Direct Compaction Drug Product Process Modeling

Alexander Russell, John Strong, Sean Garner, William Ketterhagen, Michelle Long & Maxx Capece

doi : 10.1208/s12249-021-02206-4

AAPS PharmSciTech volume 23, Article number: 67 (2022) 

Most challenges during the development of solid dosage forms are related to the impact of any variations in raw material properties, batch size, or equipment scales on the product quality and the control of the manufacturing process. With the ever pertinent restrictions on time and resource availability versus heightened expectations to develop, optimize, and troubleshoot manufacturing processes, targeted and robust science-based process modeling platforms are essential. This review focuses on the modeling of unit operations and practices involved in batch manufacturing of solid dosage forms by direct compaction. An effort is made to highlight the key advances in the past five years, and to propose potentially beneficial future study directions.

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A Strategy for the Effective Optimization of Pharmaceutical Formulations Based on Parameter-Optimized Support Vector Machine Model

Siqi Wang, Jianping Yang, Hengwei Chen, Kexin Chu, Xuefei Yu, Yaqiong Wei, Haixia Zhang, Mengjie Rui & Chunlai Feng

doi : 10.1208/s12249-022-02210-2

AAPS PharmSciTech volume 23, Article number: 66 (2022) 

Engineering pharmaceutical formulations is governed by a number of variables, and the finding of the optimal preparation is intricately linked to the exploration of a multiparametric space through a variety of optimization tasks. As a result, making such optimization activities simpler is a significant undertaking. For the purposes of this study, we suggested a prediction model that was based on least square support vector machine (LSSVM) and whose parameters were optimized using the particle swarm optimization algorithm (PSO-LSSVM model). Other in silico optimization methods were used and compared, including the LSSVM and the back propagation (BP) neural networks algorithm. PSO-LSSVM demonstrated the highest performance on the test dataset, with the lowest mean square error. In addition, two dosage forms, quercetin solid dispersion and apigenin nanoparticles, were selected as model formulations due to the wide range of formulation compositions and manufacturing factors used in their production. Three different models were used to predict the ideal formulations of two different dosage forms, and in real world, the Taguchi orthogonal design arrays were used to optimize the formulations of each dosage form. It is clear that the predicted performance of two formulations using PSO-LSSVM was both consistent with the outcomes of the Taguchi orthogonal planned experiment, demonstrating the model’s good reliability and high usefulness. Together, our PSO-LSSVM prediction model has the potential to accurately predict the best possible formulations, reduce the reliance on experimental effort, accelerate the process of formulation design, and provide a low-cost solution to drug preparation optimization.

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Preparation and Characterization of Furosemide Solid Dispersion with Enhanced Solubility and Bioavailability

Fangfang Zhang, Jingwei Mao, Guangyan Tian, Hulin Jiang & Qingri Jin

doi : 10.1208/s12249-022-02208-w

AAPS PharmSciTech volume 23, Article number: 65 (2022) 

Furosemide (FMD), as a potent circulating diuretic, is commonly used for the treatment of hypertension and edema arising from cardiac, renal, and hepatic failure. However, the low solubility of furosemide restricts its dissolution and bioavailability. In this study, Polyvinylpyrrolidone K30 (PVP-K30), mesoporous (Syloid 244FP, Syloid XDP 3050), and non-mesoporous (Aeroperl 300, Aerosil 200) silica were chosen as combined carrier to develop novel amorphous solid dispersions of furosemide, and then its dissolution and bioavailability were evaluated. Characterization study included XRD, DSC, TGA, SEM, FT-IR, and molecular docking. We found that FMD:PVP-K30:244FP achieved its best performance in terms of dissolution at the ratio of 1:1:1 when PVP-K30 and mesoporous silica Syloid 244FP (244FP) were chosen as combined carrier. SEM, DSC, and XRD studies indicated that furosemide existed in an amorphous form in the solid dispersion. FT-IR and molecular docking analysis showed that there might be an intermolecular interaction between FMD and the carrier. Moreover, the in vivo pharmacokinetics study revealed that the bioavailability of solid dispersion in rats had significant improvement. In particular, Cmax and AUClast were greatly increased by 2.69- and 2.08-fold in the solid dispersion (FMD-PVP-K30-244FP) group, respectively, and the relative bioavailability was 208.00%. In conclusion, the solid dispersion (FMD-PVP-K30-244FP) can significantly improve the solubility and oral bioavailability of furosemide. Mesoporous silica can be used as an excellent carrier material for furosemide, which can provide new ideas and methods for improving the stability of solid dispersion and further improving the dissolution of insoluble drugs.

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Correction to: In Vivo and In Vitro Taste Assessment of Artesunate-Mefloquine, Praziquantel, and Benznidazole Drugs for Neglected Tropical Diseases and Pediatric Patients

Janine Boniatti, Marcelo R. R. Tappin, Rafaela G. da S Teixeira, Tamires de A V Gandos, Luis P. S. Rios, Izabelle A. M. Ferreira, Karina C. Oliveira, Sabrina Calil-Elias, Aila K. M. Santana, Laís B. da Fonseca, Flavio M. Shimizu, Olívia Carr, Osvaldo N. Oliveira Jr, Fabio M. L. Dantas, Fabio C. Amendoeira & Alessandra L. Viçosa

doi : 10.1208/s12249-022-02216-w

AAPS PharmSciTech volume 23, Article number: 64 (2022) 

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Development and Validation of HPLC Method for Efinaconazole: Application to Human Nail Permeation Studies

Praveen Kolimi, Vijay Kumar Shankar, Abhishek Shettar, Srinath Rangappa, Michael A. Repka & S. Narasimha Murthy

doi : 10.1208/s12249-021-02196-3

AAPS PharmSciTech volume 23, Article number: 63 (2022) 

Efinaconazole is the first azole derivative approved by FDA for the topical treatment of onychomycosis. The objective of present study was to develop and validate HPLC method for estimation of efinaconazole in ex vivo human nail permeation study samples. The chromatographic analysis was performed on a HPLC system equipped with diode array detector. The efinaconazole and internal standard (IS) were extracted from the human nail samples by using the protein precipitation method. The samples were injected on to 5 ?m Polar C18 100Å, 4.6 mm × 150 mm column. The mobile phase consisted of 0.01 M potassium dihydrogen phosphate: acetonitrile (36:64) and eluent was monitored at 205 nm. The chromatographic separation of drug and analyte was achieved using isocratic elution at flow rate of 1 mL/min with a total run time of 15 min. The efinaconazole and IS were eluted at 6.4 ± 0.5 and 8.3 ± 0.5 min, respectively. The developed method was validated as per FDA guidelines, and the results met with acceptance criteria. The method developed was specific, and the analyte concentrations were linear at range of 50 to 10000 ng/mL (R2 ? 0.9981). The validated HPLC method was applied for quantifying efinaconazole in human nail permeation study samples. The permeation of efinaconazole was increased by twofolds with Labarfac CC (15135.4 ± 2233.9 ng/cm2) compared to formulations containing Transcutol P (6892.0 ± 557.6 ng/cm2) and Labrasol (7266.1 ± 790.6 ng/cm2). The study results demonstrate that developed efinaconazole HPLC method can be employed for formulation evaluation and clinical studies.

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QbD Approach towards Robust Design Space for Flutamide/PiperineSelf-Emulsifying Drug Delivery System with Reduced Liver Injury

Mithun Saha, Pallabi Sikder, Aditi Saha, Sharha Shah, Sharmin Sultana, Tushar Emran, Ananna Banik, Zahidul Islam, Muhammad Saiful Islam, Shazid Md. Sharker & Hasan Mahmud Reza

doi : 10.1208/s12249-022-02213-z

AAPS PharmSciTech volume 23, Article number: 62 (2022) 

Flutamide which is used to treat prostate cancer and other diseases induces liver damage during and after the therapy. The aim of this study was to develop a flutamide/piperineco-loaded self-emulsifying drug delivery system (FPSEDDS) to inhibit flutamide-induced liver injury by utilizing piperine as a metabolic inhibitor. The development of SEDDS was carried out following a quality by design (QbD) approach. The risk assessment study was performed to identify critical quality attributes (CQAs) and critical material attributes (CMAs)/critical process parameters (CPPs). I-optimal mixture design was executed with three CMAs as the independent variables and CQAs as the dependable variables. The effectiveness of optimized SEDDS to circumvent flutamide-induced hepatotoxicity was assessed in mice. The numerical optimization suggested an optimal formulation with a desirability value of 0.621, using CQAs targets as optimization goals with 95% prediction intervals (? = 0.05). The optimal formulation exhibited the grade A SEDDS characteristics with the guarantee of high payloads in self-formed oily droplets. The design space was also obtained from the same optimization goals. All CQA responses of verification points were found within the 95% prediction intervals of the polynomial models, indicating a good agreement between actual versus predicted responses within the design space. These obtained responses also passed CQAs acceptance criteria. Finally, hematoxylin-eosin staining revealed the minimal flutamide-induced hepatotoxicity from the optimal SEDDS formulation as compared to the control and flutamide/piperine normal suspension. We demonstrate that the piperine containing optimized SEDDS formulation developed by QbD significantly reduces the flutamide-induced liver injury in mice.

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Transdermal Enhancement Strategy of Lappaconitine: Alteration of Keratin Configuration by Counter-Ion

Mingxin Li, Chao Liu, Yu Cai, Haoyuan Song & Liang Fang

doi : 10.1208/s12249-021-02190-9

AAPS PharmSciTech volume 23, Article number: 61 (2022) 

The objective of this study was to develop a lappaconitine (LA) transdermal patch with counter-ion to increase the transdermal permeability of the drug, and a theory of counter-ion altering the conformation of the skin keratin was put forward based on the in vitro skin permeation study and physicochemical properties of ion-pairs. Formulation factors including pressure sensitive adhesives (PSAs), drug-loading, counter-ions and molar ratios of counter-ion were screened by in vitro skin permeation study. The optimized formulation was composed of 7% LA, 1.5 mole cinnamic acid and AAOH (PSA containing hydroxyl group synthesized by our laboratory) as an adhesive matrix. The optimized patch was evaluated by the pharmacokinetic and analgesic pharmacodynamic studies. AUC0–t and pain inhibition ratio of the optimized patch were 2450.40 ± 848.52 h ng/mL and 81.18%, which showed good absorption into the skin and excellent analgesic effect. The mechanism of facilitated transdermal drug permeation by counter-ion was investigated by ATR-FTIR, thermal analysis, FTIR, XPS and molecular docking. The results indicated that after the formation of ion-pairs, the excess counter-ions would alter the conformation of the skin keratin, thus increasing the transdermal penetration of LA. In conclusion, the LA patch was successfully optimized, and the effect of counter-ions on the skin was clarified at the molecular level. These findings provided additional references for the application of counter-ion in the transdermal drug delivery system.

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Implementing the Design of Experiments (DoE) Concept into the Development Phase of Orodispersible Minitablets (ODMTs) Containing Melatonin

Arkadiusz Hejduk, Micha? Te?yk, Emilia Jakubowska, Klaudia Krüger & Janina Lulek

doi : 10.1208/s12249-021-02185-6

AAPS PharmSciTech volume 23, Article number: 60 (2022) 

Development of orodispersible minitablets (ODMTs) requires consideration of aspects related to small dimensions, while ensuring short disintegration time with sufficient mechanical stability. In order to meet these and other critical quality attributes (CQAs), quality by design is encouraged. According to this approach, formulation and compression process factors were systematically studied using design of experiments (Plackett-Burman for screening purposes, full and fractional factorial design for in-depth characterization) to understand their influence on CQAs of orodispersible minitablets containing melatonin. Mathematical models describing the relationships between processing variables and attributes such as resistance to crushing and disintegration time were successfully developed, characterized by high coefficients of determination (R2adj = 0.90–0.97) and prediction errors in the range (+2.4 to ?10.8%). In conclusion, based on these models, the design space was created for melatonin ODMTs, ensuring the product’s quality and process robustness. Moreover, the study demonstrated the suitability of texture analysis as an alternative to compendial measurement methods of resistance to crushing and disintegration time.

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Computational Modeling of Drying of Pharmaceutical Wet Granules in a Fluidized Bed Dryer Using Coupled CFD-DEM Approach

Hossain Aziz, Syed N. Ahsan, Giovanni De Simone, Yijie Gao & Bodhisattwa Chaudhuri

doi : 10.1208/s12249-021-02180-x

AAPS PharmSciTech volume 23, Article number: 59 (2022) 

Drying of wet granules in a fluidized bed dryer is an important part of the pharmaceutical tablet manufacturing process. Complicated gas-solid flow patterns appear in the fluidized bed dryer, and interphase momentum, heat, and mass transfer happen during the drying process. A coupled computational fluid dynamics (CFD)-discrete element method (DEM)-based approach was used to model the drying process of pharmaceutical wet granules in a fluidized bed dryer. The evaporation of water from the surfaces of the particles and the cohesion force between the particles due to the formation of liquid bridges between the particles were also considered in this model. The model was validated by comparing the model predictions with the experimental data available from the literatures. The validated model was used to investigate the drying kinetics of the wet granules in the fluidized bed dryer. The results from numerical simulations showed that the dynamics and rate of increase of temperature of wet particles were considerably different from those of dry particles. Finally, the model was used to investigate the effects of inlet air velocity and inlet air temperature on the drying process. The model predicted increase in drying rate with the increase of inlet air velocity and inlet air temperature. This model can help not only to understand the multiphase multicomponent flow in fluidized bed dryer but also to optimize the drying process in the fluidized bed dryer.

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Optimization of Spray-Drying Process Parameters to Study Anti-Sticking Effect of Hydroxypropyl Methyl Cellulose-VLV on Corni fructus Extracts

Hong Cheng, Chenghao Lu, Gangfeng Xu, Lijie Zhao, Min Lu & Youjie Wang

doi : 10.1208/s12249-022-02215-x

AAPS PharmSciTech volume 23, Article number: 58 (2022)

To prevent the sticking of Corni fructus extract (CFE) during spray drying, the anti-sticking effects of different excipients were compared. Hydroxypropyl methylcellulose (HPMC)-VLV showed a higher powder yield at a lower dosage (8% of total solids), and a lower solution viscosity, compared with HPMC-E5. Therefore, HPMC-VLV is a more effective excipient for reducing CFE sticking during spray drying. The spray-drying process parameters were optimized by central composite rotatable design/response surface methodology, and spray drying was conducted under the following conditions: Inlet air temperature, 126 °C; atomization pressure, 1.05 bar; pump speed, 7.7 mL/min. Scanning electron microscopy showed that the powder comprised shrunken spherical particles with particle sizes in the range of 2–30 ?m. Analysis of dynamic surface tension and chemical elements on the powder surface showed that HPMC-VLV rapidly moved to the droplet surface owing to its surface activity. HPMC covered the droplet surface and reduced surface tension, achieving an anti-sticking effect. In conclusion, HPMC-VLV at a solid content of 8% significantly improved the spray drying and reduced sticking of CFE. The spray-drying process parameters were nonlinearly related to the dry product yield.

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The Optimized Formulation of Tamoxifen-Loaded Niosomes Efficiently Induced Apoptosis and Cell Cycle Arrest in Breast Cancer Cells

Iman Akbarzadeh, Mahsa Farid, Mehrnoosh Javidfar, Negar Zabet, Bahare Shokoohian, Mandana Kazem Arki, Anastasia Shpichka, Hassan Noorbazargan, Hamid Asadzadeh Aghdaei, Nikoo Hossein-khannazer, Peter Timashev, Pooyan Makvandi & Massoud Vosough

doi : 10.1208/s12249-022-02212-0

AAPS PharmSciTech volume 23, Article number: 57 (2022) 

The aim, as proof of concept, was to optimize niosomal formulations of tamoxifen in terms of size, morphology, encapsulation efficiency, and release kinetics for further treatment of the breast cancer (BC). Different assays were carried out to evaluate the pro-apoptotic and cytotoxicity impact of tamoxifen-loaded niosomes in two BC cells, MDA-MB-231 and SKBR3. In this study, tamoxifen was loaded in niosomes after optimization in the formulation. The formulation of niosomes supported maximized drug entrapment and minimized their size. The novel formulation showed improvement in storage stability, and after 60 days only, small changes in size, polydispersity index, and drug entrapment were observed. Besides, a pH-dependent release pattern of formulated niosomes displayed slow release at physiological pH (7.4) and a considerable increase of release at acidic pH (5.4), making them a promising candidate for drug delivery in the BC treatment. The cytotoxicity study exhibited high biocompatibility with MCF10A healthy cells, while remarkable inhibitory effects were observed after treatment of cancerous lines, MDA-MB-231, and SKBR3 cells. The IC50 values for the tamoxifen-loaded niosomes were significantly less than other groups. Moreover, treatment with drug-loaded niosomes significantly changed the gene expression pattern of BC cells. Statistically significant down-regulation of cyclin D, cyclin E, VEGFR-1, MMP-2, and MMP-9 genes and up-regulation of caspase-3 and caspase-9 were observed. These results were in correlation with cell cycle arrest, lessoned migration capacity, and increased caspase activity and apoptosis induction in cancerous cells. Optimization in the formulation of tamoxifen-loaded niosomes can make them a novel candidate for drug delivery in BC treatment.

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Creation of Hydrochlorothiazide Pharmaceutical Cocrystals Via Hot-Melt Extrusion for Enhanced Solubility and Permeability

Sagar Narala, Dinesh Nyavanandi, Abdullah Alzahrani, Suresh Bandari, Feng Zhang & Michael A. Repka

doi : 10.1208/s12249-021-02202-8

AAPS PharmSciTech volume 23, Article number: 56 (2022) 

Crystal engineering is an emerging tool for altering the physicochemical properties of drug candidates. The objective of the current investigation was to develop cocrystals of hydrochlorothiazide (HCT) with coformers such as nicotinamide (NIC), resorcinol (RSL), and catechol (CAT) using hot-melt extrusion (HME) technology. The liquid-assisted grinding (LAG) method was used to prepare cocrystals by grinding the drug and coformer in a definite molar ratio as a reference and to check the feasibility of cocrystal formation. Cocrystals were prepared using HME and evaluated with differential scanning calorimetry, Fourier transform infrared spectroscopy, X-ray diffractometry, and scanning electron microscopy and compared with LAG cocrystals. Barrel temperature was the critical process parameter for producing high-quality cocrystals in HME. All cocrystals exhibited improved solubility compared to the native drug, and HCT-NIC cocrystals showed a two-fold increase in solubility. Similarly, HCT-RSL and HCT-CAT showed higher solubility profiles and improved diffusion/permeability characteristics compared to that of the pure HCT due to the drug-coformer interactions in the cocrystals. In this study, the solubility of the coformer was the key factor determining cocrystal solubilization. However, hot-melt extrusion is an alternative technology for creating pharmaceutical cocrystals and has potential for industrial scale-up.

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Non-ionic Surfactants as a P-Glycoprotein(P-gp) Efflux Inhibitor for Optimal Drug Delivery—A Concise Outlook

Sachin Rathod, Heta Desai, Rahul Patil & Jayant Sarolia

doi : 10.1208/s12249-022-02211-1

AAPS PharmSciTech volume 23, Article number: 55 (2022) 

Significant research efforts have been devoted to unraveling the mystery of P-glycoprotein(P-gp) in drug delivery applications. The efflux membrane transporter P-gp is widely distributed in the body and accountable for restricting drug absorption and bioavailability. For these reasons, it is the primary cause of developing multidrug resistance (MDR) in most drug delivery applications. Therefore, P-gp inhibitors must be explored to address MDR and the low bioavailability of therapeutic substrates. Several experimental models in kinetics and dynamic studies identified the sensitivity of drug molecules and excipients as a P-gp inhibitor. In this review, we aimed to emphasize nonionic surface-active agents for effective reversal of P-gp inhibition. As it is inert, non-toxic, noncharged, and quickly reaching the cytosolic lipid membrane (the point of contact with P-gp efflux protein) enables it to be more efficient as P-gp inhibitors. Moreover, nonionic surfactant improves drug absorption and bioavailability through the various mechanism, involving (i) association of drug with surfactant improves solubilization, facilitating its cell penetration and absorption; (ii) weakening the lateral membrane packing density, facilitating the passive drug influx; and (iii) inhibition of the ATP binding cassette of transporter P-glycoprotein. The application of nonionic surfactant as P-gp inhibitors is well established and supported by various experiments. Altogether, herein, we have primarily focused on various nonionic surfactants and their development strategies to conquer the MDR-causing effects of P-gp efflux protein in drug delivery.

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Design of a Long-Acting Rivastigmine Transdermal Delivery System: Based on Computational Simulation

Xue Han, Jingchuan Liu, Xiaoyue Hu, Wei Wang & Qing Wang

doi : 10.1208/s12249-021-02207-3

AAPS PharmSciTech volume 23, Article number: 54 (2022) 

The purpose of our study was using a computational simulation to develop a long-acting patch of rivastigmine (RVS). A range of patch formulations were screened including pressure sensitive adhesive (PSA), pharmaceutical excipients, and controlled release membranes using transfer simulation based on a mathematical model. Diffusion dynamics parameters for simulated operations were acquired through in vitro release tests (IVRT) and in vitro skin permeation tests (IVPT). The mechanism of controlled release was studied by FTIR (Fourier transform infrared), DSC (differential scanning calorimeter) and molecular docking. Results of a rat in vitro permeation profile showed excellent correlation with the in vivo deconvolution profile (R2=0.998). Experiments testified to transfer of RVS at a relatively uniform speed with high skin permeation (2531.2±142.46 ?g/cm2) in 72 h. Pharmacokinetic data obtained in vivo also confirmed stable plasma concentrations over 72 h for the optimized patch, and significant prolongation of both Tmax (11.20±1.79 h) and MRT0-t (33.91±5.33 h). Cmax was controlled with AUC0-t (267.34±24.46 h ng/ml), which was closely comparable to parameters of a commercial Exelon® Patch. The successful development of a long-acting patch of RVS thus underscores the potential of computer aided design in a context of promnesic transdermal delivery.

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Simplified Model-Dependent and Model-Independent Approaches for Dissolution Profile Comparison for Oral Products: Regulatory Perspective for Generic Product Development

Sivacharan Kollipara, Rajkumar Boddu, Tausif Ahmed & Siddharth Chachad

doi : 10.1208/s12249-021-02203-7

AAPS PharmSciTech volume 23, Article number: 53 (2022) 

Dissolution profile comparison among different formulations plays a critical role during new drug as well as generic product development. In the generic product development, dissolution profile comparison is a mandate for biowaivers (BCS-based, for lower strengths and IVIVC-based biowaivers) and also from quality control perspective. Even though traditionally similarity factor or f2 is used as a metric for dissolution profile comparison, it comes with multiple limitations and requirements (e.g., number of time points and variability). To overcome this, regulatory agencies suggested model-independent (e.g., MSD) and model-dependent (e.g., zero order, Weibull) dissolution profile comparison methods. Although most of regulatory guidance documents mention about such approaches, their usage in reality is limited probably due to lack of clear, detailed, and step-wise procedure. In this context, the present article describes simplistic yet detailed procedures of dissolution profile comparison with case studies covering generic product development scenario’s from a regulatory perspective. Detailed review of regulatory guidances from various agencies was made along with examples of such approaches in regulatory submissions. Data from three formulations—Formulations A, B, and C—were utilized to perform dissolution profile comparison using MSD, zero-order, and Weibull release profile–based comparisons. Dissolution profile comparisons were made using all of these three approaches complying with regulatory requirements. These examples demonstrated value and utility of these approaches and the simplified and detailed procedure explained in this manuscript can be adapted for generic product applications.

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Comparison of HPMC Inhalation-Grade Capsules and Their Effect on Aerosol Performance Using Budesonide and Rifampicin DPI Formulations

Li Ding, Ashlee D. Brunaugh, Rishi Thakkar, Christian Lee, Qingyan Jenny Zhao, Justin Kalafat, Mohammed Maniruzzaman & Hugh D. C. Smyth

doi : 10.1208/s12249-021-02175-8

AAPS PharmSciTech volume 23, Article number: 52 (2022) 

Despite the fact that capsules play an important role in many dry powder inhalation (DPI) systems, few studies have been conducted to investigate the capsules’ interactions with respirable powders. The effect of four commercially available hydroxypropyl methylcellulose (HPMC)inhalation-grade capsule types on the aerosol performance of two model DPI formulations (lactose carrier and a carrier-free formulation) at two different pressure drops was investigated in this study. There were no statistically significant differences in performance between capsules by using the carrier-based formulation. However, there were some differences between the capsules used for the carrier-free rifampicin formulation. At 2-kPa pressure drop conditions, Embocaps® VG capsules had a higher mean emitted fraction (EF) (89.86%) and a lower mean mass median aerodynamic diameter (MMAD) (4.19 µm) than Vcaps® (Capsugel) (85.54%, 5.10 µm) and Quali-V® I (Qualicaps) (85.01%, 5.09 µm), but no significant performance differences between Embocaps® and ACGcaps™ HI. Moreover, Embocaps® VG capsules exhibited a higher mean respirable fraction (RF)/fine particle fraction (FPF) with a 3-µm–sized cutoff (RF/FPF< 3 µm) (33.05%/35.36%) against Quali-V® I (28.16%/31.75%) (P?<?0.05), and a higher RF/FPF with a 5-µm–sized cutoff (RF/FPF< 5 µm) (49.15%/52.57%) versus ACGcaps™ HI (38.88%/41.99%) (P?<?0.01) at 4-kPa pressure drop condition. Aerosol performance variability, pierced-flap detachment, as well as capsule hardness and stiffness, may all influence capsule type selection in a carrier-based formulation. The capsule type influenced EF, RF, FPF, and MMAD in the carrier-free formulation.

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Preparation and Evaluation of Polyvinylpyrrolidone Electrospun Nanofiber Patches of Pioglitazone for the Treatment of Atopic Dermatitis

Rana Obaidat, Ayat Abu Shameh, Mohannad Aljarrah & Rania Hamed

doi : 10.1208/s12249-021-02204-6

AAPS PharmSciTech volume 23, Article number: 51 (2022) 

Nanofibers have many promising biomedical applications. They can be used for designing transdermal and dermal drug delivery systems. This project aimed to prepare and characterize polyvinylpyrrolidone-based nanofibers as a dermal and transdermal drug delivery system using pioglitazone. Pioglitazone is an oral antidiabetic drug. In addition, it can act as an inflammatory process modulator, making it a good candidate for managing different skin inflammatory conditions such as atopic dermatitis, skin ulcers, and diabetic foot wound healing. Several nanofiber formulations were prepared using the electrospinning method at different drug loadings, polyvinylpyrrolidone concentrations, and flow rates. A cast film with the exact composition of selected nanofiber formulations was prepared as a control. Nanofibers were characterized using a scanning electron microscope to calculate the diameter. Fourier-transform infrared spectroscopy, differential scanning calorimetry, thermogravimetric analysis, and powder X-ray diffraction were performed for physical and biochemical characterizations. In vitro release, drug loading efficiency, and swelling studies were performed. Ex vivo permeation studies were performed using Franz diffusion cells with or without applying a solid microneedle roller. Round uniform nanofibers with a smooth surface were obtained. The diameter of nanofibers was affected by the drug loading and polymer concentration. Fourier-transform infrared spectra showed a potential physical interaction between the drug and the polymer. According to X-ray diffraction, pioglitazone existed in an amorphous form in prepared nanofibers, with partial crystallinity in the casted film. Nanofibers showed a higher swelling rate compared to the casted film. The drug dissolution rate for nanofibers was 2.3-folds higher than the casted films. The polymer concentration affected the drug dissolution rate for nanofibers; however, drug loading and flow rate did not affect the drug dissolution rate for nanofibers. The application of solid microneedles slightly enhances the total amount of drug permeation. However, it did not affect the flux of the drug through the separated epidermis layer for pioglitazone. The drug permeation flux in nanofibers was approximately five times higher than the flux of the casted film. It was observed that pioglitazone is highly retained in skin layers.

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Optimization and Application of an Efficient and Stable Inhalation Exposure System for Rodents

Zi Fan, Bo Zhou, Yujia Liu, Wu Sun, Yuntao Fang, Hongguo Lu, Dongya Chen, Kuikui Lu, Xinyue Wu, Tian Xiao, Wenjing Xie & Qian Bian

doi : 10.1208/s12249-021-02191-8

AAPS PharmSciTech volume 23, Article number: 50 (2022) 

Inhalation is a promising and challenging method in pharmaceutical and biological science research. A stable environment is critical in dynamic inhalation administration. However, the establishment of a stable inhalation system is very challenging. Indacaterol glycopyrronium bromide inhalation powder (IM/GP mixed powder) is composed of indacaterol maleate and glycopyrronium bromide powder to treat chronic obstructive pulmonary disease (COPD). The aim of this study is to build suitable inhalation conditions and then to evaluate the pulmonary safety of this drug in Sprague-Dawley(SD) rats. In the research, through the coordination of the atomization flow, air pump flow, and scraper speed, aerosols were stabilized at 200 ± 20% mg/m3, and then rats were nose-only administered with the IM/GP mixed powder, Ultibro, and lactose-magnesium stearate mixed powder at 2.6 mg/kg/day for 14 days and 14 days of recovery period, respectively. After exposure, hematology, inflammatory cytokines in rats bronchoalveolar lavage fluid (BALF) and serum, histopathological examination were performed. Results showed that the stability of powder aerosols can be realized under the atomization generation flow: 10 L/min, sampling flow: 2 L/min, system pumping capacity: 10 L/min and powder scraper speed: 8–10 L/min, and there were no significant adverse effects on body weight, clinic signs, hematology, and pathology in rats. Overall, the results suggested that the IM/GP mixed powder inhalation at the dose of 2.6 mg/kg/d can be reached when the aerosol concentration is within the range of 200 ± 20% mg/m3, and there were no pulmonary toxicity effects in rats.

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Transdermal Delivery of Curcumin-Loaded Solid Lipid Nanoparticles as Microneedle Patch: an In Vitro and In Vivo Study

Ankitha Prabhu, Jobin Jose, Lalit Kumar, S Salwa, M Vijay Kumar & Seyed Mohammad Nabavi

doi : 10.1208/s12249-021-02186-5

AAPS PharmSciTech volume 23, Article number: 49 (2022) 

Curcumin is well known for its neuroprotective effect, and also able to alleviate Parkinsonian features. Clinical application of curcumin is limited due to its low bioavailability. Hence, we hypothesized that the microneedles (MN) containing drug-loaded solid lipid nanoparticles (SLNs) may be able to improve its bioavailability and efficacy. The SLNs were prepared with microemulsion technique using glyceryl monostearate as a lipid and tween 80 as a stabilizer. The particle size, polydispersity index, zeta potential, and entrapment efficiency of prepared SLNs were determined. The optimized formulation was incorporated into microneedle arrays using micromolding technique and fabricated microneedle patch were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, optical microscopy, ex vivo permeation studies, histology studies, and fluorescent microscopy. The fabricated microneedle patch was also evaluated for neuroprotective activity and skin irritation potential. Fourier transform infrared spectroscopy studies of SLNs and microneedles confirmed the chemical compatibility of excipients with curcumin. The developed microneedles were also found to be non-irritant with decreased degree of bradykinesia, high motor coordination, and balance ability. The study provided a theoretical basis for the use of novel microneedle containing curcumin-loaded solid lipid nanoparticles as a useful tool for the treatment of Parkinson’s disease.

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Solid Dispersions of Gefitinib Prepared by Spray Drying with Improved Mucoadhesive and Drug Dissolution Properties

Wesam W. Mustafa, John Fletcher, Mouhamad Khoder & Raid G. Alany

doi : 10.1208/s12249-021-02187-4

AAPS PharmSciTech volume 23, Article number: 48 (2022) 

Gefitinib is a tyrosine kinase inhibitor that is intended for oral administration yet suffers poor bioavailability along with undesirable side effects. To enhance its solubility and allow colon targeting, gefitinib (ZD) and blends of different ratios of polymers (ternary dispersion) were prepared in organic solution, and solid dispersions were generated employing the spray drying (SD) technique. The methylmethacrylate polymer Eudragit S 100 was incorporated for colon targeting; polyvinylpyrrolidone (PVP) and hydroxypropyl methyl cellulose (HPMC) were utilised to improve the solubility of ZD. SEM, DSC, XRPD, FT-IR, dissolution and cytotoxicity studies were undertaken to characterise and evaluate the developed formulations. SEM images revealed that the rod-shaped crystals of ZD were transformed into collapsed spheres with smaller particle size in the spray-dried particles. DSC, FTIR and XRPD studies showed that ZD loaded in the spray-dried dispersions was amorphous. ZD dissolution and release studies revealed that while a significant (P < 0.05) increase in the ZD dissolution and release was observed from HPMC-based solid dispersion at pH 7.2 (up to 95% in 15 h), practically no drug was released at pH 1.2 and pH 6.5. Furthermore, the HPMC-based solid dispersions displayed enhanced mucoadhesive properties compared with PVP-based ones. Interestingly, cell viability studies using the neutral red assay showed that PVP and HPMC-based solid dispersions had no additional inhibitory effect on Caco-2 cell line compared to the pure drug.

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Assessment of Abrasion-Induced Visual Defects in Twin Screw Wet Granulation Using Wall Friction Measurements

Judith Menth, Martin Maus & Karl G. Wagner

doi : 10.1208/s12249-021-02140-5

AAPS PharmSciTech volume 23, Article number: 47 (2022) 

Starting point of the presented study were abrasion effects occurring during a twin screw wet granulation (TSG) process of a new chemical entity (NCE) formulation, resulting in gray spots on the final tablets. Several actions and systematic changes of equipment and process parameter settings of TSG process were conducted which reduced the visual defect rate of the tablets, i.e., gray spots on the surface, below the specification limit. To understand the rationale and mechanism behind these improvements, correlations of defect rates and wall friction measurements using a Schulze ring shear tester were evaluated. To check the suitability of the method, a broad range of wall materials as well as powder formulations at various moisture levels were investigated with regard to their wall friction angle. As differences in wall friction angle could be detected, further experiments were conducted using wall material samples made out of different screw materials for TSG. Evaluation of these screw wall material samples gave first hints, which screw materials should be preferred in regard of friction for TSG process. In the finally presented case study, wall friction measurements were performed using the above mentioned NCE formulation with known abrasion issues at TSG processing. The results confirmed that changes which led to a reduced visual defect rate of tablets correlated with a decreased wall friction angle. The results suggest wall friction measurements as a potent tool for equipment selection and establishment of a suitable process window prior to conducting TSG experiments.

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Transdermal Film Loaded with Avanafil Ultra-deformable Nanovesicles to Enhance its Percutaneous Absorption and Bioavailability

Omar D. Al-hejaili, Abdullah A. Alamoudi, Osama A. A. Ahmed & Khalid M. El-Say

doi : 10.1208/s12249-021-02195-4

AAPS PharmSciTech volume 23, Article number: 46 (2022) 

The in vitro dissolution of Avanafil (AVA) is the rate-limiting step for its bioavailability. Also, it undergoes the first-pass metabolism, and its absorption is altered significantly in the presence of food. So, our study aimed to overcome the previous hurdles and improve the AVA bioavailability by its incorporation in the ultra-deformable nanovesicles, transfersomes (TRF), then loading these nanovesicles in transdermal films. The AVA-loaded TRF formulation was optimized using Draper-Lin small composite design (D-LSCD). The optimized AVA-loaded TRF was evaluated for quality attributes and assessed for skin permeation using a fluorescence laser microscope and for pharmacokinetic parameters after topical application on the rats. The optimized AVA-loaded TRF showed a vesicle size of 97.75 nm, a zeta potential of ?28.83 mV, and entrapment efficiency of 95.14% with good deformability and release profile. The intense discoloration in the deep skin layers of the rats indicated the permeation efficiency of AVA-loaded TRF films. The pharmacokinetic parameters specified the augmented absorption extent with Cmax of 254.66 ± 8.02 ng/mlversus 70.33 ± 3.05 ng/ml which reflected on the AUC0-inf that has a value of 2050.45 ± 159.14 ng/ml h versus 497.34 ± 102.61 ng/ml h for the optimized AVA-loaded TRF film and raw AVA-loaded film, respectively. These promising results wide open the field for broader clinical application of this alternative delivery pathway for superior bioavailability, efficacy, and patient compliance and satisfaction.

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Cyclodextrin/Adamantane-Grafted Polyethylene Glycol–Based Self-assembling Constructs for Topical Delivery of Ketorolac Tromethamine: Formulation, Characterization, and In Vivo Studies

Ahmed A. H. Abdellatif, Ahmed M. Mohammed, Gamal Zayed, Saleh Abd El-Rasoul, Saud Almawash, Mohamed A. Safwat & Shaaban K. Osman

doi : 10.1208/s12249-021-02188-3

AAPS PharmSciTech volume 23, Article number: 45 (2022) 

Topical formulation of non-steroidal anti-inflammatory drugs (NSAIDs) exhibits many advantages over the oral administration route, such as avoiding the direct effect on GIT and avoiding the poor oral bioavailability of such drugs. Our study aims to develop a new self-assembling construct based on the hydrophobic interaction between adamantane terminated poly (ethylene glycol) polymers and polymerized ?-cyclodextrin. The viscous constructs were developed from direct mixing of host and guest polymer solutions, indicating spontaneous formation without cross-linkers. The modified system was evaluated by different analyses, including X-ray diffractometry, electron microscopy, isothermal titration calorimetry, and rheological analysis. Moreover, such a system’s ability for drug loading and release was investigated via the in vitro release of ketorolac tromethamine (KT) as a model of NSAIDs. Finally, the prepared formulas were applied on a rat paw edema model to prove the enhanced anti-inflammatory activities. The obtained results indicated that the modified constructs have a rubbery porous structure with an amorphous nature. Also, from rheological results, the modified system exhibited a viscous behavior with higher loss modulus (G?) compared with storage (G?). The inclusion complexation between cyclodextrin and adamantane moieties was proved by the recorded high binding constants with a 1:1 stoichiometric ratio. Furthermore, the results showed the successful KT incorporation into the modified system and quantitatively released through a semi-permeable membrane in a sustained fashion (over 24 h). Finally, the in vivo results of the medicated constructs showed a significant inhibition of the induced inflammation and swelling, indicating that the modified construct has a great utility for safe non-irritating topical delivery applications.

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Scrutinizing the Feasibility of Nonionic Surfactants to Form Isotropic Bicelles of Curcumin: a Potential Antiviral Candidate Against COVID-19

Dina B. Mahmoud, Mohamed Mofreh Bakr, Ahmed A. Al-karmalawy, Yassmin Moatasim, Ahmed El Taweel & Ahmed Mostafa

doi : 10.1208/s12249-021-02197-2

AAPS PharmSciTech volume 23, Article number: 44 (2022)

Investigating bicelles as an oral drug delivery system and exploiting their structural benefits can pave the way to formulate hydrophobic drugs and potentiate their activity. Herein, the ability of non-ionic surfactants (labrasol®, tween 80, cremophore EL and pluronic F127) to form curcumin loaded bicelles with phosphatidylcholine, utilizing a simple method, was investigated. Molecular docking was used to understand the mechanism of bicelles formation. The % transmittance and TEM exhibited bicelles formation with labrasol® and tween 80, while cremophor EL and pluronic F127 tended to form mixed micelles. The surfactant-based nanostructures significantly improved curcumin dissolution (99.2 ± 2.6% within 10 min in case of tween 80-based bicelles) compared to liposomes and curcumin suspension in non-sink conditions. The prepared formulations improved curcumin ex vivo permeation over liposomes and drug suspension. Further, the therapeutic antiviral activity of the formulated curcumin against SARS-CoV-2 was potentiated over drug suspension. Although both Labrasol® and tween 80 bicelles could form bicelles and enhance the oral delivery of curcumin when compared to liposomes and drug suspension, the mixed micelles formulations depicted superiority than bicelles formulations. Our findings provide promising formulations that can be utilized for further preclinical and clinical studies of curcumin as an antiviral therapy for COVID-19 patients.

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Novel Co-crystals and Eutectics of Febuxostat: Characterization, Mechanism of Formation, and Improved Dissolution

Moksh Jagia, Dnyaneshwar P. Kale, Arvind Kumar Bansal & Sarsvatkumar Patel

doi : 10.1208/s12249-021-02182-9

AAPS PharmSciTech volume 23, Article number: 43 (2022) 

Co-crystallization studies were undertaken to improve the solubility of a highly water-insoluble drug febuxostat (FXT), used in the treatment of gout and hyperuricemia. The selection of co-crystal former (CCF) molecules such as 1-hydroxy 2-naphthoic acid (1H-2NPH), 4-hydroxy benzoic acid (4-HBA), salicylic acid (SAC), 5-nitro isophthalic acid (5-NPH), isonicotinamide (ISNCT), and picolinamide (PICO) was based on the presence of complementary functional groups capable of forming hydrogen bond and the ?pKa difference between FXT and CCF. A liquid-assisted grinding (LAG) method was successfully employed for the rapid screening of various pharmaceutical adducts. These adducts were characterized based on their unique thermal (differential scanning calorimetry) and spectroscopic (Fourier transform infrared and Raman spectroscopy) profiles. Binary phase diagrams (BPD) were plotted to establish a relationship between the thermal events and adduct formed. Powder X-ray diffraction (PXRD) studies were carried out to confirm the formation of eutectic/co-crystal. Thermogravimetric analysis (TGA) was also performed for the novel co-crystals obtained. The propensity for strong homo-synthons over weak hetero-synthons and strong hetero-synthons over weak homo-synthons during supramolecular growth resulted in the formation of eutectics and co-crystals respectively. FXT:1H-2NPH (1), FXT:4-HBA (1), FXT:SAC (1, 2), and FXT:5-NPH (2-1) gave rise to pure eutectic systems, while FXT:ISNCT (2-1) and FXT:PICO (1) gave rise to novel co-crystals with characteristic DSC heating curves and PXRD pattern. Additionally, the impact of microenvironmental pH and microspeciation profile on the improved dissolution profile of the co-crystals was discussed.

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Solubility Study of Acetylsalicylic Acid in Ethanol + Water Mixtures: Measurement, Mathematical Modeling, and Stability Discussion

Ali Nokhodchi, Taravat Ghafourian, Nour Nashed, Kofi Asare-Addo, Elmira Behboudi, Yasaman Sefid-Sefidehkhan, Aynaz Zarghampour, Elaheh Rahimpour & Abolghasem Jouyban

doi : 10.1208/s12249-021-02192-7

AAPS PharmSciTech volume 23, Article number: 42 (2022) 

Solubility determination of poorly water-soluble drugs is pivotal for formulation scientists when they want to develop a liquid formulation. Performing such a test with different ratios of cosolvents with water is time-consuming and costly. The scarcity of solubility data for poorly water-soluble drugs increases the importance of developing correlation and prediction equations for these mixtures. Therefore, the aim of the current research is to determine the solubility of acetylsalicylic acid in binary mixtures of ethanol+water at 25 and 37°C. Acetylsalicylic acid is non-stable in aqueous solutions and readily hydrolyze to salicylic acid. So, the solubility of acetylsalicylic acid is measured in ethanolic mixtures by HPLC to follow the concentration of produced salicylic acid as well. Moreover, the solubility of acetylsalicylic acid is modeled using different cosolvency equations. The measured solubility data were also predicted using PC-SAFT EOS model. DSC results ruled out any changes in the polymorphic form of acetylsalicylic acid after the solubility test, whereas XRPD results showed some changes in crystallinity of the precipitated acetylsalicylic acid after the solubility test. Fitting the solubility data to the different cosolvency models showed that the mean relative deviation percentage for the Jouyban-Acree model was less than 10.0% showing that this equation is able to obtain accurate solubility data for acetylsalicylic acid in mixtures of ethanol and water. Also, the predicted data with an average mean relative deviation percentage (MRD%) of less than 29.65% show the capability of the PC-SAFT model for predicting solubility data. A brief comparison of the solubilities of structurally related solutes to acetylsalicylic acid was also provided.

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Progress and Principle of Drug Nanocrystals for Tumor Targeted Delivery

Meng Bai, Mingshi Yang, Junbo Gong, Hui Xu & Zhenping Wei

doi : 10.1208/s12249-021-02200-w

AAPS PharmSciTech volume 23, Article number: 41 (2022) 

Drugs are referred to as drug nanocrystals when they exist as nanoscale crystal structures. This kind of nanocarrier has been widely utilized to increase the solubility and absorption for poorly aqueous soluble drugs after oral administration, or prolong the drug circulation when intravenous administration. The systemic cytotoxicity caused by antitumor drugs usually come from the nonspecific drug distribution. To solve the disadvantage of poor targetability, drug nanocrystals for tumor targeted delivery have been developed in recent years. In this review, the targeting mechanisms of various surface modified drug nanocrystals are introduced with the focus on passive targeting, active targeting and stimuli-responsive targeting in details. Function and application of common surface modified materials are also discussed.

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Characterization of the Morphological Nature of Hollow Spray Dried Dispersion Particles Using X-ray Submicron-Computed Tomography

John F. Gamble, Mike Tobyn, Shawn Zhang, Aiden Zhu, Jakub Šalplachta, Jan Matula, Tomáš Zikmund, Jozef Kaiser & Peter Oberta

doi : 10.1208/s12249-021-02184-7

AAPS PharmSciTech volume 23, Article number: 40 (2022)

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A Customized Screening Tool Approach for the Development of a Self-Nanoemulsifying Drug Delivery System (SNEDDS)

Fabian-Pascal Schmied, Alexander Bernhardt, Andrea Engel & Sandra Klein

doi : 10.1208/s12249-021-02176-7

AAPS PharmSciTech volume 23, Article number: 39 (2022) 

The present study focused on establishing a novel, (pre-)screening approach that enables the development of promising performing self-nanoemulsifying drug delivery systems (SNEDDSs) with a limited number of experiments. The strategic approach was based on first identifying appropriate excipients (oils/lipids, surfactants, and co-solvents) providing a high saturation solubility for lipophilic model compounds with poor aqueous solubility. Excipients meeting these requirements were selected for SNEDDS development, and a special triangular mixture design was applied for determining excipient ratios for the SNEDDS formulations. Celecoxib and fenofibrate were used as model drugs. Formulations were studied applying a specific combination of in vitro characterization methods. Specifications for a promising SNEDDS formulation were self-imposed: a very small droplet size (<?50 nm), a narrow size distribution of these droplets (PDI?<?0.15) and a high transmittance following SNEDDS dispersion in water (>?99% in comparison with purified water). Excipients that provided a nanoemulsion after dispersion were combined, and ratios were optimized using a customized mapping method in a triangular mixture design. The best performing formulations were finally studied for their in vitro release performance. Results of the study demonstrate the efficiency of the customized screening tool approach. Since it enables successful SNEDDS development in a short time with manageable resources, this novel screening tool approach could play an important role in future SNEDDS development.

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Effect of Manufacturing Process on the Retention of Abuse-Deterrent Properties of PEO-Matrix Tablets

Leyla Rezaei, Saikishore Meruva & Maureen D. Donovan

doi : 10.1208/s12249-021-02169-6

AAPS PharmSciTech volume 23, Article number: 38 (2022) 

Polyethylene oxide (PEO) is a widely used polymer in the development of abuse-deterrent oral formulations. Different manufacturing processes including direct compression (DC) followed by sintering, wet granulation (WG) followed by compression and sintering, and hot melt extrusion (HME) can be used to manufacture abuse-deterrent oral drug products. Three different manufacturing processes (DC, WG, HME) were evaluated to test the retention of their abuse-deterrent features following attempts to grind the tablets or extrudates. In vitro drug release studies were conducted on 10% and 32% drug-loaded tablets/extrudates prepared using these manufacturing methods, and the release profiles from all formulations showed good extended-release properties. Drug content analysis on the granules obtained from tablets prepared by direct compression showed non-uniform drug distribution where an unexpectedly high drug content was present in the smallest size (<?250 µm) granules, sizes which are likely to be inhaled by abusers. Granules from tablets prepared by wet granulation showed improved drug distribution across all granule sizes formed after grinding. Drug content testing on the granules obtained from extrudates prepared using hot melt extrusion showed excellent drug content uniformity along with sufficient strength to resist grinding into smaller particles. The retention of the abuse-deterrent properties of a dosage form following attempts to extract or abuse the drug is an important product characteristic, and the product design, formulation components, and manufacturing processes can all play critical roles in the retention of the desired abuse-deterrent properties.

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Orally Disintegrating Tablet Manufacture via Direct Powder Compression Using Cellulose Nanofiber as a Functional Additive

Shohei Nakamura, Tomomi Fukai & Takatoshi Sakamoto

doi : 10.1208/s12249-021-02194-5

AAPS PharmSciTech volume 23, Article number: 37 (2022) 

In recent years, orally disintegrating (OD) tablets have been continuously improved to increase efficacy. Herein, we focused on the benefits of cellulose nanofiber (CNF), a highly functional material, in OD tablet manufacturing. We studied its effects on the physical properties of tablets during manufacture. The analyzed tablet formulations included different content CNF (0–50%; 6 preparations), lactose hydrate, acetaminophen, and magnesium stearate (Mg-St). We measured the angles of repose and evaluated the flowability of the powder. Tablets were prepared on a tabletop and rotary tableting presses, whereafter their weight, drug content, hardness, friability, and disintegration time were evaluated. Although CNF addition slightly reduced powder flowability, continuous tableting was feasible via direct powder compression. Tablet hardness (~40 N) was comparable between CNF-containing (20%) tablets and those prepared with crystalline cellulose under 10 kN compression force. Disintegration time (~30 s) was similar between CNF-supplemented tablets and those supplemented with low-substituted hydroxypropyl cellulose, crospovidone, or croscarmellose sodium. At higher CNF fractions, tablet hardness increased, while friability decreased. Adding ?30% CNF prolonged the tablet disintegration time. To set the optimized manufacturing condition for ensuring the desired tablet physical properties, we created contour plots for evaluating the effects of CNF concentration and compression force on hardness and disintegration time. A CNF concentration of 10–20% and a compression force of 12–13 kN would allow for the preparation of tablets with a hardness ?30 N and a disintegration time ?60 s. Altogether, addition of CNF to the OD tablet formulation for direct powder compression enhanced hardness and disintegration.

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In Situ Liquid Crystal Gel as a Promising Strategy for Improving Ocular Administration of Dexamethasone: Preparation, Characterization, and Evaluation

Wenqing Wu, Wenxuan Cao, Jingbao Chen, Ye Cai, Baoqi Dong & Xiaoqin Chu

doi : 10.1208/s12249-021-02193-6

AAPS PharmSciTech volume 23, Article number: 36 (2022) 

The purpose of this study was to design an in situ liquid crystal gel (ISLG) as an ophthalmic drug delivery system for dexamethasone (DEX) to enhance its eye retention and ocular bioavailability. The in situ liquid crystal gels (ISLGs) were prepared using a phytantriol/PEG400/water (65:30:5, w/w) ternary system. Polarized light microscope (PLM), small-angle X-ray scattering (SAXS), and rheology analysis confirmed that the internal structure of the preparations was Pn3m cubic phase liquid crystal gels with pseudoplastic fluid properties. Meanwhile, in vitro release behavior of the preparations conforms to the Higuchi equation. Corneal penetration experiments showed that compared with DEX sodium phosphate eye drops, DEX-ISLGs(F2) produced a 5.45-fold increase in the Papp value, indicating a significant enhancement of corneal penetration. In addition, in vivo experiments have confirmed that the ISLGs have better biocompatibility and longer retention time in the cornea. Simultaneously, corneal hydration level, eye irritation experiments, and histological observations proved the safety of the preparations. Pharmacokinetic studies have shown that the ISLG could maintain the DEX concentration in aqueous humor for at least 12 h after administration, which significantly improves the bioavailability of the drug. Collectively, these results indicated that ISLG would be a potential drug carrier for the treatment of diabetic retinopathy (DR).

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Preparation and Characterization of Stable Amorphous Glassy Solution of BCS II and IV Drugs

Sathish Dharani, Khaldia Sediri, Phillip Cook, Rajendran Arunagiri, Mansoor A. Khan & Ziyaur Rahman

doi : 10.1208/s12249-021-02198-1

AAPS PharmSciTech volume 23, Article number: 35 (2022) 

The focus of the present investigation was to develop amorphous glassy solutions (AGSs) of BCS Class II and IV drugs using sucrose acetate isobutyrate (SAIB). The drugs studied were rifaximin (RFX), dasatinib (DST), aripiprazole (APZ), dolutegravir (DLT), cyclosporine (CYS), itraconazole (ITZ), tacrolimus (TAC), sirolimus (SRL), aprepitant (APT), and carbamazepine (CBZ). AGSs were prepared by dissolving known quantity of the drug in the SAIB at 120 (TAC and APZ), 140 (CYS) or 150 oC (RFX, DST, DLT, ITZ, SRL, APT, and CBZ). They were characterized visually and by NIR, NIR hyperspectroscopy (NIR-H), and XRPD. Stability were determined by exposing open vials to 40 oC/75% RH for a week. AGSs behave like a glassy solid at room temperature and liquified above 60 oC. The solubility of APT, DLT, SRL, APZ, RFX, CBZ, TAC and CYS in SAIB was 0.4±0.0, 1.7±0.4, 1.9±0.0, 21.6±2.6, 36.4±0.9, 76.5±4.0, 115.1±2.3, and 239.0±12.6 mg/g, respectively. NIR, NIR-H, and XRPD data indicated the amorphous nature of the AGSs. Furthermore, AGSs were stable against devitrification on exposure to high temperature and humidity. In summary, SAIB can be employed to develop stable AGSs of poorly soluble drugs to increase dissolution, and oral bioavailability with the addition of hydrophilic excipients.

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Formulation and Evaluation of Topical Biodegradable Films Loaded with Levofloxacin Lipid Nanocarriers

Rania S. Abdel-Rashid, Eman S. El-leithy & Raghda Abdel-monem

doi : 10.1208/s12249-021-02189-2

AAPS PharmSciTech volume 23, Article number: 34 (2022) 

Skin ulcers have increased sharply due to rise in the incidence of obesity and diabetes. This study investigated lipid nanocarriers as a strategy to improve the efficacy of levofloxacin (LV) in penetrating skin. Two surfactant types and different lipid mixtures were used in preparation of lipid nanocarriers. Mean particle size, percentage entrapment efficiency (%EE), in vitro release, and antimicrobial activity were examined. The selected formula was incorporated into a chitosan (CS) film that was subjected to physic-chemical characterization and ex vivo permeation study. The selected formula showed particle size, PDI, and ZP: 80.3 nm, ?0.21, and ?26 mV, respectively, synchronized with 82.12 %EE. In vitro release study showed slow biphasic release of LV from lipid nanocarriers. The antimicrobial effect illustrated statistically significant effect of lipid nanocarriers on decreasing the minimum effective concentration (MIC) of LV, particularly against E. coli. The optimized nanocarriers’ formula loaded into CS film was clear, colorless, translucent, and smooth in texture. Based on the release profiles, it could be speculated that the CS film loaded with LV nanocarriers can maintain the antibacterial activity for 4 consecutive days. Thus, the local delivery of the drug in a sustained release manner could be predicted to enhance the therapeutic effect. Further clinical studies are strongly recommended.

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Bimatoprost-Loaded Silica Shell–Coated Nanoparticles-Laden Soft Contact Lenses to Manage Glaucoma: In Vitro and In Vivo Studies

He Xiaojie, Jiang Fagang, Jing Jun, Wang Chunfang, Li Chengquan & Wang Xinghua

doi : 10.1208/s12249-021-02199-0

AAPS PharmSciTech volume 23, Article number: 33 (2022) 

Currently, glaucoma is managed by frequent instillation of bimatoprost eye drop therapy, which showed very poor ocular bioavailability. Contact lens is widely used as medical device to improve the drug retention on the ocular tissues. However, the traditional methods of drug loading in the contact lens matrix showed high burst release and changes the optophysical properties of the contact lens material. In this paper, a novel bimatoprost-loaded silica shell nanoparticles-laden soft contact lenses were developed to achieve sustain drug delivery without altering the optophysical properties of the contact lens. Silica-shell nanoparticles were prepared using octyltrimethoxysilane (OTMS) and microemulsion. Traditional soaking method (SM-BT), direct bimatoprost loading method (DL-BT), and microemulsion-laden contact lens (ME-BT) were developed for comparison. The silica shell-coated nanoparticles-laden soft contact lenses (SiS-BT) showed improved swelling, transmittance, oxygen permeability, and lysozyme adherence compared to SM-BT, DL-BT, and ME-BT lenses. The DL-BT and ME-BT batch showed high bimatoprost lost/leaching during extraction and sterilization steps, with low cumulative drug release. Also, SiS-BT lens showed sustain bimatoprost release for 96 h. In a rabbit tear fluid model, the SiS-BT lens showed high bimatoprost concentration for 72 h compared to ME-BT lens and eye drop therapy. Based on histopathological studies of cornea, the SiS-BT lens was found to be safe for human applications. The data demonstrated the novel application of silica shell nanoparticles to deliver bimatoprost from the contact lens for extended period of time without altering the optophysical properties of the contact lens.

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Nanostructured Lipid Carriers as a Novel Strategy for Topical Antifungal Therapy

Naiane Carvalho Nogueira, Laisa Lis Fontinele de Sá & André Luis Menezes de Carvalho

doi : 10.1208/s12249-021-02181-w

AAPS PharmSciTech volume 23, Article number: 32 (2022)

Nanostructured lipid carriers (NLC) were developed as an alternative carrier system optimizing limitations found in topical treatments for superficial fungal infections, such as limited permeation through the skin. However, few published studies are focused on standardization and characterization of determinant variables of these lipid nanosystems’ quality. Thus, this systematic review aims to compile information regarding the selection of lipids, surfactants, and preparation method that intimately relates to the final quality of this nanotechnology. For this, the search was carried with the following descriptors: 'nanostructured lipid carriers', 'topical', 'antifungal' separated by the Boolean operators 'and', present in the titles of the databases: Science Direct, Scopus and Pubmed. The review included experimental articles focused on the development of nanostructured lipid carriers targeted for topical application with antifungal activity, published from 2015 to 2021. Review articles, clinical studies, and studies on the development of other nanocarriers intended for other routes of administration were excluded from the study. The research included 26 articles, of which 58% were developed in India and Brazil, 53% published in the years 2019 and 2020. As for the selection of antifungal drugs incorporated into NLCs, the azole class had a preference over other classes, voriconazole being incorporated into 5 of the 26 developed NLC studied. It was also observed a predominance of medium chain triglycerides (MCT) as a liquid lipid and polysorbate 80 as a surfactant. Among other results, this review compiles the influences of each of the variables discussed in the quality parameters of NLCs, in order to guide future research involving the development of this technology.

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Preparation and Evaluation of rhINF-?-2b Sodium Hyaluronate Cross-Linked Porous Microspheres: Characterization, Sustained-Release Properties, and Antitumor Activity

Hongfei Liu, Yi Zou, Jie Zhu, Haibing He, Yingshu Feng, Caleb Kesse Firempong, Yang Yu & Changshan Sun

doi : 10.1208/s12249-021-02178-5

AAPS PharmSciTech volume 23, Article number: 31 (2022) 

Recombinant human interferon ?-2b (rhINF-?-2b), like most proteins, has several shortcomings such as relatively short half-life, low therapeutic index, high circulating drug fluctuations, and rapid degradation which could hinder its effective delivery. Novel electrostatic spray and ion exchange drug-loading techniques were combined to formulate rhINF-?-2b sodium hyaluronate cross-linked porous sustained-release microspheres (rhINF-?-2b-SHCPM), a protein delivery system. The different properties of rhINF-?-2b-SHCPM including the physicochemical nature, in vitro release behavior, and antitumor activity were evaluated. The loading rate (10.31 ± 0.94%) and encapsulation efficiency (89.09 ± 2.37%) of rhINF-?-2b-SHCPM produced acceptable values. The in vitro cumulative release rate of rhINF-?-2b-SHCPM within 24 h was also 86.26 ± 2.11% with a much better sustained release effect. Thus, the half-life (10.763 h) and retention time (14.067 h) of rhIFN?-2b-SHCPM were significantly prolonged with enhanced bioavailability (43,198.387 ng/L*h) and decreased peak concentration (15,266.4 ngL-1) compared with the free rhIFN?-2b protein (0.912 h, 0.952 h, 34,749.048 ng/L*h, and 48,870.2 ngL-1, respectively). The in vitro anti-proliferative activity and in vivo tumor inhibitory rate of rhIFN?-2b-SHCPM also increased by 90 and 55.86%, respectively, compared with the free rhIFN?-2b solution. The findings significantly supported a well-developed protein delivery system with improved sustained release, acceptable bioavailability, and increased antitumor activities.

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Correction to: Primaquine Loaded Solid Lipid Nanoparticles (SLN), Nanostructured Lipid Carriers (NLC), and Nanoemulsion (NE): Effect of Lipid Matrix and Surfactant on Drug Entrapment, in vitro Release, and ex vivo Hemolysis

Kai-Wei Wu, Corinne Sweeney, Narendar Dudhipala, Prit Lakhani, Narayan D. Chaurasiya, Babu L. Tekwani & Soumyajit Majumdar

doi : 10.1208/s12249-021-02171-y

AAPS PharmSciTech volume 23, Article number: 30 (2022) 

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Preparation and Anti-tumor Study of Dextran 70,000-Selenium Nanoparticles and Poloxamer 188-Selenium Nanoparticles

Zhenzhen Wang, Liyuan Ji, Yimeng Ren, Menghan Liu, Xiaoyu Ai & Cheng Yang

doi : 10.1208/s12249-021-02141-4

AAPS PharmSciTech volume 23, Article number: 29 (2022) 

The anti-tumor effect of selenium nanoparticles (SeNPs) has received more and more attention. However, the clinical application of SeNPs is not optimistic due to the poor stability. To improve the stability of SeNPs, many polymers are used to modify the SeNPs. However, most of the polymers are not approved by FDA. It is significant to develop a SeNPs product with good stability for clinic application. Dextran 70,000 (T70) and poloxamer 188 (P188) are FDA-approved pharmaceutical injection excipients. In this study, we decorate SeNPs with T70 and P188 and assess the physicochemical characterization, storage stability, and anti-tumor activities of T70-SeNPs and P188-SeNPs. Transmission electron microscopy (TEM) shows that T70-SeNPs and P188-SeNPs are spherical particles with particle sizes of 110 nm and 60 nm respectively. Fourier-Transform Infrared Spectra (FT-IR) show that T70 or P188 can interact with SeNPs through hydrogen bonding. Stability study shows that P188-SeNPs freeze-dried powder and T70-SeNPs freeze-dried powder remain stable at 4? for 6 months. T70-SeNPs and P188-SeNPs can aggregate in cell matrix and play an anti-tumor role to HepG2 by promoting apoptosis, increasing reactive oxygen species (ROS) content and reducing mitochondrial membrane potential (MMP). This study can provide reference for industrial production of SeNPs products.

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Optimization of Spray-Drying Parameters for Formulation Development at Preclinical Scale

Marika Nespi, Robert Kuhn, Chun-Wan Yen, Joseph W. Lubach & Dennis Leung

doi : 10.1208/s12249-021-02160-1

AAPS PharmSciTech volume 23, Article number: 28 (2022) 

Spray-drying dispersion (SDD) is a well-established manufacturing technique used to prepare amorphous solid dispersions (ASDs), allowing for poorly soluble drugs to have improved bioavailability. However, the process of spray-drying with multiple factors and numerous variables can lead to a lengthy development timeline with intense resource requirements, which becomes the main obstacle limiting spray-drying development at the preclinical stage. The purpose of this work was to identify optimized preset parameters for spray-drying to support the early development of ASDs suitable for most circumstances rather than individual optimization. First, a mini-DoE (Design of Experiment) study was designed to evaluate the critical interplay of two key variables for spray-drying using a BUCHI B-290 mini spray dryer: solid load and atomizing spray gas flow. The critical quality attributes (CQAs) of the ASDs, including yield, particle size, morphology, and in vitro release profile, were taken into account to identify the impact of the key variables. The mini-DoE results indicated that a 5% solid load (w/v %) and 35 mm height atomizing spray gas flow were the most optimized parameters. These predefined values were further verified using different formulation compositions, including various polymers (Eudragit L100-55, HPMCAS-MF, PVAP, and PVP-VA64) and drugs (G-F, GEN-A, Indomethacin, and Griseofulvin), a range of drug loading (10 to 40%), and scale (200 mg to 200 g). Using these predefined parameters, all ASD formulations resulted in good yields as well as consistent particle size distribution. This was despite the differences in the formulations, making this a valuable and rapid approach ideal for early development. This strategy of leveraging the preset spray-drying parameters was able to successfully translate into a reproducible and efficient spray-drying platform while also saving material and reducing developmental timelines in early-stage formulation development.

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Strategies for Liposome Drug Delivery Systems to Improve Tumor Treatment Efficacy

Jia Wang, Junbo Gong & Zhenping Wei

doi : 10.1208/s12249-021-02179-4

AAPS PharmSciTech volume 23, Article number: 27 (2022) 

In the advancement of tumor therapy, in addition to the search for new antitumor compounds, the development of nano-drug delivery systems has opened up new pathways for tumor treatment by addressing some of the limitations of traditional drugs. Liposomes have received much attention for their high biocompatibility, low toxicity, high inclusivity, and improved drug bioavailability. They are one of the most studied nanocarriers, changing the size and surface characteristics of liposomes to better fit the tumor environment by taking advantage of the unique pathophysiology of tumors. They can also be designed as tumor targeting drug delivery vehicles for the precise delivery of active drugs into tumor cells. This paper reviews the current development of liposome formulations, summarizes the characterization methods of liposomes, and proposes strategies to improve the effectiveness of tumor treatment. Finally, it provides an outlook on the challenges and future directions of the field.

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Unexplored Excipients in Biotherapeutic Formulations: Natural Osmolytes as Potential Stabilizers Against Thermally Induced Aggregation of IgG1 Biotherapeutics

Purva P. Bhojane, Srishti Joshi, Sushree Jagriti Sahoo & Anurag S. Rathore

doi : 10.1208/s12249-021-02183-8

AAPS PharmSciTech volume 23, Article number: 26 (2022) 

Monoclonal antibodies (mAbs), while incredibly successful, are prone to a variety of degradation pathways, the most significant of which is aggregation. One of the most commonly used strategy to overcome protein aggregation is addition of excipients to the formulation. Osmolytes such as trehalose, sucrose, and glycine are widely used. In this paper, we explore potential use of naturally occurring osmolytes such as betaine, sarcosine, ectoine, and hydroxyectoine for reducing aggregation of mAb therapeutics. Experimentation has been performed on two IgG1 mAbs via accelerated stability studies. A variety of analytical tools have been used for monitoring the impact, dynamic light scattering (DLS) for colloidal stability, Fourier transform infrared (FTIR) spectroscopy and fluorescence spectroscopy for conformational stability and the higher order structure (HOS), and differential scanning calorimetry (DSC) for thermal stability. No significant impact of osmolyte addition was observed on protein structure, on comparative Fc receptor (FcRn) binding, and on biocompatibility as per our hemolytic assay. Our results rank the osmolytes’ stabilizing trend to be sarcosine > betaine > hydroxyectoine > ectoine. Sarcosine emerged as the most successful osmolyte rendering highest degree of protection against aggregation. Our data support the prospect of using these osmolytes as successful excipients for mAb formulations.

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Advances in Delivery of Chemotherapeutic Agents for Cancer Treatment

Asmita Yadav, Sakshi Singh, Harmik Sohi & Shweta Dang

doi : 10.1208/s12249-021-02174-9

AAPS PharmSciTech volume 23, Article number: 25 (2022) 

Presently, most of the treatment strategies for cancer are focused on the surgical removal of cancerous tumors, along with physical and chemical treatment such as radiotherapy and chemotherapy, respectively. The primary issue associated with these methods is the inhibition of normal cell growth and serious side effects associated with systemic toxicity. The traditional chemotherapeutics which were delivered systemically were inadequate and had serious dose limiting side effects. Recent advances in the development of chemotherapeutics have simultaneously paved the way for efficient targeted drug delivery. Despite the advances in the field of oncogenic drugs, several limitations remain, such as early blood clearance, acquired resistance against cytotoxic agents, toxicity associated with chemotherapeutics, and site-specific drug delivery. Hence, this review article focuses on the recent scientific advancements made in different types of drug delivery systems, including, organic nanocarriers (polymers, albumins, liposomes, and micelles), inorganic nanocarriers (mesoporous silica nanoparticles, gold nanoparticles, platinum nanoparticles, and carbon nanotubes), aptamers, antibody–drug conjugates, and peptides. These targeted drug delivery approaches offer numerous advantages such as site-specific drug delivery, minimal toxicity, better bioavailability, and an increased overall efficacy of the chemotherapeutics.

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Metamorphosis of Twin Screw Extruder-Based Granulation Technology: Applications Focusing on Its Impact on Conventional Granulation Technology

Rajat Radhakrishna Rao, Abhijeet Pandey, Aswathi R. Hegde, Vijay Induvadan Kulkarni, Chetan Chincholi, Vinay Rao, Indu Bhushan & Srinivas Mutalik

doi : 10.1208/s12249-021-02173-w

AAPS PharmSciTech volume 23, Article number: 24 (2022) 

In order to be at pace with the market requirements of solid dosage forms and regulatory standards, a transformation towards systematic processing using continuous manufacturing (CM) and automated model-based control is being thought through for its fundamental advantages over conventional batch manufacturing. CM eliminates the key gaps through the integration of various processes while preserving quality attributes via the use of process analytical technology (PAT). The twin screw extruder (TSE) is one such equipment adopted by the pharmaceutical industry as a substitute for the traditional batch granulation process. Various types of granulation techniques using twin screw extrusion technology have been explored in the article. Furthermore, individual components of a TSE and their conjugation with PAT tools and the advancements and applications in the field of nutraceuticals and nanotechnology have also been discussed. Thus, the future of granulation lies on the shoulders of continuous TSE, where it can be coupled with computational mathematical studies to mitigate its complications.

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Vitamin E Oil Incorporated Liposomal Melphalan and Simvastatin: Approach to Obtain Improved Physicochemical Characteristics of Hydrolysable Melphalan and Anticancer Activity in Combination with Simvastatin Against Multiple Myeloma

Unnam Sambamoorthy, Arehalli S. Manjappa, Bhanoji Rao Muddana Eswara, Arun Kumar Sanapala & Naidu Nagadeepthi

doi : 10.1208/s12249-021-02177-6

AAPS PharmSciTech volume 23, Article number: 23 (2022) 

The objective of this research was to develop vitamin E oil (VEO)-loaded liposomes for intravenous delivery and to study the VEO effect on melphalan (MLN) loading, release, and stability. Further, the research aim was to determine the in vitro anticancer activity and in vivo systemic toxicity of MLN and simvastatin (SVN) combinations, for repurposing SVN in multiple myeloma. The liposomes were prepared by thin-film hydration technique. The optimized liposomes were surface modified with Pluronic F108, lyophilized, and evaluated for mean particle size, MLN content and release behavior, and in vitro hemolysis, cytotoxicity, and macrophage uptake characteristics. Further, in vivo acute toxicity of plain MLN?+?SVN combination was determined in comparison to their liposomal combination. The VEO alone and in combination with D-?-tocopheryl polyethylene glycol 1000 succinate (TPGS) has significantly increased the MLN and SVN loading. The reconstituted liposomes showed the mean particle size below 200 nm (cryo-transmission electron microscope analysis also revealed the liposome formation). In presence of VEO, the liposomes have shown substantially controlled drug release, lower hemolysis, sustained cytotoxicity, lower phagocytosis, and moderately improved chemical stability. Besides, the effect of liposomal combination on mice bodyweight is found substantially lower than the plain drug combination. In conclusion, the VEO could be used along with phospholipids and cholesterol to develop liposomal drugs with improved physicochemical characteristics. Further, the interesting cytotoxicity study results indicated that SVN could be repurposed in combination with anticancer drug MLN against multiple myeloma; liposomal drugs could be preferred to obtain improved efficacy with decreased systemic toxicity.

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In Vivo and In Vitro Taste Assessment of Artesunate-Mefloquine, Praziquantel, and Benznidazole Drugs for Neglected Tropical Diseases and Pediatric Patients

Janine Boniatti, Marcelo R. R. Tappin, Rafaela G. da S Teixeira, Tamires de A V Gandos, Luis P. S. Rios, Izabelle A. M. Ferreira, Karina C. Oliveira, Sabrina Calil-Elias, Aila K. M. Santana, Laís B. da Fonseca, Flavio M. Shimizu, Olívia Carr, Osvaldo N. Oliveira Jr, Fabio M. L. Dantas, Fabio C. Amendoeira & Alessandra L. Viçosa

doi : 10.1208/s12249-021-02162-z

AAPS PharmSciTech volume 23, Article number: 22 (2022) 

The assessment of drug taste is crucial for pediatric treatments so that formulations can be developed to enhance their effectiveness. In this study, in vivo and in vitro methods were applied to evaluate the taste of tablets of three drugs administered to children without taste-masking excipients to treat tropical diseases, namely artesunate-mefloquine (ASMQ), praziquantel (PZQ), and benznidazole (BNZ). In the first method, a model of rat palatability was adapted with recirculation to ensure sample dispersion, and the data were analyzed using ANOVA (single factor, 95%). The taste assessment results (in vivo) indicated an aversion to the three medicines, denoted by the animals retracting themselves to the bottom of the box after the first contact with the drugs. For the placebo samples, the animals behaved normally, indicating that taste perception was acceptable. The second method was based on the in vitro analysis of capacitance data from a homemade impedimetric electronic tongue. Consistent with the in vivo taste assessment results, the data points obtained with PZQ, ASMQ, and BNZ were far away from those of their placebos in a map built with the multidimensional projection technique referred to as Interactive Document Mapping (IDMAP). A combined analysis of the results with the two methods allowed us to confirm the bitterness of the three drugs, also pointing to electronic tongues as a promising tool to replace in vivo palatability tests.

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In Vitro Modeling of Skin Barrier Disruption and its Recovery by Ceramide-Based Formulations

Barbora Amélie ?u?íková-Kindlová, Aneta Vovesná, Anna Nová?ková & Jarmila Zbytovská

doi : 10.1208/s12249-021-02154-z

AAPS PharmSciTech volume 23, Article number: 21 (2022) 

Disrupted skin barrier, one of the severe attributes of inflammatory skin diseases, is caused by lower content and pathological changes of lipids in the uppermost skin layer—stratum corneum (SC). Restoring skin barrier with native skin lipids, especially ceramides (Cers), appears to be a promising therapy with minimum side effects. For testing the efficiency of these formulations, suitable in vitro models of the skin with disrupted barriers are needed. For the similarity with the human tissue, our models were based on the pig ear skin. Three different ways of skin barrier disruption were tested and compared: tape stripping, lipid extraction with organic solvents, and barrier disruption by sodium lauryl sulfate. The level of barrier disruption was investigated by permeation studies, and parameters of each method were modified to reach significant changes between the non-disrupted skin and our model. Fourier transform infrared (FTIR) spectroscopy was employed to elucidate the changes of the skin permeability on the molecular scale. Further, the potential of the developed models to be restored by skin barrier repairing agents was evaluated by the same techniques. We observed a significant decrease in permeation characteristics through our in vitro models treated with the lipid mixtures compared to the untreated damaged skin, which implied that the skin barrier was substantially restored. Taken together, the results suggest that our in vitro models are suitable for the screening of potential barrier repairing agents.

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Increase in Dissolution Rate of Zotepine via Nanomilling Process — Impact of Dried Nanocrystalline Suspensions on Bioavailability

Komal Parmar & Kirti Oza

doi : 10.1208/s12249-021-02172-x

AAPS PharmSciTech volume 23, Article number: 20 (2022) 

Zotepine is an atypical antipsychotic drug used in the treatment of schizophrenia. However, its poor dissolution properties limit its therapeutic efficacy. In this investigation, a series of nanosuspension-containing zotepine were prepared employing media milling method with an aim to improve its dissolution properties and oral bioavailability. Briefly, Box-Behnken design was applied to investigate the influence of various independent variables such as X1- amount of stabilizer, X2- amount of milling agent, and X3- milling time on the performance of the formulation. Dissolution studies revealed enhancement of dissolution rate as compared to pure drug. Solid state characterization (DSC, PXRD, and SEM) studies demonstrated no polymorphic changes in drug after lyophilization of media-milled nanosuspension. In vivo pharmacokinetic studies of lyophilized nanosuspension was carried out in rat and the results exhibited significant improvement in Cmax and AUC0-t, about 450.0 and 287.45%, respectively, suggesting amelioration in oral bioavailability by 2.87-fold higher as compared to pure drug. Accelerated stability studies of the optimized lyophilized formulation at 40°C and 75% RH suggested stability of the nanocrystals for at least a 6-month period. The obtained nanocrystals successfully showed dissolution enhancement and improved oral bioavailability of poorly water-soluble drug, zotepine.

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The Identification of Quality Risk Factors for Non-biological Complex Drugs and Epilepsy Drugs Using Statistical Analysis of Formulation-Based Recalls in the USA

Emily A. Kerstiens, Stephen R. Byrn & Kari L. Clase

doi : 10.1208/s12249-021-02165-w

AAPS PharmSciTech volume 23, Article number: 19 (2022) 

Pharmaceutical companies use the quality by design (QbD) approach to build high-quality drug products. A thorough understanding of risk factors is required to successfully employ QbD. In order to better understand risk factors that potentially impact drug product quality and inform future QbD approaches, we hypothesized root causes of drug product recalls based on publicly available data and a retroactive analysis of drug products recalled by the United States Food and Drug Administration (USFDA) from 2012 to 2018. We focused on two categories of drug products that pose unique regulatory challenges and an increased risk of shortage that could hinder the adequate supply of quality medicine to the patient. Knowing the significant risk factors from previous drug product recalls can help inform QbD and avoid future recalls. Quality recall reasons were studied individually to find risk factors associated with each recall category. Logistical regression statistical tests were done in R using a significance level of 0.05 to find correlations between a recalled product and its manufacturing information such as excipients and manufacturing steps. The results showed significant positive and negative correlations, such as products containing magnesium stearate are more likely to be recalled for impurities and degradation. This information could be used in the future to inform the design and manufacturing of drug products, ensuring consumers receive high-quality products with a low risk of recall.

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A Novel Computational Approach Coupled with Machine Learning to Predict the Extent of Agglomeration in Particulate Processes

Kushal Sinha, Eric Murphy, Prashant Kumar, Kirsten A. Springer, Raimundo Ho & Nandkishor K. Nere

doi : 10.1208/s12249-021-02083-x

AAPS PharmSciTech volume 23, Article number: 18 (2022)

Solid particle agglomeration is a prevalent phenomenon in various processes across the chemical, food, and pharmaceutical industries. In pharmaceutical manufacturing, agglomeration is both desired in unit operations like wet granulation and undesired in unit operations such as agitated filter drying of highly potent active pharmaceutical ingredients (API). Agglomeration needs to be controlled for optimal physical properties of the API powder. Even after decades of work in the field, there is still very limited understanding of how to quantify, predict, and control the extent of agglomeration, owing to the complex interaction between the solvent and the solid particles and stochasticity imparted by mixing. Furthermore, a large size of industrial scale particulate process systems makes it computationally intractable. To overcome these challenges, we present a novel theory and computational methodology to predict the agglomeration extent by coupling the experimental measurements of agglomeration risk zone or “sticky zone” with discrete element method. The proposed model shows good agreement with experiments. Further, a machine learning model was built to predict agglomeration extent as a function of input variables, such as material properties and processing conditions, in order to build a digital twin of the unit operation. While the focus of the present study is the agglomeration of particles during industrial drying processes, the proposed methodology can be readily applied to numerous other particulate processes where agglomeration is either desired or undesired.

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Spherical Agglomerates of Lactose Reduce Segregation in Powder Blends and Improve Uniformity of Tablet Content at High Drug Loads

Dejan Lameši?, Blaž Grilc, Robert Roškar, Selina Kolokytha, Jürgen Hofmann, Andreas Malekos, Rolf Kaufmann & Odon Planinšek

doi : 10.1208/s12249-021-02150-3

AAPS PharmSciTech volume 23, Article number: 17 (2022) 

We report here on improved uniformity of blends of micronised active pharmaceutical ingredients (APIs) using addition of spherical agglomerates of lactose and enhanced blend flow to improve tablet content uniformity with higher API loads. Micromeritic properties and intra-particle porosity (using nano-computed X-ray tomography) of recently introduced spherical agglomerates of lactose and two standard lactose grades for the direct compression processes were compared. Powder blends of the individual lactose types and different micronised API drug loads were prepared and subjected to specific conditions that can induce API segregation. Tablet content uniformity during direct compression was related to the lactose material attributes. The distinctive micromeritic properties of the lactose types showed that spherical agglomerates of lactose had high intra-particle porosity and increased specific surface area. The stability of binary blends after intense sieving was governed by the intra-particle porosity and surface roughness of the lactose particles, which determined the retention of the model substance. Greater intra-particle porosity, powder specific surface area, and particle size of the spherical agglomerates provided greater adhesion of micronised particles, compared to granulated and spray-dried lactose. Thus the spherical agglomerates provided enhanced final blend flow and uniformity of tablet content at higher drug loads.

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Recent Advances in Enhancement of Dissolution and Supersaturation of Poorly Water-Soluble Drug in Amorphous Pharmaceutical Solids: A Review

Qin Shi, Fang Li, Stacy Yeh, Sakib M. Moinuddin, Junbo Xin, Jia Xu, Hao Chen & Bai Ling

doi : 10.1208/s12249-021-02137-0

AAPS PharmSciTech volume 23, Article number: 16 (2022)

Amorphization is one of the most effective pharmaceutical approaches to enhance the dissolution and oral bioavailability of poorly water-soluble drugs. In recent years, amorphous formulations have been experiencing rapid development both in theoretical and practical application. Based on using different types of stabilizing agents, amorphous formulations can be mainly classified as polymer-based amorphous solid dispersion, coamorphous formulation, mesoporous silica-based amorphous formulation, etc. This paper summarizes recent advances in the dissolution and supersaturation of these amorphous formulations. Moreover, we also highlight the roles of stabilizing agents such as polymers, low molecular weight co-formers, and mesoporous silica. Maintaining supersaturation in solution is a key factor for the enhancement of dissolution profile and oral bioavailability, and thus, the strategies and challenges for maintaining supersaturation are also discussed. With an in-depth understanding of the inherent mechanisms of dissolution behaviors, the design of amorphous pharmaceutical formulations will become more scientific and reasonable, leading to vigorous development of commercial amorphous drug products.

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Immunological Assessment of Chitosan or Trimethyl Chitosan-Coated PLGA Nanospheres Containing Fusion Antigen as the Novel Vaccine Candidates Against Tuberculosis

Sirwan Zare, Mona Kabiri, Yousef Amini, Adel Najafi, Fatemeh Mohammadpour, Seyed Hasan Ayati, Amin Reza Nikpoor & Mohsen Tafaghodi

doi : 10.1208/s12249-021-02146-z

AAPS PharmSciTech volume 23, Article number: 15 (2022) 

The crucial challenge in tuberculosis (TB) as a chronic infectious disease is to present a novel vaccine candidate that improves current vaccination and provides efficient protection in individuals. The present study aimed to evaluate the immune efficacy of multi-subunit vaccines containing chitosan (CHT)- or trimethyl chitosan (TMC)-coated PLGA nanospheres to stimulate cell-mediated and mucosal responses against Mycobacterium Tuberculosis (Mtb) in an animal model. The surface-modified PLGA nanoparticles (NPs) containing tri-fusion protein from three Mtb antigens were produced by the double emulsion technique. The subcutaneously or nasally administered PLGA vaccines in the absence or presence of BCG were assessed to compare the levels of mucosal IgA, IgG1, and IgG2a production as well as secretion of IFN-?, IL-17, IL-4, and TGF-? cytokines. According to the release profile, the tri-fusion encapsulated in modified PLGA NPs demonstrated a biphasic release profile including initial burst release on the first day and sustained release within 18 days. All designed PLGA vaccines induced a shift of Th1/Th2 balance toward Th1-dominant response. Although immunized mice through subcutaneous injection elicited higher cell-mediated responses relative to the nasal vaccination, the intranasally administered groups stimulated robust mucosal IgA immunity. The modified PLGA NPs using TMC cationic polymer were more efficient to elevate Th1 and mucosal responses in comparison with the CHT-coated PLGA nanospheres. Our findings highlighted that the tri-fusion loaded in TMC-PLGA NPs may represent an efficient prophylactic vaccine and can be considered as a novel candidate against TB.

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A Compact Model for Lyophilizer Equipment Capability Estimation

Petr Kazarin, William Kessler, Emily Gong, Seongkyu Yoon, Huolong Liu, Richard Marx, Robin Bogner & Alina Alexeenko

doi : 10.1208/s12249-021-02167-8

AAPS PharmSciTech volume 23, Article number: 14 (2022) 

This work presents a compact model for the equipment capability limit of a common configuration of pharmaceutical lyophilizers, a product chamber separated from the condenser by a duct and isolation valve, at a wide range of design parameters. The equipment capability limit is one of the most important characteristics determining the lyophilization design space for a particular product, container, and equipment combination. Experimental measurements of equipment capability are time-consuming and expensive, especially at the production scale. Numerical modeling using computational fluid dynamics may reduce the number of experiments and provide insights into the physics of the process with high resolution. The computational fluid dynamics (CFD) modeling has been used in this work to develop a compact model for lyophilizer equipment capability. This eliminates the need for end users to create a full CFD model of the equipment and process. Full CFD and compact model simulations for laboratory and pilot-scale lyophilizers have been compared with tunable diode laser absorption spectroscopy measurements of the water vapor mass flow during ice slab tests. The compact model results average deviation from the experimental data is within 10%, whereas the full CFD simulations are within 5%. The compact model is based on several key parameters which are the main characteristics of a lyophilizer affecting the equipment capability curve. These parameters are discussed, and their effect on the modeling results is shown.

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Development, Optimization, and Pharmacokinetics Study of Bufalin/Nintedanib Co-loaded Modified Albumin Sub-microparticles Fabricated by Coaxial Electrostatic Spray Technology

Peng Chen, Shengzhe Lu, Bin Pan & Ying Xu

doi : 10.1208/s12249-021-02163-y

AAPS PharmSciTech volume 23, Article number: 13 (2022) 

Coaxial electrostatic spray technology has received extensive attention in fabricating micro/nanoparticles for drug delivery. However, there are few reports on applying this technology in preparing albumin nanoparticles. In this study, the bufalin (BF) and nintedanib (NDNB) co-loaded ursodeoxycholic acid and p-biguanides benzoic acid decorated albumin sub-microparticles (BN-DUB subMPs) were fabricated by coaxial electrostatic spray technology and optimized by central composite design. Five percent of albumin (contained 0.7% polyethylene oxide) solution was selected as the shell solution which ejected through outer axis with the flow rate of 0.07 mm/min, while the core solution which contained by BF and NDNB ethanol solution was ejected through inner axis with the flow rate of 0.05 mm/min. In vitro cell studies revealed that the modified albumin possessed good biocompatibility. What’s more, the BN-DUB subMPs enhanced the inhibitory effect on the growth of LLC cells efficiently. The pharmacokinetics study showed that the t1/2 and AUC0-t of BN-DUB subMPs increased significantly compared with that of the drug solution, which indicated the improved in vivo stability of modified albumin nanoparticles. Thus, this study provided a novel and simple technical platform for the development of albumin-based drug carriers.

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Fabrication of Stable Apigenin Nanosuspension with PEG 400 as Antisolvent for Enhancing the Solubility and Bioavailability

Renjie Xu, Cuiping Jiang, Lijing Zhou, Bin Li, Yi Hu, Yujie Guo, Xuecheng Xiao & Shan Lu

doi : 10.1208/s12249-021-02164-x

AAPS PharmSciTech volume 23, Article number: 12 (2022) 

The purpose of this paper is to prepare a stable apigenin nanosuspension with a drug concentration of 1.11 mg/mL through green and efficient antisolvent method. Compared with the traditional preparation process that may use toxic reagents, in this study, a green and effective strategy was applied for the preparation of stable apigenin nanosuspension by using an antisolvent method with PEG 400 as antisolvent to improve the solubility and bioavailability. It was found that the particle size of apigenin nanosuspension was about 280 nm, and the solubility and dissolution of the nanosuspension were 33 and 3 times higher than that of the apigenin, respectively. Pharmacokinetic study showed that the Cmax and AUC 0–8 h values of the nanosuspension in fasting rats achieved about 6- and 2.5-fold enhancement than that of the apigenin, respectively. Stability test showed that the apigenin nanosuspension could be stored stably for 12 months at 25?. Taken together, the antisolvent method with PEG 400 was proven to be a green and effective method to prepare the stable nanosuspension of poorly soluble drugs.

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Multi-disciplinary Approach for Drug and Gene Delivery Systems to the Brain

Nkafu Bechem Ndemazie, Andriana Inkoom, Ellis Fualefeh Morfaw, Taylor Smith, Monica Aghimien, Dexter Ebesoh & Edward Agyare

doi : 10.1208/s12249-021-02144-1

AAPS PharmSciTech volume 23, Article number: 11 (2022)

Drug delivery into the brain has for long been a huge challenge as the blood–brain barrier (BBB) offers great resistance to entry of foreign substances (with drugs inclusive) into the brain. This barrier in healthy individuals is protective to the brain, disallowing noxious substances present in the blood to get to the brain while allowing for the exchange of small molecules into the brain by diffusion. However, BBB is disrupted under certain disease conditions, such as cerebrovascular diseases including acute ischemic stroke and intracerebral hemorrhage, and neurodegenerative disorders including multiple sclerosis (MS), Alzheimer’s disease (AD), Parkinson’s disease (PD), and cancers. This review aims to provide a broad overview of present-day strategies for brain drug delivery, emphasizing novel delivery systems. Hopefully, this review would inspire scientists and researchers in the field of drug delivery across BBB to uncover new techniques and strategies to optimize drug delivery to the brain. Considering the anatomy, physiology, and pathophysiological functioning of the BBB in health and disease conditions, this review is focused on the controversies drawn from conclusions of recently published studies on issues such as the penetrability of nanoparticles into the brain, and whether active targeted drug delivery into the brain could be achieved with the use of nanoparticles. We also extended the review to cover novel non-nanoparticle strategies such as using viral and peptide vectors and other non-invasive techniques to enhance brain uptake of drugs.

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Sialic Acid Conjugated Chitosan Nanoparticles: Modulation to Target Tumour Cells and Therapeutic Opportunities

Rafquat Rana, Sarita Rani, Vipin Kumar, Kartik T. Nakhate, Ajazuddin & Umesh Gupta

doi : 10.1208/s12249-021-02170-z

AAPS PharmSciTech volume 23, Article number: 10 (2022) 

Targeted delivery of therapeutics forestalls the dreadful delocalized effects, drug toxicities and needless immunosuppression. Cancer cells are bounteous with sialic acid and the differential expression of glycosyl transferase, glycosidase and monosaccharide transporter compared to healthy tissues. The current study entails the development and characterisation of sialic acid (SA)–labelled chitosan nanoparticles encapsulating gemcitabine (GEM). Chitosan (CS) was conjugated with SA using coupling reaction and characterised spectroscopically. Furthermore, different concentrations of chitosan and tripolyphosphate (TPP) were optimised to fabricate surface modified chitosan nanoparticles. SA conjugated chitosan nanoparticles encapsulating GEM (SA-CS_GEM NPs) of 232?±?9.69 nm with narrow distribution (PDI?<?0.5) and zeta potential of???19?±?0.97 mV was fabricated. GEM was successfully loaded in the SA-CS NPs, depicting prolonged and biphasic drug release pattern more elated at low pH. Pronounced cellular uptake (FITC tagged) and cytotoxicity (IC50 487.4 nM) was observed in SA-CS_GEM NPs against A549 cells. IC50 for SA-CS_GEM NPs plunged with an increase in the time points from 24 to 72 h. Concentration-dependent haemolytic study confirmed significant haemocompatibility of SA-CS_GEM NPs. Pharmacokinetic study was performed on Sprague–Dawley rats and the kinetic parameters were calculated using PKSolver 2.0. Results demonstrated a consequential refinement of 2.98 times in modified SA-CS_GEM NPs with a significant increase in retention time, bioavailability and elimination half-life, and decrease in elimination rate constant and volume of distribution in comparison to CS_GEM NPs. Therefore, SA-CS shell core nanoparticles could be a beneficial approach to target and treat NSCLC (non-small cell lung cancer) and direct for research possibilities to target the other tumour cells.

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Intra-articular Injection of Lornoxicam and MicroRNA-140 Co-loaded Cationic Liposomes Enhanced the Therapeutic Treatment of Experimental Osteoarthritis

Kongfang He, Xiaoyu Huang, Rumeng Shan, Xuehua Yang, Ruonan Song, Fei Xie & Guihua Huang

doi : 10.1208/s12249-021-02149-w

AAPS PharmSciTech volume 23, Article number: 9 (2022) 

Osteoarthritis is a chronic joint disease characterized by chronic inflammation, progressive destruction of articular cartilage, and subchondral bone sclerosis. When compared to individual treatment, the combined administration of genes and small-molecule drugs for osteoarthritis may not only provide superior inflammation control and pain relief, but may also repair cartilage damage. Here, cationic liposomes (CL) were used to deliver small hydrophobic drugs and microRNA into chondrocytes to treat osteoarthritis. Lornoxicam cationic liposomes (Lnxc-CL) were prepared by film dispersion, and loaded with microRNA-140 (miR-140) by electrostatic interaction to obtain cationic liposomes co-loaded with lornoxicam and miR-140 (Lnxc-CL/miR-140). The prepared Lnxc-CL/miR-140 had a particle size of 286.6?±?7.3 nm, polydispersity index (PDI) of 0.261?±?0.029 and zeta potential of 26.5?±?0.5 mV and protected miR-140 from RNase degradation for 24 h. Lnxc-CL/miR-140 was evaluated for its ability to regulate gene expression in chondrocytes in vitro and to provide in vivo therapeutic effects for knee osteoarthritis in rats. The results of in vitro uptake experiments and polymerase chain reaction (PCR) analysis showed that Lnxc-CL/miR-140 efficiently delivered miR-140 into chondrocytes and up-regulated the expression of miR-140 and COL2A1 mRNA. Pharmacodynamics studies demonstrated that Lnxc-CL/miR-140 effectively treated osteoarthritis by eliminating joint inflammation and repairing damaged cartilage cells, with superior therapeutic effects compared to Lnxc or miR-140 alone. Overall, the findings of this study support the co-delivery of Lnxc and miR-140 with cationic liposomes as a potential new therapeutic strategy for the treatment of osteoarthritis.

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3D Printed Personalized Medicine for Cancer: Applications for Betterment of Diagnosis, Prognosis and Treatment

Harshada Bhuskute, Pravin Shende & Bala Prabhakar

doi : 10.1208/s12249-021-02153-0

AAPS PharmSciTech volume 23, Article number: 8 (2022) 

Cancer treatment is challenging due to the tumour heterogeneity that makes personalized medicine a suitable technique for providing better cancer treatment. Personalized medicine analyses patient-related factors like genetic make-up and lifestyle and designs treatments that offer the benefits of reduced side effects and efficient drug delivery. Personalized medicine aims to provide a holistic way for prevention, diagnosis and treatment. The customization desired in personalized medicine is produced accurately by 3D printing which is an established technique known for its precision. Different 3D printing techniques exhibit their capability in producing cancer-specific medications for breast, liver, thyroid and kidney tumours. Three-dimensional printing displays major influence on cancer modelling and studies using cancer models in treatment and diagnosis. Three-dimensional printed personalized tumour models like physical 3D models, bioprinted models and tumour-on-chip models demonstrate better in vitro and in vivo correlation in drug screening, cancer metastasis and prognosis studies. Three-dimensional printing helps in cancer modelling; moreover, it has also changed the facet of cancer treatment. Improved treatment via custom-made 3D printed devices, implants and dosage forms ensures the delivery of anticancer agents efficiently. This review covers recent applications of 3D printed personalized medicine in various cancer types and comments on the possible future directions like application of 4D printing and regularization of 3D printed personalized medicine in healthcare.

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Transfersomes: a Revolutionary Nanosystem for Efficient Transdermal Drug Delivery

Muhammad Waseem Akram, Humzah Jamshaid, Fiza Ur Rehman, Muhammad Zaeem, Jehan zeb Khan & Ahmad Zeb

doi : 10.1208/s12249-021-02166-9

AAPS PharmSciTech volume 23, Article number: 7 (2022)

Transdermal delivery system has gained significance in drug delivery owing to its advantages over the conventional delivery systems. However, the barriers of stratum corneum along with skin irritation are its major limitations. Various physical and chemical techniques have been employed to alleviate these impediments. Among all these, transfersomes have shown potential for overcoming the associated limitations and successfully delivering therapeutic agents into systemic circulation. These amphipathic vesicles are composed of phospholipids and edge activators. Along with providing elasticity, edge activator also affects the vesicular size and entrapment efficiency of transfersomes. The mechanism behind the enhanced permeation of transfersomes through the skin involves their deformability and osmotic gradient across the application site. Permeation enhancers can further enhance their permeability. Biocompatibility; capacity for carrying hydrophilic, lipophilic as well as high molecular weight therapeutics; deformability; lesser toxicity; enhanced permeability; and scalability along with potential for surface modification, active targeting, and controlled release render them ideal designs for efficient drug delivery. The current review provides a brief account of the discovery, advantages, composition, synthesis, comparison with other cutaneous nano-drug delivery systems, applications, and recent developments in this area.

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Ofloxacin-Loaded Niosome-Laden Contact Lens: Improved Properties of Biomaterial for Ocular Drug Delivery

Jiayong Liu & Xue Wang

doi : 10.1208/s12249-021-02157-w

AAPS PharmSciTech volume 23, Article number: 6 (2022) 

Currently, bacterial conjunctivitis is managed by multiple antibiotic eye-drop solution, which is highly inefficient due to low ocular bioavailability and frequent dosing. Therapeutic soft contact lenses can be used to sustain the release of ocular drugs. However, the conventional soaking method (economic and widely used) showed low drug uptake and high burst release, and the optophysical properties of the contact lens were altered for clinical application. In this paper, novel ofloxacin-loaded niosomes were developed to increase the drug loading capacity of contact lenses while also sustaining ocular drug delivery. Ofloxacin-loaded niosomes were prepared by the thin film hydration technique with three levels of cholesterol. The niosome-laden contact lenses (OFL-Nio-L) led to improved optophysical properties (swelling, transmittance, oxygen permeability) and lysozyme adherence compared to the conventional soaked contact lens (CV-OFL-L). The in vitro drug release data of CV-OFL-L showed high burst release, while OFL-Nio-L lenses showed sustained release up to 48–96 h. In a rabbit tear fluid model, the OFL-Nio-100-L lens showed a high drug concentration at all-time points compared to the CV-OFL-L and eye-drop solution. The efficacy study in the rabbit model showed improved healing effect with OFL-Nio-100-L lens compared to frequent eye-drop therapy. In conclusion, the paper demonstrated the successful application of niosomes to deliver ofloxacin using contact lens without affecting the critical lens properties to substitute eye-drop therapy.

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Developing a Biorelevant Dissolution Method for an Extrudable Core System (ECS) Osmotic Tablet

Raymond Chen, Andrew Blanchard, Joseph Kushner, Brent Harrington, Jia Liu & Vincent DeMatteo

doi : 10.1208/s12249-021-02110-x

AAPS PharmSciTech volume 23, Article number: 5 (2022)

The objective of this work is to develop a biorelevant dissolution method to support the clinical study for In Vitro In Vivo Correlation (IVIVC) of the first commercially approved single-layer extrudable core system (ECS) osmotic tablet — the 11 mg tofacitinib modified-release tablet. The dissolution conditions were selected through analysis of experimental work including several designed experiments (DoE). The Apparatus 2 (paddles) was selected over the Apparatus 1 (baskets) to minimize the dissolution test variability. The paddle speed was kept at 50 rpm to be conservative and because higher paddle speed did not offer statistically significant improvement in dissolution test variability. The buffer of 50 mM potassium phosphate at pH 6.8 was selected over other buffers at lower or acid pH as the in vivo drug release is expected to occur in the small intestinal region, where the pH is approximately neutral. Finally, the statistically designed experiments proved that use of the Japanese basket sinkers was effective in reducing dissolution variability and eliminating the artificial shift in dissolution profile caused by final pink color-coated tablets sticking to the dissolution vessel. Discriminatory power of the method was verified and the method was validated per ICH and FDA guidelines. Since a Level A IVIVC is established from the analysis of the results of both in vivo clinical study and in vitro dissolution testing, the method is proven to be biorelevant. It also serves a suitable quality control dissolution method.

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Development, Characterization, and Optimization of a Novel Abiraterone Acetate Formulation to Improve Biopharmaceutical Attributes Aided by Pharmacokinetic Modelling

Sandeep Dahiya, Ketan Savjani & Jignasa Savjani

doi : 10.1208/s12249-021-02168-7

AAPS PharmSciTech volume 23, Article number: 4 (2022) 

Abiraterone acetate has very low bioavailability and drastic food effect to warrant a dosing regimen under fasting state only. Therefore, we aimed to develop and optimize a liquisolid compact formulation of abiraterone acetate to improve biopharmaceutical attributes aided by pharmacokinetic modelling and achieve dose reduction with no food effect on the formulation. Preliminary studies highlighted the importance of the selection of olive oil as a compatible vehicle. The pharmacokinetic model, integrated with gastrointestinal physiology, was used to predict fasted and fed state pharmacokinetic parameters. Optimization of the liquisolid formulation containing abiraterone acetate was carried at more than five times lower dose, i.e. 190 mg, compared to 1000 mg. A central composite design (CCD) was used to identify optimal levels of formulation factors, namely the amount of vehicle (olive oil), the amount of coating agent (silicon dioxide), and the amount of surfactant (polysorbate 80). Graphical optimization using the selected models in conjunction with maximization of the desirability was used to identify the optimized liquisolid formulation. The predicted pharmacokinetic parameters (fasted Cmax 901.83 ng/mL, fasted AUCinf 2723.82 ng·h/mL, fed Cmax 1024.34 ng/mL, and fed AUCinf 3041.83 ng·h/mL) of the optimized formulation were acceptable. Overall, the liquisolid compact formulation of abiraterone acetate was successfully developed and optimized. In vitro solubility and dissolution results aided by pharmacokinetic modelling also showed improved predicted bioavailability with greater than five times reduction in dose and elimination of food effect.

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Quantification of Compatibility Between Polymeric Excipients and Atenolol Using Principal Component Analysis and Hierarchical Cluster Analysis

Barbara Rojek, Maria Gazda & Marek Wesolowski

doi : 10.1208/s12249-021-02143-2

AAPS PharmSciTech volume 23, Article number: 3 (2022) 

An important challenge to overcome in the solid dosage forms technology is the selection of the most biopharmaceutically efficient polymeric excipients. The excipients can be selected, among others, by compatibility studies since incompatibilities between ingredients of the drug formulations adversely affect their bioavailability, stability, efficacy, and safety. Therefore, new, fast, and reliable methods for detecting incompatibility are constantly being sought. Hence, the purpose of this work was to assess the usefulness of a heating, cooling, and reheating differential scanning calorimetry (DSC) program for detecting potential incompatibilities between atenolol, an active pharmaceutical ingredient (API), and polymeric excipients. Hot-stage microscopy (HSM), Fourier transform infrared (FTIR) spectroscopy, and powder X-ray diffraction (PXRD) were used as supporting techniques. Additionally, principal component analysis (PCA) and hierarchical cluster analysis (HCA) served as tools to support the interpretation of the data acquired from the DSC curves and FTIR spectra. As the alterations in the shape of the DSC peak of atenolol which are indicative of incompatibility are visible only on the cooling and reheating curves of the mixtures, the DSC heating–cooling–reheating program was found to be very useful for identifying potential incompatibilities in the binary mixtures of atenolol and polymeric excipients. The melting and recrystallization of atenolol alone and in its mixtures were also confirmed by HSM, while FTIR displayed changes in the spectra of mixtures due to incompatibility. These studies revealed that atenolol is incompatible with hydroxyethylcellulose, hypromellose, and methylcellulose. PXRD measurements at room temperature revealed that the crystallinity of atenolol did not change in these mixtures. However, its crystallinity was reduced in the mixtures previously heated up to 155 °C and then cooled to 25 °C.

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Inclusion Complexes of Daidzein with Cyclodextrin-Based Metal–Organic Framework-1 Enhance Its Solubility and Antioxidant Capacity

Yutaka Inoue, Masaaki Yoshida, Toshinari Ezawa, Takashi Tanikawa, Florencio Arce Jr, Gerard Lee See, Junki Tomita, Mitsuaki Suzuki & Toshio Oguchi

doi : 10.1208/s12249-021-02151-2

AAPS PharmSciTech volume 23, Article number: 2 (2022) 

Daidzein, an aglycone-type isoflavone, is useful in the prevention of atherosclerotic cardiovascular diseases. However, the solubility of daidzein remains relatively low even with pharmaceutical interventions (e.g., ?-cyclodextrin inclusion complex). In the present study, daidzein-cyclodextrin-metal organic framework solid dispersion complexes were prepared by the solvent evaporation method. The physicochemical properties of the complex and its effect on the solubility of daidzein were evaluated. The enhancement effect of a cyclodextrin-metal organic framework on the antioxidant properties of daidzein was verified using a diphenyl-picrylhydrazyl radical scavenging test. Powder X-ray diffraction results showed that the characteristic diffraction peaks of daidzein and cyclodextrin-metal organic framework disappeared and new peaks (2??=?7.1°, 16.5°) were observed. FT-IR measurements showed that the peak derived from the carbonyl group of daidzein shifted to the lower wavenumber. NOESY 1H-1H NMR showed cross peaks at the proton on the resorcinol side of daidzein and the proton (H-5, H-6) in a cyclodextrin-metal organic framework. Dissolution rate of daidzein at 5 min in distilled water was 0.06% for daidzein alone while the daidzein inclusion complex was about 100%. When fasted state simulated intestinal fluid was used, the dissolution rate of the daidzein complex was about 71% compared with that of daidzein alone (~?3.0%) at 5 min. The daidzein inclusion complex improved the antioxidant capacity to?~?1.3 times (17.8 µg/mL) compared to the IC50 of daidzein alone (22.9 µg/mL). Preparations of cyclodextrin-metal organic framework inclusion complexes will be a platform in developing pharmaceutical formulations to enhance the bioavailability and activity of drugs.

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The Influence of Relative Humidity and Storage Conditions on the Physico-chemical Properties of Inhalation Grade Fine Lactose

Milica Stankovic-Brandl, Sarah Zellnitz, Paul Wirnsberger, Mirjam Kobler & Amrit Paudel

doi : 10.1208/s12249-021-02159-8

AAPS PharmSciTech volume 23, Article number: 1 (2022) 

Dry powder inhalers (DPIs) are favorable devices for the delivery of dry formulations to the lungs; still, they largely fail to deliver higher doses of active pharmaceutical ingredient (API) to the lower airways. Addition of fine particles of excipient (fines) to the blend of API and carrier was shown to improve aerosolization performance. Lactose monohydrate is ubiquitous excipient used for this purpose. Lactose exists in a thermodynamically stable crystalline form; however, processes like milling, sieving, or even mixing may induce alteration of crystalline structure and introduce amorphous domains, which could further affect the physico-chemical properties of the material. Therefore, the aim of this work is a detailed characterization of two commercially available types of inhalation grade fine lactose powders (Inhalac 400 and Inhalac 500) prepared using different air-jet milling parameters, with a focus on impact of storage conditions on material properties. We found that the different milling parameters resulted in variable particle size distribution (PSD), and thus surface areas, variable initial amorphous content, cohesivity, flowability, and moisture sorption of materials. In addition, exposure of fine powders to higher humidity reduced the amorphous content present in the materials, but also affected agglomeration tendency and dispersion behavior of both powders. We believe the obtained findings to be important for the aerosolization performance of carrier-based DPIs containing fines and thus need to be duly considered during formulation development.

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