simin dadashzadeh
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Background
Lately, there has been increasing interest in the benefits of metal-organic frameworks, and among them, zeolitic imidazolate frameworks (ZIF - 8) stand out as one of the most commonly employed systems owing to their unique characteristics.
ObjectivesGiven that properties like particle size play a key role in biomedical applications of nanoparticles, optimizing the synthesis conditions becomes crucial. Additionally, it is essential to label these nanoparticles to track them effectively within the body.
MethodsZeolitic imidazolate frameworks nanoparticles were synthesized under various conditions, including high and room temperature, using two different solvents: Water and methanol. Modifications were made to the reaction temperature and the ratio of reactants to improve the outcomes. Particle size and size distribution were assessed in all conditions. Additionally, the radiolabeling of nanoparticles was examined using four different methods to identify the method with the highest efficiency and radiochemical purity.
ResultsThe optimum conditions for ZIF-8 synthesis were determined at 50°C using methanol as the solvent. A reactant weight ratio of 1: 2 (zinc nitrate to 2-methylimidazole) was utilized. The most effective radiolabeling approach involved using tin chloride as a reducing agent, with the reaction mixture maintained at a temperature of 70°C for 30 minutes.
ConclusionsIn this study, the optimum conditions were successfully identified for synthesizing and labeling ZIF-8 nanoparticles. These nanoparticles have the potential to serve as effective carriers for diagnostic and therapeutic agents.
Keywords: Metal-Organic Frameworks, Synthesis, Radiolabeling, Optimization -
Background
Amphotericin B (AmB) is the first-line drug to treat invasive fungal infections. However, its delivery to the body and clinical use faces many challenges because of its poor solubility, poor pharmacokinetics, and severe nephrotoxicity.
ObjectivesDue to the necessity for designing safer and more effective nanocarriers for AmB and the importance of preclinical pharmacokinetic studies in evaluating these novel drug delivery systems, the present study was framed to explore the influence of rat strain on the pharmacokinetic profile of this drug.
MethodsTwenty-four Wistar and Sprague–Dawley (SD) rats were intravenously injected with 1 mg/kg AmB as Fungizone or AmBisome, which are the two most commonly marketed formulations of the drug. Blood samples were collected before and at regular intervals up to 24 h after administration. Drug concentration was analyzed by a validated HPLC method, and pharmacokinetic parameters were determined by the non-compartmental method.
ResultsIrrespective of the type of formulation, the AUC0-t and AUC0-∞ values were significantly higher (P < 0.001), and Cl as an important PK parameter was markedly lower (P < 0.001) in SD rats compared to the Wistar strain. For Fungizone, the mean Cl values in SD and Wistar rats were 206.90 and 462.95 mL/h/kg (P < 0.001), respectively. The apparent volume of distribution (Vss) was also lower in SD rats compared to Wistar; however, for AmBisome, the difference in Vss was not statistically significant. Our further investigation suggested that the higher amount of total protein in the SD strain may justify the higher plasma concentrations and lower Cl and Vss of amphotericin B in this strain compared to the Wistar strain.
ConclusionsOverall, following intravenous administration of AmB, there were significant differences in the pharmacokinetic parameters of the drug between two rat strains for both formulations. The obtained data is important for correctly interpreting experimental data from different research groups.
Keywords: Amphotericin B, Pharmacokinetics, Inter-Strain Differences, Wistar Rat, Sprague–Dawley Rat -
Background
Cerasomes, due to their external siloxane network, demonstrate markedly higher physicochemical stability and, therefore, easier handling and storage than liposomes.
ObjectivesThe main objective of this study was to compare the pharmacokinetics (PK) of cerasome and liposome following intravenous administration. The PK of PEGylated and non-PEGylated cerasomes was also compared to see whether the presence of a hydrophilic siloxane network on the surface of cerasomes can play the role of polyethylene glycol (PEG) in increasing the blood circulation of these vesicles.
MethodsSilver sulfide (Ag2S) quantum dots (Qds)-loaded PEGylated and non-PEGylated cerasomes and PEGylated liposomes were fabricated and thoroughly characterized in terms of particle size, polydispersity index, zeta potential, entrapment efficiency, and in vitro stability. For pharmacokinetic evaluation, the free Qds and the selected formulations were intravenously injected into rats, and blood samples were collected for up to 72 hours. Pharmacokinetic parameters were calculated by the non-compartmental method.
ResultsBoth cerasomal and liposomal carriers significantly improved the PK of Qds. For example, the elimination half-life (t1/2) and the area under the plasma concentration-time curve from time 0 to time infinity (AUC0-∞) for the free Qds were 4.39 h and 8.01 µg/mL*h and for cerasomal and liposomal formulations were 28.82 versus 26.95 h and 73.25 versus 62.02 µg/mL*h, respectively. However, compared to each other, the plasma concentration-time profiles of PEGylated cerasomes and liposomes displayed similar patterns, and the statistical comparison of their pharmacokinetic parameters did not show any significant difference between the two types of carriers. For PEGylated cerasomes, t1/2 and AUC0-∞ values were respectively 1.6 and 3.3 times greater than the classic cerasome, indicating that despite the presence of a hydrophilic siloxane network, the incorporation of PEG is necessary to reduce the clearance of cerasomes.
ConclusionsThe comparable PK of PEGylated cerasomes and liposomes, along with the higher physicochemical stability of cerasomes, can be considered an important advantage for the clinical application of cerasomes. Additionally, the easy surface functionalizing ability of cerasomes confers a dual advantage over liposomes. The study findings also showed that the presence of a hydrophilic siloxane network on the surface of cerasomes alone is not enough to make them circulate long.
Keywords: Cerasomes, Pharmacokinetics, Liposomes, PEGylated, Siloxane Network, Ag 2 S Qds -
Background
Efavirenz nanosuspensions (EZ-NSs) were developed by the wet milling method as the most promising top-down nanosizing technique. Different process and formulation parameters were studied and optimized to produce appropriate EZ-NS in suitable conditions to enhance drug dissolution.
MethodsIn the preliminary studies, various polymeric stabilizers, including Pluronic F68, sodium carboxymethylcellulose (CMC), hydroxypropyl methylcellulose (HPMC), and polyvinyl alcohol (PVA), as well as different sizes and weight of milling beads were used to prepare NSs. The effect of sodium lauryl sulfate (SLS) concentration on the NS properties was also evaluated. The influence of other formulation and process parameters, including polymer concentration, milling speed, and milling time, on the particle size and distribution of NSs were investigated using Box-Behnken design. The optimized freeze-dried nanosuspension was characterized by redispersibility, physicochemical properties, and stability.
ResultsA combination of PVA and SLS was selected as steric and electrostatic stabilizers. The optimum EZ-NS displayed a uniform size distribution with a mean particle size and zeta potential of 254.4 nm and 21.1 mV, respectively. The solidified nanosuspension was well redispersed to the original nanoparticles. Significantly enhanced aqueous solubility (about 11-fold) and accelerated dissolution rate were observed for the optimized formulation. This could be attributed to the reduced particle size and partial amorphization of EZ during the preparation process, studied by X-ray diffraction. Accelerated studies confirmed the stability of the optimum freeze-dried formulation over the examined period of three months.
ConclusionsOptimization of different variables led to the formation of EZ-NSs with desired properties through wet milling in a very short time compared to the previous study and therefore reduced production costs. This formulation seems to be a suitable approach for solubility and dissolution enhancement of EZ and may have a great potential to improve the drug's oral bioavailability.
Keywords: Efavirenz, Nanosuspension, Wet Milling, Optimization, Box-Behnken, Dissolution -
Background
Despite the advantages of direct intratumoral (IT) injection, the relatively rapid withdrawal of most anti-cancer drugs from the tumor due to their small molecular size limits the effectiveness of this method of administration. To address these limitations, recently, increasing attention has been directed to using slow-release biodegradable delivery systems for IT injection.
ObjectivesThis study aimed to develop and characterize a doxorubicin-loaded DepoFoam system as an efficient controlled-release carrier to be employed for locoregional drug delivery in cancer treatment.
MethodsMajor formulation parameters, including the molar ratio of cholesterol to the main lipid [Chol/egg phosphatidylcholine (EPC)], triolein (TO) content, and lipid-to-drug molar ratio (L/D), were optimized using a two-level factorial design approach. The prepared batches were evaluated for encapsulation efficiency (EE) and percentage of drug release (DR) after 6 and 72 hours as dependent variables. The optimum formulation (named DepoDOX) was further evaluated in terms of particle size, morphology, zeta potential, stability, Fourier-transform infrared spectroscopy, in vitro cytotoxicity, and hemolysis.
ResultsThe analysis of factorial design indicated that TO content and L/D ratio had a negative effect on EE; between these two, TO content had the greatest effect. The TO content was also the most significant component, with a negative effect on the release rate. The ratio of Chol/EPC showed a dual effect on the DR rate. Using a higher percentage of Chol slowed down the initial release phase of the drug; nevertheless, it accelerated the DR rate in the later slow phase. DepoDOX were spherical and honeycomb-like structures (≈ 9.81 μm) with a desired sustained release profile, as DR lasted 11 days. Its biocompatibility was confirmed by the results of cytotoxicity and hemolysis assays.
ConclusionsThe in vitro characterization of optimized DepoFoam formulation demonstrated its suitability for direct locoregional delivery. DepoDOX, as a biocompatible lipid-based formulation, showed appropriate particle size, high capability for encapsulating doxorubicin, superior physical stability, and a markedly prolonged DR rate. Therefore, this formulation could be considered a promising candidate for locoregional drug delivery in cancer treatment.
Keywords: Multivesicular Liposomes, Doxorubicin, Intratumoral Injection, Drug Delivery, Locoregional -
Allogeneic hematopoietic stem cell transplantation (AHSCT) is a major method of treatmentfor different hematologic and congenital disease. Graft versus host disease (GvHD) is a lifethreateningadverse effect of AHSCT. Cyclosporine is the most important and common agentfor GvHD prophylaxis. Because of variable and unpredictable pharmacokinetics of cyclosporinethat produces different responses in each patients group and clinical setting, there are still lots ofuncertainties about its optimal method of administration and monitoring of this drug. Frequentblood samples in eight different times were taken for cyclosporine quantification in twentyAHSCT recipients and pharmacokinetic parameters determined in both intravenous (IV) and oraladministration and monitoring parameters assessed accordingly. Of pharmacokinetic parametersmean ± SD area under concentration – time curve (AUC), clearance, and half-life were estimatedto be 5492 ± 1596 ng.h/mL, 19.44 ± 6.61 L/h, and 11.8 ± 5.4 h for IV and 7637.7 ± 2739.8 ng.h/mL, 19.42 ± 6.62 L/h, and 11.16 ± 5.9 h for oral administration, respectively. Appropriate oral tointravenous dosing ratio found to be about 1.6. Of monitoring parameters, C0.5 h and C6 showedthe highest coefficient of determination for regression between single points and total area undercurve. Evaluation of pharmacokinetic parameters derived from concentration versus time curveshowed that the appropriate oral/IV is 1.6 for maintenance GvHD prophylaxis for outpatientscould be helpful. Cyclosporine plasma concentration at 0.5 and 6 h after IV administrationshowed the highest correlation with AUC of this drug.
Keywords: cyclosporine, Pharmacokinetics, hematopoietic stem cell transplantation, graft versus host disease, Oral, Intravenous -
هدف
کورکومین، یک ترکیب پلی فنولی آبگریز است و دارای طیف گسترده ای از کاربردهای بیولوژیکی از جمله درمان سرطان می باشد.اما کاربرد برجسته آن در معالجه سرطان به دلیل حلالیت و فراهمی زیستی ضعیف محدود شده است. سیکلودکسترین ها نانوکپسول های طبیعی تشکیل شده از واحد های گلوکزی هستند، یکی از خصوصیات آنها ایجاد کمپلکس با مولکول های مهمان آبگریز در نانو حفره خود می باشد. در این مطالعه، به منظور بهبود حلالیت، فراهمی زیستی و اثربخشی کورکومین، کمپلکس های گنجایشی β-سیکلودکسترین-کورکومین تهیه و اثر آن روی سلول های سرطانی و نرمال بررسی شد.
مواد و روش هادر این مطالعه ابتدا کمپلکس های β-سیکلودکسترین-کورکومین توسط روش فریزدرای تهیه و تشکیل این کمپلکس ها توسط طیف سنجی فلویورسانس بررسی شد. سپس بازده انکپسولاسیون کورکومین در β-سیکلودکسترین در هر غلظت محاسبه گردید. بعد از بررسی رهایش کورکومین از β-سیکلودکسترین در دماهای مختلف، میزان تاثیرگذاری این کمپلکس ها روی سلول های سرطانی و سالم با استفاده از آزمون MTT بررسی شد.
یافته هابازده کپسوله سازی کورکومین در β-سیکلودکسترین 32/1±92/33 درصد است. مطالعات طیف سنجی فلویورسانس تشکیل یک کمپلکس گنجایشی پایدار را تایید کرد. نتایج نشان داد، رهایش کورکومین از β-سیکلودکسترین در شرایط دمایی سلول های سرطانی (°C 42) نسبت به سلول های سالم و دمای محیط بیشتر است. نتایج آزمون MTT نشان داد که کورکومین کپسوله شده در β-سیکلودکسترین اثر مهارکنندگی چشمگیری نسبت به کورکومین آزاد بر تکثیر سلول های سرطانی دارد.
نتیجه گیرینتایج، شواهد قابل قبولی در مورد اثر بازدارنده تکثیر سلولی کمپلکس های β-سیکلودکسترین-کورکومین، روی رده های سرطانی نشان داد در حالی که اثر قابل توجهی روی سلول های سالم مشاهده نشد.
کلید واژگان: کورکومین، β-سیکلودکسترین، کمپلکس های گنجایشی، سرطانAimsCurcumin (CUR) is a hydrophobic polyphenol compound and possesses a wide range of biological applications including cancer therapy. However, its prominent application in cancer treatment is limited due to poor solubility and bioavailability. Cyclodextrins (CDs) as natural nanocapsules are comprised of glucose units. One of the characteristics of them are created complex with hydrophobic guest molecules in nanopores. In this study, in order to improve the solubility, bioavailability and efficacy of CUR, we have prepared β-cyclodextrin-curcumin (β-CD-CUR) inclusion complexes and its effect on cancer and normal cells was examined.
Materials & MethodsIn this study, first β-CD-CUR complexes were prepared using freeze-drying method and formation of these complexes were characterized by fluorescence spectroscopy. The encapsulation efficiency of CUR in β-CD was calculated for each concentration. After investigating the release of CUR from β-CD at different temperatures, therapeutic effects of β-CD-CUR inclusion complexes for cancer and normal cell lines were evaluated by MTT assay.
FindingsThe CUR encapsulation efficiency in β-CD was 33.92 ± 1.32%. Fluorescence spectroscopic studies confirmed formation of stable inclusion complex. The results also showed that CUR release from β-CD was higher in thermal conditions of cancer cells (42 ° C) than in normal cells and ambient temperatures. The results of MTT assay showed that encapsulated CUR in β-CD had a significant inhibitory effect on proliferation of cancer cells compared to free CUR.
Conclusionresults provided acceptable evidence for cell proliferation inhibition of β-CD-CUR complexes on cancer cells. There were no adverse effects detected for normal cells.
Keywords: Curcumin, β-cyclodextrin, Inclusion complexes, Cancer -
The present study aimed at exploring the potential of the P-glycoprotein (P-gp) transporters as a barrier to the repaglinide (REG) epithelial permeability. In-vitro intestinal absorption models, the everted gut sac, and Caco-2 cell line, were used to study the possible role of P-gp in intestinal transport of REG. In the everted gut sacs, apparent permeability coefficients showed cargo concentration dependency transport over the concentration of 40 µM, indicating involvement of a saturable mechanism in REG absorption (Papp were 1.23 × 10 -5and 3.29 × 10 -5at drug concentrations of 40 and 100 μM, respectively). Adding verapamil (100 μM), valspodar (5 μM) and ketoconazole (10 μM) significantly enhanced the permeability of REG across mucosal to serosal in the rat jejunum (P < 0.05) suggesting role of CYP 3A4 and/or efflux transporters in oral bioavailability of REG. However, the results of Caco-2 cell experiments indicated low efflux ratios (less than 2) and insignificant involvement of P-gp efflux pumps in REG intestinal transport. Given that Caco-2 cells do not express adequate level of CYP 3A4, the current study suggests that the presystemic metabolism by cytochrome P450 (and not ejection by P-gp) may play a significant role in limiting the oral absorption of REG in small intestine.Keywords: Repaglinide, Caco-2 Cells, Everted gut sac, P-glycoprotein, Permeability
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Poor penetration of vancomycin into Central Nervous System (CNS) can lead to treatmentfailure. The aim of this study was to evaluate and compare CSF concentration and serumpharmacokinetics of high dose vancomycin by continuous infusion vs. intermittent infusion inpost neurosurgical meningitis patients. Twenty patients were divided into two groups. Patientsin intermittent infusion group received vancomycin as a loading dose of 25 mg/kg over twohours, followed by 25 mg/kg over two hours every 12 h. In the Continuous Infusion group,patients received vancomycin as a loading dose of 25 mg/kg over two hours, followed by 50mg/kg/day by continuous infusion. In the intermittent infusion group, mean ± SD of serumtrough, peak and CSF concentrations were 17.49 ± 2.46 mg/L, 41.33 ± 2.73 mg/L, and 4.83± 1.05 mg/L, respectively. Mean of CSF/trough% ratio was 27.39 ± 2.43%. A positive linearcorrelation was found between the serum trough levels and CSF levels (r = 0.970, P < 0.001).In continuous infusion group, mean ± SD of serum and CSF concentrations were 24.76 ± 2.02mg/L and 6.20 ± 1.31 mg/L respectively. Mean ± SD of CSF/serum% ratio was 24.84% ±3.54%. The serum and CSF levels revealed positive linear correlation (r = 0.902, P < 0.001).The mean of CSF concentration in CI group was 6.20 ± 1.31 mg/L which was significantlyhigher than II group (4.83 ± 1.05 mg/L, P < 0.019). CSF/serum ratio did not show anysignificant difference between the two groups. Continuous infusion of vancomycin makes itpossible to achieve faster and constant target level in serum but did not have any significanteffect on the penetration (CSF/Serum ratio) of vancomycin in to the CNS.Keywords: Vancomycin, Pharmacokinetics, Meningitis, Infusions, Central Nervous System
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The aim of current study was to investigate the effect of Brij decoration of liposomes on in vitro and in vivo characteristics of the nanocarriers. Two hydrophilic Brij surfactants (Brij 35 and Brij 78) with almost similar molecular weight but differing in acyl chain were incorporated into liposomal bilayers at two percentages (5% and 10%). Conventional liposomes (CL) containing egg phosphatidylcholine and cholesterol as well as Brij-enriched liposomal dispersions were prepared and characterized. In vivo pharmacokinetics of various liposomal formulations and drug solution (six groups) was studied after intravenous administration to rats. Conventional and Brij enriched DOX liposomes had small size within 82-97 nm and showed homogenous distribution (PDI < 0.1). Drug encapsulation was higher than 97% in all liposomes. The drug release profiles proved sustained DOX release from various formulations. Based on the results of in vivo studies, all five liposomes increased drug exposure and plasma concentration in comparison to free drug. However, DOX liposomes enriched with 5% of either Brij 35 or Brij 78 showed higher AUC values and lower clearance. Overall, Brij surfactants (5% of bilayer lipids) could potentially be used to improve liposomal pharmacokinetic parameters.Keywords: liposomes, Pharmacokinetics, Brij, doxorubicin, stealth properties
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The present study was conducted to investigate the performance of different size reduction techniques including probe sonication, extrusion, and high pressure homogenization for nanosizing of niosomes. Also, the effects of cholesterol content and surfactant type on the size and poly dispersity index (PDI) of the formulations were evaluated. Various niosomal formulations composed of Brij 72, Span 60, or Tween 60 were prepared and then, to reduce vesicle size and minimize the PDI, the niosomes were treated by various post-processing procedures. Surfactant type showed a significant effect on the particle size of the niosomes. The particle size of Tween 60 niosomes was significantly larger than those of Span 60 and Brij 72 niosomes (P < 0.05), indicating that at the same cholesterol content, niosomes composed of a surfactant with a higher HLB value show larger particle size than those with a lower HLB value. The influences of cholesterol content as well as downsizing methods, on the particle size and distribution of niosomes were significantly dependent on the surfactant composition of the niosomes. Extrusion and probe sonication were found to be the most efficient methods for size reduction of the Tween 60 and Span 60 niosomes, while for downsizing of Brij 72 niosomes, all employed methods were efficient and resulted in the approximately similar size of about 200 nm. In conclusion, the selection of an efficient method for nanosizing of niosomes and also achievement of a desired size range, and homogeneity highly depends on the niosome composition, particularly on the employed surfactant type.Keywords: Particle size, Niosomes, Probe sonication, Extrusion, High pressure homogenizer
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Nonsteroidal anti-inflammatory drugs (NSAIDs) act mainly via inhibition of prostaglandins synthesis by inhibition of cyclooxygenase (COX) isoenzymes (COX1 and COX 2). Selective COX-2 inhibitors which are also known as coxibs provide the main therapeutic effects of NSAIDs. Zarghi et al. reported 6-benzoyl-2-(4-(methylsulfonyl)phenyl)quinoline-4-carboxylic acid (AZGH 101) as a novel derivative of ketoprofen with improved selectivity index (COX-1/COX-2 inhibitory potency) in comparison with ketoprofen.
In this study the log P and stability of AZGH 101 was evaluated and the pharmacokinetic characteristics of this compound were investigated following intravenous (10 mg/kg), and oral administration (20 mg/kg), to Wistar rats.
As the data demonstrated the AZGH 101 classified as lipid soluble compound and had suitable stability according to forced degradation protocol ICH guideline for new drug substance. This derivative absorbs, distributes and eliminates similar in both sexes. The AUC 0-∞, absolute bioavailability, Cl and Vd were not different in both sexes.
According to the obtained data the AZGH 101 has not a sex dependent pharmacokinetic in Wistar rats.Keywords: pharmacokinetic, ketoprofen, selective COX-2 inhibitors, AZGH 101, Wistar rat -
Specific delivery of therapeutic agents to solid tumors and their bioavailability at the target site are the most clinically important and challenging goals in cancer therapy. Liposomes are promising nanocarriers and have been well investigated for cancer therapy. In spite of preferred accumulation in tumors via the enhanced permeability and retention (EPR) effect, inefficient drug release at the target site and endosomal entrapment of long circulating liposomes are very important obstacles for achieving maximum anticancer efficacy. Thus, additional strategies such as stimulus-sensitive drug release are necessary to improve efficacy. Stimuli-sensitive liposomes are stable in blood circulation, however, activated by responding to external or internal stimuli and control the cargo release at the target site. This review focuses on state of the art of stimuli-responsive liposomes. Both external stimuli-responsive liposomes, including hyperthermia (HT), magnetic, light, and ultrasound-sensitive liposomes and internal stimuli (pH, reduction, and enzyme) responsive liposomes are covered.Keywords: Liposomes, Cancer, Stimuli-responsive, Thermosensitive, Magnetoliposomes, Light, Ultrasound, pH, Redox, Enzyme
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Nanocrystals of tadalafil, a poorly water-soluble drug, were successfully prepared by sonoprecipitation technique for improving the solubility and dissolution rate. Tween80 was selected as an efficient surfactant to inhibit aggregation in stabilization of drug nanocrystals. Response surface methodology based on central composite design (CCD) was utilized to evaluate the formulation factors affecting the size of nanosuspensions. Under optimum conditions, relatively spherical nanocrystals with a mean particle size of 358.47±11.95 nm were obtained. FTIR analysis indicated that the precipitated nanoparticles had the same chemical structure as the raw tadalafil. By DSC analysis, no substantial crystalline change was found in the nanocrystals compared with the unprocessed drug. In addition, the dissolution rate of the processed tadalafil nanocrystals in 120 min was significantly increased (3.61-fold) as compared to that of the raw material. Therefore, it was concluded that the sonoprecipitation technique could be a simple and useful technique to prepare poorly water-soluble drug particles with reduction in particle size, a narrow particle size distribution and enhanced dissolution properties.Keywords: tadalafil, poorly water-soluble drug, antisolvent precipitation-ultrasonication method, Nanocrystals, dissolution enhancement
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Coxibs such as celecoxib, rofecoxib and valdecoxib are introduced as selective COX-2 inhibitors to the market. It has been reported that inhibition of COX-2 beside traditional effects of NSAIDs, reduces the risk of colorectal, breast and lung cancers and slow the progress of Alzheimers disease. Zarghi et al. reported 8-benzoyl-2-(4-(methylsulfonyl)phenyl)quinoline-4-carboxylic acid (AZGH 102) as a novel compound with similar IC50 to celecoxib besides improved selectivity index (COX-1/COX-2 inhibitory potency) in comparison with celecoxib.
In this study the physicochemical properties of AZGH 102 such as solubility, log P and stability was evaluated and the pharmacokinetic characteristics of this compound following intravenous (10 mg/kg), and oral administration (20 mg/kg), to male and female Wistar rats were investigated.
As the data demonstrated the AZGH 102 classified as lipophil compound and had suitable stability. This derivative absorbs and distributes faster in female than male. The AUC 0-∞, absolute bioavailability, Cl and Vd were different in both sexes.
According to the obtained data the AZGH 102 has a sex dependent pharmacokinetic in Wistar rats.Keywords: pharmacokinetic, sex-dependent, ketoprofen, selective COX-2 inhibitors, AZGH 102 -
Glaucoma is a common progressive eye disorder and the treatment strategies will benefit from nanoparticulate delivery systems with high drug loading and sustained delivery of intraocular pressure lowering agents. Niosomes have been reported as a novel approach to improve drug low corneal penetration and bioavailability characteristics. Along with this, poor entrapment efficiency of hydrophilic drug in niosomal formulation remains as a major formulation challenge. Taking this perspective into consideration, dorzolamide niosomes were prepared employing two different loading methodologies (passive and remote loading methods) and the effects of various formulation variables (lipid to drug ratio, cholesterol percentage, drug concentration, freeze/thaw cycles, TPGS content, and external and internal buffer molarity and pH) on encapsulation efficiency were assessed. Encapsulation of dorzolamide within niosomes increased remarkably by the incorporation of higher cholesterol percentage as well as increasing the total lipid concentration. Remote loading method showed higher efficacy for drug entrapment compared to passive loading technique. Incorporation of TPGS in bilayer led to decrease in EE, however, retarded drug release rate. Scanning electron microscopy (SEM) studies confirmed homogeneous particle distribution and spherical shape with smooth surface. In conclusion, the highest encapsulation can be obtained using phosphate gradient method and 50% cholesterol in Span 60 niosomal formulation.Keywords: Niosome, glaucoma, dorzolamide, thin film hydration method, phosphate gradient method
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BackgroundCervical cancer has been shown to be highly associated with human papillomavirus (HPV) infection. The viral oncogenes E6 and E7 are constantly expressed by the tumor cells and are therefore potent targets for therapeutic genetic vaccination. In the present study, it was investigated the potential effect of HPV-16 E6, E7 and L1 co-administration to activate specific cytotoxic T lymphocytes in tumor mice models.MethodsThe HPV-16 E6, E7 and L1 genes from Iranian isolate were separately inserted into the mammalian expression vector, pcDNA3, to construct the DNA vaccine candidates. Tumor-bearing Animals (C57BL/6 mice) were immunized with the vaccine candidate; then, Lymphocyte Proliferation Assay (LPA) and relative tumor volume measurements were carried out in order to examine the immunological effects of the vaccine.ResultsObtained results showed that co-administration of the HPV-16 E6, E7 and L1 DNA induced HPV-16 specific cellular immune responses and also protected against TC-1-induced tumor in vivo compared with negative controls.ConclusionThe results showed that mixed delivery systems might be valuable to improve the magnitude of the induced immune responses and confirmed therapeutic effects of HPV-16 E6, E7 through cytotoxic T lymphocyte induction and illustrate the new promising role for HPV-16 L1 CTL epitopes as a suitable CTL inducer.Keywords: pcDNA3, E6, pcDNA3, E7, pcDNA3, L1, immunocellular responses
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A validated HPLC method was developed to determine doxorubicin concentration in a small volume of rat plasma (60 µl) with convenient fluorescence detection. Sample preparation includes a simple one-step liquid-liquid extraction using minimum amount of organic solvent, with extraction recoveries more than 95%. The analysis was accomplished using PerfectSil C18 column maintained at 35 °C and a mobile phase consisted of acetonitrile and water (32:68, v/v; pH=2.6). The flow-rate was kept at 1 mL/min and column effluent was monitored with a fluorescence detector at an excitation and emission wavelength of 470 and 555 nm, respectively. The detection limit was 5 ng/mL. No analytical interference was observed from endogenous components in rat plasma. This method was feasibly applied to the pharmacokinetic study of 5 mg/kg of doxorubicin after intravenous administration to rats.Keywords: Doxorubicin, HPLC, Fluorescence, Pharmacokinetics, Rat plasma
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A bioequivalence study of two verapamil formulations (generic verapamil tablets and Isoptin® tablets) was performed by comparing pharmacokinetic parameters of the parent drug and its major metabolite, norverapamil following a single dose administration of 80 mg verapamil hydrochloride in 22 healthy volunteers according to a randomized, two-period, crossover-design study. Moreover, the feasibility of proving bioequivalence of verapamil oral dosing form by means of norverapamil pharmacokinetic parameters was evaluated. Concentrations of verapamil and norverapamil were quantified in plasma using a validated high-performance liquid chromatography (HPLC) with fluorescence detection. The 90% CIs for the log-transformed ratios of verapamil Cmax and AUC0–∞ were 73 to 101 and 80 to 103, respectively. Similarly, the corresponding ranges for norverapamil were 80-100 and 84-103, respectively. According to the parent drug data, the 90% confidence intervals around the geometric mean ratio of AUC happened to fit within preset bioequivalence limits of 80–125%, whereas those for Cmax did not. The 90% confidence intervals for both Cmax and AUC of norverapamil met preset bioequivalence limits. The AUC and Cmax of metabolite, when compared to parent drug, showed a much lower degree of variability and the 90% confidence intervals of the metabolite were therefore narrower than those of the parent drug. These observations indicate that bioequivalence studies using metabolite, norverapamil, could be a more suitable and preferable approach to assess bioequivalence of verapamil formulations due to its much lower variability and therefore lower number of volunteers that are required to conduct the study.Keywords: Bioequivalence study, Pharmacokinetics, Verapamil, Norverapamil, High variability
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Chemotherapy research highly prioritizes overcoming the multidrug resistance (MDR) in human tumors. Liposomal formulation of fluoxetine, as a fourth generation chemosensitizer, was constructed and characterized for percent entrapment, release profile, morphology, particle size, zeta potential and stability. Liposomes were prepared using different active loading techniques. The influence of different formulation variables such as loading methodology, type of main lipid, addition of PEGylated lipid and cholesterol percentage was evaluated to achieve required entrapment efficiency, in vitro release behavior and stability. The studied parameters had significant effect on physicochemical characteristics of the nanocarriers. High fluoxetine encapsulation efficiency (83% ± 3%) and appropriate particle size (101 ± 12 nm) and zeta potential (-9 ± 2 mv) were achieved for PEGylation liposomes composed of DSPE-PEG, DSPC and cholesterol at respective molar ratio of 5:70:25. An in vitro fluoxetine release of about 20% in 48 h was observed from optimum formulation. Atomic force microscopy (AFM) studies confirmed homogeneous distribution of particles and spherical shape with smooth surface. The optimum formulation was stable for 9 days when incubated at 37°C. The results of this study are very encouraging for application of the developed fluoxetine liposomal formulation in drug-resistant tumor models.Keywords: Fluoxetine, Nanoliposomes, Formulation parameters, PEGylation, Drug, resistant tumors
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The purpose of the present study was to investigate the effect of polyethylene glycol (PEG) molecular weights (6000, 12000 and 20000) as solid dispersion (SD) carriers on the dissolution behavior of simvastatin. SDs with various drug: carrier ratios were prepared by solvent method and evaluated for dissolution rate. Differential scanning calorimetry (DSC), X-ray diffraction (XRD), infrared spectroscopy and solubility studies were also performed on the optimum SD formulation. Samples prepared with all three types of PEG showed improved drug dissolution compared to intact drug and corresponding physical mixtures. Meanwhile, the best result was obtained by PEG 12000 with drug: carrier ratio of 1:7 which showed a 3-fold increase in dissolution rate compared to the intact drug. Based on DSC and XRD, no crystalline change occurred during the sample preparation. Solubility studies revealed that increasing the PEG molecular weight resulted in higher phase solubility of drug. In addition, saturated solubility of the optimum SD was significantly higher than that of intact drug and the related physical mixture (24.83, 8.74 and 8.88 μg/mL, respectively) that could be due to the decreased particle size and aggregation. The results confirmed the influence of PEG molecular weight on drug dissolution rate from solid dispersion systems.Keywords: PEG molecular weight, Simvastatin, Solid dispersion, Dissolution, Solubility
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Etoposide, a widely used anticancer drug, exhibits low and variable oral bioavailability mainly because of being substrate for the efflux transporter, P-glycoprotein (P-gp). Therefore, the present study was aimed to investigate the effect of D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and PEG 400 as P-gp inhibitors on the intestinal absorption of etoposide. Everted sacs of rat small intestine were incubated in Krebs buffer solution which contained etoposide in the absence or presence of various concentrations of TPGS or PEG 400. The effect of verapamil as a known P-gp inhibitor on the absorption of drug was also studied.The absorptive transport of etoposide was significantly enhanced (p < 0.001) in the presence of verapamil (100 µg/mL) and TPGS (over the concentration range of 0.002-0.1 mg/mL), suggesting that the inhibition of P-gp located in the intestine may be involved in the enhancement of etoposide absorption. However, the addition of PEG 400 at various concentrations (0.05, 0.1 and 0.5% w/v) had no effect on the etoposide transport. No significant difference was found between the permeability values in the absence and presence of the maximum concentration of TPGS for two transport markers, lucifer yellow and imipramine, indicating that the enhancement in etoposide permeability in the presence of TPGS was not due to the compromise in tight junctions or membrane integrity of epithelial cells.The results of the study suggest that the use of TPGS as a safe excipient in etoposide formulations may enhance the oral bioavailability of etoposide and result in a predictable oral absorption.Keywords: Etoposide_Vitamin E TPGS_Everted gut sac_Permeability_P_glycoprotein
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The uptake and transport of 9-nitrocamptothecin (9-NC), a potent anticancer agent, across Caco-2 cell monolayers was studied as a free and PLGA nanoparticle loaded drug. Different sizes (110 to 950 nm) of 9-nitrocamptothecin nanoparticles using poly (lactic-glycolic acid) were prepared by via the nanoprecipitation method. The transport of nanoparticles across the Caco-2 cell monolayer as a function of incubation time and concentration was evaluated for each different nanoparticle formulation. The amount of 9-NC transported from the apical to the basolateral side and the uptake of the drug into the cells was determined by HPLC. The uptake of intact nanoparticles into Caco-2 cells was visualized by confocal laser scanning microscopy using 6-coumarin as a fluorescent marker. The study demonstrated that Caco-2 cell uptake and transport of encapsulated 9-nitrocamptothecin is significantly affected by the diameter of the carrier and incubation time. In addition it was shown to be independent of concentration. The results indicated a significant accumulation of the drug in the cell membrane and an enhanced diffusion across the cell membrane. There was also a sustained release of characteristics pertaining to polymeric carriers that provided prolonged drug availability for absorptive cells.
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Abstract: The pharmacokinetic parameters and bioavailability of diltiazem following a single oral administration of a generic diltiazem 60 mg tablet (Sobhan Pharmaceuticals, Iran) were compared to those of a reference product (Entrydil, Orion Pharmaceuticals, Finland). Twelve healthy male volunteers received a single oral dose of either formulation following overnight fasting in a double blind, randomized, crossover study. Blood samples were collected at selected times during 24 h and diltiazem plasma concentrations were determined with a sensitive HPLC method. Individual pharmacokinetic parameters, t1/2, t1/2(abs), K, Ka, Tmax, Cmax, Vd/F, Cl/F, AUC0-24 and AUC0-∞ were calculated. No significant differences were observed in pharmacokinetic parameters between two formulations. The 90% confidence intervals for the test/reference geometric mean ratios of Cmax, AUC0-24 AUC0-∞ and Cmax/AUC0-∞ were within the conventional bioequivalence range of 0.8 - 1.25. In-vitro parameters of mean dissolution time (MDT) and time for 70 % dissolution (T70) were also determined. There was a significant difference between the MDT for two dosage forms (p<0.0001). It was concluded that despite of a higher dissolution rate, the test product of diltiazem is bioequivalent to the reference product with respect to the rate and extent of absorption.
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