Oxidized cellulose-based material, method for obtaining same and use thereof as compress

Abstract

The present invention relates to a method of obtaining a solid material based on a polymer having its cellobiose units exhibiting the following characteristics: at least some of the cellobiose units have at least one carboxylic acid function attached to the C.sub.6 carbon, the other C.sub.6 carbons having a primary alcohol function attached thereto; and at least some of the cellobiose units have at least one of the two rings open between the C.sub.2 and C.sub.3 carbons, the other C.sub.2 and C.sub.3 carbons forming a ring and having an alcohol function attached thereto. Such a material, advantageously a textile, may be used as a compress.

Claims

1. A method of obtaining a solid material based on a polymer comprising cellobiose units, wherein: at least some of the cellobiose units have at least one carboxylic acid function attached to the C.sub.6 carbon, the other C.sub.6 carbons having a primary alcohol function attached thereto; and at least some of the cellobiose units have at least one of the two rings open between the C.sub.2 and C.sub.3 carbons, the other C.sub.2 and C.sub.3 carbons forming a ring and having an alcohol function attached thereto, said method comprising the following steps: a first step of placing in contact a solid material based on polymer containing cellobiose units and an oxidizing mixture comprising a hypohalite, a halite, and an oxoammonium salt or a precursor of said salt, wherein the first step is carried out at neutral or acidic pH, and wherein the solid material comprises an assembly of yarns or fibers that form a unitary entity that is insoluble in water at said pH; and then a second step of placing in contact the material comprising the assembly of yarns or fibers that form a unitary entity thus processed and a solution of periodic acid or of a salt thereof, wherein the solid material so obtained has a degree of oxidation which corresponds to the conversion of alcohol and/or aldehyde functions in the cellobiose units into carboxylic acid functions, of greater than 10% calculated by the mass of said carboxylic acid functions contained in 100 g of the solid material.

2. The method according to claim 1, wherein said method comprises a third step of placing in contact the material having been submitted to the first two steps and a halite solution.

3. The method according to claim 2, wherein the halite solution comprises from 0.0025 to 0.012 mole of halite per gram of polymer.

4. The method according to claim 2, wherein the third step is carried out at a pH in the range from 5 to 7.

5. The method according to claim 2, wherein the third step is carried out at a temperature greater than 15° C.

6. The method according to claim 2, wherein the third step is carried out for a duration in the range from 0.25 to 2 hours.

7. The method according to claim 1, wherein the oxidizing mixture comprises from 0.0003 to 0.0006 mole of oxoammonium salt or a precursor of said salt, per gram of polymer.

8. The method according to claim 1, wherein the oxidizing mixture comprises from 0.0006 to 0.0049 mole of hypohalite per gram of polymer.

9. The method according to claim 1, wherein the oxidizing mixture comprises from 0.006 to 0.025 mole of halite per gram of polymer.

10. The method according to claim 1, wherein the first step is carried out at a pH in the range from 5 to 7.

11. The method according to claim 1, wherein the first step is carried out at a temperature greater than 40° C.

12. The method according to claim 1, wherein the first step is carried out for a duration in the range from 1 to 6 hours.

13. The method according to claim 1, wherein the solution of periodic acid or of a salt thereof comprises from 0.003 to 0.012 mole of periodic acid, or of a salt thereof, per gram of polymer.

14. The method according to claim 1, wherein the second step is carried out at a pH in the range from 2 to 5.

15. The method according to claim 1, wherein the second step is carried out at a temperature in the range from 5 to 60° C.

16. The method according to claim 1, wherein the second step is carried out for a duration in the range from 1 to 6 hours.

17. The method according to claim 1, wherein the first step is stopped by addition of an excess quantity of primary alcohol.

18. The method according to claim 1, said method optionally comprising a third step of placing in contact the material having been submitted to the first two steps and a halite solution, wherein between the first two steps and/or after the second step and/or after the third step, the material is incubated in a protonation medium.

19. The method according to claim 18, wherein after the material is incubated in the protonation medium, the material is submitted to washing and optionally drying.

20. The method according to claim 1, wherein the oxidizing mixture comprises: from 0.0003 to 0.0006 mole of TEMPO per gram of polymer; from 0.0006 to 0.0049 mole of sodium hypochlorite per gram of polymer; and from 0.006 to 0.025 mole of sodium chlorite per gram of polymer.

21. The method according to claim 1, wherein the first step generates no aldehyde functions at the C.sub.6 carbon of the cellobiose units.

Description

EXAMPLES OF EMBODIMENT

(1) The invention and the resulting advantages will better appear from the non-limiting embodiments discussed hereafter.

(2) These examples are based on fabrics made from knitted yarns of regenerated cellulose (or viscose), in crochet or jersey stitch.

(3) I/Method of Obtaining the Solid Cellulosic Material 1) First step:

(4) This step enables to partially oxidize the cellulose via the conversion of primary alcohol functions attached to the C.sub.6 carbon of the cellobiose units into carboxylic acid functions.

(5) The general conditions of this step are described in Table 1 hereafter:

(6) TABLE-US-00001 TEMPO (mole per gram of from 0.0003 to 0.0006, for example cellulose) 0.0006 NaClO (mole per gram of from 0.0006 to 0.0049, for example cellulose) 0.0012 NaClO.sub.2 (mole per gram of from 0.006 to 0.025, for example 0.012 cellulose) pH of the reaction medium from 5 to 7, for example 5.8 Temperature (° C.) 60 Duration of the reaction (h) from 1 to 6, typically from 4 to 5

(7) Under a ventilator, 200 ml of a sodium acetate buffer solution (0.5 M, pH=5.8) are placed in a 1-1 Erlenmeyer, after which 0.12 mole of NaClO.sub.2 is added. 10 g of knitted regenerated cellulose are then placed in the NaClO.sub.2 solution. 0.006 mole of TEMPO and an aqueous solution of NaClO with 2% of active chlorine (0.012 mol) are then added to the reaction mixture. The total volume of the reaction mixture is 500 ml. The Erlenmeyer is closed and placed in a thermostatic water bath maintained at a 60° C. temperature for a duration from 1 to 6 h, and typically from 4 to 5 h. The oxidation is stopped by addition of an excess of ethanol.

(8) The partially oxidized cellulose fabric is wrung and then incubated for 12 h in an aqueous solution of N HCl on an orbital shaker. The aqueous solution of N HCl is renewed and the incubation is carried on for 2 h.

(9) The partially oxidized cellulose fabric is wrung and then washed with 50% ethanol for 1h on an orbital shaker. This operation is repeated twice. The fabric is then wrung, and then washed with 95% ethanol for 1 h on an orbital shaker, and then finally wrung and air-dried under a ventilator for at least 12 h. 2) Second step:

(10) This step enables to open the ring between the C.sub.2 and C.sub.3 carbons of the cellobiose units. Simultaneously, the alcohol functions attached to these carbons are oxidized into aldehyde functions.

(11) The general conditions of this sten are disclosed in Table 2 hereafter:

(12) TABLE-US-00002 NaIO.sub.4 (mole per gram of cellulose) from 0.003 to 0.012, for example 0.006 pH of the reaction medium from 2 to 5, for example 3 Temperature (° C.) from 5 to 60, for example 35 Duration of the reaction (h) from 1 to 6, for example 3

(13) 10 g of the material obtained at the end of the first partial oxidation step are mixed with 0.06 mole of periodate ion in a 1-1 Erlenmeyer. The total volume of the reaction mixture is 500 ml. The pH is adjusted to 3 and the reaction is carried out under stirring for 3 h, at a 35° C. temperature and away from light. The cellulosic material is then rinsed twice with distilled water before being submitted to an acidification and to a washing with ethanol, as described hereabove. 3) Third step (optional):

(14) This step enables to oxidize the aldehyde functions attached to the C.sub.2 and C.sub.3 carbons of the cellobiose units into carboxylic acid functions.

(15) The general conditions of this sten are disclosed in Table 3 hereafter:

(16) TABLE-US-00003 NaClO2 (mole per gram of from 0.0025 to 0.012, for example 0.006 cellulose) pH of the reaction medium from 5 to 7, for example 5.8 Temperature (° C.) greater than 15° C., for example, 35° C. Duration of the reaction (h) from 0.25 to 2, for example 1

(17) 10 g of the material obtained at the end of the first two steps are mixed with 0.06 mole of sodium chlorite prepared in an acetic buffer at pH 5.8. The reaction is carried out for 30 minutes, at ambient temperature. The total volume of the reaction mixture is approximately 150 ml. The cellulosic material is then rinsed twice with distilled water before being submitted to an acidification and to a washing with ethanol, as described hereabove. The material is then dried. 4) Monitoring of the forming of aldehyde functions:

(18) The presence of aldehyde functions has been monitored by means of reactant Purpald® which reveals their presence by the appearing of an intense purple color.

(19) The intensity of this coloring has been graded for different products: from 0 for a solution having no purple coloring to +++ for a very intense purple solution.

(20) The results are disclosed in Table 4 hereafter:

(21) TABLE-US-00004 Cellulose Cellulose Non-processed textile textile cellulose after the after the Tested product textile first step second step Surgicel ® Intensity of the 0 0 + + + + + purple coloring

(22) These experiments show that the first step generates no aldehyde function at the C.sub.6 level, while the second step causes at the same time the opening of the ring between the C.sub.2 and C.sub.3 carbons and the generation of aldehyde functions at the level of these carbons. This test is also positive on a Surgicel® compress obtained by a NO.sub.2 processing.

(23) II/Evaluation of the Physical Properties of the Material 1) Degree of oxidation of the obtained fabric:

(24) The degree of oxidation of the partially oxidized cellulose fabric represents the mass of carboxylic acid groups contained in 100 g of said fabric. This value is measured by titrimetry, according to the calcium exchange method described by Sobue and Okubo, and recommended by the United States Pharmacopeia (USP, 1990).

(25) The degree of oxidation of different fabrics (test 1: crochet; test 2: jersey), obtained by means of the method in two steps (TEMPO/NaClO/NaClO.sub.2 followed by NaIO.sub.4), has been measured.

(26) The experimental conditions and the measured degrees of oxidation are disclosed in Table 5 hereafter:

(27) TABLE-US-00005 Test 1 Test 2 Step Nature of the cellulose fabric crochet Jersey 1 TEMPO (mol/g of cellulose) 0.0006 0.0006 NaClO (mol/g of cellulose) 0.0012 0.0012 NaClO.sub.2 (mol/g of cellulose) 0.012 0.012 Temperature (° C.) 60 60 Duration of the reaction (h) 6 6 2 NaIO.sub.4 (mol/g of cellulose) 0.006 0.006 Temperature (° C.) 35 35 Duration of the reaction (h) 3 3 Degree of product oxidation (%) 13.44 13.55

(28) As a conclusion, the oxidation rate is sufficient for the material obtained by means of the method according to the invention to have good haemostatic properties. 2) Stability of the obtained fabric:

(29) The obtained partially oxidized cellulose fabric keeps an excellent mechanical resistance after 1 month, in a stove at 60° C.

(30) This sample keeps a fine aspect, with no degradation. This same sample has been sterilized by irradiation with β rays, and has then been submitted to an aging process which has caused no degradation of the fabric.

(31) A stability equivalent to that of the Surgicel® product has also been observed after 3 month at 25° C. and in controlled humidity, or after a 60° C. thermal stress. 3) Apparent degree of polymerization of the obtained fabric:

(32) The apparent degree of polymerization has been measured by the viscosity measurement according to standard NF G06-037 (December 1981).

(33) The obtained results are disclosed in Table 6 hereafter:

(34) TABLE-US-00006 Product Degree of polymerization Non-processed cellulose 270 Surgicel ® (reference product) 20 Crochet (Test 1) 20 Jersey (Test 2) 20

(35) As a conclusion, the method according to the present invention results in a material (tests 1 and 2) with an apparent polymerization degree, measured by the viscosity, of the same order as the reference product (Surgicel®).

(36) III/Evaluation of the Preclinical Properties of the Material 1) Absorption:

(37) The preclinical studies have been carried out by means of 3 types of implants according to standard ISO10993-6 (2007): Surgicel®, taken as a reference; implant Test1 corresponds to a jersey-type material, processed according to the first oxidation reaction (NaClO, TEMPO, and NaClO.sub.2) for 6 hours, and then according to the second periodate oxidation reaction for 6 hours; implant Test2 has been submitted to a processing equivalent to that of Test1, except for the duration of the second periodate oxidation reaction, of 3 hours only.

(38) These studies have been carried out on 6 female rats of the Sprague-Dawley strain. The incision areas have been shaved, the rats have been anaesthetized. 2 incisions on each side of the spine have been made (one so-called cranial incision and one so-called caudal incision). 4 implants of 1×1 cm have been placed per animal. The cutaneous incisions have been closed with clips.

(39) After 14 days, the rats have been sacrificed by inhalation of CO.sub.2. The products have been taken off and the implantation sites have been removed and macroscopically analyzed.

(40) The presence of a necrosis, of an exudate, of a neovascularization, and of an encapsulation have been evaluated at the implantation site, by means of a scoring chart. The rating scale is the following: absent (0); light reaction (1); moderate reaction (2); strong reaction (3); severe reaction (4).

(41) For the absorption, the residual persistence of the product is evaluated. The scale is the following: grade (0) is given in case of a total degradation; grade (1) is given if there remain small fragments of the product; grade (2) is given in case of a moderate persistence; grade (3) is given when the product is intact.

(42) The results are disclosed in Table 7 hereafter:

(43) TABLE-US-00007 Average of the scores (n = 3 rats, 4 implantation sites for each product*) Test1 Test2 Reference Condition (periodate = 6 h) (periodate = 3 h) (Surgicel ®) necrosis 0 0 0 exudate 0 0 0.25 neovascularization 0.5 0.5 0.5 encapsulation 0 0 0 absorption 0.25 1 0.67 *only three implantation sites have been evaluated for the reference product (Surgicel ®).

(44) At J14, a light to moderate reaction of the test products and of the control compress can be observed (exudate and neovascularization). The test products are mainly absorbed; for product Test1, 3 sites are totally absorbed out of 4 and 1 site has small fragments; for product Test2, 3 sites are not absorbed; finally, for the control product, 2 sites out of three are absorbed and 1 site exhibits a moderate persistence.

(45) Thus, the material obtained by the method according to the invention has a absorption speed comparable to reference commercial product Surgicel®, and even better, if it is considered that the fabric used in this study has a grammage greater than that of Surgicel®.

(46) Further, these studies show that the longer duration of the periodate oxidation reaction, the faster the absorption. Thus, the control of the duration of the second step of the method according to the invention enables to modulate the absorption speed of the cellulosic material, according to the applications for which it is intended. 2) Haemostasis:

(47) The haemostatic performance has been tested on the processed cellulosic textile on animals on a per-operative bleeding model versus reference product Surgicel®. The methodology comprises creating, on pigs, lesions of square shape and of predetermined surface area on organs (spleen and liver) and then to cover the wounds thus created with the compresses to be tested.

(48) The observations bear on the behavior in contact with blood and the time necessary to establish the haemostasis (see Table 8 hereafter). The spleen and liver have been selected as test organs since both the nature of their tissue and the intensity of the bleeding that they generate are different.

(49) TABLE-US-00008 Haemostasis time Processed cellulose Organ textile Surgicel ® spleen 9 minutes 10 minutes liver 2 min 45′.sup.  3 min .sup. 

(50) A haemostatic behavior of the tested cellulosic textile comparable to that of the reference product can be observed, whatever the tested organ: the behavior in contact with blood is identical to that of the reference and the time necessary to obtain the stopping of the bleeding is equivalent for each considered organ.

(51) This study enables to highlight the haemostatic power of the material.

(52) IV/Characteristics of the Product Obtained by Inversion of Steps 1 and 2:

(53) The general conditions are listed in Table 9 hereafter:

(54) TABLE-US-00009 NaIO.sub.4 (mole per gram of cellulose) 0.006 pH of the reaction medium 3.0 Temperature (° C.) 35° C. Duration of the reaction 3 h

(55) Step 1:

(56) 10 g of cellulose are mixed with 0.06 mole of periodate ion in a 1-1 Erlenmeyer. The total volume of the reaction mixture is 505 ml. The pH is adjusted to 3.0 and the reaction is carried out in a water bath under discontinuous stirring for 3 h, at a 35° C. temperature and away from light. The obtained cellulosic material is then rinsed twice with purified water before undergoing an acidification and then washed several times with ethanol. After being wrung, the material is dried for 16 h under an air flow.

(57) Step 2:

(58) The previous material, obtained in the dry state, is submitted to reaction TEMPO/NaClO/NaClO.sub.2. The general conditions are listed in Table 10 hereafter:

(59) TABLE-US-00010 TEMPO (mole per gram of cellulose) 0.0006 NaClO (mole per gram of cellulose) 0.0012 NaClO.sub.2 (mole per gram of cellulose) 0.012 pH of the reaction medium 5.8 Temperature (° C.) 60 Duration of the reaction 5 h

(60) Under a ventilator, 200 ml of a buffer solution tampon of sodium acetate (0.5 M, pH=5.8) are placed in a 1-1 Erlenmeyer, after which 0.12 mole of NaClO.sub.2 are added. 10.1 g of the previously obtained material are then placed in the NaClO.sub.2 solution. 0.006 mole of TEMPO and an aqueous solution of NaClO with 2% of active chlorine (0.012 mol) are then added to the reaction mixture. The reaction volume is adjusted to 500 ml with sodium acetate buffer solution. The Erlenmeyer is closed and placed in a thermostatic water bath at 60° C. for 5 h.

(61) At the end of the reaction, the textile has disappeared from the reaction medium. The reaction medium is then precipitated in the presence of ethanol but the obtained precipitate is inexploitable.

REFERENCES

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(65) Sobue H, Okubo M. 1956. Determination of carboxyl group in cellulosic materials with the “dynamic ion exchange method”. Tappi, 39(6) :415.