Denatured globular protein and bile salt-coated nanoparticles for poorly water-soluble drugs: Penetration across the intestinal epithelial barrier into the circulation system and enhanced oral bioavailability.
Oral drug delivery is the most preferred route for patients; however, the low solubility of drugs and the resultant poor absorption compromise the benefits of oral administration. On the other hand, for years, the overwhelmingly accepted mechanism for enhanced oral absorption using lipid nanocarriers was based on the process of lipid digestion and drug solubilization in the small intestine. Few reports indicated that other bypass pathways are involved in drug absorption in the gastrointestinal tract (GIT) for oral delivery of nanocarriers. Herein, we report a new nanoemulsion system with a denatured globular protein with a diameter of 30 nm, soybean protein isolates (SPI), and bile salt as emulsifiers, aiming to enhance the absorption of insoluble drugs and explore other pathways for absorption. A BCS class II drug, fenofibrate (FB), was used as the model drug. The SPI and bile salt-coated Ns with a diameter of approximately 150 nm were prepared via a high-pressure homogenizing procedure. Interestingly, the present Ns could be converted to solid dosage form using fluid-bed coating technology, maintaining a nanoscale size. Most importantly, in a model of in situ rat intestinal perfusion, Ns could penetrate across the intestinal epithelial barrier into the systemic circulation and then obtain biodistribution into other tissues. In addition, Ns significantly improved FB oral absorption, exhibited as a greater than 2- and 2.5-fold increase in Cmax and AUC0-t, respectively, compared to the suspension formulation. Overall, the present Ns are promising nanocarriers for the oral delivery of insoluble drugs, and the penetration of intact Ns across the GIT barrier into systemic circulation may be a new strategy for improved drug absorption with the use of nanocarriers.
Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
Wei
W
He
Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
Ke
K
Yang
Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China; Jiangsu Aosaikang Pharmaceutical Co., Ltd., Nanjing 210009, PR China.
Lifang
L
Fan
Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
Yaqi
Y
Lv
Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
Zhu
Z
Jin
Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
Shumin
S
Zhu
Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
Chao
C
Qin
Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China.
Yiao
Y
Wang
Department of Pharmaceutics, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: lifangyin_@163.com.
Lifang
L
Yin
D000284:Administration, Oral; D000818:Animals; D001647:Bile Acids and Salts / Q000008:administration & dosage* / Q000737:chemistry* / Q000493:pharmacokinetics; D001682:Biological Availability; D018938:Caco-2 Cells; D002470:Cell Survival / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D004337:Drug Carriers / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D004655:Emulsions / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics; D011345:Fenofibrate / Q000008:administration & dosage / Q000097:blood* / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D007408:Intestinal Absorption; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry / Q000648:ultrastructure; D010316:Particle Size; D011489:Protein Denaturation; D051381:Rats; D012995:Solubility; D030262:Soybean Proteins / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics; D013535:Suspensions / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014867:Water / Q000737:chemistry
D001647:Bile Acids and Salts; D004337:Drug Carriers; D004655:Emulsions; D030262:Soybean Proteins; D013535:Suspensions; D014867:Water; D011345:Fenofibrate
Absorption mechanism; Acetone (PubChem CID: 180); Coumarin 6 (PubChem CID: 100334); DiR (PubChem CID: 25195411); Fenofibrate (PubChem CID: 3339); Fenofibric acid (PubChem CID: 64929); Fluorescein isothiocyanate (PubChem CID: 18730); Globular protein; Insoluble drug; MTT (PubChem CID: 16218671); Nanoemulsions; Pharmacokinetics; Phosphotungstic acid (PubChem CID:16212977); Sodium deoxycholate (PubChem CID: 23668196); Solidification; Trehalose (PubChem CID: 7427)