Medical adhesives for stopping heavy bleeding and sealing leakages

Abstract

The present invention relates to a method that includes providing a formulation having an isocyanate-functional prepolymer and a curing component comprising an amino-functional aspartic ester of the general formula (I) ##STR00001##
applying the formulation to a cell tissue; and curing the formulation such that the loss of blood (haemostatic) or tissue fluids is staunched or leaks in cell tissues are sealed.

Claims

1. A method of staunching the loss of blood (haemostatic) or tissue fluids comprising: a. providing a formulation comprising A) an isocyanate-functional prepolymer obtained from A1) an aliphatic isocyanate and A2) a polyol component having a number-average molecular weight of greater than or equal to 400 g/mol and an average OH functionality of 2 to 6, B) a curing component comprising B1) an amino-functional aspartic ester of the general formula (I) ##STR00004## where X is an organic radical obtained by removing the primary amino groups from 2 methyl 1,5-diaminopentane, R.sub.1 and R.sub.2 are ethyl and n is 2 b. applying the formulation to a cell tissue; wherein the cell tissue comprises human or animal tissue; and c. curing the formulation such that the loss of blood (haemostatic) or tissue fluids is staunched, wherein the formulation is applied in an in vivo application or an in vitro application.

2. The method according to claim 1, wherein the curing component further comprises organic fillers which have a viscosity as measured to DIN 53019 at 23° C. in the range of from 10 to 6000 mPas.

3. The method according to claim 2, wherein the formulation further comprises reaction products of the isocyanate-functional prepolymer with the organic fillers.

4. The method according to claim 1, wherein the formulation further comprises reaction products of the isocyanate-functional prepolymer with the amino-functional aspartic ester.

5. The method according to claim 4, wherein the formulation further comprises reaction products of the isocyanate-functional prepolymer with organic fillers.

6. The method according to claim 1, wherein the curing component further comprises organic fillers which have a viscosity as measured to DIN 53019 at 23° C. in the range of from 10 to 6000 mPas and wherein the formulation further comprises reaction products of the isocyanate-functional prepolymer with the amino-functional aspartic ester and the organic fillers.

7. The method according to claim 1, wherein the polyol component has a number-average molecular weight of 4000 to 8500 g/mol.

8. The method according to claim 1, wherein the polyol component comprises a polyalkylene oxide polyether.

9. The method according to claim 8, wherein the polyalkylene oxide polyether contain from 60% to 90% of ethylene oxide-based units, based on the total amount of alkylene oxide units.

10. The method according to claim 2, wherein the organic fillers comprise polyether polyols.

11. The method according to claim 1, wherein the formulation is cured for a period of time from 30 seconds to 10 minutes.

12. The method according to claim 1, wherein the formulation is cured for a period of time from 30 seconds to 2 minutes.

Description

EXAMPLES

(1) Unless indicated otherwise, all percentages are by weight.

(2) PEG=polyethylene glycol

Example 1 Prepolymer A

(3) 465 g of EMI and 2.35 g of benzoyl chloride were charged to a 1 l four-necked flask. Over the course of 2 h at 80° C. 931.8 g of a polyether having an ethylene oxide content of 71% and a propylene oxide content of 29% (based in each case on the total alkylene oxide content), prepared starting from TMP (3-functional), were added, with subsequent stirring for 1 h. Subsequently the excess HDI was removed by thin-film distillation at 130° C. and 0.1 torr. This gave 980 g (71%) of the prepolymer, with an NCO content of 2.53%. The residual monomer content was <0.03% HDI.

Example 2 Aspartate B

(4) Under a nitrogen atmosphere 2 mol of diethyl maleate were slowly admixed dropwise with 1 mol of 2-methyl-1,5-diaminopentane, at a rate such that the reaction temperature did not exceed 60° C. Subsequently the mixture was heated to 60° C. until diethyl maleate was no longer detectable in the reaction mixture. The product was purified by distillation.

Example 3 Application of the Formulations Essential to the Invention for Staunching Severe Bleeding and Sealing Leaks

(5) The formulations essential to the invention were applied by means of a commercial two-chamber applicator with static mixer. One chamber contained a mixture of 0.45 g of PEG 200 and 0.55 g of aspartate B. The second chamber contained 4 g of prepolymer A. Pressing down on the ram resulted in mixing of the two components.

(6) In vivo experiments on haemostasis—animal model: rat

(7) The experiment was carried out with a Wistar rat weighing 350 grams. Anaesthesia was induced with diethyl ether and subsequently, intraperitoneally, using ketamine/xylazine. Subsequently the trachea was intubated with a 14-gauge venous catheter. Ventilation was carried out with an air/oxygen mixture (FiO2=0.5). The rat was fixed to a heated support. Preparation for surgery was carried out aseptically and with local infiltration of lidocaine.

(8) The abdomen was opened up by means of anterior longitudinal and transverse abdominal section, providing wide access to the liver and to the spleen.

Example 3a—Diffuse Bleeding

(9) The surface of the liver was injured using sandpaper, producing diffuse bleeding. The formulation essential to the invention was applied to the surface of the liver. After about 2 minutes the film had cured and had staunched the bleeding of the liver surface.

Example 3b—Liver Resection

(10) The tip of the left lobe of the liver was removed. This produced a cut area of approximately 1 cm.sup.2, running transversely through the hepatic tissue, with severe bleeding. The formulation essential to the invention was applied, and staunched the bleeding within 2 minutes.

Example 3c—Pulmonary Aspiration

(11) The rib cage was opened by medial sternotomy and widened with a right-lateral thoracotomy. The tip of the middle lobe of the right-hand lung was cut off, producing a wound area approximately 1 cm.sup.2 in size. This resulted in strong venous and also strong arterial bleeding. Moreover, a medium-sized bronchus had been severed, resulting in an air leak. The tissue adhesive was applied to the wound area of the lung, and immediately staunched the venous and the arterial bleeding. With regard to the air leak, a large air bubble formed in the adhesive and burst, and there continued to be a fistula of air. After about 1 minute a drop of the adhesive was applied again to the air leak and pressed down firmly using a plastic spatula. This sealed the air leak.

(12) After 3 minutes in all the film was cured and had successfully staunched the bleeds and sealed the air leak.

Example 3d—Aspiration of the Ascending Aorta

(13) The ascending aorta was exposed and prepared. The ascending aorta was aspirated generously with a 0.5 mm thick needle, producing a squirting bleed. The formulation essential to the invention was applied to the bleed and pressed gently onto the hole using a plastic spatula. Bleeding came to a halt within 2 minutes.

(14) In vivo experiments on haemostasis—animal model: pig

(15) The experiment was carried out on a female 30 kg domesticated pig under inhalative mask anaesthesia. Incision of the skin was carried out ventrally to the sternocleidomastoid muscle, on the left-hand side. The carotid aorta was exposed in the region of the bulb. The carotid aorta is found to have a diameter of approximately 5-6 mm.

Example 3e—Minor Arterial Bleeding

(16) Using a scalpel, the carotid artery was opened in the region of the bulb by careful preparation in such a way that there was a minor squirting bleed from the artery. After brief initial rinsing of the mixing canula, approximately 4 ml of the formulation essential to the invention were applied to the source of the bleeding, and compressed by means of compression through surrounding tissue, in particular through the sternocleidomastoid muscle. The bleeding halted after about 1½ min. The surrounding tissue had been bonded to the carotid artery. A pulse could be felt on the carotid artery, distal to the site of the incision.

Example 3f—Severe Arterial Bleeding

(17) Using vessel scissors, the carotid artery was opened over half the circumference. In the course of this operation, a severe squirting arterial bleed developed. 5 ml of the formulation essential to the invention were applied to the site of the bleed and compressed with the surrounding tissue over about 2 min. The bleeding came to a halt after 2 minutes.

Example 3g—Venous Bleeding

(18) The right aural vein was opened using a scalpel over a length of approximately 10 mm, resulting in a severe bleed. The formulation essential to the invention was applied without compression. The bleed came to a halt after about 1 minute.