Formulation and Characterization of Ursodeoxycholic Acid Nanosuspension Based on Bottom-Up Technology and Box-Behnken Design Optimization

被引:3
作者
Boscolo, Oriana [1 ,2 ,3 ]
Flor, Sabrina [1 ,2 ,3 ]
Salvo, Leandro [1 ,2 ]
Dobrecky, Cecilia [1 ,2 ,4 ]
Hoecht, Christian [2 ,4 ]
Tripodi, Valeria [2 ,3 ,5 ]
Moretton, Marcela [1 ,2 ,3 ]
Lucangioli, Silvia [1 ,2 ,3 ]
机构
[1] Univ Buenos Aires, Fac Farm & Bioquim, Dept Tecnol Farmaceut, C1113AAD, Buenos Aires, Argentina
[2] Univ Buenos Aires, Fac Farm & Bioquim, Inst Tecnol Farmaceut & Biofarm InTecFyB, C1113AAD, Buenos Aires, Argentina
[3] Consejo Nacl Invest Cient & Tecn CONICET, C1425FQB, Buenos Aires, Argentina
[4] Univ Buenos Aires, Fac Farm & Bioquim, Dept Farmacol, C1113AAD, Buenos Aires, Argentina
[5] Univ Buenos Aires, Fac Farm & Bioquim, Dept Ciencias Quim, C1113AAD, Buenos Aires, Argentina
关键词
nanosuspension; ursodeoxycholic acid; Box-Behnken design; bottom-up technology; IN-VITRO; DRUG NANOSUSPENSIONS; ORAL BIOAVAILABILITY; LIPID NANOPARTICLES; DELIVERY; LYOPHILIZATION; NANOCRYSTALS; DISSOLUTION; STABILITY;
D O I
10.3390/pharmaceutics15082037
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Background: Ursodeoxycholic acid (UDCA) is a therapeutic agent used for the treatment of cholestatic hepatobiliary diseases in pediatric patients. It is a bile acid that presents high lipophilicity, and it belongs to Class II of the Biopharmaceutical Classification System (BCS), which exhibits low water solubility and high intestinal permeability, which leads to poor oral absorption. The objective of this work was to design and optimize UDCA nanosuspensions by means of the precipitationultrasonication method to improve the solubility, dissolution, and oral bioavailability of UDCA. Methods: A three-level, three-factor Box-Behnken design was used to optimize formulation variables and obtain uniform, small-particle-size UDCA nanosuspensions. The independent variables were: stabilizer percentage (X-1), amplitude (X-2), and sonication time (X-3), and the dependent variable was the particle size (Y-1). In the precipitation-ultrasonication method, UDCA was dissolved in acetone:PEG 400 (1:1 v/v) and quickly incorporated into the antisolvent (pre-cooled aqueous dispersion of HPMC E-15 0.3%), by means of intense sonication at 50 W for 5 min, controlling temperature through an ice water bath. The lyophilization efficacy was evaluated by means of a cryoprotective efficacy test, working with 10% maltose at 80 degrees C. The nanosuspensions were characterized by dynamic light scattering (DLS), X-ray diffraction, and scanning electron microscopy (SEM). The physicochemical stability was determined at 25 degrees C and 4 degrees C at 7, 14, 30, and 60 days, and the UDCA content was analyzed via HPLC-UV. An in vitro dissolution assay and an oral bioavailability study were performed in male Wistar rats. Results: A significant impact was achieved in the optimized nanosuspension with 0.3% (stabilizer), 50 W (amplitude), and 5 min (sonication time), with a particle size of 352.4 nm, PDI of 0.11, and zeta potential of 4.30 mV. It presented adequate physicochemical stability throughout the study and the UDCA content was between 90% and 110%. In total, 86% of UDCA was dissolved in the in vitro dissolution test. The relative oral bioavailability was similar without significant statistical differences when comparing the lyophilized nanosuspension and the commercial tablet, the latter presenting a more erratic behavior. The pharmacokinetic parameters of the nanosuspension and the commercial tablet were T-max (1.0 +/- 0.9 h vs. 2.0 +/- 0.8 h, respectively), C-max (0.558 +/- 0.118 vs. 0.366 +/- 0.113 mu M, respectively), DCmax (0.309 +/- 0.099 vs. 0.232 +/- 0.056, respectively), AUC (4.326 +/- 0.471 vs. 2.188 +/- 0.353 mu g/mL.h, respectively, p < 0.02), and IAUC0- 24h (2.261 +/- 0.187 mu g/mL.h vs. 1.924 +/- 0.440 mu g/mL.h, respectively). Conclusions: The developed nanosuspension presents an appropriate dosage and administration for pediatric patients. On the other hand, it exhibits an adequate absorption and UDCA oral bioavailability.
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页数:18
相关论文
共 73 条
[1]   Freeze-drying of nanoparticles: Formulation, process and storage considerations [J].
Abdelwahed, Wassim ;
Degobert, Ghania ;
Stainmesse, Serge ;
Fessi, Hatem .
ADVANCED DRUG DELIVERY REVIEWS, 2006, 58 (15) :1688-1713
[2]   Design and characterization of loratadine nanosuspension prepared by ultrasonic-assisted precipitation [J].
Alshweiat, Areen ;
Katona, Gabor ;
Csoka, Ildiko ;
Ambrus, Rita .
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 2018, 122 :94-104
[3]   Recent Advances in Nanosuspension Technology for Drug Delivery [J].
Arora, Daisy ;
Khurana, Bharat ;
Rath, Goutam ;
Nanda, Sanju ;
Goyal, Amit K. .
CURRENT PHARMACEUTICAL DESIGN, 2018, 24 (21) :2403-2415
[4]   Freeze Drying of Nanosuspensions, 2: the Role of the Critical Formulation Temperature on Stability of Drug Nanosuspensions and Its Practical Implication on Process Design [J].
Beirowski, Jakob ;
Inghelbrecht, Sabine ;
Arien, Albertina ;
Gieseler, Henning .
JOURNAL OF PHARMACEUTICAL SCIENCES, 2011, 100 (10) :4471-4481
[5]  
Boscolo O., 2022, RPS PHARM PHARM REP, V2, prqac006, DOI [10.1093/rpsppr/rqac006, DOI 10.1093/RPSPPR/RQAC006]
[6]  
Boscolo O., 2018, J PHARM PHARMACOL, V6, P448, DOI [10.17265/2328-2150/2018.05.002, DOI 10.17265/2328-2150/2018.05.002]
[7]   Pharmaceutical suspensions of ursodeoxycholic acid for pediatric patients: in vitro and in vivo studies [J].
Boscolo, Oriana ;
Salvo, Leandro ;
Dobrecky, Cecilia ;
Fissore, Eliana N. ;
Buontempo, Fabian ;
Tripodi, Valeria ;
Lucangioli, Silvia E. .
PHARMACEUTICAL DEVELOPMENT AND TECHNOLOGY, 2021, 26 (05) :599-609
[8]   Determination of ursodeoxycholic acid in pharmaceutical preparations by capillary electrophoresis with indirect UV detection [J].
Chang, HY ;
Kuo, CH ;
Sun, SW .
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS, 2003, 32 (4-5) :949-956
[9]   Development of highly stabilized curcumin nanoparticles by flash nanoprecipitation and lyophilization [J].
Chow, Shing Fung ;
Wan, Ka Yee ;
Cheng, Kwok Kin ;
Wong, Ka Wai ;
Sun, Changquan Calvin ;
Baum, Larry ;
Chow, Albert Hee Lum .
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, 2015, 94 :436-449
[10]   Lyoprotective Effects of Mannitol and Lactose Compared to Sucrose and Trehalose: Sildenafil Citrate Liposomes as a Case Study [J].
de Jesus Valle, Maria Jose ;
Alves, Andreia ;
Coutinho, Paula ;
Prata Ribeiro, Maximiano ;
Maderuelo, Cristina ;
Sanchez Navarro, Amparo .
PHARMACEUTICS, 2021, 13 (08)