Native Cyclodextrins as Complexation Agents for Pterostilbene: Complex Preparation and Characterization in Solution and in the Solid State

Pterostilbene (3,5-dimethoxy-4′-hydroxystilbene, PTB) is a natural dietary stilbene, occurring primarily in blueberries and Pterocarpus marsupium heartwood. The interest in this compound is related to its different biological and pharmacological properties, such as its antioxidant, anti-inflammatory, and anticarcinogenic activities and its capacity to reduce and regulate cholesterol and blood sugar levels. Nevertheless, its use in therapy is hindered by its low aqueous solubility; to overcome this limitation we studied the feasibility of the use of cyclodextrins (CDs) as solubility-enhancing agents. CDs are natural macrocyclic oligomers composed of α-d-glucose units linked by α-1,4 glycosidic bonds to form torus-shaped molecules, responsible for inclusion complex formation with organic molecules. In particular, the aim of this study was to evaluate the feasibility of complexation between PTB and native CDs using various preparative methods. The isolated solid products were characterized using differential scanning calorimetry (DSC), simultaneous thermogravimetric/DSC analysis (TGA/DSC), Fourier transform infrared (FT-IR) spectroscopy, and X-ray diffraction (XRD) on powder and single crystals. The results indicated little or no evidence of the affinity of PTB to complex with α-CD using the kneading method. However, with β-CD and γ-CD thermal analysis revealed an interaction which was also corroborated by FT-IR and 1H-NMR spectroscopy. With β-CD, a hydrated complex of PTB was isolated and its characterization by single-crystal XRD revealed, for the first time, the mode of inclusion of the PTB molecule in the cavity of a CD. To complement the solid-state data, liquid-phase studies were carried out to establish the effect of CDs on the aqueous solubility of PTB and to determine the complex stoichiometries and the association constants for complex formation. Phase-solubility studies showed AL-type profiles for α- and β-CD and a BS profile for γ-CD, with K1:1 values of 1144, 4950, and 133 M−1 for α-CD·PTB, β-CD·PTB, and γ-CD·PTB, respectively. The stoichiometry of CD·PTB complexes, determined by Job’s method, revealed for each system a 1:1 molar ratio. The dissolution rate of PTB was approximately doubled just by employing simple physical mixtures, but the best performance was achieved by products obtained via kneading and co-precipitation, which effected the complete dissolution of PTB in 40 and 20 min for β-CD and γ-CD, respectively

Drug Release Kinetics and Front Movement in Matrix Tablets Containing Diltiazem or Metoprolol/ λ

In this work we investigated the moving boundaries and the associated drug release kinetics in matrix tablets prepared with two complexes between λ-carrageenan and two soluble model drugs, namely, diltiazem HCl and metoprolol tartrate aiming at clarifying the role played by drug/polymer interaction on the water uptake, swelling, drug dissolution, and drug release performance of the matrix. The two studied complexes released the drug with different mechanism indicating two different drug/polymer interaction strengths. The comparison between the drug release behaviour of the complexes and the relevant physical mixtures indicates that diltiazem gave rise to a less soluble and more stable complex with carrageenan than metoprolol. The less stable metoprolol complex afforded an erodible matrix, whereas the stronger interaction between diltiazem and carrageenan resulted in a poorly soluble, slowly dissolving matrix. It was concluded that the different stability of the studied complexes affords two distinct drug delivery systems: in the case of MTP, the dissociation of the complex, as a consequence of the interaction with water, affords a classical soluble matrix type delivery system; in the case of DTZ, the dissolving/diffusing species is the complex itself because of the very strong interaction between the drug and the polymer

Study of hydrogels based on polyacrilamide as new controlled release dosage forms produced by frontal polymerization

The work purpose was the evaluation of the potential application of the Frontal Polymerization (FP) technique as a new method for the preparation of controlled release dosage forms based on polyacrilamide, in which the drug loading and the polymer preparation occur at the same time

Electrochemotherapy of Deep-Seated Tumors: State of Art and Perspectives as Possible “EPR Effect Enhancer” to Improve Cancer Nanomedicine Efficacy

Surgical resection is the gold standard for the treatment of many kinds of tumor, but its success depends on the early diagnosis and the absence of metastases. However, many deep-seated tumors (liver, pancreas, for example) are often unresectable at the time of diagnosis. Chemotherapies and radiotherapies are a second line for cancer treatment. The “enhanced permeability and retention” (EPR) effect is believed to play a fundamental role in the passive uptake of drug-loaded nanocarriers, for example polymeric nanoparticles, in deep-seated tumors. However, criticisms of the EPR effect were recently raised, particularly in advanced human cancers: obstructed blood vessels and suppressed blood flow determine a heterogeneity of the EPR effect, with negative consequences on nanocarrier accumulation, retention, and intratumoral distribution. Therefore, to improve the nanomedicine uptake, there is a strong need for “EPR enhancers”. Electrochemotherapy represents an important tool for the treatment of deep-seated tumors, usually combined with the systemic (intravenous) administration of anticancer drugs, such as bleomycin or cisplatin. A possible new strategy, worthy of investigation, could be the use of this technique as an “EPR enhancer” of a target tumor, combined with the intratumoral administration of drug-loaded nanoparticles. This is a general overview of the rational basis for which EP could be envisaged as an “EPR enhancer” in nanomedicine

Nose-to-Brain Delivery of Antioxidants as a Potential Tool for the Therapy of Neurological Diseases

Oxidative stress has a key role in the pathogenesis of neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Huntington’s diseases and can be an important cause of the damages in cerebral ischemia. Oxidative stress arises from high levels of reactive oxygen species (ROS). Consequently, on this rational base, antioxidants (many of natural origin) are proposed as potential drugs to prevent ROS noxious actions because they can protect the target tissues from the oxidative stress. However, the potential of antioxidants is limited, owing to the presence of the blood–brain barrier (BBB), which is difficult to cross with a consequent low bioavailability of the drug into the brain after systemic (intravenous, intraperitoneal, oral) administrations. One strategy to improve the delivery of antioxidants to the brain involves the use of the so-called nose-to-brain route, with the administration of the antioxidant in specific nasal formulations and its passage to the central nervous system (CNS) mainly through the olfactory nerve way. In the current literature, many examples show encouraging results in studies carried out in cell cultures and in animal models about the potential neuroprotective effects of antioxidants when administered through the nose. This review concerns the nose-to-brain route for the brain targeting of antioxidants as a potential tool for the therapy of neurological diseases

Uptake in the Central Nervous System of Geraniol Oil Encapsulated in Chitosan Oleate Following Nasal and Oral Administration

The pharmacological activities of geraniol include anticancer and neuroprotective properties. However, its insolubility in water easily induces separation from aqueous formulations, causing administration difficulties. Here we propose new emulsified formulations of geraniol by using the amphiphilic polymer chitosan-oleate (CS-OA) as surfactant to combine mucoadhesive and absorption enhancer properties with stabilization effects on the oil dispersion. The formulation based on CS-OA 2% (w/w) (G-CS-OA-2.0%) showed viscosity values compatible with oral and nasal administration to rats, and mean diameter of the dispersed phase of 819 ± 104 nm. G-CS-OA-2.0% oral administration sensibly increases the geraniol bioavailability with respect to coarse emulsions obtained without CS-OA (AUC values in the bloodstream were 42,713 ± 1553 µg∙mL-1∙min and 2158 ± 82 µg∙mL-1∙min following administration of 50 mg/kg or 1 mg/kg, respectively), and enhances the aptitude of geraniol to reach the central nervous system from the bloodstream (AUC values in the cerebrospinal fluid were 7293 ± 408 µg∙mL-1∙min and 399 ± 25 µg∙mL-1∙min after oral administration of 50 mg/kg or 1 mg/kg, respectively). Moreover, relevant geraniol amounts were detected in the cerebrospinal fluid following the G-CS-OA-2% nasal administration (AUC values in the cerebrospinal fluid were 10,778 ± 477 µg∙mL-1∙min and 5571 ± 290 µg∙mL-1∙min after nasal administration of 4 mg/kg or 1 mg/kg, respectively)