Is it advantageous to use quality by design (QbD) to develop nanoparticle-based dosage forms for parenteral drug administration?

Parenteral administration is one of the most commonly used drug delivery routes for nanoparticle-based dosage forms, such as lipid-based and polymeric nanoparticles. For the treatment of various diseases, parenteral administration include intravenous, subcutaneous, and intramuscular route. In drug development phase, multiparameter strategy with a focus on drug physicochemical properties and the specificity of the administration route is required. Nanoparticle properties in terms of size and targeted delivery, among others, are able to surpass many drawbacks of conventional dosage forms, but these unique properties can be a bottleneck for approval by regulatory authorities. Quality by Design (QbD) approach has been widely utilized in development of parenteral nanoparticle-based dosage forms. It fosters knowledge of product and process quality by involving sound scientific data and risk assessment strategies. A full and comprehensive investigation into the state of implementation and applications of the QbD approach in these complex drug products can highlight the gaps and challenges. In this review, the analysis of critical attributes and Design of Experiment (DoE) approach in different nanoparticulate systems, together with the proper utilization of Process Analytical Technology (PAT) applications are described. The essential of QbD approach for the design and development of nanoparticle-based dosage forms for delivery via parenteral routes is discussed thoroughly.

Leveraging a multivariate approach towards enhanced development of direct compression extended release tablets.

Extended release formulations play a crucial role in the pharmaceutical industry by maintaining steady plasma levels, reducing side effects, and improving therapeutic efficiency and compliance. One commonly used method to develop extended release formulations is direct compression, which offers several advantages, such as simplicity, time savings, and cost-effectiveness. However, successful direct compression-based extended release formulations require careful assessment and an understanding of the excipients' attributes. The scope of this work is the characterization of the compaction behavior of some matrix-forming agents and diluents for the development of extended release tablets. Fifteen excipients commonly used in extended release formulations were evaluated for physical, compaction and tablet properties. Powder properties (e.g., particle size, flow properties, bulk density) were evaluated and linked to the tablet's mechanical properties in a fully integrated approach, and data were analyzed by constructing a principal component analysis (PCA). Significant variability was observed among the various excipients. The present work successfully demonstrates the applicability of PCA as an effective tool for comparative analysis, pattern and clustering recognition and correlations between excipients and their properties, facilitating the development and manufacturing of direct compressible extended release formulations.

Role of nanotechnology in the prolonged release of drugs by the subcutaneous route.

INTRODUCTION: Subcutaneous physiology is distinct from other parenteral routes that benefit the administration of prolonged-release formulations. A prolonged-release effect is particularly convenient for treating chronic diseases because it is associated with complex and often prolonged posologies. Therefore, drug-delivery systems focused on nanotechnology are proposed as alternatives that can overcome the limitations of current therapeutic regimens and improve therapeutic efficacy. AREAS COVERED: This review presents an updated systematization of nanosystems, focusing on their applications in highly prevalent chronic diseases. Subcutaneous-delivered nanosystem-based therapies comprehensively summarize nanosystems, drugs, and diseases and their advantages, limitations, and strategies to increase their translation into clinical applications. An outline of the potential contribution of quality-by-design (QbD) and artificial intelligence (AI) to the pharmaceutical development of nanosystems is presented. EXPERT OPINION: Although recent academic research and development (R&D) advances in the subcutaneous delivery of nanosystems have exhibited promising results, pharmaceutical industries and regulatory agencies need to catch up. The lack of standardized methodologies for analyzing in vitro data from nanosystems for subcutaneous administration and subsequent in vivo correlation limits their access to clinical trials. There is an urgent need for regulatory agencies to develop methods that faithfully mimic subcutaneous administration and specific guidelines for evaluating nanosystems.

Implementation of Quality by Design (QbD) for development of bilayer tablets.

Bilayer tablets offer various drug release profiles for individual drugs incorporated in each layer of a bilayer tablet, which is rarely achievable by conventional tablets. These tablets also help avoid physicochemical incompatibilities between drugs and excipients. Successful manufacturing of such more complex dosage forms depends upon screening of material attributes of API and excipients as well as optimization of processing parameters of individual unit operations of the manufacturing process that must be strictly monitored and controlled to obtain an acceptable drug product quality and performance in order to achieve safety and efficacy per regulatory requirements. Optimizing formulation attributes and manufacturing processes during critical stages, such as blending, granulation, pre-compression, and main compression, can help avoid problems such as weight variation, segregation, and delamination of individual layers, which are frequently faced during the production of bilayer tablets. The main objective of this review is to establish the basis for the implementation of Quality by Design (QbD) system principles for the design and development of bilayer tablets, encompassing the preliminary and systematic risk assessment of critical material attributes (CMAs) and critical process parameters (CPPs) with respect to in-process and finished product critical quality attributes (CQAs). Moreover, the applicability of the QbD methodology based on its purpose is discussed and complemented with examples of bilayer tablet technology.

IgG functionalized polymeric nanoparticles for oral insulin administration.

The oral route is the best way to administer a drug; however, fitting peptide drugs in this route is a major challenge. In insulin cases, less than 0.5% of the administered dose achieves systemic circulation. Oral delivery by nanoparticles can increase insulin permeability across the intestinal epithelium while maintaining its structure and activity until release in the gut. This system can be improved to increase permeability across intestinal cells through active delivery. This study aimed to improve a nanoparticle formulation by promoting functionalization of its surface with immunoglobulin G to increase its absorption by intestinal epithelium. The characterization of formulations showed an adequate size and a good entrapment efficiency. Functionalized nanoparticles led to a desirable increase in insulin release time. Differential scanning calorimetry, infrared spectroscopy and paper chromatography proved the interactions of nanoparticle components. With immunoglobulin G, the nanoparticle size was slightly increased, which did not show aggregate formation. The developed functionalized nanoparticle formulation proved to be adequate to carry insulin and potentially increase its internalization by epithelial gut cells, being a promising alternative to the existing formulations for orally administered low-absorption peptides.

Comparison of ELISA and HPLC-MS methods for the determination of exenatide in biological and biotechnology-based formulation matrices.

The development of biotechnology-based active pharmaceutical ingredients, such as GLP-1 analogs, brought changes in type 2 diabetes treatment options. For better therapeutic efficiency, these active pharmaceutical ingredients require appropriate administration, without the development of adverse effects or toxicity. Therefore, it is required to develop several quantification methods for GLP-1 analogs products, in order to achieve the therapeutic goals, among which ELISA and HPLC arise. These methods are developed, optimized and validated in order to determine GLP-1 analogs, not only in final formulation of the active pharmaceutical ingredient, but also during preclinical and clinical trials assessment. This review highlights the role of ELISA and HPLC methods that have been used during the assessment for GLP-1 analogs, especially for exenatide.

Comparison of ELISA and HPLC-MS methods for the determination of exenatide in biological and biotechnology-based formulation matrices / 药物分析学报

The development of biotechnology-based active pharmaceutical ingredients, such as GLP-1 analogs, brought changes in type 2 diabetes treatment options. For better therapeutic efficiency, these active pharmaceutical ingredients require appropriate administration, without the development of adverse effects or toxicity. Therefore, it is required to develop several quantification methods for GLP-1 analogs products, in order to achieve the therapeutic goals, among which ELISA and HPLC arise. These methods are developed, optimized and validated in order to determine GLP-1 analogs, not only in final formu-lation of the active pharmaceutical ingredient, but also during preclinical and clinical trials assessment. This review highlights the role of ELISA and HPLC methods that have been used during the assessment for GLP-1 analogs, especially for exenatide.

Lower serum fibroblast activation protein shows promise in the exclusion of clinically significant liver fibrosis due to non-alcoholic fatty liver disease in diabetes and obesity.

UNLABELLED: Non-alcoholic fatty liver disease (NAFLD) is common in diabetes and obesity but few have clinically significant liver fibrosis. Improved risk-assessment is needed as the commonly used clinical-risk algorithm, the NAFLD fibrosis score (NFS), is often inconclusive. AIMS: To determine whether circulating fibroblast activation protein (cFAP), which is elevated in cirrhosis, has value in excluding significant fibrosis, particularly combined with NFS. METHODS: cFAP was measured in 106 with type 2 diabetes who had transient elastography (Cohort 1) and 146 with morbid obesity who had liver biopsy (Cohort 2). RESULTS: In Cohort 1, cFAP (per SD) independently associated with median liver stiffness (LSM) ≥ 10.3 kPa with OR of 2.0 (95% CI 1.2-3.4), p=0.006. There was 0.12 OR (95% CI 0.03-0.61) of LSM ≥ 10.3 kPa for those in the lowest compared with the highest FAP tertile (p=0.010). FAP levels below 730 pmol AMC/min/mL had 95% NPV for LSM ≥ 10.3 kPa and reclassified 41% of 64 subjects from NFS 'indeterminate-risk' to 'low-risk'. In Cohort 2, cFAP (per SD), associated with 1.7 fold (95% CI 1.1-2.8) increased odds of significant fibrosis (F ≥ 2), p=0.021, and low cFAP reclassified 49% of 73 subjects from 'indeterminate-risk' to 'low-risk'. CONCLUSIONS: Lower cFAP, when combined with NFS, may have clinical utility in excluding significant fibrosis in diabetes and obesity.

Protein-ligand docking in the new millennium--a retrospective of 10 years in the field.

Protein-ligand docking is currently an important tool in drug discovery efforts and an active area of research that has been the subject of important developments over the last decade. These are well portrayed in the rising number of available protein-ligand docking software programs, increasing level of sophistication of its most recent applications, and growing number of users. While starting by summarizing the key concepts in protein-ligand docking, this article presents an analysis of the evolution of this important field of research over the past decade. Particular attention is given to the massive range of alternatives, in terms of protein-ligand docking software programs currently available. The emerging trends in this field are the subject of special attention, while old established docking alternatives are critically revisited. Current challenges in the field of protein-ligand docking such as the treatment of protein flexibility, the presence of structural water molecules and its effect in docking, and the entropy of binding are dissected and discussed, trying to anticipate the next years in the field.

Insulin-loaded nanoparticles are prepared by alginate ionotropic pre-gelation followed by chitosan polyelectrolyte complexation.

Alginate nanoparticles were prepared from dilute alginate sol by inducing a pre-gel with calcium counter ions, followed by polyelectrolyte complex coating with chitosan. Particles in the nanometer size range were obtained with 0.05% alginate and 0.9 mM Ca2+. The mean particle size was influenced by time and stirring speed of nanoparticle preparation, by alginate guluronic acid content and chitosan molecular weight and by the initial alginate:chitosan mass ratio. The association efficiency of insulin into alginate nanoparticles, as well as loading capacity were mainly influenced by the alginate:chitosan mass ratio. Under optimized size conditions, the association efficiency and loading capacities were as high as 92% and 14.3%, respectively. Approximately 50% of the protein was partially retained by the nanoparticles in gastric pH environment up to 24 hours while a more extensive release close to 75% was observed under intestinal pH conditions. Mild formulation conditions, optimum particle size range obtained, high insulin entrapment efficiency, and resistance to gastrointestinal release seem to be synergic and promising factors toward development of an oral insulin delivery form.

Microencapsulation of lipophilic drugs in chitosan-coated alginate microspheres.

Chitosan-coated alginate microspheres containing a lipophilic marker dissolved in an edible oil, were prepared by emulsification/internal gelation and the potential use as an oral controlled release system investigated. Microsphere formation involved dispersing a lipophilic marker dissolved in soybean oil into an alginate solution containing insoluble calcium carbonate microcrystals. The dispersion was then emulsified in silicone oil to form an O/W/O multiple phase emulsion. Addition of an oil soluble acid released calcium from carbonate complex for gelation of the alginate. Chitosan was then applied as a membrane coat to increase the mechanical strength and stabilize the microspheres in simulated intestinal media. Parameters studied included encapsulation yield, alginate concentration, chitosan molecular weight and membrane formation time. Mean diameters ranging from 500 to 800 micron and encapsulation yields ranging from 60 to 80% were obtained. Minimal marker release was observed under simulated gastric conditions, and rapid release was triggered by transfer into simulated intestinal fluid. Higher overall levels of release were obtained with uncoated microspheres, possibly due to binding of marker to the chitosan membrane coat. However the slower rate of release from coated microspheres was felt better suited as a delivery vehicle for oil soluble drugs.

Cytochrome c binds to lipid domains in arrays of mitochondrial outer membrane channels.

Computer-averaged electron microscopic images of negatively stained crystalline arrays of fungal mitochondrial outer-membrane channels in the presence and absence of cytochrome c were compared. Neither the apo- nor the holo- forms of cytochrome c significantly changed the stain distribution in the protein regions of the channel arrays. However, both forms of cytochrome c caused significant stain exclusion from the lipid domains in the arrays, suggesting binding of the polypeptides at these loci. The implications of binding of apocytochrome c to clusters of exposed phospholipids on the mitochondrial outer membrane are discussed with respect to the mechanism of uptake of this polypeptide by mitochondria.