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Fabrication and evaluation of valsartan-polymer- surfactant composite nanoparticles by using the supercritical antisolvent process.

Kim MS, Baek IH - Int J Nanomedicine (2014)

Bottom Line: Spherical composite nanoparticles with a mean size smaller than 400 nm, which contained valsartan, were successfully fabricated by using the SAS process.In addition, there was a positive linear correlation between the pharmacokinetic parameters and the in vitro dissolution efficiency.Therefore, the preparation of composite nanoparticles with valsartan-hydroxypropyl methylcellulose and poloxamer 407 by using the SAS process could be an effective formulation strategy for the development of a new dosage form of valsartan with high oral bioavailability.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.

ABSTRACT
The aim of this study was to fabricate valsartan composite nanoparticles by using the supercritical antisolvent (SAS) process, and to evaluate the correlation between in vitro dissolution and in vivo pharmacokinetic parameters for the poorly water-soluble drug valsartan. Spherical composite nanoparticles with a mean size smaller than 400 nm, which contained valsartan, were successfully fabricated by using the SAS process. X-ray diffraction and thermal analyses indicated that valsartan was present in an amorphous form within the composite nanoparticles. The in vitro dissolution and oral bioavailability of valsartan were dramatically enhanced by the composite nanoparticles. Valsartan-hydroxypropyl methylcellulose-poloxamer 407 nanoparticles exhibited faster drug release (up to 90% within 10 minutes under all dissolution conditions) and higher oral bioavailability than the raw material, with an approximately 7.2-fold higher maximum plasma concentration. In addition, there was a positive linear correlation between the pharmacokinetic parameters and the in vitro dissolution efficiency. Therefore, the preparation of composite nanoparticles with valsartan-hydroxypropyl methylcellulose and poloxamer 407 by using the SAS process could be an effective formulation strategy for the development of a new dosage form of valsartan with high oral bioavailability.

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Correlation between the in vitro dissolution efficiency and in vivo pharmacokinetic parameters.Notes: (A) AUC0–24h; (B) Cmax.Abbreviations: AUC0–24 h, area under the concentration-time curve; Cmax, peak concentration; DE, dissolution efficiency; R2, coefficient of determination.
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f7-ijn-9-5167: Correlation between the in vitro dissolution efficiency and in vivo pharmacokinetic parameters.Notes: (A) AUC0–24h; (B) Cmax.Abbreviations: AUC0–24 h, area under the concentration-time curve; Cmax, peak concentration; DE, dissolution efficiency; R2, coefficient of determination.

Mentions: To determine whether there was a correlation between in vitro dissolution and in vivo parameters, a regression analysis was conducted by using DE%, Cmax, and AUC0→24 h. As shown in Figure 7, there was a positive linear correlation between the pharmacokinetic parameters (Cmax and AUC0→24 h) and the DE% calculated in pH 1.2 and pH 4.0 dissolution media (R2>0.90). However, there was a poor correlation with DE% calculated in pH 6.8 dissolution media compared to that calculated in the other dissolution medium. Valsartan contains a tetrazole derivative-containing acid (pKa =4.73) as well as carboxylic-group acids (pKa =3.9) groups, which may influence its solubility in a pH-dependent manner, resulting in an extremely low dissolution rate at acidic pH conditions. However, valsartan showed a high dissolution rate for raw material and composite nanoparticles with pH 6.8 dissolution medium compared to that observed with an acidic pH dissolution medium. Thus, a poor correlation between dissolution data and pharmacokinetic data was observed for the pH 6.8 dissolution medium compared to that observed for the other dissolution medium. In fact, the oral bioavailability of valsartan was increased by enhancing the in vitro dissolution in pH 1.2 and pH 4.0 dissolution media, in agreement with our previous in vitro–in vivo correlation results using a spray-dried emulsion containing valsartan. The dissolution of valsartan was very slow due to poor water solubility at low pH because of its carboxylic acid-containing molecular structure. Generally, the oral absorption of a drug is proportional to the dissolution process within the gastrointestinal tract.28 Therefore, the dissolution and solubilization steps could be rate-limiting for the absorption of a poorly water-soluble drug. In this study, the supersaturated solution of valsartan induced by composite nanoparticles resulted in increased absorption through the gastrointestinal epithelial membrane, thereby enhancing the oral bioavailability of valsartan. Considering the intrinsic solubility of valsartan and the physiological pH conditions of the gastrointestinal tract, it is important to increase the extent and rate of dissolution at conditions below pH 4.0 to develop a new dosage form of valsartan with high oral bioavailability.


Fabrication and evaluation of valsartan-polymer- surfactant composite nanoparticles by using the supercritical antisolvent process.

Kim MS, Baek IH - Int J Nanomedicine (2014)

Correlation between the in vitro dissolution efficiency and in vivo pharmacokinetic parameters.Notes: (A) AUC0–24h; (B) Cmax.Abbreviations: AUC0–24 h, area under the concentration-time curve; Cmax, peak concentration; DE, dissolution efficiency; R2, coefficient of determination.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230178&req=5

f7-ijn-9-5167: Correlation between the in vitro dissolution efficiency and in vivo pharmacokinetic parameters.Notes: (A) AUC0–24h; (B) Cmax.Abbreviations: AUC0–24 h, area under the concentration-time curve; Cmax, peak concentration; DE, dissolution efficiency; R2, coefficient of determination.
Mentions: To determine whether there was a correlation between in vitro dissolution and in vivo parameters, a regression analysis was conducted by using DE%, Cmax, and AUC0→24 h. As shown in Figure 7, there was a positive linear correlation between the pharmacokinetic parameters (Cmax and AUC0→24 h) and the DE% calculated in pH 1.2 and pH 4.0 dissolution media (R2>0.90). However, there was a poor correlation with DE% calculated in pH 6.8 dissolution media compared to that calculated in the other dissolution medium. Valsartan contains a tetrazole derivative-containing acid (pKa =4.73) as well as carboxylic-group acids (pKa =3.9) groups, which may influence its solubility in a pH-dependent manner, resulting in an extremely low dissolution rate at acidic pH conditions. However, valsartan showed a high dissolution rate for raw material and composite nanoparticles with pH 6.8 dissolution medium compared to that observed with an acidic pH dissolution medium. Thus, a poor correlation between dissolution data and pharmacokinetic data was observed for the pH 6.8 dissolution medium compared to that observed for the other dissolution medium. In fact, the oral bioavailability of valsartan was increased by enhancing the in vitro dissolution in pH 1.2 and pH 4.0 dissolution media, in agreement with our previous in vitro–in vivo correlation results using a spray-dried emulsion containing valsartan. The dissolution of valsartan was very slow due to poor water solubility at low pH because of its carboxylic acid-containing molecular structure. Generally, the oral absorption of a drug is proportional to the dissolution process within the gastrointestinal tract.28 Therefore, the dissolution and solubilization steps could be rate-limiting for the absorption of a poorly water-soluble drug. In this study, the supersaturated solution of valsartan induced by composite nanoparticles resulted in increased absorption through the gastrointestinal epithelial membrane, thereby enhancing the oral bioavailability of valsartan. Considering the intrinsic solubility of valsartan and the physiological pH conditions of the gastrointestinal tract, it is important to increase the extent and rate of dissolution at conditions below pH 4.0 to develop a new dosage form of valsartan with high oral bioavailability.

Bottom Line: Spherical composite nanoparticles with a mean size smaller than 400 nm, which contained valsartan, were successfully fabricated by using the SAS process.In addition, there was a positive linear correlation between the pharmacokinetic parameters and the in vitro dissolution efficiency.Therefore, the preparation of composite nanoparticles with valsartan-hydroxypropyl methylcellulose and poloxamer 407 by using the SAS process could be an effective formulation strategy for the development of a new dosage form of valsartan with high oral bioavailability.

View Article: PubMed Central - PubMed

Affiliation: College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.

ABSTRACT
The aim of this study was to fabricate valsartan composite nanoparticles by using the supercritical antisolvent (SAS) process, and to evaluate the correlation between in vitro dissolution and in vivo pharmacokinetic parameters for the poorly water-soluble drug valsartan. Spherical composite nanoparticles with a mean size smaller than 400 nm, which contained valsartan, were successfully fabricated by using the SAS process. X-ray diffraction and thermal analyses indicated that valsartan was present in an amorphous form within the composite nanoparticles. The in vitro dissolution and oral bioavailability of valsartan were dramatically enhanced by the composite nanoparticles. Valsartan-hydroxypropyl methylcellulose-poloxamer 407 nanoparticles exhibited faster drug release (up to 90% within 10 minutes under all dissolution conditions) and higher oral bioavailability than the raw material, with an approximately 7.2-fold higher maximum plasma concentration. In addition, there was a positive linear correlation between the pharmacokinetic parameters and the in vitro dissolution efficiency. Therefore, the preparation of composite nanoparticles with valsartan-hydroxypropyl methylcellulose and poloxamer 407 by using the SAS process could be an effective formulation strategy for the development of a new dosage form of valsartan with high oral bioavailability.

Show MeSH
Related in: MedlinePlus