In recent years, the “quality by design” (QbD) approach has been used for developing pharmaceutical formulations. This is particularly important for complex dosage forms such as topical semisolid products. The first step for developing a product using this efficient approach is defining the quality target product profile (QTPP), a list of quality attributes (QAs) that are required to be present in the final product. These quality attributes are affected by the ingredients used as well as manufacturing procedure parameters. Hence, critical material attributes (CMAs) and critical process parameters (CPPs) need to be specified. Possible failure modes of a topical semisolid product can be determined based on the physiochemical properties of ingredients and manufacturing procedures. In this review, we have defined and specified QTPP, QAs, CMAs and CPPs that are required for developing a topical semisolid product based on the QbD approach.

Rheological characteristics and shear response have potential implication in defining the pharmaceutical equivalence, therapeutic equivalence, and perceptive equivalence of commercial topical products. Three creams (C1 and C3 as oil-in-water and C2 as water-in-oil emulsions), and two gels (G1 and G2 carbomer-based) were characterized using the dynamic range of controlled shear in steady-state flow and oscillatory modes. All products, other than C3, met the Critical Quality Attribute criteria for high zero-shear viscosity (η₀) of 2.6 × 10⁴ to 1.5 × 10⁵ Pa∙s and yield stress (τ₀) of 55 to 277 Pa. C3 exhibited a smaller linear viscoelastic region and lower η₀ (2547 Pa∙s) and τ₀ (2 Pa), consistent with lotion-like behavior. All dose forms showed viscoelastic solid behavior having a storage modulus (G′) higher than the loss modulus (G″) in the linear viscoelastic region. However, the transition of G′ > G″ to G″ > G′ during the continual strain increment was more rapid for the creams, elucidating a relatively brittle deformation, whereas these transitions in gels were more prolonged, consistent with a gradual disentanglement of the polymer network. In conclusion, these analyses not only ensure quality and stability, but also enable the microstructure to be characterized as being flexible (gels) or inelastic (creams).

Curcumin is a natural product with chemopreventive and other properties that are potentially useful in treating skin diseases, including psoriasis and melanoma. However, because of the excellent barrier function of the stratum corneum and the relatively high lipophilicity of curcumin (log P 3.6), skin delivery of curcumin is challenging. We used the principles of a Quality by Design (QbD) approach to develop nanoemulsion formulations containing biocompatible components, including Labrasol and Lecithin as surfactants and Transcutol and ethanol as cosurfactants, to enhance the skin delivery of curcumin. The nanoemulsions were characterised by cryo-SEM, Zeta potential, droplet size, pH, electrical conductivity (EC) and viscosity (η). Physicochemical long-term stability (6 months) was also investigated. The mean droplet sizes as determined by dynamic light scattering (DLS) were in the lower submicron range (20–50 nm) and the average Zeta potential values were low (range: −0.12 to −2.98 mV). Newtonian flow was suggested for the nanoemulsions investigated, with dynamic viscosity of the nanoemulsion formulations ranging from 5.8 to 31 cP. The droplet size of curcumin loaded formulations remained largely constant over a 6-month storage period. The inclusion of terpenes to further enhance skin permeation was also examined. All nanoemulsions significantly enhanced the permeation of curcumin through heat-separated human epidermal membranes, with the greatest effect being a 28-fold increase in maximum flux (J_max) achieved with a limonene-based nanoemulsion, compared to a 60% ethanol in water control vehicle. The increases in curcumin flux were associated with increased skin diffusivity. In summary, we demonstrated the effectiveness of nanoemulsions for the skin delivery of the lipophilic active compound curcumin, and elucidated the mechanism of permeation enhancement. These formulations show promise as delivery vehicles for curcumin to target psoriasis and skin cancer, and more broadly for other skin delivery applications.

The topical delivery route is proposed as an alternative or adjunctive approach to melanoma treatment, since the target site for melanoma treatment—the epidermal basal layer—is potentially accessible by this route. Microemulsion systems are effective delivery vehicles for enhanced, targeted skin delivery. This work investigated the effect of Rose Bengal (RB) and RB-loaded self-emulsifying microemulsions (SEMEs) on growth inhibition of human melanoma and normal skin cell monolayers, the safety of the excipients incorporated in SEMEs on human cell lines, and the in-vitro human skin penetration of RB delivered in SEMEs and control solution. Cellular toxicity was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and the growth inhibitory mechanism of RB was investigated by flow cytometry using PI staining. Unloaded SEMEs caused reduced cellular toxicity compared to the surfactant excipient, Labrasol^®. RB-loaded SEMEs increased cell growth inhibition compared to the RB aqueous solution. Flow cytometry revealed apoptotic cells after treatment with RB-loaded SEMEs, indicating that apoptosis may be one of the mechanisms of cell death. Preliminary results of multiphoton microscopy with fluorescence lifetime imaging (MPM-FLIM) analysis showed deeper penetration with greater skin concentrations of RB delivered from SEMEs compared to the RB aqueous solution. This study highlights the enhanced skin penetration and antimelanoma effects of RB loaded in a SEME system.

Human skin provides an effective route of delivery for selected drugs. Topical penetration of molecules is largely attributed to passive diffusion, and the degree of penetration can be represented by in silico, in vitro, and ex vivo models. Percutaneous absorption of pharmaceutical ingredients is a delicate balance between the molecular properties of the drug, the skin properties of the patients, and the formulation properties. Understanding this interplay can aid in the development of products applied to the skin. The kinetics of percutaneous absorption and an understanding of the rate-limiting steps involved can facilitate the optimization of these systems and enhance the degree to which skin drug delivery can be achieved. Solute–vehicle, vehicle–skin, and solute–skin interactions contribute notably to product release as well as the rate of absorption and diffusion across skin layers. These interactions alter the degree of permeation by interfering with the skin barrier or solubility and thermodynamic activity of the active pharmaceutical ingredient. This article aims to provide a concise understanding of some of the factors involved in the skin absorption of topical products, i.e., the pharmacokinetics of percutaneous absorption as well as the solute–vehicle–skin interactions that determine the rate of release of products and the degree of drug diffusion across the skin.