An Alternative Device for the Topical Treatment of Oral Cancer: Development and Ex-Vivo Evaluation of Imiquimod-Loaded Polysaccharides Formulations.

The topical use of imiquimod (IMQ), a non-specific immune response modifier, showed to be a promising therapeutic option for the early-stage treatment of some type of oral cancer, even when performed with a formulation (Aldara®) developed and approved for skin application. The aim of this work was the development of buccal formulations for the topical administration of IMQ with improved mucosal retention and reduced trans-mucosal permeation when compared to the reference formulation. Three different hydrogels based on carboxymethyl chitosan (CMChit), sodium alginate (A), and xanthan gum (X) in different combinations were prepared, and the loading of imiquimod was successfully performed by using a micellar formulation based on d-α-tocopheril polyethylene glycol 100 succinate (TPGS). Except for CMChit formulation, in all the other cases, the performance in vitro on the mucosa resulted comparable to the commercial formulation, despite the drug loading being 50-fold lower. Converting the gels in films did not modify the IMQ accumulated with respect to the correspondent gel formulation but produced as a positive effect a significant reduction in the amount permeated. Compared to the commercial formulation, this reduction was significant (p < 0.01) in the case of X film, resulting in an improvement of the retained/permeated ratio from 1 to 5.44. Mucoadhesion evaluation showed similar behavior when comparing the developed gels and the commercial formulation, and an excellent bioadhesion was observed for the films.

Histological and Molecular Evidence of the Positive Performance of Glycerol-Plasticized Chitosan-Alginate Membranes on Skin Lesions of Hyperglycemic Mice.

The purpose of this study was to investigate tissue repair of excisional wounds in hyperglycemic animals treated with chitosan-alginate membranes (CAM) produced in the presence of glycerol. 8-week C57B1 male mice were divided into normoglycemic animals with a 0.9% saline solution topical treatment (CTSF); hyperglycemic animals with 0.9% saline solution topical treatment (DMSF) and hyperglycemic animals with glycerol-plasticized chitosan-alginate membrane topical treatment (DMCAM). On post-wound day three, the DMCAM group presented a lower number of leukocytes, mature mastocytes, a higher number of vessels (p < 0.05), and active mastocytes (p < 0.05) when compared to the CTSF and DMSF groups. There were no differences regarding the distribution, deposition, organization, and thickness of collagen fibers. On day 7 there were no differences in the analysis of fibroblasts, mastocytes, and TGF−ß1 and VEGF expressions among the groups. Regarding collagen fibers, the DMCAM group presented slight red-orange birefringence when compared to the CTSF and DMSF groups. On day 14 there was a slight concentration of thinner elastic fibers for the DMCAM group, with a greater reorganization of papillary skin and improved red-orange birefringence collagen fibers, as well as net-shaped orientation, similar to intact skin. In addition, improved elastic fiber organization distributed in the entire neo-dermis and a larger presence of elaunin fibers were observed, in a similar pattern found in the intact skin. The use of CAM in cutaneous lesions boosted tissue repair since there was a smaller number of inflammatory cells and mastocytes, and an improvement in collagen deposition and collagen fibers. These results demonstrate the high potential of plasticized chitosan-alginate membrane for skin wound dressing of hyperglycemic patients.

Polymeric Biomaterials for Topical Drug Delivery in the Oral Cavity: Advances on Devices and Manufacturing Technologies.

There are several routes of drug administration, and each one has advantages and limitations. In the case of the topical application in the oral cavity, comprising the buccal, sublingual, palatal, and gingival regions, the advantage is that it is painless, non-invasive, allows easy application of the formulation, and it is capable of avoiding the need of drug swallowing by the patient, a matter of relevance for children and the elderly. Another advantage is the high permeability of the oral mucosa, which may deliver very high amounts of medication rapidly to the bloodstream without significant damage to the stomach. This route also allows the local treatment of lesions that affect the oral cavity, as an alternative to systemic approaches involving injection-based methods and oral medications that require drug swallowing. Thus, this drug delivery route has been arousing great interest in the pharmaceutical industry. This review aims to condense information on the types of biomaterials and polymers used for this functionality, as well as on production methods and market perspectives of this topical drug delivery route.

Improvement of Imiquimod Solubilization and Skin Retention via TPGS Micelles: Exploiting the Co-Solubilizing Effect of Oleic Acid.

Imiquimod (IMQ) is an immunostimulant drug approved for the topical treatment of actinic keratosis, external genital-perianal warts as well as superficial basal cell carcinoma that is used off-label for the treatment of different forms of skin cancers, including some malignant melanocytic proliferations such as lentigo maligna, atypical nevi and other in situ melanoma-related diseases. Imiquimod skin delivery has proven to be a real challenge due to its very low water-solubility and reduced skin penetration capacity. The aim of the work was to improve the drug solubility and skin retention using micelles of d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS), a water-soluble derivative of vitamin E, co-encapsulating various lipophilic compounds with the potential ability to improve imiquimod affinity for the micellar core, and thus its loading into the nanocarrier. The formulations were characterized in terms of particle size, zeta potential and stability over time and micelles performance on the skin was evaluated through the quantification of imiquimod retention in the skin layers and the visualization of a micelle-loaded fluorescent dye by two-photon microscopy. The results showed that imiquimod solubility strictly depends on the nature and concentration of the co-encapsulated compounds. The micellar formulation based on TPGS and oleic acid was identified as the most interesting in terms of both drug solubility (which was increased from few µg/mL to 1154.01 ± 112.78 µg/mL) and micellar stability (which was evaluated up to 6 months from micelles preparation). The delivery efficiency after the application of this formulation alone or incorporated in hydrogels showed to be 42- and 25-folds higher than the one of the commercial creams.