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However, a further elevation in this sonication period resulted in the re-aggregation of these particles. This trend is in accordance with results obtained by others where they observed the formation of larger droplets as an outcome of longer sonication or homogenization time The Pareto chart Fig. Lyoprotectant are commonly used to stabilize the particles and protect them from degradation during freeze-drying and storage Regarding the type of lyoprotectant used in this study, these significant changes in particle size may be related with the behavior of each lyoprotectant during freeze-drying, and the adsorption of lyoprotectant on the surface of nanoparticles.

It is clear that trehalose is more effective in obtaining smaller nanoparticles Fig. This 2. This is in accordance with previous papers that confirmed that trehalose which is a non-reducing sugar could be the most preferable lyoprotectant of choice because of its merits over the other sugars; including a very low chemical reactivity, a higher glass transition temperature Tg, less hygroscopicity, in addition to the absence of internal hydrogen bounds, allowing a more flexible formation of hydrogen bonds with nanoparticles during the freeze-drying process However, mannitol was proved to be more effective in obtaining a higher EE value according to our experimental work.

Trehalose was investigated before regarding its effect on the secondary structure of insulin, and the results showed that it highly affected the conformational stability of the peptide; so it might not be the best choice to encapsulate peptide drugs In addition to that; mannitol is able to form crystal morphology which is confirmed later in this paper by DSC and XRD and this might be attributed to the stability of peptide. It is also apparent from the statistical analysis presented in the Pareto chart and surface plot Fig.

When the level of lyoprotectant continued increasing, the amount of entrapped Lira significantly decreased, which could be the result of smaller NPs obtained with a higher lyoprotectant level, and thus less sufficient surface area for entrapping the drug. This formation of smaller droplets may be due to the higher amount of stabilizer present as compared to the non-sufficient amount of stabilizer when using a lower amount of this phase. It was also recently reported that increasing the continuous phase volume:organic phase ratio had led to particle size reduction Regarding PDI values, a significant increase in size distribution was observed when the volume of the external aqueous phase was higher, as shown by the Pareto chart and surface plot Fig.

This observation might be attributed to a reduction of shear stress during the homogenization process Besides, the phase ratio was the highly influential factor affecting the surface charge as increasing the external aqueous phase volume led to a significant increase in the zeta potential value Fig. The EE exhibited a significant upward trend when increasing the volume of the external aqueous phase, as presented in the Pareto chart and surface plot Fig.

However, other published papers assumed that a relatively higher volume ratio of the external aqueous phase was beneficial for maximizing the drug encapsulated in the NPs as a higher outer aqueous phase volume can speed up the solidification time evaporation of ethyl acetate and formation of NPs , while the smaller the volume of this outer aqueous phase, the longer the time required for solidification, thus over this time Lira may leak to the outer phase due to its hydrophilicity The three replications of center checkpoint formulations were prepared and evaluated for the particle size, EE, PDI and zeta potential to evaluate the reproducibility of the generated models and estimate the experimental error.

The minor differences between the predicted values and the average of experimental values confirm the validity of this design in providing a good prediction of the four tested responses. After establishing the polynomial equations describing the relationship between the CPPs, CMAs and the examined responses namely; particle size, EE, PDI and zeta potential, the optimization process was conducted. Among the four responses, size and EE were the highly critical quality attributes of nanoparticles being significantly affected by almost all the tested variables which is in accordance with the estimated severity scores of CQAs that was calculated previously at the initial risk assessment process.

Therefore, the deign space DS was optimized Fig. The desirability plots and graphical design space representing the optimum levels of factors required to prepare the optimized formula. Since the optimized formula was homogeneous in accordance with low PDI we selected two images as representative for the sample. The results revealed that Lira loaded PLGA NPs were spherical with quite a smooth surface and they had homogeneous distribution which is in agreement with the above-mentioned results that demonstrated low PDI values for all formulations.

Figure S 3.

There were no clear differences between the spectra of the blank NPs and Lira loaded NPs which is also expected as the drug loading is very small when compared to the polymer amount. For the temperature range examined, the PLGA thermogram exhibited a glass transition point at The DSC thermogram of pure Lira revealed a peak at XRD studies further verified the amorphous nature of both PLGA and pure Lira as they showed no characteristic peaks in their diffractograms which is in accordance with the results of DSC thermograms Fig.

As depicted in Fig. S 5 , mannitol remained in crystalline state after freeze drying which is due to the property of mannitol to recrystallize at low cooling rates rather than rapid cooling. The crystallization of this lyoprotectant could have a negative effect on the stability of NPs as it is able to limit the formation of these hydrogen bonds 30 , and this can explain why trehalose was more efficient than mannitol at preventing the aggregation of NPs and thus minimizing the Z-average.

There was no difference between the diffractograms of the loaded and blank PLGA NPs which is explained in literature as a result of the successful encapsulation of the peptide drug inside the polymeric nanoparticles without change in its physical state 45 , and this is in accordance with the DSC results. As the spectra in Fig. Since the preservation of the secondary structural integrity of a peptide drug in the nanocarrier is critical for its biological efficacy, the secondary structure of Lira extracted from NPs was compared to that of native Lira.

The CD spectra of native Lira Fig. The present study is the first published work that substantiated the application of rational QbD-based methodology for the optimization of a GLP-1 analog loaded nanocarrier system. This work demonstrated the importance of implementing DOE within QbD philosophy in the early stage of Liraglutide containing NPs development due to the complexity of this system.

After establishing the design space, with the minimum particle size and maximum EE, the optimized formula was successfully prepared meeting the targeted CQAs. This optimized Lira loaded PLGA NPs formula was also successful in maintaining the native structure of Lira and could be promising for the oral delivery. Thus, in vitro release kinetics, cytotoxicity, intestinal permeability and in vivo studies will be further conducted on this formula.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. National Center for Biotechnology Information , U. Pharmaceutical Research. Pharm Res. Published online May Author information Article notes Copyright and License information Disclaimer. Corresponding author.

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Received Jan 17; Accepted Apr 1. Methods PLGA NPs were prepared by means of double emulsion solvent evaporation method and optimized by applying 7-factor 2-level Plackett-Burman screening design. Results Spherical shaped NPs with homogeneous distribution, Conclusion Lira-PLGA NPs with the required Critical Quality Attributes CQAs were successfully designed by implementing a 7-factor 8-run Plackett Burman design into the extended Quality by Design QbD model, to elucidate the effect of formulation and process variables on the particle size, size-distribution, encapsulation efficiency and surface charge.

Open in a separate window. Electronic supplementary material The online version of this article Introduction A current scenario in pharmaceutical development is inclined towards employing rational Quality by Design QbD strategy 1 , 2 which has been adopted by the pharmaceutical industry to guarantee the quality of drug products 3. Design of Experiment Study Using Plackett Burman Design PB design is the most widely used method among the various screening designs used for the determination of the most influential factors affecting the pharmaceutical development as it has many advantages: it screens a large number of variables and identifies the highly influential ones with relatively few runs, while assuring a good degree of accuracy.

Table 1 Levels of the Selected Critical Factors. Circular Dichroism CD was performed to evaluate the conformational stability of Lira loaded into the prepared polymeric NPs. The polynomial equation obtained for the fitted full model explaining the effect of formulation and process variables on the mean particle size is: Table 3 Experimental Responses Results in PBD. PBD-F8 Effect of Polymer Amount It is apparent from Fig. Surface plot showing the effect of examined variables on EE Y3. Effect of Liraglutide Amount The positive effect that Lira has on the 2nd emulsification and both final particle size Fig.

Effect of Lyoprotectant Type and Concentration Lyoprotectant are commonly used to stabilize the particles and protect them from degradation during freeze-drying and storage Placket Burman Design: Model Validation The three replications of center checkpoint formulations were prepared and evaluated for the particle size, EE, PDI and zeta potential to evaluate the reproducibility of the generated models and estimate the experimental error.

CD Since the preservation of the secondary structural integrity of a peptide drug in the nanocarrier is critical for its biological efficacy, the secondary structure of Lira extracted from NPs was compared to that of native Lira.

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Conclusion and Future Perspectives The present study is the first published work that substantiated the application of rational QbD-based methodology for the optimization of a GLP-1 analog loaded nanocarrier system. Electronic supplementary material ESM 1 1. References 1. Adaptation of the quality by design concept in early pharmaceutical development of an intranasal nanosized formulation. Int J Pharm. A mesmerising novel of the film industry and one man's life that charts a path for all of us.

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By Pietro Colangelo. Dissipative superfluids, from cold atoms to quark matter. By Cristina Manuel. Transport coefficients in high temperature gauge theories, 2. Beyond leading log. Download pdf. Remember me on this computer. Enter the email address you signed up with and we'll email you a reset link. Need an account? Click here to sign up.