pH-sensitive nanoparticles for oral insulin delivery
Inventors
Zhang, Lijuan • Ling, Li • ZHOU, Li Ying • WU, Zhi Min • GUO, Xin Dong • Jiang, Wei • Luo, Qian • Qian, Yu
Assignees
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Publication Number
US-8859004-B2
Publication Date
2014-10-14
Expiration Date
Abstract
The present invention discloses the pH-sensitive nanoparticles composed of pH-sensitive polymer, hydrophobic material, internal stabilizer, external stabilizer content and insulin drug. The present invention also includes a method for preparation of pH-sensitive nanoparticles, in particular, a multiple emulsions solvent evaporation method. The pH-sensitive nanoparticles of the present invention show good pH-sensitive property with 100-300 nanometer particle size. Significant decrease in blood glucose level is observed in streptozotocin (STZ)-induced diabetic rats and the bioavailability of insulin is more than 10% after oral administration of the insulin-loaded pH-sensitive nanoparticles.
Core Innovation
The invention relates to a method of preparing pH-sensitive insulin-loaded nanoparticles. The method forms an internal water phase (W1) by mixing insulin with an internal stabilizer, and forms an oil phase (O) by dissolving a hydrophobic polymer and a pH-sensitive polymer in a solvent of dichloromethane and acetone to create an initial W1/O system.
The method further forms a double emulsion by first ultrasonic emulsification to create an initial emulsion (W1/O), and then second ultrasonic emulsification to create a double emulsion (W1/O/W2). The external phase (W2) includes an external aqueous stabilizer, and the pH-sensitive insulin-loaded nanoparticles are produced from the double emulsion by subsequent solvent evaporation and downstream solid recovery operations.
The process ends with evaporation of the solvent, water washing, centrifugation, and freeze drying to form the pH-sensitive insulin-loaded nanoparticles. The approach is described as producing nanoparticles with particle size in the range of about 100–300 nm and improved insulin encapsulation compared with prior art, together with enhanced in vivo performance in STZ-induced diabetic rats following oral administration.
Claims Coverage
Independent claim clm-00001 covers a pH-sensitive insulin-loaded nanoparticle preparation method that includes forming an initial W1/O emulsion and then a double W1/O/W2 emulsion via first and second ultrasonic emulsification, followed by solvent evaporation, water washing, centrifugation, and freeze drying. The claim includes inventive features involving specified internal and external stabilizer phases, specified polymer molecular-weight ranges, and a dichloromethane/acetone solvent system with a defined volume ratio, yielding particles for oral delivery.
Initial W1/O emulsion from insulin internal stabilizer
Mixing one part of insulin and two parts of an internal stabilizer to form solution A (internal water phase W1) and forming an initial emulsion (W1/O) by combining solution A with an oil phase solution B via first ultrasonic emulsification.
Oil phase with hydrophobic polymer and pH-sensitive polymer in dichloromethane/acetone
Dissolving one part of a hydrophobic polymer with a molecular weight from 20,000 to 40,000 daltons and two parts of pH-sensitive polymer in a solvent of dichloromethane and acetone with a volume ratio of 4:1 to 3:1 to form solution B (oil phase O).
Double W1/O/W2 emulsion using external aqueous stabilizer and second ultrasonic emulsification
Forming solution C as an external phase (W2) comprising an external aqueous stabilizer with a molecular weight from 31,000 to 50,000 daltons, then forming a double emulsion (W1/O/W2) by combining the initial emulsion (W1/O) with solution C via second ultrasonic emulsification.
Solvent evaporation, washing, centrifugation, and freeze drying to form nanoparticles
Forming the pH-sensitive insulin-loaded nanoparticles by evaporation of the solvent, water washing, centrifugation of the nanoparticles, and freeze drying after the double emulsion formation.
Across the independent claim, the core inventive coverage is directed to producing pH-sensitive insulin-loaded nanoparticles by building a W1/O initial emulsion from an insulin/internal stabilizer water phase and an oil phase containing specified polymers in dichloromethane/acetone, converting it into a W1/O/W2 double emulsion using an external aqueous stabilizer and second ultrasonic emulsification, and isolating freeze-dried nanoparticles via evaporation, washing, and centrifugation.
Stated Advantages
Improved insulin encapsulation compared with prior art.
Enhanced in vivo performance in STZ-induced diabetic rats after oral administration.
Oral insulin bioavailability reported as greater than 10% (BA_R about 11.25%).
Documented Applications
Oral delivery of insulin using pH-sensitive insulin-loaded nanoparticles, with evaluation in STZ-induced diabetic rats by measuring blood glucose reduction and oral insulin bioavailability (BA_R).
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