Journal of Pharmaceutical Innovation最新文献

Purpose

The study aimed to develop and optimize apremilast (APST) solid dispersion formulations using copovidone (Kollidon VA64) as the carrier and vitamin E TPGS as the surfactant to enhance solubility and dissolution, and to utilize in silico Physiologically Based Biopharmaceutics Modeling (PBBM) in GastroPlus to simulate the in vivo behaviour of the optimized formulation, predicting its potential for enhancing oral bioavailability.

Methods

Solid dispersion formulations of APST were prepared via the hot melt extrusion (HME) technique, utilizing copovidone (commercially known as Kollidon VA64) as the polymeric carrier. The selection of suitable polymeric carriers as well as surfactant was initially performed through phase solubility studies. The second-generation amorphous solid dispersion (ASD) was formulated with Kollidon VA64. Following this, the third-generation solid dispersions were engineered by choosing vitamin E TPGS as the surfactant carrier, a decision informed by comprehensive screening studies. The formulation of these batches employed a twin-screw configuration in the HME process. Design of Experiments (DoE) approach was utilized to ascertain the optimal ratio of drug: polymer: surfactant to achieve maximum solubility and dissolution enhancement. Drug release studies were conducted in 6.8 phosphate buffer solution. The developed formulations were subjected to a variety of characterization techniques to assess their properties. Stability studies were conducted for the final formulation over a period of up to three months.

Results

Based on the DoE studies, the optimized formulation was identified as APST with copovidone (Kollidon VA64) in a 1:5 ratio, supplemented with 3% vitamin E TPGS. Furthermore, PBBM in GastroPlus was utilized to simulate the in vivo behaviour of the optimized formulation.

Conclusion

The amorphous solid dispersion (ASD) of APST, developed via the HME technique, demonstrated a substantial enhancement in solubility, exhibiting an increase of up to 248-fold relative to the unprocessed drug over a 24-hour period. A noteworthy increase in the percentage of drug release during dissolution was observed in comparison to the pure drug. The observed improvements in solubility and dissolution were corroborated through PBBM in GastroPlus, thereby suggesting a viable strategy for enhancing the oral bioavailability of APST. This investigation effectively illustrates the formulation of a third-generation ASD of APST, significantly ameliorating its solubility and pharmacokinetic parameters, and indicating potential for industrial-scale manufacturing.

Purpose

Study the structure and content trend over time of the FDA GMP Warning Letters for their roles in effective communication.

Methods

The structure and content trend over time of Warning Letters are studied using a combination of parsing text based on function, manual coloring and Python automation.

Results

The observed trends using these methods indicate that the content of suggestions on how to respond to a Warning Letter, for third party participation and further reading consistently increases over time.

Conclusions

Warning Letters have become increasingly informative, showing FDA’s good practice of transparency as a way to improve regulatory effectiveness.

Purpose

The predictive modeling approach to assess long-term stability performance of pharmaceuticals by using short-term accelerated stability is of significant value to accelerate development timelines, enhance stability confidence, and improve product quality and regulatory compliance. Herein, the head-to-head quantitative comparison of predictive stability models developed by two independent statistical tools was conducted as a unique approach to assess and qualify the model parameters, the statistical tools, and stability predictions.

Methods

The moisture-modified Arrhenius equation and two independent statistical tools including ASAPprime^® and JMP^® software were utilized to develop predictive pharmaceutical stability models for a humidity independent case study and a humidity dependent case study.

Results

Various temperature and humidity stress conditions were utilized to develop stability models with ASAPprime^® and JMP^® softwares to provide a reasonably accurate fit as the coefficient of determination R² was not less than 0.99. Many statistical tools including leverage plot, p value, three-dimension plot in JMP^® models were employed to provide unique visual extrapolation. ASAPprime^® model offered database of packaging and excipient to enable assessing package protection, which JMP^® model lacked. The prediction outcomes of the stability models were later confirmed by the independent long-term stability data.

Conclusion

Both humidity independent and humidity dependent cases were investigated in the predictive stability modeling approach with success. This approach is applicable and is aligned with global regulatory agency expectations of using science, data, and statistical tools to de-risk stability concerns, enable early and fast decision making, and enhance product quality in pharmaceutical development.

Purpose

This research aimed to produce zein-based bilayer nanofibers to sustain the release of crocin. Zein and gelatin were blended to form the drug-eluting layer, while polycaprolactone (PCL) was used to fabricate the backing layer.

Methods

Bilayer nanofibers were fabricated through sequential electrospinning. For fabricating the drug-eluting layer, zein solutions at the concentrations of 30% and 40% w/v were prepared and blended with gelatin solution (20% w/v) at four zein/gelatin solution mass ratios. After finding the optimized solution, PCL (12% w/v) was electrospun on the drug-eluting layer. The prepared nanofibers were characterized regarding morphology, FTIR, XRD, water contact angle, swelling, in vitro release, and mechanical properties. Molecular docking studies were also used to demonstrate interactions in crocin-zein and crocin-gelatin complexes.

Results

SEM micrographs showed that the ideal nanofibers consisted of zein 40% w/v and gelatin 20% w/v with a zein/gelatin solution mass ratio of 80:20. These nanofibers had an average diameter of ~ 500 nm and showed a good yield in the production process. Solid state characterizations (FTIR and XRD) demonstrated compatibility between crocin and the polymers. The bilayer nanofibers exhibited sustained release of crocin (up to 56.6% in 5 days) by preventing the shrinkage of the zein/gelatin nanofibers. Additionally, the bilayer nanofibers exhibited improved mechanical properties. Computational characterization showed favorable binding energies of -5.9 kcal/mol for the gelatin-crocin complex and -5.6 kcal/mol for the zein-crocin complex.

Conclusion

Based on the findings, it appears that the zein-based bilayer nanofibers could be an effective delivery system for crocin, potentially providing a sustained release for localized applications.

Graphical Abstract

Purpose

The objectives of the study are to obtain silver nanoparticles using Anthemis tricolor in an environmentally friendly, economical, and more effective way with green synthesis and also to determine the most appropriate parameters by examining the effects of preparation conditions on particle size, polydispersity index, and zeta potential using factorial design and further to compare the bioactivity results between water extract and silver nanoparticles. Thus, it is aimed to shed light on further studies on the lightening effects of nanoparticles on the skin.

Methods

In this study, silver nanoparticles were synthesized by reduction using Anthemis tricolor water extract and silver nitrate solution. Then, various characterization methods (Ultraviolet-Visible Spectroscopy, X-Ray Diffraction analysis) were studied. In addition, the effects of incubation temperature, silver nitrate solution concentration, and extract volume on particle size, zeta potential, and polydispersity index were investigated, and optimum parameters were determined. In addition, antioxidant activities of water extract and silver nanoparticles (DPPH Radical Scavenging Activity, ABTS Radical Cation Scavenging Activity, and Cupric Reducing Antioxidant Capacity) and tyrosinase inhibitory activities were determined.

Results

According to the results, it was observed that biosynthesis took place with the absorption peak at 440 nm. In addition, changes in peak intensities and shifts in values that occur at the end of nanoparticle formation were determined by Fourier Transform Infrared Spectroscopy. Cubic morphology was determined by Scanning Electron Microscopy. The existence of (111), (200), (220) and (311) planes was proved by X-ray diffraction analysis, confirming the existence of silver nanoparticles in a cubic structure. The optimized parameters were determined for silver nanoparticles obtained by incubating 5 ml of an extract with 1 mM silver nitrate solution at 25 °C. Polydispersity index, zeta potential, and particle size values were in the appropriate range. On the other hand, it was observed than silver nanoparticles’ antioxidant and tyrosinase inhibitory activities were higher than those the water extract.

Conclusion

It was concluded that Anthemis tricolor could be presented as an effective, stable, reducing agent. It also suggested that it can be used due to its antioxidant and tyrosinase inhibitory activities and directed to further studies for skin-lightening preparations.

Purpose

As a strategic emerging and high-tech industry in China, the pharmaceutical industry is significantly impacted by the establishment of free trade zones (FTZs). However, current research on the effects of China’s FTZ establishment has mainly focused on qualitative studies from a macro perspective, such as economic growth, with fewer studies providing direct quantitative evaluations from the perspective of the micro industry. This paper aims to explore the policy effects and mechanisms that promote the high-quality development of the pharmaceutical manufacturing industry, taking industrial structure upgrading as the entry point.

Methods

Based on 2009–2021 provincial-level panel data, this paper constructs an evaluation index system for the high-quality development of the pharmaceutical manufacturing industry and calculates the high-quality development level of this industry in the first three FTZ batches. It empirically examines the impact of FTZ policies on the high-quality development of the industry by adopting time-varying difference-in-differences (DID) and spatial DID methods.

Results

Overall, pilot FTZ establishment can significantly promote the high-quality development of the pharmaceutical industry. Regarding spatial effects, pilot FTZ establishment has a spatial spillover effect that promotes the high-quality development of the industry in neighboring regions. Regarding the driving mechanism, the effect of pilot FTZ establishment occurs mainly through industrial structure upgrading, which enhances the high-quality development level of the pharmaceutical industry. Regarding regional comparison, coastal pilot FTZ establishment has a smaller promoting effect on the high-quality development of the industry than inland pilot FTZ establishment.

Conclusion

This paper reveals the impact of pilot FTZ establishment on the high-quality development of the pharmaceutical manufacturing industry and the impact path from the perspective of institutional change, providing factual evidence at the institutional level for interpreting the driving factors of the high-quality development of this industry.

Purpose

Nanoparticle tracking analysis (NTA) is an emerging technique for the analysis of particles in the submicron range of 50–1000 nm. It tracks the Brownian motion of individual particles and calculates the diffusion coefficient and subsequently the hydrodynamic diameter based on the Stokes-Einstein equation. In this study, we provide guidance on the capabilities and limitations using NTA for particle analysis.

Method

We have used polystyrene (PS) particle size standards to evaluate various experimental parameters such as the influence of particle concentration, measurement temperature, and neutral density (ND) filter on sizing and counting. We have also used bimodal samples in different ratios to assess the resolution power of NTA as well as trimodal samples to evaluate two different analysis algorithms.

Results

Within the working range of 10⁶–10⁹ particles/mL, lower particle concentrations of monomodal samples lead to an increase in the detected particle size but allow for more accurate particle concentration measurements. The measurement temperature in the range of 21 °C to 29 °C causes a trend of increasing particle size up to 8 % with increasing temperature. The use of a neutral density filter increases the accuracy of particle size measurements for larger particles, e.g., 800 nm PS beads. The analysis of bimodal or trimodal samples is challenging due to variations in the readout depending on instrument settings and experimental parameters.

Conclusion

In this study, we have addressed several experimental parameters that affect the measurements, and we aim to provide guidance to the scientific community using NTA analysis.

Purpose

The study is aimed at the quantitative analysis of Labetalol utilizing Box-Benken design, where higher order response surfaces are generated and optimized for a significant model using fewer runs than a usual factorial technique.

Method

The kinetic spectrophotometric methods were established to compute labetalol in pharmaceutical formulations. Initial rate and fixed-time methods were developed to determine labetalol with the mixture of potassium iodate and potassium iodide at room temperature to produce a stable yellow-coloured product that absorbs at 351 nm. The optimization was reached using the Box-Behnken experimental design involving response surface methodology. Four significant factors were investigated: labetalol volume, reaction time, potassium iodate and potassium iodide volume against response absorbance. The two and three-dimensional response surface plots revealed the significance of each parameter on the response and the correlation between them. The importance of statistical analysis and polynomial equations on the model’s efficacy. The developed method was also validated according to International Conference on Harmonization guidelines, and outcomes were accurate and precise within the limit.

Results

The linearity was in the range of 0.25–49.9 µg/mL. The analysis of the different calibrations suggests excellent linearity ranging from 0.9928-0.9988. The limit of detection (LOD) and limit of quantitation (LOQ) are in the range of 0.28-0.35 µg/mL and 0.92-1.16 µg/m, respectively. In comparing the proposed method with the reference one, the recovery ranges of the initial rate, fixed time and the reference methods were in the range of 99.34–99.57, 99.43-99.56, and 98.56-98.99, respectively.

Conclusion

The proposed method is simple, environmentally friendly, and involves cost-effective instruments. The proposed method’s greenness report was compared to the reference-reported traditional methods using the analytical Eco-Scale evaluation tool. The reported approach was greener regarding using perilous reagents, energy consumption, and waste production. Therefore, the proposed strategies could be safely applicable in pharmaceutical formulations, biological fluids, and wastewater samples to quantify labetalol.