Rita Ambrus

Investigation of preparation parameters to improve the dissolution of poorly water-soluble meloxicam.

The rate of dissolution of drugs remains one of the most challenging aspects in formulation development of poorly water-soluble drugs. The meloxicam, a low molecular analgetic for oral administration, exhibits a slow dissolution. To improve the dissolution rate, the drug was formulated in a nanosuspension by using an emulsion-diffusion method, high-pressure homogenization or sonication. Optimization of the technological parameters (organic solvents, stabilizers, homogenization procedure and recovery of particles) allowed the formation of nanosuspensions with a particle size of 200-900 nm. SEM imaging confirmed the nanosized drug particles. Use of an SMCR method on the XRPD patterns of the nanosuspensions revealed the crystalline form of the drug and the strong interaction between meloxicam and the stabilizer. The rate of dissolution of the dried meloxicam nanosuspension was enhanced (90% in 5 min), relative to that of raw meloxicam (15% in 5 min), mainly due to the formation of nanosized particles. These results indicate the suitability of formulation procedure for preparation of nanosized poorly water-soluble drug with significantly improved in vitro dissolution rate, and thus possibly enhance fast onset of therapeutic drug effect.

Betulinic Acid in Complex with a Gamma-Cyclodextrin Derivative Decreases Proliferation and in Vivo Tumor Development of Non-Metastatic and Metastatic B164A5 Cells

Betulinic acid, a very promising anti-melanoma agent, has very low water solubility that causes low bioavailability. To overcome this inconvenience, a highly water-soluble cyclodextrin was used (octakis-[6-deoxy-6-(2-sulfanyl ethanesulfonic acid)]-γ-cyclodextrin). The complex was physico-chemically analyzed using differential scanning calorimetry (DSC), X-ray and scanning electron microscopy (SEM) methods and then in vitro tested for its antiproliferative activity by the MTT assay and by cell cycle analysis. Finally, the complex was tested in vivo using an animal model of murine melanoma developed in C57BL/6J mice, where it caused a reduction in tumor volume and weight. The study revealed the beneficial influence of betulinic acid inclusion into the cyclodextrin in terms of antiproliferative activity and in vivo tumor development.

Water-soluble loratadine inclusion complex: analytical control of the preparation by microwave irradiation.

The majority of active pharmaceutical ingredients are poorly soluble in water. The rate-determining step of absorption is the dissolution of these drugs. Inclusion complexation with cyclodextrin derivatives can lead to improved aqueous solubility and bioavailability of pharmacons due to the formation of co-crystals through hydrogen-bonding between the components. Inclusion complexes of loratadine were prepared by a convenient new method involving microwave irradiation and the products were compared with those of a conventional preparation method. Dissolution studies demonstrated that the solubility and rate of dissolution of loratadine increased in both of the methods used. The interactions between the components were investigated by thermal analysis and Fourier Transform Infrared studies. The microwave treatment did not cause any chemical changes in the loratadine molecule.

Applicability of sucrose laurate as surfactant in solid dispersions prepared by melt technology.

This study focused on an investigation of the applicability of sucrose laurate as surfactant in solid dispersions. Although this surfactant has a US Drug Master File, it has not been used so far in internal pharmaceutical products. High drug-loaded solid dispersion systems consisting of gemfibrozil as a model drug and PEG 6000 as a carrier, with or without sucrose laurate (D1216), were prepared by the melting method. Cytotoxicity studies on Caco-2 monolayer cells were also performed, in order to gain information on the applicability of D1216 in oral formulations. The results showed that the presence of the surface-active agent did not affect the solid-state characteristics of the model drug significantly. A markedly improved dissolution of gemfibrozil from the ternary solid dispersion systems was observed as compared with the binary solid dispersion systems. The optimum concentration range of the D1216 in the formulations was determined to be 5-10%. The effective final concentrations of D1216 in the dissolution experiments proved to be non-toxic towards CaCo-2 cells. The results suggest the potential use of D1216 in innovative internal pharmaceutical formulations.

Genistein in 1:1 Inclusion Complexes with Ramified Cyclodextrins: Theoretical, Physicochemical and Biological Evaluation

Genistein is one of the most studied phytocompound in the class of isoflavones, presenting a notable estrogenic activity and in vitro and/or in vivo benefits in different types of cancer such as those of the bladder, kidney, lung, pancreatic, skin and endometrial cancer. A big inconvenience for drug development is low water solubility, which can be solved by using hydrophilic cyclodextrins. The aim of this study is to theoretically analyze, based on the interaction energy, the possibility of a complex formation between genistein (Gen) and three different ramified cyclodextrins (CD), using a 1:1 molar ratio Gen:CD. Theoretical data were correlated with a screening of both in vitro and in vivo activity. Proliferation of different human cancer cell lines, antimicrobial activity and angiogenesis behavior was analyzed in order to see if complexation has a beneficial effect for any of the above mentioned activities and if so, which of the three CDs is the most suitable for the incorporation of genistein, and which may lead to future improved pharmaceutical formulations. Results showed antiproliferative activity with different IC50 values for all tested cell lines, remarkable antimicrobial activity on Bacillus subtilis and antiangiogenic activity as revealed by CAM assay. Differences regarding the intensity of the activity for pure and the three Gen complexes were noticed as explained in the text. The data represent a proof that the three CDs can be used for furtherer research towards practical use in the pharmaceutical and medical field.

Betulin Complex in γ-Cyclodextrin Derivatives: Properties and Antineoplasic Activities in In Vitro and In Vivo Tumor Models

Given the present high incidence of melanoma and skin cancer, interest in potential drugs of plant origin has increased significantly. Pentacyclic lupane-type triterpenes are widely distributed in plants, offering numerous pharmacological benefits. Betulin is an important compound in the bark of Betula pendula Roth and has important therapeutic properties, including antitumor activities. Its biological effect is limited by its poor water solubility, which can be improved by cyclodextrin complexation. The best results have been obtained by using a novel cyclodextrin derivative, octakis-[6-deoxy-6-(2-sulfanyl ethanesulfonate)]-γ-CD. The complexes between betulin and the previously mentioned cyclodextrin were analyzed by scanning electron microscopy (SEM)and differential scanning calorimetry (DSC) and pharmacologically evaluated in vitro (MTT and immunocytochemistry tests) and in vivo in C57BL/6J mice. The solubility of betulin is improved by cyclodextrin complexation, which creates a stable complex that improves the in vitro and in vivo properties of the active compound.

In vitro and in vivo characterization of meloxicam nanoparticles designed for nasal administration.

The nasal pathway represents a non-invasive route for delivery of drugs to the systemic circulation. Nanonization of poorly soluble drugs offers a possibility to increase dissolution properties, epithelial permeability or even bioavailability. The aim of the present study was to use in vitro methods to screen formulations which were intended for nasal application, and to perform animal experiments for recognizing the differences in plasmakinetics of intranasal- and oral-administered meloxicam nanoparticles. Due to nanonization the solubility of meloxicam elevated up to 1.2mg/mL, additionally the extent of dissolution also increased, complete dissolution was observed in 15 min. Favorable in vitro diffusion profile of meloxicam nanoparticles was observed and their epithelial permeability through human RPMI2650 cells was elevated. The pharmacokinetic parameters were significantly increased when meloxicam was administered as nanoparticles to rats either nasally (increase of Cmax 2.7-fold, AUC 1.5-fold) or orally (increase of C(max) 2.4-fold, AUC 2-fold) as compared to physical mixture of the drug and the excipients.

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.

Analysis of co-spray-dried meloxicam-mannitol systems containing crystalline microcomposites

The crystal size, form, wettability and rate of dissolution of a drug are factors limiting its nasal or pulmonary administration. The aim of this work was to achieve an ideal crystal habit, good wettability and the rapid release of meloxicam (MEL), a poorly water-soluble non-steroidal anti-inflammatory drug. The structures of MEL and the carrier-based systems were analysed by differential scanning calorimetry, X-ray diffractometry and Fourier transform infrared spectroscopy. The particle size and morphology were investigated by laser diffraction and SEM analyses. The novelty of this work was the use of a co-spray-drying technique, which resulted in mannitol-based crystalline microcomposites (1-6 μm) containing MEL microcrystals (1-5 μm). The particle size and form of the MEL microcrystals were adjusted by a top-down method. The presence of mannitol (with a MEL:mannitol mass ratio of 1:1) with additives ensured the homogeneous distribution of MEL in the microcomposites with good wettability and rapid release (100% MEL within 5 min).

Polymorph screening of an active material.

Polymorph screening is currently one of the most important tasks for innovators and for generic companies from both pharmaceutical and intellectual property rights aspects. The different polymorphs have different physicochemical properties, such as the crystal polymorph-dependent solubility which influences the bioavailability. A former drug candidate obtained from Sanofi Pharmaceutical Company (Hungary) was investigated to explore its polymorphism, to distinguish the morphologies generated by analytical examinations and to investigate their relative stabilities. An Avantium Crystal 16 automatic laboratory reactor system was used for the polymorph studies and the studies of their dissolution. Eight polymorphs were obtained by crystallization and transformation methods then characterized by XRPD, DSC, and Raman spectroscopy, scanning electron microscopy, and light microscopy. All the morphologies could be stored in solid without any form transformation for a long time (2 years investigated). According to the first relative stability results, Form I, III, IVa, V, VI, VII are unambiguously metastable forms. Form II and IVb have similar thermodynamic stabilities, that were higher than those of the other polymorphs. A special dissolution medium was developed in which the eight polymorphs showed clear differences in the rate of dissolution.