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In recent years, with the increased use of antibiotics and immunosuppres-sive agents, there was an increased incidence of oral mycosis and Candida albicans is the most common etiologic agent in oropharyngeal candidiasis, especially in patients with HIV. The aim of this work is to develop a new dosage form containing miconazole (MN) to be topically applied on oral mucosa, allowing for a massive penetration of the drug in the tissue. The vehicle for the drug delivery was lipid microparticles incorporated in a hydrophilic gel. The lipospheres were obtained by hot melt encapsulation method using as matrix ingredients a mixtures of esters of fatty acids with higher fatty alcohols, having low melting point and a composition similar to that of some lipid membrane components The microparticles were characterized for particle size (by laser light scattering), entrapment efficiency (by UV-Vis analysis) morphology (optical microscopy) and physical state (DSC) The hydrophilic gel contained also lemon essence to enhance the palatability of product and increase the compliance of patient. The oral tissue penetration of MN released from the lipospheres alone or incorporated in gel was evaluated ex-vivo using franz diffusion cell and buccal porcine mucosa. The results were compared with behaviour of commercial Daktarin® oral gel. The lipid microparticles increase significantly the accumulative uptake of MN in buccal mucosa over the marketed gel and showed a considerably enhanced mucosa targeting effect, even at very low doses. These results indicate that the studied lipospheres/gel formulation may be a promising carrier for topical delivery of MN in the oral cavity.

The aim of this study was to investigate the potential for systemic administration of Methimazole (MMI) through the buccal mucosa as an alternative route for drug delivery. Considering that the most important restriction in buccal drug delivery could be the low permeability of the mucosa, the ability of MMI to cross the mucosal barrier was assessed. Permeation of MMI through porcine buccal mucosa was investigated ex vivo using Franz type diffusion cells, buffer solution simulating saliva or natural human saliva as donor phase. The collected data suggested that buccal mucosa does not hinder MMI diffusion and the drug crosses the membrane (Js = 0.068 mg cm-2 h-1 and Kp = 0.065 cm h-1). Matrix tablets, suitable for administration on buccal mucosa, were then designed and prepared by direct compression of MMI loaded matrices (70% w/w) using Eudragit® RS 100 as a matrixing, low permeable, pH-independent, mucoadhesive and insoluble agent. The matrix tablets were evaluated in vitro for dissolution; however, the drug was discharged too rapidly from tablets. To obtain drug release rate suitable to maintain constant drug levels in the central compartment the tablets were coated with lipophilic material (glycerol tristearate). In ex vivo permeation experiments, therapeutically MMI plasma levels were obtained when matrix tablets were coated with 0.10 mm thick lipophilic coating film. Coated tablets placed on buccal porcine mucosa provides optimal drug release rate. Coated buccal matrix tablets may represent a potential alternative dosage form for systemic delivery of MMI in hyperthyroidism management.

Drug delivery to the CNS is subject to the permeability limitations imposed by the BBB that regulates movements of actives in and out of the brain. During the drug discovery phase a key aspect could be the selection of the compounds properties crucial for brain penetration. Novel CNS-targeted neurotherapeutics should possess the optimal characteristics that allow passive diffusion through the BBB via the transcellular route, or have the structural features necessary to serve as a substrate for one of the endogenous transport systems of the BBB. An attractive and rewarding chemistry-based strategy, employed to increase the CNS transport of poorly penetrating therapeutic agents, is the transient chemical modification. This approach could improve physicochemical, biopharmaceutical, pharmacokinetic and drug delivery properties of active agents that overcome barriers to a drug’s usefulness. With the aim of mask functional groups and modify the physicochemical properties relevant to bioavailability, in this work CNS-actives were covalently linked to different aminoacidic moieties. The chemical structure of the derivatives and Log D were determined. Chemical stability was evaluated in simulated biological fluids. Enzymatic stability was assessed ex vivo. The effects of derivatives were observed in vitro and their availability was measured in rat brain tissue. Finally, cellular toxicity was established. Our data support that aminoacids could be considered as good masking agents for CNS-targeted drugs.

Purpose. Problems with the limited availability of human hepatocytes for cell transplantation may be overcome by improving the efficiency of their cryopreservation. TRH-loaded liposomes could enhance epatocyte viability by regulating the intracellular uptake of the cryoprotectant [1]. Methods. TRH-loaded liposomes were prepared by film hydration method (EPC, sodium cholate, 200mM TRH solution) [2]. Liposomal size was determined by dynamic light scattering. Intraliposomal TRH content was measured using the Megazyme spectrophotometric method. After incubation (1-5 h, 37°C, 5% CO2, 95% RH) of human hepatocytes with TRH-loaded liposomes or equivalent TRH solution, intracellular sugar content was determined. Cell viability was evaluated by trypan blue exclusion. Results. Size analysis (320.2 nm diameter) and distribution (93.40.4%) suggested formation of highly homogeneous, reproducible Small Unilamellar Vesicles (SUVs). Encapsulation efficiency was 332% w/w. After incubation of hepatocytes with loaded liposomes, intracellular TRH content was about 0.1 mg/million of cells and the cell viability (858%) was unvarying and comparable to the control. By contrast, after incubation with TRH solution, hepatocyte viability dropped to 485%. Conclusions. TRH-loaded SUVs seem a useful tool in controlling intracellular uptake of the cryoprotectant. [1] Katenz E. et al., Liver Tranplantation 45 (2007) 13-38. [2] Chiantia S. et al., Langmuir 21 (2005) 4108-4116.

Dopamine delivery to the central nervous system (CNS) undergoes the permeability limitations of blood-brain barrier (BBB) which is a selective interface that excludes most water-soluble molecules from entering the brain. Neutral amino acids permeate the BBB by specific transport systems. Conden- sation of dopamine with neutral amino acids could afford potential prodrugs able to interact with the BBB endogenous transporters and easily enter the brain. The synthesis and characterization of the dopamine derivative 2-amino-N-[2-(3,4-dihydroxy-phenyl)-ethyl]-3-phenyl-propionamide (7) is de- scribed. The chemical and enzymatic stability of 7 was evaluated. The molecular weight (300 Da) and Log P app (0.76) indicated that the physico-chemical characteristics of compound 7 are adequate to cross biological membranes. Compound 7 was enzymatically cleaved to free dopamine in rat brain homogenate (t 1/2 ¼ 460 min). In human plasma, the t 1/2 of 7 was estimated comparable to that re- ported for l -DOPA. In view of a possible oral administration of 7, studies of its chemical behavior under conditions simulating those of the gastrointestinal tract showed that no dopamine production occurred; furthermore, 7 is able to permeate through a simulated intestinal mucosal membrane. The collected data suggest that compound 7 could be considered a very valuable candidate for subse- quent in vivo evaluation.