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. 2019 Apr 1:14:2267-2280.
doi: 10.2147/IJN.S194934. eCollection 2019.

Formulation design, characterization, and in vitro and in vivo evaluation of nanostructured lipid carriers containing a bile salt for oral delivery of gypenosides

Gang Yang  1 , Feihua Wu  1 , Minyan Chen  1 , Jian Jin  1 , Rong Wang  1 , Yongfang Yuan  1
Affiliations

Formulation design, characterization, and in vitro and in vivo evaluation of nanostructured lipid carriers containing a bile salt for oral delivery of gypenosides

Gang Yang et al. Int J Nanomedicine. .

Abstract

Background: Gypenosides (GPS) have been used as traditional medicine for centuries with various pharmacological effects. However, its therapeutic effects were restricted owing to the poor lipid and water solubility and low absorption. This study aimed to develop nanostructured lipid carriers (NLCs) containing a bile salt formulation (sodium glycocholate, SGC) for GPS, and to evaluate the potential of the GPS-SGC-NLCs as an oral delivery system.

Methods: The preparation of GPS-SGC-NLCs was investigated using a single-factor test and a central composite design of response surface methodology. In vitro release and pharmacokinetics studies were used to evaluate the dissolution and bioavailability of GPS. Furthermore, In vivo imaging and in situ intestinal perfusion studies were performed to investigate the absorption of the preparations in the gastrointestinal tract.

Results: The optimised formulation yielded nanoparticles with an approximate diameter of 146.7 nm, polydispersity of 0.137, zeta potential of -56.0 mV, entrapment efficiency of 74.22% and drug loading of 4.89%. An in vitro dissolution analysis revealed the sustained release of contents from GPS-SGC-NLCs over 48 h with 56.4% of the drug released. A pharmacokinetic analysis revealed an 8.5-fold increase of bioavailability of the GPS-SGC-NLCs compared with GPS powder. In vivo imaging and in situ intestinal perfusion studies showed that SGC-NLCs could significantly increase the absorption of GPS in intestinal tract. In vitro cytotoxicity evaluated using Caco-2 cells demonstrated that GPS-SGC-NLCs decrease the cytotoxicity of the drug.

Conclusion: The SGC-NLC formulation can significantly improve the absorption of GPS, which provides an effective approach for enhancing the oral absorption of drugs.

Keywords: bile salt; bioavailability; gypenosides; in vitro release; nanostructured lipid carriers.

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Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Effect of optimization of the process parameters of high pressure homogenization method; particle size (A) and polydispersity index (B) are used as the indexes.
Figure 2
Figure 2
Response surface models showing the influence of the factors on the responses. Notes: Three dimensional response surface plots showing the effects of (X1) total lipids concentration (%), (X2) ratio of liquid lipid to total lipid (%), and (X3) surfactant concentration (%) on the responses of Y1 (A), Y2 (B), and Y3 (C). Y1 is the response of the mean particle size, Y2 of entrapment efficiency, and Y3 of drug loading.
Figure 3
Figure 3
Particle size (A) and zeta potential (B) of GPS SGC NLCs. Abbreviation: GPS SGC NLCs, gypenosides loaded nanostructured lipid carriers containing a bile salt.
Figure 4
Figure 4
Transmission electron micrograph of GPS SGC NLCs. Abbreviation: GPS SGC NLCs, gypenosides loaded nanostructured lipid carriers containing a bile salt.
Figure 5
Figure 5
Differential scanning calorimetry curves of (A) GMS, (B) SGC, (C) GPS SGC NLCs, (D) physical mixture, (E) GPS, and (F) cryoprotectant. Abbreviations: GMS, glycerol monostearate; SGC, sodium glycocholate; GPS, gypenosides; GPS SGC NLCs, gypenosides loaded nanostructured lipid carriers containing a bile salt.
Figure 6
Figure 6
X ray diffraction analyses of (A) cryoprotectant, (B) GPS, (C) physical mixture, (D) GPS SGC NLCs, (E) SGC, and (F) GMS. Abbreviations: GMS, glycerol monostearate; SGC, sodium glycocholate; GPS, gypenosides; GPS SGC NLCs, gypenosides loaded nanostructured lipid carriers containing a bile salt.
Figure 7
Figure 7
In vitro release of GPS, GPS-NLCs, and GPS-SGC-NLCs in phosphate buffered solution (pH =6.8). Abbreviations: GPS, gypenosides; GPS-NLCs, gypenosides-loaded nanostructured lipid carriers; GPS-SGC-NLCs, gypenosides-loaded nanostructured lipid carriers containing a bile salt.
Figure 8
Figure 8
In vivo plasma concentration–time profiles. Levels of GPS following oral administration of GPS powder suspension, GPS-NLCs, and GPS-SGC-NLCs (n=6). Note: The data for the drug-time curve within first two hours shown in the blue dashed line box is presented in the inset. Abbreviations: GPS, gypenosides; GPS NLCs, gypenosides loaded nanostructured lipid carriers; GPS SGC NLCs, gypenosides loaded nanostructured lipid carriers containing a bile salt.
Figure 9
Figure 9
Luminescence imaging of gastrointestinal tract at different time following oral administration of Cy5.5 solution, Cy5.5 NLCs, and Cy5.5 SGC NLCs. Abbreviations: Cy5.5 NLCs, Cy5.5 loaded nanostructured lipid carriers; Cy5.5 SGC NLCs, Cy5.5 loaded nanostructured lipid carriers containing a bile salt.
Figure 10
Figure 10
Papp of GPS powder suspension, GPS NLCs, and GPS SGC NLCs (n=6). (Compared with GPs powder, *P<0.05; compared with GPS NLCs, #P<0.05). Abbreviations: GPS, gypenosides; GPS NLCs, gypenosides loaded nanostructured lipid carriers; GPS SGC NLCs, gypenosides loaded nanostructured lipid carriers containing a bile salt.
Figure 11
Figure 11
Results of the MTT assay with Caco 2 cells. Data were given as mean ± SD (n=6). *P<0.05, **P<0.01 compared with GPS powder. Abbreviations: GPS, gypenosides; SGC, sodium glycocholate; NLCs, nanostructured lipid carriers; MTT, 3 (4,5 dimethylthiazol 2 yl) 2,5 diphenyltetrazoliumbromide.
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