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Transdermal microneedles have demonstrated promising potential as an alternative to typical drug administration routes for the treatment of various diseases. As microneedles offer lower administration burden with enhanced patient adherence and reduced ecological footprint, there is a need for further exploitation of microneedle devices. One of the main objectives of this work was to initially develop an innovative biobased photocurable resin with high biobased carbon content comprising isobornyl acrylate (IBA) and pentaerythritol tetraacrylate blends (50:50 wt/wt). The optimization of the printing and curing process resulted in µNe3dle arrays with durable mechanical properties and piercing capacity. Another objective of the work was to employ the 3D printed hollow µNe3dles for the treatment of osteoporosis in vivo. The 3D printed µNe3dle arrays were used to administer denosumab (Dmab), a monoclonal antibody, to osteoporotic mice, and the serum concentrations of critical bone minerals were monitored for six months to assess recovery. It was found that the Dmab administered by the 3D printed µNe3dles showed fast in vitro rates and induced an enhanced therapeutic effect in restoring bone-related minerals compared to subcutaneous injections. The findings of this study introduce a novel green approach with a low ecological footprint for 3D printing of biobased µNe3dles, which can be tailored to improve clinical outcomes and patient compliance for chronic diseases.
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Background: Luteolin (LUT) is a bioactive compound with several pharmacological activities including anticancer effect. Doxorubicin (DOX) is an anthracycline chemotherapeutic drug that have proven to be effective in treating various types of cancers. Polymeric micelles (PMs) containing biologically active materials have emerged as prospective dosage forms with high drug-loading, which can add therapeutic benefit to the poorly water-soluble compounds and novel chemical entities. PMs are effective in delivering several drugs, such as anticancer drugs, antifungal drugs, flavonoids and drugs targeting the brain. The aim of the current study is to develop PMs for LUT and DOX as a combined delivery system for cancer therapy. Methods: PMs were prepared using 2.5% of each of LUT and DOX with varying compositions of Poloxamer 188, Poloxamer 407, Vitamin E (TPGS), Poloxamer 123 and Gellucire 44/14 at room temperature. Particle size, polydispersity index, zeta potential, were achieved using Zetasizer Nano particle size analyzer and the sizes were further confirmed with transmission electron microscopy (TEM). Prepared PMs were further characterized using powder X-ray diffraction (PXRD) and fourier transform infrared spectroscopy (FTIR). An MTT assay was performed on breast cancer (MCF-7) cells and liver cancer (HepG2) cells to determine the cytotoxic effect of the different PMs formulations. Results: PMs were successfully developed and optimized using 74.3% Poloxamer 407 with 20.7% Vitamin E (TPGS), and 70% Poloxamer 407 with 25% Gellucire 44/14, respectively. The droplet size and polydispersity index were found to be 62.03 ± 3.99 nm, 91.96 ± 5.80 nm and 0.33 ± 0.05, 0.59± 0.03, respectively for PMs containing TPGS and Gellucire 44/14. Zeta potentials of the PMs containing TPGS and Gellucire 44/14 were recorded as -2.27 ±0.11mV and -7.78 ± 0.10 mV, respectively. The PMs showed a spherical structure with approximately 50-90 nm range evident by TEM analysis. The PXRD spectra of PMs powder presented the amorphization of LUT and DOX. The FTIR spectra of LUT-loaded and DOX-loaded PMs were identical, suggesting consistent PMs composition. The MTT assay showed that the representative combined drug loaded PMs treatment led to a reduction in the viability of MCF-7 and HepG2 cells compared to drug free PMs and pure LUT, DOX alone. Conclusions: PMs with LUT and DOX exhibited significant cytotoxic effects against breast and liver cancer cells and could thus be an important new pharmaceutical formulation to treat cancer.
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Gene editing technologies (GETs) could induce gene knockdown or gene knockout for biomedical applications. The clinical success of gene silence by RNAi therapies pays attention to other GETs as therapeutic approaches. This review aims to highlight GETs, categories, mechanisms, challenges, current use, and prospective applications. The different academic search engines, electronic databases, and bibliographies of selected articles were used in the preparation of this review with a focus on the fundamental considerations. The present results revealed that, among GETs, CRISPR/Cas9 has higher editing efficiency and targeting specificity compared to other GETs to insert, delete, modify, or replace the gene at a specific location in the host genome. Therefore, CRISPR/Cas9 is talented in the production of molecular, tissue, cell, and organ therapies. Consequently, GETs could be used in the discovery of innovative therapeutics for genetic diseases, pandemics, cancer, hopeless diseases, and organ failure. Specifically, GETs have been used to produce gene-modified animals to spare human organ failure. Genetically modified pigs are used in clinical trials as a source of heart, liver, kidneys, and lungs for xenotransplantation (XT) in humans. Viral, non-viral, and hybrid vectors have been utilized for the delivery of GETs with some limitations. Therefore, extracellular vesicles (EVs) are proposed as intelligent and future cargoes for GETs delivery in clinical applications. This study concluded that GETs are promising for the production of molecular, cellular, and organ therapies. The use of GETs as XT is still in the early stage as well and they have ethical and biosafety issues.
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Edición Génica , Trasplante de Órganos , Animales , Humanos , Porcinos , Edición Génica/métodos , Sistemas CRISPR-Cas/genética , Técnicas de Transferencia de Gen , Terapia GenéticaRESUMEN
This study aims to highlight the potential use of cTNAs in therapeutic applications. The COVID-19 pandemic has led to significant use of coding therapeutic nucleic acids (cTNAs) in terms of DNA and mRNA in the development of vaccines. The use of cTNAs resulted in a paradigm shift in the therapeutic field. However, the injection of DNA or mRNA into the human body transforms cells into biological factories to produce the necessary proteins. Despite the success of cTNAs in the production of corona vaccines, they have several limitations such as instability, inability to cross biomembranes, immunogenicity, and the possibility of integration into the human genome. The chemical modification and utilization of smart drug delivery cargoes resolve cTNAs therapeutic problems. The success of cTNAs in corona vaccine production provides perspective for the eradication of influenza viruses, Zika virus, HIV, respiratory syncytial virus, Ebola virus, malaria, and future pandemics by quick vaccine design. Moreover, the progress cTNAs technology is promising for the development of therapy for genetic disease, cancer therapy, and currently incurable diseases.
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Amyloid-ß1-42 (Aß42) peptide aggregate formation in the brain plays a crucial role in the onset and progression of Alzheimer's disease. According to published research, the Aß monomer's amino acid residues KLVFF (16-20) self-associate to create antiparallel ß-sheet fibrils. Small compounds can prevent self-assembly and destroy Aß fibrils by attaching to the Aß16-20 regions of Aß42. To enhance biological characteristics and binding affinity to the amyloid beta peptide, ß-sheet breaker small molecules can be developed and modified with various scaffolds. In the current study, a novel series of 2,3-disubstitutedbenzofuran derivatives was designed and created by fusing the benzofuran core of a known iron chelator, neuroprotective, and neurorestorative agent, like VK-28, with a motif found in the structure of a known muscarinic inhibitor and amyloid binding agent, like SKF-64346. Measurements of the binding affinity and in vitro aggregation inhibition of the Aß42 peptide were made using the thioflavin T (ThT) test. Using AutoDock 4.2 software, molecular docking studies of the synthesized compounds were performed on the monomer and fibril structures of amyloid beta peptide. The compounds 8a-8g exhibited strong binding energy and affinity to Aß fibrils as well as a 50%-67% reduction of the growth of Aß aggregation. Finally, the positive traits of our recently synthesized compounds make them excellent candidates for additional in vivo testing as a "ß-sheet breaking agent."
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Humanos , Péptidos beta-Amiloides/metabolismo , Simulación del Acoplamiento Molecular , Fragmentos de Péptidos/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Conformación Proteica en Lámina beta , Aminoácidos , Amiloide/químicaRESUMEN
Lymphatic drug targeting is an effective approach for targeting immunomodulators, and chemotherapeutic drugs at a specific organ or cellular location. The cellular, paracellular, and dendritic cell trafficking machinery are involved in the lymphatic transport of therapeutic agents. The engineering of triggered and hybrid lymphatic drug delivery systems (LDDS) is a promising strategy to fight cancer metastasis and microbial pandemics. Hybrid lymphatic drug delivery systems can be tailored and developed by grafting the conventional LDDS with biological agents. Thus, hybrid LDDS could collect the benefits of conventional and biological delivery systems. Moreover, the fabrication of triggered LDDS increases drug accumulation in the lymphatic system in the response to an internal stimulus such as pH, and redox status or external such as magnetic field, temperature, and light. Stimuli-responsive LDD systems prevent premature release of payload and mediate selective drug biodistribution. This improves therapeutic impact and reduces the systemic side effect of anticancer, immunomodulatory, and antimicrobial therapeutics. This review highlights the challenges and future horizons of nanoscaled-triggered LDDS and their influence on the lymphatic trafficking of therapeutic molecules.
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Sistemas de Liberación de Medicamentos , Nanopartículas , Distribución Tisular , Temperatura , Nanopartículas/químicaRESUMEN
Gefitinib (GEF) is utilized in clinical settings for the treatment of metastatic lung cancer. However, premature drug release from nanoparticles in vivo increases the exposure of systemic organs to GEF. Herein, nanostructured lipid carriers (NLC) were utilized not only to avoid premature drug release but also due to their inherent lymphatic tropism. Therefore, the present study aimed to develop a GEF-NLC as a lymphatic drug delivery system with low drug release. Design of experiments was utilized to develop a stable GEF-NLC as a lymphatic drug delivery system for the treatment of metastatic lung cancer. The in vitro drug release of GEF from the prepared GEF-NLC formulations was studied to select the optimum formulation. MTT assay was utilized to study the cytotoxic activity of GEF-NLC compared to free GEF. The optimized GEF-NLC formulation showed favorable physicochemical properties: <300 nm PS, <0.2 PDI, <−20 ZP values with >90% entrapment efficiency. Interestingly, the prepared formulation was able to retain GEF with only ≈57% drug release within 24 h. Furthermore, GEF-NLC reduced the sudden exposure of cultured cells to GEF and produced the required cytotoxic effect after 48 and 72 h incubation time. Consequently, optimized formulation offers a promising approach to improve GEF's therapeutic outcomes with reduced systemic toxicity in treating metastatic lung cancer.
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Antineoplásicos , Neoplasias Pulmonares , Nanopartículas , Nanoestructuras , Humanos , Portadores de Fármacos , Gefitinib , Lípidos , Sistemas de Liberación de Medicamentos , Antineoplásicos/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Tamaño de la PartículaRESUMEN
Lymphatic drug delivery (LDD) is an attractive option for the prevention and treatment of cancer metastasis. This study aims to develop TPGS decorated nanostructure lipid carrier gefitinib loaded (TPGS-NLC-GEF). Biocompatibility and cytotoxicity were studied using erythrocytes and A549 cell lines. Furthermore, cellular uptake of the prepared TPGS-NLC was studied using 5-carboxyfluorescein (5-CF). Pharmacokinetic, biodistribution, and chylomicron-block flow studies were performed using male Wister Albino rats to investigate the influence of TPGS-NLC on plasma concentration-time profile, organ deposition, and LDD of GEF. The present results indicated that the prepared TPGS-NLC and TPGS-NLC-GEF formulation had a particle size range of 268 and 288 nm with a negative zeta-potential value of - 29.3 and - 26.5 mV, respectively. The in-vitro release showed burst drug release followed by sustained release. In addition, the biosafety in the term of the hemocompatibility study showed that the prepared formulation was safe at the therapeutic level. Additionally, an in-vitro cytotoxicity study showed that the TPGS-NLC was able to enhance the activity of GEF against the A549 cell line. The cellular uptake study showed the ability of TPGS-NLC to enhance 5-CF internalization by 12.6-fold compared to the 5-CF solution. Furthermore, the in-vivo study showed that TPGS-NLC was able to enhance GEF bioavailability (1.5-fold) through lymphatic system which was confirmed via the indirect chylomicron-block flow method. The tissue distribution study showed the ability of lipid nanoparticles to enhance lung drug deposition by 5.8-fold compared to a GEF suspension. This study concluded that GEF-NLC-GEF is an encouraging approach for the treatment of metastatic lung cancer through lymphatic delivery, enhanced bioavailability, and reduced systemic toxicity.
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Portadores de Fármacos , Nanopartículas , Masculino , Disponibilidad Biológica , Quilomicrones , Portadores de Fármacos/química , Gefitinib , Nanopartículas/química , Tamaño de la Partícula , Distribución Tisular , Ratas , AnimalesRESUMEN
Purpose: The present study aimed to develop gefitinib-loaded solid lipid nanoparticles (GEF-SLN), and GEF-loaded PEGylated SLN (GEF-P-SLN) for targeting metastatic lung cancer through the lymphatic system. Methods: The prepared SLNs were characterized in terms of physicochemical properties, entrapment efficiency, and in-vitro release. Furthermore, ex-vivo permeability was investigated using the rabbit intestine. Cytotoxicity and apoptotic effects were studied against A549 cell lines as a model for lung cancer. Results: The present results revealed that the particle size and polydispersity index of the prepared formulations range from 114 to 310 nm and 0.066 to 0.350, respectively, with negative zeta-potential (-14 to -27.6). Additionally, SLN and P-SLN showed remarkable entrapment efficiency above 89% and exhibited sustained-release profiles. The permeability study showed that GEF-SLN and GEF-P-SLN enhanced the permeability of GEF by 1.71 and 2.64-fold, respectively, compared with GEF suspension. Cytotoxicity showed that IC50 of pure GEF was 3.5 µg/mL, which decreased to 1.95 and 1.8 µg/mL for GEF-SLN and GEF-P-SLN, respectively. Finally, the apoptotic study revealed that GEF-P-SLN decreased the number of living cells from 49.47 to 3.43 when compared with pure GEF. Conclusion: These results concluded that GEF-P-SLN is a promising approach to improving the therapeutic outcomes of GEF in the treatment of metastatic lung cancer.
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Neoplasias Pulmonares , Nanopartículas , Animales , Portadores de Fármacos/química , Gefitinib/uso terapéutico , Lípidos/química , Liposomas , Neoplasias Pulmonares/tratamiento farmacológico , Sistema Linfático , Nanopartículas/química , Tamaño de la Partícula , Polietilenglicoles/uso terapéutico , ConejosRESUMEN
Various chitosan (CS)-based nanoparticles (CS-NPs) of ciprofloxacin hydrochloride (CHCl) have been investigated for therapeutic delivery and to enhance antimicrobial efficacy. However, the Box-Behnken design (BBD)-supported statistical optimization of NPs of CHCl has not been performed in the literature. As a result, the goal of this study was to look into the key interactions and quadratic impacts of formulation variables on the performance of CHCl-CS-NPs in a systematic way. To optimize CHCl-loaded CS-NPs generated by the ionic gelation process, the response surface methodology (RSM) was used. The BBD was used with three factors on three levels and three replicas at the central point. Tripolyphosphate, CS concentrations, and ultrasonication energy were chosen as independent variables after preliminary screening. Particle size (PS), polydispersity index (PDI), zeta potential (ZP), encapsulation efficiency (EE), and in vitro release were the dependent factors (responses). Prepared NPs were found in the PS range of 198-304 nm with a ZP of 27-42 mV. EE and drug release were in the range of 23-45% and 36-61%, respectively. All of the responses were optimized at the same time using a desirability function based on Design Expert® modeling and a desirability factor of 95%. The minimum inhibitory concentration (MIC) of the improved formula against two bacterial strains, Pseudomonas aeruginosa and Staphylococcus aureus, was determined. The MIC of the optimized NPs was found to be decreased 4-fold compared with pure CHCl. The predicted and observed values for the optimized formulation were nearly identical. The BBD aided in a better understanding of the intrinsic relationship between formulation variables and responses, as well as the optimization of CHCl-loaded CS-NPs in a time- and labor-efficient manner.
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Quitosano , Nanopartículas , Ciprofloxacina/farmacología , Portadores de Fármacos , Tamaño de la Partícula , Proyectos de InvestigaciónRESUMEN
OBJECTIVES: To detect the cotinine and nicotine serum concentrations of female and male C57BL/6J mice after a 4-week exposure to electronic (e)-cigarette vapors using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). METHODS: This experimental study was carried out at an animal facility and laboratories, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia, between January and August 2020. A 4-week exposure to e-cigarettes was carried out using male and female mice and serum samples were obtained for cotinine and nicotine quantification using UPLC-MS/MS. The chromatographic procedures involved the use of a BEH HSS T3 C18 column (100 mm x 2.1 mm, 1.7 µm) with acetonitrile as a mobile phase and 0.1% formic acid (2:98 v/v). RESULTS: The applied methodology has highly efficient properties of detection, estimation, and extraction, where the limit of quantification (LOQ) for nicotine was 0.57 ng/mL and limit of detection (LOD) for nicotine was 0.19 ng/mL, while the LOQ for cotinine was 1.11 ng/mL and LOD for cotinine was 0.38 ng/mL. The correlation coefficient was r2>0.99 for both compounds. The average recovery rate was 101.6±1.33 for nicotine and 100.4±0.54 for cotinine, while the precision and accuracy for cotinine and nicotine were less than 6.1. The serum cotinine level was higher in males (433.7±19.55) than females (362.3±16.27). CONCLUSION: This study showed that the gender factor might play a crucial role in nicotine metabolism.
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Cigarrillo Electrónico a Vapor , Sistemas Electrónicos de Liberación de Nicotina , Animales , Cromatografía Líquida de Alta Presión/métodos , Cromatografía Liquida/métodos , Cotinina/química , Cotinina/metabolismo , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Nicotina , Espectrometría de Masas en Tándem/métodosRESUMEN
The present study aimed to engineer a nanoscale lipid-based lymphatic drug delivery system with D-α-Tocopherol polyethylene glycol 1000 succinate to combat the lymphatic metastasis of lung cancer. The nanoscale lipid-based systems including GEF-SLN, GEF-NLC, and GEF-LE were prepared and pharmaceutically characterized. In addition, the most stable formulation (GEF-NLC) was subjected to an in vitro release study. Afterward, the optimized GEF-NLC was engineered with TPGS (GEF-TPGS-NLC) and subjected to in vitro cytotoxicity, and apoptotic studies using the A549 cells line as a surrogate model for lung cancer. The present results revealed that particle size and polydispersity index of freshly prepared formulations were ranging from 198 to 280 nm and 0.106 to 0.240, respectively, with negative zeta potential ranging from - 14 to - 27.6.mV. An in vitro release study showed that sustained drug release was attained from GEF-NLC containing a high concentration of lipid. In addition, GEF-NLC and GEF-TPGS-NLC showed remarkable entrapment efficiency above 89% and exhibited sustained release profiles. Cytotoxicity showed that IC50 of pure GEF was 11.15 µg/ml which decreased to 7.05 µg/ml for GEF-TPGS-NLC. The apoptotic study revealed that GEF-TPGS-NLC significantly decreased the number of living cells from 67 to 58% when compared with pure GEF. The present results revealed that the nanoscale and lipid composition of the fabricated SLN, NLC, and LE could mediate the lymphatic uptake of GEF to combat the lymphatic tumor metastasis. Particularly, GEF-TPGS-NLC is a promising LDDS to increase the therapeutic outcomes of GEF during the treatment of metastatic lung cancer.
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Neoplasias Pulmonares , Nanopartículas , Células A549 , Línea Celular Tumoral , Portadores de Fármacos , Sistemas de Liberación de Medicamentos/métodos , Gefitinib , Humanos , Lípidos , Neoplasias Pulmonares/tratamiento farmacológico , Tamaño de la Partícula , Vitamina ERESUMEN
BACKGROUND: Bacterial ghosts are the evacuated bacterial cellular membranes from most of the genetic and protein contents which preserved their surface characters. Recently, bacterial ghosts exploited for different biomedical applications, for instance, vaccination. The purpose of this study is to measure the immunogenic protective response of bacterial ghosts of Salmonella Typhimurium in animals and to allow future testing this response in humans. The immunologic response was qualitatively, quantitatively, and functionally measured. We have measured the humoral and cellular immune responses, such as immunoglobulins elevation (IgG), increased granulocytes, serum antibacterial activity, clearance of virulence in feces and liver, and the survival rate. RESULTS: The bacterial ghosts' vaccine was able to protect 100% of subcutaneously vaccinated rats and 75% of adjuvant subcutaneously vaccinated rats. The lowest survival rate was in the orally vaccinated group (25%). The maximum level of serum IgG titers, as well as serum and feces bactericidal activity (100% eradication), was exhibited in the subcutaneously vaccinated group with adjuvant vaccines followed by the subcutaneously vaccinated one. Additionally, the highest granulocytes' number was observed in the adjuvant vaccine subcutaneously immunized group. The bacterial load in liver homogenate was eliminated in the subcutaneously vaccinated rats after the virulence challenge. CONCLUSIONS: The bacterial ghosts of Salmonella enterica serovar Typhimurium that prepared by Tween 80 Protocol showed an effective vaccine candidate that protected animals, eliminated the virulence in feces and liver. These findings show that chemically induced bacterial ghosts of Salmonella Typhimurium can be a promising vaccine.
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Enfermedades de los Roedores , Salmonelosis Animal , Vacunas contra la Salmonella , Animales , Anticuerpos Antibacterianos , Formación de Anticuerpos , Vacunas Bacterianas , Ratas , Salmonelosis Animal/prevención & control , Salmonella typhimurium , Vacunas AtenuadasRESUMEN
Luteolin (LUT) is a natural pharmaceutical compound that is weakly water soluble and has low bioavailability when taken orally. As a result, the goal of this research was to create self-nanoemulsifying drug delivery systems (SNEDDS) for LUT in an attempt to improve its in vitro dissolution and hepatoprotective effects, resulting in increased oral bioavailability. Using the aqueous phase titration approach and the creation of pseudo-ternary phase diagrams with Capryol-PGMC (oil phase), Tween-80 (surfactant), and Transcutol-HP (co-emulsifier), various SNEDDS of LUT were generated. SNEDDS were assessed for droplet size, polydispersity index (PDI), zeta potential (ZP), refractive index (RI), and percent of transmittance (percent T) after undergoing several thermodynamic stability and self-nanoemulsification experiments. When compared to LUT suspension, the developed SNEDDS revealed considerable LUT release from all SNEDDS. Droplet size was 40 nm, PDI was <0.3, ZP was -30.58 mV, RI was 1.40, percent T was >98 percent, and drug release profile was >96 percent in optimized SNEDDS of LUT. For in vivo hepatoprotective testing in rats, optimized SNEDDS was chosen. When compared to LUT suspension, hepatoprotective tests showed that optimized LUT SNEDDS had a substantial hepatoprotective impact. The findings of this investigation suggested that SNEDDS could improve bioflavonoid LUT dissolution rate and therapeutic efficacy.
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Sistemas de Liberación de Medicamentos , Hígado/efectos de los fármacos , Luteolina/farmacología , Nanopartículas/química , Sustancias Protectoras/farmacología , Administración Oral , Animales , Tetracloruro de Carbono/farmacología , Emulsiones/administración & dosificación , Emulsiones/metabolismo , Emulsiones/farmacología , Hígado/metabolismo , Luteolina/administración & dosificación , Luteolina/metabolismo , Masculino , Nanopartículas/administración & dosificación , Nanopartículas/metabolismo , Tamaño de la Partícula , Sustancias Protectoras/administración & dosificación , Sustancias Protectoras/metabolismo , Ratas , Ratas Wistar , Solubilidad , TermodinámicaRESUMEN
Bacterial ghosts (BGs) are empty cell envelopes of nonliving evacuated bacterial cells. They are free from their cytoplasmic contents; however, they sustain their cellular 3D morphology and antigenic structures, counting on bioadhesive properties. Lately, they have been tested as an advanced drug delivery system (DDS) for different materials like DNA, peptides, or drugs, either single components or combinations. Different studies have revealed that, BG DDS were paid the greatest attention in recent years. The current review explores the impact of BGs on the field of drug delivery and drug targeting. BGs have a varied area of applications, including vaccine and tumor therapy. Moreover, the use of BGs, their synthesis, their uniqueness as a delivery system and application principles in cancer are discussed. Furthermore, the safety issues of BGs and stability aspects of using ghost bacteria as delivery systems are discussed. Future perspective efforts that must be followed for this important system to continue to grow are important and promising.
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Between 293.2 and 313.2 K and at 0.1 MPa, the solubility of the weak base, cinnarizine (CNZ) (3), in various {Transcutol-P (TP) (1) + water (2)} combinations is reported. The Hansen solubility parameters (HSP) of CNZ and various {(TP) (1) + water (2)} mixtures free of CNZ were also predicted using HSPiP software. Five distinct cosolvency-based mathematical models were used to link the experimentally determined solubility data of CNZ. The solubility of CNZ in mole fraction was increased with elevated temperature and TP mass fraction in {(TP) (1) + water (2)} combinations. The maximum solubility of CNZ in mole fraction was achieved in neat TP (5.83 × 10-2 at 313.2 K) followed by the minimum in neat water (3.91 × 10-8 at 293.2 K). The values of mean percent deviation (MPD) were estimated as 2.27%, 5.15%, 27.76%, 1.24% and 1.52% for the "Apelblat, van't Hoff, Yalkowsky-Roseman, Jouyban-Acree, and Jouyban-Acree-van't Hoff models", respectively, indicating good correlations. The HSP value of CNZ was closed with that of neat TP, suggesting the maximum solubilization of CNZ in TP compared with neat water and other aqueous mixtures of TP and water. The outcomes of the apparent thermodynamic analysis revealed that CNZ dissolution was endothermic and entropy-driven in all of the {(TP) (1) + water (2)} systems investigated. For {(TP) (1) + water (2)} mixtures, the enthalpy-driven mechanism was determined to be the driven mechanism for CNZ solvation. TP has great potential for solubilizing the weak base, CNZ, in water, as demonstrated by these results.
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Cinarizina/química , Glicoles de Etileno/química , Termodinámica , Agua/química , SolubilidadRESUMEN
PURPOSE: The aim of the study was to evaluate physicians' perception of the concept of pharmacokinetics and therapeutic drug monitoring (PK/TDM) and their use in clinical practice. METHODS: A novel, structured, self-administered questionnaire was designed, validated and distributed to physicians in 3 major cities in Saudi Arabia (Riyadh, Jeddah, Dammam) during a 4-month period. Data were collected on demographics, knowledge and practice of PK/TDM. Attitudes toward integrating these skills into daily clinical practice were also investigated. RESULTS: A total of 724 physicians completed the survey and included in the study. European and North American physicians were found to be more exposed to PK/TDM than other physicians. About 70% of the participants stated that they have applied PK/TDM in their practice, at least, once and most of these were consultants. Only 4.3% of respondents had never checked organ function prior to prescribing narrow therapeutic index drugs. Although the majority (78.4%) perceived PK/TDM as very important to their practice, only 35.3% have tried to calculate drug PK parameters for their patients when necessary. CONCLUSION: The result of this study showed that the knowledge of physicians about PK/TDM was inadequate. Moreover, the utilization of competent clinical pharmacists trained in PK/TDM was low. An interdisciplinary educational program between the physicians and pharmacist in PK/TDM will lead to a better health care outcome.
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The study aims to design a novel combination of drug-free solid self-nanoemulsifying drug delivery systems (S-SNEDDS) + solid dispersion (SD) to enhance cinnarizine (CN) dissolution at high pH environment caused by hypochlorhydria/achlorhydria. Drug-loaded and drug-free liquid SNEDDS were solidified using Neusilin® US2 at 1:1 and 1:2 ratios. Various CN-SDs were prepared using freeze drying and microwave technologies. The developed SDs were characterized by differential scanning calorimetry (DSC) and X-ray powder diffraction (XRD). In-vitro dissolution studies were conducted to evaluate CN formulations at pH 6.8. Drug-free S-SNEDDSs showed acceptable self-emulsification and powder flow properties. DSC and XRD showed that CN was successfully amorphized into SDs. The combination of drug-free S-SNEDDS + pure CN showed negligible drug dissolution due to poor CN migration into the formed nanoemulsion droplets. CN-SDs and drug-loaded S-SNEDDS showed only 4% and 23% dissolution efficiency (DE) while (drug-free S-SNEDDS + FD-SD) combination showed 880% and 160% enhancement of total drug release compared to uncombined SD and drug-loaded S-SNEDDS, respectively. (Drug-free S-SNEDDS + SD) combination offer a potential approach to overcome the negative impact of hypochlorhydria/achlorhydria on drug absorption by enhancing dissolution at elevated pH environments. In addition, the systems minimize the adverse effect of adsorbent on drug release.
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Graphene oxide (GO), due to its 2D planar structure and favorable physical and chemical properties, has been used in different fields including drug delivery. This study aimed to investigate the impact of different process parameters on the average size of drug-loaded PEGylated nano graphene oxide (NGO-PEG) particles using design of experiment (DoE) and the loading of drugs with different molecular structures on an NGO-PEG-based delivery system. GO was prepared from graphite, processed using a sonication method, and functionalized using PEG 6000. Acetaminophen (AMP), diclofenac (DIC), and methotrexate (MTX) were loaded onto NGO-PEG particles. Drug-loaded NGO-PEG was then characterized using dynamic light scattering (DLS), Fourier transform infrared (FTIR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), XRD. The DLS data showed that the drug-loaded NGO-PEG suspensions were in the size range of 200 nm-1.3 µm. The sonication time and the stirring rate were found to be the major process parameters which affected the average size of the drug-loaded NGO-PEG. FTIR, DSC, XRD, and SEM demonstrated that the functionalization or coating of the NGO occurred through physical interaction using PEG 6000. Methotrexate (MTX), with the highest number of aromatic rings, showed the highest loading efficiency of 95.6% compared to drugs with fewer aromatic rings (diclofenac (DIC) 70.5% and acetaminophen (AMP) 65.5%). This study suggests that GO-based nano delivery systems can be used to deliver drugs with multiple aromatic rings with a low water solubility and targeted delivery (e.g., cancer).
Asunto(s)
Sistemas de Liberación de Medicamentos/métodos , Grafito/química , Nanopartículas/química , Acetaminofén/administración & dosificación , Acetaminofén/química , Rastreo Diferencial de Calorimetría , Diclofenaco/administración & dosificación , Diclofenaco/química , Portadores de Fármacos/química , Metotrexato/administración & dosificación , Metotrexato/química , Microscopía Electrónica de Rastreo , Estructura Molecular , Nanopartículas/administración & dosificación , Tamaño de la Partícula , Polietilenglicoles/química , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Difracción de Rayos XRESUMEN
The solubilization, Hansen solubility parameters (HSPs), and thermodynamic properties of delafloxacin (DLN) in various unique combination of Transcutol-HP® (THP) and 1-butyl-3-methyl imidazolium hexafluorophosphate ionic liquid (BMIM-PF6) mixtures were evaluated for the first time in this research. The 'mole fraction solubilities (x3)' of DLN in different (THP + BMIM-PF6) compositions were determined at 'T = 298.2-318.2 K' and 'p = 0.1 MPa'. The HSPs of DLN, neat THP, neat BMIM-PF6, and binary (THP + BMIM-PF6) compositions free of DLN were also determined. The x3 data of DLN was regressed using 'van't Hoff, Apelblat, Yalkowsky-Roseman, Jouyban-Acree and Jouyban-Acree-van't Hoff models' with overall error values of less than 3.0%. The highest and lowest x3 value of DLN was recorded in neat THP (5.48 × 10-3 at T = 318.2 K) and neat BMIM-PF6 (6.50 × 10-4 at T = 298.2 K), respectively. The solubility of DLN was found to be enhanced significantly with an arise in temperature in all (THP + BMIM-PF6) compositions including pure THP and pure BMIM-PF6. However, there was slight increase in DLN solubility with increase in THP mass fraction in all (THP + BMIM-PF6) mixtures. The HSP of pure THP and pure BMIM-PF6 were found very close to each other, suggesting the great potential of both solvents in DLN solubilization. The maximum solute-solvent interactions at molecular level were recorded in DLN-THP compared to DLN-BMIM-PF6. An 'apparent thermodynamic analysis' study indicated an 'endothermic and entropy-driven dissolution' of DLN in all (THP + BMIM-PF6) compositions including neat THP and BMIM-PF6.