Enhancement of Drug Dissolution of Erlotinib Tablets by Micronization Technique Using Pharmaceutical Experimental Design

Lung cancer is the second most frequent cancer and among the top cause of death worldwide. Chemotherapy is the main therapeutic option for non-small-cell lung cancer (NSCLC), which accounts for the majority of all lung malignancies. The aim of the current work was to develop a tablet formulation having increased drug release profile to improve the bioavailability in order to reduce the dose of the drug. In this present study, Erlotinib tablet was prepared using micronization technique which showed increase drug release profile. Film-coated tablets containing Erlotinib hydrochloride (150 mg) were prepared by dry granulation technique and coated using Opadry ready-mix. Tablets were characterized for Hardness, Friability, Potency and Drug release profile. Drug release was checked in 0.1 N HCL containing 0.5 % SLS and biorelevant dissolution media up to 60 minutes. Tablets of the selected batch were subjected to dissolution in biorelevant media and compare with reference product. The improvement in the drug release was observed in the biorelevant media in comparison with reference product. The in-vitrodissolution data demonstrated the potential of micronization technology to prepare tablets with improved bioavailability of the drug.

Evaluating pediatric and adult simulated fluids solubility: Abraham solvation parameters and multivariate analysis

Purpose To understand drug solubilization as a function of age and identify drugs at risk of altered drug solubility in pediatric patients. To assess the discrimination ability of the Abraham solvation parameters and age-related changes in simulated media composition to predict in vitro drug solubility differences between pediatric and adult gastrointestinal conditions by multivariate data analysis. Methods Differences between drug solubility in pediatric and adult biorelevant media were expressed as a % pediatric-to-adult ratio [Sp/Sa (%)]. Solubility ratios of fourteen poorly water-soluble drugs (2 amphoteric; 4 weak acids; 4 weak bases; 4 neutral compounds) were used in the analysis. Partial Least Squares Regression was based on Abraham solvation parameters and age-related changes in simulated gastrointestinal fluids, as well as their interactions, to predict the pediatric-to-adult solubility ratio. Results The use of Abraham solvation parameters was useful as a theory-informed set of molecular predictors of drug solubility changes between pediatric and adult simulated gastrointestinal fluids. Our findings suggest that the molecular solvation environment in the fasted gastric state was similar in the pediatric age-groups studied, which led to fewer differences in the pediatric-to-adult solubility ratio. In the intestinal fasted and fed state, there was a high relative contribution of the physiologically relevant surfactants to the alteration of drug solubility in the pediatric simulated conditions compared to the adult ones, which confirms the importance of an age-appropriate composition in biorelevant media. Conclusion Statistical models based on Abraham solvation parameters were applied mostly to better understand drug solubility differences in adult and pediatric biorelevant media.

MPTHub: an open-source software for characterizing the transport of particles in biorelevant media

The study of the transport of particles in different environments plays an essential role in understanding interactions with humans and other living organisms. Importantly, obtained data can be directly used for multiple applications in fields such as fundamental biology, toxicology or medicine. Particle movement in biorelevant media can be readily monitored using microscopy and converted into time-resolved trajectories using freely available tracking software. However, translation into tangible and meaningful parameters is time-consuming and not always intuitive. Thus, we developed a new software - MPTHub - as an open-access, stand-alone, user-friendly tool for the rapid and reliable analysis of particle trajectories extracted from video microscopy. The software was programmed using Python and allowed to import and analyze trajectory data, and export relevant data such as individual and ensemble time-averaged mean square displacements and effective diffusivity, and anomalous transport exponent. Data processing was reliable, fast (total processing time of less than 10 sec) and required minimal memory resources (up to a maximum of around 150 MB in RAM). Demonstration of software applicability was conducted by studying the transport of different polystyrene nanoparticles (100-200 nm) in mucus surrogates. Overall, MPTHub represents a freely available software tool that can be used even by unexperienced users for studying the transport of particles in biorelevant media.

Development of a Gastro-retentive Dosage Form of a New Promising Anti-tuberculosis Drug Macozinone

Introduction. Due to increase in the frequency of detecting cases of tuberculosis caused by strains of mycobacteria with resistance not only to traditional, but also recently introduced into clinical circulation anti-tuberculosis drugs, it is urgent to search for and develop new drugs that can be effective against multidrug-resistant (MDR-TB) and extensively drug resistant (XDR-TB) strains. One of the most promising classes of such compounds are fluorine derivatives of benzothiazinones, and particularly compound PBTZ169 (INN macozinone). This antibiotic has a high specificity against mycobacteria tuberculosis (M. tuberculosis), inhibiting one of the key enzymes of cell wall synthesis. However, macozinone as an active pharmaceutical ingredient has significant features of physical and chemical properties that hinder the development of oral dosage forms based on it. It is classified as class IV by BCS and is characterized by a very low solubility and lipophilicity, a pronounced dependence of dissolution rate on the pH of the medium, and very low bioavailability when taken orally.Aim. To substantiate the target profile, critical quality attributes and to develop a prototype of an oral dosage form with modified release of macozinone, allowing to maximize its pharmacological activity.Materials and methods. Using pharmaceutical substance macozinone hydrochloride and various excipients, experimental tablets with a dosage of 500 mg macozinone were developed. The influence of the composition of the media and the added excipients on the solubility of macozinone in various biorelevant media, the degree of swelling in the liquid and the degree of mucoadhesion of the experimental tablets to the mucus of the pig stomach were evaluated. The HPLC method was used to evaluate the kinetics of the release of the active substance.Results and discussion. In this work, the expediency of creating macozinone-containing gastro-retentive dosage forms with a slow release of the active substance, the delay mechanism of which is provided by swelling and increased adhesion to the gastric mucosa, has been substantiated. Various tablet samples were experimentally tested in which the modification of the release of the active substance and the degree of swelling and mucoadhesion were varied by introducing various excipients into the formulations, including known swelling and bioadhesive matrix agents.Conclusion. According to the results of the experiments, samples of high-dose (500 mg) swellable and mucoadhesive tablets created by the technology of two-stage granulation with the inclusion of macozinone - hydroxypropyl-beta-cyclodextrin mixtures in the primary granules and introduction of combinations of soluble and insoluble hydrophilic matrix agents into the intergranular space were recognized as the most promising for subsequent pharmacokinetic studies.

Concentration and Composition Dependent Aggregation of Pluronic- and Poly-(2-Oxazolin)-Efavirenz Formulations in Biorelevant Media

Interactions of intestinal fluids with polymer excipients, drugs and their formulations are not fully understood. Here, diffusion ordered spectroscopy (DOSY) and nuclear Overhauser effect spectroscopy (NOESY), complemented by cryo-TEM were employed to address this. Efavirenz as model drug, the triblock copolymers Pluronic F-127 (PF127) and poly(2-oxazolin) based pMeOx-b-pPrOzi-b-pMeOx (pOx/pOzi) and their respective formulations were studied in simulated fed-state intestinal fluid (FeSSIF). For the individual polymers, the bile interfering nature of PF127 was confirmed and pure pOx/pOzi was newly classified as non-interfering. A different and more complex behaviour was observed if EFV was involved. The formulations showed multi-facetted concentration and composition dependent aggregation. This demonstrates that separate evaluation of polymers or drugs in biorelevant media is not sufficient and their mixtures need to be carefully studied.<br>

Concentration and Composition Dependent Aggregation of Pluronic- and Poly-(2-Oxazolin)-Efavirenz Formulations in Biorelevant Media

Interactions of intestinal fluids with polymer excipients, drugs and their formulations are not fully understood. Here, diffusion ordered spectroscopy (DOSY) and nuclear Overhauser effect spectroscopy (NOESY), complemented by cryo-TEM were employed to address this. Efavirenz as model drug, the triblock copolymers Pluronic F-127 (PF127) and poly(2-oxazolin) based pMeOx-b-pPrOzi-b-pMeOx (pOx/pOzi) and their respective formulations were studied in simulated fed-state intestinal fluid (FeSSIF). For the individual polymers, the bile interfering nature of PF127 was confirmed and pure pOx/pOzi was newly classified as non-interfering. A different and more complex behaviour was observed if EFV was involved. The formulations showed multi-facetted concentration and composition dependent aggregation. This demonstrates that separate evaluation of polymers or drugs in biorelevant media is not sufficient and their mixtures need to be carefully studied.<br>

Edelfosine nanoemulsions inhibit tumor growth of triple negative breast cancer in zebrafish xenograft model

Triple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells’ proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.

Enhanced Dissolution of Naproxen by Combining Cocrystallization and Eutectic Formation

Improving dissolution properties of active pharmaceutical ingredients (APIs) is a critical step in drug development with the increasing occurrence of sparingly soluble APIs. Cocrystal formation is one of the methods to alter the physicochemical properties of APIs, but its dissolution behavior in biorelevant media has been scrutinized only in recent years. We investigated the combined strategy of cocrystallization and eutectic formation in this regard and utilized the cocrystal model system of naproxen and three pyridinecarboxamide isomers. Binary melting diagrams were constructed to discover the eutectic compositions of the three cocrystals with excess amounts of pyridinecarboxamides. The melt–crystallized eutectics and cocrystals were compared in their dissolution behaviors with respect to neat naproxen. The eutectics enhanced the early dissolution rates of the cocrystals in both the absence and presence of biologically relevant bile salt and phospholipid components, whereas the cocrystal dissolution was expedited and delayed, respectively. The combined strategy in the present study will be advantageous in maximizing the utility of the pharmaceutical cocrystals.