Green synthesised zinc oxide nanoparticles reveal potent in vivo and in vitro antibacterial efficacy against Proteus mirabilis isolates.

Currently, the spread of antimicrobial resistance dissemination is expanding at an accelerated rate. Therefore, numerous researchers haveinvestigatedalternative treatments in an effort to combat this significant issue. This study evaluated the antibacterial properties of zinc-oxide nanoparticles (ZnO NPs) synthesised by Cycas circinalis against Proteus mirabilis clinical isolates. HPLC was utilised for the identification and quantification of C. circinalis metabolites. The green synthesis of ZnO NPs has been confirmed using UV-VIS spectrophotometry. The Fourier transform infrared spectrum of metal oxide bonds has been compared to the free C. circinalis extract spectrum. The crystalline structure and elemental composition were investigated using X-ray diffraction and Energy-dispersive X-ray techniques. The morphology of nanoparticles was assessed by scanning and transmission electron microscopies, which revealed an average particle size of 26.83 ± 5.87 nm with spherical outlines. The dynamic light scattering technique confirms the optimum stability of ZnO NPs with a zeta potential value equal to 26.4 ± 0.49 mV. Using agar well diffusion and broth microdilution methods, we elucidated the antibacterial activity of ZnO NPs in vitro. MIC values for ZnO NPs ranged from 32 to 128 µg/mL. In 50% of the tested isolates, the membrane integrity was compromised by ZnO nanoparticles. In addition, we assessed the in vivo antibacterial capacity of ZnO NPs by a systemic infection induction using P. mirabilis bacteria in mice. The bacterial count in the kidney tissues was determined, and a significant decrease in CFU/g tissues was observed. The survival rate was evaluated, and the ZnO NPs treated group had higher survival rates. The histopathological studies demonstrated that kidney tissues treated with ZnO NPs had normal structures and architecture. Moreover, the immunohistochemical examinations and ELISA revealed that ZnO NPs substantially decreased the proinflammatory mediators NF-kß, COX-2, TNF-α, IL-6, and IL-1ß in kidney tissues. In conclusion, the results of this study suggest that ZnO NPs are effective against bacterial infections caused by P. mirabilis.

Molding as Innovative Technology for Personalized Tablet Production.

The future of dosage form design is expected to move towards the production of personalized dosage forms tailored to each patient. The 3D printer was introduced to solve that problem but is not easy to use in a pharmacy. Herein, a new 3D mold technology is adopted for tablet manufacturing. Preparation of amlodipine tablets was used as a Biopharmaceutics Classification System Class 1 drug model to study this technology. Different concentrations of either starch or Avicel-based formulations and different concentrations of hydroxypropyl methylcellulose as a binder for mass formation were used. The mass formed for each formula was cast into the mold for tablet preparation. Different non-pharmacopeial and pharmacopeial quality-control tests of the prepared tablets by using the 3D mold were compared to a marketed tablet product of amlodipine. 3D-molded tablets showed compliance properties with the tablet pharmacopeial quality standard. Studying the equivalence of the 3D mold tablets to the brand marketed product under biowaiver conditions was carried out. The difference and similarity factors studies of molded tablets prepared using starch or Avicel as a filler and 2.5% of hydroxypropyl methylcellulose showed acceptable characters to the drug brand name. It is predicted that by using this simple technique, it would be possible to produce tablets with designed disintegration and release profiles, which could potentially allow the tailoring of the drug release and hence personalize the medicine for each patient.

An Industrial Procedure for Pharmacodynamic Improvement of Metformin HCl via Granulation with Its Paracellular Pathway Enhancer Using Factorial Experimental Design.

BACKGROUND: Sorbitan monostearate is a surfactant used in the food industry. It was proved as a penetration enhancer to metformin HCl via a paracellular pathway. It is solid at room temperature and has a low melting point. Therefore, it was selected, as a granulating agent for metformin HCl. METHODS: Multi-level factorial design was applied to determine the optimized formula for industrial processing. The selected formulations were scanned using an electron microscope. Differential scanning calorimetry was used to ascertain the crystalline state of a drug. A modified non-everted sac technique, suggested by the authors, was used to evaluate the in vitro permeation enhancement of the drug. To simulate the emulsification effect of the bile salt, a tween 80 was added to the perfusion solution. As a pharmacodynamic marker, blood glucose levels were measured in diabetic rats. RESULTS: The results showed that drug permeability increases in the presence of tween 80. Drug permeability from granules increased than that of the pure drug or pure drug with tween 80. The prepared granules decreased blood glucose levels of diabetic rats than the pure drug and drug plus tween 80. There was an excellent correlation between the results of the drug permeation percent in vitro and the dropping of blood glucose level percent in vivo. CONCLUSION: Improving the drug permeation and consequently, the drug pharmacodynamic effect in addition to an excellent micromeritics property of the prepared drug granules showed the dual enhancement effect of the suggested industrial procedure. Therefore, we suggest the same industrial procedure for other class III drugs.

Metformin hydrochloride entrapment in sorbitan monostearate for intestinal permeability enhancement and pharmacodynamics.

Penetration enhancement of metformin hydrochloride via its molecular dispersion in sorbitan monostearate microparticles is reported. This represents basic philosophy to maximize its entrapment for maximum penetration effect. Drug dispersion in sorbitan monostearate with different theoretical drug contents (TDC) were prepared. Products showed excellent micromeritics and actual drug content (ADC) increased by increasing TDC. The partition coefficient of the drug products showed huge improvement. This indicates the drug entrapped in the polar part of sorbitan monostearate as a special image which effects on the drug release. The drug permeation profiles from the different products are overlapped with nearly equal permeation parameters. The permeation results suggested the main driving force for improving the drug paracellular pathway is its dispersion in sorbitan monostearate and is independent of ADC. Pharmacodynamic of the products showed a significant improvement than the drug alone at p ˂ 0.05. ANOVA test indicated the insignificant pharmacodynamic difference between the low, middle, and high ADC of the products. An excellent correlation founded between the drug permeation and pharmacodynamic precents. Drug permeation driving force via the paracellular pathway is its entrapment in sorbitan monostearate and independent on ADC. The technique is simple and the products had excellent micromeritics.

Formulation and Bioavailability of Novel Mucoadhesive Buccal Films for Candesartan Cilexetil in Rats.

Candesartan cilexetil (CC) is an antihypertensive drug. It has low solubility and faces hepatic first-pass metabolism after oral ingestion. We formulated bioadhesive buccal films and studied the respective drug pharmacokinetics. Different bioadhesive films were prepared (40, 80, 120, 160, 200, and 240 mg CC per film) by using the solvent casting method. The drug concentrations used affect the drug entrapment mechanism, which was reflected in the film physicochemical properties like thickness, weight, drug content, bioadhesion, and drug release. Low drug concentration (F2, 40 mg per film) led to minute drug crystal dispersion while increasing the drug concentration (F7, 240 mg per film) showed drug crystal encapsulation, which affects the drug release. The drug pharmacokinetic from the prepared films was studied compared to the oral form by serial blood sampling via an inserted catheter in the carotid of rats. High-Performance Liquid Chromatography assay was used to measure the plasma concentration of CC in different forms. Compared to other films, the F2 showed the highest maximal concentration (Cmax) and the lowest elimination half-life (t1/2). Bioadhesion buccal film of CC has better bioavailability, especially at low concentrations. The ease, robustness, and ruggedness of the preparation suggests the same procedure for drugs like CC.

Repurposing of Guanabenz acetate by encapsulation into long-circulating nanopolymersomes for treatment of triple-negative breast cancer.

Poor patient response and limited treatment modalities are the major challenges against combating triple-negative breast cancer (TNBC). The high related mortality urges for novel cancer therapeutics. Guanabenz acetate (GA) is an orphan antihypertensive drug with a short half-life. Re-purposing (GA) by developing a polymersome (PS)-based cancer nanomedicine is an innovative approach in treating TNBC. Formulation and optimization of GA-loaded PEGylated Polycaprolactone PS through different process variables (solvent selection, the order of addition, pH of the aqueous phase, and drug to polymer ratio) were achieved by the nanoprecipitation method. The in vitro cellular uptake, anti-cancer, and anti-metastatic activity of GA and GA-loaded PS were tested in MDA-MB 231(TNBC cell line) and MCF-7 cell line. Western blot analysis was performed to elucidate the molecular anti-cancer mechanism. The in vivo biodistribution study and antitumor activity were investigated in the TNBC-xenograft model implanted in mice. Under optimized formulation conditions, GA-loaded PS had a nanosize of 90.5 nm with PDI < 0.2, a zeta potential -9.11 mV, drug encapsulation efficiency of 92.11% and sustained drug release for 6-days. GA-loaded PS exhibited enhanced cellular uptake and achieved a significantly lower IC50 in both breast cancer cell lines compared to free GA. Treatment with GA-loaded PS (60 µM) showed a significant reduction of 60.5 and 78.1% in cancer migration and metastasis in the case of MDA-MB 231 and MCF-7, respectively. Besides, drug-loaded PS increased phosphorylation of translational regulator eIF2α and decreased expression of Rac1 which were essential for decreasing cancer cell survival and metastasis. In vivo biodistribution study of GA-loaded PS showed long-circulating PS with high passively targeted tumor accumulation. Treatment with GA-loaded PS resulted in a significant decrease in tumor size and weight compared to free GA. In conclusion, GA-loaded PS is a new promising cancer therapeutics for the treatment of TNBC.

Polymeric nanoencapsulation of zaleplon into PLGA nanoparticles for enhanced pharmacokinetics and pharmacological activity.

Zaleplon (ZP) is a sedative and hypnotic drug used for the treatment of insomnia. Despite its potent anticonvulsant activity, ZP is not commonly used for the treatment of convulsion since ZP is characterized by its low oral bioavailability as a result of poor solubility and extensive liver metabolism. The following study aimed to formulate specifically controlled release nano-vehicles for oral and parenteral delivery of ZP to enhance its oral bioavailability and biological activity. A modified single emulsification-solvent evaporation method of sonication force was adopted to optimize the inclusion of ZP into biodegradable nanoparticles (NPs) using poly (dl-lactic-co-glycolic acid) (PLGA). The impacts of various formulation variables on the physicochemical characteristics of the ZP-PLGA-NPs and drug release profiles were investigated. Pharmacokinetics and pharmacological activity of ZP-PLGA-NPs were studied using experimental animals and were compared with generic ZP tablets. Assessment of gamma-aminobutyric acid (GABA) level in plasma after oral administration was conducted using enzyme-linked immunosorbent assay. The maximal electroshock-induced seizures model evaluated anticonvulsant activity after the parenteral administration of ZP-loaded NPs. The prepared ZP-PLGA NPs were negatively charged spherical particles with an average size of 120-300 nm. Optimized ZP-PLGA NPs showed higher plasma GABA levels, longer sedative, hypnotic effects, and a 3.42-fold augmentation in oral drug bioavailability in comparison to ZP-marketed products. Moreover, parenteral administration of ZP-NPs showed higher anticonvulsant activity compared to free drug. Oral administration of ZP-PLGA NPs achieved a significant improvement in the drug bioavailability, and parenteral administration showed a pronounced anticonvulsant activity.

Preparation, and Assessment of Antidermatophyte Activity of Miconazole-Urea Water-Soluble Film.

Cutaneous mycoses, particularly tinea pedis caused by Trichophyton rubrum, are commonly known infections in humans. They are still considered as a major public health problem worldwide affecting the quality of life due to prolonged period of treatment and development of drug resistance, which leads to recurrence of infections. The objective of our study was to assess the effectiveness of miconazole in the presence and absence of urea, as a penetration enhancer, against T. rubrum and to formulate both of them in a water-soluble film to be applied topically for the purpose of treating tinea pedis caused by this fungus. Drug combination revealed synergism where miconazole minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) (0.5 and 1 mg/L) were considerably declined to 0.001 and 0.004 mg/L, respectively, when combined with 20% urea. This enhanced drug interaction activity against the test strain was explained by the alterations raised on the morphology and ultrastructures observed microscopically. Minimal fungicidal dose of miconazole/urea combination displayed plasmolysis and shrink cytoplasm; however, necrotic cells with punctured walls and degraded cytoplasmic content were observed at high fungicidal dose. Water-soluble films, prepared using increasing values of miconazole MFC and urea, were transparent, smooth, uniform, and flexible. Their physicochemical characters showed homogeneity in weight, thickness, drug content, and folding endurances with normal surface pH values, indicating the reproducibility of the preparation method. The novel simulation model for the film mechanism of action supported the idea and the suggested application method of the new dosage form. Evaluation of these films was carried in vitro using disk diffusion assay as well as in vivo using guinea pig dermatophytosis model. The in vitro assessment revealed an increase in the inhibition zone diameters in a concentration-dependent manner upon using 10 or 20% of urea combined with miconazole. In vivo test showed that combination of 0.004 mg/L miconazole with 20% urea (M + U20) showed the highest efficacy percentage (95.83%), which was statistically superior to the infected untreated control (p < 0.001) in fungal burden reduction as well as improvement in clinical scores (p < 0.001). This work supports the hypothesis and suggests a new promising dosage form for the treatment of T. rubrum infections.

Paracellular Pathway Enhancement of Metformin Hydrochloride via Molecular Dispersion in Span 60 Microparticles.

Surfactants are well known as permeation enhancers. Span 60 microparticles encapsulating different concentrations of metformin HCl were prepared by using rapid congeal melting technique. Electro-scanning microscope showed smooth surface but less round microparticles. The actual drug content was nearly equal in the different particle sizes of the microparticles. Differential scanning calorimetry results indicated the molecular distribution of the drug molecules with no evidence of drug thermal degradation. The drug release profile from the microparticles has, in each case, burst and there was incomplete drug release. The drug partition coefficient is markedly enhanced as a result of its molecular dispersion in Span 60, indicating the increasing of the drug lipophilicity as a result of its encapsulation in the polar part of the surfactant. Non-everted sac was used to study the drug permeability after solving its critical points. Compared to pure drug, the permeability profile of the drug increased from the Span 60-encapsulated drug, with a total permeation of 68% and drug absorption enhancement of 253%. The drug permeation enhancement mechanism was suggested to be molecular dispersion in the matrix, which is emulsified by Tween 80, and this leads to increasing the hydrophilic paracellular pathway of the drug. Considering the emulsification system of the GIT, which emulsifies the Span 60 instead of Tween 80, a huge improvement of the biopharmaceutics classification system class III permeability and consequently bioavailability could be expected. In addition, this study will open the door to the use of the same technique for enhancing the drug absorption mechanisms by the paracellular pathway for rapid and complete pharmacological effect.