Polymeric Emulsion Technology Applied to Tretinoin

The Microsponge Delivery System (MDS) is a controlled drug delivery system that encapsulates the active drug, releasing it over time; and in response to a trigger such as rubbing, changes in pH, or increased temperature. The technology was developed over 30 years ago,¹ and is widely used in cosmetics, skin care products available over-the-counter or through prescription, and sunscreens.²It consists of porous, polymeric microspheres (polyol-prepolymer-2) forming multiple interconnecting spaces that serve as a drug reservoir and mimicking a rigid sponge. Microspheres vary in size from 5-300μm and the sizes of these porous structures determine the amount and rate of drug release. For example, a typical 25μm sphere can have as many as 250,000 pores. Microspheres do not penetrate the skin; they sit on top of the skin and slowly release tretinoin to potentially reduce any irritation. The empty spheres may stay on the skin and collect lipophilic materials such as sebum and be washed away when the skin is cleansed.Microspheres delay the onset of irritation, but do not reduce the cumulative irritation when compared with other tretinoin formulations.³ Another safety concern is the potential bacterial contamination of materials entrapped in the microsponge. Bacteria cannot penetrate into the tunnel structure of the microsphere because the pore diameter, which ranges from 0.007 to 0.2μm, is smaller than bacteria. In addition to any drug delivery benefits, they are capable of absorbing skin secretions, reducing oiliness and shine from the skin. In the case of tretinoin microsphere formulations, the drug is encapsulated in copolymer particles measuring 17-27μm and released gradually into the skin.Additional benefits of the MDS include improved photostability, improved compatibility with benzoyl peroxide (BP), and reduced irritation potential. Tretinoin formulations (ie, gels, creams, and lotions) have been reported to be unstable on the skin under bright artificial light or sunlight. When combined with a strong oxidizing agent such as BP and antibiotic such as erythromycin, and subjected to fluorescent light for 24 hours, tretinoin photodegradation in tretinoin 0.025% gel increased to 89% and 95%.^4,5 Tretinoin in a microsphere formulation did not undergo such degradation; 98% of tretinoin tested remained stable after 24 hours exposure to fluorescent light, incandescent light, or darkness^.5 A similar protective effect was seen after exposure to simulated solar UV irradiation for 6 hours; 84% of the initial tretinoin remained stable in the microsphere formulation, compared with only 10% in tretinoin 0.025% gel.⁶ Irradiation of a tretinoin microsphere-BP-erythromycin combination resulted in a 94% to 95% tretinoin recovery rate after 8 hours and 86% to 87% recovery rate after 24 hours of exposure to incandescent or fluorescent light.⁵After 6 hours of simulated solar light, 81% of the combination remained stable compared with 0% in tretinoin 0.025% gel.⁶ The practical benefits of these findings were demonstrated in a phase 4 study of tretinoin microsphere 0.04% plus BP 5% wash, where patients who cleansed their face with BP 5% wash followed by tretinoin each morning and those who cleansed in the morning and applied tretinoin microsphere 0.04% gel each evening had a similar response.⁷Application of the MDS to the skin has demonstrated the ability to reduce the irritancy of tretinoin. However, one disadvantage of tretinoin microsphere 0.1% gel is its rough or ‘gritty’ texture when spread onto the skin, due to the nature of the microsponges and some patients find this unpleasant. Also, a ‘burst effect’ can occur as tretinoin is released from microspheres attributed to the deposition of drug at or close to the outermost parts of the microsphere walls.⁸ This burst delivery of tretinoin may cause drying and peeling that could progress to uncomfortable scaling and redness of the skin and impact adherence. This new technology may be able to improve on the advances already made with the MDS system.

The role of particle size reduction and particle engineering is another important aspect of formulation development in acne. Micronization is a valuable technique for products with poor water solubility and bioavailability. It increases the dissolution rate of drugs through an increased surface area. However, as compared to the effect on dissolution properties, decrease in particle size has comparatively little effect on the solubility of the drug substance as it does not alter the solid-state properties.Tretinoin has a very low water solubility (less than 0.2μg/ml) which can limit its utility without formulation technology.⁹ In addition, the