First steps in the formulation of praziquantel nanosuspensions for pharmaceutical applications

Praziquantel (PZQ), a broad spectrum anthelmintic drug, cannot be found in acceptable dosage forms for elderly patients, paediatric patients, and for veterinary use. In fact, very little has been done up to now in the formulation of liquid dosage forms, being they always formulated for parenteral administration. To beat this important challenge, it was accomplished a comprehensive analysis of the influence of two elementary physicochemical aspects, i.e. surface thermodynamic and electrokinetic properties, on the colloidal stability of PZQ nanosuspensions. The hydrophobic character of the drug, intensely determining the flocculation curves, was confirmed by the thermodynamic characterization. The electrophoretic characterization, in combination with the sedimentation and relative absorbance versus time curves, highlighted that the electrical double layer thickness and the surface charge can play an essential role in the stability of the pharmaceutical colloid. Finally, it was demonstrated that controlling the pH values and the incorporation of electrolytes can help in formulating PZQ aqueous nanosuspensions with appropriate stability and redispersibility behaviours for pharmaceutical use.Fil: Martinez, Noelia Anabel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; ArgentinaFil: Fernández Álvarez, Fátima. Universidad de Granada; EspañaFil: Delgado, Ángel V.. Universidad de Granada; EspañaFil: Badillo García, María Luisa. Universidad de Granada; EspañaFil: Raba, Julio. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; ArgentinaFil: Cerutti, Estela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - San Luis. Instituto de Química de San Luis. Universidad Nacional de San Luis. Facultad de Química, Bioquímica y Farmacia. Instituto de Química de San Luis; ArgentinaFil: Arias, José L.. Universidad de Granada; Españ

Spray congealing: An emerging technology to prepare solid dispersions with enhanced oral bioavailability of poorly water soluble drugs

The low and variable oral bioavailability of poorly water soluble drugs remains a major concern for the pharmaceutical industry. Spray congealing is an emerging technology for the production of solid dispersion to enhance the bioavailability of poorly soluble drugs by using low-melting hydrophilic excipients. The main advantages are the absence of solvents and the possibility to obtain spherical free-flowing microparticles (MPs) by a relatively inexpensive, simple, and one-step process. This review aims to fully describe the composition, structure, physico-chemical properties, and characterization techniques of spray congealed-formulations. Moreover, the influence of these properties on the MPs performance in terms of solubility and dissolution enhancement are examined. Following, an overview of the different spray congealed systems developed to increase the oral drug bioavailability is provided, with a focus on the mechanisms underpinning the bioavailability enhancement. Finally, this work gives specific insights on the main factors to be considered for the rational formulation, manufacturing, and characterization of spray congealed solid dispersions

Stabilizing agents for drug nanocrystals: effect on bioavailability

Peer reviewe

Formulation and Evaluation of Polymeric Nanoparticles as Carriers of Rosuvastatin Calcium for Oral Administration

This study is to formulate and evaluate oral nanoparticulate drug delivery of rosuvastatin calcium used in the treatment of hypercholesterolemia. Management of hypercholesterolemia continues to be challenging with the currently available drugs due to poor bioavailability by the oral route and due to toxicity which occur at higher doses. Since, the preferred route of oral administration is limited to those drug molecules due to its poor solubility and/or poor permeability across the gastric mucosa. A large majority of the new chemical entities (NCE) and many existing drug molecules are poorly soluble and/or poorly permeable, thereby limiting their potential uses and increasing the difficulty of formulating bioavailable drug products. These limitations necessitate urgent requirement of novel drug delivery which do not suffer from such problems. Rosuvastatin calcium is a potent inhibitor of HMG CoA reductase, which is widely used in the treatment of hypercholesterolemia and may decrease the relative risk of heart attack and stroke. Currently this drug is administered orally as tablets. Since the drug is sparingly soluble and poorly permeable (partition coefficient (octanol/water) – 0.13 at pH 7.0) across the gastric mucosa, the drug displays oral bioavailability (absolute bioavailability-20%) problems in conventional dosage forms. Reported side effects are myopathy, rhabdomyolysis which occur at higher doses. Thus it could be a promising candidate in nanoparticulate drug delivery taking into accounts its poor solubility and poor permeability. Nanoparticulate drug delivery systems appear to be promising for improving bioavailability of drugs. These nanoparticulate systems are a type of colloidal drug delivery systems where the particle size varies from 10nm – 1000 nm in diameter. Nanoparticles have important potential application for the administration of therapeutic, diagnostic agents and represent very promising drug delivery system of controlled and targeted drug release. Though a wide range of polymers are being used for the development of nanoparticles, the present study included Eudragit L-100 and Eudragit S-100 as polymers and Pluronic and PVA as stabilizers

Taste Masking of Bitter Drugs

Taste masking of Active Pharmaceutical Ingredients (APIs) is critical in the development of solid oral dosage forms, since it is related to patient compliance, especially for pediatric populations. Therefore, it is essential to improve the existing methodologies and to develop new approaches that allow assessment of taste-masking efficacy. The current work focused on the production of taste-masked formulations of a bitter model drug substance and an appropriate excipient, using different co-precipitation processes: Stirred Reactor, Adaptive Focused Acoustics (AFA) technology and Microfluidization, for benchmarking purposes regarding taste masking properties. Thus, an experimental design of experiments was conducted to study the effect of different formulation variables (drug loading, feed solids concentration and solvent/antisolvent volume ratio) in the critical quality attributes of the spray-dried co-precipitated powders (drug’s solid state, morphology and particle size and dissolution performance). The encapsulation efficiency (EE) was then evaluated by using different dissolution methods and also surface characterization techniques (Scanning Electron Microscopy – Energy Dispersive X-ray Spectroscopy (SEM-EDS) and X-ray Photoelectron Spectroscopy (XPS)). Formulations were taste masked using any of the processes disclosed in this work. One of the formulations produced by Microfluidization technology, was the best regarding encapsulation efficiency, presenting a lower drug release in simulated salivary fluid within the first 5 minutes and the best encapsulation efficiency estimated by means of XPS. This can be explained by a high shear rate mixture provided by Microfluidization technology. Moreover, the pH shifts dissolution results for specific formulations and a commercial product (coated tablet) revealed similar dissolution profiles, meaning that the solubility of the drug substance (in the stomach and the upper intestine) seems not to be impacted by the processes used. According with the taste masking assessment techniques, EDS analysis presented some limitations and, in this case, it was proved not to be adequate, contrary to XPS which results corroborated the dissolution ones

Formulation and Evaluation of Polymeric Nanoparticles as Carriers of Rosuvastatin Calcium for Oral Administration.

A fundamental unit operation having important applications in pharmacy. It helps in improving solubility and bioavailability, reducing toxicity, enhancing release and providing better formulation opportunities for drugs. In most of the cases, size reduction is limited to micron size range, for example, various pharmaceutical dosage forms like powder, emulsion, suspension etc. Drugs in the nanometer size range enhance performance in a variety of dosage forms. Major advantages of nanosizing include increased surface area, enhanced solubility, increased rate of dissolution, increased oral bioavailability, more rapid onset of therapeutic action, less amount of dose required, decreased fed/fasted variability and decreased patient-to-patient variability the nanoprecipitation was a useful method for the successful incorporation of rosuvastatin calcium with high entrapment efficiency. The solubility and ex vivo intestinal permeability studies suggested that the nanoparticle formulations can improve the bioavailability of the rosuvastatin calcium by improving its solubility and permeability across intestinal membrane. Furthermore, it could be presumed that if the nanometer range particles were obtained, the bioavailability might be increased. Hence, we can conclude that polymeric nanoparticles enhance the bioavailability of poorly water soluble and low lipophilic drug like rosuvastatin calcium as a drug delivery system

Development and Characterization of an Antimicrotubular Taxane Loaded MPEG‐b‐PCL Nanoparticles

The present work entitled, “Development and characterisation of an Antimicrotubular Taxane loaded MPEG-b-PCL Nanoparticles” was aimed to develop a nanoparticulate drug delivery system of an anticancer drug Paclitaxel using a biodegradable amphiphilic diblock MPEG-b- PCL copolymer. The main objective of the work was to develop a controlled release dosage form of Paclitaxel nanoparticles for reducing severe side effects associated with conventional delivery system like paclitaxel injection(Taxol), because of the low solubility of paclitaxel in water, it was first dissolved in Cremophore EL (polyethoxylated castor oil) and Ethanol and then administered, use of this solvent mixture cause serious side effects like sever hypersensitivity reactions, neurotoxicity, nephrotoxicity and hypotensive reactions on iv administration. So, the inclusion of Paclitaxel in nanoparticle formulations has proved to be a good approach to eliminate effects of Cremophore EL and Ethanol. The preformulation studies were performed by using infrared spectroscopy, the obtained spectra revealed the absence of molecular interactions between the Paclitaxel, MPEG-b-PCL copolymer and PVA used in the formulation

NaDES as a green technological approach for the solubility improvement of BCS class II APIs: An insight into the molecular interactions

Recently, Natural Deep Eutectic Solvents (NaDES) have emerged as potential solvents for boosting drug bioavailability. In this work, the mechanism of solubility enhancement of some APIs belonging to BCS class II (tolbutamide, nimesulide, domperidone and cinnarizine) in these eutectic bio-solvents was investigated in order to get deeper insights into the molecular interactions between the NaDES components and the selected drugs. Different NaDES formulations based on choline chloride, proline, solid organic acids (citric, tartaric and malic acid), sugars (glucose and xylitol) and water were prepared by mild heating (70 °C). Characterization of unloaded NaDES (pH, Karl Fisher titration, viscosity and FTIR analysis) indicated that the type of Hydrogen Bond Acceptor (HBA) and Hydrogen Bond Donor (HBD), their molar ratio as well as water amount strongly affect the extent of H-bonding interactions. Hard gelatin capsules filled with NaDES maintained their integrity until 6 months, proving that all water molecules participate in H-bond network. APIs' solubility enhancement was significant in all NaDES with respect to buffer solutions (pH 1.2 and 6.8). Analysing NaDES having Choline as HBA, it was found that the solubility of smaller molecules increased using larger HBD, while higher molecular weight APIs can be better inserted into the network formed by smaller HBD. NOE experiments demonstrated the formation of a robust supramolecular structure among the protons of choline, those of organic acid and water. In addition, 1D ROESY spectra revealed for the first time the crucial role of choline (methyl groups) in establishing hydrophobic interactions with the relative aliphatic or aromatic portion of the drugs. These data suggest the complex structure of the API-NaDES supramolecular assembly and underline that drug solubility is dependent on a balance network of H-bonds and hydrophobic interactions as well. Understanding the type of interactions between the API and NaDES is essential for their use as effective solubilisation aid

Chitosan-based nanodelivery systems applied to the development of novel triclabendazole formulations.

Triclabendazole is a poorly-water soluble (0.24 μg/mL) compound classified into the Class II/IV of the Biopharmaceutical Classification System. It is the drug of choice to treat fascioliasis, a neglected parasitic disease worldwide disseminated. Triclabendazole is registered as veterinary medicine and it is only available for human treatment as 250 mg tablets. Thus, the aim of this work was to develop novel drug delivery systems based on nanotechnology approaches. The chitosan-based nanocapsules and nanoemulsions of triclabendazole were fully characterized regarding their particle size distribution, polydispersity index and zeta potential, in-vitro release and stability in biological media. Cytotoxicity evaluation and cellular uptake studies using CaCo-2 cell line were also investigated. The results indicated an average hydrodynamic size around ~160 nm were found for unloaded nanoemulsions which were slightly increased up to ~190 nm for loaded one. In contrast, the average hydrodynamic size of the nanocapsules increased from ~160 nm up to ~400 nm when loaded with triclabendazole. The stability studies upon 30 days storage at 4, 25 and 37°C showed that average size of nanoemulsions was not modified with varying amounts of loaded TCBZ while an opposite result was seen in case of loaded nanocapsules. In addition, a slight reduction of zeta potential values over time was observed in both triclabendazole nanosystems. Release of TCBZ from nanoformulations over 6 h in simulated gastric fluid was 9 to 16-fold higher than with untreated TCBZ dispersion. In phosphate buffer saline solution there was no drug release for neither nanocapsules nor nanoemulsions. Cell viabilities studies indicated that at certain concentrations, drug encapsulation can lower its cytotoxic effects when compared to untreated drug. Confocal laser scanning microscopy study has shown that nanocapsules strongly interacted with Caco-2 cells in vitro which could increase the passage time of triclabendazole after oral administration. The results of this study constitute the first step towards the development of nanoformulations intended for the oral delivery of anti-parasitic drugs of enhanced bioavailability