IE47606B1

IE47606B1 - Absorbable hemostatic composition

Info

Publication number: IE47606B1
Application number: IE2393/78A
Authority: IE
Original assignee: Ethicon Inc
Priority date: 1977-12-05
Filing date: 1978-12-04
Publication date: 1984-05-02
Also published as: IL56110A; FR2410477B1; GB1584080A; IL56110A0; FR2410477A1; MY8200056A; HK34681A; HU179969B; CA1119515A; DE2852319C2; DE2852319A1; IN149490B; IE782393L

Abstract

An absorbable hemostatic surgical composition for the control of osseous hemorrhage comprising from 10 to 50 percent by weight of a hemostatic powder comprising a mixture of fibrin and collagen powders in a water-soluble, biocompatible base containing a tackifying agent. A preferred formulation contains approximately equal proportions of fibrin and collagen in an aqueous glycerol base and is a putty-like semisolid which when packaged in a syringe, plastic envelope, or aluminum tube, may be extruded from the package as required for use.

Description

This invention, relates to a bone sealant, and more particularly, to an absorbable, semisolid composition for the con5 trol of osseous hemorrhage.

Various substances and compositions have been employed by members of the medical profession to control the bleeding from cut bone surfaces. One class of materials used for the con trol of this type of hemorrhage is called bone wax. Bone waxes are used for the purpose of controlling hemorrhages from the cut surfaces of bones, such as those of the skull, by forcibly smear ing the wax over the out surface so that the material acts mechanically to occlude and seal the open ends of the bleeding osseous vessels and sinuses.

Bone waxes used in surgery today are generally prepared from refined beeswax which has been admixed with other nonabsorbable and water insoluble hydrocarbons and vegetable oils. Certain disadvantages inhere in these bone wax compositions, as for example, relatively poor adhesion properties, separation of wax components and the hard, brittle state of the wax at room temperatures requiring use at elevated temperatures.

U.S. Patent No. 3,395,217 discloses nonabsorbable bone wax compositions comprised of low molecular weight ethylene oo25 polymer waxes containing from about 15 to about 40 percent by weight of another unsaturated constituent and having molecular -2476 0 6 weights in the range of 1000 to 4000. These waxes have a semisolid consistency such that they can be kneaded between the fingers when at room temperature and have the right amount of tack and adhesion so that they can be easily manipulated in the hands of the surgeon or applied by any suitable applicator suoh as a gloved finger, spatula or appropriate disposable applicator.

Absorbable bone waxes have also been suggested. U.S. Patent No. 2,772,999 describes a bone wax comprised of a water soluble innocuous base and free acid cellulose glycolic acid ether or free acid cellulose hydroxypropionic acid ether as a hemostatic agent. The composition also preferably contains a tackifier such as cellulose glycolic aoid ether salt or cellulose hydroxypropionic acid ether salt (preferably sodium salt) and water as a plasticizer.

The Annals of Surgery 132, 1128 (1950) describes an absorbable hemostatic bone wax containing powdered oxidized cellulose as the hemostatic agent in a base of polyethylene glycol.

The base is a mixture of high and low molecular weight polyethylene glycols selected to provide the malleability and con20 sistency of material desired for this application.

The present invention provides a new absorbable bone sealant which is a putty-like semisolid at room temperature.

The softness of the composition allows the material to be packaged in a syringe, plastic or coated paper envelope, or aluminum or glass tube from which it may be extruded or dispensed in desired amounts during use. The sealant has sufficient tack so that it adheres to bone surfaces, yet is easily manipulated in the hands of the surgeon without crumbling or sticking to the surgeon's gloves. -347606 Absorbable bone sealant compositions of the present invention comprise a mixture of from 10 to 50 percent by weight of the total composition of a hemostatic powder in a water-soluble bicompatible base, optionally contain5 ing a small amount of tackifying agent, the hemostatic powder comprising a mixture of fibrin and collagen powders, preferably in substantially equal proportions. The base is preferably a mixture of water and a poly-ol such as glycerol, and the tackifying agent, if present, is prefer10 ably a polyglucoside such as dextran. The sealant is formulated to the consistency of a semisolid which is extrudable from a large orifice syringe. The composition is packaged in a syringe, plastic envelope, or aluminum tube and sterilized by radiation. During use, small amounts of the sealant may be exturded from the package as required by the surgeon. The composition is effective to control osseous hemorrhage from cut bone and does not interfere with subsequent healing and rejoining of bone parts.

It is desirable that hemostatic compositions of the present invention, which comprise a mixture of a hemostatic powder, an innocuous absorbable base, and,preferably, a tackifying agent should be formulated to obtain a semisolid material which may be readily spread upon the surface of cut bone in order to arrest the flow of blood.

Fibrin powder useful in the present invention may be ob tained from human or animal blood according to the method disclosed in U.S. Patent No. 3,523,807. - 4 47606 . The fibrin powder is preferably reduced to a particle size of 500 microns or smaller, and most preferably to a size of about 200 microns. The fibrin powder thus obtained comprises,together with the collagen powder, fraa IG to 50 percent hy weight of the total hemostatic canpositiai.

Collagen powder, useful in the present invention, is a finely divided, fluffy material which may be prepared according to the method disclosed in U.S. Patent No. 3,742,955.

The collagen powder is preferably reduced to a particle size of 2 mm or less, and most preferably to less than 1 mm.

The collagen powder and fibrin pcwder are preferably mixed in a ratio of 40-95 percent by weight fibrin, 5-60 percent by weight collagen, in order to obtain a final product having the desired characteristics of softness and malleability. In a particularly preferred composition of this invention, substantially equal proportions of fibrin and collagen powders are used with good results. 2o The base component of the hemostatic composition may be an aqueous solution of a single substance or a mixture of two or more water-soluble innocuous substances. Substances suitable as bases include nonvolatile compatible poly-ol compounds such as glycerol, propylene glycol, polymerized low molecular weight aliphatic glycols such as polymerized ethylene glycol and low molecular weight ethers or esters of polyglycols such as the -547606 methyl, ethyl, or propyl ethers of polyethylene glycols and the acetic or propionic esters of polyethylene or polypropylene glycols. Glycerol and polyethylene glycols are the preferred base materials, and polymerized ethylene glycols having a molecular weight in the range of 200 to 4000 and a consistency varying from a liquid of low viscosity to that of a waxy solid may be found suitable. If desired, a polymerized ethylene glycol having a molecular weight of 1000 to 4000 may be used in combination with a polymerized ethylene glycol having a molecular weight of 200 to 600.

In addition to the hemostatic agent and innocuous base, the bone wax composition may also contain a tackifier such as a polyglucoside, gelatin or collagen gel polyvinyl pyrrolidone, cellulose ester- or other derivative of cellulose such as oxi15 dized cellulose, a water-soluble starche, or a sugar. A preferred polyglucoside is dextran while a preferred cellulose derivative is cellulose glycolic acid ether salt or cellulose hydroxypropionic acid ether salt, most preferably the sodium salt The powdered fibrin hemostatic material and. tackifying agent, if 20 present, should desirably he thoroughly -dispersed in the aqueous base to provide a semisolid canpositicn which is readily spreadable cn the surface of cut bone. The desired consistency of the composition is obtained by proper selection of the base material and the amount of water admixed therewith.

The following examples are provided to further illustrate preferred embodiments of the present invention: -647606 EXAMPLE I A hemostatic composition was prepared by thoroughly dispersing the following materials in the indicated proportions: Hemostatic Agent Fibrin powder (200 microns) - 17.5 g Collagen powder (2 mm) - 17.5 g Tackifying Agent Dextran (MW 60,000-90,000) - 8.0 g Base Glycerol - 30.0 g Water - 27.0 g Total . 100 g The composition had a semisolid, putty-like, slightly sticky consistency. When loaded in a 1 cc hypodermic syringe with the needle removed, the mixture was readily extruded through the 1.6 mm diameter opening of the syringe to form a ribbon of ’ material ready for use.

EXAMPLE II An extruded ribbon, 10 mm in length by 1.6 mm in diameter of the hemostatic composition of Example I was implanted in the lumbar muscles of 12 CFY strain rats weighing 250-300 kg. Two rats were sacrificed after 3, 7, 14, 28, 49, and 70 days, and the implant sites examined to determine absorption rates and tissue reaction to the bone sealant. The bone sealant was substantially completely absorbed by the 14th day with only few remnants of collagen being detectable. No trace of the sealant was found after 28 days. No abnormal tissue reaction was ob20 served during the test. -747606 EXAMPLE III Fourteen white male CFY rats, weighing 200-250 g, were anesthetized, and under surgically sterile conditions, the frontal and parietal bones of the skull were exposed. Four holes were made, one in each quadrant of the skull, using a 2 mm burr on an electric drill. The parietal hole on one side was filled with a complete plug of the bone sealant of Example I, and the parietal hole on the other side plugged with a commercial bone wax control. One frontal hole was treated by spreading a small amount o'f the bone sealant of Example I on the cut surface, while the other hole was similarly treated with the bone wax control.

After 14 days, 12 rats were sacrificed and the wounds examined to determine the histological effects of the bone sealant and bone wax. The remaining 2 rats were sacrificed and ex15 amined after 28 days. The following results were noted with no significant differences between the 14- and 28-day examination periods. -847606 A. Bone Sealant of Example I i. Plugged holes. Holes filled with tissue and bony edges lined with a layer of osteoblasts. There was considerable evi5 dence of new bone formation in the area. ii. Smeared holes. Similar to plugged holes, but connective tissue depressed below the level of the skull surface.

B. Bone Wax Control i. Plugged holes. Holes remained filled with a solid plug of wax which was easily removed. Hole was thickly roofed by connective tissue with evidence of a much thinner tissue floor. There was no indication of any significant tissue activity in plug area. ii. Smeared holes. Generally filled with connective tissue, but with fragments of wax visible in many cases.

The composition of Example I is a specific illustration of a generally preferred hemostatic composition having the following range of formulation: Fibrin powder - 15-25% Collagen powder - 15-25% Dextran - 5-10% Glycerol - 20-40% Water - 20-30% The precise composition illustrated in Example I was selected from the above general formulation to provide a desir30 able combination of properties, particularly consistency and adhesion or tack. Optimum formulations may vary somewhat from that given in Example I depending upon the particular properties of the individual ingredients.

Claims

1. An absorbable hemostatic composition for use in the control of osseous hemorrhage comprising from 10 to 50 percent by weight of the total composition of a hemostatic pcwder in a water-soluble, biocanpatible base, said hemostatic powder comprising a mixture of fibrin 5 and collagen powders.

2. The composition of Claim 1 wherein the particle size of the fibrin powder is less than about 500 microns, and the particle size of the collagen powder is less than about 2 mm.

3. The composition of Claim 1 wherein said biocompat10 ible base comprises a mixture of water and a poly-ol.

4. The composition of Claim 3 wherein said poly-ol is selected from the group consisting of glycerol, propylene glycol, low molecular weight poly(alkylene) glycols, and low molecular weight ethers or esters of poly(alkylene) glycols. 15 5. The composition of Claim 3 wherein the poly-ol is glycerol and the ratio of glycerol to water is from '2:1 to 1:2. - 10 47606 6. A composition of Claim 1 comprising, in addition to the hemostatic powder and base, a tackifier. 7. A composition of Claim 6 wherein the tackifier is selected from the group consisting of polyglucosides, gelatin,

5. Collagen gels, polyvinyl pyrrolidone, cellulose esters, oxidized cellulose, water-soluble starches, and sugars. 8. A composition of Claim 7 wherein the tackifier is dextran. 9. A composition of Claim 8 wherein the dextran is 10 present in an amount of from 5 to 10 percent by weight of the composition. 10. A composition of Claim 1 wherein the hemostatic powder comprises from 40 to 95 percent by-Weight fibrin powder and from 5 to 60 percent by weight collagen powder. 15 11. An absorbable hemostatic composition for use in the control of osseous hemorrhage comprising, by weight, 15-25% fibrin powder 15-25% collagen powder

6. 7-10% dextran 20-40% glycerol 20-30% water 11 47606

7. 12. The composition of Claim 11 wherein the particle size of the fibrin powder is less than about 500 microns and the particle size of the collagen powder is less than about 2 mm.

8. 13. The composition of Claim 11 wherein the molecular 5 weight of the dextran is in the range of :from 60,000 to 90,000. Ϊ4. A hemostatic composition as claimed in any of Claims 1 to 13 and substantially as described in the foregoing Examples.