For an effective in vivo delivery, digestion and absorption of a soluble active ingredient, there is a need for a control system which can protect the encapsulated soluble active ingredient in the stomach under high acidic conditions with a low pH, and can release the content slowly in the intestinal tract requiring relatively long retention time. The encapsulation of an active ingredient is essential to achieve the control system. Encapsulation technique is a process by which a soluble active ingredient in a solid, a liquid or a gas state is coated with or entrapped within another material or system so that the soluble active ingredient is released under specific conditions. Generally, synthetic or natural polymers are used as a capsule material.
Chitosan is a natural cationic polysaccharide produced by deacetylation of chitin and has excellent biodegradable and biocompatible characteristics with low toxicity [J. Microencapsulation 2000, 17, 625˜638]. It has a good gel and film forming character and can easily bind with anionic materials due to its multivalent cations [J. Chem. Technol. Biotechnol. 1990, 49, 395˜404], and it shows excellent mucoadhesiveness to mucosal tissues such as intestinal tract [J. Pharm. Sci. 2003, 92, 567˜576]. Therefore several researches on the effective in vivo delivery of pharmaceuticals or functional materials via encapsulation using chitosan has been conducted.
An emulsion cross-linking method [Int. J. Pharm. 1994, 11, 217˜222], an emulsion droplet coalescence method [Pharm. Res. 1999, 16, 1830˜1835], a reverse micellar method [J. Controlled Release 2001, 17, 317˜323], a spray-drying method [Int. J. Pharm., 1994, 217˜222], an O/W/O multiple emulsion method [Korean Patent Application No. 10-2005-0014831] and the like have been broadly used to prepare the capsule using chitosan.
Since chitosan itself cannot be used to prepare a capsule, ionic gelation methods have been developed to form a capsule within a short period through a rapid cross-linking reaction between multivalent cationic chitosan and anionic counter-ions as a cross-linking agent. The ionic gelation can form an insoluble membrane on the surface of the polymer via the cross-linking reaction, and the encapsulation process is completed through a phase separation. The capsules prepared as above are composed of synthetic or natural polymers and provide controlled release of the content. The release rate of the content is controlled by chemical structure, thickness and size of the capsule membrane, the concentration of the ingredient composing the capsule, the concentration of the content, the concentration of cross-linking agents, a media pH and the like [Int. J. Pharm. 2004, 274, 1˜33; J. Controlled Release, 2004, 150, 5˜28].
As a cross-linking agent added for the ionic gelation of chitosan, glutaraldehyde and sulfuric acid have been used [J. Microencapsulation 1998, 15, 373˜382; J. Microencapsulation 2002, 19, 173˜180; Korean Patent Nos. 10-1998-0056584 and 10-2003-0085599]. However, due to their toxicity it is impossible to apply glutaraldehyde and sulfuric acid directly to foods, and they are only restrictively used in a pharmaceutical field.
Recently, there have been developed techniques of preparing a chitosan capsule by using a low toxic cross-linking agent for in vivo drug delivery. Moliaro et al. [Biomaterials 2002, 23, 2717˜2722] and Eve Ruel-Gariepy et al. [European J. Pharmaceutics and Biopharmaceutics 2004, 57, 53˜63] have developed a drug delivery system capable of forming a chitosan gel through heat treatment by adding glycerolphosphate which can provide a counter-ion to a chitosan solution. Besides, there are several cross-linking agents for chitosan, for example, alginic acid [U.S. Pat. No. 6,365,187 B2; U.S. Pat. No. 6,534,091 B1] and polymers such as sodium carboxymethyl cellulose and xanthan gum [Korean Patent Publication No. 2006-0016164, Korean Patent Publication No. 2001-0025930]. Particularly, it is a general trend that a chitosan capsule is prepared by using tripolyphosphate (TPP) as a cross-linking agent [Int. J. Pharm. 2002, 249, 165˜174; J. Pharm. Sci. 2002, 91, 1396˜1404; Int. J. Pharm. 2003, 250, 215˜226; Int. J. Pharm. 2006, 311, 187˜195]. However, such methods have problems of a low encapsulation yield, a complicated manufacturing process, excessive release and degradation of a drug in the stomach, excessive inhibition of drug release, or the like. Thus, although the use of chitosan for the encapsulation of a soluble active ingredient has many advantages as described above, its commercialization and application are restricted. Therefore, it is necessary to prepare a chitosan capsule using a new type of a cross-linking agent to achieve a high encapsulation yield and a protection against high acidity in the stomach while a gradual release of an active ingredient in the intestine.
USPTO Backgrounds
USPTO Backgrounds