SLN enriched hydrogels for dermal application: Full factorial design study to estimate the relationship between composition and mechanical properties

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Abstract

When considering dermal administration of cosmeceuticals and/or drugs, the stratum corneum layer of the skin, has a barrier function that limits the penetration of active substances to the targeted skin tissues. Solid lipid nanoparticles/SLNs are colloidal carrier systems, which show superiority in dermal administration of cosmeceuticals/drugs. This superiority results from the ability of the SLNs to penetrate the skin layers easily. However, the main problem in dermal administration of colloidal drug systems is the need for a suitable semisolid vehicle for application as well as patient compliance. The main purpose of this study is to investigate the relationship between hydrogels and SLNs by using 32 full factorial design which simplifies the process by establishing the relationship between variables. Two different types of gel forming agent, hydroxypropyl methylcellulose or Carbopol 934 P, in three different polymer concentration used for preparation of SLN-enriched hydrogels. Formulations evaluated for their hardness and cohesiveness by using 32 full factorial design and the optimum formulations obtained for both gelling agents. As a result, mechanical properties of hydrogels consisting either hydroxypropyl methylcellulose or Carbopol 934 P revealed promotive results for dermal application of SLNs. The type and concentration of the gel-forming agent which is selected as a semisolid carrier for lipid nanoparticles are basic parameters affecting the dermal behavior of the system.

Introduction

Dermal route is the first choice in the local treatment of skin-related diseases such as psoriasis, atopic dermatitis, and eczema and skin cancer. This application site is also used for cosmeceuticals which are between pharmaceuticals and cosmetics, to act as anti-aging; anti-wrinkle agent or to treat hyperpigmentation (Lohani et al., 2014). The active ingredients used both in the treatment of skin diseases and cosmeceutical purposes can be applied to the skin in the form of conventional semi-solid preparations such as cream, gel or ointment. However, these conventional carriers are designed to provide an emollient or protective effect and thus they may not be sufficient to overcome the stratum corneum which is the protective layer of the skin. Therefore only superficial effect may be achieved. Another problem of conventional semisolids is the need of high concentration of active substance to be effective (Gupta et al., 2012). The choice of appropriate drug delivery system for dermal administration is important in terms of the degree of percutaneous absorption. The prosperity of therapy for both cosmeceutical and therapeutic effect depends on the penetration of active ingredients into the relevant skin layer as well as the abundance of active components deposited in the deeper skin tissue within a certain period of time.

Being the largest organ of the body, skin acts as a natural principal barrier against the external environment. Nano-sized colloidal drug delivery systems are one of the ways of targeting drugs to the skin layers by overcoming this barrier function. Furthermore; nano-structures, particularly, lipid-based carriers, liposomes, nano or microemulsions and lipid nanoparticles have great progress in the last few decades for the local treatment of skin diseases and they are also used as cosmeceuticals. (Prow et al., 2011; Gupta et al., 2012). However, these nanostructures cannot be applied to the skin alone; they must be incorporated into a suitable semisolid vehicle for application as well as patient compliance. Hydrogel formulations are the most preferred systems for this purpose. In these systems, polymers which bind with solvent molecules form three dimensional hydrophilic structures. They have unique properties when applied to the skin such as being oil-free, easily spreadable, and easily removable.

Hydrogels that localize drug loaded nanoparticles at the site of application should exhibit appropriate viscosity and bioadhesive properties while no irritant and sensitizing effects are observed, and more importantly, in terms of noninvasive techniques, hydrogels are the most convenient way of applying nanoparticles and drug targeting with nanoparticles. Among the various types of polysaccharides, cellulose derivatives such as hydroxypropyl methylcellulose, and polyacrylic acid derivatives such as carbomers, xanthan gum and chitosan are the most preferred gelling agents for dermal drug delivery in literature (Valenta and Auner, 2004; Rehman and Zulfakar, 2014). In this study, hydrogels were prepared with either Carbopol 934 P or hydroxypropyl methylcellulose (HPMC K15 M). HPMC is a neutral, hydrophilic, swellable polymer with semisolid consistency, can rapidly hydrate, and has good gelling characteristics with very low toxicity. Due to its jelly-like structure HPMC hydrogels preserve their shape during the storage, spread and adhere to skin surfaces (Vlaia et al., 2001). Carbopol is a cationic, mucoadhesive polymer which is synthesized by cross-linking of the allyl sucrose. It has strong in situ gelling property and it is safe and provides controlled release due to its high molecular weight. The ease of spreading and application of carbopol based hydrogels improve patient compliance. Also, a hydrogel structure can be obtained at concentrations as low as 0.5–2 % (Ramasamy et al., 2012; Kaur et al., 2018).

The main purpose of this study is to investigate the relationship between hydrogel formulations and solid lipid nanoparticles (SLNs) by using factorial design. One of the chosen semisolid carrier systems is neutral and the other is positively charged, and they are both preferred for patient use in either cosmeceuticals or semisolid pharmaceuticals. SLNs, which are promising drug delivery systems for dermal application, have been proven to be effective against various skin conditions. This superiority results from the ability of the SLNs to penetrate the skin layers easily (Pardeike et al., 2009; Jensen et al., 2011; Escobar-Chávez et al., 2012). SLNs are colloidal drug delivery systems produced with lipids in solid state at both body and room temperature such as fatty acids, triglycerides, partial glycerides and waxes or mixtures of them. Their physiological lipid composition allows them to acquire biocompatible and biodegradable properties. When SLNs applied to the skin, they form an adhesive film on the skin surface and it causes an increase in the occlusive effect. Trans epidermal water loss (TEWL) decreases due to increased occlusive effect thus an increase in skin hydration can be achieved. This behavior of SLNs in dermal application is the main mechanism that weakens the barrier property of stratum corneum. Active substance reaches the deep skin cells easily and dermal drug targeting can be achieved due to the increase in skin hydration. Moreover, controlled drug release and enhanced long-term stability can be achieved by using SLNs (Wissing et al., 2001; Wissing and Müller, 2003).

Rheological and mechanical features are two of the most important properties of both cosmeceuticals and semi-solid pharmaceuticals that should be evaluated since they can be used as models of real situations. Parameters such as ease of removal from the container, skin spreadability and adhesive properties within acceptable viscosity are important in choosing a suitable formulation. Besides, patient acceptability and use are highly influenced by the mechanical parameters of the formulations. Texture profile analysis (TPA) is a suitable method for determining the mechanical properties of semi-solids and hydrogels. TPA method can provide information on transferring or applying the formulations from the measured parameters such as the hardness (firmness), compressibility, cohesiveness, elasticity (springiness) and adhesiveness of a pharmaceutical/cosmeceutical formulation (Jones et al., 1997). Incorporation of a particulate system into a hydrogel can also affect the rheological and textural properties of the final product (Silva et al., 2012). Thus, it is important to investigate the rheological behavior together with texture properties for SLN incorporated hydrogel systems.

Since pharmaceutical development from the formulation steps to finished product is an intensive and highly complex procedure, the pharmaceutical product must provide a certain quality for patient in all cases. Formulation development studies contain complex variables of active ingredients, raw materials or production method and all steps of the production should be elaborated conscientiously. Design of Experiment (DoE) is the most frequently used optimization method since the early 2000s in formulation development. DoE is an efficient and effective approach for finding the relationships between the selected independent variables and the responses obtained with a limited number of experiments (Sengel-Turk and Hascicek, 2017). The optimized formulation can be achieved with the mathematical equations generated from the DoE approach and response surface methodology (RSM) can also be used to model formulation optimization and predict responses.

In brief, the focus of the study is designed to examine the properties of the finished dermal products for cosmeceutical and pharmaceutical approaches; which are of great importance in patient compliance. A systematic screening study was employed to establish the relationship between particulate systems for targeting the active substances to the skin layers and the textural properties of the hydrogel used as a carrier. The 32 full factorial design with center points was applied to optimize the formulations. Then further texture properties such as compressibility, elasticity, adhesiveness and also viscosity features were investigated.

Section snippets

Materials

Tristearin and Hydroxypropyl methyl cellulose (HPMC K15 M) were obtained from Sigma Aldrich (USA). Tween 80; Carbopol 934 P (C934 P), and trietanolamine were purchased from Fluka (USA), Noveon (USA) and Merck (Germany) respectively. All other chemicals were of analytical reagent grade.

Preparation of solid lipid nanoparticles

High-pressure microfluidics technique was selected to produce tristearin based solid lipid nanoparticles since it is an organic solvent free method. Briefly, solid lipid was melted at 70 °C in a water bath; at the

Basic features of the SLNs

Tristearin based SLN formulation was successfully produced through high-pressure microfluidics technique. As nanoparticles should ensure the successful skin permeation of the entrapped drugs and also penetration of the active molecules into the relevant skin layers, the main key features of a nano-sized drug delivery system which is designed for dermal application are the particle size, size distribution and the surface charge. The basic characteristics of the developed SLN formulation are

Conclusion

Concerning topical administration; most of the products in the market are in the form of conventional semisolids such as cream, lotion or gel although the superiorities of nano-carrier systems, especially lipid-based ones in dermal application have been proved by many studies. The fact remains that, drug or cosmeceutical active substances loaded nanocarriers should be formulated in a semisolid carrier in order to apply to the skin. In this study, the behavior of hydrogels to be used as

Declaration of Competing Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

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