Novel fast dissolving freeze dried sublingual baicalin tablets for enhanced hepatoprotective effect: in-vitro characterization, cell viability, and in-vivo evaluation.

Baicalin (BG), a natural product, has been used in the prevention and treatment of drug-induced liver injury (DILI); however, its poor solubility and extensive liver metabolism limit its pharmacological use. The aim of the present study was the formulation of fast-dissolving freeze-dried sublingual tablets (FFSTs) to increase BG dissolution, avoid first-pass metabolism, and overcome swallowing difficulties. FFSTs were prepared following a 23 factorial design. The effect of three independent variables namely matrix former, Maltodextrin, concentration (4%, and 6%), binder concentration (2%, and 3%), and binder type (Methocel E5, and Methocel E15) on the FFSTs' in-vitro disintegration time and percentage dissolution was studied along with other tablet characteristics. Differential scanning calorimetry, scanning electron microscopy, in-vitro HepG2 cell viability assay, and in-vivo characterization were also performed. F8 (6% Maltodextrin, 2% Mannitol, 2% Methocel E5), with desirability of 0.852, has been furtherly enhanced using 1%PEG (F10). F10 has achieved an in-vitro disintegration time of 41 secs, and 60.83% in-vitro dissolution after 2 min. Cell viability assay, in-vivo study in rats, and histopathological studies confirmed that pretreatment with F10 has achieved a significant hepatoprotective effect against acetaminophen-induced hepatotoxicity. The outcome of this study demonstrated that FFSTs may present a patient-friendly dosage form against DILI.

Hyaluronic Acid Conjugated Metformin-Phospholipid Sonocomplex: A Biphasic Complexation Approach to Correct Hypoxic Tumour Microenvironment.

PURPOSE: Development of hyaluronic acid conjugated metformin-phospholipid sonocomplexes (HA-MPS), a biphasic complexation product compiled for enhancing both the lipophilicity and targeting potential of Metformin (MET) to CD44 receptors on pancreatic cancer. METHODS: MET was chemically conjugated to hyaluronic acid (HA) via amide coupling reaction. Then, the HA conjugated MET was physically conjugated to Lipoid™S100 via ultrasound irradiation. A combined D-optimal design was implemented to statistically optimize formulation variables. The HA-MPS were characterized through solubility studies, partition coefficient, drug content uniformity, particle size and zeta potential. The optimized HA-MPS was tested via proton nuclear magnetic resonance, infrared spectroscopy to elucidate the nature of physicochemical interactions in the complex which was further scrutinized on molecular level via molecular docking and dynamic simulation. RESULTS: The solubility and partition studies showed a lipophilicity enhancement up to 67 folds as they adopted inverted micelles configuration based on the packing parameter hypothesis. The optimized HA-MPS showed 11.5 folds lower IC50, extra 25% reduction in oxygen consumption rate, better reduction in hypoxia-inducible factor and reactive oxygen species in MiaPaCa-2 cells. CONCLUSION: These results proved better internalization of MET which was reflected by abolishing hypoxic tumour microenvironment, a mainstay toward a normoxic and less resistant pancreatic cancer.