Rational Design of Topical Semi-Solid Dosage Forms-How Far Are We?

Specific aspects of semi-solid dosage forms for topical application include the nature of the barrier to be overcome, aspects of susceptibility to physical and chemical instability, and a greater influence of sensory perception. Advances in understanding the driving forces of skin penetration as well as the design principles and inner structure of formulations, provide a good basis for the more rational design of such dosage forms, which still often follow more traditional design approaches. This review analyses the opportunities and constraints of rational formulation design approaches in the industrial development of new topical drugs. As the selection of drug candidates with favorable physicochemical properties increases the speed and probability of success, models for drug selection based on theoretical and experimental approaches are discussed. This paper reviews how progress in the scientific understanding of mechanisms and vehicle-influence of skin penetration can be used for rational formulation design. The characterization of semi-solid formulations is discussed with a special focus on modern rheological approaches and analytical methods for investigating and optimizing the chemical stability of active ingredients in consideration of applicable guidelines. In conclusion, the combination of a good understanding of scientific principles combined with early consideration of regulatory requirements for product quality are enablers for the successful development of innovative and robust semi-solid formulations for topical application.

Development and validation of a selective marker-based quantification of polysorbate 20 in biopharmaceutical formulations using UPLC QDa detection.

Polysorbates are widely used as non-ionic surfactant in biopharmaceutical formulations. Recently, the degradation of polysorbate moved into the focus of attention, because in several published studies it was described, that stability issues in polysorbate containing formulations were observed leading to the formation and appearance of sub-visible and visible particles. For this reason, monitoring of polysorbate and its degradation products is of importance throughout the development of parenterals. The aim of the study was to develop a method for the selective marker-based quantification of adequate polysorbate 20 components of interest without the need to apply derivatization or complex detection techniques. A single quadrupole mass (QDa) detector was used coupled to an ultra-high performance liquid chromatography (UPLC) system. Method development was based on a reversed phase-high performance liquid chromatography assay coupled to a charged aerosol detector (RP-HPLC CAD). Instead of a charged aerosol detector (CAD) a QDa detector was used in order to significantly improve the selectivity. The focus of this study is the development of the QDa based method for the analysis of polysorbate 20. Modifications of the mobile phase and the type of chromatography column allowed the separation of several components of polysorbate 20 from polar non-esterified to apolar higher order species. In addition, a multitude of components could be quantified by their individual m/z values. The peak assignment identified 676 compounds which originated from polysorbate 20. Some of these were selected and defined as marker components. It was shown that the developed method is capable to determine polysorbate 20 in different biopharmaceutical formulations. The proposed assay is based on a smart sample preparation as well as a unique calibration procedure that make the determination of several selected components achievable. Furthermore, it was successfully demonstrated that the analytical procedure is valid to reliably quantify several polysorbate 20 components at its 100% level (corresponds to 0.4 mg/mL intact polysorbate 20) and even at lower concentrations that occur e.g. in case of polysorbate 20 degradation. In conclusion, the method is beneficial to determine selected polysorbate 20 species during formulation development of biopharmaceuticals as well as during stability testing and trouble shooting.

Investigation of the Compatibility of the Skin PAMPA Model with Topical Formulation and Acceptor Media Additives Using Different Assay Setups.

The Skin Parallel Artificial Membrane Permeability Assay (PAMPA) is a 96-well plate-based skin model with an artificial membrane containing free fatty acid, cholesterol, and synthetic ceramide analogs to mimic the stratum corneum (SC) barrier. The current study evaluates the compatibility of lipophilic solvents/penetration enhancer, topical emulsions containing different emulsifier systems, and organic acceptor media additives with the artificial membrane of the assay. Additionally, different assay setups (standard setup: donor in bottom plate versus modified setup: donor in top plate) were compared. Methylparaben (MP), ethylparaben (EP), and propylparaben (PP) were used as model permeants and internal standards for proper assay execution. The permeation order of the parabens (MP > EP > PP) remained the same with different lipophilic solvents, and the ranking of lipophilic solvents was comparable under standard and modified conditions (isopropyl myristate, IPM > dimethyl isosorbide, DMI ≥ propylene glycol, PG > diisopropyl adipate, DIPA). Pre-incubation of the Skin PAMPA plates with IPM, DIPA, and DMI, as well as with formulations that contain non-ionic emulsifiers, and acceptor solutions containing DMSO or EtOH (≤ 50%) for 4 h did not increase the percentage of permeated parabens in the main experiment, suggesting that those compounds do not make the artificial membrane more permeable. High-resolution mass spectrometry confirmed that acceptor solutions with ≤ 50% DMSO or EtOH do not extract stearic acid, cholesterol, and certramides at standard assay conditions. Hence, if certain constraints are considered, the Skin PAMPA model can be used as a pre-screening tool for topical formulation selection.

Correlation of hydrotropic solubilization by urea with logD of drug molecules and utilization of this effect for topical formulations.

Solubilization of drugs in aqueous phases of liquid and semisolid environment is typically achieved by co-solvents or surfactants. On contrast, solubilization by means of hydrotropic agents, i.e., small hydrophilic organic compounds like urea or citric acid, is little explored in the context of pharmaceutical formulations. Especially, with regard to topical dosage forms, however, hydrotropic solubilization can provide valuable alternatives to establish solubilization approaches. A difficulty of employing hydrotropic solubilization was that its extent could not be predicted for different drug molecules. Using a chemically heterogeneous set of 12 compounds relevant for dermatology (with overall 16 different logD values tested), we were able to demonstrate that hydrotropic effects of urea can be predicted by logD values of drugs. All compounds with logD values between 2 and 4.5 showed a solubility enhancement factor (EF) of >5 in 40% aqueous solutions of urea. For logD values below 2 or above 5, only EF<5 were found. For some compounds, e.g., diclofenac (pH 4) and prednicarbate could achieved only EF>5 at 5% urea and EF>250 at 20% urea.