Application of standard cell cultures and 3D in vitro tissue models as an effective tool in drug design and development.

Cell culture systems are essential tools used in a wide range of biomedical and clinical studies. Two dimensional cell culture models (2D) provide basic information on cytotoxicity, penetration and accumulation of drugs in cells and they are of outmost importance when selecting new compounds of the desired biopharmaceutical properties as candidates for novel drugs. The improvement over 2D growing cells are three dimensional (3D) tissue models that mimic in vivo conditions and the functions of living tissue more accurately. These models reduce the cost of drug development, enable more efficient drug screening, minimise failure rate in medicine discovery and eliminate animal use during experiments. The article provides an overview of 2D cell cultures and 3D tissue models - their properties, basic procedures, conditions of culturing and applications.

Original research paper. Characterization and taste masking evaluation of microparticles with cetirizine dihydrochloride and methacrylate-based copolymer obtained by spray drying.

Taste of a pharmaceutical formulation is an important parameter for the effectiveness of pharmacotherapy. Cetirizine dihydrochloride (CET) is a second-generation antihistamine that is commonly administered in allergy treatment. CET is characterized by extremely bitter taste and it is a great challenge to successfully mask its taste; therefore the goal of this work was to formulate and characterize the microparticles obtained by the spray drying method with CET and poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate 1:2:1 copolymer (Eudragit E PO) as a barrier coating. Assessment of taste masking by the electronic tongue has revealed that designed formulations created an effective taste masking barrier. Taste masking effect was also confirmed by the in vivo model and the in vitro release profile of CET. Obtained data have shown that microparticles with a drug/polymer ratio (0.5:1) are promising CET carriers with efficient taste masking potential and might be further used in designing orodispersible dosage forms with CET.

Taste-masking assessment of orally disintegrating tablets and lyophilisates with cetirizine dihydrochloride microparticles.

Orally disintegrating tablets and oral lyophilisates are novel attractive dosage forms that disintegrate or dissolve in the buccal cavity within seconds without necessity of drinking. The major limitation in designing of these dosage forms is unpleasant taste of the drug substance. Cetirizine dihydrochloride is a H1-antihistamine substance indicated for the treatment of allergy. It is characterized by extremely bitter taste, therefore in order to deliver cetirizine dihydrochloride using orodispersible formulations, effective taste-masking is required. The aim of this study was to investigate whether microparticles containing cetirizine dihydrochloride could be successfully used to formulate orally disintegrating tablets by direct compression method and oral lyophilisates by freeze-drying process. Taste masking of cetirizine dihydrochloride was achieved by the spray-drying technique using Eudragit® E PO as the drug agent carrier. Based on the preliminary studies, optimal compositions of microparticles, tablets and lyophilisates were chosen. Obtained dosage forms were characterized for drug content, disintegration time and mechanical properties. In order to determine whether the microparticles subjected to direct compression and freeze-drying process effectively mask the bitter taste of cetirizine dihydrochloride, the in vivo and in vitro evaluation was performed. The results showed that designed formulates with microparticles containing cetirizine dihydrochloride were characterized by appropriate mechanical properties, uniformity of weight and thickness, short disintegration time, and the uniform content of the drug substance. Taste-masking assessment performed by three independent methods (e-tongue evaluation, human test panel and the in vitro drug release) revealed that microparticles with Eudragit® E PO are effective taste - masking carriers of cetirizine dihydrochloride and might be used to formulate orally disintegrating tablets and oral lyophilisates.

PREPARATION AND CHARACTERIZATION OF ORALLY DISINTEGRATING LORATADINE TABLETS MANUFACTURED WITH CO-PROCESSED MIXTURES.

The aim of this study was to develop orally disintegrated tablets (ODT) with loratadine using Parteck ODT and Ludiflash--new commercially available tableting excipients based on co-processed mannitol. ODT containing loratadine were prepared with 3% addition of various superdisintegrants (AcDiSol, Kollidon CL-F and Kollidon CL-SF) by direct compression method. Obtained tablets were characterized for friability, pore structure, and wetting and disintegration time measured by four independents methods. In order to identify possible interactions between loratadine and the excipients, differential scanning calorimetry was used. The results showed that all formulated ODT were characterized by appropriate mechanical properties (friability < 1%), the uniform content of the drug substance and pleasant mouth feeling. Disintegration time below 30 s was observed in formulations with crospovidones as disintegrant.

EVALUATION OF ALGINATE MICROSPHERES WITH METRONIDAZOLE OBTAINED BY THE SPRAY DRYING TECHNIQUE.

In the present study, nine formulations (F1-F9) of alginate microspheres with metronidazole were prepared by the spray drying technique with using different drug:polymer ratio (1:2, 1:1, 2:1) and different sodium alginate concentration (1, 2, 3%). The obtained microspheres were characterized for size, morphology, drug loading, (potential and swelling degree. Mucoadhesive properties were examined using texture analyzer and three different models of adhesive layers--gelatin discs, mucin gel and porcine vaginal mucosa. In vitro drug release, mathematical release profile and physical state of microspheres were also evaluated. The obtained results indicate that sodium alginate is a suitable polymer for developing mucoadhesive dosage forms of metronidazole. The optimal formulation F3 (drug:polymer ratio 1:2 and 1% alginate solution) was characterized by the highest metronidazole loading and sustained drug release. The results of this study indicate promising potential of ALG microspheres as alternative dosage forms for metronidazole delivery.

Development and Evaluation of Liquid and Solid Self-Emulsifying Drug Delivery Systems for Atorvastatin.

The objective of this work was to design and characterize liquid and solid self-emulsifying drug delivery systems (SEDDS) for poorly soluble atorvastatin. To optimize the composition of liquid atorvastatin-SEDDS, solubility tests, pseudoternary phase diagrams, emulsification studies and other in vitro examinations (thermodynamic stability, droplet size and zeta potential analysis) were performed. Due to the disadvantages of liquid SEDDS (few choices for dosage forms, low stability and portability during the manufacturing process), attempts were also made to obtain solid SEDDS. Solid SEDDS were successfully obtained using the spray drying technique from two optimized liquid formulations, CF3 and OF2. Despite liquid SEDDS formulation, CF3 was characterized by lower turbidity, higher percentage transmittance and better self-emulsifying properties, and based on the in vitro dissolution study it can be concluded that better solubilization properties were exhibited by solid formulation OF2. Overall, the studies demonstrated the possibility of formulating liquid and solid SEEDS as promising carriers of atorvastatin. SEDDS, with their unique solubilization properties, provide the opportunity to deliver lipophilic drugs to the gastrointestinal tract in a solubilized state, avoiding dissolution-a restricting factor in absorption rate of BCS Class 2 drugs, including atorvastatin.

Alginate microspheres obtained by the spray drying technique as mucoadhesive carriers of ranitidine.

The present study is aimed at formulation of alginate (ALG) microspheres with ranitidine (RNT) by the spray drying method. Obtained microspheres were characterized for particle size, surface morphology, entrapment efficiency, drug loading, in vitro drug release and zeta potential. Mucoadhesive properties were examined by a texture analyser and three types of adhesive layers--gelatine discs, mucin gel and porcine stomach mucosa. Microspheres showed a smooth surface with narrow particle size distribution and RNT loading of up to 70.9%. All formulations possessed mucoadhesive properties and exhibited prolonged drug release according to the first-order kinetics. DSC reports showed that there was no interaction between RNT and ALG. Designed microspheres can be considered potential carriers of ranitidine with prolonged residence time in the stomach.

Vaginal chitosan tablets with clotrimazole-design and evaluation of mucoadhesive properties using porcine vaginal mucosa, mucin and gelatine.

Topical administration of clotrimazole represents the common use therapy in the antimycotic genitourinary tract treatment. Due to the fast self-cleaning action of the vagina, commercially available vaginal dosage forms with clotrimazole cannot assure prolonged contact time with mucosa, therefore the main objective of this study was to develop a dosage form for vaginal administration of clotrimazole using chitosan-a biodegradable and biocompatible derivative of chitin. Tablets mucoadhesive properties were examined using texture analyser under the presence of porcine vaginal mucosa and two different models of adhesive layers- mucin gel and gelatine discs. In addition, friability, hardness, swelling behaviour, residence time, surface morphology of the performed tablets, the in vitro release profile of clotrimazole and clotrimazole release kinetics were determined. The release of clotrimazole from formulations with 25 or 40% of chitosan (F2 and F3) followed non Fickian diffusion through chitosan-gel layer and was retarded up to 6 h. Additionally, tablets F2 showed the best results in terms of mucoadhesive properties and appeared to be a good alternative to commercially available antimycotic vaginal dosage forms.