Absorbent for treating wound
阅读说明：本技术 治疗伤口的吸收剂 (Absorbent for treating wound ) 是由 瓦迪姆·瓦列耶维奇·克朗加兹 谢威 林忠建 于 2018-11-27 设计创作，主要内容包括：本发明提供包含止血组合物套装的治疗伤口的吸收剂试剂盒,所述止血组合物套装至少包括(1)第一止血组合物,所述第一止血组合物包括选自环糊精和葡聚糖的第一交联多糖,和(2)第二止血组合物,所述第二止血组合物包括选自环糊精和葡聚糖的第二交联多糖。在一些实施方案中,第一止血组合物具有第一交联度,并且第二止血组合物具有比第一交联度更高的第二交联度。本发明还提供通过从所公开的止血组合物套装中选择止血组合物,并向伤口部位施用所选择的止血组合物来治疗伤口的方法。(The present invention provides an absorbent kit for treating a wound comprising a hemostatic composition set comprising at least (1) a first hemostatic composition comprising a first cross-linked polysaccharide selected from the group consisting of a cyclodextrin and a dextran, and (2) a second hemostatic composition comprising a second cross-linked polysaccharide selected from the group consisting of a cyclodextrin and a dextran. In some embodiments, the first hemostatic composition has a first degree of cross-linking and the second hemostatic composition has a second degree of cross-linking that is higher than the first degree of cross-linking. The invention also provides methods of treating a wound by selecting a hemostatic composition from the disclosed hemostatic composition set and applying the selected hemostatic composition to the wound site.)
1. An absorbent kit for treating a wound, the kit comprising:
a hemostatic composition kit comprising at least (1) a first hemostatic composition comprising a first cross-linked polysaccharide selected from the group consisting of cyclodextrins and dextran, wherein the first hemostatic composition has a first degree of cross-linking, and (2) a second hemostatic composition comprising a second cross-linked polysaccharide selected from the group consisting of cyclodextrins and dextran, wherein the second hemostatic composition has a second degree of cross-linking that is higher than the first degree of cross-linking.
2. An absorbent kit for treating a wound according to claim 1, wherein the first and second hemostatic compositions each comprise a cross-linked beta-cyclodextrin.
3. An absorbent kit for treating a wound according to claim 1, wherein the first and second hemostatic compositions are each in powder form.
4. An absorbent kit for the treatment of wounds according to claim 3, comprising a pharmaceutically acceptable diluent for reconstitution of any of the first and second hemostatic compositions.
5. An absorbent kit for treating a wound according to claim 1, wherein the first and second hemostatic compositions each comprise a respective cross-linking agent selected from the group consisting of: diglycidyl ether, epichlorohydrin, diisocyanate, dicarboxylic acid chloride, dicarboxylic acid, acid anhydride, poly (d, 1-lactic acid), citric acid, glycerol, dialdehyde, diacid chloride, and epoxide.
6. An absorbent kit for treating a wound according to claim 5, wherein the first and second hemostatic compositions differ from one another in at least one of amount and type of the respective cross-linking agent.
7. An absorbent kit for treating a wound according to claim 1, wherein the first and second hemostatic compositions each have an expansion capacity of about 38% to about 1600%.
8. An absorbent kit for treating a wound according to claim 1, wherein the second hemostatic composition is configured to absorb less fluid than the first hemostatic composition.
9. An absorbent kit for treatment of wounds according to claim 1, comprising at least one additive selected from the group consisting of water-soluble antimicrobial drugs, enzymes and growth factor agents.
10. An absorbent kit for treatment of wounds according to claim 1, wherein either of said first and second hemostatic compositions is mixed with at least one agent selected from the group consisting of: blood coagulation factors, fibrin, preservatives, antimicrobial agents, vitamins, micronutrients, antibiotic agents and antifungal agents.
11. A method of treating a wound, the method comprising:
selecting a hemostatic composition from a hemostatic composition set comprising at least (1) a first hemostatic composition comprising a first cross-linked polysaccharide selected from the group consisting of cyclodextrins and dextran, wherein the first hemostatic composition has a first degree of cross-linking, and (2) a second hemostatic composition comprising a second cross-linked polysaccharide selected from the group consisting of cyclodextrins and dextran, wherein the second hemostatic composition has a second degree of cross-linking that is higher than the first degree of cross-linking; and
Applying the selected hemostatic composition to the wound site.
12. The method of claim 11, wherein the hemostatic composition is selected according to a desired expansion capacity.
13. The method of claim 11, wherein the first and second hemostatic compositions each comprise a respective cross-linking agent selected from the group consisting of: diglycidyl ether, epichlorohydrin, diisocyanate, dicarboxylic acid chloride, dicarboxylic acid, acid anhydride, poly (d, 1-lactic acid), citric acid, glycerol, dialdehyde, diacid chloride, and epoxide.
14. The method of claim 13, wherein the first and second hemostatic compositions differ from each other in at least one of an amount and a type of the respective cross-linking agent.
15. The method of claim 11, wherein the hemostatic composition is selected according to a reaction parameter selected from the group consisting of reaction time, reaction temperature, and combinations thereof.
16. The method of claim 11, wherein the first and second hemostatic compositions each have an expansion capacity of about 38% to about 1600%.
17. The method of claim 11, wherein the second hemostatic composition is configured to absorb less fluid than the first hemostatic composition.
18. The method of claim 11, wherein the selected hemostatic composition is administered in powder form.
19. The method of claim 11, wherein prior to being applied to the wound site, either of the first and second hemostatic compositions is mixed with at least one agent selected from the group consisting of: blood coagulation factors, fibrin, preservatives, antimicrobial agents, vitamins, micronutrients, antibiotic agents and antifungal agents.
20. The method of claim 11, wherein at least one additive selected from the group consisting of water-soluble antimicrobial drugs, enzymes, and growth factor agents is administered with the selected hemostatic composition.
Background
Currently, hemostatic agents and sealants are used as an aid to stop bleeding, including bleeding, during surgery. FDA has approved for example
Gelatin is derived from animal products such as tendon collagen and skin. Certain hemostatic compositions of non-animal origin, such as polyanhydroglucuronic acid (polyhydroxyglucuronic acid), are of interest due to concerns about allergy to bovine animal-derived materials.
Disclosure of Invention
The present invention provides an absorbent kit for treating a wound comprising a hemostatic composition set comprising at least (1) a first hemostatic composition comprising a first cross-linked polysaccharide selected from the group consisting of a cyclodextrin and a dextran, and (2) a second hemostatic composition comprising a second cross-linked polysaccharide selected from the group consisting of a cyclodextrin and a dextran. In some embodiments, the first hemostatic composition has a first degree of cross-linking and the second hemostatic composition has a second degree of cross-linking that is higher than the first degree of cross-linking.
Currently, many hemostatic compositions for patients comprise animal-derived starting materials (e.g., gelatin) for preparing a hemostatic matrix. The compositions of the present invention use non-animal polysaccharide/starch polymers to prepare the hemostatic matrix.
In each or any of the above or below embodiments, the first and second hemostatic compositions can each include a cross-linked beta-cyclodextrin.
In each or any of the above or below embodiments, the first and second hemostatic compositions may each be in powder form.
In each or any of the above or below embodiments, the absorbent kit for the treatment of a wound may comprise a pharmaceutically acceptable diluent for reconstitution of any of the first and second hemostatic compositions.
In each or any of the above or below embodiments, the first and second hemostatic compositions may each comprise a respective cross-linking agent selected from the group consisting of: diglycidyl ether, epichlorohydrin, diisocyanate, dicarboxylic acid chloride, dicarboxylic acid, acid anhydride, poly (d, 1-lactic acid), citric acid, glycerol, dialdehyde, diacid chloride, and epoxides.
In each or any of the above or below embodiments, the first and second hemostatic compositions can differ from each other in at least one of an amount and a type of the respective cross-linking agent.
In each or any of the above or below embodiments, the first and second hemostatic compositions can each have an expansion capacity of about 38% to about 1600%.
In each or any of the above or below embodiments, the second hemostatic composition may be configured to absorb less fluid than the first hemostatic composition.
In each or any of the above or below embodiments, the absorbent kit for treating a wound may comprise at least one additive selected from the group consisting of water-soluble antimicrobial drugs, enzymes, and growth factor agents.
In each or any of the above or below embodiments, any of the first and second hemostatic compositions may be mixed with at least one agent selected from the group consisting of: blood coagulation factors, fibrin, preservatives, antimicrobial agents, vitamins, micronutrients, antibiotic agents and antifungal agents.
The invention also provides a method of treating a wound. The method comprises selecting a hemostatic composition from a hemostatic composition set comprising at least (1) a first hemostatic composition comprising a first cross-linked polysaccharide selected from the group consisting of cyclodextrin and dextran, wherein the first hemostatic composition has a first degree of cross-linking, and (2) a second hemostatic composition comprising a second cross-linked polysaccharide selected from the group consisting of cyclodextrin and dextran, wherein the second hemostatic composition has a second degree of cross-linking higher than the first degree of cross-linking. Applying the selected hemostatic composition to the wound site.
In each or any of the above or below embodiments, the hemostatic composition may be selected according to a desired expansion capacity.
In each or any of the above or below embodiments, the hemostatic composition may be selected according to a reaction parameter selected from the group consisting of reaction time, reaction temperature, and combinations thereof.
In each or any of the above or below embodiments, the selected hemostatic composition may be administered in powder form.
In each or any of the above or below embodiments, prior to being applied to the wound site, either of the first and second hemostatic compositions may be mixed with at least one agent selected from the group consisting of: blood coagulation factors, fibrin, preservatives, antimicrobial agents, vitamins, micronutrients, antibiotic agents and antifungal agents.
In each or any of the above or below embodiments, at least one additive selected from the group consisting of water-soluble antimicrobial drugs, enzymes, and growth factor agents may be administered with the selected hemostatic composition.
It is therefore an advantage of the present invention to provide a wound treatment absorbent kit having a set of hemostatic compositions that have a high degree of water absorption and that can rapidly expand for filling bleeding wounds.
It is a further advantage of the present invention to provide a process wherein the degree of water absorption and swelling can be controlled by varying the degree of crosslinking.
Additional features and advantages of the disclosed kits and methods are described in and will be apparent from the following detailed description and accompanying drawings. The features and advantages described herein are not all-inclusive and, in particular, many additional features and advantages will be apparent to one of ordinary skill in the art in view of the drawings and specification. Moreover, not all advantages listed herein are necessarily required of any particular embodiment. Moreover, it should be noted that the language used in the specification has been principally selected for readability and instructional purposes, and not to limit the scope of the inventive subject matter.
Drawings
Fig. 1 is a graph showing the water absorption kinetics of a crosslinked β -cyclodextrin polymer according to one embodiment of the present invention.
FIG. 2 shows FLOSEAL and FLOSEAL according to embodiments of the present inventionGraph of the water absorption kinetics of G-25, G-50, G-75 crosslinked dextran-based polymers.
Fig. 3 is a graph showing the degree of swelling caused by water absorption of a hydrophilic polymer relative to the degree of crosslinking thereof according to an embodiment of the present invention.
Detailed Description
The present invention provides an absorbent kit for treating a wound comprising a hemostatic composition set comprising at least (1) a first hemostatic composition comprising a first cross-linked polysaccharide selected from the group consisting of a cyclodextrin and a dextran, and (2) a second hemostatic composition comprising a second cross-linked polysaccharide selected from the group consisting of a cyclodextrin and a dextran. The hemostatic composition may be selected according to the desired expansion capacity. For example, the degree of water absorption and swelling can be controlled by varying the degree of crosslinking.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. The following references provide one skill in the general definition of many of the terms used in this invention: singleton et al, DICTIONARY of microbiology AND MOLECULAR BIOLOGY (DICTIONARY OFMICROBIOLOGY AND MOLECULAR BIOLOGY) (2 nd Ed., 1994); cambridge scientific and technological dictionary (THE CAMBRIDGEDICTIONARY OF SCIENCE AND TECHNOLOGY) (Walker, eds., 1988); GENETICS vocabulary (theogsasy OF GENETICS) 5 th edition, r.rieger et al (eds.), Springer Verlag (1991); and Hale & Marham, the Huppe-Colins DICTIONARY OF BIOLOGY (THE HARPER COLLINS DICTIONARY OF BIOLOGY) (1991).
As used in the present invention and the appended claims, unless the context clearly dictates otherwise, integers not having a particular number include plural integers as well as singular integers.
The following terms as used herein have the meanings assigned to them unless otherwise specified.
The term "about" or "approximately" refers to an acceptable error for a particular value as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the term "about" or "approximately" means within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" refers to within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% of a given value or range. Whenever the term "about" or "approximately" precedes the first value in a series of two or more values, it is understood that the term "about" or "approximately" applies to each value in the series.
"hemostatic composition" refers to a composition for stopping or reducing bleeding caused by injury or surgery and/or promoting the coagulation cascade. "flowable" composition or "hydrogel" refers to a substantially liquid, slightly viscous solution, solid, semi-solid, pseudoplastic, or plastic structure containing an aqueous component to produce a gelatinous or jelly-like mass or paste-like solution having the properties of being capable of flowing through a syringe or other device and being administered to a subject. The flowable hydrogel is a liquid, slightly viscous solution or a paste-like solution at room temperature and at body temperature. In some embodiments, a flowable composition is a composition that retains a shape when extruded through a syringe or other device for administration to a subject.
The absorbent kit for the treatment of wounds of the present invention comprises a hemostatic composition set comprising at least (1) a first hemostatic composition comprising a first cross-linked polysaccharide selected from the group consisting of a cyclodextrin and a dextran, and (2) a second hemostatic composition comprising a second cross-linked polysaccharide selected from the group consisting of a cyclodextrin and a dextran. Cyclodextrins are of three types: alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin. Alpha-cyclodextrin, beta-cyclodextrin and gamma-cyclodextrin consist of six, seven and eight alpha- (1, 4) -linked glucose monomers, respectively. By nature, cyclodextrins have a hydrophilic outer surface and a lipophilic central cavity. In some embodiments, the first and second hemostatic compositions may each include a cross-linked beta-cyclodextrin. In some embodiments, at least one of the first and second hemostatic compositions comprises a cross-linked dextran. The glucan has a chain length of 3-2000 kilodaltons.
In some embodiments, the first and second hemostatic compositions may each be crosslinked by carboxyl groups to form gel molecules that are readily capable of polar fluid absorption with swelling. In some embodiments, the crosslinking agent is selected from: diglycidyl ether, epichlorohydrin, diisocyanate, dicarboxylic acid chloride, dicarboxylic acid, acid anhydride, poly (d, 1-lactic acid), citric acid, glycerol, dialdehyde, diacid chloride, and epoxide.
In some embodiments, the absorbent kit for treating wounds may include at least one additive selected from the group consisting of water-soluble antimicrobial drugs, enzymes, and growth factor agents. In some embodiments, either of the first and second hemostatic compositions may be mixed with at least one agent selected from the group consisting of: blood coagulation factors, fibrin, preservatives, antimicrobial agents, vitamins, micronutrients, antibiotic agents and antifungal agents.
In some embodiments, each of the first and second hemostatic compositions may be in powder form. In some embodiments, a majority of the particles (e.g., more than 50% w/w, more than 80% w/w, or more than 90% w/w) included in the powdered hemostatic composition may have a particle size of 10 to 1000 μ ι η, 50 to 800 μ ι η, 50 to 700 μ ι η, 150 to 700 μ ι η, 200 to 700 μ ι η, 300 to 550 μ ι η, or 350 to 550 μ ι η. The hemostatic composition in powder form can be stable for long periods of time even at elevated temperatures (e.g., above 20 ℃, above 30 ℃, or even above 40 ℃). In some embodiments, the hemostatic composition has a water content of less than 15% (w/w), less than 10% (w/w), less than 5% (w/w), or less than 1% (w/w).
In some embodiments, the absorbent kit for the treatment of wounds can include a pharmaceutically acceptable diluent for reconstitution of either of the first and second hemostatic compositions. The powdered hemostatic compositions according to the present invention may rapidly expand upon exposure to a fluid (i.e., a pharmaceutically acceptable diluent) and, in this expanded form, can assist in the formation of a flowable paste that can be applied to a wound site. In some embodiments, the pharmaceutically acceptable diluent is an aqueous solution and may contain a diluent selected from NaCl, CaCl2Sodium acetate, sodium lactate, sodium citrate, sodium caprate and mannitol. For example, the pharmaceutically acceptable diluent comprises water for injection, and-each independently-50 to 200mM NaCl (e.g., 150mM), 10 to 80mM CaCl2(e.g., 40mM), 1 to 50mM sodium acetate (e.g., 20mM), and up to 10% w/w mannitol (e.g., 2% w/w). In some embodiments, the diluent may also include a buffer or buffer system to buffer the pH of the reconstituted dry composition to, for example, a pH of 3.0 to 10.0, a pH of 6.4 to 7.5, or a pH of 6.9 to 7.1.
In some embodiments, the first and second hemostatic compositions are each liquid-absorbing. For example, upon contact with a liquid, such as an aqueous solution or suspension (particularly a buffer or blood), the hemostatic composition absorbs the liquid and will exhibit a degree of swelling depending on the degree of hydration. The hemostatic composition may have an expansion capacity of about 38% to about 1600%, about 300% to about 1600%, about 400% to about 1300%, about 500% to about 1100%, or about 600% to about 900% by weight, depending on the use requirements or preferences of the particular hemostatic composition. Such equilibrium expansion can be controlled, for example, by varying the degree of crosslinking, which in turn is achieved by varying the crosslinking conditions, such as the type of crosslinking agent, the duration of exposure of the crosslinking agent, the concentration of the crosslinking agent, the crosslinking temperature, and the like.
Substances with different equilibrium expansion values behave differently in different applications. In some embodiments, the hemostatic composition may be selected according to the desired expansion capacity. In some embodiments, the hemostatic composition may be selected according to a reaction parameter selected from the group consisting of reaction time, reaction temperature, and combinations thereof. The ability to control cross-linking and balance swelling allows the compositions of the present invention to be optimally used for a variety of purposes: while rapid expansion may not be desirable in certain applications (e.g., neurosurgical applications), it may be desirable in trauma/military-type wounds.
The invention further provides a method of treating a wound. The method comprises selecting a hemostatic composition from a hemostatic composition set comprising at least (1) a first hemostatic composition comprising a first cross-linked polysaccharide selected from the group consisting of cyclodextrin and dextran, wherein the first hemostatic composition has a first degree of cross-linking, and (2) a second hemostatic composition comprising a second cross-linked polysaccharide selected from the group consisting of cyclodextrin and dextran, wherein the second hemostatic composition has a second degree of cross-linking higher than the first degree of cross-linking. Applying the selected hemostatic composition to the wound site.
While in certain embodiments, the dried composition may be administered directly to the target site (and optionally, contacted with a pharmaceutically acceptable diluent at the target site if necessary), it is contemplated that the dried hemostatic composition is contacted with a pharmaceutically acceptable diluent prior to administration to the target site in order to obtain a flowable hemostatic composition in a wet form (e.g., a hydrogel form). In some embodiments, either of the first and second hemostatic compositions may be mixed with at least one agent selected from the group consisting of: blood coagulation factors, fibrin, preservatives, antimicrobial agents, vitamins, micronutrients, antibiotic agents and antifungal agents. In some embodiments, at least one additive selected from the group consisting of water-soluble antimicrobial drugs, enzymes, and growth factor agents may be administered with the selected hemostatic composition. Once applied to a wound, the hemostatic, cross-linked polysaccharide polymers according to the invention form an effective matrix that can form a blood flow barrier. In particular, the swelling properties of the hemostatic polymer may make it a mechanical barrier that effectively inhibits bleeding and re-bleeding processes.
The following are non-limiting examples of hemostatic compositions according to the present invention. It will be appreciated by a person skilled in the art that variations of the following embodiments are possible within the scope of the invention, which is limited only by the claims.
Example 1
Beta-cyclodextrin is incorporated into a cross-linked polymer network of varying cross-link density. To obtain a high degree of crosslinking, about 10g of beta-cyclodextrin was mixed with about 10ml of epichlorohydrin and heated to about 90 ℃ while stirring in a 200ml three-necked flask equipped with a long back condenser of about 20 cm. A50% sodium hydroxide solution was slowly added dropwise to obtain a whitish precipitate. Heating was continued for about 2 hours with strong stirring. After cooling to room temperature, the gelled polymer was spooned out of the flask, washed repeatedly first with distilled water on a buchner funnel, followed by acetone, and dried in a vacuum oven at-30 torr and 50 ℃ overnight. The yield was 80% by weight.
A low degree of crosslinking was obtained using β -cyclodextrin with a polypropylene glycol diglycidyl ether PEG-DGE crosslinker (molecular weight 380 a.u.). About 8g of beta-cyclodextrin was mixed with 20ml of 50% sodium hydroxide and heated to about 130 ℃ while stirring in a 200ml three-necked flask equipped with a long back condenser of about 20 cm. After reaching 130 ℃, 20ml of PEG-DGE was added dropwise with vigorous stirring. The precipitate was stirred at 130 ℃ for more than about 2 hours and about 3ml of triethylamine was added. The mixture was left to stir overnight. After cooling to room temperature, a gel with strong gelling power (rubber gel) was obtained. The light brown portion was removed by repeated washing on a buchner funnel. The yield was 62% by weight.
The kinetics of fluid absorption were monitored using thermomechanical analysis (TMA) to measure the expansion due to fluid absorption. The swelling kinetics were obtained by measuring the swelling of the resin in a defined cylindrical volume by TMA as a function of time after the addition of water to the resin. The experimental results shown in fig. 1 list the following relationship between swelling level and degree of cross-linking in β -cyclodextrin: epichlorohydrin with a high degree of crosslinking causes less swelling, while diglycidyl ether with a low degree of crosslinking causes more swelling. Such a variety of swelling properties may be desirable to enable the clinician to select a particular absorbent/sealant for the depth and type of wound.