Effect of HPMC and mannitol on drug release and bioadhesion behavior of buccal discs of buspirone hydrochloride: In-vitro and in-vivo pharmacokinetic studies

This study aimed to develop a novel sustained release pellet of loxoprofen sodium (LXP) by coating a dissolution-rate controlling sub-layer containing hydroxypropyl methyl cellulose (HPMC) and citric acid, and a second diffusion-rate controlling layer containing aqueous dispersion of ethyl cellulose (ADEC) on the surface of a LXP conventional pellet, and to compare its performance in vivo with an immediate release tablet (Loxinon®). A three-level, three-factor Box-Behnken design and the response surface model (RSM) were used to investigate and optimize the effects of the citric acid content in the sub-layer, the sub-layer coating level, and the outer ADEC coating level on the in vitro release profiles of LXP sustained release pellets. The pharmacokinetic studies of the optimal sustained release pellets were performed in fasted beagle dogs using an immediate release tablet as a reference. The results illustrated that both the citric acid (CA) and ADEC as the dissolution- and diffusion-rate controlling materials significantly decreased the drug release rate. The optimal formulation showed a pH-independent drug release in media at pH above 4.5 and a slightly slow release in acid medium. The pharmacokinetic studies revealed that a more stable and prolonged plasma drug concentration profile of the optimal pellets was achieved, with a relative bioavaibility of 87.16% compared with the conventional tablets. This article provided a novel concept of two-step control of the release rate of LXP, which showed a sustained release both in vitro and in vivo.

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Design and Characterization of Combinational Domperidone-Famotidine Floating Drug Delivery System - In vitro and In vivo studies

Ars Pharmaceutica (Internet) ◽

10.30827/ars.v62i2.15810 ◽

2021 ◽

Vol 62 (2) ◽

pp. 144-162

Author(s):

Mounika Chidurala ◽

Raveendra Reddy J

Keyword(s):

Drug Release ◽

Oral Administration ◽

Quality By Design ◽

Release Kinetics ◽

Cost Effective ◽

Fickian Diffusion ◽

In Vivo Studies ◽

Pharmacokinetic Studies

Introduction: The drawbacks assosiated with oral administration of drugscan be controlled or minimized by gastro retentive formulations that remain buoyant within the stomach for an extended time by providing prolonged gastric retention and releasethe drug in an exceedingly extended manner thereby improving bioavailability. The current research was to develop and optimize Domperidone and Famotidine floating tablets with extended release by Quality by Design approach. Method: Based on QTPP (Quality Target Product Profile), CQAs (Critical Quality Attributes)wereidentified. Risk analysis by the evaluation of formulation and process parameters showed that optimizing the levels of polymers could reduce high risk to achieve the target profile. A 23factor experimental design with midpoints was selected for statistical analysis and optimization. Results: HPMC K100 and Carbopol 934P had a positive effect while ethyl cellulose demonstrated a negative effect on the selected responses. Drug release kinetics followed the first-order release with Higuchi diffusion and Fickian diffusion. Optimized formula satisfying all the required parameters was selected and evaluated. The predicted response values were in close agreement with experimental response values. Abdominal X-ray imaging after oral administration of the tablets on a healthy rabbit’s stomach confirmed the extended floating behavior with shorter lag time. In vivo, pharmacokinetic studies in rabbits revealed that the optimized formulation exhibited prolonged drug release with enhanced Cmax, tmax, AUCo-t, and t1/2 of an optimized product when compared to the marketed product. Conclusions: It has been concluded that the application of Quality by Design in the formulation and optimization reduced the number of trials to produce a cost-effective formula.

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Quality by Design enabled anti-hypertensive Floating drug delivery system by Risk assessment and Design of Experiment (DoE) – In vitro – In vivo correlation studies

Current Drug Therapy ◽

10.2174/1574885516666210609123207 ◽

2021 ◽

Vol 16 ◽

Author(s):

Mounika Chidurala ◽

Raveendra Reddy J

Keyword(s):

Drug Release ◽

Risk Analysis ◽

Quality By Design ◽

Release Kinetics ◽

Cost Effective ◽

Fickian Diffusion ◽

In Vivo Studies ◽

Pharmacokinetic Studies

Background: The present research aimed to develop and optimize extended-release floating tablets of Sacubitril and Valsartan through Quality by Design (QbD) approach. Risk analysis by formulation assessment and process parameters showed that optimizing the levels of the polymer will minimize high risk to meet the target profile. A two (2) level three (3) full factorial experimental design along with midpoints was carefully chosen for optimization and statistical analysis. Based on the literature, the independent and dependent variables were selected. Results: HPMC K100, Carbopol 934P had a positive effect, whereas Ethylcellulose had a negative effect on Floating time, drug release at 2 h, drug release at 12 h and, 50% responses. Drug release kinetics followed the first-order release with Higuchi and Fickian diffusion. Contour and overlay plots were utilized for an assortment of design space and optimized formula. ANOVA results of all the factors exhibited significance at p<0.05. Abdominal X-ray imaging of the optimized tablets on healthy rabbit’s stomach confirmed the floating behavior for more than 12 h. In vivo pharmacokinetic studies in rabbits showed that the optimized formulation exhibited prolonged and extended drug release with improved Cmax, tmax, AUCo-t, and t1/2 of test product when compared to marketed product. IVIVC model was developed by using dissolution data of in vitro and pharmacokinetics data of in-vivo by de-convolution method (Wagner-Nelson method). Conclusion: The Quality by Design implementation in the formulation and optimization abridged the number of trials to produce a cost-effective formula. In vivo studies confirmed that the formula was successfully developed with extended floating time (12 h) and drug release by risk analysis and experimental designs. Level A correlation was observed which confirmed a good correlation between in vitro and in vivo data.

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Nose to Brain Delivery of Phenytoin Sodium Loaded Nano Lipid Carriers: Formulation, Drug Release, Permeation and In Vivo Pharmacokinetic Studies

Pharmaceutics ◽

10.3390/pharmaceutics13101640 ◽

2021 ◽

Vol 13 (10) ◽

pp. 1640

Author(s):

Sreeja C. Nair ◽

Kollencheri Puthenveettil Vinayan ◽

Sabitha Mangalathillam

Keyword(s):

Drug Release ◽

Olfactory Epithelium ◽

Drug Transport ◽

Ex Vivo ◽

Medical Attention ◽

Pharmacokinetic Studies ◽

Phenytoin Sodium ◽

Drug Solution

An acute epileptic seizure is a seizure emergency fatal condition that requires immediate medical attention. IV phenytoin sodium remains the second line therapeutic agent for the immediate treatment of status epilepticus. Phenytoin sodium formulated as nanolipid carriers (NLCs) seems to be promising as an intranasal delivery system for controlling acute seizures. Three different nanosized phenytoin sodium loaded NLCs (<50 nm, 50–100 nm and >100 nm) were prepared by melt emulsification and was further characterised. In vitro drug release studies showed immediate drug release from phenytoin sodium loaded NLCs of <50 nm size, which is highly essential for acute seizure control. The ex vivo permeation study indicated greater permeation from <50 nm sized NLC through the olfactory epithelium compared to thecontrol drug solution. Invivo pharmacokinetic studies revealed higher drug concentration in CSF/brain within 5 min upon intranasal administration of <50 nm sized phenytoin sodium NLCs than the control drug solution and marketed IV phenytoin sodium, indicating direct and rapid nose to brain drug transport through the olfactory epithelium. The study has shown that formulation strategies can enhance olfactory uptake, and phenytoin sodium NLCs of desired particle sizes (<50 nm) offer promising potential for nose to brain direct delivery of phenytoin sodium in treating acute epileptic seizures.

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OPTIMIZATION OF STATISTICALLY DESIGNED ACECLOFENAC FAST DISSOLVING TABLETS EMPLOYING STARCH GLUTAMATE AS A NOVEL SUPERDISINTEGRANT

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2020v12i1.34987 ◽

2019 ◽

pp. 77-88

Author(s):

R. SANTOSH KUMAR ◽

SAHITHI MUDILI

Keyword(s):

Drug Release ◽

Peak Plasma ◽

Peak Plasma Concentration ◽

In Vitro Dissolution ◽

Pharmacokinetic Studies ◽

Disintegration Time ◽

Short Period ◽

Dissolution Efficiency

Objective: To optimize aceclofenac fast dissolving tablets employing starch glutamate as novel superdisintegrant by 23factorial design to improve bioavailability and enhance patient compliance. Methods: Starch glutamate was prepared by the esterification process. Starch glutamate physical and micromeritics properties had been evaluated and the prepared starch glutamate was used as a superdisintegrant for the formulation of the fast dissolving tablets of aceclofenac by direct compression method and optimized by employing 23factorial design. The prepared aceclofenac fast dissolving tablets were evaluated for post compression parameters as well as in vitro and in vivo release characteristics. Optimized formulation stability studies were performed at accelerated conditions for 6 mo as per ICH and WHO guidelines. Results: The prepared starch glutamate was amorphous, insoluble in aqueous and organic solvents were tested. Fast dissolving tablets of aceclofenac were formulated by employing starch glutamate as a superdisintegrant showed good tablet properties and showed an increased dissolution efficiency of the drug. Among all the formulations (F1 to F8), the formulation F8 containing 5% concentration of starch glutamate, croscarmellose sodium and, crospovidone as a superdisintegrants showed 99.7±0.15% of drug release within 5 min. Whereas the formulation F2 containing 5% concentration of starch glutamate, drug release characters were comparable to the formulation F8. Optimized formulation F2 attained peak plasma concentration within a short period and showed increased relative bioavailability of the drug. Conclusion: From the physical properties, disintegration time, in vitro dissolution studies and pharmacokinetic studies, it was concluded that fast dissolving tablets of aceclofenac tablets formulated by employing starch glutamate as a superdisintegrant enhanced the dissolution efficiency and improved the bioavailability of the drug as compared to the pure drug and stable.

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Steroid Eluting Esophageal-Targeted Drug Delivery Devices for Treatment of Eosinophilic Esophagitis

Polymers ◽

10.3390/polym13040557 ◽

2021 ◽

Vol 13 (4) ◽

pp. 557

Author(s):

Alka Prasher ◽

Roopali Shrivastava ◽

Denali Dahl ◽

Preetika Sharma-Huynh ◽

Panita Maturavongsadit ◽

...

Keyword(s):

Drug Delivery ◽

Drug Release ◽

Porcine Model ◽

Pharmacokinetic Studies ◽

Specific Drug ◽

In Vitro Drug Release ◽

Release Studies ◽

3D Printed

Eosinophilic esophagitis (EoE) is a chronic atopic disease that has become increasingly prevalent over the past 20 years. A first-line pharmacologic option is topical/swallowed corticosteroids, but these are adapted from asthma preparations such as fluticasone from an inhaler and yield suboptimal response rates. There are no FDA-approved medications for the treatment of EoE, and esophageal-specific drug formulations are lacking. We report the development of two novel esophageal-specific drug delivery platforms. The first is a fluticasone-eluting string that could be swallowed similar to the string test “entero-test” and used for overnight treatment, allowing for a rapid release along the entire length of esophagus. In vitro drug release studies showed a target release of 1 mg/day of fluticasone. In vivo pharmacokinetic studies were carried out after deploying the string in a porcine model, and our results showed a high local level of fluticasone in esophageal tissue persisting over 1 and 3 days, and a minimal systemic absorption in plasma. The second device is a fluticasone-eluting 3D printed ring for local and sustained release of fluticasone in the esophagus. We designed and fabricated biocompatible fluticasone-loaded rings using a top-down, Digital Light Processing (DLP) Gizmo 3D printer. We explored various strategies of drug loading into 3D printed rings, involving incorporation of drug during the print process (pre-loading) or after printing (post-loading). In vitro drug release studies of fluticasone-loaded rings (pre and post-loaded) showed that fluticasone elutes at a constant rate over a period of one month. Ex vivo pharmacokinetic studies in the porcine model also showed high tissue levels of fluticasone and both rings and strings were successfully deployed into the porcine esophagus in vivo. Given these preliminary proof-of-concept data, these devices now merit study in animal models of disease and ultimately subsequent translation to testing in humans.

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Design and in vivo Evaluation of Manidipine by Self-Nanoemulsifying Drug Delivery Systems

International Journal of Pharmaceutical Sciences and Drug Research ◽

10.25004/ijpsdr.2019.110609 ◽

2019 ◽

Vol 11 (06) ◽

Author(s):

S Srikanth Reddy ◽

G Suresh

Keyword(s):

Drug Delivery ◽

Particle Size ◽

Drug Release ◽

Spherical Shape ◽

Pharmacokinetic Studies ◽

In Vivo Evaluation ◽

Enhanced Solubility ◽

Pure Drug

The current research is aimed at developing liquid self-nanoemulsifying drug delivery system (liquid-SNEDDS) of Manidipine for enhanced solubility and oral bioavailability. The Manidipine SNEDDS are formulated with excipients comprising of Capmul MCM (oil phase), Transcutol P (surfactant) Lutrol L 300 as co-surfactant. The prepared fifteen formulations of Manidipine SNEDDS analysed for emulsification time, percentage transmittance, particle size, in vitro drug release, and stability studies. In vivo pharmacokinetic studies of the optimized formulation were carried out in Wistar rats in comparison with control (pure drug). The morphology of Manidipine SNEDDS indicates spherical shape with uniform particle distribution. The percentage drug release from optimized formulation F14 is 98.24 ± 5.14%. The particle size F14 formulation was 22.4 nm and Z-Average 23.3 nm. The PDI and zeta potential of Manidipine SNEDDS optimized formulation (F14) were 0.313 and-5.1mV respectively. From in vivo bioavailability data the optimized formulation exhibited a significantly greater Cmax and Tmax of the SNEDDS was found to be 3.42 ± 0.46ng/ml and 2.00 ± 0.05 h respectively. AUC0-∞ infinity for formulation was significantly higher (11.25 ± 3.45 ng.h/ml) than pure drug (7.45 ± 2.24ng. h/ml). Hence a potential SNEDDS formulation of Manidipine developed with enhanced solubility and bioavailability.

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Formulation and Evaluation of Bilayer Matrix Tablets of Nebivolol Hydrochloride and Valsartan

Journal of Drug Delivery and Therapeutics ◽

10.22270/jddt.v9i4-s.3257 ◽

2019 ◽

Vol 9 (4-s) ◽

pp. 82-93

Author(s):

Selvi Arunkumar ◽

L. Srinivas ◽

D. Satyavati ◽

C. Emmanuel

Keyword(s):

Drug Release ◽

Sustained Release ◽

Immediate Release ◽

Matrix Tablets ◽

Pharmacokinetic Studies ◽

Drug Content ◽

Bilayer Tablets ◽

Nebivolol Hydrochloride

The present study is an attempt to develop bilayer matrix tablets of Nebivolol Hydrochloride and Valsartan with immediate release for Nebivolol Hydrochloride and sustained release for Valsartan. Superdisintegrants such as sodium starch glycolate and Crosscarmellose sodium were evaluated for immediate release of Nebivolol Hydrochloride and polymers HPMC K100M and K4M for sustained release of Valsartan. Preformulation studies were performed prior to compression. The compressed bilayer tablets were evaluated for weight variation, thickness, hardness, friability, drug content and in vitro drug release using USP dissolution apparatus type 2 in 0.01N HCl and phosphate buffer pH 6.8. All the pre and post compression parameters were found to be within the acceptable limits. The results of dissolution show that the formulations B3 was the best of all immediate and sustained release layer batches. The release kinetics of Valsartan was subject to curve fitting analysis in order to identify the best fit kinetic model. The regression analysis proves that the best formulations follow zero order release and drug release by diffusion process based on Fick’s law of diffusion. The data for stability studies infer no considerable change in drug content and dissolution rates as per ICH guidelines. The best formulation B3 was subjected to in vivo pharmacokinetic studies in rabbit model. In vitro, In vivo correlation (IVIVC) showed considerable linearity. Hence a novel bilayer tablet formulation of Nebivolol Hydrochloride and Valsartan was successfully developed by combining both immediate (IR) and sustained (SR) release layers. Keywords: Bilayer tablets, fixed unit dosage form, Nebivolol hydrochloride, Valsartan, LC-MS analysis.

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Factors Contributing to Drug Release From Enteric-Coated Omeprazole Capsules: An In Vitro and In Vivo Pharmacokinetic Study and IVIVC Evaluation in Beagle Dogs

Dose-Response ◽

10.1177/1559325820908980 ◽

2020 ◽

Vol 18 (1) ◽

pp. 155932582090898

Author(s):

Cheng Cui ◽

Jiabei Sun ◽

Xueqing Wang ◽

Zhenxi Yu ◽

Yaqin Shi

Keyword(s):

Drug Release ◽

Critical Factor ◽

Pharmacokinetic Studies ◽

Beagle Dogs ◽

Enteric Coating ◽

Coating Materials ◽

Enteric Coated ◽

Release Profiles

This study was performed to explore factors influencing the release of the proton pump inhibitor omeprazole from enteric-coated capsules in vitro and absorption in vivo in beagle dogs. Enteric-coated pellets with different enteric coating materials and coating levels were designed and prepared. All self-prepared formulations were characterized in vitro as well as in vivo and compared to the brand and generic commercial products. Evaluation of the corresponding release profiles suggested that coating material was the most critical factor. Enteric coating level determined the lag time before initiation of drug release, and subcoating level affected the drug release rate. Pharmacokinetic studies were performed in beagle dogs to further confirm the influence of formulation factors on drug absorption. Medium at pH 6.8 was a more biorelevant condition for in vitro drug release tests, although medium at pH 6.0 was better for discriminating release profiles of different formulations. A multiple level C in vitro/in vivo correlation was preliminarily established by which Tmax and Cmax of omeprazole formulations could be predicted with release parameters such as Tlag and T25. These results may facilitate quality evaluation and potentially improve the clinical efficacy of generic omeprazole products.

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Novel Methotrexate-Loaded Zein Nanoparticles With Improved and Extended Biopharmaceutical Performance: QbD-Steered Development, and Extensive In Vitro and In Vivo Evaluation

10.21203/rs.3.rs-850909/v1 ◽

2021 ◽

Author(s):

Atul Jain ◽

Teenu Sharma ◽

Rajendra Kumar ◽

Sumant Saini ◽

Jasleen Kaur ◽

...

Keyword(s):

Drug Release ◽

Kinetic Modelling ◽

Dissolution Kinetic ◽

Pharmacokinetic Studies ◽

Factor Screening ◽

In Vivo Evaluation ◽

Extension Mechanism ◽

Point To Point

Abstract The current work entails QbD-enabled preparation of methotrexate-loaded nanoparticles (NPs) using zein as the release-controlling natural polymer. Initially, quality risk estimationand factor screening studies using Taguchi design were undertaken to delineate “vital few” process and material attributes among “plausible so many”. Further, formulation optimization using central composite design and validation using correlation plots and percent predictive bias was carried out. Optimized NPs exhibited mean size of 159 nm, zeta potential of 14.85 mV and entrapment of 50.23%. In vitro dissolution kinetic modelling unearthed non-Fickian drug release extension mechanism from the proposed zein NPs. In vitro MTT and apoptosis assay using MCF-7 cells and cellular uptake studies using Caco-2 cells indicate remarkably superior anticancer potential of zein NPs over pure methotrexate, ascribable to their nanometric size and cationic nature. In vivo pharmacokinetic studies in rat construed significant enhancement by 2.15-fold in AUC48h (p<0.001), 1.30-fold in Cmax (p<0.05), 3.67-fold in Tmax (p<0.001), and 1.38-fold in T1/2 (p<0.01), along with notably reduced variability in biopharmaceutical performance. Establishment of significant point-to-point level A in vitro/in vivo correlations (IVIVC) and kinetic modeling construed the robustness and prognostic ability of drug release studies. Robustness of the nanoformulation was ratified under refrigerated storage through six months’stability studies. Overall, the studies unequivocally indicate development of a stable nanoparticulate formulation with significantly enhanced extent, extension and consistency of biopharmaceutical performance, along with improved anticancer potential of methotrexate.

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