Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
2001-10-19
2004-04-06
Wilson, James O. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S124000
Reexamination Certificate
active
06716970
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel water soluble, randomly substituted partial N-, partial O-acetylated chitosan or derivatives thereof, and preserving compositions containing water soluble, randomly substituted partial N-, partial O-acetylated chitosan, chitosan or derivatives thereof and novel processes for making water-soluble randomly substituted partial N-, partial O-acetylated chitosan, chitosan or derivatives thereof.
BACKGROUND OF THE INVENTION
Ophthalmic products intended for repeated use after opening, that is “multi-dose” products, must be preserved to minimize contamination with microorganisms during use. Preservatives that are used in ophthalmic solutions are often irritating to the eye, and at worst, may damage eye tissue after repeated use. Preservative problems may be worsened in contact lens solutions when a contact lens that has been exposed to a preservative in a lens care solution acts as a reservoir that concentrates the preservative in the eye.
In the United States, acceptably preserved pharmaceutical products, including ophthalmic, nasal and otic preparations, must achieve minimum performance standards when tested according to the procedures of the United States Pharmacopoeia Preservative Efficacy Test (PET). According to the PET protocol, adequately preserved formulations must reduce 0 day challenge inocula and 14 day re-challenge inocula of the bacteria
Staphylococcus aureus, Pseudomonas aeruginosa
and
Escherichia coli
by at least 99.99% (3 logs) within 14 and 28 days after the challenge date. In the fungal challenge portion of the PET, preserved formulations must not allow any growth of
Aspergillus niger
and
Candida albicans
within 14 and 28 days following the 0 day challenge. To demonstrate preservative efficacy for contact lens care products, a modified PET procedure is required by the FDA wherein a re-challenge of the test solutions is done on day 14 after the 14 day organism concentrations are determined.
Chitosan, the de-acetylation product of chitin, is a non-toxic biopolymer with weak antimicrobial activity. Heretofore, the use of chitosan to preserve pharmaceutical compositions has been hampered by its insolubility at pH above 6 and also because the antimicrobial activity of Chitosan in acidic solutions, by itself, is too low to meet PET requirements. Chitosan's water solubility at near neutral pH can be improved by derivatization with hydrophilic functional groups, such as carboxymethyl or glycol substituents, or by selective N-acetylation of commercially available chitosans.
Considerable efforts have been made to extend the water solubility of chitosan at neutral pH. In Sannan et al., Makromol Chem. 177, 3589 (1976), it was reported that, by treatment of chitin with alkali under homogeneous conditions, chitin with about 50% deacetylation became water-soluble. However, long reaction time and large quantities of solvent are required in some stages, including neutralization of the reaction mixture and removal of the resulting salt. This laborious process would be troublesome especially in large-scale production.
Kurita et al., Carbohydrate Polymers 16, 83 (1991), also discloses preparing water-soluble chitosan with about 50% N-acetylation by acetylating a 90% deacetylated chitosan with a complex solvent system, comprising aqueous acetic acid/methanol/pyridine. Kurita et al. describes that the resultant partially N-acetylated chitosan is water soluble, if the degree of acetylation is controlled at 50% and the acetyl groups are distributed randomly. However, the huge excess of pyridine solvent used by the Kurita method made this process impractical. Furthermore, the reaction products have limited water solubility at neutral pH because heterogeneous reaction conditions were employed that restrict uniform, random acetylation. Specifically, Kurita's chitosan reactant was not soluble in the reaction mixture, but instead it was dispersed as a swollen gel which hindered complete availability of reaction sites. In this case, the acetylation reaction would be favored in those chain segments that were most exposed and free to the reaction mixture, while other parts of the gel would be comparatively less acetylated due to steric interference from adjacent polymer chain segments. When taken as a whole, the polymer chain is not uniformly random, but instead is comprised of blocks of higher and lower acetylation.
Kubota et al., Polymer Journal. 29, 123 (1997), reported to have a facile preparation of water-soluble N-acetylated chitosan. In this reference, the chitosan is degraded by treatment with NaBO
3
, and the depolymerized product is then N-acetylated with acetic anhydride in aqueous acetic acid. Since both physical-chemical and biological properties of chitosan are dependent upon the chemistry of the polymer, such as the random distribution of a definite amount of acetyl groups and the molecular weight of the polymer, this process, which involves depolymerization, might alter the biological properties of chitosan.
SUMMARY OF INVENTION
The present invention is directed to a pharmaceutical preserving composition comprising: (a) at least one chitosan or chitosan derivative, and (b) at least one buffer solution.
The present invention is further directed to a method of preserving a contact lens solution, comprising mixing a contact lens solution with the composition comprising: (a) at least one chitosan or chitosan derivative, and (b) at least one buffer.
Moreover, the present invention relates to a method of disinfecting a contact lens, comprising soaking the contact lens with the composition comprising: (a) at least one chitosan or chitosan derivative, and (b) at least one buffer solution for a suitable period of time.
The present invention also is directed to a composition comprising (a) at least one chitosan or chitosan derivative, and (b) at least one buffer solution, wherein the at least one chitosan or chitosan derivative is prepared by a method comprising the steps of dissolving the at least one chitosan or chitosan derivative into an aqueous acidic solution and reacting the chitosan with an acetylating agent in the presence of a phase transfer reagent.
The present invention is further directed to a process for producing a water soluble, randomly substituted partial N-, partial O-acetylated chitosan or chitosan derivative, comprising the steps of dissolving a chitosan or chitosan derivative in an aqueous acidic solution and reacting the chitosan or chitosan derivative with an acetylating agent in the presence of a phase transfer reagent. In a further aspect, the invention relates to the product made by such a process.
The present invention is further directed to a water soluble, randomly substituted partial N-, partial O-acetylated chitosan or derivative thereof represented by the formula (I),
wherein R
1
, R
2
and R
3
are independently H or C(O)CH
3
, wherein the chitosan or derivative thereof is partially acetylated such that R
1
has a degree of substitution of C(O)CH
3
of from about 24 to about 55%, and R
2
has a degree of substitution of C(O)CH
3
of from about 1 to about 60%, m is greater than 25, wherein the partial N-, partial O-acetylated chitosan or derivative thereof is randomly substituted and is water soluble.
In another aspect, the invention provides a pharmaceutical preserving composition comprising:
(a) at least one water soluble, randomly substituted partially N-, partial O-acetylated chitosan or derivative, of formula (I),
(b) and at least one buffer solution.
In yet another aspect, the invention provides a pharmaceutical preserving composition comprising the product formed from mixing components (a) and (b) as described in the above aspect.
In another aspect, the invention provides a phamaceutical preserving composition comprising:
(a) at least one water soluble, randomly substituted partial N-, partial O-acetylated chitosan or derivative,
(b) and at least one buffer solution,
wherein the at least one water soluble, randomly substituted partial N-, partial O-acetylated chitosan or
Bergbauer Katrina L.
Hung William M.
Su Kai C.
Wang Guigui
Adjuvant Pharmaceuticals, LLC
Maier Leigh C.
Merchant & Gould LLC
Wilson James O.
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