Haemostatic substance

The invention relates to a hemostatic mass consisting of a powdered and / or fibrous oxidized cellulose uniformly distributed in a binder composition comprising a binder, a plasticizer and optionally further additives. The hemostatic composition is characterized in that the binder is selected from the group consisting of sodium monocarboxylic cellulose, sodium carboxymethylcellulose, oxidized starch, polyvinyl pyrrolidone of K = 60-120 according to Fikentscher and mixtures thereof, and that the oxidized cellulose is cellulose selectively oxidized to monocarboxylic cellulose and 9 to 25.6% of uronic carboxyl groups in the form of an acid and / or a salt thereof. The hemostatic mass is malleable, thermoplastic, absorbable by living animal tissue, and its form is determined by the purpose of its use.

The invention relates to a hemostatic mass which is malleable, in particular thermoplastic, absorbable by living animal tissue and whose embodiment is intended for its use, e.g. % of powdered and / or fibrous oxidized cellulose evenly distributed in the binder composition comprising a binder, a plasticizer and optionally other additives.

Currently, various hemostatic materials formed either wholly or only partially from oxidized cellulose are used. In the first case, the oxidized cellulose is in the form of a powder or fabric, while in the second case it is usually in the form of a powder forming one of the components of the hemostatic material. While these materials are effective for eradicating severe capillary bleeding or parenchymatic organ bleeding, their performance is less suitable for use in surgical procedures, amputations, and the like.

For example, in the description of the invention to MS. No. 185,366 discloses a process for the production of woven cellulose oxidized selectively to monocarboxylic cellulose by treating wood pulp or cotton cellulose with an oxidizing mixture of nitric acid and sodium nitrite phlegmatized by heat exposure at a temperature of 110 to 140 ° C. Then, the oxidized cellulose is stabilized and / or converted to its calcium, sodium or other salt, then dewatered and dried, and the oxidized pre-oxidized cellulose material is treated with high energy ionizing radiation up to 100 kGy. Following this radiation irradiation, the oxidized cellulosic material can be turned into a powder by grinding either in a dry state on a knife or pin mill, or in the wet state in the form of a suspension on a Hollander or Jordan mill and the like. Although it is a very gentle technology, preventing unwanted degradation of the cellulosic material and allowing it to achieve an even degree of oxidation, the woven or powdered form of the final product limits to a certain extent its use; it is less suitable for local hemostasis of body cavities, bone marrow bleeding, or for surgical superficial application requiring suture fixation.

U.S. Pat. No. 3,122,479 discloses a blood-wettable and blood-absorbing solid hemostatic surgical dressing containing brittle powdered cellulose that is oxidized by nitrogen dioxide and degraded by time-temperature interaction, and wherein the binder is uniformly dispersed and relatively insoluble in the cellulose. water, absorbable by living animal tissue and selected from the group consisting of carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and mixtures thereof. This oxidized cellulose has a relatively acidic pH, i.e. between 2.0 and 6.5. The hemostatic surgical dressing just described has several drawbacks resulting from the type of hemostatic and binder used. Relatively acidic pH can cause patient irritation. Degradation of oxycellulose, carried out only by the synergy of time and heat, is inadequate and causes prolongation of the absorbability of hemostatics by living animal tissue to approximately two weeks. The binders used are relatively insoluble in water, which is adversely affected when the dressing is applied, since it delays the contact of the powdered oxidized cellulose with the bleeding site. A further disadvantage of said binders is their single purpose, i.e. only binder; the binder only ensures the cohesion of the dressing components, but does not participate in the healing effect of the dressing.

The aforementioned disadvantages are to at least predominantly eliminate a hemostatic mass which is malleable, in particular thermoplastic, absorbable by living animal tissue, and whose embodiment is intended for its use, for example in the form of petrolatum, paste, putty, foil, suppository or even deposition on a substrate, and which consists of powdered and / or fibrous oxidized cellulose uniformly distributed in a binder mixture containing a binder, according to the invention, the binder contained in the binder mixture is selected from the group consisting of sodium carboxymethylcellulose, sodium monocarboxylcellulose and / or oxidized starch and sodium monocarboxylic cellulose and / or polyvinylpyrrolidone with a Fikentscher constant of K = 60 up to 120, wherein the oxidized cellulose is cellulose selectively oxidized to monocarboxylcellulose, containing 9 to 25.6% uronic carboxyl groups in the form of an acid and / or a salt thereof, with a pH in the range of 6.5 to 7.5. In particular, the salt of the oxidized cellulose may be a calcium or sodium ferrous salt of monocarboxylic cellulose. Oxidized cellulose is degraded not only by the effect of time and heat, but also by high-energy ionizing radiation, which ensures uniform destruction of the oxidized cellulose and thus positively affects the hemostatic effect.

Most of the proposed binders are both binder and hemostatics; especially sodium monocarboxylic cellulose is an excellent and easily absorbable hemostatic. Oxidized starch, which is water-soluble, also partially acts as a hemostatic.

The same is true of sodium carboxymethylcellulose after exposure to the high-energy ionizing radiation employed in the present invention. The proposed hemostatic mass does not exhibit undesirable changes in its color and remains permanently cohesive and malleable, which is important for its use in various medical procedures. Two-stage oxidation, i. The hemostatic effect is immediate, within 2 minutes perfect hemostasis is achieved and the mass is absorbed without traces in the body within 48 to 72 hours.

Samples of the hemostatic mass according to the invention were tested preclinically with a good result. Sheep aged 1.5 to 2 years were used for the experiments. Bones from limbs into which holes were drilled were used to test the effects of the preparation. The right anterior and posterior limbs of the animal were used as controls, the left anterior and posterior limbs were used to monitor the effect of hemostatic matter. The animals were sacrificed after 24 and 48 hours, followed by 7, 14 and 21 days. All limbs and parenchymatous organs were removed for histological examination. The bones of the animal were sacrificed, fixed with 10% formaldehyde, and decalcified in Chelaton III for 1 to 3 months.

The most pronounced macroscopic and microscopic differences were found by day 7 after surgery, microscopic differences were observed until day 21, although their extent was clearly decreasing. The main differences were hematoma filling and bleeding of periosteum and soft tissues in control limbs. Only the microscopic residues of hematoma, fibrin, and the later onset proliferation of the young bone lamellae on the inner periphery of the bone openings were recorded in animals treated with the haemostatic mass of the invention.

In all sacrificed animals, the following organs were collected as a standard for hisiological examination: liver parenchyma, spleen, kidney and lungs. No significant pathological changes were found in any of these organs, no remnants of the hemostatic preparation were detected microscopically.

The above comparison showed that the hemostatic mass is biologically tolerant to the organism, does not interfere with healing processes, does not induce an undesirable immunobiological reaction, is non-irritating at the site and surroundings of application and does not induce sensitivity in the patient; the neutral pH of the oxidized cellulose in the form of salts also contributes to this circumstance. The absorption time of hemostasis in the body can be shortened by the addition of a mixture of dialyzed and lyophilized proteolytic enzymes trypsin and chymotrypsin.

Further advantages of the invention will become apparent from the description of the exemplary embodiments thereof, however, they do not exhaust all possibilities of using the subject matter of the invention.

Example 1

A hemostatic mass in the form of a sealant suitable for stopping bone bleeding is produced as follows:

A mixture of 1785 g is prepared, which consists of 1100 g of distilled water, 650 g of glycerol and 35 g of polyvinylpyrrolidone of K = 90, which can be replaced with an equal amount of monocarboxylic cellulose sodium.

The mixture is then divided into two parts, the first of which is 75% by weight, i.e. 1340 g, and the other 25%, i.e., 445 grams of the mixture. For this, 1000 g of monocarboxylic cellulose calcium are gradually added to the first part of the mixture and the mixture is homogenized in a malaxer for about 20 minutes. The above-mentioned second portion, weighing 445 grams, is then added to the homogenized mixture and the mixture is again homogenized for about 10 minutes, transforming it into a perfectly gelatinous mass.

This is followed by shaping the gelatinous mass into the desired shape, for example, balls, rollers, cones, suppositories. The hemostatic mass thus produced, replacing the known, so-called bone waxes, is wrapped in a hermetic suitable container and sterilized, here by gamma irradiation.

Example 2

A hemostatic mass in the form of a mastic suitable for the manufacture of suppositories is prepared as follows:

A powdered monocarboxylic cellulose calcium powder having a particle size of about 100 μΐη is prepared by multiple milling using a knife mill and a pin rotary mill.

Then, a mixture consisting of 50% by weight of monocarboxylic cellulose powder of calcium with 46% by weight of glycerol and 4% by weight of polyvinylpyrrolidone of K = -90 is mixed and homogenized in a malaxer to form a ductile mass.

From this mass, heated to 50 to 80 ° C, suppositories of the desired shape and size are formed. The suppositories are then placed in a container which is hermetically sealed and sterilized by gamma irradiation. However, sterilization can be performed in another way.

Suppositories are suitable for use in dental surgery, for local hemostasis of body cavities, for filling of bleeding bone marrow etc.

Example 3

A hemostatic mass in the form of a sealant suitable for the manufacture of suppositories and similar three-dimensional materials is prepared as follows:

a part by weight of calcium monocarboxylic cellulose in the form of fibers of less than 4 mm in length prepared by coarse milling in a rotary knife mill is homogenized in a malaxer with 1 part by weight of a 2% solution of sodium monocarboxylic cellulose and oxidized starch in glycerol and water in a ratio of wherein both are present in the same amount, and with 0.5 part by weight of 96% ethanol per ductile mass.

1.0 to 6.0 parts by weight of a mixture of dialyzed and lyophilized proteolytic enzymes of trypsin and chymotripsin are added per 100 parts by weight of the mixture so as to control the resorbability time of the final product.

The hemostatic mass thus produced is packaged in a suitable hermetically sealed container and then sterilized. The product is intended for use as a hemostatic in bone surgery, dentistry, etc.

Example 4

A hemostatic mass in the form of a foil intended for rapid application to a bleeding surface is prepared as follows:

In the dutch mill, an oxidized cotton gauze, which is the monocarboxylic cellulose calcium salt, is ground into short fibers and subjected to high-energy ionizing radiation up to 100 kGy prior to grinding. The grinding is carried out in an aqueous medium or in a 1: 1 by volume mixture of isopropyl alcohol-water. After draining to a dry matter content of 60 to 70%, the ground fibers, 9 parts by weight, are mixed in the malaxer with 1 part by weight binder, here monocarboxylic cellulose sodium, 2 parts by weight glycerol as plasticizer, and 8 parts by weight distilled water used as a wetting agent.

This homogenized mixture is then calendered by two counter-rotating rollers to form a film of selected thickness. The film is gently dried at ambient temperature, then wrapped in a suitable hermetic package and finally sterilized, here by gamma irradiation.

In this hemostatic mass, the monocarboxylcellulose sodium acts as an active binder, so-called. that it exhibits both a binding and a hemostatic effect.

Example 5

The hemostatic mass in the form of a sticky petrolatum applied to a supporting surface substrate, intended for rapid surface application with the possibility of thigh fixation, is produced as follows:

% by weight of the powdered monocarboxylic cellulose calcium prepared by ball milling is mixed and homogenized with 40% by weight of monocarboxylic cellulose sodium and 40% by weight of glycerol. It is possible to replace the monocarboxylcellulose sodium salt in this mixture either with an equal amount of polyvinylpyrrolidone of K * = 90 or with a 1: 1 weight ratio of monocarboxylcellulose sodium and polyvinylpyrrolidone of K = 90.

The hemostatic mass thus formed is applied to a conventional carrier substrate, which is here a textile fabric, an oxidized cellulose fabric or knitted fabric, on a conventional three-roll applicator. The product is packed in a suitable container, which is hermetically sealed and then sterilized by gamma irradiation; However, other suitable sterilization methods may also be chosen.

Example 6

A hemostatic mass in the form of a plastic film suitable for rapid application to a bleeding surface is prepared as follows:

First, a base solution is prepared consisting of 65 parts by weight of glycerol, 35 parts by weight of polyvinylpyrrolidone of K = 90 or sodium carboxymethylcellulose and 600 parts by weight of 85% pure ethanol.

Thereafter, 50 parts by weight of monocarboxylic cellulose calcium salt in the form of a powder having a particle size of about 100 μιη are added to 100 parts by weight of the basic solution to form the actual coating composition.

This coating composition is applied to a Teflon or polyethylene backing by means of a casting tray with an adjustable slot. The height of the slit is selected according to the desired thickness of the resulting film, which after 4-6 hours of drying the film at a temperature of 34 to 45 ° C corresponds to about half the height of the slit; for example, at a slot height of 1 mm, a foil having a thickness of 0.5 mm is obtained. The plasticity of the film depends on the degree of drying. The finished film is removed from the support and placed in a hermetically sealed container, such as an aluminum foil coated with polyethylene, and sterilized.

Example 7

The haemostatic mass in the form of an adhesive dispersion, applied to a flat support substrate and designed to eradicate capillary bleeding from a larger area, with the possibility of stitch fixation, is prepared as follows:

The procedure of Example 6 is followed except that the coating composition formed is applied to a woven or knitted area of ​​a fabric consisting of oxidized cellulose.

Example 8

The hemostatic mass in the form of a plastic film combined with an oxidized cellulose textile fabric is prepared as follows:

The procedure of Example 6 is followed except that a woven or knitted sheet of oxidized cellulose fabric is crushed into the resulting film formed by pouring the coating composition onto a Teflon or polyethylene backing after partially drying it to bond the fabric to the film.

Example 9

A hemostatic mass in the form of a suppository is prepared as follows:

up to 40 g of modified starch, here oxidized potato starch, is added to 100 ml of distilled water, where it is allowed to be greased at 65 ° C, followed by the addition of 5 to 20 ml of glycerin and 60 to 80 g of oxycellulose powder. Everything is thoroughly homogenized in the malaxer for about 20 minutes.

The mass obtained is formed by compression into the desired suppository shape, which is then frozen. After removal from the freezer, the suppositories are thawed, then dried slightly to prevent loss of formability, and packaged in hermetic containers in which they are sterilized, here by gamma irradiation. Freezing creates a starch sponge in the suppositories which receives liquid in an amount equal to 2-8 times its weight.

The formability of the suppository composition can be increased by adding 2 to 10% by weight of polyvinylpyrrolidone or carboxymethylcellulose. The suppository thus produced is characterized in that, when inserted into the bleeding cavity, the starch sponge sucks in blood, thereby expanding the suppository and thereby completely filling the cavity and the suppository mass adheres to the walls of the cavity so as to increase the hemostatic effect of the suppository; it can be said that there is a self-shaping of the suppository according to the shape of the bleeding cavity.

It is clear from the description of the examples that all embodiments of the hemostatic mass are based essentially on the same components and that they differ in formability, adhesion to different surfaces, oxidized cellulose content, kind of binder and suitability for use in surgery. The hemostatic mass according to the invention can be said to have the following general composition:

up to 85% by weight of a hemostatic of the above composition, up to 50% by weight of a binder selected from said group, up to 35% by weight of a plasticizer and up to 40% by weight of a wetting agent.

All components of the hemostatic mass are physiologically safe, non-toxic, soluble in body fluids and chemically stable. Haemostatic specimens were tested preclinically and partially clinically with good results.