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.

Chitosan-coated alginate (CCA) nanoparticles for augmentation of topical antihistaminic activity of diphenhydramine: in-vitro optimization, skin histopathology and pharmacodynamic studies with in vitro/in vivo correlation.

OBJECTIVE: The aim of the present study was to formulate chitosan-coated alginate nanoparticles containing the drug diphenhydramine hydrochloride (DHH). SIGNIFICANCE: Diphenhydramine hydrochloride (DHH) is the prototype of H1-antihistaminic drugs. It is a lipophilic drug, that easily crosses the blood-brain barrier when taken orally causing decrements in alertness and performance. Multiple applications of topical drug products are required. Thus, drug incorporation in nanocarriers would increase the skin penetration powers increasing the drug efficacy. METHODS: Chitosan-coated alginate (CCA) nanoparticles were prepared via polyelectrolyte complex technique adopting 23 full factorial designs. Three factors, namely, alginate concentration, drug-to-alginate ratio and CaCl2 volume, each in two levels were studied. The prepared formulae were evaluated utilizing entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP) and in vitro release. The characterization process was then followed by optimization. RESULTS: At alginate conc. of 1%, drug to alginate ratio of 2:1 and CaCl2 volume of 4 mL, NP8 was chosen as a candidate formula. Histopathological examination on shaved rat dorsal skin disclosed the safety of NP8 with no signs of necrosis or even inflammation. The enhanced topical delivery of diphenhydramine hydrochloride enclosed in the developed nanoparticles was further proved by induction of allergic reaction using intradermal histamine injection. The results revealed the superior ability of NP8 to decrease the diameter of the formed wheal in comparison to the marketed DHH product. CONCLUSION: Thus, CCA nanoparticles are considered candidate nanocarriers for fortifying the topical antihistaminic activity of DHH.

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.

Zaleplon loaded bi-layered chronopatch: A novel buccal chronodelivery approach to overcome circadian rhythm related sleep disorder.

The aim of this study was to develop a novel buccal bi-layered chronopatch capable of eliciting pulsatile release pattern of drugs treating diseases with circadian rhythm related manifestation. Zaleplon (ZLP) was used as a model drug intended to induce sleep and to treat middle of night insomnia. The chronopatch was prepared adopting double casting technique. The first layer was composed of a controlled release patch containing ZLP-Precirol melt granules intended to release ZLP in a sustained manner to maintain sleep and to prevent early morning awakening. The second layer was composed of a fast release lyophilized buccal disc containing ZLP loaded SNEDDS (Z-SNEDDS) intended for rapid sleep induction. Pharmacokinetic parameters of ZLP from the chronopatch were compared to those of the immediate release capsule, Siesta®, as reference in Mongrel dogs using a randomized crossover design. The appearance of two peaks having two Cmax and Tmax proved the pulsatile release pattern. The increase in relative bioavailability of ZLP from the chronopatch was 2.63 folds. The results revealed the ability of the developed ZLP loaded bi-layered chronopatch to be a candidate for overcoming early morning awakening without middle of night dose administration.