Enteric-coated capsule containing cationic nanoparticles for oral insulin delivery
View Patent ↗The invention relates to an enteric-coated capsule containing cationic nanoparticles for oral insulin delivery, in particular to a type of cationic nanoparticle including a polycationic and mucoadhesive polymer and a biodegradable polymer, wherein each of the nanoparticles has positive surface charge and enhanced permeability for paracellular insulin delivery; the enteric-coated capsule further includes a pH-sensitive polymer as the coating. The enteric-coated capsule containing cationic nanoparticles, when being orally administered to a subject, are configured to prevent the acidic degradation of the active substance such as insulin before being released from said cationic nanoparticles to a specific absorption site along the gastrointestinal tract.
1. A composition comprising an enteric-coated capsule enclosing a plurality of nanoparticles and a solubilizer, wherein each of said plurality of nanoparticles further comprises a polycationic polymer, a biodegradable polymer that is a copolymer which is degradable by hydrolysis following exposure to physiological environment of human intestine, a bioactive substance and a stabilizer; said solubilizer is trehalose in a concentration of 1.5% w/w or w/v.
2. The composition of claim 1 , wherein the polycationic polymer is a copolymer of acrylic and methacrylic acid esters with quaternary ammonium cations having a molecular weight from 150 to 200 kDa.
3. The composition of claim 1 , wherein the biodegradable polymer is poly(lactic acid-co-glycolic acid) having a molecular weight from 20 to 40 kDa.
4. The composition of claim 1 , wherein the enteric-coated capsule further comprises a hard gelatin capsule and a pH-sensitive coating layer which is coated on the surface of said hard gelatin capsule in order to form said enteric-coated capsule, said pH-sensitive coating layer being composed of a polymer which is selected from the group consisting of hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, ethyl acrylate and methyl methacrylate.
5. The composition of claim 1 , wherein the stabilizer is a polyvinyl alcohol.
6. The composition of claim 1 , wherein said bioactive substance is encapsulated in each of said plurality of nanoparticles; said plurality of nanoparticles are further encapsulated in said enteric-coated capsule.
7. The composition of claim 1 , wherein said bioactive substance is insulin.
8. The composition of claim 1 , wherein said nanoparticles are mucoadhesive when surrounding medium is at a pH between 6.0 and 7.4 which is similar to the pH of an intestinal medium.
9. The composition of claim 1 is administered orally to a subject in needs thereof, wherein the bioactive substance is released from said nanoparticles to the upper region of the small intestine of the subject with a controlled release profile of T max at about 10 hours and C min at about 58.9%.
10. The composition of claim 7 , wherein said insulin is selected from the group consisting of regular insulin and insulin analogs.
11. A method of preparing cationic nanoparticles of claim 1 , comprising:
(a) forming a double emulsions comprising an insulin solution, a polycationic polymer, a biodegradable polymer, a stabilizer and an organic solvent;
(b) forming insulin-loaded nanoparticles by evaporation of the organic solvent from said double emulsions;
(c) forming purified insulin-loaded nanoparticles by centrifugation and washing the nanoparticles for three times; and
(d) forming the cationic nanoparticles by freeze-drying the purified insulin-loaded nanoparticles overnight.
12. The method of claim 11 , wherein each of the nanoparticles has a mean particle size about 250-300 nanometers.
13. The method of claim 11 , wherein the insulin solution contains an insulin molecule selected from the group consisting of regular insulin and insulin analog.
14. The method of claim 11 , wherein the polycationic polymer is a copolymer of acrylic and methacrylic acid esters with quaternary ammonium cations having a molecular weight from 150 to 200 kDa.
15. The method of claim 11 , wherein the biodegradable polymer is poly(lactic acid-co-glycolic acid) having a molecular weight from 20 to 40 kDa.
16. The method of claim 11 , wherein the stabilizer is a polyvinyl alcohol.
17. The method of claim 11 further comprising:
(a) filling a hard gelatin capsule with the cationic nanoparticles; and
(b) forming an enteric-coated capsule by coating a pH-sensitive coating polymer on the surface of the hard gelatin capsule.