Formulation, Optimization and Evaluation of Nanoparticulate Oral Fast Dissolving Film Dosage Form of Nitrendipine

Neha Vishal Gandhi, Uday Arvind Deokate & Sachidanand Shankar Angadi

doi : 10.1208/s12249-021-02100-z

22, Article number: 218 (2021)

The primary objective of the present research work was to develop nanoparticles incorporating (nanoparticulate) fast dissolving (orodispersible) film evincing enhanced solubility and bioavailability of nitrendipine (NIT). An antisolvent sonoprecipitation method was employed to produce the NIT nanosuspension (NS), which was optimized using the 32 optimal response surface design and then the optimized one was evaluated for various parameters (Gandhi et al., AAPS PharmSciTech 22 (1):1–15, 2021). The NIT nanoparticulate orodispersible film (N-ODF) was prepared utilizing the nanosuspension by the solvent casting method using the Vijay film-forming instrument. The N-ODF was optimized by the 23 full factorial design and was evaluated for several parameters. The optimized NS depicted a particle size of 505.74 ± 15.48 nm with a polydispersity index (PDI) of 0.083 ± 0.006 (Fig. 1b). The NIT nanoparticles showed a striking increment in saturation solubility (26.14 times), when compared with plain NIT (2). The developed NIT N-ODF exhibited thickness (0.148 ± 0.008 mm), folding endurance (280.33 ± 5.51 times), surface pH (6.86 ± 0.05), tensile strength (8.25 ± 0.13 kg/cm2), % elongation (63.5 ± 1.97%), and disintegration time (24.60 ± 1.31 s) to be within the standard intended limit. The in vitro dissolution study unveiled 100.28 ± 2.64% and 100.68 ± 2.50% of NIT release from lyophilized nanocrystals (in 8 min) and N-ODF (in 3.5 min), respectively, whereas the conventional NIT tablet took 30 min to release 99.94 ± 1.57% of NIT (Gandhi et al., AAPS PharmSciTech 22 (1):1–15, 2021). The in vivo pharmacokinetic study in rabbits inferred the achievement of significantly (p < 0.05) higher bioavailability of NIT on release from N-ODF in comparison to the conventional NIT tablet. Thus, the generation of N-ODF can be considered as a propitious move toward improving the efficacy of NIT to treat hypertension and angina pectoris.

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Puerarin Loaded PLGA Nanoparticles: Optimization Processes of Preparation and Anti-alcohol Intoxication Effects in Mice

Qin Han, Kejie Chen, Cunli Su, Xin Liu & Xiaoming Luo

doi : 10.1208/s12249-021-02092-w

22, Article number: 217 (2021) 

To improve the bioavailability of puerarin in liver, the optimized preparation method of puerarin-PLGA nanoparticles (Pue-PLGA-nps) and the effect of Pue-PLGA-nps on alcoholism mice were studied. The preparation of Pue-PLGA-nps was optimized by the Box-Behnken design and response surface methodology (RSM). To estimate the anti-alcoholism of Pue-PLGA-nps in vivo, drunkenness incubation period and sober time of mice were detected, and Morris water maze (MWM) test was performed. AST, ALT, and SOD were used to determine the damages and oxidative stress in the liver, as well as histopathological observation of the liver. The optimal preparation conditions of Pue-PLGA-nps in RSM were as follows: the drug-material ratio was 1:1.4, the reaction temperature was 65°C, and the reaction time was 13 min. The drug entrapment efficiency of Pue-PLGA-nps was 90.6% and closely up to 98.9% of the standard prediction value. The results in vivo showed that the Pue-PLGA-nps significantly increased the drunkenness incubation period in comparison with the model group and decreased drunkenness sober time and landing time in MWM in comparison with the model group and puerarin group (P<0.05) . The contents of AST and ALT in the liver of Pue-PLGA-nps group were significantly lower than those of model group and Puerarin group (P<0.05), and the activity of SOD in the liver of Pue-PLGA-nps group was higher than that of model group (P<0.05). By histopathological observation, moreover, Pue-PLGA-nps significantly attenuated the impairment of the liver caused by alcoholism. In conclusion, through BBD and RSM, the process conditions of the Pue-PLGA-nps were successfully optimized. The Pue-PLGA-nps exerted higher bioavailability and better effect of anti-alcoholism than puerarin, indicating PLGA nanoparticles could be potential to deliver drug.

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Eudragit S-100 Surface Engineered Nanostructured Lipid Carriers for Colon Targeting of 5-Fluorouracil: Optimization and In Vitro and In Vivo Characterization

Kruti Borderwala, Sachin Rathod, Sarita Yadav, Bhavin Vyas & Pranav Shah

doi : 10.1208/s12249-021-02099-3

22, Article number: 216 (2021) 

5-Fluorouracil (5-FU) is the most preferred chemotherapeutic agent in the management of colon cancer but is associated with poor therapeutic efficacy and lack of site specificity. Hence, it was aimed to employ Eudragit S100 surface engineered 5-FU nanostructured lipid carriers for the spatial and temporal release of the drug for the treatment of colon cancer. Hot high-pressure homogenization (HPH) technique was employed in the preparation of 5-FU-NLCs. The optimization of 5-FU-NLCs was performed using a Quality by Design (QbD) approach. A 32 factorial design was employed wherein the relationship between independent variables [amount of oleic acid (X1) and concentration of Tween®80 (X2)] and dependent variables [particle size (Y1) and % entrapment efficiency (Y2)] was studied. Optimized 5-FU-NLCs were surface treated to obtain Eudragit S100-coated 5-FU-NLCs (EU-5-FU-NLCs). The evaluation parameters for 5-FU-NLCs and EU-5-FU-NLCs included surface morphology, particle size, PDI, and zeta potential. In vitro release from EU-5-FU-NLCs revealed a selective and controlled 5-FU release in the colonic region for 24 h. In vitro cytotoxicity (MTT assay) was performed against Caco-2 cancer cells, wherein EU-5-FU-NLCs exhibited a 2-fold greater cytotoxic potential in comparison to a 5-FU solution (5-FU-DS). Oral administration of EU-5-FU-NLCs in Albino Wistar rats depicted a higher Cmax (2.54 folds) and AUC (11 folds) as well as prolonged Tmax (16 folds) and MRT (4.32 folds) compared to 5-FU-DS confirming higher bioavailability along with the spatial and temporal release in the colonic region. Thus, a multifaceted strategy involving abridgement of nanotechnology along with surface engineering is introduced for effective chemotherapy of colon cancer via oral administration of 5-FU with uncompromised safety and higher efficacy.

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Biorelevant In Vitro Skin Permeation Testing and In Vivo Pharmacokinetic Characterization of Lidocaine from a Nonaqueous Drug-in-Matrix Topical System

Emileigh Greuber, Kip Vought, Kalpana Patel, Hiroaki Suzuki, Kazuhiro Usuda, Akira Shiramizu, Luana Pesco Koplowitz, Barry Koplowitz, Howard I. Maibach & Dmitri Lissin

doi : 10.1208/s12249-021-02101-y

22, Article number: 215 (2021)

Recently, lidocaine topical systems utilizing nonaqueous matrices have been developed and provide efficient lidocaine delivery through the skin, such that lower concentrations of drug provide equivalent or greater drug delivery than drug-in-matrix hydrogel lidocaine patches. This study characterizes drug delivery from a nonaqueous lidocaine topical system with increasing drug load both in vitro and in vivo. Topical systems formulated with either 1.8% or 5.4% lidocaine were applied to healthy volunteers’ backs (n = 15) for 12 h in a single-center, open-label, four-treatment, four-period crossover pharmacokinetic study. Subjects were dosed with either three 1.8% systems or one, two, or three 5.4% systems in each period. Blood was collected for up to 48 h, and plasma lidocaine levels were measured with a validated HPLC method. In parallel, human and mouse skin models characterized the in vitro skin permeation profile. The pharmacokinetic profile was linear between one, two, and three lidocaine 5.4% applications. Application of three lidocaine 1.8% systems (108 mg lidocaine) was bioequivalent to one lidocaine 5.4% system (108 mg lidocaine). Both topical systems remained well adhered to the skin and irritation was mild. The 5.4% system had approximately threefold higher skin permeability than the 1.8% system in the mouse and human skin models. The results indicate increasing the drug load by three times results in triple the drug delivery both in vivo and in vitro. The relationship between the in vitro permeation and in vivo absorption correlates and is nonlinear.

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Targeting Some Enzymes with Repurposing Approved Pharmaceutical Drugs for Expeditious Antiviral Approaches Against Newer Strains of COVID-19

Swati Sucharita Mohanty, Chita Ranjan Sahoo & Rabindra Nath Padhy

doi : 10.1208/s12249-021-02089-5

22, Article number: 214 (2021)

At present, global vaccination for the SARS-CoV2 virus 2019 (COVID-19) is 95% effective. Generally, viral infections are arduous to cure due to the mutating nature of viral genomes, with the consequent quick development of resistance, posing significant fatalities or hazards. The novel corona viral strains are increasingly lethal than earlier variants, as those evolve faster than imagined. Despite the emergence of several present innovative treatment options, the vaccines, and available drugs, the latter still are the needs of the time. Therefore, repurposing the approved pharmaceutical drugs of a well-known safety profile would be ascertained to provide faster antiviral approaches for the newer strains of COVID-19. Recently, a combination of remdesivir, which has a competitively inhibitory effect on the nucleotide uptake in the virus, and the merimepodibs, an inhibitor of the enzyme inosine monophosphate dehydrogenase, which has a role in the synthesis of nucleotides of guanine bases, is in use in phase 2 clinical trials. However, new investigations suggest that using remdesivir, there is no statistically significant difference with uncertain clinical importance for moderate COVID-19 patients. Herein, an intellectual selection of approved drugs based on the safety profile is described, to target any essential enzymes that are required for the virus-receptor contact, fusion, and/or different stages of the life cycle of this virus, should help to screen drugs against newer strains of COVID-19.

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Nanoparticles and Nanostructured Films with TGF-?3: Preparation, Characterization, and Efficacy

Ipek Baysal, Goksu Ozcelikay, Samiye Yabanoglu-Ciftci, Bercis Imge Ucar, Ayse Gencer & Betul Arica-Yegin

doi : 10.1208/s12249-021-02097-5

22, Article number: 213 (2021)

TGF-?3 has been reported to have a strong therapeutic efficacy in wound healing when externally administered, but TGF-?3’s active form is rapidly metabolized and removed from the body. Therefore, a drug delivery system that can provide a new non-toxic and an effective treatment that could be locally applied and also be able to protect the stability of the protein and provide controlled release is required. The aim of the study is to prepare and characterize nanoparticles and nanostructured films with TGF-?3 and to evaluate in vitro cytotoxicity of the loaded nanoparticles. PCL-based films containing TGF-?3 or TGF-?3-loaded PLGA nanoparticles were prepared with non-toxic modified solvent displacement method. The particle size and protein loading efficiency of TGF-?3-loaded PLGA nanoparticles were 204.9 ± 10.3 nm and 42.42 ± 2.03%, respectively. In vitro release studies of TGF-?3-loaded PLGA nanoparticle formulations revealed that the protein was completely released from the nanoparticles at the end of 24 h. In vitro release profile of film formulation containing TGF-?3-loaded nanoparticles was similar. TGF-?3 released from nanoparticles do not have a significant effect on proliferation of HepG2 cells demonstrating their biocompatibility. Additionally, prepared films were tested with in vivo wound healing mouse model and showed to heal significantly faster and with improved scarring. PCL films loaded with TGF-?3 or TGF-?3 nanoparticles prepared in this study may be an effective treatment approach for wound healing therapy after injury.

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Sustained Delivery of Timolol Using Nanostructured Lipid Carriers-Laden Soft Contact Lenses

Chenfei Tian, Lu Zeng, Le Tang, Jingni Yu & Mei Ren

doi : 10.1208/s12249-021-02096-6

22, Article number: 212 (2021) 

The contact lens prepared by the conventional soaking method using timolol-soaking solution showed poor drug uptake and high burst release with altered critical lens properties. In this study, timolol-loaded nanostructured lipid carriers (NLCs) were prepared and evaluated for enhanced timolol uptake and sustained release for the effective management of glaucoma. The characterization studies indicated that timolol-loaded NLCs were spherical in shape with an average size of 130–138 nm and a zeta potential of ?46.6 to 51.3 mV. Critical lens properties such as swelling, optical transmittance, and protein adherence were improved with NLC-laden lenses compared to the conventional soaked lenses (SM-TB). Moreover, SM-TB lens showed low timolol uptake, high burst release, and short release duration up to 24 h compared to timolol-NLC-laden lens that showed high timolol uptake, and the cumulative release was sustained up to 96 h. The ability to sustain timolol release improved proportionally with an increase in the amount of Capmul MCMC8 (liquid lipid) in NLCs. In addition, NLC-laden lens was found to be safe according to the results of ocular irritation and histopathological studies. In the rabbit tear fluid model, NLC-30%-Cap-CL batch showed high timolol concentration at all time points up to 60 h. Further, pharmacodynamic study showed sustained reduction in IOP by NLC-30%-Cap-CL batch for 96 h compared to 48 h and 6 h with SM-TB lens and eye drop solution, respectively. In conclusion, NLCs enhanced timolol uptake in the contact lens from the soaking solution using soaking method with improved in vitro and in vivo results for better clinical outcomes in the patients with glaucoma.

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Near-Infrared Hyperspectral Imaging as a Monitoring Tool for On-Demand Manufacturing of Inkjet-Printed Formulations

Sandra Stranzinger, Matthias Wolfgang, Emma Klotz, Otto Scheibelhofer, Patrizia Ghiotti, Johannes G. Khinast, Wen-Kai Hsiao & Amrit Paudel

doi : 10.1208/s12249-021-02091-x

22, Article number: 211 (2021) 

This study evaluates the potential use of near-infrared hyperspectral imaging (NIR-HSI) for quantitative determination of the drug amount in inkjet-printed dosage forms. We chose metformin hydrochloride as a model active pharmaceutical ingredient (API) and printed it onto gelatin films using a piezoelectric inkjet printing system. An industry-ready NIR-HSI sensor combined with a motorized movable linear stage was applied for spectral acquisition. Initial API-substrate screening revealed best printing results for gelatin films with TiO2 filling. For calibration of the NIR-HSI system, escalating drug doses were printed on the substrate. After spectral pre-treatments, including standard normal variate (SNV) and Savitzky-Golay filtering for noise reduction and enhancement of spectral features, principal component analysis (PCA) and partial least squares (PLS) regression were applied to create predictive models for the quantification of independent printed metformin hydrochloride samples. It could be shown that the concentration distribution maps provided by the developed HSI models were capable of clustering and predicting the drug dose in the formulations. HSI model prediction showed significant better correlation to the reference (HPLC) compared to on-board monitoring of dispensed volume of the printer. Overall, the results emphasize the capability of NIR-HSI as a fast and non-destructive method for the quantification and quality control of the deposited API in drug-printing applications.

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Correction to: Effect of Packaging Materials and the Leached Iron on the Stability of Butorphanol Tartrate Injection

Zijun Dai, Chunmei Zhu, Jinyuan Lyu, Chunfeng Liu, Jiajian Xu, Haoxiang Wu & Fuli Zhang

doi : 10.1208/s12249-021-02077-9

22, Article number: 210 (2021)

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Fabrication, Evaluation, In Vivo Pharmacokinetic and Toxicological Analysis of pH-Sensitive Eudragit S-100-Coated Hydrogel Beads: a Promising Strategy for Colon Targeting

Sadia Rehman, Nazar Muhammad Ranjha, Hina Shoukat, Asadullah Madni, Faiz Ahmad, M. Rafi Raza, Qazi Adnan Jameel, Abdul Majeed & Nasreen Ramzan

doi : 10.1208/s12249-021-02082-y

22, Article number: 209 (2021)

The aim of present research aims to fabricate a system of enteric coating of hydrogel beads with pH-sensitive polymer, which shows solubility at pH > 7, and explore their potential to target the colon for drug delivery. Hydrogel beads were fabricated through the extrusion-dripping technique followed by ion gelation crosslinking. Moreover, freeze-thaw cycle was implemented for crosslinking of polyvinyl alcohol (PVA)/Ca-alginate blend beads. The oil-in-oil solvent evaporation method was adopted for the Eudragit coating of hydrogel beads using different coat: core ratios (4:1 or 8:1). Coated and uncoated hydrogel beads were evaluated by in vitro physicochemical properties, swelling and drug release behaviours, and in vivo pharmacokinetics, swelling, and toxicity evaluation. Diclofenac sodium was loaded as an experimental drug. Drug entrapment efficiency for the PVA/Ca-alginate beads was calculated as 98%, and for Ca-alginate beads, it came out to a maximum of 74%. Drug release study at various pH suggested that, unlike uncoated hydrogel beads, the coated beads delay the release of diclofenac sodium in low pH of the gastric and intestinal environment, thus targeting the colon for the drug release. It was concluded that Eudragit S-100-coated hydrogel beads could serve as a more promising and reliable way to target the colon for drug delivery.

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Physiologically Based Pharmacokinetic Models Are Effective Support for Pediatric Drug Development

Kefei Wang, Kun Jiang, Xiaoyi Wei, Yulan Li, Tiejie Wang & Yang Song

doi : 10.1208/s12249-021-02076-w

22, Article number: 208 (2021)

Pediatric drug development faces many difficulties. Traditionally, pediatric drug doses are simply calculated linearly based on the body weight, age, and body surface area of adults. Due to the ontogeny of children, this simple linear scaling may lead to drug overdose in pediatric patients. The physiologically based pharmacokinetic (PBPK) model, as a mathematical model, contributes to the research and development of pediatric drugs. An example of a PBPK model guiding drug dose selection in pediatrics has emerged and has been approved by the relevant regulatory agencies. In this review, we discuss the principle of the PBPK model, emphasize the necessity of establishing a pediatric PBPK model, introduce the absorption, distribution, metabolism, and excretion of the pediatric PBPK model, and understand the various applications and related prospects of the pediatric PBPK model.

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Physicochemical Characterization and Biopharmaceutical Evaluation of ZWF: A Novel Anticancer Drug for the Treatment of Non-small Cell Lung Cancer

Lina Zhao, Li He, Yuan Chen, Tongchao Xia, Le Li, Shengyan Wang, Xu Bao & Junyi Yang

doi : 10.1208/s12249-021-02084-w

22, Article number: 207 (2021) 

The orally available novel small molecule drug ZWF is under preclinical development for an anticancer purpose. The present study aimed to assess the viability of developing ZWF as a form of oral formulation for clinical application based on the principles of biopharmaceutics and pharmacokinetics. The crucial physicochemical properties of ZWF were determined by in vitro assays. The in situ gastrointestinal absorption characteristics and in vivo pharmacokinetic behaviors of ZWF in rats were characterized. The solubility of ZWF showed a highly pH-dependent profile, decreasing from 25,392.89 to 20.48 ?g/mL as the solution pH increased from 1.0 to 5.8. In PBS with a pH of 1.0 to 5.8, the LogP value of ZWF ranged from ?2.35 to 2.20 and was gradually increased as the pH value increased. ZWF was partially absorbed in the stomach, and the favorable absorption sites were the duodenum, jejunum, and ileum. Pharmacokinetic studies showed that the AUC(0-t) and Cmax values of ZWF after its oral administration as a suspension prepared with 0.5% CMC-Na were increased by 18.97% and 40% than that with normal saline, providing a model oral formulation of ZWF with ideal bioavailability and system exposure in rats. From the perspective of oral absorption, ZWF possessed appealing qualities as a drug candidate and could be prepared as an oral preparation for clinical application. The present study has established a fundamental foundation for the development and quality evaluation of the ZWF oral formulations.

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The Study of Ginger-Derived Extracellular Vesicles as a Natural Nanoscale Drug Carrier and Their Intestinal Absorption in Rats

Fulong Man, Chen Meng, Yang Liu, Yuchen Wang, Yun Zhou, Jinqian Ma & Rong Lu

doi : 10.1208/s12249-021-02087-7

22, Article number: 206 (2021)

Extracellular vesicles have been widely used in drug delivery systems and clinical studies as a new natural nanoscale drug carrier. Most of these studies focused on the extracellular vesicles from animals, but few involved in the extracellular vesicles from edible plants. This study was the first to explore the potential and value of ginger-derived extracellular vesicles (GDEVs) as drug carrier by using the content ratio method and to further study their intestinal absorption in rats. In this experiment, GDEVs were extracted and purified by ultrahigh-speed centrifugation. GDEVs were saucer-like with a particle size of 70.09±19.24 nm and a zeta potential of ?27.70±12.20 mV. In this experiment, high-performance liquid chromatography was used to explore the difference in gingerol content between GDEVs and ginger slices. Under the same mass, the contents of 6-gingerol (6G), 8-gingerol (8G), and 10-gingerol (10G) in GDEVs were 10.21-fold, 22.69-fold, and 32.36-fold of those in ginger slices, respectively. In this experiment, the absorption kinetics and absorption site of GDEVs were investigated using in situ single-pass intestinal perfusion method in rats. GDEVs could be absorbed by the small intestine in the concentration range of 15–60 mg/mL, and the absorption trend of different intestinal segments was duodenum > jejunum > ileum. These results indicated that GDEVs had good loading capacity and significant prospects as a carrier of the drug delivery system. At the same time, combining the oil-water partition coefficient (6G < 8G < 10G) of three gingerol compounds, we speculated that the loading capacity of GDEVs increased with the increase of the lipid solubility of the compounds. This study fully demonstrated the potential and value of ginger-derived extracellular vesicles as natural nanocarrier and provided an important reference for the further application of plant-derived extracellular vesicles in the drug delivery system.

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Preparation and Characterization of Electrospun Polylactic Acid (PLA) Fiber Loaded with Birch Bark Triterpene Extract for Wound Dressing

Tianyuan Fan & Rolf Daniels

doi : 10.1208/s12249-021-02081-z

22, Article number: 205 (2021)

Drug-loaded electrospun fibers have attracted increasing attention as a promising wound dressing material due to their capability of preventing from infections and inflammation and maintaining an appropriate environment for wound healing. In this study, polylactic acid (PLA), which is widely used in wound management, was chosen as electrospinnable polymer. A triterpene extract (TE) from the outer bark of birch known for its anti-inflammatory, antiviral, antibacterial, and wound healing effects was chosen to produce TE-loaded PLA electrospun fibers for wound dressing. A binary solvent system of dichloromethane (DCM) and dimethyl sulfoxide (DMSO) was employed, and the ratio of the solvents was optimized for preparing smooth and uniform fibers. The morphology of TE-loaded PLA electrospun fibers was investigated by scanning electron microscopy (SEM). The entrapment of TE in PLA fibers was confirmed by confocal laser scanning microscopy (CLSM). Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) were used to analyze the solid state of TE in PLA fibers. The release behavior of TE was assayed by a shaking flask method for a period of 96 h. The results revealed that TE-loaded electrospun PLA microfibers could be reliably prepared and are promising future candidates in wound therapy.

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