PRODUCTS FOR TREATING BLEEDING WOUNDS

Abstract

The invention relates to products in the form of pads or films for treating bleeding wounds, said products being formed from an organic polymer material that contains at least one particulate, crystalline inorganic polyphosphate finely divided in the organic polymer material, and the polyphosphate having a solubility in deionized water at 20° C. of less than 5 g/L, particularly less than 1 g/L, and the anion of the polyphosphate on average (number average) having at least four phosphorus atoms per polyphosphate anion.

Claims

1. An agent for use in treating bleeding wounds in mammals, in the form of a flexible sheet material formed from an organic polymer material comprising at least one particulate crystalline inorganic polyphosphate, wherein the organic polymer material forms a sheet-like matrix in which the particles of the particulate crystalline inorganic polyphosphate are present in the organic polymer material in finely divided form, the polyphosphate at 20° C. having a solubility in deionized water of less than 5 g/L and the anion of the polyphosphate having an average (number average) of at least four phosphorus atoms per polyphosphate anion.

2. The agent as claimed in claim 1, wherein the polyphosphate is selected from alkali metal polyphosphates, alkaline earth metal polyphosphates, and ammonium polyphosphates.

3. The agent as claimed in either of the preceding claims, wherein the polyphosphate is a sodium polyphosphate.

4. The agent as claimed in any of the preceding claims, wherein the particles of the polyphosphate have a mass-median particle diameter, determined by static laser-light scattering, within a range from 5 to 40 μm.

5. The agent as claimed in any of the preceding claims, comprising the polyphosphate in an amount within a range from 1% to 30% by weight based on the total weight of the agent.

6. The agent as claimed in any of the preceding claims, wherein the organic polymer material is thermoplastic.

7. The agent as claimed in claim 6, wherein the organic polymer material comprises as the principal constituent, based on the organic polymers contained therein, at least one polymer selected from polyhydroxyalkanoates, polylactides, aliphatic-aromatic polyesters, aliphatic-aromatic polyamides, polyolefins, polysiloxanes, and mixtures thereof.

8. The agent as claimed in claim 7, wherein the organic polymer material comprises as the principal constituent, based on the organic polymers contained therein, i. a mixture of at least one polylactide and at least one aliphatic-aromatic polyester; or ii. at least one copolyester of a hydroxybutyric acid with a hydroxyalkanoic acid having 6 to 12 carbon atoms, or a mixture of such a copolyester with polylactide.

9. The agent as claimed in any of claims 6 to 8 in the form of a film.

10. The agent as claimed in claim 9, wherein the ratio of film thickness to median particle diameter of the particulate polyphosphate is within a range from 0.5:1 to 5:1.

11. The agent as claimed in any of claims 1 to 5, wherein the organic polymer material is in the form of a hydrogel based on an organic polymer.

12. The agent as claimed in claim 11, wherein the organic polymer material comprises as the principal constituent, based on the organic polymers contained therein, at least one hydrogel-forming polysaccharide, in particular at least one crosslinked carboxylated polysaccharide.

13. The agent as claimed in either of claim 11 or 12, wherein the organic hydrogel-forming polysaccharide is a cross-linked alginate.

14. The agent as claimed in any of claims 11 to 13 in the form of a pad.

15. The agent as claimed in any of the preceding claims, which is packaged sterile.

16. The agent as claimed in any of the preceding claims for use in surgical interventions, particularly in operations on internal organs.

17. The agent as claimed in any of the preceding claims, for use in patients who have previously been treated with an agent that reduces blood clotting or who have a coagulopathy.

18. A process for producing the agent as claimed in any of the preceding claims, comprising the incorporation of the polyphosphate and optionally further hemostatic agents into the organic polymer material.

Description

[0098] The agents of the invention are elucidated in more detail by the figures and examples that follow.

[0099] Starting Materials: [0100] PBAT: Polybutylene adipate terephthalate, Ecoflex® from BASF SE, Ludwigshafen; [0101] PBST: Polybutylene succinate terephthalate from IRe Chemicals Ltd., South Korea; [0102] PLA: Polylactic acid PLA 2003D, from Nature Works; [0103] Chalk: Commercially available chalk powder having a d.sub.50 value of 1 μm, product from Omya GmbH, Cologne; [0104] Talc: Commercially available talc having a d.sub.50 value of 2.2 to 15 μm; [0105] Maddrell salt: High-molecular-weight crystalline sodium polyphosphate in the form of a powder having a d.sub.50 value of 15 μm, a proportion of soluble constituents of <3% by weight, a degree of crystallinity of >95%, an average number of P atoms per polyphosphate anion of 44, and a phosphate content of 70% by weight, calculated as P.sub.2O.sub.5; [0106] Sodium alginate: Hewigum Na 1 from Hewico Produktions u. Handels GmbH having a loss on drying of <15% by weight and a particle size of 177 μm, the 1% by weight solution of which in water at 22° C. having a viscosity of 700 mPas; [0107] CaSO.sub.4: Calcium sulfate dihydrate powder, analytical grade, having a d.sub.50 value of 10 μm (Luxopharm® F211 from SRL Pharma, Ludwigshafen); [0108] TSPP: Tetrasodium pyrophosphate E450 (iii), BK Giulini, Ladenburg.

[0109] General Production Procedure for Films

[0110] Please specify production procedure for extrusion, with process parameters, e.g.:

[0111] A compound was produced from the starting materials listed in Table 1 in a TSA model EMP 26-40 extruder having a D/L ratio of 26:40 operated at a screw speed of 200 rpm, a nozzle upstream pressure of 14 to 15 bar, and the temperature profile shown in Table 1a.

[0112] The respective compound was processed into a film having an average thickness of 15 μm in a Leistritz model ZSE 40 film extruder having a D/L ratio of 26:40 operated at a screw speed of 180 rpm and a nozzle upstream pressure of 11 to 12 bar.

TABLE-US-00001 TABLE 1 Film Film Film Film Film Film Starting material 1 2 3 4 5 5 PBAT [% by weight] 63.0 63.0 63.0 63.0 63.0 0 PBST [% by weight] 0 0 0 0 0 63.0 PLA [% by weight] 10.0 10.0 10.0 11.0 15.0 10.0 Processing aid 1 1.0 1.0 1.0 1.0 1.0 1.0 [% by weight] Processing aid 2 0.5 0.5 0.5 0.5 0.5 0.5 [% by weight] Chalk [% by weight] 12.5 15.5 10.5 12.5 10.5 12.5 Talc [% by weight] 8.0 0 0 4.0 0 8.0 Maddrell salt [% by 5.0 10.0 15.0 8.0 10.0 5.0 weight]

TABLE-US-00002 TABLE 1a Zone 1 2 3 4 5 6 7 8 nozzle Nominal 140 150 155 160 170 175 170 160 Actual 140 150 160 170 170 175 171 162

[0113] General Production Procedure for Pads Made from Hydrogels

[0114] Sodium alginate and tetrasodium pyrophosphate were dissolved in water in a beaker in the amounts shown in Table 2. To this were successively added with stirring, in the amounts shown in Table 2, solid Maddrell salt and calcium sulfate dihydrate powder, tetrasodium pyrophosphate and the mixture was then stirred for a further 40 sec or 90 sec at the stirring speed shown in Table 2. Approx. 75 ml portions of the suspension thus obtained were poured into Petri dishes having a diameter of 8.5 cm and the dishes were left for 1 h at 23° C. This afforded pads having a thickness of 15 mm, a Maddrell salt content of 9% by weight, and a water content of about 85% by weight.

TABLE-US-00003 TABLE 2 Experiment 1 Experiment 2 Experiment 3 Starting material Alginate [g] 7.2 7.2 6.8 CaSO.sub.4 [g] 5.2 5.2 4.9 TSPP [g] 1.0 1.5 1.6 Maddrell salt [g] 20 20 20 Deionized water [g] 188 188 188 Reaction parameters Stirring speed [rpm] 1000 1000 1000 Stirring time [sec] 90 40 40 Product characteristics flexible flexible flexible Water content [% by 84.9%   84.72%    84.95%    weight] Content of Maddrell 9% 9% 9% salt [% by weight]

[0115] The following investigations were carried out to determine the hemostatic effect of the sheet materials of the invention by comparison with a commercially available wound dressing.

[0116] The wound dressings employed were the inventive film 3 shown in Table 1, hereinafter referred to as TS, and the commercial kaolin-containing textile wound dressing QuickClot Combat Gauze® (Z-Medica), hereinafter RS.

[0117] 26 domestic pigs (79±2.4 kg) were divided into two groups, which were treated either with film TS (n=14) or with wound dressing RS (n=12). After measurement of baseline systemic hemodynamics and local transit time flow measurement (TTFM) on the femoral artery, a standardized complex groin injury was executed by means of a 4.7 mm puncture of the femoral artery proximal to the flow probe. Uncontrolled bleeding was facilitated in order to achieve a target arterial systolic pressure of less than 60 mmHg as an indicator of severe shock. All wound dressings were applied for 5 minutes, with application of 200 mmHg continuous pressure. After 5 minutes the pressure was released and hemostasis was restored. The hemodynamic baseline values were restored by volume replacement and catecholamines and hematological parameters were recorded for two hours. Response-variable data were presented in the form of a failure time distribution, the time to event being defined as the time to cessation of hemostasis or until the end of the experiment. The data were analyzed by the Kaplan-Meier method and with the aid of several Cox regressions. Independent variables included directly measured hemodynamic variables and the difference between the values for the event time, which were calculated as the difference from baseline and from shock induction.

[0118] In all 26 of the 26 animals, the wound dressing achieved hemostasis during revival after the shock event. Renewed bleeding occurred in 10 out of the 26 treated pigs. 3/12 (25%) of the animals treated with RS and 7/14 (50%) of the animals treated with TS had renewed bleeding (p=0.19). The time to renewed bleeding showed no significant difference between the groups (median: TS 45 min vs. RS 50 min, p<0.983). There was no statistically significant difference in femoral arterial blood flow between the two groups and the result was comparable.