Comparative analysis of oral and local intraovarian administration of metformin and nanoparticles (NPs11) in alleviating testosterone-induced polycystic ovary syndrome in rats.

Polycystic ovary syndrome (PCOS) is an endocrine and metabolic dysfunction. This study aims to compare the oral and local treatments of metformin or its nanoparticles (NPs11) for ameliorating PCOS in rats. Rats were divided into 4 groups: the control group with no drug treatment; the PCOS group, where subcutaneous testosterone was given (10 mg/kg/day) for 28 days; the MET group, where metformin was administered orally or locally; and the NP group, where metformin NPs11 were also administered orally or locally. Oral administrations were for 21 days, while local injection was performed once surgically. After 7 weeks, all rats were sacrificed; blood glucose and serum hormonal levels and lipid profile were estimated, and the ovaries were assessed by histopathological, Ki-67 immunohistochemical, and histomorphometric evaluations. Blood glucose levels were significantly decreased in groups of orally administered metformin or NPs11 only, while the most efficient option for modulating PCOS-induced hormonal and lipid profile changes was intraovarian injection of NPs11. The ovaries of PCOS rats demonstrated large follicular cysts, massive collagen depositions, and attenuated Ki-67 immunoexpression. Also, the PCOS group revealed a significant decrease in the count of all stages of growing follicles, corpora lutea, granulosa cell layer thickness, and surface area of corpora lutea, in addition to an increase in the number of atretic follicles and follicular cysts, theca cell layer thickness, and surface area of the follicular cysts. All these parameters were recovered with metformin or their NPs11 treatments in different degrees, while local injection of NPs11 was the best option.

Novel resveratrol smart lipids; design, formulation, and biological evaluation of anticancer activity.

PURPOSE: Although resveratrol (RES) is an efficacious molecule, its therapeutic activity is impeded by significant limitations, such as rapid oral absorption, poor oral bioavailability, and low water solubility. Therefore, the preparation of RES in different pharmaceutical carriers represents an important tool to enhance its therapeutic applications. This study aims to potentiate the anti-cancer activity of RES by formulating it into a novel nanocarrier called Smart Lipid. METHODS: RES-loaded Smart Lipids were prepared by high-shear hot homogenization method utilizing a 21 × 32 factorial design with three factors at different levels: the total lipid concentration, the concentration of surfactant, and the type of surfactant. The responses were evaluated based on entrapment efficiency percentages and particle size. RESULTS: Our novel optimized RES-loaded Smart Lipid formula showed small particle size (288.63 ± 5.55 nm), good zeta potential (-16.44 ± 0.99 mV), and an entrapment efficiency of 86.346 ± 3.61% with spherical, clearly distinct, and no signs of fusion by transmission electron microscopy. Further characterization was done using differential scanning calorimetry, which showed no interaction between the drug and other components as the optimum lyophilized formula showed a peak at 54.75°C, which represents the lipid mixture, with an undetectable characteristic peak of the drug, which indicates entrapment of the drug, and the structure of the compounds was confirmed by Fourier transform-infrared spectroscopy, in which the majority of the drug's characteristic peaks disappeared when loaded into Smart Lipid, which may indicate Smart Lipid's ability to reduce the stretching and bending between bonds in RES. In addition, the optimized formula showed a sustained release pattern compared to RES suspension. Finally, the cytotoxic activity of the optimized RES-loaded Smart Lipid on different cell lines (human breast adenocarcinoma (MCF7), human hepatocellular carcinoma (HepG2), and human colon cancer cells (HT29)) was assessed through MTT assay (7-fold reduction in the IC50, from 3.7 ± 0.5 µM for free RES to 0.5 ± 0.033 µM for Smart Lipid loaded formula against MCF7, 3-fold reduction in the IC50 against HepG2 cells, from 10.01 ± 0.35 to 3.16 ± 0.21 µMm, and a more than 10-fold reduction in the IC50 from more than 100 to 10 ± 0.57 µM against HT-29 cells) and its effect on cell cycle progression and apoptosis induction were assessed using flow cytometry and annexin V kit, respectively. Our results showed that RES-loaded Smart Lipid significantly reduced cell viability, induced cell cycle arrest at G0/G1 phase, and apoptosis compared to free formula and free RES suspension. CONCLUSION: Loading RES into this novel kind of nanocarrier enhanced RES absorption, cellular accumulation, and improved its anticancer properties.

Enhancing Pharmacokinetics and Pharmacodynamics of Rosuvastatin Calcium through the Development and Optimization of Fast-Dissolving Films.

Rosuvastatin (RSV) is a widely used cholesterol-lowering medication, but its limited bioavailability due to its susceptibility to stomach pH and extensive first-pass metabolism poses a significant challenge. A fast-dissolving film (FDF) formulation of RSV was developed, characterized, and compared to the conventional marketed tablet to address this issue. The formulation process involved optimizing the thickness, disintegration time, and folding durability. All formulations were assessed for in vitro disintegration, thickness, folding endurance, in vitro dissolution, weight, and content uniformity. The study's results revealed that the optimized RSV-FDF displayed a significantly faster time to maximum plasma concentration (tmax) of 2 h, compared to 4 h for the marketed tablet. The maximum plasma concentration (Cmax) for the RSV-FDF (1.540 µg/mL ± 0.044) was notably higher than that of the marketed tablet (0.940 µg/mL ± 0.017). Additionally, the pharmacodynamic assessment in male Wistar rats demonstrated that the optimized RSV-FDF exhibited an improved lipid profile, including reduced levels of low-density lipoproteins (LDLs), elevated high-density lipoproteins (HDLs), decreased triglycerides (TGs), and lower very-low-density lipoproteins (VLDLs) compared to the conventional tablet. These findings underscore the potential of RSV-FDFs as a promising alternative to enhance the bioavailability and therapeutic efficacy of rosuvastatin in treating dyslipidemia. The faster onset of action and improved lipid-lowering effects make RSV-FDFs an attractive option for patients requiring efficient cholesterol management.

Niosomal formulation of mefenamic acid for enhanced cancer targeting; preparation, characterization and biodistribution study using radiolabeling technique.

BACKGROUND: This work aimed to prepare niosomal formulations of an anticancer agent [mefenamic acid (MEF)] to enhance its cancer targeting. 131I was utilized as a radiolabeling isotope to study the radio-kinetics of MEF niosomes. METHODS: niosomal formulations were prepared by the ether injection method and assessed for entrapment efficiency (EE%), zeta potential (ZP), polydispersity index (PDI) and particle size (PS). MEF was labeled with 131I by direct electrophilic substitution reaction through optimization of radiolabeling-related parameters. In the radio-kinetic study, the optimal 131I-MEF niosomal formula was administered intravenously (I.V.) to solid tumor-bearing mice and compared to I.V. 131I-MEF solution as a control. RESULTS: the average PS and ZP values of the optimal formulation were 247.23 ± 2.32 nm and - 28.3 ± 1.21, respectively. The highest 131I-MEF labeling yield was 98.7 ± 0.8%. The biodistribution study revealed that the highest tumor uptake of 131I-MEF niosomal formula and 131I-MEF solution at 60 min post-injection were 2.73 and 1.94% ID/g, respectively. CONCLUSION: MEF-loaded niosomes could be a hopeful candidate in cancer treatment due to their potent tumor uptake. Such high targeting was attributed to passive targeting of the nanosized niosomes and confirmed by radiokinetic evaluation.

Design and Optimization of Omeprazole-Curcumin-Loaded Hydrogel Beads Coated with Chitosan for Treating Peptic Ulcers.

This study aimed to formulate a pharmaceutical dosage form containing omeprazole (OMP) and curcumin (CURC) to treat experimental peptic ulcers. OMP and CURC were preliminarily complexed with hydroxypropyl-ß-cyclodextrin for enhancing their solubilization. After that, the combined complex (CURC/OMP) was loaded to alginate beads to sustain their release and then coated with chitosan. Finally, we tested the anti-ulcerogenic impact of the best formula versus free OMP or OMP-only-loaded beads. The formulated spherical beads' diameter ranged from a minimum value of 1.5 ± 0.08 mm to 2.6 ± 0.24 mm; the swelling results ranged from 400.00 ± 8.5% to 800.00 ± 6.2%. The entrapment efficiency was in a range from 60.85 ± 1.01% to 87.44 ± 1.88%. The optimized formula (F8) showed a maximum EE% (87.44 ± 1.88%), swelling (800.00 ± 6.2%), and diameter in the range of 2.60 ± 0.24, with a desirability of 0.941. In the first hour following the administration of the free drug complex, 95% of OMP and 98% of CURC were released. This is unacceptable for medications that require a delayed release in the stomach. The initial drug release from hydrogel beads was 23.19% for CURC and 17.19% for OMP after 2 h and 73.09% for CURC and 58.26% for OMP after 12 h; however, after 24 h, 87.81% of CURC and 81.67% of OMP had been released. The OMP/CURC beads showed a more stable particle size (0.52 ± 0.01 mm) after 6 weeks. In conclusion, the OMP/CURC hydrogel beads give stronger anti-ulcer effectiveness compared to free OMP, CURC-only beads, and OMP-only-loaded beads, indicating a prospective application for managing peptic ulcers.

Influence of Surface-Modification via PEGylation or Chitosanization of Lipidic Nanocarriers on In Vivo Pharmacokinetic/Pharmacodynamic Profiles of Apixaban.

Nanostructured lipid carriers (NLCs) have been proven to significantly improve the bioavailability and efficacy of many drugs; however, they still have many limitations. These limitations could hinder their potential for enhancing the bioavailability of poorly water-soluble drugs and, therefore, require further amendments. From this perspective, we have investigated how the chitosanization and PEGylation of NLCs affected their ability to function as a delivery system for apixaban (APX). These surface modifications could enhance the ability of NLCs to improve the bioavailability and pharmacodynamic activity of the loaded drug. In vitro and in vivo studies were carried out to examine APX-loaded NLCs, chitosan-modified NLCs, and PEGylated NLCs. The three nanoarchitectures displayed a Higuchi-diffusion release pattern in vitro, in addition to having their vesicular outline proven via electron microscopy. PEGylated and chitosanized NLCs retained good stability over 3 months, versus the nonPEGylated and nonchitosanized NLCs. Interestingly, APX-loaded chitosan-modified NLCs displayed better stability than the APX-loaded PEGylated NLCs, in terms of mean vesicle size after 90 days. On the other hand, the absorption profile of APX (AUC0-inf) in rats pretreated with APX-loaded PEGylated NLCs (108.59 µg·mL-1·h-1) was significantly higher than the AUC0-inf of APX in rats pretreated with APX-loaded chitosan-modified NLCs (93.397 µg·mL-1·h-1), and both were also significantly higher than AUC0-inf of APX-Loaded NLCs (55.435 µg·mL-1·h-1). Chitosan-coated NLCs enhanced APX anticoagulant activity with increased prothrombin time and activated partial thromboplastin time by 1.6- and 1.55-folds, respectively, compared to unmodified NLCs, and by 1.23- and 1.37-folds, respectively, compared to PEGylated NLCs. The PEGylation and chitosanization of NLCs enhanced the bioavailability and anticoagulant activity of APX over the nonmodified NLCs; this highlighted the importance of both approaches.

In Vitro Cytotoxicity and In Vivo Antitumor Activity of Lipid Nanocapsules Loaded with Novel Pyridine Derivatives.

This study demonstrates high drug-loading of novel pyridine derivatives (S1-S4) in lipid- and polymer-based core-shell nanocapsules (LPNCs) for boosting the anticancer efficiency and alleviating toxicity of these novel pyridine derivatives. The nanocapsules were fabricated using a nanoprecipitation technique and characterized for particle size, surface morphology, and entrapment efficiency. The prepared nanocapsules exhibited a particle size ranging from 185.0 ± 17.4 to 223.0 ± 15.3 nm and a drug entrapment of >90%. The microscopic evaluation demonstrated spherical-shaped nanocapsules with distinct core-shell structures. The in vitro release study depicted a biphasic and sustained release pattern of test compounds from the nanocapsules. In addition, it was obvious from the cytotoxicity studies that the nanocapsules showed superior cytotoxicity against both MCF-7 and A549 cancer cell lines, as manifested by a significant decrease in the IC50 value compared to free test compounds. The in vivo antitumor efficacy of the optimized nanocapsule formulation (S4-loaded LPNCs) was investigated in an Ehrlich ascites carcinoma (EAC) solid tumor-bearing mice model. Interestingly, the entrapment of the test compound (S4) within LPNCs remarkably triggered superior tumor growth inhibition when compared with either free S4 or the standard anticancer drug 5-fluorouracil. Such enhanced in vivo antitumor activity was accompanied by a remarkable increase in animal life span. Furthermore, the S4-loaded LPNC formulation was tolerated well by treated animals, as evidenced by the absence of any signs of acute toxicity or alterations in biochemical markers of liver and kidney functions. Collectively, our findings clearly underscore the therapeutic potential of S4-loaded LPNCs over free S4 in conquering EAC solid tumors, presumably via granting efficient delivery of adequate concentrations of the entrapped drug to the target site.

Development of Novel pH-Sensitive Eudragit Coated Beads Containing Curcumin-Mesalamine Combination for Colon-Specific Drug Delivery.

This research aims to develop a drug delivery system that effectively treats colitis while administering curcumin/mesalamine by coating alginate/chitosan beads with Eudragit® S-100 to target the colon. Beads were tested to determine their physicochemical characteristics. Coating with Eudragit® S-100 prevents drug release at a pH of less than 7; this was demonstrated by in-vitro release conducted in a medium with gradually varying pH to mimic circumstances in various regions of the gastrointestinal tract. This study examined the efficacy of the coated beads in treating acetic acid-induced colitis in rats. Results showed that spherical beads were formed with an average diameter of 1.6-2.8 mm, and the obtained swelling ranged from 409.80% to 890.19%. The calculated entrapment efficiency ranged from 87.49% to 97.89%. The optimized formula F13 (which was composed of mesalamine-curcumin active ingredients, Sodium alginate as a gelling agent, chitosan as a controlled release agent, CaCl2 as a crosslinking agent, and Eudragit S-100 as a pH-sensitive coating agent) demonstrated the best entrapment efficiency (97.89% ± 1.66), swelling (890.19% ± 60.1), and bead size (2.7 ± 0.62 mm). In formulation #13, which was coated with Eudragit S 100, curcumin (6.01 ± 0.04%) and mesalamine (8.64 ± 0.7%), were released after 2 h at pH 1.2; 6.36 ± 0.11% and 10.45 ± 1.52% of curcumin and mesalamine, respectively, were then released after 4 h and at pH 6.8. Meanwhile, at pH 7.4, after 24 h, approximately 85.34 ± 2.3% (curcumin) and 91.5 ± 1.2% (mesalamine) were released. Formula #13 significantly reduced the colitis, and this suggests that the developed hydrogel beads can be used for delivering curcumin-mesalamine combinations to treat ulcerative colitis after adequate research.

Radioiodinated acemetacin loaded niosomes as a dual anticancer therapy.

A niosomal formula of acemetacin was developed to improve its tumor targeting and radio-kinetic evaluation was performed using 131I. Niosomes were prepared by ether injection method and characterized for particle size (PS), polydispersity index (PDI), zeta potential (ZP), entrapment efficiency (EE%) and in vitro drug release. Factors affecting radiolabeling with 131I were studied and optimized. Radio-kinetic evaluation was done for 131I-ACM optimum niosomal formula by intravenous (I.V) administration to solid tumor bearing mice and compared to I.V 131I-ACM solution as a control. The average droplet size, zeta potential and in vitro release after 24 h for the optimum formula were 315.23 ± 5.37 nm, -9.16 ± 2.91 and 76 %, respectively. The greatest labeling yield of 131I-ACM was 93.1 ± 1.1 %. Radio-kinetic evaluation showed a maximum tumor uptake of 5.431 %ID/g for 131I-ACM niosomal formula and 2.601 %ID/g for 131I-ACM solution at 60 min post I.V. injection. As a conclusion, niosomal formula increased tumor uptake of ACM by passive targeting of the nanosized niosomes. In addition, chemotherapeutic effect of ACM and radiotherapeutic effect of 131I were successfully combined in one treatment regimen using 131I-ACM niosomes which could be used as a hopeful dual anticancer therapy.

Design, Formulation, and Characterization of Valsartan Nanoethosomes for Improving Their Bioavailability.

The objective of this study was to formulate and evaluate valsartan (VLT) ethosomes to prepare an optimized formula of VLT-entrapped ethosomes that could be incorporated into a sustained release transdermal gel dosage form. The formulation of the prepared ethosomal gel was investigated and subjected to in vitro drug release studies, ex vivo test, and in vivo studies to assess the effectiveness of ethosomal formulation in enhancing the bioavailability of VLT as a poorly soluble drug and in controlling its release from the transdermal gel dosage form. The acquired results are as follows: Dependent responses were particle size, polydispersity index, zeta potential, and entrapment efficiency. The optimized VLT-ETHs had a nanometric diameter (45.8 ± 0.5 nm), a negative surface charge (-51.4 ± 6.3 mV), and a high drug encapsulation (94.24 ± 0.2). The prepared VLT ethosomal gel (VLT-ethogel) showed a high peak plasma concentration and enhanced bioavailability in rats compared with the oral solution of valsartan presented in the higher AUC (0-∞). The AUC (0-∞) with oral treatment was 7.0 ± 2.94 (µg.h/mL), but the AUC (0-∞) with topical application of the VAL nanoethosomal gel was 137.2 ± 49.88 (µg.h/mL), providing the sustained release pattern of VLT from the tested ethosomal gel.

Formulation and Evaluation of Novel Additive-Free Spray-Dried Triamcinolone Acetonide Microspheres for Pulmonary Delivery: A Pharmacokinetic Study.

This work aimed to establish a simple method to produce additive-free triamcinolone acetonide (TAA) microspheres suitable for pulmonary delivery, and therefore more simple manufacturing steps will be warranted. The spray-drying process involved the optimization of the TAA feed ratio in a concentration range of 1-3% w/v from different ethanol/water compositions with/without adding ammonium bicarbonate as a blowing agent. Characterization of the formulas was performed via scanning electron microscopy, Fourier-transform infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffraction. Our results indicated that the size and morphology of spray-dried TAA particles were dependent on the feed and solvent concentrations in the spray-dried formulations. Furthermore, adding the blowing agent, ammonium bicarbonate, did not produce a significant enhancement in particle characteristics. We prepared additive-free TAA microspheres and found that TAA formulation #1 had optimal physical properties in terms of diameter (2.24 ± 0.27 µm), bulk density (0.95 ± 0.05), tapped density (1.18 ± 0.07), and flowability for deposition during the pulmonary tract, from a centric airway to the alveoli as indicated by Carr's index = 19 ± 0.01. Hence, formulation #1 was selected to be tested for pharmacokinetic characters. Rats received pulmonary doses of TAA formula #1 and then the TTA concentration in plasma, fluid broncho-alveolar lavage, and lung tissues was determined by HPLC. The TAA concentration at 15 min was 0.55 ± 0.02 µg/mL in plasma, 16.74 ± 2 µg/mL in bronchoalveolar lavage, and 8.96 ± 0.65 µg/mL in lung homogenates, while at the 24 h time point, the TAA concentration was 0.03 ± 0.02 µg/mL in plasma, 1.48 ± 0.27 µg/mL in bronchoalveolar lavage, and 3.79 ± 0.33 µg/mL in lung homogenates. We found that TAA remained in curative concentrations in the rat lung tissues for at least 24 h after pulmonary administration. Therefore, we can conclude that additive-free spray-dried TAA microspheres were promising for treating lung diseases. The current novel preparation technology has applications in the design of preparations for TAA or other therapeutic agents designed for pulmonary delivery.

Formulation and Characterization of Metformin-Loaded Ethosomes for Topical Application to Experimentally Induced Skin Cancer in Mice.

To achieve the best treatment of skin cancer, drug penetration inside the deepest layers of the skin is an important scientific interest. We designed an ethosome formulation that serves as a carrier for metformin and measured the in vitro skin permeation. We also aimed to measure the antitumor activity of the optimal ethosomal preparation when applied topically to chemically induced skin cancer in mice. We utilized a statistical Box-Behnken experimental design and applied three variables at three levels: lecithin concentration, cholesterol concentration and a mixture of ethanol and isopropyl alcohol concentrations. All formulations were prepared to calculate the entrapment efficiency %, zeta potential, size of the vesicles and drug release % after 1, 2, 4, 8 and 24 h. The size of the vesicles for the formulations was between 124 ± 14.2 nm and 560 ± 127 nm, while the entrapment efficiency was between 97.8 ± 0.23% and 99.4 ± 0.24%, and the drug release % after 8 h was between 38 ± 0.82% and 66 ± 0.52%. All formulations were introduced into the Box-Behnken software, which selected three formulations; then, one was assigned as an optimal formula. The in vivo antitumor activity of metformin-loaded ethosomal gel on skin cancer was greater than the antitumor activity of the gel preparation containing free metformin. Lower lecithin, high ethanol and isopropyl alcohol and moderate cholesterol contents improved the permeation rate. Overall, we can conclude that metformin-loaded ethosomes are a promising remedy for treating skin cancers, and more studies are warranted to approve this activity in other animal models of skin cancers.

Preparation and Characterization of a Novel Mucoadhesive Carvedilol Nanosponge: A Promising Platform for Buccal Anti-Hypertensive Delivery.

Carvedilol (CRV) is a non-selective third generation beta-blocker used to treat hypertension, congestive heart failure and angina pectoris. Oral administration of CRV showed poor bioavailability (25%), which might be ascribed to its extensive first-pass metabolism. Buccal delivery is known to boost drugs bioavailability. The aim of this study is to investigate the efficacy of bilosomes-based mucoadhesive carvedilol nanosponge for enhancing the oral bioavailability of CRV. The bilosomes were prepared, optimized and characterized for particle size, surface morphology, encapsulation efficiency and ex-vivo permeation studies. Then, the optimized formula was incorporated into a carboxymethyl cellulose/hydroxypropyl cellulose (CMC/HPC) composite mixture to obtain buccal nanosponge enriched with CRV bilosomes. The optimized bilosome formula (BLS9), showing minimum vesicle size, maximum entrapment, and highest cumulative in vitro release, exhibited a spherical shape with 217.2 nm in diameter, 87.13% entrapment efficiency, and sustained drug release for up to 24 h. In addition, ex-vivo drug permeation across sheep buccal mucosa revealed enhanced drug permeation with bilosomal formulations, compared to aqueous drug suspension. Consecutively, BLS9 was incorporated in a CMC/HPC gel and lyophilized for 24 h to obtain bilosomal nanosponge to enhance CRV buccal delivery. Morphological analysis of the prepared nanosponge revealed improved swelling with a porosity of 67.58%. The in vivo assessment of rats indicated that CRV-loaded nanosponge efficiently enhanced systolic/diastolic blood pressure, decreased elevated oxidative stress, improved lipid profile and exhibited a potent cardio-protective effect. Collectively, bilosomal nanosponge might represent a plausible nanovehicle for buccal delivery of CRV for effective management of hypertension.

Tailoring Apixaban in Nanostructured Lipid Carrier Enhancing Its Oral Bioavailability and Anticoagulant Activity.

Apixaban (Apx), an oral anticoagulant drug, is a direct factor Xa inhibitor for the prophylaxis against venous thromboembolism. Apx has limited oral bioavailability and poor water solubility. The goal of this study was to improve the formulation of an Apx-loaded nanostructured lipid carrier (NLC) to increase its bioavailability and effectiveness. As solid lipid, liquid lipid, hydrophilic, and lipophilic stabilizers, stearic acid, oleic acid, Tween 80, and lecithin were used, respectively. Utilizing Box-Behnken design, the effects of three factors on NLC particle size (Y1), zeta potential (Y2), and entrapment efficiency percent (Y3) were examined and optimized. The optimized formula was prepared, characterized, morphologically studied, and pharmacokinetically and pharmacodynamically assessed. The observed responses of the optimized Apx formula were 315.2 nm, -43.4 mV, and 89.84% for Y1, Y2, and Y3, respectively. Electron microscopy revealed the homogenous spherical shape of the NLC particles. The in vivo pharmacokinetic study conducted in male Wistar rats displayed an increase in AUC and Cmax by 8 and 2.67 folds, respectively, compared to oral Apx suspension. Moreover, the half-life was increased by 1.94 folds, and clearance was diminished by about 8 folds, which makes the NLC formula a promising sustained release system. Interestingly, the pharmacodynamic results displayed the superior effect of the optimized formula over the drug suspension with prolongation in the cuticle bleeding time. Moreover, both prothrombin time and activated partial thromboplastin time are significantly increased. So, incorporating Apx in an NLC formula significantly enhanced its oral bioavailability and pharmacodynamic activity.

Starch Nanoparticles for Enhancement of Oral Bioavailability of a Newly Synthesized Thienopyrimidine Derivative with Anti-Proliferative Activity Against Pancreatic Cancer.

PURPOSE: This research aimed to improve water solubility and oral bioavailability of a newly synthesized thienopyrimidine derivative (TPD) with anti-pancreatic cancer activity by loading on starch nanoparticles (SNPs). METHODS: TPD was synthesized, purified and its ADME behavior was predicted using Swiss ADME software. A UV spectroscopy method was developed and validated to measure TPD concentration at various dosage forms. SNPs loaded with TPD (SNPs-TPD) were prepared, characterized for particle size, polydispersity index, zeta potential, transmission electron microscopy, Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), entrapment efficiency, in-vitro release, and in-vivo animal study. RESULTS: The Swiss ADME results showed that TPD can be administered orally; however, it has low oral bioavailability (0.55) and poor water solubility. The significant regression coefficient of the calibration curve (r2 = 0.9995), the precision (%RSD < 0.5%) and the accuracy (99.46-101.72%) confirmed the efficacy of the developed UV method. SNPs-TPD had a spherical monodispersed (PDI= 0.12) shape, nanoparticle size (22.98 ± 4.23) and good stability (-21 ± 4.72 mV). Moreover, FT-IR and DSC revealed changes in the physicochemical structure of starch resulting in SNPs formation. The entrapment efficiency was 97% ± 0.45%, and the in-vitro release showed that the SNPs enhanced the solubility of the TPD. The in-vivo animal study and histopathology showed that SNPs enhanced the oral bioavailability of TPD against solid Ehrlich carcinoma. CONCLUSION: SNPs-TPD were superior in drug solubility and oral bioavailability than those obtained from TPD suspension.

Fluticasone propionate-loaded solid lipid nanoparticles with augmented anti-inflammatory activity: optimisation, characterisation and pharmacodynamic evaluation on rats.

This work aimed to elaborate an optimised fluticasone propionate (FP)-loaded solid lipid nanoparticles (SLNs) to enhance FP effectiveness for topical inflammatory remediation. The influences of drug amount, lipid, and surfactant ratios, on drug release pattern and stability were investigated utilising Box-Behnken design. Elaboration, characterisation, and pharmacodynamic evaluation in comparison with the marketed formulation (Cutivate® cream, 0.05%w/w FP), were conducted for the optimised SLNs. The optimised SLNs with a size of 248.3 ± 1.89 nm (PDI = 0.275) and -32.4 ± 2.85 mV zeta potential were evidenced good stability physiognomies. The optimised SLNs pre-treated rats exhibited non-significant difference in paw volume from that of the control group and showed a significant reduction in both PGE2 and TNF-α levels by 51.5 and 61%, respectively, in comparison with the Carrageenan group. The optimised FP-loaded SLNs maximised the efficacy of FP towards inflammation alleviation that increase its potential as efficient implement in inflammatory skin diseases remediation.

Comprehensive Study of Atorvastatin Nanostructured Lipid Carriers through Multivariate Conceptualization and Optimization.

The aim of the current study is to establish a comprehensive experimental design for the screening and optimization of Atorvastatin-loaded nanostructured lipid carriers (AT-NLCs). Initially, combined D-optimal screening design was applied to find the most significant factors affecting AT-NLCs properties. The studied variables included mixtures of solid and liquid lipids, the solid/liquid lipid ratio, surfactant type and concentration, homogenization speed as well as sonication time. Then, the variables homogenization speed (A), the ratio of solid lipid/liquid lipid (B), and concentration of the surfactant (C) were optimized using a central composite design. Particle size, polydispersity index, zeta potential, and entrapment efficiency were chosen as dependent responses. The optimized AT-NLCs demonstrated a nanometric size (83.80 ± 1.13 nm), Polydispersity Index (0.38 ± 0.02), surface charge (-29.65 ± 0.65 mV), and high drug incorporation (93.1 ± 0.04%). Fourier Transform Infrared Spectroscopy (FTIR) analysis showed no chemical interaction between Atorvastatin and the lipid mixture. Differential Scanning Calorimetry (DSC) analysis of the AT-NLCs suggested the transformation of Atorvastatin crystal into an amorphous state. Administration of the optimized AT-NLCs led to a significant reduction (p < 0.001) in serum levels of rats' total cholesterol, triglycerides, and low-density lipoproteins. This change was histologically validated by reducing the relevant steatosis of the liver.

Impact of the mucoadhesive lyophilized wafer loaded with novel carvedilol nano-spanlastics on biochemical markers in the heart of spontaneously hypertensive rat models.

The purpose of this investigation was to encapsulate carvedilol, a model beta-blocker antihypertensive into nano-spanlastics, followed by incorporation into 1% CMC wafer to afford a mucoadhesive buccal drug delivery system, targeting to sidestep the first-pass metabolism, improving the drug absorption and pharmacological effect, achieving non-invasive buccal delivery for treating hypertension. Carvedilol-loaded nano-spanlastics were rendered by ethanol injection technique, using 23 factorial design. The effect of formulation variables was investigated on nano-spanlastic characteristics. The optimal nano-spanlastic formulation (S2; containing 20% Brij 97) exhibited particle size (239.8 ± 5 nm), entrapment efficiency (98. 16 ± 1.44%), deformability index (8.74 ± 0.42 g), and the flux after 24 h (Jmax) (22.5 ± 0.25 (µg/cm2/h) with enhancement ratio 2.87 as well as excellent stability after storage. Permeation study verified the preeminence of the S2 formula. A confocal laser scanning microscope showed deep penetration of S2 through sheep buccal mucosa formula compared to rhodamine B solution. S2-based wafer showed acceptable characters (pH, swelling, drug content, residence time, and release rate). In vivo studies (pharmacodynamic study and biochemical evaluation) showed considerable improvement in blood pressure, the profile of the lipid, oxidant stress biomarkers, and cardiac markers. Histopathological studies revealed the superiority of S2 wafer in the protection of heart tissues over Carvid®. The results achieved indicate that nano-spanlastic-based wafer offers a promising improving trans-buccal carvedilol delivery system. Graphical abstract.

Influence of formulation variables on miconazole nitrate-loaded lipid based nanocarrier for topical delivery.

The purpose of this study was to develop miconazole nitrate (MN) based solid lipid nano-carrier formulae for topical delivery to enhance its antifungal effectiveness. Miconazole nitrate loaded Solid lipid nanoparticles (MN-SLNs) were formulated using a high shear homogenization technique characterized by particle size, polydispersity index (PI), trapping efficiency (EE percent), drug loading (DL percent) and zeta potential (ZP) characteristics. Furthermore, the optimized formulae were investigated for in-vitro release, ex-vivo study, skin toxicity test, and antifungal activity. With a particle size range of 244.2 ± 27.2 nm to 493.6 ± 35.3 nm, the selected MN-SLNs were spherical shaped. A high EE product percentage ranging from 79.38 ± 2.35 percent to 95.92 ± 6.12 percent and Zeta potential ZP values ranging from-21.6 ± 7.05 mV to-31.4 ± 6.84 mV suggesting strong stability was achieved. A controlled release of MN from the SLNs up to 48 h was shown in-vitro release study. The ex-vivo study showed that the selected MN-SLN (F4) mixture exhibited higher MN flux in the skin than a 1% MN solution. Moreover, selected MN-SLN (F4) has demonstrated a higher zone of inhibition against Candida albicans than a simple drug solution. MN-SLN (F4) had the lowest toxicity value for the skin. Besides, the MN-SLNs (F4) substantially reported antifungal activity with the least histopathological improvements compared to MN-solution utilizing immune-suppressing albino rats with induced candidiasis fungal infection. It can be fulfilled that SLNs can be acquired as a promising carrier for topical delivery of poorly soluble MN.

Development of Betamethasone Dipropionate-Loaded Nanostructured Lipid Carriers for Topical and Transdermal Delivery.

INTRODUCTION: Betamethasone dipropionate is a highly effective corticosteroid anti-inflammatory. However, the main drawback of its topical use is the limited skin penetration into deeper skin layers. Also, its systemic use has shown many side effects. OBJECTIVE: The goal of this research was to formulate betamethasone dipropionate in nanostructured lipid carriers (NLC) formulae that contain oleic acid to aid its penetration to deeper skin layers and to aid absorption to local regions upon topical application. METHODS: NLC formulae were prepared by high shear homogenization then sonication. Formulae were characterized for their particle size, size distribution, electric potential, occlusion factor, entrapment efficiency, drug loading, transmission electron microscopy, in vitro drug release, and ex vivo skin penetration. Compatibility of ingredients with drug was tested using differential scanning calorimetry. Formulae were shown to have appropriate characteristics. NLC formulae were superior to traditional topical formulation in drug release. RESULTS: Upon testing ex vivo skin penetration, betamethasone dipropionate prepared in NLC formulae was shown to penetrate more efficiently into skin layers than when formulated as a traditional cream. NLC formulation that contained higher percentage of oleic acid showed higher penetration and higher amount of drug to pass through skin. CONCLUSION: In general, NLC with lower oleic acid percentage was shown to deliver betamethasone dipropionate more efficiently into deeper skin layers while that of a higher oleic acid percentage was shown to deliver the drug more efficiently into deeper skin layers and through the skin, transdermally.