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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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Scanning electron micrographs (A), kinetic solubility profile (B), differential scanning calorimetry thermograms (C), and powder X-ray diffraction patterns (D) of valsartan–polymer composite nanoparticles prepared by using the SAS process.Abbreviations: HPC, hydroxypropyl cellulose; HPMC, hydroxypropyl methylcellulose; PVP, polyvinylpyrrolidone; PVP VA64, polyvinylpyrrolidone-vinyl acetate; SAS, supercritical antisolvent.
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f1-ijn-9-5167: Scanning electron micrographs (A), kinetic solubility profile (B), differential scanning calorimetry thermograms (C), and powder X-ray diffraction patterns (D) of valsartan–polymer composite nanoparticles prepared by using the SAS process.Abbreviations: HPC, hydroxypropyl cellulose; HPMC, hydroxypropyl methylcellulose; PVP, polyvinylpyrrolidone; PVP VA64, polyvinylpyrrolidone-vinyl acetate; SAS, supercritical antisolvent.

Mentions: In this study, valsartan–polymer–surfactant composite nanoparticles were fabricated using the SAS process to enhance the dissolution and oral bioavailability of valsartan. Valsartan–polymer nanoparticles were prepared to screen HPC, HPMC, PVP K30, and PVP VA64 polymers. As shown in Figure 1 and Table 1, valsartan–HPMC nanoparticles were spherical and had a mean particle size of 277.3 nm, resulting in a specific surface area of 60.23 m2/g. For HPC, the mean particle size was greater than that of valsartan–HPMC nanoparticles, but the difference was not statistically significant (P>0.1). The mean particle size and specific surface area of PVP K30 composite nanoparticles were larger than those of valsartan–HPMC nanoparticles, whereas they were smaller for PVP VA64 particles. The crystallinity of valsartan within composite nanoparticles was determined by using DSC and PXRD. The DSC curve of valsartan exhibited an endothermic peak at approximately 96°C with an enthalpy of 37.06 J/g, corresponding to its melting point. However, the endothermic peak of valsartan was not detected for all composite particles prepared by using the SAS process. In addition, the characteristic crystalline valsartan peaks were not observed in the PXRD patterns of all composite particles (Figure 1). Therefore, the crystallinity of valsartan dramatically decreased, indicating that it was in an amorphous form within the composite nanoparticles (at 20% drug loading within the composite). The kinetic solubility test showed that the maximum valsartan concentration in valsartan–HPMC nanoparticles was 205 μg/mL, and that the concentration at 24 hours was 187 μg/mL. In general, a supersaturated state induced by the amorphous drug is thermodynamically unstable for poorly water-soluble drug-polymer composites, resulting in return to the equilibrium state through drug precipitation.21,22 Drug precipitation has to be inhibited to improve drug absorption from the gastrointestinal tract. Polymers can reduce drug precipitation and maintain the supersaturated state by inhibiting nucleation and crystal growth via surface and steric stabilization, and/or specific interactions with the drug such as hydrogen bonding, hydrophobic interactions, and complex formation.23,24 HPMC has many hydroxyl groups that act as both hydrogen bond acceptors and donors for APIs. This hydrogen bonding is attributed to positive effect for solubilization of poorly water-soluble APIs.25 In fact, valsartan’s solubility was the highest in the 5% HPMC aqueous solution compared to that in hydroxypropyl-β-cyclodextrin (HP-β-CD), PVP K30, and PVP VA64 in our previous study.8 In this study, the HPMC polymer was most effective in preventing valsartan precipitation, followed by HPC. Previously, kinetic solubility tests showed that the oral absorption of poorly water-soluble drugs was strongly correlated to the degree of supersaturation and its maintenance over extended periods. Therefore, HPMC was selected as the polymer for preparation of valsartan composite nanoparticles by using the SAS process.


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

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

Scanning electron micrographs (A), kinetic solubility profile (B), differential scanning calorimetry thermograms (C), and powder X-ray diffraction patterns (D) of valsartan–polymer composite nanoparticles prepared by using the SAS process.Abbreviations: HPC, hydroxypropyl cellulose; HPMC, hydroxypropyl methylcellulose; PVP, polyvinylpyrrolidone; PVP VA64, polyvinylpyrrolidone-vinyl acetate; SAS, supercritical antisolvent.
© Copyright Policy
Related In: Results  -  Collection

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

f1-ijn-9-5167: Scanning electron micrographs (A), kinetic solubility profile (B), differential scanning calorimetry thermograms (C), and powder X-ray diffraction patterns (D) of valsartan–polymer composite nanoparticles prepared by using the SAS process.Abbreviations: HPC, hydroxypropyl cellulose; HPMC, hydroxypropyl methylcellulose; PVP, polyvinylpyrrolidone; PVP VA64, polyvinylpyrrolidone-vinyl acetate; SAS, supercritical antisolvent.
Mentions: In this study, valsartan–polymer–surfactant composite nanoparticles were fabricated using the SAS process to enhance the dissolution and oral bioavailability of valsartan. Valsartan–polymer nanoparticles were prepared to screen HPC, HPMC, PVP K30, and PVP VA64 polymers. As shown in Figure 1 and Table 1, valsartan–HPMC nanoparticles were spherical and had a mean particle size of 277.3 nm, resulting in a specific surface area of 60.23 m2/g. For HPC, the mean particle size was greater than that of valsartan–HPMC nanoparticles, but the difference was not statistically significant (P>0.1). The mean particle size and specific surface area of PVP K30 composite nanoparticles were larger than those of valsartan–HPMC nanoparticles, whereas they were smaller for PVP VA64 particles. The crystallinity of valsartan within composite nanoparticles was determined by using DSC and PXRD. The DSC curve of valsartan exhibited an endothermic peak at approximately 96°C with an enthalpy of 37.06 J/g, corresponding to its melting point. However, the endothermic peak of valsartan was not detected for all composite particles prepared by using the SAS process. In addition, the characteristic crystalline valsartan peaks were not observed in the PXRD patterns of all composite particles (Figure 1). Therefore, the crystallinity of valsartan dramatically decreased, indicating that it was in an amorphous form within the composite nanoparticles (at 20% drug loading within the composite). The kinetic solubility test showed that the maximum valsartan concentration in valsartan–HPMC nanoparticles was 205 μg/mL, and that the concentration at 24 hours was 187 μg/mL. In general, a supersaturated state induced by the amorphous drug is thermodynamically unstable for poorly water-soluble drug-polymer composites, resulting in return to the equilibrium state through drug precipitation.21,22 Drug precipitation has to be inhibited to improve drug absorption from the gastrointestinal tract. Polymers can reduce drug precipitation and maintain the supersaturated state by inhibiting nucleation and crystal growth via surface and steric stabilization, and/or specific interactions with the drug such as hydrogen bonding, hydrophobic interactions, and complex formation.23,24 HPMC has many hydroxyl groups that act as both hydrogen bond acceptors and donors for APIs. This hydrogen bonding is attributed to positive effect for solubilization of poorly water-soluble APIs.25 In fact, valsartan’s solubility was the highest in the 5% HPMC aqueous solution compared to that in hydroxypropyl-β-cyclodextrin (HP-β-CD), PVP K30, and PVP VA64 in our previous study.8 In this study, the HPMC polymer was most effective in preventing valsartan precipitation, followed by HPC. Previously, kinetic solubility tests showed that the oral absorption of poorly water-soluble drugs was strongly correlated to the degree of supersaturation and its maintenance over extended periods. Therefore, HPMC was selected as the polymer for preparation of valsartan composite nanoparticles by using the SAS process.

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