GB1593513A - Method of preparing oxidized cellulose and salts thereof - Google Patents

Description

(54) METHOD OF PREPARING OXIDIZED CELLULOSE AND SALTS THEREOF (71) We, STATNI VYSKUMNY USTAV TEXTILNI, a State Enterprise organized and existing under the laws of Czechoslovakia, of No. 2 Ujezu, Liberec, Czechoslovakia do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to a method of preparing oxidized cellulose or a salt thereof, these substances being of use in medical practice to stop bleeding.

In surgical operations as well as with various traumatic injuries there is encountered a serious problem of how to stop bleeding. Conventional haemostatics generally cannot be left in situ in the organism and have to be removed therefrom.

The practical application of haemostatics based on oxycellulose and salts thereof is difficult in practice due to a poor chemical stability of oxidized cellulose manifesting itself by yellowing and strength loss. Natural ageing accompanied by degration of the oxidized material is accelerated by the action of heat, moisture and light. The causes of the low chemical stability of oxycellulose have been subjected to intense study, and it has been proved that during the oxidation a more or less intense destruction of the cellulose macromolecule occurs depending on the reaction conditions. The degraded cellulose molecules then easily undergo continuing oxidation on the second and third carbon positions with a simultaneous conversion of ketonic and aldehydic groups to carboxylic groups, and successively degrade to physiologically ineffective low molecular weight products.

A previously proposed process of preparing oxycellulose substantially comprises the following four essential steps: (1) oxidation of cellulose; (2) stabilisation of oxycellulose; (3) neutralisation of oxycelluldse (preparation of celluronic acid salts); and (4) final steps (impregnation, drying, sterilization, finishing).

The aforementioned steps form the subject matter of several patents. The cellulose to be used can be of various origins, for example wood or cotton, in the form of, for example, fibers, knitwork, gauze, wadding or paper. In pursuing a homogeneous structure of oxidized cellulose, fibres of regenerated cellulose such as viscose and cuprammonium, glossy fibres in the form of 150 den. yarn having fibrils of 2-4 den. and an average polymerization degree of 200 to 500, have proved most preferable. Of these the knitwork form is most suitable for surgical purposes since it possesses excellent shape adaptability. Blended or integrated materials of rayon staple fibres, viscose sponge and Cellophane (Trade Mark) can also be oxidized.

The problems of the oxidation of cellulose for preparing oxycellulose for medical purposes have been solved in recent patent literature predominantly by using gaseous or liquid NO2 (nitrogen dioxide), or a mixture of nitrogen oxides arising from the degradation of alkali nitrites by nitric acid. The use of liquid NO2 in an inert medium of chlorinated hydrocarbons (tetrachloromethane) has been taught by U.S. Patent No. 3,364,200 (1968). Oxidation reactions in the liquid phase are more controllable, enable a better contact between the reaction constituents, and the final product is consequently more homogeneous. In U.S. Patent No.

3,516,416 (1970), the oxidation is carried out above the boiling point of NO2 (21 C).

According to U.S. Patent No. 3,491,766 (1970) it has been recommended, in order to attain a higher reaction speed, to add to the liquid NO2 about 8% by weight of water. Another method has been taught by U.S. Patent No. 3,577,994 (1971), wherein a cellulosic material is first wetted by a mixture of liquid NO2 and 8% by weight of water and then exposed to hot NO2. The last mentioned method is said to be advantageous when applied to a continuous process.

Common disadvantages of all the afore-mentioned processes in which nitrogen oxides in the liquid or gaseous phase or diluted with an inert substance are used for oxidizing cellulosic materials, are a technically complex plant (sorption of final gases), expensive raw materials e.g. liquid NO2 (Freons (Trade Mark) and difficult regeneration of the latter.

British Patent Specification No. 709,684 (1954) has proposed to use for oxidizing cellulosic material nitrogen oxides (NO2, N2O3) liberated in the reaction of an alkali nitrite with a mixture of nitric and sulphuric acids, the latter assuming the function of an oxidation catalyst. A certain acceleration of the oxidation speed is offset, however, by an increased degradation of cellulose macromolecules and consequently by a lower chemical stability of the product. The negative influence of sulphuric acid on cellulosic materials is known from the technology of cellulose nitrate production.

The stabilization of cellulose is a relevant factor on which the lifetime of the final product depends. To this purpose, all the acidity and the oxidation byproducts have to be eliminated from the material to be oxidized. The difficulty of this is caused by unfavourable mechanical characteristics of oxycellulose which do not allow the application of methods familiar in, for instance, the textile technology of cellulose derivative manufacture, such as steaming or alkali boiling. According to U.S. Patent No. 3,364,200, the stabilization is effected by employing either high vacuum, or washing-through of the oxycellulose by aliphatic alcohols having from two to four carbon atoms; further, it is recommended that the contact of the oxycellulose with water should be minimised thereby fighting the negative effects of hydrolysis which lead to a reduction of chemical stability.However, the use of high vacuum in the stabilization of acidic oxycellulose has proved to be technically feasible only with difficulty and in the case where non-volatile oxidation products are eliminated, hardly practical. It is admitted that the washing-through of the acidic oxycellulose by alcohols makes a contribution to the cellulose stabilizing process, due to the relative cheapness of alcohols.

An interesting but rather theoretical solution of the stability problem is the method suggested by Kaverznervova et al wherein a reaction with hydroxylamine under rise of oxime is used for blocking keto-groups; the thus treated oxycellulose specimen possesses an excellent chemical stability, and the harmful influence of keto-groups upon the oxycellulose stability has been proved thereby.

An elegant solution of the oxycellulose stability problem is contained in U.S.

Patent No. 3,666,750 (1972) wherein the use of alkali boron hydrides in an alkaline media at pH 9 to 12 has been suggested. The claimed process has been designed for stabilizing haemostatic pads made of oxidized cellulose. However, as excessively alkaline media are apt to impair the strength of the oxidized material, the process does appear to be suitable for the preparation of any other haemostatic material types such as, for example, gauze bandages, integrated materials (knitwork from staple fibres) and surgical suture threads.

It is true that some other technological steps of the oxycellulose production have been described in the abovementioned patent specifications but they do not form the subject matter thereof. Thus, for instance, in U.S. Patent No. 3,364,200 it has been recommended to dry the oxidized material, most preferably by an air stream at a room temperature. Oxycellulose designed for medical applications cannot be sterilized except under cold conditions as for example by ethylene oxide diluted with carbon dioxide, or by irradiating with isotopes such as Co60, or by formalin vapours. Immediately after the sterilization the oxycellulose is packed under hermetic conditions.

Advantages of the cellulose oxidized by means of nitric acid have been known for many years. However, the oxidized cellulose prepared by previously-proposed methods has a plurality of disadvantages such as instability at normal room temperatures, physical instability, an excesive number of capillary voids permeable by somatic fluids, and non-adherence to bleeding tissues so that it has to be held close to them for a time in order to obtain the desired haemostyptic effect. Apart from this, it is considerably inhomogeneous as far as its composition is concerned so that one portion thereof may be resorbed by the tissue within about seven days while an adjacent portion may resist the resorption for fourteen or more days; this may provoke tissue irritations.

A common disadvantage of the previously-proposed methods of cellulose treatment, which is intimately connected with the technology of resorbable materials in general, resides in a relative complexity of individual steps and, consequently, in a poor quality of the final product containing a considerable residue of non-reacted cellulose which is responsible for non-standard resorption by live tissues.

In previously proposed methods of preparing and treating cellulosic materials, there arise certain amounts of indefinable nitroxidizing derivatives which, depending on time, enable the formation of nitrogen oxides which act in the air tight package interior and tend successively to destroy the material. Such an uncontrolled process results in progressive modifications of both the physical and mechanical properties of the material, in particular brittleness of cellulose fibres gradually continuing up to the coherence degradation thereof. The resulting oxycellulose types simultaneously exhibit undesirable colour characteristics, or an uneven effect on the dye-stuff used.

According to the present invention there is provided a method of preparing oxidized cellulose or a salt thereof comprising oxidising cellulosic material, stabilising the oxidized cellulose and/or converting the oxidized cellulose to its calcium, sodium or ammonium salt, and exposing the resulting material to a radiation dose of up to 105 J.kg.-'5 wherein the cellulose is oxidized with nitric acid in the presence of phlegmatized alkali nitrite.

A preferable method of the invention comprises oxidizing cellulose of wood or cotton origin by the action of an oxidizing liquor comprising nitric acid and sodium nitrite, stabilizing the prepared oxycellulose and impregnating same, after a contingent neutralization and final treatment or finishing of the resulting materials wherein the oxidation reaction is catalyzed by phlegmatized sodium nitrite whereupon the oxidized cellulose is stabilized and/or converted to its calcium, sodium or ammonium salt, drained, dried, or, contingently, impregnated or otherwise finished, and that the cellulosic material preoxidized in such nitroxidative manner within a period of from 20 to 30 hours, is exposed to a radiation dose of up to 105 J.kg-", Suitable radiation sources for providing such a dose are electromagnetic ionising radiations such as that of Co60 which provides y radiation in the transition E1 (1.33 MeV) to E2 (1.17 MeV) or alternatively by using accelerated electrons having an energy of up to 8MeV. The choice being dependent upon thickness and weight of cellulosic material.

For the oxidation of cellulose a mixture of nitric acid having a concentration of from 60 to 70 per cent is preferably used in admixture with sodium nitrite phlegmatized by exposure to heat at a temperature of from 105 to 2700 C, preferably 110 to 1400C, the ratio of the nitric acid to the phlegmatized sodium nitrite being from 20:1 to 100:1 weight parts.

Phlegmatized as used herein means having an induced extraordinary resistance to the action of diluted (say 60 to 70 per cent) nitric acid and consequently having increased stability towards chemical decomposition for an extended period of time.

The stabilization is preferably effected by alternate absorption and subsequent centrifuging-off operations on the material using an aqueous-alcoholic solution of urea or its N,N-disubstituted alkyl or acyl derivatives having concentration of urea or its derivatives of from 5 to 10 per cent by weight and a concentration of aliphatic alcohol with from one to four carbon atoms, preferably isopropanol, of from 25 to 75 per cent by weight.

The preoxidized cellulose may be converted to a calcium, sodium or ammonium salt thereof by four or five repetitions of alternate absorption and subsequent centrifuging-off an aqueous-alcoholic or aqueous-acetonic solution of an equimolar mixture of chloride and acetate of calcium, sodium or ammonium, the concentration of said mixture being from 2 to 15 per cent by weight and the concentration of alcohol, e.g. isopropanol or acetone, being from 25 to 50 per cent by weight.

The preoxidized cellulose or salt thereof may be washed through by alternate absorption and subsequent centrifuging-off of an aqueous acetone solution having an acetone concentration of from 25 to 75 per cent by weight.

The preoxidized cellulose or salt thereof, once washed through, is preferably drained by repeated absorption of acetone of at least 90 percent by weight concentration.

To improve the usefulness of the oxidized cellulose, it is advisable to impregnate the same or salts thereof. Thus, for example, to suppress dusting, the oxidized cellulose or salt thereof is impregnated by absorption and subsequent centrifuging-off of an alcoholic, e.g. ethanol or ketonic, e.g. acetonic, solution of polyvinyl pyrrolidone and glycerine (polyvinyl pyrrolidone Fikentscher K-value 90 to 120:-- Fikentscher K-value is defined by the equation 71e 75k2 log log Z=( +k)c 770 1+1 5k wherein 77e is viscosity of solution, woo is viscosity of solvent, Z is relative viscosity, k is constant =K.10-3 for polymers except NC which is K.10-4, c is concentration of volume per cent.

NB. K-value is to be calculated on the basis of viscosity measurements of low concentrated solutions i.e. less than one per cent), having a polyvinyl pyrrolidone concentration of from I to 5 per cent by weight and glycerine concentration of from 1 to 5 per cent by weight, the alcohol or ketone concentration in the solution being at least 90 per cent by weight.

By means of polyvinyl pyrrolidone it is also possible to affix to the oxidized cellulose other preparations such as sedatives, antibiotics, or the like. Likewise the oxidized cellulose or salt thereof can be impregnated in such a way that it is wetted by a 2 to 3 percent solution of carboxymethyl cellulose in a 15 to 35 percent aqueous glycerine solution with 0.002 to 0.1 per cent chloride of 3,7 bismethylamino - phenazothionium, dried and finally exposed to a radiation dose of up to 7.5x104 J.kg-'.

Another substantial refinement of the oxidized cellulose or salt thereof is obtained by treating it with dialysed and/or lyophilized proteolytic enzymes with exposure to a radiation dose of 2.5xl04 J.kg-' Considerable advantages are brought about by the process wherein the oxidized cellulose or salts thereof is treated with a proteinaceous substance having a haemostyptic effect, of the human blood thrombin type, whereupon it is exposed to a radiation dose of 2.5x104 J.kg-'.

For some medical applications, it is preferable that the cellulose or salts thereof, before exposure to the oxidation liquor or to the radiation dose, is comminuted to powder form.

Among characteristic features of the present invention are a materialpreserving technology ensuring a high chemical stability of the final product, and an inexpensive and simple manufacturing process preventing exhaust of nitrous gases.

The material-preserving technology preventing the undesirable degradation of cellulosic material is given by the oxidation and stabilisation conditions. The use of phlegmatized alkali nitrite enables an oxidizing liquor with a high nitrous acid content to be prepared. Such a nitrous acid content is in turn responsible for a relatively high oxidation speed and consequently for a reduction in the reaction time. Examples of the relationship between the nitrous acid concentration in the oxidizing liquor, the oxidation period and the oxidation degree are hereunder tabulated: HNO2 Oxidation Oxidation concentration period degree 1.8--2.00/, 24 hours 8.4 S COOH 28 hours 9.2% COOH 32 hours 10.0% COOH 2.2-2.4% 24 hours 12.3% COOH 28 hours 13.5 COOH 32 hours 14.2 /" COOH 2.6-2.8% 24 hours 15.70 COOH 28 hours 16.9 COOH 32 hours 17.4% COOH To achieve an even oxidation degree throughout the whole cellulose mass, the oxidation liquor is preferably agitated by a recycling pump.To prevent losses of nitrous gases, the outlet of the recycling pump is located below the level of the oxidizing bath and the reactor is water-sealed. Spent oxidation liquor, after having been buffered to the desired pH-value, is returned into the manufacturing process.

By using urea for quickly eliminating the acidity immediately after the oxidation of the cellulosic material, hydrolysis of the cellulose chain is prevented.

Urea having a weakly alkaline character is capable of stabilizing the cellulosic material before the continuing action of nitrogen oxide in accordance with the following equation: 2 HNo2+Co(NH2)2=2N2+Co2+3H2o The remaining acidity and the physiologically ineffective oxidation products are reliably removable by washing-through with diluted acetone. The excellent stabilizing effect of acetone is well-known from the technology of cellulose nitrate production.

Oxycellulose in the form of gauze fabric, and particularly a calcium salt thereof, has a low abrasion resistance which may even decrease due to the natural ageing, so that the oxidized material tends to dust when being applied. Such undesirable dusting can be substantially limited by applying a physiologically harmless impregnation. This condition is complied with by polyvinyl pyrrolidone (PVP).

The simplicity and inexpensiveness of the method for preparing oxycellulose and salts thereof result from the possible use of conventional manufacturing plant and a relatively inexpensive raw material basis. Since in the process practically no gas is given out it is unnecessary to erect absorption towers. The application of the proposed washing through step of absorption and subsequent centrifuging-off of a washing liquor leads, if considering an excellent washing effect, to the minimization of the liquor consumption and thus enables an economical regeneration of organic solvent by distillation. Likewise the regeneration of neutralizing solutions is effected, in the process of preparing oxycellulose salts, within a recycle.

Concentrated acetone used for draining the oxycellulose before drying is returned to the manufacture and after the concentration thereof has been adjusted (dilution), it is reused for the washing-through step.

In the cellulose preoxidized in such a nitroxidative manner, preferably within a period of from 20 to 30 hours, carboxy groups are formed on the C6 atom and a partial degradation of the pyran bridge of the Cl and C5 atoms occurs, this degradation is accompanied by successive oxygen bonding on the Cl in the form of a keto group, in dependence on the preoxidation period. Progressively an oxidative degradation occurs at the joint between the pyran cycles in the Cl and C4 positions together with the formation of a keto group on the C4 while a fraction of equivalent portion of one double bond on the basic carbon skeleton on the C3 arises.

The effect of the ionizing radiation (e.g. y-rays or high energy electrons) on the structure of preoxidized cellulose is displayed by a radical and energetic excitation of atomic groups in the molecular skeleton and by an even destruction of both constitutional and interchain bonds. After irradiation by doses of up to lx 105 J.kg-' a radical energetic excitation of atomic groups, substantially predominates which depends upon the oxidation degree of the atomic groups, whereas the carbon bond destruction is negligible and statistically evenly distributed. On the other hand, if applying radiation doses of 2.5x 106 J.kg-', it is the rate of degradation of the intercarbon bonds that prevails whereby the progressive degradation of the molecular structure will continue.

With cellulosic materials preoxidized within a period of from 24 to 38 hours and irradiated by doses of up to lx 105 J.kg-', the energetic excitation of the atomic groups at Cl and C6 is balanced. The C5 and partly the C2 groups in materials preoxidized for from 24 to 28 hours remain uneffected by radiation doses of up to lox 10' J.kg-', due to a relatively low degree of pyran cycle disiunction during the preoxidation.

Progressively with the increase of the preoxidation period to more than 30 hours, the excitation of the C5 group, due to the irradiation, rises to the maximum of 38 hours preoxidation. The excitation of the C4 group, due to the irradiation of up to lox 10' J.kg-' decreases during the preoxidation within from 24 to 38 hours to the benefit of carbon groups carrying double bonds on the skeleton.

With the salts of the oxidized cellulose prepared in the present manner, proteinaceous substances with a haemostyptic effect are preferably used e.g.

human blood thrombin SEVAC having a concentration of from 50 to 150 NIH.

The oxycellulose can be provided with a superficial finish by scattering sterile dialyzed and lyophilized proteolytic enzymes trypsin and chymotrypsin onto the half-wet loosely spread out material.

The method of preparing resorbable materials by the method of the invention is particularly advantageous in that it does not give rise to undesirable nitrogen oxides and prevents secondary effects thereof on the substrate. The final product, even if stored for a long time, does not exhibit brittleness and dusting. It permanently remains coherent elastic and adaptable to shape. No modifications in colour characteristics occur. Long-term observance of the above-mentioned properties is very important from the applicability viewpoint, and allows various medical applications.

By due control of the preoxidation process and the radiation in the present method a product with the desired properties is obtainable. The term of resorbability of the product in an organism can be controlled in dependence on the mode of refining it.

The conditions given for saturation of reactive atomic groups or blocking thereof are influenced by the process of oxycellulose degradation. Due to such an influence, the affinity of the oxidized cellulose to basic, especially thiazine dyestuffs, rises. The use of a retarding effect of e.g. the chloride of 3,7methylaminophenazothionium (methylene blue) on the ageing of the final oxycellulose product and salts thereof has been achieved. This could be explained by probable blocking of OH groups and carboxyl groups of glucoside residue by electropositive dimethylamino groups of the dyestuff.

Embodiments of the present invention will now be described by way of illustration in the following Examples, in which the ratio of oxidation liquor is always given in per cent by weight, or weight parts.

EXAMPLE I A gauze fabric having appropriate mechanical properties and maximum haemostyptic effect was prepared, the fabric being quickly and completely resorbable in the organism. For oxidation a hydrophilic cotton gauze was employed, containing more than 99 /,, by weight of alpha-cellulose and weighing about 30 grammes per square metre. The fabric was loose folded onto two support frames made of stainless steel. Each frame took up a sheet of 100 metres length and 80 centimetres width.

In a hot air drying plant thermal exposure of sodium nitrite was effected at 110"C for 4 to 6 hours. The exposed nitrite, still in a warm state, was comminuted to a coarse powder and cooled under hermetic conditions. Then it was dosed to 64 to 66 per cent (by weight) nitric acid so that the resulting oxidizing liquor contained 2.8 to 3.0 /" by weight of nitrous acid. The reaction of the phlegmatized nitrite with nitric acid took place slowly without any gas generation.

The frames with the gauze fabric thereon were immersed in the oxidizing liquor and a recirculation pump was switched on. An oxidizing reactor of a prismatic shape was heated by means of a hot-water circuit to a temperature of from 20 to 230C. The liquor ratio was 1:40 up to 1:80 weight parts. The reaction was terminated after 24 hours.

The oxidation liquor was then extracted into a reserve tank and the frames with the oxidized material thereon were subjected to intense washing for several minutes. Thereupon they were removed from the oxidizing vessel and placed for a short time in a trough containing a solution of from 5 to 7% by weight of urea in a water/acetone or water/ethanol or water/isopropanol mixture (always in 1:I ratio).

The oxidized material was then taken off the support frames and centrifuged for 2 to 3 minutes in a centrifugal separator.

The process continued by eliminating the remaining acidity traces from the material by absorption and subsequent centrifuging-off of an aqueous acetone solution having about 28 per cent by weight acetone concentration. The process was carried out four to six times, until the pH-value (4.5-5) remained unaffected.

The displacement of water and drying were then effected. For this purpose, acetone of at least 90 per cent by weight concentration was twice absorbed into the material and separated therefrom by centrifuging. The drained oxycellulose was wound onto a perforated drum and dried by sucking-through air at 38"C. After the material had been cut to the desired dimensions, it was hermetically packed and irradiated by a dose of 105 J.kg-'.

Analysis of the thus-prepared oxidized gauze fabric gave the following results: carboxyl group contents 14 to 18% solubility in n/10 NaOH 100% ash contents 0.22% bound nitrogen contents 0.43% EXAMPLE 2 For the oxidation there were used either refined cotton linters designed for preparing cellulose derivatives, or glossy rayon staple fibres of about 2 denier titre.

The mode of preparing the oxidation liquor was the same as described in Example 1(2.8% by weight nitrous acid content).

The oxidation was effected in an oval oxidizing tank provided with a heating jacket and two peg agitators for periodically stirring the contents. A liquor ratio of 1:50 to 1:70 (weight parts) was employed. The reaction was terminated within 20 to 24 hours at an oxidizing liquor temperature of 22 to 240C. The tank contents were then discharged into a centrifuge and after separating the acid, the oxidized material was briefly washed through by water and centrifuged again. After stabilization by a urea solution, and washing-off of the remaining acidity (as referred to in Example 1) the material was neutralized.

The neutralizing solution contained equimolar calcium chloride and acetate in amount of 6% by weight dissolved in an aqueous isopropanol solution containing 33% by volume of isopropanol. After the neutralizing solution had been absorbed into the oxidized material, the latter was centrifuged at room temperature and an acidic filtrate was returned to a reserve tank. In order to eliminate the acidity arising during the neutralization, a diluted acetone solution (28% by weight) was absorbed into the material and then separated therefrom by centrifuging. The following step was again absorption of the neutralizing solution, centrifuging-off and eliminating the acidity. The whole cycle was repeated until the pH of the neutralizing solution filtrate had attained a value of 6.0 to 6.5; this occurred, as a rule, after the third or fourth cycle.The neutralizing solution filtrate was buffered by an addition of 1020% by weight calcium hydroxide pulp to pH 6.06.5 and recycled.

The calcium salt of oxycellulose is insoluble in water. After repeatedly washing-through by absorption and subsequent centrifuging-off of water, the material was placed in a beater in which, depending on the desired fineness degree, it was converted into a pulp within a period of two to six hours. After centrifuging and displacing water by twice repeated absorption of acetone having a concentration of at least 90% by weight, the wet mass was crushed, laid on screens and dried in a hot-air drying plant at 380C.

The thus treated product was then irradiated by a dose of 5x104 J.kg-' whereupon a mixture thereof (100 weight parts) with 6,000 to 8,000 NIH of human blood thrombin SEVAC and 1.0 to 6.0 weight parts of a mixture of dialyzed and lyophilized proteolytic enzymes trypsin and chymotrypsin was prepared. Finally, the mixture was homogenised for a short time, hermetically packed and irradiated by a dose of 2.5x104 J.kg-'.

EXAMPLE 3 A freely water-soluble sodium salt of oxycellulose in the form of gauze fabric was prepared. A stabilized preoxidized cellulose was prepared in the process as described in Example 1. In this case the oxidising liquor contained 2.7% by weight of nitrous acid and the reaction time was 28 hours at an oxidising liquor temperature of from 19 to 220C.

The stabilized and acid-free oxidised gauze fabric was placed for 30 minutes in a neutralizing liquor at room temperature and periodically agitated therein. The liquor contained 5% by weight of an equimolar sodium acetate and chloride mixture in a 28% by weight aqueous isopropanol solution. The liquor ratio was 1:20 weight parts. The initial pH-value of 6.9 decreased after the reaction to 5.3. The neutralized oxycellulose was centrifuged and twice washed through by absorption and subsequent centrifuging-off of diluted acetone of 50% by weight concentration.

Finally, the water was displaced by concentrated acetone, and the material was dried, packed and irradiated by a dose of 5x104 J.kg-'.

An analysis of the thus prepared sodium salt of oxycellulose in the form of gauze fabric showed the following values: carboxyl group contents 14 to 17% solubility in n/10 NaOH 100% ash contents 14.5 to 15.6% sodium contents 6.5 to 7.0% bound nitrogen contents 0.51% EXAMPLE 4 Preoxidized cellulose or a salt thereof in the form of woven or knitted fabric prepared according to Examples 1, 2 and 3 was refined in order to prevent the final product, even after a long storing period, from becoming brittle and dusty. The essential water portion was displaced from the oxidised material by absorption and subsequent centrifuging-off of concentrated acetone. Then an impregnating solution containing a mixture of 2% by weight of polyvinyl pyrrolidine (e.g.

Ruviscol K 90), 5% by weight of glycerine and 0.05% by weight of methylene blue in a concentrated acetone solution (at least 90%) was absorbed into the material and centrifuged off. After the fibrous material had been dried at 380C, it was impregnated, the impregnation contents being dependent on the degree of centrifuging. The dry material was cut to a desired size, hermetically packed and irradiated by a dose of 105 J.kg-'. During the storage the final product is stable, coherent, elastic and able to be shaped into pads of any size.

WHAT WE CLAIM IS: 1. A method of preparing oxidized cellulose or a salt thereof, comprising oxidizing cellulose material, stabilising the oxidized cellulose and/or converting the oxidized cellulose to its calcium, sodium or ammonium salt, and exposing the resulting material to a radiation dose of up to 105 J.kg-', wherein the cellulose is oxidized with nitric acid in the presence of phlegmatized (as hereinbefore defined) alkali nitrite.

2. A method as claimed in claim 1, wherein the starting cellulosic material is of wood or cotton origin.

3. A method as claimed in claim 1 or 2, wherein the nitric acid together with the phlegmatized alkali nitrate form an oxidizing liquor in which the cellulose material may be oxidized.

4. A method as claimed in any one of the preceding claims, wherein the nitroxidation is performed over a period of from 20 to 30 hours.

5. A method as claimed in any one of the preceding claims, wherein the nitric acid has a concentration of from 60 to 70 per cent by weight.

6. A method as claimed in any one of the preceding claims, wherein the alkali nitrite is sodium nitrite phlegmatized by heating at a temperature of from 105 to 270"C.

7. A method as claimed in claim 6, wherein the sodium nitrite has been phlegmatized by heating to a temperature of from 110 to l400C.

8. A method as claimed in claim 6 or 7, wherein the nitric acid is in admixture with the sodium nitrite in a ratio of from 20:1 to 100:1 by weight.

9. A method as claimed in any one of the preceding claims, wherein the stabilisation is effected by alternate absorption into and subsequent centrifugingoff from the material of an aqueous-alcoholic solution of urea or an N,Ndisubstituted alkyl or acyl derivative thereof having a concentration of from 5 to 10 per cent by weight and a concentration of aliphatic alcohol with from one to four carbon atoms of from 25 to 75 per cent by weight.

10. A method as claimed in any one of the preceding claims wherein the oxidized cellulose is converted to the calcium, sodium or ammonium salt thereof by quintupled alternate absorption into and subsequent centrifuging-off from the material of an aqueous-alcoholic or aqueous-acetonic solution of an equimolar mixture of the chloride and acetate of calcium, sodium or ammonium, the concentration of said mixture being 2 to 15 per cent by weight and the concentration of alcohol or acetone being from 25 to 50 per cent by weight.

11. A method as claimed in claim 10, wherein the alcohol is isopropanol.

12. A method as claimed in any one of the preceding claims, wherein the oxidized cellulose or salt thereof is washed through by alternate absorption and subsequent centrifuging-off of an aqueous acetone solution having an acetone concentration of from 25 to 75 per cent by weight.

13. A method as claimed in any one of the preceding claims, wherein the oxidized cellulose or salt thereof is drained, dried, coated or impregnated prior to the exposure of radiation.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (24)

**WARNING** start of CLMS field may overlap end of DESC **. carboxyl group contents 14 to 17% solubility in n/10 NaOH 100% ash contents 14.5 to 15.6% sodium contents 6.5 to 7.0% bound nitrogen contents 0.51% EXAMPLE 4 Preoxidized cellulose or a salt thereof in the form of woven or knitted fabric prepared according to Examples 1, 2 and 3 was refined in order to prevent the final product, even after a long storing period, from becoming brittle and dusty. The essential water portion was displaced from the oxidised material by absorption and subsequent centrifuging-off of concentrated acetone. Then an impregnating solution containing a mixture of 2% by weight of polyvinyl pyrrolidine (e.g. Ruviscol K 90), 5% by weight of glycerine and 0.05% by weight of methylene blue in a concentrated acetone solution (at least 90%) was absorbed into the material and centrifuged off. After the fibrous material had been dried at 380C, it was impregnated, the impregnation contents being dependent on the degree of centrifuging. The dry material was cut to a desired size, hermetically packed and irradiated by a dose of 105 J.kg-'. During the storage the final product is stable, coherent, elastic and able to be shaped into pads of any size. WHAT WE CLAIM IS:

1. A method of preparing oxidized cellulose or a salt thereof, comprising oxidizing cellulose material, stabilising the oxidized cellulose and/or converting the oxidized cellulose to its calcium, sodium or ammonium salt, and exposing the resulting material to a radiation dose of up to 105 J.kg-', wherein the cellulose is oxidized with nitric acid in the presence of phlegmatized (as hereinbefore defined) alkali nitrite.

2. A method as claimed in claim 1, wherein the starting cellulosic material is of wood or cotton origin.

3. A method as claimed in claim 1 or 2, wherein the nitric acid together with the phlegmatized alkali nitrate form an oxidizing liquor in which the cellulose material may be oxidized.

4. A method as claimed in any one of the preceding claims, wherein the nitroxidation is performed over a period of from 20 to 30 hours.

5. A method as claimed in any one of the preceding claims, wherein the nitric acid has a concentration of from 60 to 70 per cent by weight.

6. A method as claimed in any one of the preceding claims, wherein the alkali nitrite is sodium nitrite phlegmatized by heating at a temperature of from 105 to 270"C.

7. A method as claimed in claim 6, wherein the sodium nitrite has been phlegmatized by heating to a temperature of from 110 to l400C.

8. A method as claimed in claim 6 or 7, wherein the nitric acid is in admixture with the sodium nitrite in a ratio of from 20:1 to 100:1 by weight.

9. A method as claimed in any one of the preceding claims, wherein the stabilisation is effected by alternate absorption into and subsequent centrifugingoff from the material of an aqueous-alcoholic solution of urea or an N,Ndisubstituted alkyl or acyl derivative thereof having a concentration of from 5 to 10 per cent by weight and a concentration of aliphatic alcohol with from one to four carbon atoms of from 25 to 75 per cent by weight.

10. A method as claimed in any one of the preceding claims wherein the oxidized cellulose is converted to the calcium, sodium or ammonium salt thereof by quintupled alternate absorption into and subsequent centrifuging-off from the material of an aqueous-alcoholic or aqueous-acetonic solution of an equimolar mixture of the chloride and acetate of calcium, sodium or ammonium, the concentration of said mixture being 2 to 15 per cent by weight and the concentration of alcohol or acetone being from 25 to 50 per cent by weight.

11. A method as claimed in claim 10, wherein the alcohol is isopropanol.

12. A method as claimed in any one of the preceding claims, wherein the oxidized cellulose or salt thereof is washed through by alternate absorption and subsequent centrifuging-off of an aqueous acetone solution having an acetone concentration of from 25 to 75 per cent by weight.

13. A method as claimed in any one of the preceding claims, wherein the oxidized cellulose or salt thereof is drained, dried, coated or impregnated prior to the exposure of radiation.

14. A method as claimed in claim 13, wherein the oxidized cellulose or salt

thereof is washed and then drained by repeated absorption of acetone of at least 90 per cent by weight concentration.

15. A method as claimed in claim 13, wherein the oxidized cellulose or salt thereof is impregnated by absorption and subsequent centrifuging-off of an alcoholic or ketonic solution of polyvinyl pyrrolidone and glycerine having a polyvinyl pyrrolidone concentration of from I to 5 per cent by weight and a glycerine concentration of from 1 to 5 per cent by weight, the alcohol or ketone concentration in the solution being at least 90 per cent by weight.

16. A method as claimed in claim 15, wherein the alcohol is ethanol.

17. A method as claimed in claim 15, wherein the ketone is acetone.

18. A method as claimed in claim 15, wherein the polyvinyl pyrrolidone has a Fikentschen K-value (as herein before defined) of from 90 to 120.

19. A method as claimed in claim 13, wherein the oxidized cellulose or salt thereof in wetted by a 2 to 3 per cent solution of carboxymethyl cellulose in a 15 to 35 per cent aqueous glycerine solution with 0.002 to 0.1 per cent chloride of 3,7 bis - methylamino - phenazothionium, dried and thereafter exposed to a radiation dose of up to 7.5xl04 J.kg-'.

20. A method as claimed in claim 13, wherein the oxidized cellulose or salt thereof is treated with dialysed and/or lyophilized proteolytic enzymes and exposed to a radiation dose of 2.5x104 J.kg-'.

21. A method as claimed in claim 13, wherein the oxidized cellulose or salt thereof is coated or impregnated with a proteinaceous substance having a haemostyptic effect, of the human blood thrombin type whereafter it is exposed to a radiation dose of 2.5x104 J.kg-'.

22. A method as claimed in any one of the preceding claims, wherein the cellulose or salt thereof is comminuted to powder form before being exposed to the nitric acid or to the radiation dose.

23. A method of preparing oxidised cellulose or a salt thereof, substantially as hereinbefore described with reference to any one of the Examples.

24. Oxidised cellulose whenever prepared by the method as claimed in any one of the preceding claims.