Nanoclay-Based Composite Films for Transdermal Drug Delivery: Development, Characterization, and in silico Modeling and Simulation.

Purpose: Halloysite nanotubes (HNTs) are a versatile and highly investigated clay mineral due to their natural availability, low cost, strong mechanical strength, biocompatibility, and binding properties. The present work explores its role for retarding and controlling the drug release from the composite polymer matrix material. Methods: For this purpose, nanocomposite films comprising propranolol HCl and different concentrations of HNTs were formulated using the "solution casting method". The menthol in a concentration of 1% w/v was used as a permeation enhancer, and its effect on release and permeation was also determined. Quality characteristics of the nanocomposite were determined, and in vitro release and permeation studies were performed using the Franz diffusion system. The data was analyzed using various mathematical models and permeation parameters. Optimized formulation was also subjected to skin irritation test, FTIR, DSC, and SEM study. Systemic absorption and disposition of propranolol HCl from the nanocomposites were predicted using the GastroPlus TCAT® model. Results: The control in drug release rate was associated with the higher concentration of HNTs. F8 released 50% of propranolol within 8 hours (drug, HNTs ratio, 1:2). The optimized formulation (F6) with drug: HNTs (2:1), exhibited drug release 80% in 4 hours, with maximum flux of 145.812 µg/cm2hr. The optimized formulation was found to be a non-irritant for skin with a shelf life of 35.46 months (28-30 ℃). The in silico model predicted Cmax, Tmax, AUCt , and AUCinf as 32.113 ng/mL, 16.58 h, 942.34 ng/mL×h, and 1102.9 ng/mL×h, respectively. Conclusion: The study demonstrated that HNTs could be effectively used as rate controlling agent in matrix type transdermal formulations.

SeDeM tool-driven full factorial design for osmotic drug delivery of tramadol HCl: Formulation development, physicochemical evaluation, and in-silico PBPK modeling for predictive pharmacokinetic evaluation using GastroPlus™.

The study is based on using SeDeM expert system in developing controlled-release tramadol HCl osmotic tablets and its in-silico physiologically based pharmacokinetic (PBPK) modeling for in-vivo pharmacokinetic evaluation. A Quality by Design (QbD) based approach in developing SeDEM-driven full factorial osmotic drug delivery was applied. A 24 Full-factorial design was used to make the trial formulations of tramadol HCl osmotic tablets using NaCl as osmogen, Methocel K4M as rate controlling polymer, and avicel pH 101 as diluent. The preformulation characteristics of formulations (F1-F16) were determined by applying SeDeM Expert Tool. The formulation was optimized followed by in-vivo predictive pharmacokinetic assessment using PBPK "ACAT" model of GastroPlus™. The FTIR results showed no interaction among the ingredients. The index of good compressibility (ICG) values of all trial formulation blends were ≥5, suggesting direct compression is the best-suited method. Formulation F3 and F4 were optimized based on drug release at 2, 10, and 16 h with a zero-order kinetic release (r 2 = 0.992 and 0.994). The SEM images confirmed micropores formation on the surface of the osmotic tablet after complete drug release. F3 and F4 were also stable (shelf life 29.41 and 23.46 months). The in vivo simulation of the pharmacokinetics of the PBPK in-silico model revealed excellent relative bioavailability of F3 and F4 with reference to tramadol HCl 50 mg IR formulations. The SeDeM expert tool was best utilized to evaluate the compression characteristics of selected formulation excipients and their blends for direct compression method in designing once-daily osmotically controlled-release tramadol HCl tablets. The in-silico GastroPlus™ PBPK modeling provided a thorough pharmacokinetic assessment of the optimized formulation as an alternative to tramadol HCl in vivo studies.

Green Synthesis and Characterization of Carboxymethyl Cellulose Fabricated Silver-Based Nanocomposite for Various Therapeutic Applications.

PURPOSE: The current study proposed the simple, eco-friendly and cost-effective synthesis of carboxymethyl cellulose (CMC) structured silver-based nanocomposite (CMC-AgNPs) using Syzygium aromaticum buds extract. METHODS: The CMC-AgNPs were characterized by ultraviolet (UV) spectroscopy, scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), Fourier transmission infra-red (FTIR), energy-dispersive X-ray (EDX), and dynamic light scattering (DLS) techniques. The synthesized nanocomposites were evaluated for their bactericidal kinetics, in-vivo anti-inflammatory, anti-leishmaniasis, antioxidant and cytotoxic activities using different in-vitro and in-vivo models. RESULTS: The spherical shape nanocomposite of CMC-AgNPs was synthesized with the mean size range of 20-30 nm, and the average pore diameter is 18.2 nm while the mean zeta potential of -31.6 ± 3.64 mV. The highly significant (P < 0.005) antibacterial activity was found against six bacterial strains with the ZIs of 24.6 to 27.9 mm. More drop counts were observed in Gram-negative strains after 10 min exposure with CMC-AgNPs. Significant damage in bacterial cell membrane was also observed in atomic force microscopy (AFM) after treated with CMC-AgNPs. Nanocomposite showed highly significant anti-inflammatory activity in cotton pellet induced granuloma model (Phase I) in rats with the mean inhibitions of 43.13% and 48.68% at the doses of 0.025 and 0.05 mg/kg, respectively, when compared to control. Reduction in rat paw edema (Phase II) was also highly significant (0.025 mg/kg; 42.39%; 0.05 mg/kg, 47.82%). At dose of 0.05 mg/kg, CMC-AgNPs caused highly significant decrease in leukocyte counts (922 ± 83), levels of CRP (8.4 ± 0.73 mg/mL), IL-1 (177.4 ± 21.3 pg/mL), IL-2 (83.7 ± 11.5 pg/mL), IL-6 (83.7 ± 11.5 pg/mL) and TNF-α (18.3 ± 5.3 pg/mL) as compared to control group. CMC-AgNPs produced highly effective anti-leishmaniasis activity with the viable Leishmania major counts decreased up to 36.7% within 24 h, and the IC50 was found to be 28.41 µg/mL. The potent DPPH radical scavenging potential was also observed for CMC-AgNPs with the IC50 value of 112 µg/mL. Furthermore, the cytotoxicity was assessed using HeLa cell lines with the LC50 of 108.2 µg/mL. CONCLUSION: The current findings demonstrate positive attributes of CMC fabricated AgNPs as a promising antibacterial, anti-inflammatory, anti-leishmaniasis, and antioxidant agent with low cytotoxic potential.

Investigating Halloysite Nanotubes as a Potential Platform for Oral Modified Delivery of Different BCS Class Drugs: Characterization, Optimization, and Evaluation of Drug Release Kinetics.

PURPOSE: This study systematically investigated the potential of four model drugs (verapamil HCl, flurbiprofen, atenolol, and furosemide), each belonging to a different class of Biopharmaceutics Classification Systems (BCS) to be developed into oral modified release dosage forms after loading with halloysite nanotubes (HNTs). METHODS: The drugs were studied for their loading (mass gain %) by varying solvent system, method, pH, and ratios of loading into the nanotubes using D-optimal split-plot design with the help of Design Expert software. Drug-loaded halloysites were characterized by XRD, DTA, FTIR, SEM, and HPLC-UV-based assay procedures. Dissolution studies were also performed in dissolution media with pH 1.2, 4.5, and 6.8. Moreover, the optimized samples were evaluated under stress stability conditions for determining prospects for the development of oral dosage forms. RESULTS: As confirmed with the results of XRD and DTA, the drugs were found to be converted into amorphous form after loading with halloysite (HNTs). The drugs were loaded in the range of ~7-9% for the four drugs, with agitation providing satisfactory and equivalent loading as compared to vacuum plus agitation based reported methods. FTIR results revealed either only weak electrostatic (verapamil HCl and flurbiprofen) or no interaction with the surface structure of the HNTs. The dissolution profiling depicted significantly retarded release of drugs with Fickian diffusion from a polydisperse system as a model that suits well for the development of oral dosage forms. HPLC-UV-based assay indicated that except furosemide (BCS class IV), the other three drugs are quite suitable for development for oral dosage forms. CONCLUSION: The four drugs investigated undergo phase transformation with HNTs. While agitation is an optimum method for loading drugs with various physicochemical attributes into HNTs; solvent system, loading ratios and pH play an important role in the loading efficiency respective to the drug properties. The study supports the capability of developing HNT-based modified release oral dosage forms for drugs with high solubility.

Analysis of treatment cost and persistence among migraineurs: A two-year retrospective cohort study in Pakistan.

OBJECTIVES: The persistence pattern of anti-migraine drugs' use among migraineurs is very low in the United States and different European countries. However, the cost and persistence of antimigraine drugs in Asian countries have not been well-studied. Hence, the present study aimed to evaluate the treatment cost and persistence among migraineurs in Pakistan. METHODS: Data from prescriptions collected from migraineurs who visited the Outpatient Department (OPD) of different public and private sector tertiary-care hospitals of Karachi, Pakistan were used to conduct this retrospective cohort study from 2017 to 2019. The minimum follow up period for each migraineur was about 12 months for persistence analysis while dropped-out patients data were also included in survival analysis as right censored data. Pairwise comparisons from Cox regression/hazards ratio were used to assess the predictors of persistence with the reference category of non-binary variables i.e. hazard ratio = 1 for low frequency migraineurs and NSAIDs users. Persistence with anti-migraine drugs was estimated using the Kaplan-Meier curve along with the Log Rank test. RESULTS: A total of 1597 patients were included in this study, 729 (45.6%) were male and 868 (54.3%) were female. Non-steroidal anti-inflammatory drugs (NSAIDs) were the most prescribed class of drug initially for all classes of migraineurs (26.1%). Of them, 57.3% of migraineurs discontinued their treatment, 28.5% continued while 14.8% were switched to other treatment approaches. Persistence with initial treatment was more profound in female (58.8%) patients compared to males while the median age of continuers was 31 years. The total cost of migraine treatment in the entire study cohort was 297532.5 Pakistani Rupees ($1901.1). By estimating the hazard ratios (HR) using the Cox regression analysis, it can be observed that patients with high frequency (HR, 1.628; 95%CI, 1.221-2.179; p<0.0001) migraine, depression (HR, 1.268; 95%CI, 1.084-1.458; p<0.0001), increasing age (HR, 1.293; 95%CI, 1.092-1.458; p<0.0001), combination analgesics (HR, 1.817; 95%CI, 0.841-2.725; p = 0.0004) and prophylaxis drugs (HR, 1.314; 95%CI, 0.958-1.424; p<0.0001) users were at a higher risk of treatment discontinuation. However, patients with chronic migraine (HR, 0.881; 95%CI, 0.762-0.912; p = 0.0002), epileptic seizure (HR, 0.922; 95%CI, 0.654-1.206; p = 0.0002), other comorbidities (HR, 0.671; 95%CI, 0.352-1.011; p = 0.0003) and users of triptan(s) (HR, 0.701; 95%CI, 0.182-1.414; p = 0.0005) and triptan(s) with NSAIDs (HR, 0.758; 95%CI, 0.501-1.289; p<0.0001) had more chances to continue their initial therapy. CONCLUSION: Similar to western countries, the majority of migraineurs exhibited poor persistence to migraine treatments. Various factors of improved persistence were identified in this study.

Design, Development, and Optimization of Dexibuprofen Microemulsion Based Transdermal Reservoir Patches for Controlled Drug Delivery.

The aim of the study was to develop a reservoir-type transdermal patch for a controlled delivery of dexibuprofen and to evaluate its in vivo anti-inflammatory activity in Albino Wistar rats. In order to develop these patches, six formulations of dexibuprofen microemulsion comprising ethyl oleate, Tween 80: PG (2 : 1), and water were prepared by simplex lattice design and characterized. The reservoir compartment was filled with these microemulsions and in vitro release and skin permeation were assessed. The optimized patch was obtained on the basis of the responses: Q24 and flux. The impact of drug loading, surface area, membrane thickness, adhesive, and agitation speed on drug release and permeation was also studied. The skin sensitivity reaction and in vivo anti-inflammatory activity of optimized patch were evaluated. Stability study at three different temperatures for three months was carried out. The result suggests that a membrane based patch with zero-order release rate, Q24 of 79.13 ± 3.08%, and maximum flux of 331.17 µg/cm2h can be obtained exhibiting suitable anti-inflammatory activity with no visible skin sensitivity reaction. The outcomes of stability study recommend storage of patches at 4°C having shelf-life of 6.14 months. The study demonstrates that the reservoir-type transdermal patch of dexibuprofen microemulsion has a potential of delivering drug across skin in controlled manner with required anti-inflammatory activity.