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).

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Gene therapy has emerged as an influential tool for treating the genetic and specific acquired disorders. Among all kinds of gene delivery systems, the cationic polymer polyethyleneimine (PEI) is considered as a promising non-viral gene delivery vector, although there are still concerns about its magnitude of cytotoxicity. While any cell insult leads to unfolded/misfolded protein accumulation and its consequent unfold protein response, evaluating the expression profile of ER-stress genes would be a sensitive indicator of cell stress. Beside cytotoxicity assays, real-time RT-PCR was used to investigate the effects of PEI nanoparticles on the endoplasmic reticulum. Treating Neuro2A cells revealed that PEI can induce cell toxicity in a concentration-dependent manner. Also, It increased the transcript levels of Grp78 (Bip), Atf4 and Chop, and splicing of Xbp1. To further optimize the transfection properties in Neuro2A cells, PEI was used to deliver a plasmid DNA containing GFP reporter. While different PEI/plasmid ratios revealed similar transfection efficiency, increasing the PEI/plasmid ratio led to induction of ER-stress markers. These results underscored that beside the effectiveness of PEI, using the lowest possible ratio of PEI/plasmid would minimize the detrimental effects of PEI on cells and confer it a beneficial therapeutic importance in nucleic acid delivery.

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.

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