Publications by authors named "Ramadan Al-Shdefat"

14 Publications

  • Page 1 of 1

Abemaciclib-loaded ethylcellulose based nanosponges for sustained cytotoxicity against MCF-7 and MDA-MB-231 human breast cancer cells lines.

Saudi Pharm J 2022 Jun 6;30(6):726-734. Epub 2022 Apr 6.

Department of Pharmaceutical Sciences, Faculty of Pharmacy, Jadara University, Irbid, Jordan.

Abemaciclib (AC) is a novel, orally available drug molecule approved for the treatment of breast cancer. Due to its low bioavailability, its administration frequency is two to three times a day that can decrease patient compliance. Sustained release formulation are needed for prolong the action and to reduce the adverse effects. The aim of current study was to develop sustained release NSs of AC. Nanosponges (NSs) was prepared by emulsion-solvent diffusion method using ethyl-cellulose (EC) and Kolliphor P-188 (KP-188) as sustained-release polymer and surfactant, respectively. Effects of varying surfactant concentration and drug: polymer proportions on the particle size (PS), polydispersity index (PDI), zeta potential (ζP), entrapment efficiency (%EE), and drug loading (%DL) were investigated. The results of AC loaded NSs (ACN1-ACN5) exhibited PS (366.3-842.2 nm), PDI (0.448-0.853), ζP (-8.21 to -19.7 mV), %EE (48.45-79.36%) and %DL (7.69-19.17%), respectively. Moreover, ACN2 showed sustained release of Abemaciclib (77.12 ± 2.54%) in 24 h Higuchi matrix as best fit kinetics model. MTT assay signified ACN2 as potentials cytotoxic nanocarrier against MCF-7 and MDA-MB-231 human breast cancer cells. Further, ACN2 displayed drug release property without variation in the % release after exposing the product at 25 °C, 5 °C, and 45 °C storage conditions for six months. This investigation proved that the developed NSs would be an efficient carrier to sustain the release of AC in order to improve efficacy against breast cancer.
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http://dx.doi.org/10.1016/j.jsps.2022.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9257851PMC
June 2022

Solubilization of a novel antitumor drug ribociclib in water and ten different organic solvents at different temperatures.

Drug Dev Ind Pharm 2022 Jan 21;48(1):12-20. Epub 2022 Jun 21.

Department of Clinical Pharmacy, Faculty of Pharmacy, University of Science and Technology, Irbid, Jordan.

Objective: This study reports new solubility and physicochemical data for ribociclib (RCB) in water and ten organic solvents including "methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA), n-butanol (n-BuOH), propylene glycol (PG), polyethylene glycol-400 (PEG-400), acetone, ethyl acetate (EA), Transcutol-HP (THP), and dimethyl sulfoxide (DMSO)" at 293.2-313.2 K and 101.1 kPa.

Significance: The obtained data are useful for the industrial applications of RCB.

Methods: The solubility of RCB was measured and regressed using "van't Hoff, Buchowski-Ksiazczak , the modified Apelblat, and Jouyban models."

Results: The overall deviations of <4.0% were recorded for all four models. The maximum mole fraction solubility of RCB was 2.66 × 10 in PEG-400 at 313.2 K, however, the lowest one was in the water. The RCB solubility increased with temperature and the order followed in the water and ten different organic solvents was PEG-400 (2.66 × 10) > THP (1.00 × 10) > PG (5.39 × 10) > DMSO (5.00 × 10) > n-BuOH (3.23 × 10) > acetone (3.11 × 10) > IPA (1.58 × 10) > EA (1.41 × 10) > EtOH (1.37 × 10) > MeOH (8.10 × 10) > water (2.38 × 10) at 313.2 K. The maximum solute-solvent interactions were found in RCB-PEG-400 in comparison with other combination of RCB and solvents. "Apparent thermodynamic analysis" indicated an "endothermic and entropy-driven dissolution" of RCB in water and ten organic solvents.

Conclusions: Based on all these data and observations, PEG-400 can be used as the best co-solvent for RCB solubilization.
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http://dx.doi.org/10.1080/03639045.2022.2089161DOI Listing
January 2022

Theoretical evaluation of poly(amidoamine) dendrimers with different peripheral groups as a purinethol drug delivery system in aqueous medium.

Colloids Surf B Biointerfaces 2022 Aug 4;216:112534. Epub 2022 May 4.

Department of Chemistry, University of Delhi, Delhi 110007, India.

In this work, density functional theory calculations were used to study the association of PUR with amine- and acetyl-terminated PAMAM dendrimers considering implicit solvent effect at neutral and low pH conditions. Frontier molecular orbitals' analysis indicates that the electronic properties of dendrimers are extremely sensitive to the presence of PUR molecule at both neutral and low pH conditions. Encapsulation of PUR molecule into the both amine- and acetyl-terminated PAMAM dendrimers leads to a Gibbs free energy of (ΔG) - 20.25 kcal.mol at physiological pH. The corresponding ΔG values reduce to the - 1.45 and - 0.91 kcal.mol at low pH, indicating that the drug molecule is released easily at low pH. The calculated recovery times for amine- (3.87 ×10 and 3.87 ×10, at neutral and low pH, respectively) and acetyl-terminated (5.34 ×10 and 1.81 ×10, at neutral and low pH, respectively) dendrimers suggest that acetylation can improve the release pattern of drug molecule.
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http://dx.doi.org/10.1016/j.colsurfb.2022.112534DOI Listing
August 2022

Pharmacokinetics and Bioequivalence of Two Empagliflozin, with Evaluation in Healthy Jordanian Subjects under Fasting and Fed Conditions.

Pharmaceuticals (Basel) 2022 Feb 3;15(2). Epub 2022 Feb 3.

Faculty of Pharmacy, Mutah University, Al-Karak 61710, Jordan.

The current study is a randomized, open-label, two-period, two-sequence, two-way crossover pharmacokinetic study in healthy Jordanian subjects to evaluate the pharmacokinetics and bioequivalence profile of two cases of empagliflozin 10 mg under fasting and fed conditions. The plasma concentrations of empagliflozin were determined using an HPLC-MS/MS method. Tolerability and safety were assessed throughout the study. This study included 26 subjects, 26 in both fasting and fed groups.The pharmacokinetic parameters, which included the area under the concentration-time curve from time zero to infinity (AUC) and the final quantifiable concentration (AUC), maximum serum concentration (C), and time to reach the maximum drug concentration (T) were found to be within an equivalence margin of 80.00-125.00%. The pharmacokinetic profiles show that the empagliflozin test and parent reference cases were bioequivalent in healthy subjects. The two treatments' safety evaluations were also comparable.
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http://dx.doi.org/10.3390/ph15020193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8879246PMC
February 2022

Eco-friendly stability-indicating RP-HPTLC method for sildenafil analysis, characterization and biological evaluation of its oxidized stress degradation product.

Sci Rep 2021 07 28;11(1):15358. Epub 2021 Jul 28.

Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, P.O. Box 173, Al-Kharj, 11942, Saudi Arabia.

A feasible and cost effective reverse-phase high-performance thin layer chromatography (RP-HPTLC) based method was developed for the quantification of sildenafil (SLD) using eco-friendly EtOH:HO (9.5:0.5 v/v) as mobile phase. SLD was subjected to stress conditions according to the International Conference on Harmonization (ICH) guidelines. The drug undergoes significant structural changes under oxidative stress condition to the N-oxide derivative. The oxidation product Sildenafil N-oxide (SDL N-oxide) designated in the European Pharmacopeia (EP) as impurity B was characterized utilizing 1D- and 2D-NMR as well as High Resolution Electrospray Ionization Mass Spectroscopy. The aphrodisiac potency of SDL N-oxide in comparison with SLD was evaluated in vivo using rats as experimental animal model. The evaluation based on the following parameters: mount, intromission and ejaculation latencies (ML, IL and EL, respectively), mounting and intromission frequencies (MF and IF, respectively), and postejaculatory interval (PEI). SLD N-oxide expressed similar aphrodisiac effect to SLD but with less potency. Molecular docking of SDL N-oxide along with the parent drug SLD, indicated a strong binding affinity and similar binding pattern within the active site of phosphodiesterase 5 (PDE5). However, the docking score of SLD N-oxide was slightly lower as compared to SLD in agreement with the biological study findings.
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http://dx.doi.org/10.1038/s41598-021-94854-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319155PMC
July 2021

Exploitation of Design-of-Experiment Approach for Design and Optimization of Fast-Disintegrating Tablets for Sublingual Delivery of Sildenafil Citrate with Enhanced Bioavailability Using Fluid-Bed Granulation Technique.

Pharmaceutics 2021 Jun 12;13(6). Epub 2021 Jun 12.

Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-kharj 11942, Saudi Arabia.

Sildenafil citrate undergoes first-pass metabolism, resulting in poor oral bioavailability at 25-41% of the administered dose. This study aimed to design and optimize fast-disintegrating tablets for the sublingual delivery of sildenafil citrate to improve bioavailability and facilitate rapid onset of action. The design-of-experiment (DoE) approach using 3 full factorial design was conducted to develop a new formulation of sildenafil fast-disintegrating sublingual tablets (FDSTs) using the fluid-bed granulation technique. The levels of partially pre-gelatinized starch (5-15%) and microcrystalline cellulose (10-60%) were selected as independent formulation variables. The prepared FDSTs were investigated for physical properties. Further, the optimum formulation was chosen for in vivo study in rabbits. Regression analysis showed that independent variables have a significant ( < 0.05) influence on critical attributes of FDSTs. The optimized formulation showed acceptable mechanical strength (friability < 1.0%) with very fast disintegration (14.561 ± 0.84 s) and dissolution (94.734 ± 2.76% after 15 min). Further, the optimized formulation demonstrated a significant increase ( < 0.01) in C and AUC-∞ with short t compared to the market product (Viagra). Based on these results, using the DoE approach, a high level of assurance was achieved for FDSTs' product quality and performance.
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http://dx.doi.org/10.3390/pharmaceutics13060870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231530PMC
June 2021

Solubility determination and solution thermodynamics of olmesartan medoxomil in (PEG-400 + water) cosolvent mixtures.

Drug Dev Ind Pharm 2020 Dec 19;46(12):2098-2104. Epub 2020 Nov 19.

Department of Pharmaceutical Sciences, Faculty of Pharmacy, Jadara University, Irbid, Jordan.

The solubility and solution thermodynamic properties of a weakly water-soluble compound olmesartan medoxomil (OLM) in binary 'polyethylene glycol (PEG-400) + water' cosolvent compositions were determined. The 'mole fraction solubility ( )' of OLM in binary 'PEG-400 + water' cosolvent compositions and pure solvents (PEG-400 and water) was determined at ' = 295.15-330.15 K' and ' = 0.1 MPa'. The Hansen solubility parameter (HSP) of OLM, pure PEG-400, pure water, and binary 'PEG-400 + water' cosolvent compositions free of OLM were also predicted. The obtained values of OLM were correlated using 'van't Hoff, modified Apelblat, Yalkowsky-Roseman, Jouyban-Acree and Jouyban-Acree-van't Hoff' computational models with the error values of <4.0%. The maximum and minimum value of OLM was predicted in neat PEG-400 (1.15 × 10 at  = 330.15 K) and neat water (1.90 × 10 at  = 295.15 K), respectively. The OLM HSP was predicted to be more close with that of neat PEG-400. The value of OLM was found increased significantly with increase in temperature and PEG-400 mass fraction in all 'PEG-400 + water' cosolvent compositions including neat PEG-400 and neat water. An 'apparent thermodynamic analysis' studies presented an 'endothermic and entropy-driven dissolution' of OLM in all 'PEG-400 + water' cosolvent compositions including pure PEG-400 and pure water.
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http://dx.doi.org/10.1080/03639045.2020.1847136DOI Listing
December 2020

Eluxadoline Loaded Solid Lipid Nanoparticles for Improved Colon Targeting in Rat Model of Ulcerative Colitis.

Pharmaceuticals (Basel) 2020 Sep 19;13(9). Epub 2020 Sep 19.

Department of Pharmaceutical Sciences, Faculty of Pharmacy, Jadara University, Irbid 21110, Jordan.

The aim of the current study was to evaluate the therapeutics potential of eluxadoline (ELX) loaded solid lipid nanoparticles (SLNs) in ulcerative colitis. ELX loaded SLNs were prepared using three different lipids according to the solvent emulsification technique. The optimization of prepared SLNs (F1-F3) were carried out based on size, PDI, zeta potential, percent drug entrapment (%EE), and loading (%DL). The lipid (stearic acid) based SLNs (F2) was optimized with particle size (266.0 ± 6.4 nm), PDI (0.217 ± 0.04), zeta potential (31.2 ± 5.19 mV), EE (65.0 ± 4.8%), and DL (4.60 ± 0.8%). The optimized SLNs (F2) was further evaluated by DSC, FTIR, SEM, in vitro release, and stability studies, which confirmed the successful encapsulation of ELX in SLNs. The efficacy of optimized SLNs (F2) in comparison to the pure ELX drug was assessed in acetic acid induced colitis rat models. It was observed that the delivery of ELX by SLNs alleviated the induced acetic acid colitis significantly. Thus, ELX loaded SLNs delivery to the colon has a significant potential to be developed for the treatment of ulcerative colitis.
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http://dx.doi.org/10.3390/ph13090255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7559404PMC
September 2020

Preparation, Evaluation and Bioavailability Studies of Eudragit Coated PLGA Nanoparticles for Sustained Release of Eluxadoline for the Treatment of Irritable Bowel Syndrome.

Front Pharmacol 2017 20;8:844. Epub 2017 Nov 20.

Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

Eluxadoline is a newly approved orally administered drug used for the treatment of Irritable Bowel Syndrome with Diarrhea. It is reported as a poorly water-soluble drug due to which its dissolution rate and oral bioavailability are very poor. In this work, various plain PLGA nanoparticles (NPs) (F1-F4) were prepared and optimized based on particle size, PDI, zeta potential and percent drug entrapment efficiency (EE). The developed plain NPs (F1-F4) showed average particle size ranging from 260.19 to 279.76 nm with smooth surface and EE of 17.83-56.29%. The optimized plain NPs (F3) had particle size of 273.76 ± 7.25 nm with a low PDI value 0.327, zeta potential - 30.63 ± 2.47 mV and % EE of 56.29 ± 2.56%. The optimized F3 NPs was further submitted for enteric coating using Eudragit S100 polymer and evaluated in terms of particles characterization, release and pharmacokinetic studies in rats. The bioavailability of plain and coated nanaoparticles were enhanced by 6.8- and 18.5-fold, respectively, compared to normal suspension. These results revealed that the developed coated NPs could be used for its oral delivery for an effective treatment of Irritable Bowel Syndrome with Diarrhea.
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http://dx.doi.org/10.3389/fphar.2017.00844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5702012PMC
November 2017

High throughput μ-SPE based elution coupled with UPLC-MS/MS for determination of eluxadoline in plasma sample: Application in pharmacokinetic characterization of PLGA nanoparticle formulations in rats.

J Pharm Biomed Anal 2018 Feb 28;149:172-178. Epub 2017 Oct 28.

Department of Pharmaceutics, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-kharj 11942, Saudi Arabia.

Eluxadoline is a novel μ- and κ-opioid receptor (OR) agonist and δ-OR antagonist, recently approved as a first line therapy for the treatment of irritable bowel syndrome. Due to abuse potential, poor bioavailability and high intersubject variability, a sensitive and reliable assay is prerequisite for its determination in biological samples. This work first time report the development and validation of UPLC-MS/MS assay for determination of eluxadoline in rat plasma sample using risperidone as an internal standard (IS). A high-throughput 96-well plate format μ-SPE technique was used for plasma sample extraction. The extracted samples were separated on Acquity BEH™ C column (100×2.1mm, 1.7μm) using mobile phase elution of acetonitrile: 20mM ammonium acetate (80:20, v/v) at a flow rate of 0.3mLmin. The precursor to product ion transition of m/z 570.16→118.12 (qualifier), 570.16→171.08 (quantifier) for eluxadoline, and m/z 411.18→191.07 for IS were used for MRM monitoring. The calibration curves were linear in concentration range of 0.15-50ngmL with LOD and LOQ of 0.07 and 0.15ngmL, respectively. The validation results satisfied the criteria of USFDA and SWGTOX guidelines and were within the acceptable limit. Finally, the method was successfully applied in bioavailability enhancement study of the newly developed PLGA nanoparticles and Eudragit coated PLGA nanoparticles of eluxadoline in rats.
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http://dx.doi.org/10.1016/j.jpba.2017.10.024DOI Listing
February 2018

Anticancer Efficacy of Self-Nanoemulsifying Drug Delivery System of Sunitinib Malate.

AAPS PharmSciTech 2018 Jan 15;19(1):123-133. Epub 2017 Jun 15.

Department of Pharmaceutics, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh, 11451, Saudi Arabia.

Sunitinib malate (SM) is reported as a weakly soluble drug in water due to its poor dissolution rate and oral bioavailability. Hence, in the current study, various "self-nanoemulsifying drug delivery systems (SNEDDS)" of SM were prepared, characterized and evaluated for the enhancement of its in vitro dissolution rate and anticancer efficacy. On the basis of solubilization potential of SM in various excipients, "Lauroglycol-90 (oil), Triton-X100 (surfactant) and Transcutol-P (cosurfactant)" were selected for the preparation of SM SNEDDS. SM-loaded SNEDDS were developed by spontaneous emulsification method, characterized and evaluated for "thermodynamic stability, self-nanoemulsification efficiency, droplet size, polydispersity index (PDI), zeta potential (ZP), surface morphology, refractive index (RI), the percent of transmittance (% T) and drug release profile." In vitro dissolution rate of SM was significantly enhanced from an optimized SNEDDS in comparison with SM suspension. The optimized SNEDDS of SM with droplet size of 42.3 nm, PDI value of 0.174, ZP value of -36.4 mV, RI value of 1.339, % T value of 97.3%, and drug release profile of 95.4% (after 24 h via dialysis membrane) was selected for in vitro anticancer efficacy in human colon cancer cells (HT-29) by MTT assay. MTT assay indicated significant anticancer efficacy of optimized SM SNEDDS against HT-29 cells in comparison with free SM. The results of this study showed the great potential of SNEDDS in the enhancement of in vitro dissolution rate and anticancer efficacy of poorly soluble drug such as SM.
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http://dx.doi.org/10.1208/s12249-017-0826-xDOI Listing
January 2018

New gentle-wing high-shear granulator: impact of processing variables on granules and tablets characteristics of high-drug loading formulation using design of experiment approach.

Drug Dev Ind Pharm 2017 Oct 19;43(10):1584-1600. Epub 2017 May 19.

a Department of Pharmaceutics, College of Pharmacy , Prince Sattam Bin Abdulaziz University , Al-kharj , Saudi Arabia.

The aim of this work was to study the application of design of experiment (DoE) approach in defining design space for granulation and tableting processes using a novel gentle-wing high-shear granulator. According to quality-by-design (QbD) prospective, critical attributes of granules, and tablets should be ensured by manufacturing process design. A face-centered central composite design has been employed in order to investigate the effect of water amount (X), impeller speed (X), wet massing time (X), and water addition rate (X) as independent process variables on granules and tablets characteristics. Acetaminophen was used as a model drug and granulation experiments were carried out using dry addition of povidone k30. The dried granules have been analyzed for their size distribution, density, and flow pattern. Additionally, the produced tablets have been investigated for; weight uniformity, breaking force, friability and percent capping, disintegration time, and drug dissolution. Results of regression analysis showed that water amount, impeller speed and wet massing time have significant (p < .05) effect on granules and tablets characteristics. However, the water amount had the most pronounced effect as indicated by its higher parameter estimate. On the other hand, water addition rate showed a minimal impact on granules and tablets properties. In conclusion, water amount, impeller speed, and wet massing time could be considered as critical process variables. Thus, understanding the relationship between these variables and quality attributes of granules and corresponding tablets provides the basis for adjusting granulation variables in order to optimize product performance.
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http://dx.doi.org/10.1080/03639045.2017.1326930DOI Listing
October 2017

Development and evaluation of PLGA polymer based nanoparticles of quercetin.

Int J Biol Macromol 2016 Nov 2;92:213-219. Epub 2016 Jul 2.

Center of Excellence in Biotechnology Research (CEBR), King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia.

Quercetin is the most abundant antioxidant found in the human diet. Low aqueous solubility of quercetin limits its bioavailability and hence therapeutic effects. Therefore, the aim of the present study was to develop a poly lactide-co-glycolic acid (PLGA) polymer based nanoparticles of quercetin with a view to improve its aqueous solubility and examine the effect on its antioxidant and diuretic properties. Nanoparticles of quercetin were developed by single emulsion-solvent evaporation technique and evaluated in vitro for differential scanning calorimetry (DSC), Fourier transforms infra-red (FTIR) spectroscopy, particle size, polydispersity index and drug entrapment efficiency. Among the five different formulations (F1, F2, F3, F4 and F5), F2 and F3 were optimized with an average particle size of 189nm and 186nm and high entrapment values of 86.48%, 83.71%, respectively. SEM images of confirmed that prepared nanoparticles were spherical in shape with a smooth surface. In vitro release and anti-oxidant activity confirmed significant results. Furthermore, its in vivo diuretic activity was much better as compared to pure quercetin. The overall results suggest that PLGA polymer based nanoparticle could be a potential option for quercetin delivery.
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http://dx.doi.org/10.1016/j.ijbiomac.2016.07.002DOI Listing
November 2016

Enhanced oral bioavailability of insulin-loaded solid lipid nanoparticles: pharmacokinetic bioavailability of insulin-loaded solid lipid nanoparticles in diabetic rats.

Drug Deliv 2016 Jul 27;23(6):1972-9. Epub 2015 May 27.

b Department of Pharmacology , College of Pharmacy, Prince Sattam Bin Abdulaziz University , Al-kharj , Kingdom of Saudi Arabia.

Objective: Insulin is a hormone used in the treatment of diabetes mellitus. Multiple injections of insulin every day may causes pain, allergic reactions at injection site, which lead to low patient compliance. The aim of this work was to develop and evaluate an efficient solid lipid nanoparticle (SLN) carrier for oral delivery of insulin.

Methods: SLNs were prepared by double emulsion solvent evaporation (w/o/w) technique, employing glyceryltrimyristate (Dynasan 114) as lipid phase and soy lecithin and polyvinyl alcohol as primary and secondary emulsifier, respectively, and evaluated in vitro for particle size, polydispersity index (PDI) and drug entrapment.

Results: Among the eight different developed formulae (F1-F8), F7 showed an average particle size (99 nm), PDI (0.021), high entrapment of drug (56.5%). The optimized formulation (F7) was further evaluated by FT-IR, DSC, XRD, in vitro release, permeation, stability, bioavailability and pharmacological studies. Insulin-loaded SLNs showed better protection from gastrointestinal environment as evident from the relative bioavailability, which was enhanced five times as compared to the insulin solution. A significant enhancement of relative bioavailability of insulin was observed, i.e. approximately five times of pure insulin solution when loaded in SLN (8.26% versus 1.7% only).
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http://dx.doi.org/10.3109/10717544.2015.1039666DOI Listing
July 2016
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