may be a better strategy than developing new actives.
What is “bioavailability?”
Bioavailability is defined as the penetration rate for an active to reach its site of action. This is also referred to as the flux rate or the amount of active penetrating over time (micrograms/cm2/hour). For cosmetic actives, the target usually is the lower epidermis. However, for ingredients like sunscreens, the goal is to stay on the surface of skin to assure maximum UV absorption. The challenge in formulating highly effective skin care products is getting superior bioavailability while minimizing irritation caused by other formulation ingredients that may also have penetrated. In pharmaceutics this is referred to as the therapeutic index or the benefit/risk ratio. For skin care products, unlike drugs, only an extremely low level of risk is acceptable.
Three factors that control the penetration rate of actives
The three most important factors that control the skin penetration of actives are molecular weight, C log P and charge (anionic or cationic). The highest molecular weight that an uncharged active can normally penetrate is approximately 500 Daltons. C log P is a measure of the hydrophobicity of a molecule as measured by the log of its solubility in Octanol divided by its solubility in water. Low or too high hydrophilicities can cause poor penetration. It has been shown for compounds to have a reasonable probability of penetrating, their C log P value must be between 1 and 5(1).
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What formulations affect bioavailability?
Different types of formulations can demonstrate significant differences in bioavailability. These include oil in water, water in oil, water in oil in water, polyol in oil emulsions and hydrogels.
Most methods that increase bioavailability cause a disruption of the skin’s barrier function or work by increasing active solubility in water or oil.
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- Skin barrier disruption-the Stratum Corneum is comprised of layers of keratinocytes coated with epidermal lipids. Removing, penetrating, or changing the crystallinity or structure of this lipid layer will increase active penetration.
- Solvents: Dimethyl isosorbide, ethoxydiglycol, ethanol, oleic acid
- Phospholipids have consistently been shown to increase the skin penetration of both oil and water-soluble actives. Examples include lecithin, hydrogenated lecithin, lysolecithin, and tocopheryl phosphate.
- Surfactant vesicles: Ssurfactants can form multilamellar and unilamellar vesicles with actives. Liposomes produced using phospholipids, cationic and nonionic surfactants are examples.
- Hydration can reversibly swell corneocytes and change the structure of skin lipids and increase penetration(2). Examples include the use of humectants in formulations and the multilamellar liquid crystal based oil in water emulsions.
- Occlusion: Dermatologists frequently recommend using Saran wrap to increase the efficacy of steroid creams on skin. The use of drugs with a polyethylene/mineral gel has also been used for this purpose (Plastibase).
- Physical or chemical exfoliation: Exfoliating skin before applying an active or using with an active can frequently increase product efficacy(3).
- Examples of chemical exfoliants include lactic, glycolic, salicylic acids, and N acetyl glucosamine. Physical products include abrasive creams, sponges and electric or mechanical brushes.
- Increased solubility
- Molecular complexation: Cyclodextrins (alpha, gamma, hydroxypropyl beta cyclodextrin) have a molecular cavity that can encapsulate actives improving their water solubility. The complexation is very specific to the chemical composition and shape of the active.
- Phytoglycogen has a cavity which can encapsulate many different types of actives. The complexation doesn’t appear to be as specific on the chemical properties of the active like Cyclodextrin.
- Micro/nano emulsions, micellular solutions and high shear processing can be used to significantly reduce the particle size of an active.
- Highly polar emollients are frequently needed to solubilize water insoluble actives since few are non-polar. Examples include isopropyl lauroyl sarcosinate, lauryl lactate, phenyl ethyl benzoate, dioctyl maleate, and dioctyl isosorbide. Many sunscreens have also been shown to be penetration enhancers(11).
- Increase the partitioning of active out of the formulation into skin: If an active is too compatible in the formulation, there is no driving force for it to leave the product film and penetrate. The easiest way to accomplish this is to formulate the active at its saturation point in the water or oil phase. When Retinol, for example, is formulated using a polar emollient, its irritation potential is lower versus using a non-polar emollient. This is due to slower skin penetration caused by the Retinol not partitioning as rapidly from the formulation film into skin.
- Skin barrier disruption-the Stratum Corneum is comprised of layers of keratinocytes coated with epidermal lipids. Removing, penetrating, or changing the crystallinity or structure of this lipid layer will increase active penetration.
- Prodrug approach: Chemically modifying the active and using skin enzymatic skin activity to convert to the active form once it penetrates
- Acylation of skin repair peptides is claimed to improve skin penetration by a factor 100 to 1000. This also increases the C log P.
- Charge neutralization Frequently, the bioavailability of charged actives can be increased by complexing an anionic or cationic active with a material that has an opposite charge. This is referred to as an ion pair formation and results in the charge being neutralized.
- Miscellaneous methods
- Iontophoresis is the process of enhancing the permeation of topically applied therapeutic agents through the skin by the application of electric current(4).
- Electroporation is an electrical enhancement method which involves the application of short (microsecond or millisecond), high voltage (50-1000 volts) pulses to the skin(5).
- Microporation involves the use of microneedles that are applied to the skin so that they pierce only the stratum corneum and increase skin permeability(5).
- Heat enhances the skin permeation of drugs by circulation, blood vessel wall permeability, rate-limiting membrane permeability and drug solubility(6).
- Pressure waves generated by intense laser radiation can make the stratum corneum more permeable. It is only applied for a very short time (100ns-1µs)(7).
- Sonophoresis is a technique which involves the use of ultrasonic energy to enhance skin penetration of active substances(8).
- Magnetophoresis is the application of a magnetic field to enhance drug delivery across the skin(9).
- Radiofrequency involves exposure of the skin to a high frequency alternating current of 100 KHz that results in the formation of heat-induced microchannels in the Stratum Corneum(10).
References
- https://www.organic-chemistry.org/prog/peo/cLogP.html
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849273/
- https://www.aad.org/media/news-releases/evaluate-before-you-exfoliate
- https://en.wikipedia.org/wiki/Iontophoresis
- https://www.tandfonline.com/doi/abs/10.1517/17425240902841935?journalCode=iedd20
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841791/
- https://www.sciencedirect.com/science/article/pii/S016836591300079
- https://www.researchgate.net/publication/286497155_Sonophoresis_An_overview
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5650684/
- http://www.pharmtech.com/advances-radio-frequency-transdermal-drug-delivery
- M. Branda, M. Spaldingb & C. Muellerb, Journal of Toxicology: Clinical Toxicology ,Volume 40, Issue 7, 2002.
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