Quality by Design Based Formulation Study of Meloxicam-Loaded Polymeric Micelles for Intranasal Administration

Our study aimed to develop an “ex tempore” reconstitutable, viscosity enhancer- and preservative-free meloxicam (MEL)-loaded polymeric micelle formulation, via Quality by Design (QbD) approach, exploiting the nose-to-brain pathway, as a suitable tool in the treatment of neuroinflammation. The anti-neuroinflammatory effect of nose-to-brain NSAID polymeric micelles was not studied previously, therefore its investigation is promising. Critical product parameters, encapsulation efficiency (89.4%), Z-average (101.22 ± 2.8 nm) and polydispersity index (0.149 ± 0.7) and zeta potential (−25.2 ± 0.4 mV) met the requirements of the intranasal drug delivery system (nanoDDS) and the targeted profile liquid formulation was transformed into a solid preservative-free product by freeze-drying. The viscosity (32.5 ± 0.28 mPas) and hypotonic osmolality (240 mOsmol/L) of the reconstituted formulation provides proper and enhanced absorption and probably guarantees the administration of the liquid dosage form (nasal drop and spray). The developed formulation resulted in more than 20 times faster MEL dissolution rate and five-fold higher nasal permeability compared to starting MEL. The prediction of IVIVC confirmed the great potential for in vivo brain distribution of MEL. The nose-to-brain delivery of NSAIDs such as MEL by means of nanoDDS as polymeric micelles offers an innovative opportunity to treat neuroinflammation more effectively.

Download Full-text

Development of Meloxicam-Human Serum Albumin Nanoparticles for Nose-to-Brain Delivery via Application of a Quality by Design Approach

Pharmaceutics ◽

10.3390/pharmaceutics12020097 ◽

2020 ◽

Vol 12 (2) ◽

pp. 97 ◽

Cited By ~ 4

Author(s):

Gábor Katona ◽

György Tibor Balogh ◽

Gergő Dargó ◽

Róbert Gáspár ◽

Árpád Márki ◽

...

Keyword(s):

Human Serum Albumin ◽

Zeta Potential ◽

Serum Albumin ◽

Human Serum ◽

Quality By Design ◽

Tween 80 ◽

Critical Parameters ◽

Brain Delivery

The aim of this study was to optimize the formulation of meloxicam (MEL)-containing human serum albumin (HSA) nanoparticles for nose-to-brain via a quality by design (QbD) approach. Liquid and dried formulations of nanoparticles containing Tween 80 and without the surfactant were investigated. Various properties, such as the Z-average, zeta potential, encapsulation efficacy (EE), conjugation of MEL and HSA, physical stability, in vitro dissolution, in vitro permeability, and in vivo plasma and brain distribution of MEL were characterized. From a stability point of view, a solid product (Mel-HSA-Tween) is recommended for further development since it met the desired critical parameters (176 ± 0.3 nm Z-average, 0.205 ± 0.01 PdI, −14.1 ± 0.7 mV zeta potential) after 6 months of storage. In vitro examination showed a significantly increased drug dissolution and permeability of MEL-containing nanoparticles, especially in the case of applying Tween 80. The in vivo studies confirmed both the trans-epithelial and axonal transport of nanoparticles, and a significantly higher cerebral concentration of MEL was detected with nose-to-brain delivery, in comparison with intravenous or per os administration. These results indicate intranasal the administration of optimized MEL-containing HSA formulations as a potentially applicable “value-added” product for the treatment of neuroinflammation.

Download Full-text

Bioequivalence Assessment of High-Capacity Polymeric Micelle Nanoformulation of Paclitaxel and Abraxane® in Rodent and Non-Human Primate Models Using a Stable Isotope Tracer Assay

10.1101/2021.08.20.457164 ◽

2021 ◽

Author(s):

Duhyeong Hwang ◽

Natasha Vinod ◽

Sarah L. Skoczen ◽

Jacob D. Ramsey ◽

Kelsie S. Snapp ◽

...

Keyword(s):

Stable Isotope ◽

Drug Exposure ◽

Polymeric Micelles ◽

Clinical Investigation ◽

Rhesus Macaques ◽

Physicochemical Characterization ◽

Polymeric Micelle ◽

Stable Isotope Tracer ◽

Isotope Tracer

AbstractThe in vivo fate of nanoformulated drugs is governed by the physicochemical properties of the drug and the functionality of nanocarriers. Nanoformulations such as polymeric micelles, which physically encapsulate poorly soluble drugs, release their payload into the bloodstream during systemic circulation. This results in three distinct fractions of the drug-nanomedicine: encapsulated, protein-bound, and free drug. Having a thorough understanding of the pharmacokinetic (PK) profiles of each fraction is essential to elucidate mechanisms of nanomedicine-driven changes in drug exposure and PK/PD relationships pharmacodynamic activity. Here, we present a comprehensive preclinical assessment of the poly(2-oxazoline)-based polymeric micelle of paclitaxel (PTX) (POXOL hl-PM), including bioequivalence comparison to the clinically approved paclitaxel nanomedicine, Abraxane®. Physicochemical characterization and toxicity analysis of POXOL hl-PM was conducted using standardized protocols by the Nanotechnology Characterization Laboratory (NCL). The bioequivalence of POXOL hl-PM to Abraxane® was evaluated in rats and rhesus macaques using the NCL’s established stable isotope tracer ultrafiltration assay (SITUA) to delineate the plasma PK of each PTX fraction. The SITUA study revealed that POXOL hl-PM and Abraxane® had comparable PK profiles not only for total PTX but also for the distinct drug fractions, suggesting bioequivalence in given animal models. The comprehensive preclinical evaluation of POXOL hl-PM in this study showcases a series of widely-applicable standardized studies by NCL for assessing nanoformulations prior to clinical investigation.GRAPHICAL ABSTRACT

Download Full-text

Real-time monitoring of a controlled drug delivery system in vivo: construction of a near infrared fluorescence monomer conjugated with pH-responsive polymeric micelles

Journal of Materials Chemistry B ◽

10.1039/c6tb00315j ◽

2016 ◽

Vol 4 (19) ◽

pp. 3377-3386 ◽

Cited By ~ 11

Author(s):

Li Chen ◽

Bizheng Chen ◽

Xiaodong Liu ◽

Yujie Xu ◽

Lifen Zhang ◽

...

Keyword(s):

Real Time ◽

Near Infrared ◽

Polymeric Micelles ◽

Controlled Drug Delivery ◽

Polymeric Micelle ◽

Amphiphilic Copolymer ◽

Tumor Site ◽

Ph Responsive ◽

Controlled Drug Delivery System

A self-assembled polymeric micelle from multifunctional amphiphilic copolymer with NIR and pH-sensitive groups can be used to monitor the dynamic process of its arriving at the tumor site in real time.

Download Full-text

A Systematic, Knowledge Space-Based Proposal on Quality by Design-Driven Polymeric Micelle Development

Pharmaceutics ◽

10.3390/pharmaceutics13050702 ◽

2021 ◽

Vol 13 (5) ◽

pp. 702

Author(s):

Bence Sipos ◽

Gábor Katona ◽

Ildikó Csóka

Keyword(s):

Risk Assessment ◽

Quality By Design ◽

Polymeric Micelles ◽

Risk Estimation ◽

Polymeric Micelle ◽

Extended Model ◽

Strategic Development ◽

Knowledge Based ◽

Sustainable Environment ◽

Promising Tool

Nanoparticle research and development for pharmaceuticals is a challenging task in the era of personalized medicine. Specialized and increased patient expectations and requirements for proper therapy adherence, as well as sustainable environment safety and toxicology topics raise the necessity of well designed, advanced and smart drug delivery systems on the market. These stakeholder expectations and social responsibility of pharma sector open the space and call new methods on the floor for new strategic development tools, like Quality by Design (QbD) thinking. The extended model, namely the R&D QbD proved to be useful in case of complex and/or high risk/expectations containing or aiming developments. This is the case when we formulate polymeric micelles as promising nanotherapeutics; the risk assessment and knowledge-based quality targeted QbD approach provides a promising tool to support the development process. Based on risk assessment, many factors pose great risk in the manufacturing process and affect the quality, efficacy and safety profile. The quality-driven strategic development pathway, based on deep prior knowledge and an involving iterative risk estimation and management phases has proven to be an adequate tool, being able to handle their sensitive stability issues and make them efficient therapeutic aids in case of several diseases.

Download Full-text

Development and in vitro/in vivo evaluation of a novel benznidazole liquid dosage form using a quality-by-design approach

Tropical Medicine & International Health ◽

10.1111/tmi.12980 ◽

2017 ◽

Vol 22 (12) ◽

pp. 1514-1522 ◽

Cited By ~ 7

Author(s):

Higo Fernando Santos Souza ◽

Daniel Real ◽

Darío Leonardi ◽

Sandra Carla Rocha ◽

Victoria Alonso ◽

...

Keyword(s):

Dosage Form ◽

Quality By Design ◽

Design Approach ◽

In Vivo Evaluation ◽

Quality By Design Approach ◽

Liquid Dosage Form

Download Full-text

Galactosamine-Conjugating Zwitterionic Block Copolymer for Reduction-Responsive Release and Active Targeted Delivery of Doxorubicin to Hepatic Carcinoma Cells

Journal of Nanomaterials ◽

10.1155/2020/7863709 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Jingming Zhai ◽

Biyu Zhou ◽

Yanhui An ◽

Binzhong Lu ◽

Yonggang Fan ◽

...

Keyword(s):

Cancer Treatment ◽

Targeted Delivery ◽

Polymeric Micelles ◽

Specific Binding ◽

Drug Carrier ◽

Polymeric Micelle ◽

Carcinoma Cells ◽

Active Targeting ◽

Hepatic Carcinoma

Nanocarriers with integrated advantage, such as excellent stealth property, active targeting function, and rapid intracellular drug release, are significant for cancer treatment. Herein, a biodegradable zwitterionic triblock copolymer containing disulfide-linked poly-ε-caprolactone and polycarboxybetaine methacrylate (PCB-SS-PCL-SS-PCB) was first synthesized and then partly modified with galactosamine (GAL) for constructing polymeric micelle drug carrier with multifunctionality. Polymeric micelles showed ultralow protein absorption in serum and obvious reduction-responsiveness in the presence of glutathione, provided by the zwitterionic polymer shell and the disulfide bond, respectively. Furthermore, active targeting of the carrier to hepatic carcinoma cells was achieved via GAL ligands on PCB shells due to their specific binding to asialoglycoprotein receptors on the cell surface. As expected, in vivo competition studies demonstrated that doxorubicin- (DOX-) loaded GAL-modified micelles have better anticancer effect in hepatic tumor-bearing mice than free DOX and nontargetable micelles. As a result, this novel multifunctional carrier provides a valuable strategy to design promising anticancer drug delivery systems for liver cancer treatment.

Download Full-text

A novel polymeric micelle used for in vivo MR imaging tracking of neural stem cells in acute ischemic stroke

RSC Advances ◽

10.1039/c7ra00345e ◽

2017 ◽

Vol 7 (25) ◽

pp. 15041-15052 ◽

Cited By ~ 13

Author(s):

Liejing Lu ◽

Yong Wang ◽

Minghui Cao ◽

Meiwei Chen ◽

Bingling Lin ◽

...

Keyword(s):

Stem Cells ◽

Ischemic Stroke ◽

Mr Imaging ◽

Neural Stem Cells ◽

Acute Ischemic Stroke ◽

Cholic Acid ◽

Polymeric Micelles ◽

Polymeric Micelle ◽

Biodegradable Poly

Novel cationic polymeric micelles based on biodegradable poly(aspartic acid-dimethylethanediamine)–lysine–cholic acid were synthesized for in vivo tracking therapeutic stem cells using MRI.

Download Full-text

Improved Pharmacokinetics of Icariin (ICA) within Formulation of PEG-PLLA/PDLA-PNIPAM Polymeric Micelles

Pharmaceutics ◽

10.3390/pharmaceutics11020051 ◽

2019 ◽

Vol 11 (2) ◽

pp. 51 ◽

Cited By ~ 3

Author(s):

Lu-Ying Han ◽

Yun-Long Wu ◽

Chun-Yan Zhu ◽

Cai-Sheng Wu ◽

Chun-Rong Yang

Keyword(s):

Lactic Acid ◽

Polymeric Micelles ◽

Polymeric Micelle ◽

Pluronic F127 ◽

In Vivo Experiments ◽

Poly Ethylene ◽

Metabolites Production ◽

New Formulation

Icariin (ICA) is a major flavonoid that contains the active compound Epimedii Folium. However, ICA’s pharmacokinetic characteristics remain unsatisfactory due to its low bioavailability, and hence limited drugability. In order to improve its pharmacokinetics and achieve prolonged blood circulation time, a novel polymeric micelle, made of the self-assembled micelle between poly (ethylene glycol)-poly (L-lactic acid) (PEG-PLLA) and poly (D-lactic acid)-poly(N-isopropylacrylamide) (PDLA-PNIPAM), was designed to encapsulate ICA. Our experimental results showed that this polymeric micelle formulation of ICA exhibited uniform nano-size distribution and high stability within 48 h. The new formulation also allowed sustained ICA release in an in vitro drug release study. Furthermore, in vivo experiments revealed that ICA bioavailability in the PEG-PLLA/PDLA-PNIPAM polymeric micelle formulation was significantly higher compared to ICA alone, or ICA in the traditional Pluronic F127 micelle formulation. Finally, we show that metabolite analysis confirmed that ICA within the PEG-PLLA/PDLA-PNIPAM polymeric micelle formulation provided better drug protection, reduced drug metabolites production, and decreased undesired first-pass effects. Overall, these data show that ICA within PEG-PLLA/PDLA-PNIPAM polymeric micelle formulation exhibit advantages, in terms of improved physicochemical properties, sustained release of ICA in vitro, and improved bioavailability of ICA in vivo, which represent a feasible approach for improving the drugability of pharmaceutical small molecules with low bioavailability or poor stability.

Download Full-text