Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1999-07-23
2002-04-16
Bawa, Raj (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000
Reexamination Certificate
active
06372196
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to a composition of polyanhydroglucuronic acid (PAGA) and its salts. The term polyanhydroglucuronic acid and salts thereof as used herein includes copolymers thereof, especially with anhydroglucose.
INTRODUCTION
1. Field of the Invention
Wounds occurring in human and veterinary practice often involve minor lesions such as cuts, excoriations, bums, scalds, and various kinds of open efflorescences be it of eczematous or bacterial origin. Such lesions require rapid covering to arrest bleeding, to disinfect the wound area, and to suppress secondary microbial contamination.
It is widely accepted that the healing essentially consists of three stages which may be simply defined, as: inflammatory/exsudative phase (Phase 1), proliferative phase (Phase 2), differentiation phase (Phase 3).
It is especially important for the healing process to arrest bleeding and to suppress secondary microbial contamination of the wound. Through infiltration of the, exsudate, the wound is supplied with leucocytes, neutrophilic granulocytes and monocytes, subsequently being converted to macrophages. Insufficient treatment of even minor lesions may thus give way to massive infections and to considerable complications of the healing process.
2. Description of the Related Art
The hemostatic effect of oxidised cellulose, introduced into health care practice by pioneering work of Kenyon, Nevell, Rogovin, Jasnitzky and others, has been known since the 1940's. Mechanisms underlying the hemostatic activity of PAGA have been recently explicitly reported e.g. by V A Stelmah et al. (Vestn. Beloruss. Gos. Univ., Ser. 2 (1993), (2) 43-5; cf. CA 1994:570118) to consist in an acceleration of formation of thrombi. The oxidised cellulose is prevailingly manufactured in the form of woven or knitted tissue (such as Surgicel or Interceed by Johnson & Johnson, USA). Its application is therefore mostly limited to specialised institutions such as surgical clinics or ambulances. Also, the existing products have certain contraindications due to their relatively high acidic character. Another disadvantage of the existing products is due to the fact that opening of the sterile packaging outside a sterile area may bring about bacterial contamination of both the sterile product and the wound; the same problem of course applies even to powder form packaged and sterilised in e.g. plastic bottles.
A detailed discussion regarding polyanhydroglucuronic acid and salts thereof is included in our co-pending Patent Application having the same date of filing as this application.
Pressurised aerosol packagings have been available from the 1930's, originally as insect sprays also used during World War II, using chlorofluoroalkanes as the propellant gas. They have been applied to pharmaceutical products since the 1950's, and there has been considerable development towards other types of propellants—less depleting the ozone layer and less contributing to global warming—in the last decades. However, there is no awareness of an aerosol packaged hemostatic of the polyanhydroglucuronic acid type prepared on the basis of oxidised cellulose as yet.
It is therefore the aim of the present invention to provide a product based on polyanhydroglucuronic acid and its salts for use as a sterile absorbable local hemostatic for mass usage by both layman and professional public, enabling easy and rapid application in common wounds and lesions and minimising detrimental effects on the environment.
BRIEF SUMMARY OF THE INVENTION
According to the invention, there is provided a hemostatically active aerosol composition comprising from 0.005 to 0.25 weight parts of microdispersed/microdispersable polyanhydroglucuronic acid and/or salts thereof and from 0.75 to 0.995 weight parts of a suitable dispergating/propellant system wherein the dispergating/propellant system includes liquids which are non-polar or of low polarity and have a surface tension of less than 30 mN/M and a permitivity at 10 kilohertz of less than 10. The term polyanhydroglucuronic acid and salts thereof includes copolymers thereof, especially with anhydroglucose.
The hemostatically active aerosol composition of the invention enables easy and rapid administration and ensures permanent readiness for use, sterility at repeated application, and increased stability due to exclusion of air and UV light access to the product in a pressurised aerosol packaging.
The composition may include at least one pharmaceutical adjuvant which may be selected from one or more substances having suitable anti-microbial, anti-viral, anti-mycotic and/or anti-parasitic effects.
In one embodiment of the invention, the stable microdispersed polyanhydroglucuronic acid and/or salts thereof have the form of particles of 0.1 to 80 &mgr;m preferably 5 to 15 &mgr;m, in size.
In one embodiment of the invention, the propellant used comprises aliphatic and/or alicyclic hydrocarbons with a number of carbon atoms from 1 to 6 and/or aliphatic ethers and/or fluorinated and/or perfluorinated aliphatic hydrocarbons and/or ethers, and/or carbon dioxide and/or nitrogen and/or rare gases and, as the case may be, other auxiliary substances.
The polyanhydroglucuronic acid salts are preferably selected from calcium, magnesium, sodium and/or potassium salts.
The polyanhydroglucuronic acid and/or salts thereof are preferably prepared by a method wherein a polyanhydroglucuronic acid-containing material is subjected to partial or complete hydrolysis and neutralisation in an oxidative environment, the hydrolysate undergoing fractional coagulation to form a stable microdispersed product.
This method provides stable polyanhydroglucuronic acid and salts thereof in essentially a single process carried out in a single vessel.
Preferably the hydrolysis is carried out in an aqueous solution of inorganic and/or organic salts and/or bases. Most preferably the inorganic and/or organic salts and/or bases used for hydrolysis are chlorides, sulphates, carbonates, formates, or acetates of alkali and/or alkaline earth metals, hydroxides of alkali and/or alkaline earth metals, alkylamines, or alkanolamines, in concentrations ranging from 1 to 10
−3
to 5 mol/l.
In an especially preferred embodiment of the invention the oxidative environment during hydrolysis is established by the presence of agents selected from one or more of hydrogen, sodium or magnesium peroxide, peroxacides and their salts, hypochlorites and chlorites.
Preferably the procedure is carried out at a pH of from 1 to 12, and preferably, at a temperature of from 0 to 100° C.
In a preferred embodiment of the invention the polyanhydroglucuronic acid-containing material is obtained by oxidation of a suitable polysaccharide, such as native or regenerated cellulose or starch.
The polyanhydroglucuronic acid and salts thereof preferably contain in their polymeric chain from 8 to 30 percent by weight of carboxyl groups, at least 80 percent by weight of these groups being of the uronic type, at most 5 per cent by weight of carbonyl groups, and at most 0.5 percent by weight of bound nitrogen.
Preferably the product contains at most 0.2 percent by weight of bound nitrogen in the polymeric chain.
In a preferred embodiment of the invention the molecular mass of the polymeric chain is from 1×10
3
to 3×10
3
) Daltons most preferably from 5×10
3
to 1.5×10
3
Daltons.
The content of the carboxyl groups is in the range of from 12 to 26 percent by weight and at least 95 percent of these groups are of the uronic type.
In a particularly preferred embodiment of the invention the product contains at most 1 percent by weight of carbonyl groups. Typically the carbonyl groups are intra- and intermolecular 2,6 and 3,6 hemiacetals, 2,4-hemialdals and C2-C3 aldehydes.
Because neutralisation and refining is carried out in a single operation the process is cost effective.
As the product is in a microdispersed form there is enhanced sorption and greater accessibility for blood. Therefore the biological availability is increased and a rapid o
Briestensky Jiri
Kiss Frantisek
Santar Ivan
Alpenstock Holdings Limited
Bawa Raj
Jacobson & Holman PLLC
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