International Journal of Pharmaceutics

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ISSN / EISSN : 0378-5173 / 1873-3476
Published by: Elsevier BV (10.1016)
Total articles ≅ 22,147
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Giuseppe Francesco Racaniello, Valentino Laquintana, Juliette Vergnaud, Angela Lopedota, Annalisa Cutrignelli, Antonio Lopalco, Francesco Leonetti, Massimo Franco, Mauro Fiume, Paola Pontrelli, et al.
Published: 21 September 2021
International Journal of Pharmaceutics; https://doi.org/10.1016/j.ijpharm.2021.121128

Abstract:
Purified Glycogen (PG) is a highly hyper branched carbohydrate, characterized by high water solubility and very moderate increase in viscosity. The dendrimeric structure of PG, appropriately functionalized, makes it an alternative to current synthetic gene delivery agents. The present study explores the preparation of purified glycogen polycationic derivatives (PGPDs), developed and characterized starting from a single step reaction between PG and N,N-dialkylamino alkyl halides. Subsequently PGPDs were used for the complexation of a model siRNA nucleic acid, a transfection reagent siRNA and a fluorescein-labelled dsRNA oligomer. PGPDs-siRNA complexes were fully characterized by agarose gel electrophoresis and their efficacy was assessed by both confocal microscopy and transfection assays on breast and renal cancer cells. Results proved that PGPDs-siRNA complexes were efficient and not cytotoxic, maintaining their spherical and dendrimeric structure and, particularly, were able to effectively transfect the target cells by releasing the siRNA.
Daniel J Munt, Yongyue Qi,
Published: 21 September 2021
International Journal of Pharmaceutics; https://doi.org/10.1016/j.ijpharm.2021.121127

Abstract:
In vitro diffusion testing of topical formulations has long been examined using Franz diffusion chambers, however, Franz chambers are typically used with relatively large volumes, lack the air/membrane interface present in vivo, and do not account for changes in formula characteristics as solvent evaporates. Here we present our patented Munt-Dash diffusion chamber designed for direct spray application onto a model membrane. Diffusion characteristics from topical spray formulations utilizing both the Munt-Dash chamber and Franz diffusion chambers were evaluated and compared. Using diclofenac sodium and lidocaine hydrochloride as model drugs and shed snakeskin as a model for stratum corneum, test solutions were applied to Franz diffusion chambers using a pipette and to the Munt-Dash chamber using a high-speed syringe pump and sprayer. Both chambers presented permeability data consistent with previously reported in vitro and in vivo studies. Significant differences were observed in permeability by formulation and temperature. This suggests that although Franz chambers produce relevant data, the failure to account for small volumes and drying during application may produce misleading results. The Munt-Dash chamber may improve in vitro testing by providing these factors. This data suggests the Munt-Dash chamber is a suitable alternative to the Franz chamber for topical spray formulas.
Kohei Ogawa, , Kazuyuki Takata, Daiki Nomura, Yasushi Moroto, Hideyuki Kitamura, Chise Takaki, Masaki Morishita, Akira Yamamoto
Published: 21 September 2021
International Journal of Pharmaceutics; https://doi.org/10.1016/j.ijpharm.2021.121120

Abstract:
To optimize prolonged and sustained delivery of polylactide-block-polyethyleneglycol polymeric nanoparticles (PLA-PEG NPs), in terms of the PLA isomer and molecular weight, we performed orthogonal physicochemical characterization and evaluated the pharmacokinetics of tamoxifen (TAM)-loaded PLA-PEG NPs. DL-lactide- (DL-PEG NP), L-lactide- (L-PEG NPs), and stereocomplex-based (SC-PEG NPs) PLA-PEGs, with two different PLA to PEG ratios (12k-5k and 5k-5k Da) were synthesized, and NPs were prepared by anti-solvent precipitation. Size exclusion chromatography, multi-angle light scattering, dynamic light scattering, and 1H nuclear magnetic resonance studies revealed that SC-PEG NPs (12k-5k) had a compact structure and the highest PEG density, followed by L-PEG NPs (12k-5k), DL-PEG NPs (12k-5k), and all PLA-PEG NPs (5k-5k). Additionally, solid-phase extraction indicated that SC-PEG NPs (12k-5k) had the highest drug loading content and the lowest surface TAM adsorption, of the PLA-PEGs evaluated. These results were explained by the crystallinity of the PLA core, which was analyzed by X-ray diffraction. In the pharmacokinetic studies, 14C-TAM-loaded 111In-SC-PEG NPs (12k-5k) exhibited the highest area under the plasma concentration-time curve, followed by L-PEG NPs (12k-5k) and DL-PEG NPs (12k-5k), after intravenous injection in mice. These results indicate that SC-PEG NPs (12k-5k) are promising drug carriers for the sustained and prolonged delivery of TAM.
Rebeca Simancas Herbada, Ana Isabel Torres-Suárez, Francisco J. Otero-Espinar, Ana Isabel Fraguas-Sanchez, Enrique Lopez-Cabarcos, Jorge Rubio-Retama,
Published: 21 September 2021
International Journal of Pharmaceutics; https://doi.org/10.1016/j.ijpharm.2021.121121

Abstract:
The objective of this work was to evaluate the potential use of a new polymer (PAMgA) in the development sustained release matrix tablets for the treatment of bowel inflammatory diseases. For this purpose, budesonide, a highly lipophilic compound, was used as model drug. Tablets with two reticulation grades of PAMgA (PAMgA 5 and 40) and with 9 mg of budesonide were developed and characterized. All the studies were carried out using biorelevant media (FaSSGF and FaSSIF).
Fang Dou, Yixing Lu,
Published: 21 September 2021
International Journal of Pharmaceutics; https://doi.org/10.1016/j.ijpharm.2021.121123

Abstract:
This study aimed at developing a cell-based encapsulation carrier for topical delivery of bioactives to the skin. The overall objectives were to evaluate affinity of the yeast-cell based carrier to bind to the skin surface following topical application and to quantify controlled release of curcumin as a model bioactive in ex-vivo skin models using a combination of imaging, modeling and analytical measurements. Both porcine skin tissue and clinically obtained human skin biopsies were studied. The results demonstrated that upon incubation with the ex-vivo skin tissues, the cell carriers rapidly bound to the skin surface following topical delivery and provided sustained release of encapsulated curcumin. The microcarrier binding and penetration of curcumin in the dermal compartment also showed to increase with incubation time. The average flux of curcumin in human skin biopsies Jp was 0.89 ± 0.02 ug/cm2/h. These results illustrated the potential of a novel cell-based carrier for high affinity binding to skin surface, efficient encapsulation of a model bioactive and controlled release from the cell carrier to the skin with enhanced permeation to the dermis section. Overall, this study demonstrated a new class of cost-effective carriers for improving delivery of bioactives to the skin and potentially other epithelial tissues.
Wachirun Terakosolphan, Ali Altharawi, Anchisa Poonprasartporn, Richard D. Harvey, Ben Forbes,
Published: 21 September 2021
International Journal of Pharmaceutics; https://doi.org/10.1016/j.ijpharm.2021.121118

Abstract:
The quantification of drug in living cells is of increasing interest in pharmaceutical research because of its importance in understanding drug efficacy and toxicity. Label-free in situ measurement methods are advantageous for their ability to obtain chemical and time profiles without the need of labelling or extraction steps. We have previously shown that Fourier transform infrared (FTIR) spectroscopy has the potential to quantify drug in situ within living cells at micromolar level when a simple solution of drug was added to the medium. The purpose of this study was to demonstrate that the approach can evaluate more complex systems such as the effect of membrane modification by a formulation on drug uptakes. The inhaled corticosteroid, beclomethasone dipropionate (BDP), in Calu-3 respiratory epithelial cells in the absence and presence of glycerol, an excipient in some inhaled medicines was used as the model system. The FTIR method was first validated for limit of detection (LOD) and quantification according to published guidelines and the LOD was found to be ∼20 μM, good enough to quantify BDP in the living cell. The uptake of BDP by living Calu-3 cells was found to be reduced in the presence of glycerol as expected due to the stiffening of the cell membrane by the presence of glycerol in the formulation. This study demonstrates the valuable analytical capability of live-cell FTIR to study the effect of formulation on drug transport in lungs and to evaluate drug availability to intracellular targets. We conclude that FTIR has potential to contribute widely at the frontier of live-cell studies.
Haiyue Xu, Tuhin Bhowmik, Kevin Gong, Thu Ngoc Anh Huynh, Robert O. Williams Iii,
Published: 21 September 2021
International Journal of Pharmaceutics; https://doi.org/10.1016/j.ijpharm.2021.121126

Abstract:
A bivalent Norovirus vaccine candidate has been developed that contains Norovirus strain GI.1 Norwalk-virus like particles (VLP) and strain GII.4 Consensus VLPadsorbed on aluminum (oxy)hydroxide. The Norwalk and Consensus antigens have different stability profiles, making it challenging to prepare a dry powder form of the Norovirus vaccine while maintaining the potency of both antigens. In the present study, we tested the feasibility of converting the vaccine from a liquid suspension to dry powders by thin-film freeze-drying (TFFD). With the proper amount of trehalose and/or sucrose as cryoprotectant (i.e. sucrose alone at 4.55% or 5.55%, w/v, or trehalose at 3-4% with 0.55% of sucrose), TFFD can be applied to successfully convert the Norovirus vaccine candidate into dry powders without causing antigen loss or particle aggregation, while maintaining the relative potency of the antigens within a specified acceptable range. In an accelerated stability study, the potency of the antigens was also maintained in the specified acceptable range after the dry powders prepared by thin-film freeze-drying in the presence of 5.55% (w/v) of sucrose were stored for eight weeks at 40°C, 75% relative humidity. It is concluded that it is feasible to apply thin-film freeze-drying to convert Norovirus vaccine from a liquid suspension to stable dry powders.
Yanbing Wang, Xiaolei Wang, Yingni Lv, Yinghua Guo, Muye He, Minbo Lan, Yuzheng Zhao,
Published: 21 September 2021
International Journal of Pharmaceutics; https://doi.org/10.1016/j.ijpharm.2021.121125

Abstract:
Current evidence shows that oxidative stress plays an essential role in the pathogenesis and progression of inflammatory bowel disease (IBD). TotalROX (λabs/λem = 425/525 nm) is a ratiometric probe with high detection sensitivity and a superior capacity to monitor total cellular oxidative capacity. Herein, we investigated the potential of combining totalROX with an oral nanoparticle delivery system to detect the degree of colitis. This detection system also featured pH-responsive Eudragit S100, hyaluronic acid with high affinity to the CD44 receptor, and chitosan, and demonstrated improved loading efficiency and stability. An experimental mouse model of experimental colitis was induced by dextran sodium sulfate do that we could investigate the ability of our nanoparticles to target the colon and determine the degree of inflammation. We also determined and validated the positive correlation between the fluorescence intensity of the detection product (Ox670, λabs/λem = 650/675 nm) and myeloperoxidase activity (R2 = 0.97) and the histopathological score (R2 = 0.98). TotalROX had significant ability to measure reactive oxygen species (ROS) produced by cells under inflammatory conditions, as confirmed by in vitro experiments with Caco-2 cells. Collectively, the data generated demonstrate that when loaded with totalROX, these functional nanoparticles are promising tools for cellular imaging after oral administration. This is the first description of a ROS-responsive fluorescent probe to evaluate the degree of colitis in experimental animal models and provides a promising approach for the diagnosis of inflammation in IBD with fluorescence-guided colonoscopy.
Abdur Rashid, Saiqa Muneer, Jayanti Mendhi, Mohammad Zaidur Rahman Sabuj, , Yin Xiao, , Emad L Izake,
Published: 21 September 2021
International Journal of Pharmaceutics; https://doi.org/10.1016/j.ijpharm.2021.121122

Abstract:
Herein, we demonstrated the development and characterization of a dry powder inhaler (DPI) formulation of edoxaban (EDX); and investigated the in-vitro anticoagulation effect for the management of pulmonary or cerebral coagulopathy associated with COVID-19 infection. The formulations were prepared by mixing the inhalable micronized drug with a large carrier lactose and dispersibility enhancers, leucine, and magnesium stearate. The drug-excipient interaction was studied using X-Ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) methods. The drug and excipients showed no physical inter particulate interaction. The in-vitro drug aerosolization from the developed formulation was determined by a Twin Stage Impinger (TSI) at a flow rate of 60 ± 5 L /min. The amount of drug deposition was quantified by an established HPLC-UV method. The fine particle fraction (FPF) of EDX API from drug alone formulation was 7%, whereas the formulations with excipients increased dramatically to almost 7-folds up to 47 %. The developed DPI formulation of EDX showed a promising in-vitro anticoagulation effect at a very low concentration. This novel DPI formulation of EDX could be a potential and effective inhalation therapy for managing pulmonary venous thromboembolism (VTE) associated with COVID-19 infection. Further studies are warranted to investigate the toxicity and clinical application of the inhaled EDX DPI formulation.
Sushant Shete, Sai Charan Reddy, Yarlagadda Dani Lakshman, Sai Krishna Anand, Chetan Hasmukh Mehta, Usha Yogendra Nayak,
Published: 21 September 2021
International Journal of Pharmaceutics; https://doi.org/10.1016/j.ijpharm.2021.121119

Abstract:
The present study was designed to investigate the contribution of solid-state and the impact of composite drug-rich phase generated as a consequence of pH shift on the maximum achievable supersaturation of co-amorphous formulations. The co-amorphous phases of weak base-weak base-pair i.e. Ritonavir and Darunavir were prepared in anticipation of studying the effect of drug-rich phase consequent to pH shift. While the co-amorphous phases of weak base-Weak acid pair i.e. Darunavir and Indomethacin were studied to understand the manifestation of the solid-state drug: co-former miscibility in the absence of drug rich phase. Thermodynamically, the lowering of the supersaturation was found commensurate with the mole fraction of the respective component (Drug/Co-former) within the co-amorphous materials for both Darunavir: Ritonavir and Darunavir: Indomethacin pair. Kinetically, for Darunavir: Ritonavir co-amorphous materials, the shift in the pH from acidic to the neutral side led to the generation of drug-rich phase and subsequent LLPS. The free drug concentration achieved in the bulk of the solution was found dependent upon the mole fraction of the respective component within the drug-rich phase. The relative mole fraction of each component within the composite drug-rich phase is dictated by pH-dependent solubility and molecular weight of the individual components.
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