Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1999-07-26
2002-04-16
Bawa, Raj (Department: 1619)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S054000, C424S045000, C424S489000
Reexamination Certificate
active
06372718
ABSTRACT:
The present invention relates to a stable microdispersed polyanhydroglucuronic acid (PAGA) and salts thereof, especially suitable for medicinal, pharmaceutical and cosmetic products, as well as to a method of preparing the same. The term polyanhydroglucuronic acid and salts thereof as used herein includes copolymers thereof, especially with anhydroglucose.
INTRODUCTION
Besides proteins, polysaccharides represent the most widespread biopolymers found in the biosphere. As an example, up to 10
12
metric tonnes per year of cellulose, a 1, 4 &bgr;D-glucane, is synthesized in nature. Other &agr; and &bgr; glucanes bound e.g. by 1,2; 1,3; 1,4 and 1,6; or 1,2 and 1,4 glycosidic bonds in the main chain, mostly of microbial origin, gain increasing importance with ongoing research in the field. It is the presence of glucuronic acid units in the polymeric chain of the oligosaccharides or polysaccharides that, together with their molar mass and type of the principal glycosidic bond, constitutes the basis of their immunostimulative, antitumourous, anticoagulative, or else haemostyptic effects (cf. Burchard. W. Ed., Polysaccharide, Eigenschaften and Nutzung, Springer Verlag, Berlin 1985, p. 144).
Glucuronoglucanes can preferably be prepared by relatively specific selective oxidation of the primary alcoholic group at C6 carbon atom of the glucopyranosic unit of natural polysaccharides by nitrogen oxides, the C1 aldehydic group of the basic unit being protected by the glycosidic bond.
A variety of methods have been disclosed for preparing glucuronoglucanes and glucuronanes from natural glucanes, using the oxidative effects of NO
x
either in the gaseous form (Kenyon et al., Ind. Eng. Chem., 41, No 1, 2-8 (1949); DE 0941289; DE 0967144), in nonpolar reaction environment of inert liquids such as hydrogenated hydrocarbons (USSR SU 937462; U.S. Pat. No. 4,347,057; EP 0492990), or in polar environment of aqueous solutions of acids such as HNO
3
, H
3
PO
4
or their mixtures with HSO
4
, wherein the NO
x
are mostly generated directly the oxidation liquor via dosed introduction of reducing substances such as, notably, NaNO
2
(GB 709684; CS AO 185366; GB 1593513; Painter J. et al., Carbohydrate Research 140, 61 (1985); Alhaique F., Chim. Oggi 11-15, 17 (1986)), or the reaction environment is created by introducing liquid NO
x
into aqueous HNO
3
(U.S. Pat. No. 4,100,341).
A disadvantage of these known processes relates to the fact that their oxidative effects on the glucane molecule are non-uniform and only relatively specific in that besides creation of carboxyl groups of the uronic type of C6 carbon of the glucopyranosic unit, other types of successive reactions (such as formation of ONO
2
and NO groups on C6) and secondary reaction (such as formation of COOH and other oxidised groups on end carbons C1 and C4, and notably on C2 and C3 carbons) do occur. In accord with numerous publications (Kaversneva E. P., Doklady AN SSSR (U.S.S.R.) 78 (3), 481 (1951); Nevell T. P., J. Text. Ind. 42, 91 (1951); Sihtola M. et al., J. Polym. Sci, Part C, (2), 289 (1963); Pastéka M., Chemické Zvesti (Slovakia) (20), 855 (1966)), extensive testing of polyanhydroglucuronic acids prepared by the action of NO
x
has led us to the conclusion that, besides carboxyl groups on C6 carbon, several other aldehydes, ketones, and their condensation products are formed that have fundamental influence on the stability of the polyanhydoglucuronic acid product.
It is known that the presence of carbonyl groups can be limited by their back reduction to primary alcoholic groups by means of complex hydrides such as NaBH
4
(Charkin S. W. and Brown W. G., J. Am. Chem. Soc. 71, 122 (1949); Mead F. S. M., J. Text, Inst. 46, T 400 (1955)), but this process is quite expensive for industral use due to the cost of the hydrides.
The quality of the product also depends on both the input raw material and the technological method used. Natural glucanes occur in the form of fibres, globules or grains with varying degree of orderliness (crystallinity). Their oxidation and partial degradation due to the effect of NO
x
does not proceed with the same speed in crystalline and amorphous regions, so that the resulting product represents a mixture of macromolecules oxidised and degraded to various extents which may provide products which are physiologically ineffective and/or have negative effects.
It is evident from the above that the preparation of stable PAGA product having required physical and chemical characteristics, destined for pharmaceutical and cosmetic use, is in no way a simple matter.
In health care practice one often encounters cases of capillary bleeding occurring during injuries or related to surgical interventions. The healing of the wounds frequently depends on attaining rapid homeostasis and creation of coagulum, to especially serve as a protection of the wound against infection. Application of D glucurono-1, 4 &bgr;D-glucane, the so-called oxidised cellulose, as a non-toxic resorbable local haemostatics to arrest bleeding from surface injuries or parenchymatous organs, osseous bleeding, and in general wherever use of conventional styptic means may be difficult or slow in functioning and less effective, has proved especially effective in similar cases.
Experience has shown that the product should be stored at temperatures not exceeding 25° C., preferably below 10° C., protected against direct light. When these conditions are not met, the influence of light and/or elevated temperatures during storage may easily provoke degradation changes due to the instability of secondary reactive groups and, on nitrogen-containing sites. This in turn may be manifested by reduced tissue tolerability, and even virtually exclude application of the conventional product in some pharmaceutical or cosmetic preparations.
In summary, methods of preparing PAGA known thus far are based on oxidative action of NO
x
on suitable types of polysaccharides of cellulosic or microbial origin (such as scleroglucanes), possibly with subsequent reduction of the content of destabilizing groups via reduction by hydrides, the latter process being, however, relatively expensive and jeopardising the product with simultaneous reduction of the carboxyl group content via reduction of their carbonyls. No method has been found up to now for preparing stable polyanhydroglucuronic acid with broader application scope enabling a better control of the final product characteristics.
Among important disadvantages of the known methods quoted above are non-uniform degree of both oxidation and degradation of individual polysaccharide particles or fibres, non-uniform content of bound nitrogen and other destabilizing sites in the macromolecule, as well as broad distribution of their molecular masses, altogether factors which can result in non-uniformity in resorbtion in the organism on applying the product as a haemostatic or in binding other substances or drugs such as anaesthetics, antibiotics or cytostatics.
In the latter case of active substance-PAGA complexes, the presence of destabilizing groups in this otherwise important biologically degradable carrier brings about inherent instability and changes in properties with time. The same applies to formulations for pharmaceutical or cosmetic use, for which our testing has revealed discoloration with temperature and time, viscosity changes, and even phase separation, whenever unstabilized PAGA prepared by known methods was utilised.
A further deficiency of the known methods lies in the fact that PAGA prepared by NO
x
oxidation displays closed surface and low values of specific surface area (measured m
2
.g
−1
) for both fibrillar or particulate material. Whenever final product in powder form is required, the isolated bulk product has to be mechanically disintegrated, in a dry or wet process, which brings about potential contamination by impurities such as metals due to abrasion of production equipment and increases further the production costs.
A last but not least disadvantage of the conventionally prepared PAGA products is that,
Briestensky Jiri
Kiss Frantisek
Santar Ivan
Alpenstock Holdings Limited
Bawa Raj
Jacobson & Holman PLLC
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