Mucoadhesive Properties of Eudragit®RS100, Eudragit®S100, and Poly(ε-caprolactone) Nanocapsules: Influence of the Vehicle and the Mucosal Surface.

The use of polymers as mucoadhesive materials has been explored in several drug delivery systems. It is well known that the resulting mucoadhesiveness not only depends on the polymers by themselves, but also on the way they are delivered and on the application target. However, little attention has been given to the combined effect of such characteristics. Therefore, the objective of this study is to analyze the mucoadhesion resulting from combined effects of nanocapsules produced with polymers of different ionic properties, Eudragit®RS100, Eudragit®S100, or poly(ε-caprolactone), when they are incorporated into different vehicles (suspension, hydrogel, and powder) and applied on different mucosal surfaces (mucin, porcine vaginal, and buccal mucosa). Mucoadhesion was measured by a tensile stress tester. Our findings show that polymeric self-assembling as nanocapsules improved the mucoadhesion of the polymers. Eudragit®RS100 nanocapsules have the best performance, independently of the vehicle and surface used. Regarding the vehicle, hydrogels showed higher adhesion when compared to suspensions and powders. When considering different types of surfaces, mucin presented a similar pattern like the animal mucosa, but it overestimated the mucoadhesiveness of all formulations. In conclusion, this study demonstrated that the best strategy to achieve high mucoadhesive formulations is by incorporating Eudragit®RS100 nanocapsules in hydrogels. Moreover, mucin is a suitable substrate to compare and screen different formulations but not as a conclusive estimation of the mucoadhesion values that can be achieved. These results are summarized in a decision tree that can help to understand different strategies of combination of these factors and the expected outcomes.

Cationic Polymeric Nanocapsules as a Strategy to Target Dexamethasone to Viable Epidermis: Skin Penetration and Permeation Studies.

The present work aimed to evaluate the behavior of dexamethasone-loaded cationic polymericnanocapsules in hydrogels, regarding their in vitro drug release and skin drug retention and per- meation. Cationic polymeric nanocapsules prepared with Eudragit RS 100 as the polymeric wall had mean particle size of 139 +/- 3.6 nm, positive zeta potential (+11.38 +/- 1.7 mV), and high encapsulation efficiency (81 +/- 2%). After preparation, they were formulated as hydrogels, which showed non-Newtonian, plastic behavior, and acidic pH. Photon correlation spectroscopy analysis of these hydrogels demonstrated the presence of particles with mean particle size close to that of the original colloidal suspensions. The presence of dexamethasone-loaded nanocapsules in hydrogels promoted controlled drug release and an increase in the amount of drug delivered into viable epidermis, the main target tissue to topical glucocorticoid action. Moreover, the formulation did not increase the risk of drug penetration to dermis and permeation to the receptor compartment.

Hydrogel containing silibinin nanocapsules presents effective anti-inflammatory action in a model of irritant contact dermatitis in mice.

The current study developed an innovative Pemulen® TR2 hydrogel containing silibinin-loaded pomegranate oil-based nanocapsules (HP-NC SB) intending cutaneous application. The formulation anti-inflammatory activity in an in vivo model and biometric studies on the skin of healthy volunteers were also performed. The nanocapsules were prepared using the interfacial deposition of preformed polymer technique and the hydrogels were obtained by thickening of nanocapsules suspension with Pemulen® TR2. Formulations with free compound, vehicle and blank nanocapsules were also produced. The hydrogels were evaluated concerning pH, silibinin content, particle size, spreadability profile, rheology, in vitro drug release, cutaneous permeation, bioadhesive potential and cutaneous biometry evaluation. Furthermore, a model of contact dermatitis croton oil-induced in mice was performed to evaluate the hydrogels anti-inflammatory potential. The formulations presented adequate characteristics for skin administration: particle within nanometric size, pH values in the acid range, silibinin content close theoretical values (1 mg/g) and non-Newtonian pseudoplastic behavior. Nano-based hydrogels showed high bioadhesive properties, increased silibinin in vitro release profile and its retention in the stratum corneum. The best anti-inflammatory effect was exhibited by HP-NC SB, which reduced both ear edema and inflammatory cells infiltration in comparison to the induced group. Furthermore, cutaneous biometric evaluation showed that formulations containing free or nanoencapsulated silibinin caused no modification in normal skin conditions (pH, tissue hydration, transepidermal water loss and erythema). In summary, the results demonstrated that the Pemulen® TR2 hydrogel containing NC SB was successfully developed, indicating its potential as an alternative treatment for irritant contact dermatitis.

Carvedilol-loaded nanocapsules: Mucoadhesive properties and permeability across the sublingual mucosa.

Carvedilol is a drug used to treat heart failure, hypertension, and coronary artery diseases . However, it has low oral bioavailability (25-35%) due to its high first-pass hepatic metabolism. The objective of this study was to develop carvedilol-loaded mucoadhesive nanocapsules as delivery systems for the sublingual administration of the drug. Nanocapsules were prepared using poly(ε-caprolactone) (CAR-LNC) and Eudragit® RS 100 (CAR-NC) as polymeric wall. In vitro interaction of formulations with mucin was performed to predict their mucoadhesion capacity. The permeability and washability profiles of carvedilol were evaluated using porcine sublingual mucosa. The mean diameter of particles in formulations was in the nanometric range, and particles had low polydispersity and slightly acidic pH. Zeta potential values were positive for CAR-NC and negative for CAR-LNC. Encapsulation efficiency was higher than 87% and 99% for CAR-NC and CAR-LNC, respectively. Both formulations presented controlled drug release profiles and mucoadhesive properties. Carvedilol was able to permeate through the sublingual mucosa. Nanoencapsulation improved retention time on the mucosa and permeation in presence of simulated salivary flux. This study highlighted the suitability of using CAR-loaded nanocapsules in the development of innovative sublingual dosage forms.

Redispersible liposomal-N-acetylcysteine powder for pulmonary administration: development, in vitro characterization and antioxidant activity.

Liposomal dry powders of N-acetylcysteine (SD-NAC-Lip) were developed for pulmonary administration. Liposomes were prepared by reverse phase evaporation and spray dried using lactose (10%, w/w) as drying adjuvant. The powders were characterized according to process yield, drug content, residual water content, particle size distribution, morphology and redispersion behavior. In vitro aerosol performance was evaluated using an eight-stage Andersen Cascade Impactor. Moreover, in vitro antioxidant activity was determined by measuring thiobarbituric acid reactive species (TBARS) present in the lungs of healthy Wistar rats after induction of oxidation by iron/EDTA. The spray-drying process had a high yield (71%±2), drug content (mg/g) according to the expected value, moisture content below 9%, geometric mean diameter under 3µm with span value lower than 1. Spherical particles were observed by scanning electron microscopy. Liposomal dry-powders were able to recover the nanometric size of the original dispersion after their redispersion in aqueous medium, as shown by laser diffraction and transmission electron microscopy. Furthermore, the powders presented aerodynamic diameter of about 7µm and respirable fraction above 30%, indicating suitable properties for pulmonary use. The encapsulation of N-acetylcysteine in liposomes was essential to maintain its in vitro antioxidant activity after the drying process. In addition, the powder containing the encapsulated drug had better in vitro antioxidant activity than the liquid and solid formulations containing the non-encapsulated drug, which makes it a good candidate for the treatment of pulmonary diseases associated with oxidative stress.

LC-UV method to assay raloxifene hydrochloride in rat plasma and its application to a pharmacokinetic study

A specific, precise, and accurate LC-UV method was developed and validated to assay raloxifene hydrochloride in rat plasma. Raloxifene was analyzed after liquid-liquid extraction and quantified by reversed phase liquid chromatography (C18 column) using acetonitrile and ammonium acetate buffer 0.05 M (pH 4.0) as mobile phase at a flow rate of 1 mL.min-1 and UV detection at 287 nm. Retention times of raloxifene and internal standard (dexamethasone) were approximately 11 min and 14 min, respectively. Linearity was checked for a concentration range between 25 ng.mL-1 and 1000 ng.mL-1. Intra- and inter-day precision had relative standard deviation lower than 10% and 15%, respectively. Recovery from plasma was higher than 90%. Accuracy values were 98.21%, 99.70%, and 102.70% for lower, medium, and upper limits of quantification, respectively. Limit of quantification was 25 ng.mL-1. Drug stability was analyzed at room temperature using plasma kept in a freezer at -80 °C for 45 days after processing for 6 h and three freeze-thaw cycles. The advantages of the method developed include stability under different conditions and low limit of quantification. Its applicability was confirmed by the analysis of raloxifene levels in plasma samples in a designed pharmacokinetic study in rats after intravenous administration (5 mg.kg-1).