Itraconazole Loaded Biosurfactin Micelles with Enhanced Antifungal Activity: Fabrication, Evaluation and Molecular Simulation.

Itraconazole (ITZ) is a broad-spectrum antifungal for superficial subcutaneous and systemic fungal infections. This study aimed to enhance the antifungal activity of ITZ using surfactin A (SA), a cyclic lipopeptide produced by the SA-producing Bacillus strain NH-100, possessing strong antifungal activity. SA was extracted, and ITZ-loaded SA micelles formulations were prepared via a single-pot rinsing method and characterized by particle size, zeta potential, and infrared spectroscopy. In vitro dissolution at pH 1.2, as well as hemolysis studies, was also carried out. The fabricated formulations were stable and non-spherical in shape, with an average size of about 179 nm, and FTIR spectra depicted no chemical interaction among formulation components. ITZ-loaded micelles showed decreased hemolysis activity in comparison to pure ITZ. The drug released followed the Korsmeyer-Peppas model, having R2 0.98 with the diffusion release mechanism. In an acidic buffer, drug release of all prepared formulations was in the range of 73-89% in 2 h. The molecular simulation showed the outstanding binding and stability profile of the ITZ-SA complex. The aromatic ring of the ITZ mediates a π-alkyl contact with a side chain in the SA. It can be concluded that ITZ-loaded micelles, owing to significant enhanced antifungal activity up to 6-fold due to the synergistic effect of SA, can be a promising drug delivery platform for delivery of poorly soluble ITZ.

Discovery of Novel Tetramethylpyrazine Containing Chalcone Derivatives as Anti-Inflammatory Agents.

BACKGROUND: Chalcones are precursors of flavonoids and exhibit a broad spectrum of pharmacological activity. OBJECTIVE: As anti-inflammatory agents, two series of chalcone derivatives and chalcone-based oximes were synthesized and characterized. To integrate the tetramethylpyrazine moiety into these novel molecules, the multifunctional natural chemical ligustrazine was employed. METHODS: A variety of newly synthesized ligustrazine-based chalcones were utilized as precursors for the synthesis of new oximes and their inhibitory activity against COX-1, COX-2, and LOX-5 enzymes were compared. RESULTS: The conversion of ketones to their oxime derivatives increased the effectiveness of COX-1 and COX-2 inhibition. Due to the substituted ether groups, oxime derivative 5d had the lowest IC50 values of 0.027 ± 0.004 µM and 0.150 ± 0.027 µM for COX-1 and COX-2 isoenzymes, respectively. Notably, the oxime derivative's highest effectiveness is conferred by the presence of methoxymethoxy or hydroxy groups at the C-3 and C-4 positions on the phenyl ring. The 6b derivative with a long alkyl chain ether group was shown to be the most powerful 5-LOX inhibitor. All compounds were also assessed for their ability to inhibit nitric oxide generation and LPS-induced IL-6, IL-1ß, and TNF-α production in RAW 264.7 macrophages. Finally, in order to determine the structural effects responsible for the binding mechanism of compounds, they were docked into the binding sites of COX-1, COX-2, and 5-LOX, which revealed an inhibitory mechanism of action and demonstrated the relevance of various types of interactions. CONCLUSION: The findings showed that these novel compounds had a significant impact on antiinflammatory actions.

A Smart Hydrogel from Salvia spinosa Seeds: pH Responsiveness, On-off Switching, Sustained Drug Release, and Transit Detection.

BACKGROUND: The use of synthetic and semi-synthetic materials in drug delivery systems has associated drawbacks like costly synthesis, toxicity, and biocompatibility issues. Therefore, there is a need to introduce novel materials to overcome such issues. Naturally occurring and water-swellable polysaccharides are advantageous in overcoming the above-mentioned issues. Therefore, we are reporting a novel hydrogel (SSH) isolated from the seeds of Salvia spinosa as a sustained release material. METHODS: SSH was explored for its pH-dependent and salt-responsive swelling before and after compression in a tablet form. Stimuli-responsive swelling and deswelling were also monitored at pH 7.4 and pH 1.2 in deionized water (DW) and normal saline and DW and ethanol. The sustained-release potential of SSH-based tablets was monitored at gastrointestinal tract (GIT) pH. The transit of SSH tablets was ascertained through an X-ray study. RESULTS: The swelling of SSH in powder and tablet form was found in the order of DW > pH 7.4 > pH 6.8 > pH 1.2. An inverse relation was found between the swelling of SSH and the concentration of the salt solution. The SSH showed stimuli-responsive swelling and de-swelling before and after compression, indicating the unaltered nature of SSH even in a closely packed form, i.e., tablets. Sustained release of theophylline (< 80%) was witnessed at pH 6.8 and 7.4 during the 12 h study following zeroorder kinetics, and radiographic images also showed 9 h retention in GIT. CONCLUSION: These investigations showed the potential of SSH as a pH-sensitive material for sustained and targeted drug delivery.

Co-Combination of Pregabalin and Withaniacoagulans-Extract-Loaded Topical Gel Alleviates Allodynia and Hyperalgesia in the Chronic Sciatic Nerve Constriction Injury for Neuropathic Pain in Animal Model.

The current study reports the fabrication of co-combination gel using Pregabalin and Withania coagulans fruit extract to validate its effectiveness for neuropathic pain in chronic constriction injury (CCI) rat models. Three topical gels were prepared using Carbopol 934 through a pseudo-ternary phase diagram incorporating the Pregabalin (2.5%), Withania coagulans extract (2%), and co-combination of both Pregabalin (2.5%) and Withania coagulans extract (2%). Gels were characterized. FTIR showed a successful polymeric network of the gel without any interaction. The drug distribution at the molecular level was confirmed by XRD. The AFM images topographically indicated the rough surface of gels with a size range from 0.25 to 330 nm. DSC showed the disappearance of sharp peaks of the drug and extract, showing successful incorporation into the polymeric network of gels. The in vitro drug release of co-combination gel was 73% over 48 h. The mechanism of drug release by combination gel was Higuchi+ fickian with values of n (0.282) and R2 (0.947). An in vivo study for pain assessment via four methods: (i) heat hyperalgesia, (ii) cold allodynia, (iii) mechano-hyperalgesia, and (iv) dynamic mechano-allodynia, confirmed that topical treatment with co-combination gel reduced the pain significantly as indicated by the p value: R1 (p < 0.001), R2 (p < 0.001), R3 (p < 0.015), and R4 (p < 0.0344). The significance order was R2 (****) > R1 (***) > R3 (**) > R4 (*) > R5 (ns).

Appraisal of the pharmacokinetic profile, histopathology and stability studies of a fast dissolving oral film based on natural polysaccharide.

The present research is designed to evaluate the pharmacokinetic profile, histological evaluation, and stability studies of an orodispersible film (ODF) of tizanidine (TZ) and meloxicam (MX) prepared from a natural polysaccharide, i.e., xanthan gum. In vivo release study of TZ and MX was performed in rabbits and results indicated the better pharmacokinetics parameters and improved the oral bioavailability when compared to the oral aqueous suspension and solution of TZ and MX, respectively. The intermediate stability studies were performed at 30±2°C and 65±5% RH, whereas, the accelerated stability studies were carried out at 40±2°C and 75±5% RH, respectively for the duration of six months and results indicated that the ODF was stable for six months without any substantial difference in essential physico-chemical parameters, mechanical attributes, and morphological constraints. The toxicity profile of ODF was determined through histopathology of vital organs after administering the ODF to the rabbits. Histopathology revealed that the tissues of all vital organs are normal and did not exhibit any abnormalities, lesions, or hemorrhage. Therefore, the ODF prepared from xanthan gum exhibited a non-toxic and stable formulation with a better pharmacokinetics profile of MX and TZ.

Preparation, Characterization of Pregabalin and Withania coagulans Extract-Loaded Topical Gel and Their Comparative Effect on Burn Injury.

The current study depicts the comparative effects of nanogel using Withania coagulans extract, pregabalin alone, and a co-combination gel. The gels prepared were then analyzed for conductivity, viscosity, spread ability, globule size, zeta potential, polydispersity index, and TEM. The globule size of the co-combination gel, determined by zeta sizer, was found to be (329 ± 0.573 nm). FTIR analysis confirms the successful development of gel, without any interaction. Drug distribution at the molecular level was confirmed by XRD. DSC revealed no bigger thermal changes. TEM images revealed spherical molecules with sizes of 200 nm for the co-combination gel. In vivo studies were carried out by infliction of third degree burn wounds on rat skin, and they confirmed that pregabalin and Withania coagulans heals the wound more effectively, with a wound contraction rate of 89.95%, compared to remaining groups. Anti-inflammatory activity (IL-6 and TNF-α), determined by the ELISA technique, shows that the co-combination gel group reduces the maximum inflammation with TNF-α value (132.2 pg/mL), compared to the control (140.22 pg/mL). Similarly, the IL-6 value was found to be (78 pg/mL) for the co-combination gel and (81 pg/mL) in the case of the control. Histopathologically, the co-combination gel heals wounds more quickly, compared to individual gel. These outcomes depict that a co-combination gel using plant extracts and drugs can be successfully used to treat burn injury.

Linseed hydrogel based floating drug delivery system for fluoroquinolone antibiotics: Design, in vitro drug release and in vivo real-time floating detection.

Herein, we designed a novel gastroretentive drug delivery system as floating matrix tablets based on a polysaccharide material from linseeds (Linum usitatissimum L.) for fluoroquinolone antibiotics. A number of formulations were designed with a combination of linseed hydrogel (LSH) and different excipients to obtain a desired sustained release profile of moxifloxacin. The drug release study was performed basically at pH 1.2. However, the tablet may pass through the stomach to intestine due to certain reasons then it also offered sustained drug release at intestinal pH 4.5, 6.8 and 7.4, as well. Results indicated that sustained moxifloxacin release was directly proportional to the concentration of LSH and the release of drug followed non-Fickian diffusion. SEM of the tablets indicated porous nature of LSH with elongated channels which contributed to the swelling of the tablet and then facilitated the discharge of moxifloxacin from the core of the tablet. In vivo X-ray study was performed to assess disintegration and real-time floating of tablet that confirmed its presence for 6 h in the stomach. These findings indicated that LSH can be used to develop novel gastroretentive sustained release drug delivery systems with the double advantage of sustained drug release at all pH of GIT.

Formulation design, characterization and in vitro drug release study of orodispersible film comprising BCS class II drugs.

Fast dissolving orodispersible film (ODF) was prepared for concurrent administration of biopharmaceutical classification system (BCS) class II drugs, i.e., meloxicam (MX) and tizanidine (TZ), using natural (xanthan gum), semisynthetic (hydroxypropyl methylcellulose and hydroxyethyl cellulose) and synthetic (polyvinyl alcohol) polymers. Compatibility of the ingredients of ODFs was ascertained through Fourier transform infra-red spectroscopy and differential scanning calorimetry. ODFs were characterized through disintegration time, pH of the surface of film, tensile strength, folding endurance, % elongation and content uniformity (MX and TZ) which were found in the range between 17±1.3-56±3.1 s, 5.11±0.07-6.28±0.05, 14.721±1.2-33.084±3.1 N/m2, > 100, 3.33±0.53-10.04±0.77 % and 98.01-99.34 % (MX) and 97.48-99.03 % (TZ), respectively. The values of moisture uptake, moisture loss and loss on drying of all formulations were in the range from 1.06±0.09-7.51±0.93 %, 0.06±0.01-2.3±0.08 % and 0.008±0.002-0.03±0.03 %, respectively. In vitro drug release study in simulated saliva fluid of pH 7.4 has shown that > 90 % MX and TZ was released within 5 min. Visual inspection, scanning electron microscope and X-ray diffraction analysis of all ODFs expressed their smooth surfaces. ODF prepared from xanthan gum (F5) exhibited better physicochemical and mechanical properties as compared to other formulations.