Ildikó Csóka

Adaptation of the quality by design concept in early pharmaceutical development of an intranasal nanosized formulation

Regulatory science based pharmaceutical development and product manufacturing is highly recommended by the authorities nowadays. The aim of this study was to adapt regulatory science even in the nano-pharmaceutical early development. Authors applied the quality by design (QbD) concept in the early development phase of nano-systems, where the illustration material was meloxicam. The meloxicam nanoparticles produced by co-grinding method for nasal administration were studied according to the QbD policy and the QbD based risk assessment (RA) was performed. The steps were implemented according to the relevant regulatory guidelines (quality target product profile (QTPP) determination, selection of critical quality attributes (CQAs) and critical process parameters (CPPs)) and a special software (Lean QbD Software(®)) was used for the RA, which represents a novelty in this field. The RA was able to predict and identify theoretically the factors (e.g. sample composition, production method parameters, etc.) which have the highest impact on the desired meloxicam-product quality. The results of the practical research justified the theoretical prediction. This method can improve pharmaceutical nano-developments by achieving shorter development time, lower cost, saving human resource efforts and more effective target-orientation. It makes possible focusing the resources on the selected parameters and area during the practical product development.

Novel strategies in the oral delivery of antidiabetic peptide drugs – Insulin, GLP 1 and its analogs

&NA; As diabetes is a complex disorder being a major cause of mortality and morbidity in epidemic rates, continuous research has been done on new drug types and administration routes. Up to now, a large number of therapeutic peptides have been produced to treat diabetes including insulin, glucagon‐like peptide‐1 (GLP‐1) and its analogs. The most common route of administration of these antidiabetic peptides is parenteral. Due to several drawbacks associated with this invasive route, delivery of these antidiabetic peptides by the oral route has been a goal of pharmaceutical technology for many decades. Dosage form development should focus on overcoming the limitations facing oral peptides delivery as degradation by proteolytic enzymes and poor absorption in the gastrointestinal tract (GIT). This review focuses on currently developed strategies to improve oral bioavailability of these peptide based drugs; evaluating their advantages and limitations in addition to discussing future perspectives on oral peptides delivery. Depending on the previous reports and papers, the area of nanocarriers systems including polymeric nanoparticles, solid lipid nanoparticles, liposomes and micelles seem to be the most promising strategy that could be applied for successful oral peptides delivery; but still further potential attempts are required to be able to achieve the FDA approved oral antidiabetic peptide delivery system. Graphical abstract Figure. No caption available.

Development of a microparticle-based dry powder inhalation formulation of ciprofloxacin hydrochloride applying the quality by design approach

Pulmonary drug delivery of ciprofloxacin hydrochloride offers effective local antibacterial activity and convenience of easy application. Spray drying is a trustworthy technique for the production of ciprofloxacin hydrochloride microparticles. Quality by design (QbD), an up-to-date regulatory-based quality management method, was used to predict the final quality of the product. According to the QbD-based theoretical preliminary parameter ranking and priority classification, dry powder inhalation formulation tests were successfully performed in practice. When focusing on the critical parameters, the practical development was more effective and was in correlation with our previous findings. Spray drying produced spherical microparticles. The dry powder formulations prepared were examined by particle size analysis, scanning electron microscopy, Fourier-transform infrared spectroscopy, X-ray powder diffraction, differential scanning calorimetry, and in vitro drug release and aerodynamic particle size analyses were also performed. These formulations showed an appropriate particle size ranging between 2 and 4 μm and displayed an enhanced aerosol performance with fine particle fraction up to 80%.

Development of nanostructured lipid carriers containing salicyclic acid for dermal use based on the Quality by Design method

Abstract The aim of our present work was to evaluate the applicability of the Quality by Design (QbD) methodology in the development and optimalization of nanostructured lipid carriers containing salicyclic acid (NLC SA). Within the Quality by Design methology, special emphasis is layed on the adaptation of the initial risk assessment step in order to properly identify the critical material attributes and critical process parameters in formulation development. NLC SA products were formulated by the ultrasonication method using Compritol 888 ATO as solid lipid, Miglyol 812 as liquid lipid and Cremophor RH 60® as surfactant. LeanQbD Software and StatSoft. Inc. Statistica for Windows 11 were employed to indentify the risks. Three highly critical quality attributes (CQAs) for NLC SA were identified, namely particle size, particle size distribution and aggregation. Five attributes of medium influence were identified, including dissolution rate, dissolution efficiency, pH, lipid solubility of the active pharmaceutical ingredient (API) and entrapment efficiency. Three critical material attributes (CMA) and critical process parameters (CPP) were identified: surfactant concentration, solid lipid/liquid lipid ratio and ultrasonication time. The CMAs and CPPs are considered as independent variables and the CQAs are defined as dependent variables. The 23 factorial design was used to evaluate the role of the independent and dependent variables. Based on our experiments, an optimal formulation can be obtained when the surfactant concentration is set to 5%, the solid lipid/liquid lipid ratio is 7:3 and ultrasonication time is 20 min. The optimal NLC SA showed narrow size distribution (0.857 ± 0.014) with a mean particle size of 114 ± 2.64 nm. The NLC SA product showed a significantly higher in vitro drug release compared to the micro‐particle reference preparation containing salicylic acid (MP SA).

New aspects of developing a dry powder inhalation formulation applying the quality-by-design approach.

The current work outlines the application of an up-to-date and regulatory-based pharmaceutical quality management method, applied as a new development concept in the process of formulating dry powder inhalation systems (DPIs). According to the Quality by Design (QbD) methodology and Risk Assessment (RA) thinking, a mannitol based co-spray dried formula was produced as a model dosage form with meloxicam as the model active agent. The concept and the elements of the QbD approach (regarding its systemic, scientific, risk-based, holistic, and proactive nature with defined steps for pharmaceutical development), as well as the experimental drug formulation (including the technological parameters assessed and the methods and processes applied) are described in the current paper. Findings of the QbD based theoretical prediction and the results of the experimental development are compared and presented. Characteristics of the developed end-product were in correlation with the predictions, and all data were confirmed by the relevant results of the in vitro investigations. These results support the importance of using the QbD approach in new drug formulation, and prove its good usability in the early development process of DPIs. This innovative formulation technology and product appear to have a great potential in pulmonary drug delivery.

Optimization and development of stable w/o/w cosmetic multiple emulsions by means of the Quality by Design approach

The aim of our present work was to develop stable water‐in‐oil‐in‐water (w/o/w) cosmetic multiple emulsions that are proper for cosmetic use and can also be applied on the skin as pharmaceutical vehicles by means of Quality by Design (QbD) concept. This product design concept consists of a risk assessment step and also the ‘predetermination’ of the critical material attributes and process parameters of a stable multiple emulsion system. We have set up the hypothesis that the stability of multiple emulsions can be improved by the development based on such systematic planning – making a map of critical product parameters – so their industrial usage can be increased.

Study of the structure of coherent emulsions.

The object of the study was to analyse relationship between the rheological properties, thermogravimetric behaviour, physical stability, and the wetting contact angle of the lipophilic and aqueous phase of 300 creams of different compositions with a high water content (60-80%, w/w). The starting point was Jungingers theory: water is found in the cream structure in energetic (interlamellar) and steric forms (bulk water). Based on our investigations, an exponential function was found to exist between the contact angle of wetting and the slope of the TG-curves, between the contact angle of wetting and the viscosity of the creams, and between the contact angle of wetting and the evaporation rate of water. A linear relationship was found between the contact angle of wetting and the quantity of water separable by centrifugation.

Preliminary study of nanonized lamotrigine containing products for nasal powder formulation

The nasal delivery of drugs offers a great alternative route to avoid adverse events and to increase patient compliance due to its advantageous properties. Besides nasal application, topical, systemic and central effects are also available. Nasal powders (NPs) have better adhesion due to the additive polymers that may be, eg, gelling or good wettability agents; thus, their bioavailability is better compared to the liquid formulations. Using nanoparticles, innovative and more efficient products can be achieved, which may lead to the improvement of different therapies. The aim of this study was to produce NP formulations containing lamotrigine (LAM) as interactive physical mixtures and nanosized LAM-based formulations. After risk assessment of the preliminary tests, the micrometric properties (particle size and morphology) and the structural properties (differential scanning calorimetry [DSC], X-ray powder diffraction [XRPD]) were investigated; thereafter, physicochemical properties (solubility, polarity) and in vitro dissolution and diffusion profiles were also examined. These product samples showed an appropriate particle size ranging 10–25 µm, while the particle size of LAM in the products was between 120 and 230 nm and the dissolved amount of drug was >60% after 5 minutes in these cases.

Optimization of the Critical Parameters of the Spherical Agglomeration Crystallization Method by the Application of the Quality by Design Approach

This research work presents the use of the Quality by Design (QbD) concept for optimization of the spherical agglomeration crystallization method in the case of the active agent, ambroxol hydrochloride (AMB HCl). AMB HCl spherical crystals were formulated by the spherical agglomeration method, which was applied as an antisolvent technique. Spherical crystals have good flowing properties, which makes the direct compression tableting method applicable. This means that the amount of additives used can be reduced and smaller tablets can be formed. For the risk assessment, LeanQbD Software was used. According to its results, four independent variables (mixing type and time, dT (temperature difference between solvent and antisolvent), and composition (solvent/antisolvent volume ratio)) and three dependent variables (mean particle size, aspect ratio, and roundness) were selected. Based on these, a 2–3 mixed-level factorial design was constructed, crystallization was accomplished, and the results were evaluated using Statistica for Windows 13 program. Product assay was performed and it was revealed that improvements in the mean particle size (from ~13 to ~200 µm), roundness (from ~2.4 to ~1.5), aspect ratio (from ~1.7 to ~1.4), and flow properties were observed while polymorphic transitions were avoided.

Interaction Between Liposomes and Neutral Polymers: Effect of Adsorption on Drug Release

The processes of adsorption of two neutral polymers (poly(vinyl pyrrolidone), PVP and poly(vinyl alcohol), PVA) were investigated on liposomes composed of soy lecithin/dicetyl phosphate/cholesterol = 25:2:3 (molar ratio). The liposomes were prepared in buffered solution at pH = 7.4 and mixed with the solution of the measured polymers in the desired polymer/lipid (w/w) ratios. Adsorption was measured by determination of the equilibrium bulk concentration of the polymer. In the case of PVA quantitative adsorption measurements with a specific reagent were possible. Adsorption isotherms were recorded at 25 ± 1°C. It was concluded that adsorbed and unadsorbed PVA molecules are in equilibrium even at low polymer/ lipid ratios. The results were confirmed by dynamic laser light scattering (DLS), and thermal activity monitoring (TAM) experiments. Another group of the liposomes was prepared in 60 mM ammonium sulphate (pH = 5.0) and we filled the vesicles with a test dye, acridine orange (AO) using the pH-gradient (remote loading) method. The AO release property of liposomes was tested with a special vertical diffusion cell after we had made PVA adsorb on their surface in different PVA/lipid (w/w) ratios.