Fast disintegrating dosage forms of mucoadhesive-based nanoparticles for oral insulin delivery: Optimization to in vivo evaluation.

The aim of this work was to develop fast disintegrating dosage forms, including fast disintegrating tablets (FDTs) and films (FDFs), for oral insulin delivery incorporating mucoadhesive thiolated chitosan (TCS)-based nanoparticles (NPs). Cyclodextrin (CD)-insulin complexes were formed to prevent insulin from degradation and further optimally prepared NPs in order to improve the mucoadhesive properties. After that, these NPs were incorporated into the dosage forms and then evaluated for their morphology as well as physical and mechanical properties. The disintegration time, insulin content, mucoadhesive properties, insulin release, cytotoxicity, in vivo hypoglycemic effect, and stability of dosage forms were studied. Results showed that the CD-insulin complexes were successfully encapsulated into the mucoadhesive NPs. The 15 %w/w CD-insulin complex-loaded NPs, which were probably dispersed and/or fused into the dosage forms, showed promising characteristics, including rapid disintegration as well as good physical and mechanical properties to withstand erosion during handling and storage. The porous structure of the FDTs promoted liquid flow and induced rapid disintegration. The dosage forms provided buccal mucoadhesion before, during, and/or after the disintegration. The FDFs containing hydroxypropyl ß-cyclodextrin (HPßCD)-insulin complex-loaded NPs increased mucoadhesion, increasing insulin release. Furthermore, these dosage forms provided excellent in vivo hypoglycemic response with a prolonged effect in diabetic mice and had no cytotoxicity toward the gingival fibroblast cells. In addition, they were stable at temperatures between 2 and 8 °C for three months. The results indicate that these formulations could be applied as promising dosage forms for use in oral insulin delivery.

Topical Film-Forming Chlorhexidine Gluconate Sprays for Antiseptic Application.

Topical film-forming sprays of chlorhexidine gluconate (CHG-FFS) were developed for antiseptic application. Various polymers and solvents were studied for their potential as film-forming polymers and solvent systems, respectively. To produce CHG-FFS, the optimal polymer and solvent were selected, and their physicochemical properties were evaluated. The in vivo evaluation of CHG-FFS was investigated for the satisfaction of the dosage forms, time required for the film formation, film appearance, and adhesion on the skin. Antibacterial activity was also studied in vitro and in vivo. The optimized formulation was assessed for the in vitro cell line evaluations of the cytotoxicity and wound healing. The results demonstrate that Eudragit® S100, Eudragit® L100, and polyvinyl alcohol (PVA) have the ability to be used as film-forming polymers in an ethanolic solution. A clear and flexible film was obtained from transparent homogenous solutions of CHG-FFS after actuation. They generated the fast thin film formation on the skin with the satisfaction of the dosage forms. Furthermore, the formulations inhibited the growth of Staphylococcus aureus in vitro and provided antiseptic activity in vivo. However, PVA was found to be an optimal film-forming polymer for promoting CHG adhesion on the skin. The CHG-FFS obtained from the PVA also provided a CHG film, which was non-toxic to human skin cells and did not interfere with the wound healing process. Therefore, the developed CHG-FFS could be a promising candidate for topical antiseptic application.

Topical nanostructured lipid carriers of alpha-mangostin and resveratrol for synergistic antioxidant activity.

BACKGROUND: Nanostructured lipid carriers (NLCs) are interesting lipid-based carrier systems for enhancing the penetration of drugs through the skin after topical administration. OBJECTIVE: Dual drug-loaded NLCs of alpha-mangostin (M) and resveratrol (R) to enhance antioxidant activity were developed for topical delivery. METHODS: The efficacy of a combination of M and R was evaluated in terms of the antioxidant activity. M and R were loaded into the NLCs using a high shear homogenization and ultrasonication process. The particle size, zeta potential, and physical properties of the NLCs were observed. The M and R loading efficiency as well as release patterns were examined using Franz diffusion cells. Moreover, the antioxidant efficacy and in vitro cytotoxicity in the normal human fibroblast (NHF) of the NLCs were evaluated as well. RESULTS: The results found that the combination of M and R offered synergistic antioxidant activity and was successfully loaded into the NLCs with the size of a nanometer and negative zeta potential. The drugs were loaded in the NLCs as molecular dispersions and slowly released from the NLCs. Interestingly, both drugs maintained their antioxidant activity after being loaded into the NLCs and provided a higher antioxidant activity than those in the single loading of M and R, thus demonstrating that the incorporation of M and R into the NLCs allowed an enhanced antioxidant activity. Moreover, a cytotoxicity study showed that the NLCs were safe and had low cytotoxicity on the NHF cells. CONCLUSION: The M and R loaded NLCs were attractive systems for synergistic antioxidant activity for topical application.

Alpha-mangostin and resveratrol, dual-drugs-loaded mucoadhesive thiolated chitosan-based nanoparticles for synergistic activity against colon cancer cells.

Alpha-mangostin (M) and resveratrol (R), dual-drugs-loaded mucoadhesive thiolated chitosan-based nanoparticles (NPs) coated by Eudragit® S100 (S) were developed for colon-specific delivery and synergistic activity against colon cancer cells. The NPs were prepared by the ionotropic gelation method and coated with S. The particle size and zeta potential of NPs before and after the coating process were observed. The M and R loading efficiency, mucoadhesive properties, as well as release patterns were examined. Moreover, the activity against colon cancer cells of M, R, and NPs were studied for their synergistic activity. M and R-loaded NPs (MR-TNPs) were spherical in shape with sizes of around 540 nm and zeta potential of +39 mV. The S coating of MR-TNPs provided larger particle sizes which offered lower zeta potential. However, it created an increase in M and R loading, prevented M and R release at the upper gastrointestinal tract, and enhanced M and R reaching the colon. S dissolved at pH > 7.0 while thiolated chitosan formed the mucoadhesion, resulting in M and R remaining in the colon and allowing them to enter the colon cancer cells. The half-maximal inhibitory concentration values of NPs was dramatically decreased when M and R were dually loaded into the NPs, which indicated significantly higher activity against colon cancer cells. Moreover, M and R loading at this ratio applied synergistic efficiency. The results illustrated that NPs successfully loaded drugs and achieved synergistic efficiency. This system could be promising in facilitating targeted nanomedicines for the treatment of colon cancer.

Mucoadhesive chitosan and thiolated chitosan nanoparticles containing alpha mangostin for possible Colon-targeted delivery.

α-Mangostin-loaded mucoadhesive nanoparticles (NPs) were prepared for colon-targeted drug delivery against colorectal cancer cells using pH-dependent composite mucoadhesive NPs. Chitosan (CS) and thiolated chitosan (TCS) were used to form the NPs, following by genipin (GP) crosslinking and the surface modification by Eudragit® L100 (L100). The particle size, morphologies and characteristics of NPs were observed. The α-mangostin loading and release patterns were investigated. In vitro mucoadhesive properties were examined by the wash-off method. In addition, the anti-tumour activity was tested on colorectal cancer cells. The results showed that NPs were slightly oblong in shape with particle size ranging between 300 and 900 nm. The small size of NPs was found with TCS and larger NPs were observed by GP and L100 process. However, GP and L100 provided an increase in α-mangostin loading, limited the release of α-mangostin in the upper gastrointestinal tract, and enhanced α-mangostin delivery to the colon. The TCS-based NPs with GP and L100 exhibited strong mucoadhesion to colon mucosa, more than uncoated-NPs and CS-based NPs. Moreover, NPs exhibited the anti-tumour activity. Therefore, the mucoadhesive TCS-based NPs could be a promising candidate for a controlled-release drug delivery system of α-mangostin to the colon.

Enhancement of solubility and oral bioavailability of manidipine by formation of ternary solid dispersion with d-α-tocopherol polyethylene glycol 1000 succinate and copovidone.

CONTEXT: Low bioavailability of oral manidipine (MDP) is due to its low water solubility. OBJECTIVE: The objective of this study was to increase the solubility and bioavailability of MDP by fabricating ternary solid dispersion (tSD) with d-α-tocopherol polyethyleneglycol-1000-succinate and copovidone. METHODS: In this study, solid ternary phase diagram was applied in order to check the homogeneity of tSD prepared by melting and solidifying with dry ice. The physicochemical properties of different formulations were determined by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FTIR) and hot stage microscopy. Their solubility, dissolution, stability and bioavailability were also investigated. RESULTS AND DISCUSSION: The results demonstrated that tSD obtained from ternary phase diagram divided into homogeneous and non-homogeneous regions. In the homogenous region, the transparent characteristics of tSD was observed and considered as a glass solution, which have a higher MDP solubility than that in non-homogenous region. The hot stage microscopy, DSC and PXRD confirmed that solid dispersion was formed in which MDP was molecularly dispersed in the carriers, especially in the homogenous region of phase diagram. FTIR analysis demonstrated strong hydrogen bonding between amine groups of MDP and carbonyl groups of copovidone, which supported a higher solubility and dissolution of tSD. The pharmacokinetic study in Wistar rats showed that the tSD had the greatest effect on oral bioavailability. Immediate hypotensive effect of tSD was also observed in vivo. CONCLUSIONS: The improvement of stability, dissolution and oral bioavailability of MDP could be achieved by using tSD technique.

Improved stability of solid dispersions of manidipine with polyethylene glycol 4000/copovidone blends: application of ternary phase diagram.

CONTEXT: Manidipine (MDP) is generally used clinically as an antihypertensive agent; however, the bioavailability of orally administered MDP is limited due to their very low water solubility. OBJECTIVE: The objectives of this research were, therefore, to increase the solubility of MDP by the formation of ternary solid dispersions (tSD) with polyethylene glycol 4000 (PEG4000) and copovidone and to improve their stability. METHODS: Solid ternary phase diagram was constructed to find homogeneous solid dispersion region after melting and solidifying at low temperature with different quenching substances. The pulverized powder of solid dispersions was then determined, for their physicochemical properties, by differential scanning calorimetry, powder X-ray diffractometry, Fourier transform infrared (FTIR) spectroscopy and hot stage microscopy. The solubility and dissolution of MDP from the tSD were investigated. The physical stability of tSD was also determined under accelerated condition at 40 °C/75% relative humidity (RH) for 6 months. RESULTS AND DISCUSSION: The results showed that MDP was molecularly dispersed in PEG4000 and copovidone when the tSD was created from homogeneous region of solid ternary phase diagram. FTIR results confirmed that strong hydrogen bonding was presented between MDP and copovidone, leading to a significant increase in the solubility and dissolution of MDP. After storage at accelerated condition (40 °C/75%RH) for 6 months, the tSD still showed a good appearance and high solubility. CONCLUSION: The results of this study suggest that tSD prepared by melting has promising potential for oral administration and may be an efficacious approach for improving the therapeutic potential of MDP.