Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2002-10-25
2003-10-28
Barts, Samuel (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S020000, C536S123100
Reexamination Certificate
active
06638918
ABSTRACT:
TECHNICAL FIELD
The present invention relates to chitosan compositions, especially to chitosan compositions comprising nano-sized chitosan. The compositions present improved bioactivity, solubility and other properties over traditional chitosan. The invention also relates to a process for making the compositions and uses thereof.
BACKGROUND OF THE INVENTION
Chitin is the main constituent in the shells of crustaceans and is the most abundant naturally occurring biopolymer other than cellulose. Chitosan is derived from chitin and can be formed by deacetylation of chitin. Chitosan is commercially available in a wide variety of molecular weights (e.g., 10-1,000 kDa) and usually has a degree of deacetylation ranging between 70% and 90%. Chitosan is used for a wide variety of purposes including plant care, cosmetics additives, food and nutrition supplements and medical care.
The properties and applications of chitosan are strongly linked to its morphology, structure and size and these are directly related to the process used for obtaining chitosan. For reasons of clarity, the chitosan obtained as the initial product from chitin will be referred to herein as primary chitosan and the chitosan obtained from the subsequent treatment of this primary chitosan will be referred as modified chitosan.
Traditional primary or modified chitosan has a limited solubility, limited developed internal surface, large particle size, low water retention value and limited bio-availability. Traditional chitosan is usually semi-crystalline and only soluble in acidic medium, typically in a pH range from 1 to 5; this limits homogenous formulation. Another drawback of traditional chitosan being that it does not present optimum biological activity, mainly due to its dense semi-crystalline nature in solid form.
Processes for obtaining modified chitosan are known in the art. For instance, copending U.S. Ser. No. 01/15182 describes a process for the production of microcrystalline chitosan. The process involves the dissolution of primary chitosan in an aqueous acidic solution followed by the neutralization of the solution, producing an aqueous gel containing precipitated microcrystalline chitosan. According to U.S. Ser. No. 01/15182 the microcrystalline chitosan particles range in size from 2 to 20 &mgr;m and have a water solubility of at least 90% at pH of 6 after 24 hours.
For some applications it is preferred to use nanoparticulate chitosan, not only because it is more readily active for biological use but also because it presents greater solubility and a more open and finely divided architecture. Processes for obtaining nanoparticulate chitosan are described in several prior art documents. For instance, WO 01/32751 describes a process for producing nanoparticulate chitosan, with particle diameters in the range from 10 to 1,000 nm. According to the prior art invention, the chitosan is dissolved in an acidic aqueous medium and the pH of the solution is raised in the presence of a surface modifier to such an extent that the chitosan is precipitated. One of the drawbacks of this process is that the nanoparticulate chitosan has a high content of surface modifier. This can be detrimental for some applications such as pharmaceutical and cosmetic applications because the surface modifier can irritate human tissues and for plant applications because the surface modifier can be phytotoxic for plants. Furthermore, the nanoparticulate chitosan obtained according to this process can have its activity reduced because the surface active modifier can render the nanoparticulate chitosan less readily available, this is important in the case of anti-microbial (anti-bacterial, anti-fungal and anti-viral) applications.
WO 00/47177 discloses a process for producing nanoparticulate chitosan, with particle diameters in the range from 10 to 300 nm. A gas anti-solvent (GAS) process is preferably used wherein the chitosan is dissolved in solvent and a gas (CO
2
) miscible with the solvent and immiscible with chitosan, to reduce the bulk density of the solution and hence cause a reduction of the solubility limits of the chitosan in the expanded solution and thereby promoting the precipitation of chitosan. The process requires the use of high pressures and temperatures; also the recovery of precipitate from the pressurized vessel is a complex operation. This process may be convenient for lab or small scale operation, however, the scale-up of the process raises considerable problems. The resulting nanoparticulate chitosan may also retain solvent impurities giving rise to similar drawbacks as discussed herein above in relation to WO 01/32751.
In view of the above discussion, there is a need for an improved form of modified chitosan which is soluble over a wider range of pH, with a suitable viscosity, with improved bioactivity and other properties and which permits greater flexibility in formulation. There is also a need for an easy and simple process to produce nanoparticulate chitosan, free from surface modifier and with improved activity and greater flexibility in use.
SUMMARY OF THE INVENTION
The present invention relates in part to compositions comprising pure nanoparticulate chitosan, i.e. which can be made free from surface modifiers or organic solvents, wherein the chitosan presents a special morphology which allows for the compositions to have a high degree of flexibility in formulation and for the chitosan to have an increased activity. The term chitosan as used herein not only includes the natural polysaccharide &bgr;-1,4-poly-D-glucosamine obtained by deacetylation of chitin or by direct isolation from fungi but also includes synthetically produced &bgr;-1,4-poly-D-glucosamines and derivatives thereof of equivalent structure to chitosan.
According to a first aspect of the invention, there is provided a composition comprising chitosan in the form of a network of nano-sized fibres. Preferably, the fibre network has an interstitial space as determined for example by cryogenic transmission electron microscopic (cryo-TEM) imaging of at least about 60%, preferably at least about 80%, more preferably at least about 88% and especially at least about 89%. The network of nano-sized fibres is very open and very accessible. It should be understood that most of the chitosan will be in the form of a network of nano-sized fibres, however, a minor portion of the chitosan, preferably less than about 10% and more preferably less than about 5%, could be in a different form. The composition has an improved solubility over traditional forms of chitosan and is capable of producing fully homogeneous formulations in the critically important physiological pH region, for example from about 5 to about 7. As consequence, it can be used in a large number of applications. Additionally, the chitosan in the form of a network of fibres as described herein presents an increased activity. It presents superior bioactivity for plant and crop applications, enhanced delivery of chelated nutrient metals for plant care, improved efficacy as soil enhancer/conditioner, improved sebum/dandruff control in skin and hair care products, greater anti-microbiological efficacy, enhanced flocculation and absorbency efficacy, improved efficacy in odour control, oral care, etc.
By interstitial space is herein meant the average percent of open space in a two-dimensional projection of the three-dimensional chitosan fibre network. Open space is the space between the fibres of the network and is generally occupied by water or other solvent. The interstitial space is preferably measured by direct imaging cryo-TEM. A sample of the chitosan composition is diluted to 0.5% by adding water to the composition using a Vortex mixer table-top model (#12-810) (Fisher Scientific Company, Pittsburgh, Pa.) for 10 s followed by sonication using a tip sonicator Branson Sonifier S12 (Branson Sonic Power Co., Danbery, Conn.) for 10 s at 50 watts to fully disperse the sample. A 3 &mgr;l drop of the sample solution is placed on a carbon-coated lacey polymer support film mounted on a standard 300 mesh
Davison Gordon Robert
Gibbons Clyde
Konig Axel
MacGilp Neil Archibald
Milich Georgina Lyndsey Claire
Barts Samuel
Krishnan Ganapathy
Meyer Peter D.
The Procter & Gamble & Company
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