RÉSUMÉ
Micro-credentials (MCs) and digital badges (DBs) have gained popularity in recent years as a means to supplement traditional degrees and certifications. MCs and DBs can play a significant role in supporting student-centered learning by offering personalized and flexible learning pathways, emphasizing real-world relevance and practical skills, and fostering a culture of continuous learning and growth. However, barriers currently exist within health professions education, including pharmacy education, that could limit the full adoption and implementation of MCs and DBs. Research on the use of MCs and DBs in Doctor of Pharmacy degree programs is sparse. In this integrative review, literature on the use of MCs and DBs in health professions education is reviewed, and perspectives on the benefits, issues, and potential future uses within Doctor of Pharmacy degree programs are presented.
Sujet(s)
Enseignement pharmacie , Services pharmaceutiques , Pharmacie , Humains , Apprentissage , Programme d'étudesRÉSUMÉ
INTRODUCTION: The Pharmacy Curriculum Outcomes Assessment (PCOA) is a standardized exam developed by the National Association of Boards of Pharmacy (NABP) in 2008 to measure the curriculum in relation to student progress. The purpose of the study was to determine the impact of pre-admissions and pharmacy school variables on third-year student PCOA performance at a Historically Black College or University (HBCU) College of Pharmacy. METHODS: A retrospective analysis was conducted using data from three cohorts of students who took the PCOA in their third professional year from 2015 to 2017. An independent samples t-test, correlation analysis, and multivariate linear regression were conducted to determine the relationship between student characteristics and the PCOA score. RESULTS: The mean PCOA scaled score for the third-year pharmacy students was 349.6 ± 46.20 while the mean Pharmacy College Admission Test (PCAT) percentile was 62.7 ± 14.5. Most students (67%) self-identified as Black and the majority (54.9%) were female. The PCOA scores were correlated with the PCAT percentile (P < .001) and the cumulative grade point average (GPA) through the fall semester of the third professional year (P < .001). After adjusting for other factors, the cumulative GPA through the fall semester of the third professional year (P < .001) and PCAT percentiles (P < .001) remained predictive of students PCOA scores. CONCLUSIONS: The cumulative GPA through the third-year fall semester and PCAT percentiles are important factors in helping to predict PCOA scores among third year pharmacy students at a HBCU.
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Enseignement pharmacie , Pharmacie , Programme d'études , Évaluation des acquis scolaires , Femelle , Humains , Mâle , , Études rétrospectives , UniversitésRÉSUMÉ
The primary objective of the research study is to investigate Glucose (GLUT) transporter targeting of the drug (Citalopram-Hbr) for increased permeability across the Blood-Brain Barrier (BBB). The current study reports the development, physicochemical characterization, cytotoxicity analysis and in-vitro BBB permeability assessment of the Citalopram-Hbr liposomal formulations. Rat Primary Brain Microvascular Endothelial Cells (RPBECs) were used for cytotoxicity analysis and drug permeability testing. Five N-Acetyl Glucosamine (NAG) coated PEGylated multilamellar liposomal formulations were prepared and tested. Permeability of the liposomal formulations was evaluated in RPBECs monolayer. The particle size of the formulations ranged from 13 to 4259 nm. Entrapment efficiency was 50-75%. Cytotoxicity analysis indicated viability (>90%) for all five formulations (0.3-1.25 mg/ml). Apparent drug permeability (Papp) of the formulations ranged from 5.01 × 104 to 15 × 104 cm/min. The study demonstrated successful preparation of NAG-coated PEGylated multilamellar liposomal formulations with high drug entrapment efficiency. Cytotoxicity data indicated that the formulations were well tolerated by the cells up to a concentration of 1.25 mg/ml. Transport study data demonstrated that RPBMECs monolayers can be employed as a robust screening tool for future drug transport studies targeting GLUT transporter on the BBB. The drug permeability values provide a promising preliminarily proof that NAG-coated liposomal formulations can be an effective tool for BBB-GLUT transporter targeting.
RÉSUMÉ
Tenofovir, currently marketed as the prodrug tenofovir disoproxil fumarate, is used clinically to treat patients with HIV/AIDS. The oral bioavailability of tenofovir is relatively low, limiting its clinical effectiveness. Encapsulation of tenofovir within modified long-circulating liposomes would deliver this hydrophilic anti-HIV drug to the reticuloendothelial system for better therapeutic efficacy. The objectives of the current study were to prepare and pharmaceutically characterize model liposomal tenofovir formulations in an attempt to improve their bioavailability. The entrapment process was performed using film hydration method, and the formulations were characterized in terms of encapsulation efficiency and Caco-2 permeability. An efficient reverse-phase high-performance liquid chromatography method was developed and validated for tenofovir quantitation in both in vitro liposomal formulations and Caco-2 permeability samples. Separation was achieved isocratically on a Waters Symmetry C8 column using 10 mM Na2PO4/acetonitrile pH 7.4 (95:5 v/v). The flow rate was 1 mL/min with a 12 min elution time. Injection volume was 10 µL with ultraviolet detection at 270 nm. The method was validated according to United States Pharmacopeial Convention category I requirements. The obtained result showed that tenofovir encapsulation within the prepared liposomes was dependent on the employed amount of the positive charge-imparting agent. The obtained results indicated that calibration curves were linear with r2 > 0.9995 over the analytical range of 1-10 µg/mL. Inter- and intraday accuracy and precision values ranged from 95% to 101% and 0.3% to 2.6%, respectively. The method was determined to be specific and robust. Regarding the potential of the prepared vectors to potentiate tenofovir permeability through the Caco-2 model, a 10-fold increase in tenofovir apparent permeability was observed compared to its oral solution. In conclusion, this novel and validated method was successfully applied to characterize both in vitro encapsulation efficiency and Caco-2 permeability transport for the pharmaceutical assessment of novel tenofovir formulations.
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Efficacy of central nervous system-acting medications is limited by its localization and ability to cross the blood-brain barrier (BBB); therefore, the crux is in designing delivery systems targeted to cross the BBB. Toward this objective, this study proposed pegylated and glycosylated citalopram hydrobromide (Cit-HBr) liposomes as a delivery approach for brain targeting. The multicomponent liposomes were evaluated for drug encapsulation, vesicular size, size distribution, conductivity and drug release characteristics. Moreover, the interaction among the employed components was evaluated by Fourier transform infrared, differential scanning calorimetric and X-ray diffraction analysis. Through a systematic screening design of formulation and process variables in the optimization phase, an improvement of Cit-HBr loading, fine vesicular size with narrow size distribution, greater stability and sustained release features were achieved. The compatibility studies unveiled a significant interaction between Cit-HBr and dicetyl phosphate to control drug encapsulation and release properties. The optimization process showed a minimal range of design space to achieve the preset desirability; more precisely dicetyl phosphate, polyethylene glycol, N-acetyl glucosamine and freeze-thaw cycles of 3%, 5%, 4% and 2 cycles, respectively, were used. Using brain endothelial cell models, the optimized formulations showed an acceptable cell viability with preserved monolayer integrity and an enhanced flux and permeability. Thus, this study has proposed an optimized pegylated and glycosylated vector that is a promising step for brain targeting.
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The low permeability of the anti-AIDS, tenofovir, limits its antiretroviral clinical potency. The proposed study aimed at assessing the critical biological responses of tenofovir through the development and optimization of its surfactant-based niosomal gels intended for vaginal delivery. Fatty acid chain length of the amphiphile and cholesterol loading were optimized using a 3² full factorial design. Vesicular size, shape and surface charge, drug entrapment efficiency, in vitro release, and skin permeation were used to assess the gels. In addition, their biological performance on Lactobacillus crispatus viability and mucoadhesion to porcine vaginal tissue was also assessed. Within the design space, mucoadhesion percentage ranged from 6.2% to 28.6% and increased nonlinearly by decreasing niosomal vesicular size and linearly by increasing surface charge. Moreover, these gels were not cytotoxic to Lactobacillus crispatus for 48 h. For maximizing tenofovir entrapment, percutaneous permeation, and mucoadhesion while achieving sustained-release features, an optimum formulation was proposed with the shortest length of fatty chain and 0.48 mM cholesterol content. Overall, applying quality by design paradigm to the development of tenofovir niosomal gels not only offered a promising nanomedicine for the vaginal microbicide delivery but also unveiled the critical formulation interactions influencing its biological performance.
Sujet(s)
Agents antiVIH/administration et posologie , Muqueuse/métabolisme , Absorption cutanée , Peau/métabolisme , Tensioactifs/composition chimique , Vagin/métabolisme , Adénine/administration et posologie , Adénine/analogues et dérivés , Adénine/métabolisme , Adénine/pharmacocinétique , Adhésivité , Administration par voie cutanée , Administration par voie vaginale , Animaux , Agents antiVIH/métabolisme , Agents antiVIH/pharmacocinétique , Cholestérol/composition chimique , Préparations à action retardée/administration et posologie , Préparations à action retardée/métabolisme , Préparations à action retardée/pharmacocinétique , Préparation de médicament , Femelle , Hexose/composition chimique , Techniques in vitro , Phosphonates/administration et posologie , Phosphonates/métabolisme , Phosphonates/pharmacocinétique , Lapins , Solubilité , Propriétés de surface , Sus scrofa , Ténofovir , Patch transdermique , Crèmes, mousses et gels vaginauxRÉSUMÉ
Ethionamide (ETA) and pyrazinamide (PZA) are considered the drugs of choice for the treatment of multidrug-resistant tuberculosis. Current methods available in the literature for simultaneous determination of ETA and PZA have low sensitivity or involve column modifications with lipophilic cations. The aim of this study was to develop a simple and validated reversed-phase ion-pair HPLC method for simultaneous determination of ETA and PZA for the characterization of polymeric-based porous inhalable microparticles in in vitro and spiked human serum samples. Chromatographic separation was achieved on a Phenomenex C18 column (250 mm × 4.6 mm) using a Shimadzu LC 10 series HPLC. The mobile phase consisted of A: 0.01% trifluoroacetic acid in distilled water and B: ACN/MeOH at 1:1 v/v. Gradient elution was run at a flow rate of 1.5 mL/min and a fixed UV wavelength of 280 nm. The validation characteristics included accuracy, precision, linearity, analytical range, and specificity. Calibration curves at seven levels for ETA and PZA were linear in the analytical range of 0.1-3.0 µg/mL with correlation coefficient of r (2) > 0.999. Accuracy for both ETA and PZA ranged from 94 to 106% at all quality control (QC) standards. The method was precise with relative standard deviation less than 2% at all QC levels. Limits of quantitation for ETA and PZA were 50 and 70 ng/mL, respectively. There was no interference from either the polymeric matrix ions or the biological matrix in the analysis of ETA and PZA.
Sujet(s)
Antituberculeux/analyse , Éthionamide/analyse , Pyrazinamide/analyse , Algorithmes , Calibrage , Chromatographie en phase liquide à haute performance , Chromatographie d'échange d'ions , Limite de détection , Nanoparticules , Porosité , Normes de référence , Reproductibilité des résultats , SolutionsRÉSUMÉ
The aim was to investigate the potential of proliposomes to improve the permeability of tenofovir, anti-HIV, for oral delivery. Tenofovir was incorporated into phosphatidylcholine proliposomes and their absorption was determined in Caco-2 cell cultures grown on Transwell inserts using aqueous drug solutions as reference. Five batches of proliposomes were prepared with different stearylamine levels and characterized in terms of vesicular morphology, drug encapsulation efficiency (EEF), drug leakage, vesicular sizing and surface charges. Cytotoxicity of the reconstituted liposomes was evaluated by the MTT assay. The obtained results showed that increasing the incorporated percentage of stearylamine led to an increase in drug encapsulation, a slower drug leakage and larger liposomes formed. Compared to the drug solutions at corresponding concentrations, the proposed formulations showed a positive relationship (R²= 0.9756) for the influence of increasing the stearylamine percentage on reduction of mitochondrial activity. Regarding the drug permeability, enhancements of apparent permeability by 16.5- and 5.2-folds were observed for proliposomes formulations with 5% and 15% stearylamine, respectively. A good correlation was observed between the Caco-2 and dialysis models that might indicate passive diffusion as well as paracellular transport as suggested mechanisms for drug absorption. Cationic proliposomes offered a potential formulation to improve the permeation of tenofovir.
Sujet(s)
Adénine/analogues et dérivés , Inhibiteurs de protéase du VIH/administration et posologie , Liposomes , Modèles biologiques , Phosphonates/administration et posologie , Adénine/administration et posologie , Adénine/pharmacocinétique , Cellules Caco-2 , Inhibiteurs de protéase du VIH/pharmacocinétique , Humains , Microscopie électronique à balayage , Phosphonates/pharmacocinétique , Propriétés de surface , TénofovirRÉSUMÉ
Background. Although there is a reported association between lifestyle factors and metabolic syndrome, very few studies have used national level data restricted to the African Americans (AAs) in the United States (US). Methods. A cross-sectional evaluation was conducted using the National Health and Nutrition Examination Survey from 1999 to 2006 including men and nonpregnant women of 20 years or older. Multiple logistic regression models were constructed to evaluate the association between lifestyle factors and metabolic syndrome. Results. AA women had a higher prevalence of metabolic syndrome (39.43%) than AA men (26.77%). After adjusting for sociodemographic factors, no significant association was found between metabolic syndrome and lifestyle factors including alcohol drinking, cigarette smoking, and physical activity. Age and marital status were significant predictors for metabolic syndrome. With increase in age, both AA men and AA women were more likely to have metabolic syndrome (AA men: OR(adj) = 1.05, 95% CI 1.04-1.06, AA women: OR(adj) = 1.06, 95% CI 1.04-1.07). Single AA women were less likely to have metabolic syndrome than married women (OR(adj) = 0.66, 95% CI 0.43-0.99). Conclusion. Lifestyle factors had no significant association with metabolic syndrome but age and marital status were strong predictors for metabolic syndrome in AAs in the US.
RÉSUMÉ
The purpose of this study was to characterize and evaluate differences of protamine sulfate, a highly basic peptide drug, obtained from five different sources, using orthogonal thermal and spectroscopic analytical methods. Thermogravimetric analysis and modulated differential scanning calorimetry showed that all five protamine sulfate samples had different moisture contents and glass transition and melting temperatures when temperature was modulated from 25 to 270°C. Protamine sulfate from source III had the highest residual moisture content (4.7 ± 0.2%) at 105°C, resulting in the lowest glass transition (109.7°C) and melting (184.2°C) temperatures compared with the other four sources. By Fourier-transform infrared (FTIR) spectroscopy, the five sources of protamine sulfate had indistinguishable spectra, and the spectra were consistent with a predominantly random coil conformation in solution and a minor population in a ß-sheet conformation (~12%). Circular dichroism spectropolarimetry confirmed the FTIR results with prominent minima at 206 nm observed for all five sources. Finally, proton ((1)H) nuclear magnetic resonance spectroscopy showed that all five protamine sulfate sources had identical spectra with backbone amide chemical shifts between 8.20 and 8.80 ppm, consistent with proteins with predominantly random coil conformation. In conclusion, thermal analyses showed differences in the thermal behavior of the five sources of protamine sulfate, while spectroscopic analyses showed the samples had a predominantly random coil conformation with a small amount of ß-sheet present.
Sujet(s)
Protamine/composition chimique , Calorimétrie différentielle à balayage , Dichroïsme circulaire , Spectroscopie par résonance magnétique , Spectroscopie infrarouge à transformée de Fourier , ThermogravimétrieRÉSUMÉ
The purpose of this study was to utilize near-infrared (NIR) spectroscopy and near-infrared chemical imaging (NIR-CI) as non-invasive techniques to evaluate the drug loading in letrozole-loaded PLGA nanoparticle formulations prepared by the emulsification-solvent evaporation method. A Plackett-Burman design was applied to evaluate the main effects of amount of drug (X(1)), amount of polymer (X(2)), stirring rate (X(3)), emulsifier concentration (X(4)), organic to aqueous phase volume ratio (X(5)), type of organic solvent (X(6)), and homogenization time (X(7)) on drug entrapment efficiency. The influence of three different spectral pretreatment methods (multiplicative scatter correction, standard normal variate, and Savitzky-Golay second derivative transformation with third-order polynomial) and two different regression methods (PLS regression and principal component regression (PCR)) on model prediction ability were compared. PLS of spectra that were pretreated with Savitzky-Golay second derivative transformation provided better model prediction than PCR as it revealed better linear correlation (correlation coefficient of 0.991) for both calibration and prediction models. Relatively low values of root mean square errors of calibration (RMSEC = 0.748) and prediction (RMSEP = 0.786) and low standard errors of calibration (SEC = 0.758) and prediction (SEP = 0.589) suggested good predictability for estimation of the loading of letrozole in PLGA nanoparticles. NIR-CI analysis also revealed mutual homogenous distribution of both polymer and drug and was capable of clearly distinguishing the 12 formulations both quantitatively and qualitatively. In conclusion, NIR and NIR-CI could be potentially used to characterize anticancer drug-loaded nanoparticulate matrix.
Sujet(s)
Antinéoplasiques hormonaux/composition chimique , Inhibiteurs de l'aromatase/composition chimique , Vecteurs de médicaments , Acide lactique/composition chimique , Nanoparticules , Nitriles/composition chimique , Acide polyglycolique/composition chimique , Spectroscopie proche infrarouge , Technologie pharmaceutique/méthodes , Triazoles/composition chimique , Calibrage , Chimie pharmaceutique , Chromatographie en phase liquide à haute performance , Chromatographie en phase inverse , Émulsifiants/composition chimique , Méthode des moindres carrés , Létrozole , Modèles linéaires , Modèles chimiques , Modèles statistiques , Nanotechnologie , Copolymère d'acide poly(lactique-co-glycolique) , Analyse en composantes principales , Contrôle de qualité , Spectroscopie proche infrarouge/normes , Technologie pharmaceutique/normesRÉSUMÉ
The purpose of this study was to develop a robust reverse phase-HPLC method for the separation of hydrolyzed protamine sulfate peptides using a quality by design approach. A Plackett-Burman experimental design was utilized to screen the effects of mobile phase pH, flow rate, column temperature, injection volume and methanol concentration on peak resolution and USP tailing. Multivariate regression and Pareto ranking analyses showed that mobile phase pH, column temperature and injection volume were statistically significant (p<0.05) factors affecting the resolution and tailing of the peaks. A Box-Behnken experimental design with response surface methodology was then utilized to evaluate the main, interaction, and quadratic effects of these three factors on the selected responses. A desirability function applied to the optimized conditions predicted peak resolutions between 1.99 and 3.61 and tailing factor between 1.02 and 1.45 for the four peptide peaks of protamine sulfate with the following chromatographic conditions; an isocratic mobile phase consisting of 100mM monosodium phosphate buffer pH 2.25, 1.8% acetonitrile and 0.3% methanol. The injection volume was 20 µl, with a column temperature of 24 °C and a flow rate of 1.0 ml/min and a total run time of less than 25 min. The optimized chromatographic method was validated according to ICH Q2R1 guidelines and applied to separate and compare the peaks of protamine sulfate from five different sources. Analyses of the peptide peaks of the five protamine sulfate samples showed no significant differences in their compositions. The results clearly showed that quality by design concept could be effectively applied to optimize an HPLC chromatographic method for protein analysis with the least number of experimental runs possible.
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Protamine/composition chimique , Chromatographie en phase liquide à haute performance , Concentration en ions d'hydrogène , Protamine/isolement et purification , Reproductibilité des résultatsRÉSUMÉ
Levothyroxine is a narrow therapeutic index, and to avoid adverse effect associated with under or excessive dosage, the dose response is carefully titrated. The tablets are marketed with a score providing an option to split. However, there are no systematic studies evaluating the effect of splitting on dose accuracy, and current study was undertaken to evaluate effects of splitting and potential causes for uniformity failures by measuring assay and content uniformity in whole and split tablets. Stability was evaluated by assaying drug for a period of 8 weeks. Effect of formulation factors on splittability was evaluated by a systematic investigation of formulation factors by preparing levothyroxine tablets in house by varying the type of excipients (binder, diluent, disintegrant, glidant) or by varying the processing factors (granulating liquid, mixing type, compression pressure). The tablets were analyzed using novel analytical tool such as near infrared chemical imaging to visualize the distribution of levothyroxine. Assay was not significantly different for whole versus split tablets irrespective of method of splitting (hand or splitter), and splitting also had no measurable impact on the stability. Split tablets either by hand or splitter showed higher rate of content uniformity failures as compared to whole tablets. Tablet splitter produced more fragmentation and, hence, more content uniformity and friability failures. Chemical imaging data revealed that the distribution of levothyroxine was heterogeneous and was dependent on type of binder and the process used in the manufacture of tablets. Splitting such tablets could prove detrimental if sub- or super-potency becomes an issue.
Sujet(s)
Préparation de médicament/méthodes , Comprimés/composition chimique , Thyroxine/composition chimique , Stabilité de médicament , Contrôle de qualité , Reproductibilité des résultatsRÉSUMÉ
Stability of formulations over shelf-life is critical for having a quality product. Choice of excipients, manufacturing process, storage conditions, and packaging can either mitigate or enhance the degradation of the active pharmaceutical ingredient (API), affecting potency and/or stability. The purpose was to investigate the influence of processing and formulation factors on stability of levothyroxine (API). The API was stored at long-term (25 degrees C/60%RH), accelerated (40 degrees C/75%RH), and low-humidity (25 degrees C/0%RH and 40 degrees C/0%RH) conditions for 28 days. Effect of moisture loss was evaluated by drying it (room temperature, N(2)) and placed at 25 degrees C/0%RH and 40 degrees C/0%RH. The API was incubated with various excipients (based on package insert of marketed tablets) in either 1:1, 1:10, or 1:100 ratios with 5% moisture at 60 degrees C. Commonly used ratios for excipients were used. The equilibrium sorption data was collected on the API and excipients. The API was stable in solid state for the study duration under all conditions for both forms (potency between 90% and 110%). Excipients effect on stability varied and crospovidone, povidone, and sodium laurel sulfate (SLS) caused significant API degradation where deiodination and deamination occurred. Moisture sorption values were different across excipients. Crospovidone and povidone were hygroscopic whereas SLS showed deliquescence at high RH. The transient formulation procedures where temperature might go up or humidity might go down would not have major impact on the API stability. Excipients influence stability and if possible, those three should either be avoided or used in minimum quantity which could provide more stable tablet formulations with minimum potency loss throughout its shelf-life.
Sujet(s)
Excipients/composition chimique , Thyroxine/composition chimique , Préparation de médicament/méthodes , Évaluation préclinique de médicament , Stabilité de médicament , Solubilité , TempératureRÉSUMÉ
The aim of this investigation was to screen and understand the product variability due to important factors affecting the characteristics CyA-PLGA nanoparticles prepared by O/W emulsification-solvent evaporation method. Independent variables studied were cyclosporine A (CyA) (X(1)), PLGA (X(2)), and emulsifier concentration namely SLS (X(3)), stirring rate (X(4)), type of organic solvent employed (chloroform or dichloromethane, X(5)) and organic to aqueous phase ratio (X(6)). The nanoparticles properties considered were encapsulation efficiency (Y(1)), mean particle size (Y(2)), zeta potential (Y(3)), burst effect (Y(4)) and dissolution efficiency (Y(5)). The statistical analysis of the results allowed determining the most influent factors. The nanoparticles were characterized by scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray powder diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy. The factors combination showed variability of entrapment efficiency (Y(1)), mean particle size (Y(2)) and zeta potential (Y(3)) from 10.17% to 93.01%, 41.60 to 372.80 nm and 29.60 to 34.90 mV, respectively. Initially, nanoparticles showed burst effect followed by sustained release during the 7-day in vitro release study period. The dissolution efficiency (Y(5)) varied from 52.67% to 84.11%. The nanoparticles revealed Higuchi release pattern and release occurred by coupling of diffusion and erosion. In conclusion, this study revealed the potential of QbD in understanding the effect of formulation and process variables on the characteristics on CyA-PLGA nanoparticles.
Sujet(s)
Ciclosporine/administration et posologie , Vecteurs de médicaments/composition chimique , Immunosuppresseurs/administration et posologie , Acide lactique/composition chimique , Acide polyglycolique/composition chimique , Chimie pharmaceutique/méthodes , Préparations à action retardée , Diffusion , Émulsions , Excipients/composition chimique , Nanoparticules , Taille de particule , Copolymère d'acide poly(lactique-co-glycolique) , Solubilité , Solvants/composition chimique , Facteurs tempsRÉSUMÉ
The objective of this study was to evaluate near infrared (NIR) spectroscopy and imaging as approaches to assess drug contents in poly(dl-lactide-co-glycolide) (PLGA) based nanoparticles of a model protein, cyclosporine A (CyA). A 6-factors 12-runs designed set of experiments with Plackett-Burman (PB) screening was applied in order to examine the effects of drug loading (X(1)), polymer loading (X(2)), emulsifier concentration (X(3)), stirring rate (X(4)), type of organic solvent (X(5)), and ratio of organic to aqueous phases' volumes (X(6)), on drug entrapment efficiency (EFF). After omitting the factors with nonsignificant influences on EFF, a reduced mathematical relationship, EFF = 48.34 + 7.3X(1) - 29.95X(3), was obtained to explain the effect of the significant factors on EFF. Using two different sets for calibration and validation, the developed NIR calibration model was able to assess CyA contents within the 12 PB formulations. NIR spectral imaging was capable of clearly distinguishing the 12 formulations, both qualitatively and quantitatively. A good correlation with a coefficient of 0.9727 was obtained for constructing a quantile-quantile plot for the actual drug loading percentage and the % standard deviation obtained for the drug loading prediction using the hyperspectral images.
Sujet(s)
Acide lactique/composition chimique , Nanoparticules/composition chimique , Acide polyglycolique/composition chimique , Spectroscopie proche infrarouge/méthodes , Technologie pharmaceutique/méthodes , Chimie pharmaceutique/méthodes , Ciclosporine/composition chimique , Vecteurs de médicaments/composition chimique , Préparation de médicament/méthodes , Émulsifiants/composition chimique , Modèles statistiques , Taille de particule , Copolymère d'acide poly(lactique-co-glycolique) , Protéines/composition chimique , Solvants/composition chimiqueRÉSUMÉ
Several biologically relevant phospholipids were assessed as potential carriers/additives for rapidly dissolving solid formulations of piroxicam (Biopharmaceutics Classification System Class II drug). On the basis of in vitro dissolution studies, dimyristoylphosphatidylglycerol (DMPG) was ranked as the first potent dissolution rate enhancer for the model drug. Subsequently, the solid dispersions of varying piroxicam/DMPG ratios were prepared and further investigated. Within the concentration range studied (6.4-16.7 wt %), the dissolution rate of piroxicam from the solid dispersions appeared to increase as a function of the carrier weight fraction, whereas the cumulative drug concentration was not significantly affected by piroxicam/DMPG ratio, presumably due to a unique phase behavior of the aqueous dispersions of this carrier phospholipid. Solid state analysis of DMPG-based formulations reveled that they are two-component systems, with a less thermodynamically stable form of piroxicam (Form II) being dispersed within the carrier. Finally, oral bioavailability of piroxicam from the DMPG-based formulations in rats was found to be superior to that of the control, as indicated by the bioavailability parameters, cmax and especially Tmax (53 µg/mL within 2 h vs. 39 µg/mL within 5.5 h, respectively). Hence, DMPG was regarded as the most promising carrier phospholipid for enhancing oral bioavailability of piroxicam and potentially other Class II drugs.
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The objective of this study was to evaluate near infrared (NIR) spectroscopy and imaging as approaches to assess phospholipid compartment within its solid dispersion with cyclosporine A (CyA). By varying dimyristoyl phosphatidylcholine (DMPC) to CyA weight ratio, five batches were prepared by the kneading technique and characterized by DSC and FTIR. A drug/DMPC ratio of 50:1 provided an enhanced dissolution of CyA. FTIR spectra and DSC thermograms revealed a significant interaction between the drug and DMPC which suggested incorporation of CyA within the formed DMPC liposomes. The developed NIR calibration model was able to assess DMPC concentrations within the kneaded products. The calibration and prediction linear plots showed slopes of 0.9711 and 0.9915, offsets of 0.1247 and 0.1080, correlation coefficients of 0.9854 and 0.9889 and root mean square standard errors of 0.43% and 0.42%, respectively. In contrast, NIR spectral imaging was capable of clearly distinguishing the kneaded products, both qualitatively and quantitatively. NIR imaging revealed the poor powder blending efficiency of the method used to prepare physical mixture compared to the efficient distribution of the kneaded products. In conclusion, NIR spectral imaging system provides a rapid approach for acquiring high-resolution spatial and spectral information on solid dispersions.
Sujet(s)
Ciclosporine/composition chimique , Dimyristoylphosphatidylcholine/composition chimique , Spectroscopie proche infrarouge/méthodes , Calibrage , Calorimétrie différentielle à balayage , Évaluation préclinique de médicament , Modèles théoriques , Spectroscopie infrarouge à transformée de FourierRÉSUMÉ
Quality by design (QBD) refers to the achievement of certain predictable quality with desired and predetermined specifications. A very useful component of the QBD is the understanding of factors and their interaction effects by a desired set of experiments. The present project deals with a case study to understand the effect of formulation variables of nanoemulsified particles of a model drug, cyclosporine A (CyA). A three-factor, three-level design of experiment (DOE) with response surface methodology (RSM) was run to evaluate the main and interaction effect of several independent formulation variables that included amounts of Emulphor El-620 (X(1)), Capmul MCM-C8 (X(2)) and 20% (w/w) CyA in sweet orange oil (X(3)). The dependent variables included nanodroplets size (Y(1)), nanoemulsions turbidity (Y(2)), amounts released after 5 and 10min (Y(3), Y(4)), emulsification rate (Y(5)) and lag time (Y(6)). A desirability function was used to minimize lag time and to maximize the other dependent variables. A mathematical relationship, Y(5)=9.09-0.37X(1)+0.37X(2)-0.45X(3)+0.732X(1)X(2)-0.62X(1)X(3)+0.3X(2)X(3)+0.02X(1)(2)-0.28X(2)(2)+0.471X(3)(2) (r(2)=0.92), was obtained to explain the effect of all factors and their colinearities on the emulsification rate. The optimized nanodroplets were predicted to yield Y(1), Y(2), Y(3), Y(4), Y(5) and Y(6) values of 42.1nm, 50.6NTU, 56.7, 107.2, 9.3%/min and 3.5min, respectively, when X(1), X(2), and X(3) values were 36.4, 70 and 10mg, respectively. A new batch was prepared with these levels of the independent variables to yield Y(1)-Y(6) values that were remarkably close to the predicted values. In conclusion, this investigation demonstrated the potential of QBD in understanding the effect of the formulation variables on the quality of CyA self-nanoemulsified formulations.
Sujet(s)
Ciclosporine/composition chimique , Systèmes de délivrance de médicaments , Immunosuppresseurs/composition chimique , Nanotechnologie , Technologie pharmaceutique , Analyse de variance , Caprylates/composition chimique , Chimie pharmaceutique , Ciclosporine/administration et posologie , Préparation de médicament , Systèmes de délivrance de médicaments/normes , Émulsions , Analyse statistique factorielle , Glycérides/composition chimique , Immunosuppresseurs/administration et posologie , Modèles linéaires , Nanoparticules , Nanotechnologie/normes , Néphélométrie et turbidimétrie , Huiles végétales/composition chimique , Polyéthylène glycols/composition chimique , Valeur prédictive des tests , Contrôle de qualité , Reproductibilité des résultats , Solubilité , Solvants/composition chimique , Tensioactifs/composition chimique , Technologie pharmaceutique/normes , Facteurs tempsRÉSUMÉ
Previous in vitro studies suggest that erythrocytes may be a source of nitric oxide (NO) produced by nitric oxide synthase (NOS) or by oxyhemoglobin-mediated oxidation of hydroxyurea (HU). This study was performed to determine the roles of HU and NOS in the production of NO by normal and sickle erythrocytes. Red blood cells (RBCs) from normal adult hemoglobin (HbAA) and homozygous sickle cell subjects (HbSS) were incubated with PBS containing 0.2 mM hydrogen peroxide (control) for 2 h at 37 degrees C in the presence and absence of l-arginine, the substrate for NOS, and with l-arginine plus HU in the presence and absence of l-NMMA, a specific inhibitor of NOS. The nitrate and nitrite metabolites of NO, expressed as [NOx], were measured. [NOx] in the HbAA and HbSS RBC cultures was not significantly different in the presence and absence of 1.0 mM l-arginine (p>0.1). [NOx] in the HbAA and HbSS cultures treated with a clinically relevant dose of HU (1.0 mM) plus 1.0 mM l-arginine was significantly greater than that in controls incubated with PBS and with l-arginine p < 0.01. However, [NOx] in the HbAA and HbSS cultures treated with 50 microg/ml l-NMMA was not significantly different than that in the cultures treated with HU plus l-arginine in the absence of l-NMMA. These findings suggest that NOx production by erythrocytes may be increased by treatment with HU and may not be decreased by inhibiting NOS. Therefore, we conclude that a therapeutic dose of HU may increase the plasma concentration of NO by a mechanism that does not require erythrocytes NOS activity.