Preparation and Evaluation of Poly(lactic acid)/Poly(vinyl alcohol) Nanoparticles Using the Quality by Design Approach.

The aim of the study was to prepare and evaluate the potential use of poly(lactic acid)/poly(vinyl alcohol) (PLA/PVA) nanoparticle formulations as a drug delivery system. The nanoparticle formulations were successfully developed by the double emulsification/solvent evaporation method. The developed formulations were optimized using the quality by design approach of the ICH Q8 (Pharmaceutical Development) guideline. In the studies, the effects of emulsifying devices, evaporation technique, centrifugation effect, and polymer concentrations on the physicochemical parameters of the formulations were investigated to obtain the best results. Furthermore, the prepared formulations were evaluated for clarity, particle size, distribution, zeta potential, surface and morphological features, preparation efficiency, and long-term stability. Based on the obtained results, the nanoparticle formulation containing 12.5% PLA, 1% primer, and seconder PVA has a suitable particle size (181.7 ± 2.194 nm) and distribution (0.104 ± 0.049), zeta potential (-0.88 ± 0.45 mV), and high preparation efficiency (65.38%), and nanoparticles were spherical, had a smooth surface, and were stable up to 12 months. In conclusion, this novel formulation can be used as a potential drug delivery system.

Critical Tools in Tableting Research: Using Compaction Simulator and Quality by Design (QbD) to Evaluate Lubricants' Effect in Direct Compressible Formulation.

As commonly known, the product development stage is quite complex, requires intensive knowledge, and is time-consuming. The selection of the excipients with the proper functionality and their corresponding levels is critical to drug product performance. The objective of this study was to apply quality by design (QbD) principles for formulation development and to define the desired product quality profile (QTPP) and critical quality attributes (CQA) of a product. QbD is a risk- and science-based holistic approach for upgraded pharmaceutical development. In this study, Ibuprofen DC 85W was used as a model drug, Cellactose® 80 along with MicroceLac® 100 as a filler, and magnesium stearate, stearic acid, and sodium stearyl fumarate as lubricants. By applying different formulation parameters to the filler and lubricants, the QbD approach furthers the understanding of the effect of critical formulation and process parameters on CQAs and the contribution to the overall quality of the drug product. An experimental design study was conducted to determine the changes of the obtained outputs of the formulations, which were evaluated using the Modde Pro 12.1 statistical computer program that enables optimization by modeling complex relationships. The results of the optimum formulation revealed that MicroceLac® 100 was the superior filler, while magnesium stearate at 1% was the optimum lubricant. A design space that indicates the safety operation limits for the process and formulation variables was also created. This study enriches the understanding of the effect of excipients in formulation and assists in enhancing formulation design using experimental design and mathematical modeling methods in the frame of the QbD approach.

Applying Quality by Design Principles in the Development and Preparation of a New Radiopharmaceutical: Technetium-99m-Imatinib Mesylate.

The clinical impact and accessibility of 99mTc tracers for cancer diagnosis would be greatly enhanced by the availability of a new, simple, and easy labeling process and radiopharmaceuticals. In this study, Technetium-99m-imatinib mesylate ([99mTc]TcIMT) was developed and prepared as a new radiopharmaceutical for breast cancer diagnosis. The effect of critical process parameters on the product quality and stability of [99mTc]TcIMT was investigated using the quality by design concept of the ICH Q8 (Pharmaceutical Development) guideline. [99mTc]TcIMT was subjected to in vitro cell binding studies to determine healthy and cancer cell affinity using HaCaT and MCF-7 cells, respectively. The optimal radiolabeling procedure with 1 mg of IMT, 500 µg of stannous chloride, 0.1 mg of ascorbic acid, and 1mCi 99mTc radioactivity was obtained for [99mTc]TcIMT. The pH of the reaction mixture was adjusted to 10 and allowed to react for 15 min at room temperature. The radiochemical purity of [99mTc]TcIMT was found to be higher than 90% at room temperature up to 6 h. Chromatography analysis revealed >85% [99mTc]TcIMT complex formation with promising stability in saline, cell medium, and serum up to 6 h. The radiolabeled complex showed a higher cell-binding ratio to MCF-7 cells (88.90% ± 3.12) than HaCaT cells (45.64 ± 4.72) when compared to 99mTc. Our findings show that the developed preparation method for [99mTc]TcIMT falls well within the proven acceptable ranges. Applying quality by design (QbD) principles is feasible and worthwhile for the preparation of [99mTc]TcIMT. In conclusion, radiochemical purity, stability, and in vitro cell binding evaluation of the [99mTc]TcIMT complex indicate that the agent can be utilized for imaging of breast cancer cells.

QbD guided early pharmaceutical development study: Production of lipid nanoparticles by high pressure homogenization for skin cancer treatment.

This research attempts to bring together the positive aspects of lipid nanoparticles and Quality by Design (QbD) approach for developing a novel drug delivery system for skin cancers and aktinic keratosis. Lipid nanoparticles which is one of the most efficacious options for topical treatment of skin diseases were prepared due to their ability to overcome the complex structure of skin barrier and to enhance the skin penetration. Since the formulation development contains complex variables of active ingredients, raw materials or production method; all the variables of the product should be elaborated. QbD approach which refers to design and develop formulations and manufacturing processes to maintain the prescribed product quality was also successfully adopted to achieve a time- and cost-saving process ensuring a high-quality product. 5-Fluorouracil (5-FU) loaded lipid nanoparticles, both solid lipid nanoparticles and nanostructured lipid carriers, were developed and characterized by following QbD steps. Optimal lipid nanoparticle formulation with guaranteed quality which was within the design space has been reached through the artificial neural networks. The optimal lipid nanoparticle formulation which is a NLC formulation with a mean particle size of 205,8 ±â€¯9,34 nm, narrow size distribution (0.279 ±â€¯0.01) and negative zeta potantial -30,20 ±â€¯0,92 was produced by high pressure homogenization method. Cytotoxicity profiles of the optimal NLC was determined by cell culture studies on epidermoid carcinoma cells and human keratinocyte cells. Optimal NLC showed significantly higher anticancer effect on epidermoid carcinoma cells than free 5-FU and also less cytotoxicity towards human keratinocyte cells. Optimal NLC was formulated in hydrogel formulation for ease of application which has suitable occlusive and mechanical properties, viscocity and pH for patient complience. The cumulative amount of 5-FU in dermal tissues of rat skin was found 20.11 ±â€¯2.14 µg/cm2 and 9.73 ±â€¯0.87 µg/cm2 after application of NLC enriched hydrogel and 5-FU hydrogel respectively. In conclusion, this study showed that a time and cost saving process ensuring a high-quality product can be obtained by QbD guided formulation development study with the help of artificial neural networks. A novel semisolid dosage form enriched by NLC which is promising for topical treatment of skin cancers was developed.

Quetiapine Fumarate Extended-release Tablet Formulation Design Using Artificial Neural Networks.

OBJECTIVES: This design study was implemented within the scope of the quality by design approach, which included the "International Conference on Harmonization" guidelines. We evaluated the quality of a modified-release tablet formulation of quetiapine fumarate, which was designed using artificial neural networks (ANN), and determined a new formulation that was similar to the reference product. MATERIALS AND METHODS: Twelve different formulations were produced and tested. The reference product's results and our experimental results were used as outputs for the training of the ANN programs of Intelligensys Ltd. RESULTS: Dissolution tests were performed with the new formulation (F13) suggested by the INForm V.4 ANN program in three different pHs of the gastrointestinal system. The compliance of this formulation was confirmed by comparing the results with an f2 similarity test. CONCLUSION: Use of these programs supports research and development processes with multiple evaluation methods and alternative formulations may be determined faster and at lower cost.

Quality by design case study 1: Design of 5-fluorouracil loaded lipid nanoparticles by the W/O/W double emulsion - Solvent evaporation method.

With Quality by Design (QbD), a systematic approach involving design and development of all production processes to achieve the final product with a predetermined quality, you work within a design space that determines the critical formulation and process parameters. Verification of the quality of the final product is no longer necessary. In the current study, the QbD approach was used in the preparation of lipid nanoparticle formulations to improve skin penetration of 5-Fluorouracil, a widely-used compound for treating non-melanoma skin cancer. 5-Fluorouracil-loaded lipid nanoparticles were prepared by the W/O/W double emulsion - solvent evaporation method. Artificial neural network software was used to evaluate the data obtained from the lipid nanoparticle formulations, to establish the design space, and to optimize the formulations. Two different artificial neural network models were developed. The limit values of the design space of the inputs and outputs obtained by both models were found to be within the knowledge space. The optimal formulations recommended by the models were prepared and the critical quality attributes belonging to those formulations were assigned. The experimental results remained within the design space limit values. Consequently, optimal formulations with the critical quality attributes determined to achieve the Quality Target Product Profile were successfully obtained within the design space by following the QbD steps.

Bioadhesive tablets containing cyclodextrin complex of itraconazole for the treatment of vaginal candidiasis.

Itraconazole (ITR) is commonly used in the treatment of Candida infections. It has a nephrotoxic effect and low bioavailability in patients who suffer from renal insufficiency, and its poor solubility in water makes ITR largely unavailable. Cyclodextrins (CyDs) are used to form inclusion complexes with drugs to improve their aqueous solubility and to reduce their side effects. In this study, ITR was complexed with γ-cyclodextrin (γ-CyD), hydroxypropyl-ß-cyclodextrin (HP-ß-CyD), methyl-ß-cyclodextrin (Met-ß-CyD) and sulphobutyl ether-ß-cyclodextrin (SBE7-ß-CyD) to increase its water solubility and to reduce the side effects of the drug without decreasing antifungal activity. Complex formation between ITR and CyDs was evaluated using SEM, (1)H NMR and XRD studies. The antifungal activity of the complexes was analyzed on Candida albicans strains, and the susceptibility of the strains was found to be higher for the ITR-SBE7-ß-CyD complex than for the complexes that were prepared with other CyDs. Vaginal bioadhesive sustained release tablet formulations were developed using the ITR-SBE7-ß-CyD inclusion complex to increase the residence time of ITR in the vagina, thereby boosting the efficacy of the treatment. The swelling, matrix erosion and bioadhesion properties of formulations and the drug release rate of these tablets were analyzed, and the most therapeutically effective vaginal formulation was determined.

Impacts of chemical enhancers on skin permeation and deposition of terbinafine.

CONTEXT/OBJECTIVE: The addition of chemical enhancers into formulations is the most commonly employed approach to overcome the skin barrier. The objective of this work was to evaluate the effect of vehicle and chemical enhancers on the skin permeation and accumulation of terbinafine, an allylamine antifungal drug. METHODS: Terbinafine (1% w/w) was formulated as a Carbopol 934 P gel formulation in presence and absence of three chemical enhancers, nerolidol, dl-limonene and urea. Terbinafine distribution and deposition in stratum corneum (SC) and skin following 8-h ex vivo permeation study was determined using a sequential tape stripping procedure. The conformational order of SC lipids was investigated by ATR-FTIR spectroscopy. RESULTS AND DISCUSSION: Nerolidol containing gel formulation produced significantly higher enhancement in terbinafine permeation through skin and its skin accumulation was increased. ATR-FTIR results showed enhancer induced lipid bilayer disruption in SC. Urea resulted in enhanced permeation of terbinafine across the skin and a balanced distribution to the SC was achieved. But, dl-limonene could not minimize the accumulation of terbinafine in the upper SC. CONCLUSION: Nerolidol dramatically improved the skin permeation and deposition of terbinafine in the skin that might help to optimize targeting of the drug to the epidermal sites as required for both of superficial and deep cutaneous fungal infections.

A quality by design approach using artificial intelligence techniques to control the critical quality attributes of ramipril tablets manufactured by wet granulation.

Quality by design (QbD) is an essential part of the modern approach to pharmaceutical quality. This study was conducted in the framework of a QbD project involving ramipril tablets. Preliminary work included identification of the critical quality attributes (CQAs) and critical process parameters (CPPs) based on the quality target product profiles (QTPPs) using the historical data and risk assessment method failure mode and effect analysis (FMEA). Compendial and in-house specifications were selected as QTPPs for ramipril tablets. CPPs that affected the product and process were used to establish an experimental design. The results thus obtained can be used to facilitate definition of the design space using tools such as design of experiments (DoE), the response surface method (RSM) and artificial neural networks (ANNs). The project was aimed at discovering hidden knowledge associated with the manufacture of ramipril tablets using a range of artificial intelligence-based software, with the intention of establishing a multi-dimensional design space that ensures consistent product quality. At the end of the study, a design space was developed based on the study data and specifications, and a new formulation was optimized. On the basis of this formulation, a new laboratory batch formulation was prepared and tested. It was confirmed that the explored formulation was within the design space.

Towards a European strategy for medicines research (2014-2020): The EUFEPS position paper on Horizon 2020.

As to the alignment of "Horizon 2020", ir is a more integrated approach to European science policy than expressed in the proposals previously drafted, and specifically considers: (i) promoting excellence in Science, (ii) establishing a sound industrial leadership and (iii) expressing an ambition to address current and future societal challenges. In this respect, the quest for a knowledge-based economy in Europe should result in proposals for industrial and employment policies that will consolidate the major European advantages in the biomedical, healthcare and pharmaceutical sectors. Horizon 2020 also provides the possibility of adopting a more flexible and simplified management route to drive European research through innovation, research and development. What should be additionally considered? Unmet medical needs, under pressure from demographic changes, await the generation of new medicines and health technologies which will evolve into a driver for a unified European policy. We believe that this should be focused on harnessing pharmaceutical knowledge for clinical use, as part of a response to accommodate patient needs and economic growth based on a robust, scientific approach. The bolder ambition for European research is to unlock key bottlenecks currently undermining European competitiveness. The historical lack of an appropriate business/innovation environment with reduced access to adequate risk finance instruments has severed the path for economic growth and industrial development. These issues are of critical importance and a solution is urgently needed to foster translation from the university to the healthcare sector through the generation and support of start-ups, spin-offs, university-industry consortia, and other platforms, which support translational research. The ultimate goal is implementation of holistic programmes: the 'bench to bedside' paradigm of medicines and other healthcare products. The European Research Council supports the basic biomedical research programmes of long term importance for development of medicines; however, fundamental research initiatives on medicines development will not be competitive in such an environment. In order to strengthen the long term outlook, we must foster innovative research within the university sector, EUFEPS proposes that a fund for such research be set up within Horizon 2020, which would be open for individual research groups and which would include Public-Public Partnerships (complementing already existing Public-Private Partnerships). How do we look for implementation? There is an established research agenda for medicines research that is globally focused, and which incorporates a cooperative model between universities and industry, facilitating integration of complex technologies. Regulatory Science will play an important role in this integration. This agenda uses tools arising from systems approaches (including discovery with systems biology and also systems pharmacology) and has the potential for providing better knowledge management, as well as technological innovation (including manufacturing). It also addresses the drive towards personalised medicines and can, with support from both public and private sectors, foster translation of knowledge to new technologies and from that, to new medicinal products and complex integrated systems. This is a part of a strategy capable of solving unmet medical needs, which would increase the quality of life of patients suffering from chronic and debilitating diseases. The instruments to allow the development of a research agenda should strengthen existing partnerships such as the IMI-JU model; allow for the creation of European-network infrastructures that can bring together existing competences with adequate European coordination, thus promoting advanced training and continuous professional development for the pharmaceutical sciences. This will be the cornerstone of a knowledge management strategy, providing education and training for healthcare professionals and scientists. A key role for EUFEPS is to help the research community to embrace these new holistic policies applied to the spectrum of pharmaceutical, medical and cognate sciences.

Quality by design approach: application of artificial intelligence techniques of tablets manufactured by direct compression.

The publication of the International Conference of Harmonization (ICH) Q8, Q9, and Q10 guidelines paved the way for the standardization of quality after the Food and Drug Administration issued current Good Manufacturing Practices guidelines in 2003. "Quality by Design", mentioned in the ICH Q8 guideline, offers a better scientific understanding of critical process and product qualities using knowledge obtained during the life cycle of a product. In this scope, the "knowledge space" is a summary of all process knowledge obtained during product development, and the "design space" is the area in which a product can be manufactured within acceptable limits. To create the spaces, artificial neural networks (ANNs) can be used to emphasize the multidimensional interactions of input variables and to closely bind these variables to a design space. This helps guide the experimental design process to include interactions among the input variables, along with modeling and optimization of pharmaceutical formulations. The objective of this study was to develop an integrated multivariate approach to obtain a quality product based on an understanding of the cause-effect relationships between formulation ingredients and product properties with ANNs and genetic programming on the ramipril tablets prepared by the direct compression method. In this study, the data are generated through the systematic application of the design of experiments (DoE) principles and optimization studies using artificial neural networks and neurofuzzy logic programs.

Strategic funding priorities in the pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT).

Substantial changes in Pharmaceutical R&D strategy are required to address existing issues of low productivity, imminent patent expirations and pressures on pricing. Moves towards personalized healthcare and increasing diversity in the nature of portfolios including the rise of biopharmaceuticals however have the potential to provide considerable challenges to the establishment of cost effective and robust supply chains. To guarantee product quality and surety of supply for essential medicines it is necessary that manufacturing science keeps pace with advances in pharmaceutical R&D. In this position paper, the EUFEPS QbD and PAT Sciences network make recommendations that European industry, academia and health agencies focus attention on delivering step changes in science and technology in a number of key themes. These subject areas, all underpinned by the sciences allied to QbD and PAT, include product design and development for personalized healthcare, continuous-processing in pharmaceutical product manufacture, quantitative quality risk assessment for pharmaceutical development including life cycle management and the downstream processing of biopharmaceutical products. Plans are being established to gain commitment for inclusion of these themes into future funding priorities for the Innovative Medicines Initiative (IMI).

Enhanced topical delivery of terbinafine hydrochloride with chitosan hydrogels.

Chitosan-based carriers have important potential applications for the administration of drugs. In the present study, topical gel formulations of terbinafine hydrochloride (T-HCl) were prepared using different types of chitosan at different molecular weight, and the antifungal inhibitory activity was evaluated to suggest an effective formulation for the treatment of fungal infections. The characteristics of gel formulations were determined with viscosity measurements and texture profile analysis. Stability studies were performed at different temperatures during 3 months. The ex vivo permeation properties were studied through rat skin by using Franz diffusion cells. The antifungal inhibitory activity of formulations on Candida species and filamentous fungi was also examined with agar-cup method. The microbiological assay was found suitable for determination of in vitro antifungal activity of T-HCl. A marketed product was used to compare the results. The antifungal activity of T-HCl significantly increased when it was introduced into the chitosan gels. A higher drug release and the highest zone of inhibition were obtained from gels prepared with the lowest molecular weight chitosan (Protasan UP CL 213) compared to that of other chitosan gels and marketed product. These results indicated the advantages of the suggested formulations for topical antifungal therapy against Candida species and filamentous fungi.