Conjugate of polyethylene glycol and chitosan

Synthetic resins or natural rubbers -- part of the class 520 ser – Synthetic resins – Mixing of two or more solid polymers; mixing of solid...

Reexamination Certificate

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C536S055200, C514S055000

Reexamination Certificate

active

06730735

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention concerns a novel conjugate between chitosan and polyethylene glycol (PEG-chitosan conjugate) that may be used in biomedical applications and particularly in the fields of antisense and gene therapy, drug absorption enhancement and targeting using particulate carriers.
Chitosan is a biopolymer material that is derived from chitin. Chemically, chitosan is a polyglucosamine, a linear polymer of &bgr;(1→4) linked 2-amino-2-deoxy-D glucopyranose. Chitosan can be derived from chitin through a process of deacetylation. While chitin is insoluble, chitosan in its salt form can demonstrate acceptable solubilities at pHs below 7.0. Chitosan is believed to be non-toxic and can be administered to mucosal surfaces.
Various applications for chitosan have been described in the prior art including its use in wound healing, controlled drug delivery, as a bioadhesive material and to improve the solubility of poorly soluble compounds. More recently, it has been discovered that chitosan, because of its positive charge, can have an effect upon the tight junctions between cells. It has been shown to be effective in improving the paracellular transport of drugs, particularly those that are polar in character. A detailed review of the medical applications of chitosan can be found in the article by Hon in
Polysaccharaides in Medical Applications
, Ed. Dumitru, S., Dekker, New York, 1996, pages 631-649. Specific examples of medical applications for chitosan can also be found in International Application Publication No. PCT/GB90/00291, in Artursson, et al., Pharm. Res. 11, 1358, 1994, and in Illum, et al., Pharm. Res. 11, 1186, 1994.
Chitosan can be obtained in a range of molecular weights from oligomeric materials containing a few units of glucosamine through to higher molecular weight materials of more than 200,000 Daltons. In pharmaceutical applications, the higher molecular weights from 50,000 to 500,000 Daltons are normally preferred. Chitosan can also be obtained in different degrees of deacetylation, but the materials that have a deacetylation of between 60 and 90% are normally preferred. Chitosan can be obtained from various sources, including shellfish, fungi, and other materials. Apharmaceutical grade of chitosan is available from Pronova Limited of Norway.
Because chitosan carries a positive charge, it can be used to interact with negatively charged surfaces as well as with other negatively charged materials including pharmaceuticals. Chitosan can also be used to modify the surfaces of carrier particles. For example, liposomes have been described where chitosan has been bound to their surfaces (Takeuchiu, et al. (1994), Chem. Pharm. Bull. 42, 1954-1956).
Chitosan can be employed in solution, as a powder material, in microspheres, or can be used as a film-forming agent.
It is also known to modify chitosan chemically to produce derivatives with new properties. Examples include N-acylchitosans, N-carboxyalkyl chitosans, N-carboxyacyl chitosans, and O-carboxyalkyl chitosans.
Sample admixtures of chitosan and polyethylene glycol (PEG) are known. For example, chitosan/poly(ethylene oxide) polymer networks have been described by Patel and Amiji (Polymer Preprints, ACS Division of Polymer Chem. 1994, 352, 403 and ACS Symposium Series, 627, Hydrogels and biodegradable polymers for bioapplications, page 209). The hydrogel was prepared by dissolving chitosan in acetic acid to produce a solution. Polyethylene glycol having a molecular weight of 10 kilodaltons (kD) to 1 megadalton (mD) was dissolved in acetic acid and the resulting solution added to the chitosan solution to prepare a physical blend. The blend was then cross-linked with glyoxal to form the gel system. There was no suggestion in the work of Patel and Amiji to bond polyethylene glycol, also known as polyethylene oxide, directly to chitosan to form a PEG-chitosan conjugate.
Chitosan/polymer hydrogels have also been described by Peng, et al. (J. Polymer Science Part A, Polymer Chemistry 32, 591-596, 1994). Here also the chitosan and a polymer (polyoxypropylene glycol) were mixed at acidic pH and then cross-linked with glutaraldehyde.
The attachment of polyethylene glycol to polymeric materials including proteins, carbohydrates, and phospholipids is known—see, for example, the article by Zalipsky, Advances in Drug Delivery Research, 16, 157-182 (1995). This process is often referred to as PEGylation and this term will be used herein. The various chemical procedures have their advantages and disadvantages including the complexity of the method involved, the ability to control the PEGylation of the selected molecule, the reversibility or degradability of the polyethylene glycol polymer linkage, the use of expensive or toxic solvents, etc.
PCT/GB95/00686 describes microspheres for biomedical uses which contain a substantially spherical core particle of a non-water soluble polymer and an outer surface consisting substantially of a water soluble polymer. The water soluble polymer is conjugated to polyethylene glycol and the non-water soluble core particle is attached to the water soluble polymer by the polyethylene glycol (PEG) moiety. The patent application describes detailed examples using PEG-dextran conjugates. Chitosan is also mentioned as a water soluble polymer in the preparation of such microspheres, but no PEG-chitosan conjugates were actually prepared. Moreover, there was no disclosure of particles in which the PEG moieties were pendant and exposed to the external environment.
Ouchi, et al., describes the preparation of PEG-chitosan by acylating the amino groups on the polysaccharide with the monomethyl ether of PEG as the carboxylate and then covalently bonding this compound to 5-fluorouracil (5-Fu) to produce a material for cancer chemotherapy (Ouchi, et al., J. Macromol. Sci. Chem., A28, 959, 1991) (“Ouchi”). The active ester method was used to prepare the PEG-chitosan products in Ouchi and the chitosan was a low molecular weight material having a degree of polymerization of 30 which had been produced by acid treatment of chitosan. The 5-Fu attached to the end of the PEG chain in the PEG-chitosan conjugate and the resulting soluble complex was administered by injection.
Ouchi did not consider that an unmodified PEG-chitosan conjugate could be used for the delivery of anionic macromolecular drugs, such as antisense oligonucleotides and DNA (nucleic acids), nor did they consider that the unmodified conjugate could be used as a coating agent in the field of colloidal drug delivery through the interaction of the positively charged chitosan with negatively charged surfaces and negatively charged colloidal particles. Furthermore, there was no suggestion in Ouchi that such positively charged PEG-chitosan conjugates might be used to provide increased absorption of drugs across mucosal surfaces through their interaction with negatively charged mucus or negatively charged surfaces of epithelial cells.
In the field of gene therapy, it is often important to be able to compact a plasmid material comprising nucleic acids into a small particle for improved administration. The prior art describes how this may be accomplished using cationic polymers such as polylysine as well as cationic lipids (see for example Tomlinson and Rowland, J. Control. Rel. 39, 357-372 (1995), Mumper, et al., Pharm Res. 13, 701-709 (1996)). A patent application PCT/GB97/00022 describes how such compaction can also be achieved using polyamidoamines to which polyethylene glycol has been attached.
However, no examples have been reported where PEG-chitosan was used for the improved compaction of plasmid DNA.
BRIEF SUMMARY OF THE INVENTION
The invention is directed to a composition for the systemic uptake of a drug across a mucosal membrane. The composition includes a polyethylene glycol-chitosan conjugate. The conjugate includes a chitosan or a chitosan derivative moiety and a polyethylene glycol or a polyethylene glycol derivative moiety. The composition is formulated for delivery to a mucosal membrane. In a preferred embodi

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