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Nicotinamide polymeric nanoemulsified systems: a quality-by-design case study for a sustained antimicrobial activity.

Zidan AS, Ahmed OA, Aljaeid BM - Int J Nanomedicine (2016)

Bottom Line: EC, EE, particle size, polydispersity index, zeta potential, and percentage release in 24 hours were found to be in the range of 33.5%-68.8%, 53.1%-67.1%, 43.3-243.3 nm, 0.08-0.28, 9.5-53.3 mV, and 5.8%-22.4%, respectively.One-way analysis of variance and Pareto charts revealed that the experimental loadings of 2-hydroxypropyl-β-cyclodextrin and Eudragit(®) S100 were the most significant for their effects on nicotinamide EC and EE.In conclusion, the study demonstrated the potential of polymeric nanoemulsified system to sustain the release and antibacterial activity of nicotinamide.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.

ABSTRACT
Nicotinamide, the amide form of vitamin B3, was demonstrated to combat some of the antibiotic-resistant infections that are increasingly common around the world. The objective of this study was to thoroughly understand the formulation and process variabilities affecting the preparation of nicotinamide-loaded polymeric nanoemulsified particles. The quality target product profile and critical quality attributes of the proposed product were presented. Plackett-Burman screening design was employed to screen eight variables for their influences on the formulation's critical characteristics. The formulations were prepared by an oil-in-water emulsification followed by solvent replacement. The prepared systems were characterized by entrapment capacity (EC), entrapment efficiency (EE), particle size, polydispersity index, zeta potential, transmission electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, in vitro drug release, and their antibacterial activity against bacterial scrums. EC, EE, particle size, polydispersity index, zeta potential, and percentage release in 24 hours were found to be in the range of 33.5%-68.8%, 53.1%-67.1%, 43.3-243.3 nm, 0.08-0.28, 9.5-53.3 mV, and 5.8%-22.4%, respectively. One-way analysis of variance and Pareto charts revealed that the experimental loadings of 2-hydroxypropyl-β-cyclodextrin and Eudragit(®) S100 were the most significant for their effects on nicotinamide EC and EE. Moreover, the polymeric nanoemulsified particles demonstrated a sustained release profile for nicotinamide. The Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction demonstrated a significant interaction between the drug and 2-hydroxypropyl-β-cyclodextrin that might modulate the sustained release behavior. Furthermore, the formulations provided a sustained antibacterial activity that depended on nicotinamide-loading concentration, release rate, and incubation time. In conclusion, the study demonstrated the potential of polymeric nanoemulsified system to sustain the release and antibacterial activity of nicotinamide.

No MeSH data available.


Related in: MedlinePlus

Preparation technique and TEM image of nicotinamide-loaded polymeric nanoemulsified particles.Notes: Schematic development representation (A) and batch 7 TEM image (B) of nicotinamide-loaded polymeric nanoemulsified particles.Abbreviations: TEM, transmission electron microscopy; HP-β-CD, 2-hydroxypropyl-β-cyclodextrin.
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f1-ijn-11-1501: Preparation technique and TEM image of nicotinamide-loaded polymeric nanoemulsified particles.Notes: Schematic development representation (A) and batch 7 TEM image (B) of nicotinamide-loaded polymeric nanoemulsified particles.Abbreviations: TEM, transmission electron microscopy; HP-β-CD, 2-hydroxypropyl-β-cyclodextrin.

Mentions: Polymeric nanoemulsified particles were prepared by O/W emulsification technique followed by organic phase evaporation as described in Figure 1A. Transmission electron microscopy micrographs indicated that prepared nanoparticles were characterized with spherical micelles and self-organized aggregates (Figure 1B). The aim of this work was using QbD approach to develop polymeric nanoemulsified particles with potential to be incorporated into a liquid or semisolid (gel) dosage form, for implantation. Hence, the pharmaceutical development started with defining the QTPP of a low-viscosity aqueous suspension or gel with polymeric nanoemulsified particles for injection. A defined yet justified QTPP (Table 2) was used to lead the pharmaceutical development process of the proposed product that should be pharmaceutically equivalent with reference-listed drug product. Quality attributes for target drug product are presented in Table 2, and CQAs are appropriately marked and justified. Usually, quality risk management analysis is done on the basis of available literature and/or historical data. Considering that literature data in form of original scientific research publications related to the polymeric nanoemulsified particles are limited, our approach to quality risk management combined literature reference data and results derived from multivariate statistical analysis (principle component analysis [PCA] and partial least square regression) performed on experimental data of the PB design. PCA unscrambles X variables matrix into number of latent variables called principal components (PCs). PCA applied on the experimental data presented in Table 3 resulted with one PC that maximizes the explained variance in the data set. The PCA model with one PC (PC1) explains 92.8% of the variation in the data set (X). The parameter Q2 obtained with cross-validation of the model has a value of 63.9%, and it refers to the percentage of variation of all X variables that can be estimated with the model. Values of Q2 >50% would indicate a good predictability; hence, the model is acceptable, and it was used for identification of formulation and process parameters influencing polymeric nanoemulsified particles formation. Score scatter plot is a useful tool to indicate any pattern in the results (eg, clusters, trends, or outliers). Score scatter plot of performed PC X–Y analyses (Figure 2) clearly points to no clusters to be observed for the effects of the independent variables on the resultant EC, particle size, PDI, and zeta potential. On the other hand, two clusters were observed for the effect of independent variables on both EE and drug release. For EE, group 1 was closely related with volumes of aqueous and organic phases and drug level, while group 2 was correlated with Eudragit and HP-β-CD levels. For drug release response, group 1 was closely related with aqueous phase volume, sonication time, and HP-β-CD level, while group 2 was correlated with organic phase volume, sonication amplitude, and MgCl2 level. This PCA revealed the similarities and origin of differences between the samples and analysis. However, it should be noted that PCA could not detect whether the observed differences will affect the manufacturing process and product quality;24 therefore, subsequent analyses as well as sufficient process and product knowledge and understanding are required. After identification of the variables associated with two groups of results, the next step was to determine how X variables influence the investigated characteristics of the polymeric nanoemulsified particles. For this reason, multiple regression analysis was applied to the experimental results associated with particles formation (total of 12 samples; Tables 3 and 4).


Nicotinamide polymeric nanoemulsified systems: a quality-by-design case study for a sustained antimicrobial activity.

Zidan AS, Ahmed OA, Aljaeid BM - Int J Nanomedicine (2016)

Preparation technique and TEM image of nicotinamide-loaded polymeric nanoemulsified particles.Notes: Schematic development representation (A) and batch 7 TEM image (B) of nicotinamide-loaded polymeric nanoemulsified particles.Abbreviations: TEM, transmission electron microscopy; HP-β-CD, 2-hydroxypropyl-β-cyclodextrin.
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Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4835127&req=5

f1-ijn-11-1501: Preparation technique and TEM image of nicotinamide-loaded polymeric nanoemulsified particles.Notes: Schematic development representation (A) and batch 7 TEM image (B) of nicotinamide-loaded polymeric nanoemulsified particles.Abbreviations: TEM, transmission electron microscopy; HP-β-CD, 2-hydroxypropyl-β-cyclodextrin.
Mentions: Polymeric nanoemulsified particles were prepared by O/W emulsification technique followed by organic phase evaporation as described in Figure 1A. Transmission electron microscopy micrographs indicated that prepared nanoparticles were characterized with spherical micelles and self-organized aggregates (Figure 1B). The aim of this work was using QbD approach to develop polymeric nanoemulsified particles with potential to be incorporated into a liquid or semisolid (gel) dosage form, for implantation. Hence, the pharmaceutical development started with defining the QTPP of a low-viscosity aqueous suspension or gel with polymeric nanoemulsified particles for injection. A defined yet justified QTPP (Table 2) was used to lead the pharmaceutical development process of the proposed product that should be pharmaceutically equivalent with reference-listed drug product. Quality attributes for target drug product are presented in Table 2, and CQAs are appropriately marked and justified. Usually, quality risk management analysis is done on the basis of available literature and/or historical data. Considering that literature data in form of original scientific research publications related to the polymeric nanoemulsified particles are limited, our approach to quality risk management combined literature reference data and results derived from multivariate statistical analysis (principle component analysis [PCA] and partial least square regression) performed on experimental data of the PB design. PCA unscrambles X variables matrix into number of latent variables called principal components (PCs). PCA applied on the experimental data presented in Table 3 resulted with one PC that maximizes the explained variance in the data set. The PCA model with one PC (PC1) explains 92.8% of the variation in the data set (X). The parameter Q2 obtained with cross-validation of the model has a value of 63.9%, and it refers to the percentage of variation of all X variables that can be estimated with the model. Values of Q2 >50% would indicate a good predictability; hence, the model is acceptable, and it was used for identification of formulation and process parameters influencing polymeric nanoemulsified particles formation. Score scatter plot is a useful tool to indicate any pattern in the results (eg, clusters, trends, or outliers). Score scatter plot of performed PC X–Y analyses (Figure 2) clearly points to no clusters to be observed for the effects of the independent variables on the resultant EC, particle size, PDI, and zeta potential. On the other hand, two clusters were observed for the effect of independent variables on both EE and drug release. For EE, group 1 was closely related with volumes of aqueous and organic phases and drug level, while group 2 was correlated with Eudragit and HP-β-CD levels. For drug release response, group 1 was closely related with aqueous phase volume, sonication time, and HP-β-CD level, while group 2 was correlated with organic phase volume, sonication amplitude, and MgCl2 level. This PCA revealed the similarities and origin of differences between the samples and analysis. However, it should be noted that PCA could not detect whether the observed differences will affect the manufacturing process and product quality;24 therefore, subsequent analyses as well as sufficient process and product knowledge and understanding are required. After identification of the variables associated with two groups of results, the next step was to determine how X variables influence the investigated characteristics of the polymeric nanoemulsified particles. For this reason, multiple regression analysis was applied to the experimental results associated with particles formation (total of 12 samples; Tables 3 and 4).

Bottom Line: EC, EE, particle size, polydispersity index, zeta potential, and percentage release in 24 hours were found to be in the range of 33.5%-68.8%, 53.1%-67.1%, 43.3-243.3 nm, 0.08-0.28, 9.5-53.3 mV, and 5.8%-22.4%, respectively.One-way analysis of variance and Pareto charts revealed that the experimental loadings of 2-hydroxypropyl-β-cyclodextrin and Eudragit(®) S100 were the most significant for their effects on nicotinamide EC and EE.In conclusion, the study demonstrated the potential of polymeric nanoemulsified system to sustain the release and antibacterial activity of nicotinamide.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia; Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.

ABSTRACT
Nicotinamide, the amide form of vitamin B3, was demonstrated to combat some of the antibiotic-resistant infections that are increasingly common around the world. The objective of this study was to thoroughly understand the formulation and process variabilities affecting the preparation of nicotinamide-loaded polymeric nanoemulsified particles. The quality target product profile and critical quality attributes of the proposed product were presented. Plackett-Burman screening design was employed to screen eight variables for their influences on the formulation's critical characteristics. The formulations were prepared by an oil-in-water emulsification followed by solvent replacement. The prepared systems were characterized by entrapment capacity (EC), entrapment efficiency (EE), particle size, polydispersity index, zeta potential, transmission electron microscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, powder X-ray diffraction, in vitro drug release, and their antibacterial activity against bacterial scrums. EC, EE, particle size, polydispersity index, zeta potential, and percentage release in 24 hours were found to be in the range of 33.5%-68.8%, 53.1%-67.1%, 43.3-243.3 nm, 0.08-0.28, 9.5-53.3 mV, and 5.8%-22.4%, respectively. One-way analysis of variance and Pareto charts revealed that the experimental loadings of 2-hydroxypropyl-β-cyclodextrin and Eudragit(®) S100 were the most significant for their effects on nicotinamide EC and EE. Moreover, the polymeric nanoemulsified particles demonstrated a sustained release profile for nicotinamide. The Fourier transform infrared spectroscopy, differential scanning calorimetry, and X-ray diffraction demonstrated a significant interaction between the drug and 2-hydroxypropyl-β-cyclodextrin that might modulate the sustained release behavior. Furthermore, the formulations provided a sustained antibacterial activity that depended on nicotinamide-loading concentration, release rate, and incubation time. In conclusion, the study demonstrated the potential of polymeric nanoemulsified system to sustain the release and antibacterial activity of nicotinamide.

No MeSH data available.


Related in: MedlinePlus