Scale up and characterization of a cream formulation incorporating piper betle L. extract

Abstract

Hyperpigmentation is a skin disorder that causes the skin to darken in small patches of certain area or it may cover a large area of the body. This condition happens due to excessive production of melanin triggered by excessive sun exposure, hormonal changes, endocrine diseases and certain medication. Not only does it manifest itself physically it may also affect the quality of life of people who have it. The mainstay to manage this skin issues are topical skin lightening agents. Many skin lightening agents present in the market such as hydroquinone, arbutin and tretinoin have been losing interest from consumer due to the presence of adverse effects such as skin irritation contact dermatitis, ochronosis and permanent depigmentation. The alternatives that are getting people’s attention are natural based skin lightening agents due to its safety profile. Piper betle L. contains hydroxychavicol (HC) which is a phytochemical capable of conferring skin lightening activity by inhibiting tyrosinase enzyme. Formulation of a cosmetic cream containing Piper betle L was scaled up to an amount of 15 kg in a pilot plant setting. Prior to the procedure all the raw materials underwent halal endorsement by IKOP Sdn. Bhd. halal committee and identification using Attenuated Total Reflectance – Fourier Transform Infrared (ATR-FTIR). Throughout the scale up process, critical process parameters (CPP) such as temperature (75ºC), time (30 minutes) and speed (3000 rpm) of homogenization were closely monitored to ensure critical quality attributes (CQA) such as the viscosity and particle size were maintained within a desirable range. The formulation was then characterized in physical appearance, pH, particle size, zeta potential, rheological analysis, microbial limit study and HC content analysis. Stability study was then done over 6 months at conditions of 30±2 ºC and 40±2 ºC with relative humidity of 75±5% RH for both temperatures. Although there were slight deviations, the physical appearance of the cream remained stable with no phase separation or change in texture. Rheological analysis shows that the cream has a non-Newtonian flow with pseudo plastic property. While zeta potential maintained below than -50 mv. HC content was analyzed and showed that it degraded more at 40±2ºC compared to the sample stored in 30±2ºC. pH remain acidic suitable for skin application and particle sized maintained <2µm.Next an in vitro study using Franz cell diffusion set up was done using synthetic membrane and rat skin to assess the penetration of HC. Permeation studies show that HC permeate through synthetic membrane in a finite dose study setup but did not permeate through rat skin in an infinite dose study setup. However, retention of HC in the rat skin was confirmed through 24 hour skin extraction. The anatomical complexity of the rat skin may have contributed to the lack of permeation in comparison to synthetic membrane. Despite that, it is more preferable as the target site for skin lightening is at the melanocytes embedded within the epidermis. Lastly in vivo study proved that piper betle L. may confer skin lightening effect and the formulation itself may be able to improve skin barrier and skin elasticity.