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.

Incorporating sodium deoxycholate endorsed the buccal administration of avanafil to heighten the bioavailability and duration of action.

The highly effective phosphodiesterase type 5 inhibitor (avanafil; AVA) is routinely prescribed to treat erectile dysfunction. The drug has poor oral bioavailability and undergoes a significant first-pass metabolism. Therefore, altering AVA's solubility and choosing a different delivery method may boost its effectiveness. Nine different solid dispersion formulations utilizing polyvinylpyrrolidone (PVP) at three different ratios were prepared and characterized. The Box-Behnken design was employed to optimize AVA-buccal tablets. The pre-compression and post-compression characteristics of the tablets were assessed. The mucoadhesion strength of the optimized tablet was investigated using cow buccal mucosal tissue. In vivo performance of the optimized tablets was examined on human volunteers compared to the commercial tablets. PVP K90 at 2:1 drug to polymer ratio showed the highest solubilization capacity. The mucoadhesive polymer type and percentage and the mucopenetration enhancer percentage were significantly affect the mucoadhesion strength, tablet hardness, and the initial and cumulative AVA released from the prepared tablets. The optimized AVA-buccal tablet showed 4.96 folds increase in the mean residence time, higher plasma exposure, and an improvement in the relative bioavailability of AVA by 1076.27% compared with the commercial tablet. Therefore, a successful approach to deal with AVA first-pass metabolism and low bioavailability could be to employ buccal tablets containing a solubility-enhanced form of AVA.

Formulation of novel niosomal repaglinide chewable tablets using coprocessed excipients: in vitro characterization, optimization and enhanced hypoglycemic activity in rats.

Repaglinide (RPG), a monotherapy insulin secretagogue used to treat diabetes mellitus-type II yet, it suffers from poor water solubility and variable bioavailability (∼ 50%) due to hepatic first pass metabolism. In this study, 2FI I-Optimal statistical design was employed to encapsulate RPG into niosomal formulations using cholesterol,span 60 and peceolTM. The optimized niosomal formulation (ONF) showed particle size 306.60 ± 84.00 nm, zeta potential -38.60 ± 1.20 mV, polydispersity index 0.48 ± 0.05 and entrapment efficiency 92.00 ± 2.60%. ONF showed > 65% RPG release that lasted for 3.5 h, and significantly higher sustained release compared to Novonorm® tablets after 6 h (p < 0.0001). TEM for ONF showed spherical vesicles with dark core and light-colored lipid bilayer membrane. RPG peaks disappeared in FTIR confirming successful RPG entrapment. To eliminate dysphagia associating conventional oral tablets, chewable tablets loaded with ONF were prepared using coprocessed excipients; Pharmaburst® 500, F-melt® and Prosolv® ODT. Tablets showed friability <1%, hardness 3.9 ± 0.423-4.7 ± 0.410 Kg, thickness 4.1 ± 0.045-4.4 ± 0.017 mm and acceptable weight.All tablets showed robust RPG release at 30 min compared to Novonorm® tablets. At 6h, chewable tablets containing only Pharmaburst® 500 and F-melt® showed sustained and significantly increased RPG release compared to Novonorm® tablets (p < 0.05). Pharmaburst® 500 and F-melt® tablets showed rapid in vivo hypoglycemic effect with 5 and 3.5 fold significant reduction in blood glucose compared to Novonorm® tablets (p < 0.05) at 30 min. Also, at 6h the same tablets showed 1.5 and 1.3 fold significant extended reduction in blood glucose compared to the same market product (p < 0.05). It could be concluded that chewable tablets loaded with RPG ONF represent promising novel oral drug delivery systems for diabetic patients suffering from dysphagia.

Effect of nanovesicular surface-functionalization via chitosan and/or PEGylation on cytotoxicity of tamoxifen in induced-breast cancer model.

AIMS: The effect of surface-modification of Tamoxifen (Tam)-loaded-niosomes on drug cytotoxicity and bio-distribution, via functionalization with chitosan and/or PEGylation, was investigated. MATERIALS AND METHODS: Tam-loaded hybrid-nanocarriers (Tam-loaded niosomes, chitosomes, PEGylated niosomes, and PEGylated chitosomes) were formulated and characterized. KEY FINDINGS: Chitosanization with/without PEGylation proved to selectively enhance Tam-release at the cancerous-acidic micromilieu. Cytotoxic activity study showed that Tam-loaded PEGylated niosomes had a lower IC50 value on MCF-7 cell line (0.39, 0.35, and 0.27 times) than Tam-loaded PEGylated chitosomes, Tam-loaded niosomes, and Tam-loaded chitosomes, respectively. Cell cycle analysis showed that PEGylation and/or Chitosanization significantly impact Tam efficiency in inducing apoptosis, with a preferential influence of PEGylation over chitosanization. The assay of Annexin-V/PI double staining revealed that chitosanized-nanocarriers had a significant role in increasing the incidence of apoptosis over necrosis. Besides, PEGylated-nanocarriers increased apoptosis, as well as total death and necrosis percentages more than what was shown from free Tam. Moreover, the average changes in both Bax/Bcl-2 ratio and Caspase 9 were best improved in cells treated by Tam-loaded PEGylated niosomes over all other formulations. The in-vivo study involving DMBA-induced-breast cancer rats revealed that PEGylation made the highest tumor-growth inhibition (84.9 %) and breast tumor selectivity, while chitosanization had a lower accumulation tendency in the blood (62.3 ng/ml) and liver tissues (103.67 ng/ml). The histopathological specimens from the group treated with Tam-loaded PEGylated niosomes showed the best improvement over other formulations. SIGNIFICANCE: All these results concluded the crucial effect of both PEGylation and chitosan-functionalization of Tam-loaded niosomes in enhancing effectiveness, targetability, and safety.

Pairing 3D-Printing with Nanotechnology to Manage Metabolic Syndrome.

Introduction: This work was aimed to develop a Curcuma oil-based self-nanoemulsifying drug delivery system (SNEDDS) 3D-printed polypills containing glimepiride (GMD) and rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes as a model for metabolic syndrome (MS). Methods: Compartmentalized 3D printed polypills were prepared and studied in streptozotocin/poloxamer induced diabetic/dyslipidemic rats. The pharmacokinetic parameters of GMD and RSV in the prepared polypills were evaluated. Blood glucose level, lipid profile, antioxidant, and biochemical markers activities were investigated. Also, histopathological examination of the liver and pancreas was carried out. The atherosclerotic index, the area of islets of Langerhans, and liver steatosis lesion scores were calculated. Results: The developed SNEDDS-loaded GMD/RSV polypills showed acceptable quality control characteristics with a high relative bioavailability of 217.16% and 224.28% for GMD and RSV, respectively, when compared with the corresponding non-SNEDDS pills. The prepared polypills showed dramatic lowering in blood glucose levels and substantial improvement in lipid profile and hepatic serum biomarkers as well as remarkable decrease in serum antioxidants in response to Poloxamer 407 intoxication. The prepared polypills decreased the risk of atherosclerosis and coronary disease by boosting the level of high-density lipoprotein and lowering both triglyceride and low-density lipoprotein. Microscopic examination showed normal hepatic sinusoids and high protection level with less detectable steatosis in the examined hepatocytes. Normal size pancreatic islets with apparently normal exocrine acini and pancreatic duct were also noticed. Conclusion: This formulation strategy clearly shows the potential of the developed polypills in personalized medicine for treatment of patients with MS.

Fully validated UPLC-MS/MS method for quantifying Favipiravir in human plasma boosted lean six sigma: An application for a bioequivalence study.

This research developed and validated a highly sensitive and selective UPLC-MS/MS approach using a triple quadrupole mass spectrometer for quantifying favipiravir. Moreover, we introduced a study evaluating bioequivalence using two drugs, Favibrivix and Avigan, containing favipiravir. Lean Six Sigma verified the capacity and performance of the process. Protein precipitation extraction was utilized to extract favipiravir from the collected human matrices. We used an Acquity UPLCr BEH HILIC column and valproic acid as an internal standard. Furthermore, we conducted the procedure using an isocratic elution comprising acetonitrile and 0.005% ammonia in water (75:25, v/v), a flow rate of 0.25 ml/min, a temperature controlled at 10°C and an injection volume of 1.0 µl. Our UPLC-MS/MS process has a broad range (50-10,000 ng/ml) with a determination coefficient of 0.9980. We validated the method in line with the US Food and Drug Administration. The findings revealed that the test, Favibrivix 200 mg/tablet, and the reference, Avigan® 200 mg/tablet, were statistically bioequivalent in healthy Egyptian participants.

Development and validation of a ultraperformance liquid chromatography-tandem mass spectrometry method for quantifying free and total dabigatran in human plasma: An application for a bioequivalence study.

Dabigatran etexilate mesylate (DABE), a prodrug, quickly changes into dabigatran (DAB) after its oral administration. Accordingly, detecting DABE in plasma is practically unmanageable. An ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was developed and validated to compute free DAB in participants. For the first time, the central composite design, a type of response surface methodology, was applied for optimizing variables affecting the cleavage of glucuronide bond. In addition, the pharmacokinetic parameters of generic medication (okanadab) were determined, and the obtained outcomes were compared with those of the branded drug (pradaxa). The sample preparation was done using methanol as a protein precipitant and the separation was achieved using an ACQUITY UPLC BEH C18 column (2.1 × 50 mm, 1.7 µm). The elution was isocratically conducted using 10 mM ammonium formate:methanol (72:28, v/v) as a mobile phase and the flow rate was 0.25 mL/min. Multiple reaction monitoring and positive electrospray ionization were used. The determination was performed within 1 min, and the calibration growth curve was established over a range of 1.19-475 ng/mL using DAB-d3 as a tagged internal standard. Bioequivalence research was validated following the US Food and Drug Administration (US FDA) guidelines for bioanalytical procedures and acceptable outcomes were achieved. The outcomes for okanadab and pradaxa did not differ significantly.

Development of Multi-Compartment 3D-Printed Tablets Loaded with Self-Nanoemulsified Formulations of Various Drugs: A New Strategy for Personalized Medicine.

This work aimed to develop a three-dimensional printed (3DP) tablet containing glimepiride (GLMP) and/or rosuvastatin (RSV) for treatment of dyslipidemia in patients with diabetes. Curcumin oil was extracted from the dried rhizomes of Curcuma longa and utilized to develop a self-nanoemulsifying drug delivery system (SNEDDS). Screening mixture experimental design was conducted to develop SNEDDS formulation with a minimum droplet size. Five different semi-solid pastes were prepared and rheologically characterized. The prepared pastes were used to develop 3DP tablets using extrusion printing. The quality attributes of the 3DP tablets were evaluated. A non-compartmental extravascular pharmacokinetic model was implemented to investigate the in vivo behavior of the prepared tablets and the studied marketed products. The optimized SNEDDS, of a 94.43 ± 3.55 nm droplet size, was found to contain 15%, 75%, and 10% of oil, polyethylene glycol 400, and tween 80, respectively. The prepared pastes revealed a shear-thinning of pseudoplastic flow behavior. Flat-faced round tablets of 15 mm diameter and 5.6-11.2 mm thickness were successfully printed and illustrated good criteria for friability, weight variation, and content uniformity. Drug release was superior from SNEDDS-based tablets when compared to non-SNEDDS tablets. Scanning electron microscopy study of the 3DP tablets revealed a semi-porous surface that exhibited some curvature with the appearance of tortuosity and a gel porous-like structure of the inner section. GLMP and RSV demonstrated relative bioavailability of 159.50% and 245.16%, respectively. Accordingly, the developed 3DP tablets could be considered as a promising combined oral drug therapy used in treatment of metabolic disorders. However, clinical studies are needed to investigate their efficacy and safety.

Improving the Solubility and Oral Bioavailability of a Novel Aromatic Aldehyde Antisickling Agent (PP10) for the Treatment of Sickle Cell Disease.

BACKGROUND: Aromatic aldehydes, with their ability to increase the oxygen affinity of sickle hemoglobin, have become important therapeutic agents for sickle cell disease (SCD). One such compound, voxelotor, was recently approved for SCD treatment. Methyl 6-((2-formyl-3-hydroxyphenoxy)methyl) picolinate (PP10) is another promising aromatic aldehyde, recently reported by our group. Like voxelotor, PP10 exhibits O2-dependent antisickling activity, but, unlike voxelotor, PP10 shows unique O2-independent antisickling effect. PP10, however, has limited solubility. This study therefore aimed to develop oral and parenteral formulations to improve PP10 solubility and bioavailability. METHODS: Oral drug tablets with 2-hydroxypropyl beta cyclodextrin (HP-ß-CD), polyvinylpyrrolidone, or Eudragit L100-55 PP10-binary system, and an intravenous (IV) formulation with d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) or HP-ß-CD, were developed. The pharmacokinetic behavior of the formulations was studied in Sprague-Dawley rats. PP10, a methylester, and its acid metabolite were also studied in vitro with sickle whole blood to determine their effect on Hb modification, Hb oxygen affinity, and sickle red blood cell inhibition. RESULTS: Aqueous solubility of PP10 was enhanced ~5 times with the HP-ß-CD binary system, while the TPGS aqueous micelle formulation was superior, with a drug concentration of 0.502 ± 0.01 mg/mL and a particle size of 26 ± 3 nm. The oral tablets showed relative and absolute bioavailabilities of 173.4% and 106.34%, respectively. The acid form of PP10 appeared to dominate in vivo, although both PP10 forms demonstrated pharmacologic effect. CONCLUSION: Oral and IV formulations of PP10 were successfully developed using HP-ß-CD binary system and TPGS aqueous micelles, respectively, resulting in significantly improved solubility and bioavailability.

Design, optimization, and in-vivo hypoglycaemic effect of nanosized glibenclamide for inhalation delivery.

The aim of this research was the development and optimization of nanoniosomes for delivery of glibenclamide (Gbn) as hypoglycaemic agent to the lung in an inhaler dosage form. Fifteen formulae of niosomal dispersions were prepared according to Box-Behnken design. The effect of drug amount, Cholesterol molar ratio, and Hydrophilic lipophilic balance (HLB) values of the surfactant on the mean vesicle size, Zeta potential (ZP), polydispersity index (PDI), entrapment efficiency, and in-vitro released of Gbn were investigated. A quality control check was performed on an inhaler filled with the optimum nanoniosomal formula. The in-vivo hypoglycaemic effect of nanoniosomal inhalation was also evaluated. The vesicle size observed of the optimized formula was 172 ± 4.6 nm, PDI was 0.304 ± 0.06 and ZP was -49.9 ± 1.5 mv with 69 ± 9.3% in-vitro drug release after 2 h. The Cholesterol molar ratio and the HLB value showed a statistically significant effect on dependent variables. In-vivo results proved that nanoniosomes were efficiently delivered from the inhalation canister showing a mass median aerodynamic diameter of 1.4 micron. The inhaled nanoniosomal dispersion loaded with Gbn showed a decrease in blood glucose level of hyperglycaemic rats by 51.42 ± 5.2%± after 180 min which was nearly two folds compared to oral Gbn. Gibenclamide nanoniosomes inhaler could be suggested as a novel effective dosage form for the treatment of Diabetes mellitus.

Formulation and Optimization of Avanafil Biodegradable Polymeric Nanoparticles: A Single-Dose Clinical Pharmacokinetic Evaluation.

Avanafil (AVA) is a second-generation phosphodiesterase-5 (PDE5) inhibitor. AVA shows high selectivity to penile tissues and fast absorption, but has a bioavailability of about 36%. The aim was to formulate and optimize AVA-biodegradable nanoparticles (NPs) to enhance AVA bioavailability. To assess the impact of variables, the Box-Behnken design was utilized to investigate and optimize the formulation process variables: the AVA:poly (lactic-co-glycolic acid) (PLGA) ratio (w/w, X1); sonication time (min, X2); and polyvinyl alcohol (PVA) concentration (%, X3). Particle size (nm, Y1) and EE% (%, Y2) were the responses. The optimized NPs were characterized for surface morphology and permeation. Furthermore, a single-oral dose (50 mg AVA) pharmacokinetic investigation on healthy volunteers was carried out. Statistical analysis revealed that all the investigated factors exhibited a significant effect on the particle size. Furthermore, the entrapment efficiency (Y2) was significantly affected by both the AVA:PLGA ratio (X1) and PVA concentration (X3). Pharmacokinetic data showed a significant increase in the area under the curve (1.68 folds) and plasma maximum concentration (1.3-fold) for the AVA NPs when compared with raw AVA. The optimization and formulation of AVA as biodegradable NPs prepared using solvent evaporation (SE) proves a successful way to enhance AVA bioavailability.

Glibenclamide nanosuspension inhaler: development, in vitro and in vivo assessment.

Objective: The development of nanosuspension for targeted delivery of glibenclamide as hypoglycemic agent to the lung in an inhaler dosage form.Method: Glibenclamide nanosuspension formulations were prepared using Box-Behnken design to investigate the effect of independent factors on the dependent variables, Fourier-transform Infrared spectroscopy, Differential Scanning Calorimetry, evaluation of glibenclamide nanosuspension inhaler and in vivo hypoglycemic efficacy were performed to determine glibenclamide nanosuspension inhaler effect.Results: The results revealed that the mean particle sizes of the prepared nanosuspension ranged from 0.216 to 0.856 µm, zeta potential from +9 to +16 mV, the solubility ranged from 43% to 75%, the mass median aerodynamic diameter was 2.34 µm and the glucose level in rat was significantly reduced by about 60%.Conclusion: These results confirmed that glibenclamide nanosuspension inhaler enhance hypoglycemic effectiveness and reduce adverse effect of glibenclamide, opening up new dosage form in Diabetes mellitus treatment.

Tolmetin sodium-loaded thermosensitive mucoadhesive liquid suppositories for rectal delivery; strategy to overcome oral delivery drawbacks.

Tolmetin sodium (TS) is a nonsteroidal anti-inflammatory drug (NSAID) indicated for treatment of musculoskeletal issues. As other NSAID, TS displays a marked side effects on the gastro-intestinal (GI) tract after oral administration. Traditional solid suppositories can cause pain and discomfort for patients, may reach the end of the colon; consequently, the drug can undergo the first-pass effect. TS liquid suppository (TS-LS) was developed to enhance patient compliance and rectal mucosal safety in high-risk patients receiving highly NSAID therapy. This work was conducted to optimize and evaluate Poloxamer P407/P188-based thermoresponsive TS-LS by using mucoadhesive polymers such as methylcellulose (MC). TS-LS was prepared by cold method and characterized their in vitro physicochemical properties as gelation temperature (GT), gel strength, bioadhesive properties, and in vitro release. The safety of the prepared suppository on rectum, stomach, and liver was evaluated histologically. Pharmacokinetic analyses were performed to compare rectal TS-LS to orally Rhumtol® capsules. The results showed that the optimized TS-LS; composed of P407/P188/MC (21/9/0.5% w/w) displayed gelation at rectum temperature ∼32.90 °C, gel strength of 21.35 s and rectal retention force at the administration site of 24.25 × 102 dyne/cm2. Moreover, TS-LS did not cause any morphological damage to the rectal tissues. Pharmacokinetic parameters of optimized TS-LS formulation revealed 4.6 fold increase in bioavailability as compared to Rhumtol® capsules. Taken together, the results demonstrated that liquid suppository is a potential and physically safe rectal delivery carrier for improvement rectal bioavailability and in vivo safety of TS.

Probucol Self-Emulsified Drug Delivery System: Stability Testing and Bioavailability Assessment in Human Volunteers.

BACKGROUND: Self-Emulsifying Drug Delivery System (SEDDS), if taken orally, is expected to self-emulsify in GIT and improve the absorption and bioavailability. Probucol (PB) is a highly lipophilic compound with very low and variable bioavailability. OBJECTIVE: The objectives of this study were to examine the stability and conduct bioavailability of the prepared Probucol Self-Emulsified Drug Delivery System (PBSEDDS) in human volunteers. METHODS: The methods included preparation of different PBSEDDS using soybean oil (solvent), Labrafil M1944CS (surfactant) and Capmul MCM-C8 (co-surfactant). The formulations were characterized in vitro for spontaneity of emulsification, droplet size, turbidity and dissolution in water after packing in HPMC capsules. The optimized formulations were evaluated for stability at different storage temperatures and human bioavailability compared with the drug dissolved in soybean oil (reference). RESULTS: The results showed that formulations (F1-F4) were stable if stored at 20 °C. The mean (n=3) pharmacokinetic parameters for stable formulations were: The Cmax, 1070.76, 883.16, 2876.43, 3513.46 and 1047.37 ng/ml; the Tmax, 7.93, 7.33, 3.96, 3.67 and 4.67 hr.; the AUC (0-t), 41043.41, 37763.23, 75006.26, 46731.36 and 26966.43 ng.hr/ml for F1, F2, F3, F4 and reference, respectively. The percentage relative bioavailability was in this order: F3> F4> F1> F2>. CONCLUSION: In conclusion, the PBSEDDS formulations were stable at room temperature. F4 showed the highest Cmax and the shortest Tmax. All the formulations showed significant enhancement of bioavailability compared with the reference. The results illustrated the potential use of SEDDS for the delivery of probucol hydrophobic compound.

Enhancing the Therapeutic Efficacy of Tamoxifen Citrate Loaded Span-Based Nano-Vesicles on Human Breast Adenocarcinoma Cells.

Serious adverse effects and low selectivity to cancer cells are the main obstacles of long term therapy with Tamoxifen (Tmx). This study aimed to develop Tmx-loaded span-based nano-vesicles for delivery to malignant tissues with maximum efficacy. The effect of three variables on vesicle size (Y1), zeta potential (Y2), entrapment efficiency (Y3) and the cumulative percent release after 24 h (Y4) were optimized using Box-Behnken design. The optimized formula was prepared and tested for its stability in different storage conditions. The observed values for the optimized formula were 310.2 nm, - 42.09 mV, 75.45 and 71.70% for Y1, Y2, Y3, and Y4, respectively. The examination using electron microscopy confirmed the formation of rounded vesicles with distinctive bilayer structure. Moreover, the cytotoxic activity of the optimized formula on both breast cancer cells (MCF-7) and normal cells (BHK) showed enhanced selectivity (9.4 folds) on cancerous cells with IC50 values 4.7 ± 1.5 and 44.3 ± 1.3 µg/ml on cancer and normal cells, respectively. While, free Tmx exhibited lower selectivity (2.5 folds) than optimized nano-vesicles on cancer cells with IC50 values of 9.0 ± 1.1 µg/ml and 22.5 ± 5.3 µg/ml on MCF-7 and BHK cells, respectively. The promising prepared vesicular system, with greater efficacy and selectivity, provides a marvelous tool to overcome breast cancer treatment challenges.

Date seed oil loaded niosomes: development, optimization and anti-inflammatory effect evaluation on rats.

OBJECTIVE: An optimized date seed oil (DSO) loaded niosomes was formulated. SIGNIFICANCE: Maximize the extract anti-inflammatory efficacy and govern its release characteristics from nanoparticles for osteoarthritis prevention and treatment purposes. METHODS: By using Box-Behnken Design, the effect of three formulation factors on the entrapment efficiency percentage (Y1), initial DSO release percentage after 2 h (Y2), and cumulative DSO release percentage of DSO after 12 h (Y3), were optimized and studied. The optimized DSO formulation was specified, elaborated, particle size and zeta potential assessed, examined morphologically under electron and light microscope, and in vivo evaluated via carrageenan-induced rat paw edema study. RESULTS: 65.89%, 18.39%, and 58.27% were the measured responses of the optimized niosomes for Y1, Y2, and Y3, respectively. The vesicular structure of the optimized DSO loaded nano-vesicles with nano-size range and good stability features were confirmed. Furthermore, a distinguished anti-inflammatory activity in both prompt and sustained effectiveness were exhibited via the optimized DSO niosomes. Interestingly, the delayed efficacy outcomes of the extract loaded nanoparticles showed a similarity profile as well as the negative control group outcomes. CONCLUSIONS: To emphasize, DSO loading in niosomes revealed a significant enhancement toward inflammation alleviation, which offers a promising implement in osteoarthritis remediation and prohibition.

Clinical pharmacokinetic study for the effect of glimepiride matrix tablets developed by quality by design concept.

OBJECTIVE: Implementation of a new pharmaceutical technique to improve aqueous solubility and thus dissolution, enhancement of drug permeation, and finally formulation of a controlled release tablet loaded with glimepiride (GLMP). SIGNIFICANCE: Improve GLMP bioavailability and pharmacokinetics in type II diabetic patients. METHODS: Different polymers were used to enhance aqueous GLMP solubility of which a saturated polymeric drug solution was prepared and physically adsorbed onto silica. An experimental design was employed to optimize the formulation parameters affecting the preparation of GLMP matrix tablets. A compatibility study was conducted to study components interactions. Scanning electron microscope (SEM) was performed before and after the tablets were placed in the dissolution medium. An in vivo study in human volunteers was performed with the optimized GLMP tablets, which were compared to pure and marketed drug products. RESULTS: Enhancement of GLMP aqueous solubility, using the polymeric drug solution technique, by more than 6-7 times when compared with the binary system. All the studied formulation factors significantly affected the studied variables. No significant interaction was detected among components. SEM illustrated the surface and inner tablet structure, and confirmed the drug release which was attributed to diffusion mechanism. The volunteer group administered the optimized GLMP tablet exhibited higher drug plasma concentration (147.4 ng/mL), longer time to reach maximum plasma concentration (4 h) and longer t1/2 (7.236 h) compared to other groups. CONCLUSIONS: Matrix tablet loaded with a physically modified drug form could represent a key solution for drugs with inconsistent dissolution and absorption profiles.

Preparation and in vitro/in vivo evaluation of metformin hydrochloride rectal dosage forms for treatment of patients with type II diabetes.

BACKGROUND: Metformin hydrochloride (MtHCL) is an oral antidiabetic drug and has many other therapeutic benefits. It has poor bioavailability, narrow absorption window and extensive liver metabolism. Moreover, children and elders face difficulty to swallow the commercial oral tablets. OBJECTIVES: Preparation, in vitro/in vivo evaluation of MtHCL suppositories for rectal administration to solve some of these problems. METHODS: Suppository fatty bases (Witepsol®, Suppocire® and Massa®; different grades) and PEG bases 1000, 4000 and 6000 (different ratios), were used to prepare rectal suppository formulations each containing 500 mg drug. These were characterized for manufacturing defects, and pharmacotechnical performance and formulations showing superior results were subjected to bioavailability testing in human volunteers compared with the commercial oral tablet (Ref) applying LC-MS/MS developed analytical technique. RESULTS: The preparation method produced suppositories with satisfactory characteristics and free of manufacturing defects. The fatty bases were superior compared with PEG bases regarding the physical characteristics. Three formulations were chosen for bioavailability testing and the results showed comparable bioavailability compared to the Ref. CONCLUSIONS: The fatty bases showed superior characteristics compared with the PEG bases. MtHCL formulated in selected fatty bases could be a potential alternative to the commercial oral tablets particularly for pediatric and geriatric patients.

Self-Nanoemulsifying Lyophilized Tablets for Flash Oral Transmucosal Delivery of Vitamin K: Development and Clinical Evaluation.

Owing to limited solubility, vitamin K undergoes low bioavailability with large inter-individual variability after oral administration. This article aimed to prepare self-nanoemulsifying lyophilized tablets (SNELTs) for the flash oral transmucosal delivery of vitamin K. Twenty-one formulae of vitamin K self-nanoemulsifying drug delivery systems (SNEDDS) were prepared using different concentrations of vitamin K, Labrasol, and Transcutol according to mixture design. The SNEDDS was loaded on porous carriers and formulated as lyophilized tablets. The release profile and the pharmacokinetic parameters of vitamin K SNELTs were evaluated in comparison with commercial tablets and ampoules on human volunteers. Results revealed that the optimized SNEDDS showed the smallest and most stable nanoemulsion globules. SNELTs were prepared successfully and showed substantial superiority drug release compared with the commercial tablets. Interestingly, SNELTs enhanced both rate and extent of vitamin K absorption as well as relative bioavailability (169.67%) in healthy subjects compared with the commercial tablets. SNELTs revealed promising no significant difference in the area under the curve compared with the commercial intramuscular injection. SNELTs enhanced dissolution and bioavailability that expected to have the strong impact on the efficiency of vitamin K in the prophylaxis and treatment of bleeding disorders in patients with hepatic dysfunction.