Developing a quality by design approach to model tablet dissolution testing: an industrial case study

Abstract

This study applied the concept of Quality by Design (QbD) to tablet dissolution. Its goal was to propose a quality control strategy to model dissolution testing of solid oral dose products according to International Conference on Harmonization guidelines. The methodology involved the following three steps: (1) a risk analysis to identify the material- and process-related parameters impacting the critical quality attributes of dissolution testing, (2) an experimental design to evaluate the influence of design factors (attributes and parameters selected by risk analysis) on dissolution testing, and (3) an investigation of the relationship between design factors and dissolution profiles. Results show that (a) in the case studied, the two parameters impacting dissolution kinetics are active pharmaceutical ingredient particle size distributions and tablet hardness and (b) these two parameters could be monitored with PAT tools to predict dissolution profiles. Moreover, based on the results obtained, modeling dissolution is possible. The practicality and effectiveness of the QbD approach were demonstrated through this industrial case study. Implementing such an approach systematically in industrial pharmaceutical production would reduce the need for tablet dissolution testing.     

PVA-PEG physically cross-linked hydrogel film as a wound dressing: experimental design and optimization

The development of hydrogel films as wound healing dressings is of a great interest owing to their biological tissue-like nature. Polyvinyl alcohol/polyethylene glycol (PVA/PEG) hydrogels loaded with asiaticoside, a standardized rich fraction of Centella asiatica, were successfully developed using the freeze–thaw method. Response surface methodology with Box–Behnken experimental design was employed to optimize the hydrogels. The hydrogels were characterized and optimized by gel fraction, swelling behavior, water vapor transmission rate and mechanical strength. The formulation with 8% PVA, 5% PEG 400 and five consecutive freeze–thaw cycles was selected as the optimized formulation and was further characterized by its drug release, rheological study, morphology, cytotoxicity and microbial studies. The optimized formulation showed more than 90% drug release at 12?hours. The rheological properties exhibited that the formulation has viscoelastic behavior and remains stable upon storage. Cell culture studies confirmed the biocompatible nature of the optimized hydrogel formulation. In the microbial limit tests, the optimized hydrogel showed no microbial growth. The developed optimized PVA/PEG hydrogel using freeze–thaw method was swellable, elastic, safe, and it can be considered as a promising new wound dressing formulation.     

Quality by design (QbD) approach for design and development of drug-device combination products: a case study on flunisolide nasal spray

Abstract

The objective of the present study was to design and develop drug-device combination product in particular flunisolide nasal spray (FNS) using quality by design (QbD) approach. Quality target product profile (QTPP) of FNS was defined and critical quality attributes (CQAs), i.e. viscosity (cp) (Y₁) and D₅₀ droplet size distribution (DSD) (μm) (Y₂) were identified. Potential risk factors were identified using a fish bone diagram and failure mode effect analysis (FMEA) tools. Plackett–Burman and Box–Behnken designs were used for screening the significant factors and optimizing the variables range, respectively. It was observed that viscosity (cp) (Y₁) was significantly impacted by formulation variables X₁: propylene glycol (PG) (%) and X₂: polyethylene glycol (PEG) 3350 (%), while D₅₀ DSD (μm) (Y₂) was significantly impacted by formulation variables X₁: PG (%), X₂: PEG 3350 (%) and device variable X₈: delivery volume (μl). A design space plot within which the CQAs remained unchanged was established at laboratory scale. In conclusion, this study demonstrated how QbD based development approach can be applied to the development of drug-device combination products with enhanced understanding of the impact of formulation, process and device variables on CQAs of drug-device combination products.     

Development and characterization of poly(lactic-co-glycolic) acid nanoparticles loaded with copaiba oleoresin

Abstract

Copaiba oleoresin (CPO), obtained from Copaifera landgroffii, is described as active to a large number of diseases and more recently in the endometriosis treatment. In this work, poly(lactic-co-glycolic acid) (PLGA) nanoparticles containing CPO were obtained using the design of experiments (DOE) as a tool to optimize the production process. The nanoparticles optimized by means of DOE presented an activity in relation to the cellular viability of endometrial cells. The DOE showed that higher amounts of CPO combined with higher surfactant concentrations resulted in better encapsulation efficiency and size distribution along with good stability after freeze drying. The encapsulation efficiency was over 80% for all produced nanoparticles, which also presented sizes below 300?nm and spherical shape. A decrease in viability of endometrial stromal cells from ectopic endometrium of patients with endometriosis and from eutopic endometriotic lesions was demonstrated after 48?h of incubation with the CPO nanoparticles. The nanoparticles without CPO were not able to alter the cell viability of the same cells, indicating that this material was not cytotoxic to the tested cells and suggesting that the effect was specific to CPO. The results indicate that the use of CPO nanoparticles may represent a promising alternative for the treatment of endometriosis.     

Loteprednol etabonate for inflammatory conditions of the anterior segment of the eye: twenty years of clinical experience with a retrometabolically designed corticosteroid

Introduction: Topical corticosteroids are an important pharmacotherapy for the management of various inflammatory conditions affecting the anterior segment of the eye. However, medications in this class are associated with well-known risks including increased intraocular pressure (IOP) and development of cataracts. The topical corticosteroid loteprednol etabonate (LE) was developed with the specific intention of minimizing these side effects.

Areas covered: The focus of this review is to examine published efficacy and safety data for LE, a drug engineered to undergo rapid metabolism to inactive metabolites with the goal of improved safety. Two decades of clinical research focused on LE formulations are reviewed, including the use of LE in combination with tobramycin. The cumulative body of experience affirms the concept that the molecular design of LE confers certain safety benefits without compromising the desired anti-inflammatory efficacy of a topical corticosteroid.

Expert opinion: Loteprednol etabonate is a mainstay for topical therapy of a wide variety of commonplace and niche conditions of the ocular surface and the anterior segment, including in the healing post-operative patient. Its versatility and safety allow eye care providers to recommend both acute induction as well as chronic maintenance therapy with appropriate follow-up.     

The use of databases,data mining and immunoinformatics in vaccinology: where are we?

Introduction: Vaccinology has evolved from a sub-discipline focussed on simplistic vaccine development based on antibody-mediated protection to a separate discipline involving epidemiology, host and pathogen biology, immunology, genomics, proteomics, structure biology, protein engineering, chemical biology, and delivery systems. Data mining in combination with bioinformatics has provided a scaffold linking all these disciplines to the design of vaccines and vaccine adjuvants.

Areas covered: This review provides background knowledge on immunological aspects which have been exploited with informatics for the in silico analysis of immune responses and the design of vaccine antigens. Furthermore, the article presents various databases and bioinformatics tools, and discusses B and T cell epitope predictions, antigen design, adjuvant research and systems immunology, highlighting some important examples, and challenges for the future.

Expert opinion: Informatics and data mining have not only reduced the time required for experimental immunology, but also contributed to the identification and design of novel vaccine candidates and the determination of biomarkers and pathways of vaccine response. However, more experimental data is required for benchmarking immunoinformatic tools. Nevertheless, developments in immunoinformatics and reverse vaccinology, which are nascent fields, are likely to hasten vaccine discovery, although the path to regulatory approval is likely to remain a necessary impediment.     

Analogue synthesis reveals decoupling of antibiofilm and β‐lactam potentiation activities of a lead 2‐aminoimidazole adjuvant against Mycobacterium smegmatis

Biofilm formation is one of the many mechanisms bacteria utilize to survive antibiotic treatment. It has been demonstrated that when Mycobacterium tuberculosis exists in a biofilm in vitro, it expresses phenotypic resistance to antimicrobial drugs. As the in vivo survival of M. tuberculosis following drug treatment is potentially linked to a biofilm‐like expression of drug tolerance, it is hypothesized that biofilm dispersion should increase antibiotic susceptibility and reduce the duration of the current antibiotic treatment regimen. Previously, we have identified a 2‐aminoimidazole (2‐AI) compound capable of dispersing and inhibiting M. tuberculosis and M. smegmatis biofilms in vitro. Additionally, this compound potentiated the activity of carbenicillin against M. tuberculosis and, to a lesser degree, M. smegmatis. Here, we describe a SAR study on this compound evaluating each derivative for biofilm dispersion and β‐lactam potentiation capabilities against M. smegmatis. This study identified a compound that improved upon the biofilm dispersion capabilities of the lead compound. Interestingly, a different compound was identified with an increased ability to potentiate a subset of β‐lactam antibiotics. These compounds indicate that biofilm dispersion and potentiation capabilities may not be associated.     

我国药品首次工艺验证存在问题及探讨

通过调查研究的方法,找到我国制药企业在首次工艺验证中普遍存在的问题,借助对国内外法规及相关文献研究,并结合我国制药企业的现状,提出对问题的解决策略,该研究对我国制药企业有效开展首次工艺验证有一定的指导意义。     

El Registro de Gemelos de Murcia. Un recurso para la investigación sobre conductas relacionadas con la salud

Genetically informative designs and, in particular, twin studies, are the most widely used methodology to analyse the relative contribution of genetic and environmental factors to inter-individual variability. These studies basically compare the degree of phenotypical similarity between monozygotic and dizygotic twin pairs. In addition to the traditional estimate of heritability, this kind of registry enables a wide variety of analyses which are unique due to the characteristics of the sample. The Murcia Twin Registry is population-based and focused on the analysis of health-related behaviour. The observed prevalence of health problems is comparable to that of other regional and national reference samples, which guarantees its representativeness. Overall, the characteristics of the Registry facilitate developing various types of research as well as genetically informative designs, and collaboration with different initiatives and consortia.