Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-08-18
2002-10-15
Fonda, Kathleen Kahler (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C514S055000
Reexamination Certificate
active
06465626
ABSTRACT:
This invention relates to novel drug delivery compositions which provide for the improved uptake of therapeutic agents across mucosal surfaces.
Polar drugs, including high molecular weight peptides, proteins and polysaccharides, are typically not effectively absorbed across mucosal membranes, such as the gastrointestinal tract, the eye, the vagina, the nasal cavity or the rectum. Such molecules are thus normally only given by injection, which inevitably gives rise to well known problems associated with patient compliance, the cost of treatment, as well as the potentially harmful effects, such as phlebitis and pain, of the injection.
It is well known in the literature that the absorption of polar molecules across mucosal membranes may be greatly improved if they are administered in combination with so-called “absorption enhancers”. Examples of absorption enhancers which have been described in the literature include non-ionic surfactants, cyclodextrins, pholspholipids and bile salts. (For a review see Davis et al (eds.), Delivery Systems for Peptide Drugs, Plenum Press, New York, 1987; and Lee (ed.), Peptide and Protein Delivery, Marcel Dekker Inc., New York, 1991.)
EP-A-023 359 and EP-A-122 023 describe powdery pharmaceutical compositions for application to the nasal mucosa, as well as methods for the administration of such compositions. The pharmaceutical compositions allow polypeptides and derivatives thereof to be effectively absorbed through the nasal mucosa. Similarly, U.S. Pat. No. 4,226,849 describes a method for administering a powdery medicament to the nasal mucosa, in which the preferred composition has mucoadhesive properties.
Formulations based on microspheres for mucosal delivery have been described in WO 88/09163. The formulations contain certain enhancers to aid effective penetration of the mucosa by the drug. WO 89/03207 describes microsphere formulations which do not require an enhancer.
Chitosan is a derivative of chitin or poly-N-acetyl-D-glucosamine in which the greater proportion of the N-acetyl groups have been removed through hydrolysis. It is available from several suppliers including Pronova, Drammen, Norway, and, depending on the grade selected, is soluble in water and/or aqueous acid up to pH values of between 6.0 and 7.0.
Chitosan has previously been used to precipitate proteinaceous material and to make surgical sutures. It has also been employed previously in oral drug formulations in order to improve the dissolution of poorly soluble drugs (see Sawavanagi et al, Chem. Pharm. Bull., 31 (1983) 2062-2068) or for the sustained release of drugs by a process of slow erosion from a hydrated compressed matrix (Nagai et al, Proc. Jt. US Jpn. Semin. Adv. Chitin Chitosan Relat. Enzymes, 21-39, Zikakis J. P. (ed.), Academic Press, Orlando, 1984).
WO 90/09780 describes a composition comprising a drug and a polycationic substance (e.g. chitosan) that promotes the transport of the drug across mucosal membranes. The composition may also comprise microspheres of the polycationic substance.
WO 96/05810 describes a composition comprising a pharmacologically active compound and particles, preferably powders or microspheres, of chitosan or a chitosan derivative or salt, where the particles are either solidified or partially cross-linked such that they have a zeta-potential of between +0.5 and +50 mV. Solidified particles are made by treating particles made from a water soluble chitosan salt with an alkaline agent, such as sodium hydroxide, in non-acid containing water to render them insoluble.
Chitosan microspheres have also been produced for use in enhanced chromatographic separation (Li Q. et al, Biomater. Artif. Cells Immobilization Biotechnology, 21 (1993) 391-398), for the topical delivery of drugs (Machida Y., Yakugaku Zasshl., 113 (1993) 356-368), for drug targeting after injection (Ohya Y et al, J. Microencap., 10 (1993) 1-9), as an implantable controlled release delivery system (Jameela and Jayakrishnan, Biomaterials, 16 (1995) 769-775) and for the controlled release of drugs (see Bodmeier R. et al, Pharm. Res., 6 (1989) 413-417 and Chithambara et al, J. Pharm. Pharmacol., 44 1992, 283-286).
EP 454044 and EP 486959 describe polyelectrolyte microparticles or polysaccharide microspheres, including chitosan microspheres, for use in the controlled release of drugs. Chitosan microspheres crosslinked with glutaraldehyde have also been described in JP 539149.
Gelatin is a purified protein obtained either by partial acid hydrolysis (type A) or by partial alkaline hydrolysis (type B) of animal collagen. Type A gelatin is cationic with an isoelectric point between pH values of 7 and 9, whereas type B gelatin is anionic with an isoelectric point between pH values of 4.7 and 5. Gelatin is known to swell and soften when immersed in cold water, eventually absorbing between 5 and 10 times its own weight in water. It is soluble in hot water, forming a gel on cooling. Gelatin is used as a haemostatic in surgical procedures as an absorbable film or sponge, which can absorb many times its own weight in blood. It is also employed as a plasma substitute, and may be used in the preparation of pastes, pastilles, suppositories, tablets and hard and soft capsule shells for oral formulations.
The production of gelatin microspheres has been widely described in the literature. Gelatin microspheres have been produced by an emulsification method involving crosslinking with glutaraldehyde, producing microspheres of less than 2 &mgr;m in diameter (Tabata and Ikada, Pharm. Res. 6 (1989) 422-427). Cortesi et al (Int. J. Pharm. 105 (1994) 181-186), Natruzzi et al (J. Microencapsulation, 11 (1994) 294-260) and Esposito et al (Int. J. Pharm., 117 (1995) 151-158) have reported the production of microspheres of a mean diameter of 22 &mgr;m using a coacervation emulsification method. Microspheres as produced by the latter processes were not crosslinked. Microspheres of a smaller size have been produced according to a similar method by Esposito et al (Pharm. Sci. Commun. 4 (1994) 239-246). The type of gelatin (A or B) used in these studies was not specified.
The production of microspheres by complexation, between a negatively charged material such as alginate and a positively charged chitosan has been described in the literature. For example. Polk et al, J. Pharm. Sci., 83 (1994) 178-185) describes the production of clhitosan-alginate microspheres by the addition of an alginate solution to a solution of chitosan and calcium ions. The highest concentration of chitosan used in the microsphere formulations was 5.2% w/w. Similarly, the formation of complex coacervates between oppositely charged polyions, namely a positively charged chitosan and a negatively charged type B gelatin has been described by Remunan-Lopez and Bodmeier (Int. J. Pharm. 135 (1996) 63-72). These workers found the optimum chitosan:gelatin ratio to be in the range 1:10 to 1:20. The coacervate was obtained in a dry form by decanting the supernatant after centrifugation and drying at 60° C. We have now found, surprisingly, that microparticles, produced from a combination of a chitosan and a cationic type A gelatin, possess particularly advantageous properties, which enable the improved transport of therapeutic agents, including polar drugs, across mucosal surfaces such as the nasal cavity.
Thus, according to a first aspect of the invention there is provided a composition comprising a mixture of chitosan and type A. cationic, gelatin, together with a therapeutic agent (hereinafter referred to as “the compositions according to the invention”).
By “mixture of chitosan and type A gelatin” we include any composition comprising a chitosan, as defined hereinafter, and a type A gelatin, as defined hereinafter, whether a physical and/or chemical association between these two constituents exists or not.
The term “chitosan” will be understood by those skilled in the art to include all derivatives of chitin, or poly-N-aceryl-D-glucosamine (including all polyglucosamine and oligomers of glucosamine materials of different molecular weigh
Illum Lisbeth
Watts Peter James
Akin Gump Strauss Hauer & Feld L.L.P.
Fonda Kathleen Kahler
West Pharmaceutical Services Drug Delivery and Clincal Research
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