Topical delivery of niacinamide, encapsulated in niosome and proniosome carriers

Abstract

Niacinamide, better known as vitamin B3, is water soluble and takes part in oxidation-reduction reactions in the mitochondria of the skin (Bissett, 2009:438). This active possesses antiinflammatory action, decreases transepidermal water loss (TEWL) and prevents the loss of dermal collagen (Mohammed et al., 2013:192). For this reason niacinamide is an ideal product to be applied topically for the treatment of ageing, hyperpigmentation, melasma and rosacea (Gehring, 2004:88). Considering niacinamide for topical application, the physicochemical characteristics of the active, as well as the physicochemical properties of the skin must be brought into account (Barry, 2007:566). Since the skin is the outermost organ of the human body; it protects the body by acting as a barrier against the penetration of agents from the external environment (Bolzinger et al., 2012:156). This barrier function of the skin resides in the stratum corneum, which is the outermost layer of the epidermis (Feingold & Denda, 2012:263). Thus, for this reason, the barrier function of the stratum corneum makes the delivery through the skin a challenge. For an active to penetrate through the skin and concentrate in the underlying layers; the molecular size, solubility, partition coefficient and ionisation is of importance (Benson, 2012). According to Barry (2001:102), the molecular size must be less than 500 Dalton in order to penetrate the skin. The molecular size of niacinamide is 122.1 Dalton (Dollery, 1999:N62), indicating that the size of the active will be ideal for topical penetration. The solubility of niacinamide was determined in the study as 112.70 mg/ml, which according to Naik et al. (2000:319), is the ideal solubility, since it is higher than 1 mg/ml. The partition coefficient was e -0.43. This value indicates that the active is not ideal for topical penetration; since it does not possess both lipophilic and hydrophilic properties (Donnelly & Sing, 2015:13). For the active to penetrate the skin the ideal partition coefficient must be between one and three. When considering the ionisation of the active, the ionised form of a molecule is less likely to penetrate the skin than the unionised form (Donnelly and Sing, 2015:15). Niacinamide is 99.99% ionised at a pH of 7.4, causing the active to pass through the stratum corneum with difficulty. For these reasons niacinamide was encapsulated into a vesicle system in order to “mask” the physicochemical characteristics which cause a challenge to penetration through the skin. Vesicle systems are hollow particles composed of a protective layer consisting of a hydrophilic head and a hydrophobic tail (Honeywell-Nguyen & Bouwstra, 2008:206). These systems are ideal for topical delivery of actives, since they can entrap both hydrophilic and hydrophobic substances. They deliver the entrapped substance at a specific location and are non-toxic (Honeywell-Nguyen & Bouwstra, 2008:206). These systems are known as niosomes and proniosomes and the difference between them is the method of preparation (Seleci et al., 2016:4). Proniosomes are prepared to form a dry powder in order to have a longer storage life than the niosomes (Yeom et al., 2014:83), consequently, proniosomes are hydrated (just before use) to form niosomes. Although both the niosomes as well as the proniosome systems present with excellent properties, their low viscosity can be a drawback when trying to apply the dosage form. During this study, the viscosity was determined as 4.036 cP and 3.616 cP for the niosomes and proniosomes, respectively. According to Barry (2007:595), designing a product for maximum topical effect is important, but designing a product to be acceptable to the consumer is of more importance. Consumers prefer a product that can be transferred from the container easily, spreads readily and is not difficult to remove from the skin, thus, a product with poor appearance will lead to non-patient compliance (Barry, 2007:595). In order to increase the viscosity and enhance compliance only the niosomes were incorporated into a gel and a cream, since proniosomes become niosomes once hydrated. Franz cell diffusion studies were performed on the pre-formulations (niosomes and proniosomes) and on the formulations (niosome gel and niosome cream). First, the membrane diffusion studies were performed to determine if any release of the active occurred from the formulation. The preparation which presented with the highest median flux were the proniosomes (1 163.58 μg/cm2.h), followed by the niosomes (1 162.58 μg/cm2.h), then the niosome gel (1 042.08 μg/cm2.h) and lastly, the niosome cream (469.72 μg/cm2.h). During the skin diffusion studies, all the preparations presented with niacinamide in the receptor phase. The preparation with the highest median flux value in the skin diffusion studies were niosomes (0.844 μg/cm2.h), followed by the niosome gel (0.692 μg/cm2.h), the proniosomes (0.462 μg/cm2.h) and lastly, the niosome cream (0.172 μg/cm2.h). All the preparations presented with niacinamide in the stratum corneum-epidermis (SCE) and epidermis-dermis (ED). The preparation with the highest median concentration in the SCE was the niosome (2.13 μg/ml), followed by the niosome gel (1.94 μg/ml), the niosome cream (1.05 μg/ml) and lastly, the proniosomes (0.71 μg/ml). The niosomes (5.02 μg/ml) were the dispersion with the highest median concentration in the ED, followed by the niosome cream (2.86 μg/ml), the proniosomes (2.04 μg/ml) and lastly, the niosome gel (1.94 μg/ml). Since the aim of this study was to deliver the active topically, all four the preparations were successful. Stability tests were performed on the niosome gel and niosome cream for a period of three months. According to ICH (2006:3) guidelines, the formulations were stored at ± 25° C/60% RH (relative humidity), ± 30° C/65% RH and ± 40° C/75% RH to determine if any change in the physicochemical properties of the formulations occurred. The chemical stability (concentration of the active) as well as physical properties (pH, conductivity, viscosity, light microscopy changes, visual changes, mass loss and zeta-potential) were determined initially (t=0) as well as after 1, 2 and 3 months respectively. Both the formulations were stable regarding the stability of niacinamide, the pH, mass loss (only the niosome gel), light microscopy, visual appearances and zeta-potential