Nanocapsule for delivery of lipophilic compound and process of preparation thereof

Abstract

The invention relates to biocompatible polysaccharide-based nanocapsule templated on oil core of diameter not exceeding 1 μm, stabilized without low molecular weight surfactants. The nanocapsule shows long-term stability in an aqueous suspension and is able to highly efficient encapsulation of hydrophobic compounds.

What is claimed is: 
     
         1 . Nanocapsule of diameter below 1 μm, showing long-term stability in aqueous suspensions, used for delivery of lipophoilic compounds, said nanocapsule comprises:
 a) liquid core for delivery of lipophilic compounds, wherein the core material is selected from among oleic acid, isopropyl palmitate, fatty acids, oils and extracts of natural origin, especially linseed oil, soybean oil, argan oil and/or mixtures thereof; 
 b) shell made from hydrophobically modified polysaccharide selected from among chitosan derivatives, chitosan oligosaccharide derivatives, dextran, carrageenan, amylose, starch, hydroxypropyl cellulose, pullulan and glycosaminoglycans (e.g. hyaluronic acid, heparan sulfate, heparin sulfate, keratan sulfate, chondroitin sulfate, dermatan sulfate) and their derivatives, the most suitable stabilizers are believed to be hyaluronic acid, chitosan and chitosan oligosaccharide derivatives. 
 
     
     
         2 . Nanocapsule of  claim 1  wherein the degree of substitution of hydrophobic chains in said modified polysaccharide varies between 0.1-40%. 
     
     
         3 . Nanocapsule of  claim 1  wherein the shell of said capsule is made from hydrophobically modified polysaccharide selected from: Hy-Cx, CChit-C12 or oCh-C18-sulf, where:
 Hy-Cx (x=6 or 8 or 12 or 18) is hyaluronate derivative of the following structure: 
 
       
         
           
           
               
               
           
         
         where p is an integer selected from: 2, 3, 5 or 8, m is an integer equal to ca. 10 for HyC6 and HyC8, 22 for HyC12 and HyC18x or 7 for HyC18, while n is an integer equal to ca. 472 for HyC6 and HyC8, 460 for HyC12 and HyC18x or 475 for HyC18, 
         CChit-C12 is dodecyl derivative of cationically modified chitosan of the following formula: 
       
       
         
           
           
               
               
           
         
         where m is an integer equal to ca. 200, n is an integer equal to ca. 6, and p is an integer equal to ca. 88 (calculated for chitosan of molar mass equal to 100000 g/mol) 
         oCh-C18-sulf is octadecyl derivative of anionically modified chitosan oligisaccharide described by the following structure: 
       
       
         
           
           
               
               
           
         
         where m is an integer equal to ca. 9, n is an integer equal to ca. 1, and p is an integer equal to ca. 5. 
       
     
     
         4 . Nanocapsule of  claim 1  wherein the shell of said capsule is covered by ultrathin polyelectrolyte film consisted of biocompatible polyelectrolyte or its derivative of natural origin selected from among chitosan derivatives dextran, starch, hydroxypropyl cellulose, and glycosaminoglycans (e.g. hyaluronic acid, heparan sulfate, heparin sulfate, keratan sulfate, chondroitin sulfate, dermatan sulfate) and synthetic polyelectrolytes selected from among poly-L-lysine, polyornityne, poly (D-glutamic acid), derivatives of poly(lactic acid), polystyrenesulfonate, poly (diallildimethylammonium chloride), polyallylamine hydrochloride or polyethyleneimine. 
     
     
         5 . Nanocapsule of  claim 1  wherein fluorescent dye, vitamin or active pharmaceutical ingredient cab be deliver while encapsulated within oil core 
     
     
         6 . An aqueous suspension containing capsules of  claims 1 - 5 . 
     
     
         7 . A process for preparing nanocapsules for delivery of lipophilic compounds comprising the steps of:
 a) mixing aqueous and oil phase in v/v ratio varying between 10:1-10000:1, preferably 100:1;   b) mechanical—(by mixing or shaking) or ultrasound-assisted emulsification; an aqueous phase is solution of polysaccharide selected from among chitosan derivatives, chitosan oligosaccharide derivatives, dextran, carrageenan, amylose, starch, hydroxypropyl cellulose, pullulan and glycosaminoglycans (e.g. hyaluronic acid, heparan sulfate, heparin sulfate, keratan sulfate, chondroitin sulfate, dermatan sulfate) and derivatives thereof having pH in the range of 2-12, concentration 0.1-30 g/L and ionic strength between 0.001-3 M, while an oil phase is selected from among oleic acid, isopropyl palmitate, fatty acids, PROVINOL, oils and extracts of natural origin, especially linseed oil, soybean oil, argan oil and/or mixtures thereof. Importantly, said process is carried out without the use of low molecular weight surfactants.   
     
     
         8 . A process of  claim 7  wherein sonication is carried out for 15 minutes to 2 hours at temperature from 4° C. to 40° C., preferably for 30 to 60 minutes at temperature ranging within 20-35° C., especially recommended for 30 minutes at room temperature. 
     
     
         9 . A process of  claim 7  wherein sonication is carried out in switched-mode and the ultrasound pulses last 2-times shorter than the break between them. 
     
     
         10 . A process of  claim 7  wherein said nanocapsules are covered by ultrathin polyelectrolyte films obtained by layer by layer technique relying on consecutive adsorption of oppositely charged polyelectrolytes, wherein biocompatible polysaccharide or its derivative of natural origin selected from among chitosan derivatives dextran, starch, hydroxypropyl cellulose, and glycosaminoglycans (e.g. hyaluronic acid, heparan sulfate, heparin sulfate, keratan sulfate, chondroitin sulfate, dermatan sulfate) and synthetic polyelectrolytes selected from among poly-L-lysine, polyornityne, poly (D-glutamic acid), derivatives of poly(lactic acid), polystyrenesulfonate, poly (di allildimethylammonium chloride), polyallylamine hydrochloride or polyethyleneimine at concentration ranging between 0.1 g/L to 30 g/L and ionic strength varying from 0.001 to 3 M are used. 
     
     
         11 . A process of  claim 7  wherein an encapsulated hydrophobic compound is dissolved in oil phase.