Unraveling the Impact of the Oil Phase on the Physicochemical Stability and Skin Permeability of Melatonin Gel Formulations

Abstract

Melatonin’s antioxidant properties make it a valuable component in anti-aging semisolid topical products. This study explores the role of Pemulen^®, an acrylic-based viscosifying agent, in stabilizing cream-gel formulations. Remarkably, even at low concentrations (0.4%), Pemulen^® successfully produced physicochemical stable topical formulations. In this work, the impact of the ratio of the oily phase—comprising olive oil and isopropyl myristate from 0 to 20%—was investigated to understand the internal microstructure effect on skin permeability, rheological properties, and stability. The formulations exhibited pseudoplastic behavior, with a significant positive correlation (p-value < 0.1) between the oily phase ratio, viscosity, spreadability, skin adhesiveness, and permeability. Formulations without the oil phase exhibited greater skin permeability. However, higher oily phase content enhanced viscosity, spreadability, and skin adhesion. Given that melatonin primarily degrades through oxidation, incorporating antioxidant excipients in semisolid formulations is crucial for maintaining its chemical stability. A quality by design (QbD) approach was used to assess the impact of four excipients—(a) DL-α-tocopheryl acetate (0.05%), (b) ascorbic acid (0.1%), (c) ethylene diamine tetraacetic acid (0.1%), and (d) sodium metabisulphite (0.5%)—on melatonin’s stability. Our findings indicate that maintaining the physical stability of the formulation with a 20% oil phase is more critical for protecting melatonin from oxidation than merely adding antioxidant excipients.

Introduction

During aging, there is a drying process in the skin which can be locally treated by the application of topical formulations [1]. The anti-aging effects of topical formulations can be improved by the addition of antioxidant-active products such as melatonin [2,3,4,5]. However, the physicochemical properties of melatonin make it challenging, considering its poor aqueous stability and low skin permeability [6]. In recent years, the potential of melatonin beyond managing insomnia has been linked to its ability to neutralize the oxidative stress of toxic substances, modulate the inflammatory response, and prevent DNA damage [7,8]. However, much higher concentrations are required to elicit these effects, and thus, there is a need for topical formulations containing much greater concentrations than those currently available in marketed products. The development of physicochemical stable melatonin topical formulations should be guided by the application of quality by design (QbD), targeting good stability balanced with suitable skin permeability to elicit a pharmacological effect.

According to US Pharmacopeia (USP), gels are defined as a semisolid system composed of a dispersion that consists of either small inorganic particles or large organic molecules, which are surrounded and penetrated by a liquid [9]. Structurally, gels are a two-phase system where inorganic particles are dispersed, not dissolved, within the continuous phase, while large organic particles dissolve in the continuous phase, forming randomly coiled, flexible chains [10]. In contrast, creams can be defined as white heterogeneous semisolid topical products generally containing water and oily phases [11]. The incorporation of these two phases agrees with the natural presence of both water and oil secretions on the surface of the skin. Mixtures of both types of water and oil components tend to provide greater hydration and protection of the skin.

To achieve the advantages of both types of formulations, cream-gels have arisen as a hybrid product that combines the characteristics of both gels and creams. It typically has a lightweight, non-greasy texture, offering the hydration and spreadability of creams while providing the cooling, refreshing sensation of a gel. Cream-gels are formulated with polymeric emulsifiers instead of oily ones. However, formulating cream-gels is challenging, as the selected polymeric emulsifier has to balance the oil and water phases to achieve the desired texture while ensuring the product remains stable and effective [12].

In most conventional creams, the viscosity depends on the incorporation of oil components with high melting temperatures, such as cetyl alcohol or other similar excipients [13]. However, these oily creams are not well perceived by consumers and now some of those oil excipients are replaced by water viscosity agents, such as acrylic derivative polymers. Pemulen® is an acrylic derivative viscosity agent that even at small quantities, such as 0.4%, provides gels with high viscosity [14,15,16]. Interestingly, the Pemulen® TR-1 y TR-2 also has surfactant properties which are suitable to obtain stable O/W creams without the need to heat the components to elaborate the products. Cold process elaboration is important to avoid chemical degradation of thermolabile active compounds such as melatonin [17,18]. Another important characteristic of Pemulen® semisolid formulations is that when they come into contact with a saline medium such as skin, their internal structure is changed, and there is a decrease in their viscosity properties. This decrease in viscosity is related to fast component release to the medium and the consequent topical action of the active components of the cream [19,20,21,22]. Currently, it is difficult to investigate the change in viscosity during skin application, which can be defined as the resistance against the movement [23].

The first aim of this work was to study the effect of the oil ratio on the skin permeability, spreadability, and rheological characteristics of melatonin cream-gel formulations using Pemulen® as a thickening agent. The second aim of this work focused on unraveling the impact of the addition of different excipients as potential stabilizers of melatonin. The addition of the following excipients was tested using quality by design: (a) DL-α-tocopheryl acetate (0.05%), (b) ascorbic acid (0.1%), (c) ethylene diamine tetraacetic acid EDTA (0.1%) and (d) sodium metabisulphite (0.5%). Chemical stability was studied by HPLC while physical characteristics were studied through rheological, extensibility, and internal phase particle size characterization.

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Materials

Melatonin (Ph. Eur. Grade) was purchased from Fagrón Ibérica SAU (Madrid, Spain). All excipients were of Pharmacopoeia grade. Pemulen® TR-1 was supplied by Lubrizol (Madrid, Spain). Propylparaben, glycerine, olive oil and DL-α-tocopheryl acetate were purchased from Fagrón Ibérica SAU (Madrid, Spain). Isopropyl myristate, sodium EDTA, triethanolamine, ethanol 96° and sodium metabisulphite were supplied by Panreac AppliChem (Barcelona, Spain). Methylparaben was purchased from Acofarma (Madrid, Spain), ascorbic acid was supplied by Guinama (Valencia, Spain) and purified water was obtained through Elix-3® (Merck Millipore, Burlington, MA, USA). All other chemicals were of ACS reagent grade or above from Panreac AppliChem (Barcelona, Spain), and solvents were of HPLC grade (Scharlau, Madrid, Spain) and were used as supplied.

Torrado, J.J.; Anaya, B.J.; Kara, A.; Ongoren, B.; Esteban-Ruiz, S.; Laguna, A.; Guillén, A.; Saro, M.G.; Serrano, D.R. Unraveling the Impact of the Oil Phase on the Physicochemical Stability and Skin Permeability of Melatonin Gel Formulations. Gels 2024, 10, 595. https://doi.org/10.3390/gels10090595

Read also our introduction article:

CPHI Milan 2024 – with a focus on excipients