Alessandra Cristina Santos Akkari

Poloxamer-based binary hydrogels for delivering tramadol hydrochloride: sol-gel transition studies, dissolution-release kinetics, in vitro toxicity, and pharmacological evaluation

In this work, poloxamer (PL)-based binary hydrogels, composed of PL 407 and PL 188, were studied with regard to the physicochemical aspects of sol-gel transition and pharmaceutical formulation issues such as dissolution-release profiles. In particular, we evaluated the cytotoxicity, genotoxicity, and in vivo pharmacological performance of PL 407 and PL 407–PL 188 hydrogels containing tramadol (TR) to analyze its potential treatment of acute pain. Drug–micelle interaction studies showed the formation of PL 407–PL 188 binary systems and the drug partitioning into the micelles. Characterization of the sol-gel transition phase showed an increase on enthalpy variation values that were induced by the presence of TR hydrochloride within the PL 407 or PL 407–PL 188 systems. Hydrogel dissolution occurred rapidly, with approximately 30%–45% of the gel dissolved, reaching ~80%–90% up to 24 hours. For in vitro release assays, formulations followed the diffusion Higuchi model and lower Krel values were observed for PL 407 (20%, Krel =112.9±10.6 μg·h−1/2) and its binary systems PL 407–PL 188 (25%–5% and 25%–10%, Krel =80.8±6.1 and 103.4±8.3 μg·h−1/2, respectively) in relation to TR solution (Krel =417.9±47.5 μg·h−1/2, P<0.001). In addition, the reduced cytotoxicity (V79 fibroblasts and hepatocytes) and genotoxicity (V79 fibroblasts), as well as the prolonged analgesic effects (>72 hours) pointed to PL-based hydrogels as a potential treatment, by subcutaneous injection, for acute pain.

Poloxamer 407/188 binary thermosensitive hydrogels as delivery systems for infiltrative local anesthesia: Physico-chemical characterization and pharmacological evaluation

In this study, we reported the development and the physico-chemical characterization of poloxamer 407 (PL407) and poloxamer 188 (PL188) binary systems as hydrogels for delivering ropivacaine (RVC), as drug model, and investigate their use in infiltrative local anesthesia for applications on the treatment of post-operative pain. We studied drug-micelle interaction and micellization process by light scattering and differential scanning calorimetry (DSC), the sol-gel transition and hydrogel supramolecular structure by small-angle-X-ray scattering (SAXS) and morphological evaluation by Scanning Electron Microscopy (SEM). In addition, we have presented the investigation of drug release mechanisms, in vitro/in vivo toxic and analgesic effects. Micellar dimensions evaluation showed the formation of PL407-PL188 mixed micelles and the drug incorporation, as well as the DSC studies showed increased enthalpy values for micelles formation after addition of PL 188 and RVC, indicating changes on self-assembly and the mixed micelles formation evoked by drug incorporation. SAXS studies revealed that the phase organization in hexagonal structure was not affected by RVC insertion into the hydrogels, maintaining their supramolecular structure. SEM analysis showed similar patterns after RVC addition. The RVC release followed the Higuchi model, modulated by the PL final concentration and the insertion of PL 188 into the system. Furthermore, the association PL407-PL188 induced lower in vitro cytotoxic effects, increased the duration of analgesia, in a single-dose model study, without evoking in vivo inflammation signs after local injection.

Budesonide-hydroxypropyl-β-cyclodextrin inclusion complex in binary poloxamer 407/403 system for ulcerative colitis treatment: A physico-chemical study from micelles to hydrogels

Budesonide (BUD) is a glucocorticoid widely used for the treatment of ulcerative colitis. In this work, we propose the study of the system BUD-HP-β-CD inclusion complex incorporated into PL 407 and PL407-PL403 thermoreversible hydrogels, considering physico-chemical and pharmaceutical aspects. Complexation between BUD and HP-β-CD was confirmed by phase solubility studies (1:1 stoichiometry, Kc=8662.8 M(-1)), DSC, FTIR and microscopy analyzes. BUD solubility in simulated upper and lower colon fluids was improved in a dependence of HP-β-CD and PL 407 or PL407-PL403 association. Micellar hydrodynamic diameter studies showed the interaction between HP-β-CD and PL blocks, as well as the reorganization of the micellar system in the presence of BUD and its inclusion complex. Micellization temperature (Tm) was not shifted, but sol-gel phase transition studies showed that in the presence of BUD, HP-β-CD or BUD:HP-β-CD complex, the association PL407-PL403 favored the gel formation close to the physiological temperature. Physico-chemical and in vitro release assays studies revealed no competitive displacement of BUD from the HP-β-CD cavity evoked by PL407 or PL407-PL403 addition. These findings point out the BUD-HP-β-CD in PL-based hydrogels as strategies for future investigations on development of new pharmaceutical formulations for the treatment of ulcerative colitis.

Poloxamers as Drug-Delivery Systems: Physicochemical, Pharmaceutical, and Toxicological Aspects

Poloxamers (PL) are copolymers A-B-A type consisting of ethylene oxide (EO) and propylene oxide (PO) units in a triblock EOx–POy–EOx arrangement. These copolymers are interesting due to their ability for temperature-dependent gel formation, as a result of their self-assembling in micelles. Several studies have demonstrated the application of the thermoreversible copolymers as drug-delivery systems in order to prolong the drug release, to sustain the effectiveness, and also to reduce local and/or systemic toxicity, connecting the expertise of different research fields such as Biochemistry, Nanotechnology, Biopharmaceutics, Pharmacology, and Toxicology. Then, the purpose of this chapter involves a discussion about PL copolymers in the light of those research fields.

Cyclodextrin-Based Delivery Systems for Arthritic Diseases: From Development to Experimental Therapeutics

Arthritics diseases, such as rheumatoid arthritis and osteoarthritis are chronic inflammatory and one of the most prevalent health conditions that cause disability (pain and functional limitation of joints). Despite the research advances, the treatment of those pathological conditions remains ineffective, since the pharmacological therapy is palliative, reducing only the symptoms and, in some cases, the chronic progression of the disease. In this context, the development of new formulations for controlled release would be interesting for reducing the number of injections and would also increase the patient compliance. In this article, we present a review of the cyclodextrin (CD)-based delivery systems focusing from conventional guest-host inclusion complexes and CD-polysulphates, until supramolecular architectures such as drug-CD-polymers conjugates, pseudorotaxanes, hydrogels as well as double-carrier systems and other systems. In particular, this article focuses the main CD-based delivery systems described in the literature emphasizing their possible administration by intra-articular route on the treatment of arthritic diseases, concentrating on their development and also performance as in vivo experimental therapeutic systems.