阅读说明：本技术 止血糊剂及其制备方法 (Hemostatic paste and preparation method thereof ) 是由 冯登敏 滕凌 张艳慧 倪国军 万翔 李玉甫 于 2018-07-20 设计创作，主要内容包括：本发明题为“止血糊剂及其制备方法”。本发明涉及一种包含交联的羧甲基纤维素和至少一种无毒分散剂的可流动的止血糊剂。更具体地,本发明涉及一种含有柠檬酸交联的CMC的止血糊剂,该止血糊剂作为粉末悬浮或分散在第一无毒含甘油的吸湿性分散剂和包括丙二醇或1,3-丁二醇的第二无毒醇官能化分散剂的混合物中。(The present invention is entitled "hemostatic pastes and methods of making same". The present invention relates to flowable hemostatic pastes comprising crosslinked carboxymethylcellulose and at least non-toxic dispersing agents, more specifically, hemostatic pastes containing citric acid crosslinked CMC suspended or dispersed as a powder in a mixture of non-toxic, glycerol-containing, hygroscopic dispersing agents and a second non-toxic alcohol-functionalized dispersing agent comprising propylene glycol or 1, 3-butylene glycol.)

1, A flowable haemostatic paste comprising:

a. a xerogel crosslinked milled polysaccharide dispersed within a substantially anhydrous blend of:

i. a dispersant containing glycerol, and

an alcohol-functionalized dispersant selected from propylene glycol and 1, 3-butylene glycol or mixtures thereof,

wherein the paste has a moderate viscosity at rest and room temperature and provides a substantially homogeneous dispersion of the cross-linked polysaccharide.

2. The hemostatic paste of claim 1, wherein the cross-linked polysaccharide comprises carboxymethyl cellulose (CMC) cross-linked by reaction via a multifunctional carboxylic acid, wherein the acid is selected from malic acid, tartaric acid, citric acid, malonic acid, succinic acid, glutaric acid, or adipic acid or mixtures thereof.

3. The hemostatic paste of claim 2, wherein the acid is citric acid.

4. The hemostatic paste of claim 3, wherein the paste comprises:

35 to 65% by weight of citric acid crosslinked CMC suspended or dispersed in powder form in a viscous liquid mixture of a glycerol-containing hygroscopic dispersant and an alcohol-functionalized dispersant comprising propylene glycol, 1, 3-butanediol, or a mixture thereof.

5. The hemostatic paste of claim 4, wherein the crosslinked CMC is a suspended powder having an average particle size of less than 100 microns.

6. The hemostatic paste of claim 5, wherein the paste comprises less than 1% water.

7. The hemostatic paste of claim 5, wherein the paste further comprises an alkaline agent.

8. The hemostatic paste of claim 7, wherein the basic neutralizing agent comprises sodium hydroxide present at about 0.1% to 3%.

9. The hemostatic paste of claim 5 wherein glycerin-containing dispersant is present in the paste at 10 to 30% by weight and the second non-toxic dispersant is present in the paste at 10 to 30% by weight.

10. The hemostatic paste of claim 5, wherein the paste comprises propylene glycol and glycerin in a weight ratio of about 1: 0.5 to about 1: 2.

11. The hemostatic paste of claim 5, wherein the paste comprises

a. About 49% to 55% citric acid crosslinked CMC;

b. about 18% to 30% glycerin;

c. about 15% to 30% propylene glycol.

12. The hemostatic paste of claim 5, wherein the weight ratio of citric acid crosslinked CMC to glycerol-containing dispersant is about 0.9 to 1.25.

13. The hemostatic paste of claim 5, wherein the paste is carried on a substrate that is a flexible bioabsorbable sheet.

14. The hemostatic paste of claim 15, wherein the substrate comprises oxidized cellulose or polyglactin 910.

15. The hemostatic paste of claim 5, wherein the paste is disposed in a squeezable tube.

16, A method of preparing a flowable hemostatic paste, comprising the steps of:

a. crosslinking the CMC by reacting the CMC with an acid at an elevated temperature;

b. substantially drying the crosslinked CMC to form a xerogel;

c. grinding the crosslinked CMC xerogel to a powder having an average particle size of less than 100 microns;

d. adding at least selected alcohol-functionalized dispersants and glycerol-containing dispersants to the CMC xerogel, and

e. mixing to form the flowable hemostatic paste.

17. The method of making a flowable hemostatic paste of claim 16, further comprising the step of dissolving an alkaline neutralizing agent in the glycerol-containing dispersant at a temperature above 65 ℃ prior to addition to the CMC xerogel.

18, A method of making a wound dressing comprising the hemostatic paste of claim 5, comprising the steps of:

a. applying the hemostatic paste to at least sides of a flexible bioabsorbable sheet substrate.

19, method of making the wound dressing of claim 18, wherein the flexible bioabsorbable sheet is in the form of a woven mesh, a structured felt, an unstructured felt, a film, a powder, or a combination thereof, and contains or more layers of oxidized cellulose, hemostatic polymer blend, or a mixture thereof.

20, a method of using the hemostatic paste of claim 5, comprising the steps of:

a. applying the hemostatic paste, optionally carried on a flexible absorbent sheet substrate, to a bleeding tissue or wound.

Technical Field

The present invention relates generally to agents and materials for promoting hemostasis and tissue sealing, and more particularly, to fast-swelling, highly absorbent hemostatic compositions in the form of a paste comprising a mixture of cross-linked carboxymethylcellulose and or more dispersing agents, and to methods for making and using such hemostatic compositions.

Background

In many cases, animals (including humans) may bleed from wounds or during surgery, in cases bleeding is relatively light, requiring only normal blood clotting functions in addition to simple first aid application.

Bleeding during surgery can occur in a variety of forms. It may be discrete or diffuse from a large surface area. It may be from large or small vessels, high or low volume arteries (hyperbaric) or veins (hypobaric). It may be easily accessible or it may originate from a location that is difficult to access. Controlling bleeding during surgery is vital and critical to minimize blood loss, reduce postoperative complications, and shorten the length of the procedure in the operating room. The selection of an appropriate method or product for controlling bleeding depends on a number of factors including, but not limited to, bleeding severity, anatomical location of the bleeding source and proximity of adjacent critical structures, whether the bleeding is from a discrete bleeding source or from a broader surface area, visibility and accurate identification of the bleeding source, and access to the bleeding source.

Conventional methods of achieving hemostasis include the use of surgical means, sutures, ligatures or clamps, and energy-based coagulation or cauterization. When these conventional measures are ineffective or impractical, adjunct hemostatic means and products are often utilized.

Topical Absorbent Hemostats (TAH) are widely used in surgical applications, TAH encompasses various forms of products such as woven or non-woven fabric or sponge based and is typically made of at least partially resorbable materials ranging from natural polymers to synthetic polymers and combinations thereof, including lactide-glycolide based copolymers such as polyglactin910, oxidized cellulose, Oxidized Regenerated Cellulose (ORC), gelatin, collagen, chitin, chitosan, starch, etc. gelatin is used in various forms with or without topical thrombin solution in addition is a bioactive topical hemostatic product (topical thrombin solution, fibrin sealant, etc.) and a variety of synthetic topical sealants.

To improve hemostatic properties, scaffolds based on the above TAH materials can be combined with biologically derived clotting factors such as thrombin and fibrinogen.

Due to their biodegradability and their bactericidal and hemostatic properties, oxidized cellulose and oxidized regenerated cellulose have long been used as topical hemostatic wound dressings in a variety of surgical procedures, including neurosurgery, abdominal surgery, cardiovascular surgery, thoracic surgery, head and neck surgery, pelvic surgery, and skin and subcutaneous tissue surgery. Various methods are known for forming various types of hemostatic agents based on oxidized cellulose materials, whether prepared in powder, woven, nonwoven, knitted, or other form. Hemostatic wound dressings currently in use comprise a knitted or nonwoven fabric comprising Oxidized Regenerated Cellulose (ORC), which is oxidized cellulose with increased uniformity of cellulose fibers.

Fibrinogen and thrombin are key proteins involved in achieving hemostasis after vascular injury and are critical for blood clot formation. The fibrinogen and thrombin can be combined in powder form or in a non-aqueous suspension without initiating the typical clotting reaction, thereby preventing the formation of a fibrin clot until the protein is hydrated in an aqueous medium or other liquid environment in which the protein is soluble. These admixtures of proteins in powder form have a variety of potential biomedical applications, including topical hemostasis, tissue repair, drug delivery, and the like. Additionally, these admixtures of proteins in powder form can be loaded onto a carrier or substrate or other medical device to form a product that can be used, for example, as a hemostatic device.

Fibrin sealants (also known as fibrin glues) have been used clinically for decades. Typically, fibrin sealants are composed of two liquid components (a fibrinogen-containing component and a thrombin-containing component) that are cryopreserved due to their inherent instability. Sometimes fibrin sealant products consist of two lyophilized components that need to be reconstituted immediately prior to use and delivered by a combination syringe or other dual barrel delivery device. Lyophilized formulations are generally stable, but the fibrinogen component is difficult to reconstitute. Many hemostatic formulations currently available on the market or under development utilize lyophilized fibrinogen (typically in combination with lyophilized thrombin), wherein the hemostatic formulation is applied in the form of a dry powder, a semi-liquid paste, a liquid formulation or optionally disposed on a load-bearing scaffold such as an absorbent fabric scaffold.

To provide dressings with enhanced hemostatic and tissue sealing and adhesion properties, therapeutic agents (including but not limited to thrombin, fibrin, and fibrinogen) have been combined with dressing carriers or substrates (including gelatin-based carriers, polysaccharide-based carriers, glycolic acid or lactic acid-based carriers, and collagen matrices).

U.S. patent 8,858,969 entitled "hemostasis compositions, devices, and methods" discloses Hemostatic devices that include a container comprising a bottle, vial, canister, tube, or reservoir having an internal enclosure containing a flowable Hemostatic composition comprising clay dispersed in an aqueous medium, wherein at least about 50% of the clay comprises particles having a particle size between about 1nm and 10 μm, wherein the composition is a liquid that is substantially free of visible clay particles such that no appreciable number of the clay particles settle out of the liquid when at rest for at least about 12 hours, and wherein the composition is sterilized, and a dispensing means in fluid communication with the container, wherein the device is configured such that the dispensing means is capable of dispensing the Hemostatic composition directly from the container to a bleeding area of an animal or human.

U.S. patent publication 2014/0369991 entitled "Formulations for Wound Therapy" discloses pharmaceutical compositions comprising an absorbent carrier of a biocompatible, biodegradable polymer and a dispersion comprising about 0.1mg/cm at least partially through or on the absorbent carrier²To 15mg/cm²In an amount of about 0.01IU/cm and/or containing fibrinogen²To 500IU/cm²Wherein the microparticles further comprise a glassy carrier.

U.S. patent publication 2016/0206773 entitled "Composition and Method for storing hemorrhages, Infection, and associated sealing in variations Types of wooden or Burns" discloses compositions comprising a hydrogel matrix comprising at least polymers crosslinked to both hyaluronic acid and alginic acid via ionic or covalent bonds, wherein the at least polymers are selected from chitosan, poly L-lysine, or combinations thereof.

U.S. patent 9,265,858 entitled "Dry haemostasis composition" discloses a process for preparing a Dry composition suitable for use in haemostasis and wound healing comprising the sequential steps of a) providing a cross-linked biocompatible polymer in powder form, one or more polyols and an aqueous medium, wherein the one or more polyols are selected from sugar alcohols and sugars, b) mixing the biocompatible polymer, one or more polyols and the aqueous medium to obtain a paste, and c) freeze drying the paste to produce a Dry composition, wherein the Dry composition is capable of being reconstituted without mechanical mixing to form a substantially homogeneous paste, wherein the Dry composition comprises from 10% w/w to 60% w/w of one or more polyols.

U.S. patent No. 2,772,999 entitled "Hemostatic therapeutic compositions and methods" discloses surgical compositions for blood coagulation comprising a Hemostatic amount (at least about 2%) of a cellulose derivative selected from the group consisting of free cellulose glycolate ethers and free cellulose hydroxypropionate ethers, the cellulose derivative having a degree of substitution of at least about 0.5 and a degree of neutralization in the approximate range of 0 to 60% but low enough such that the cellulose has a free carboxyl content of at least 0.5 per glucose unit.

U.S. patent publication 2004/0101548 entitled "Hemostatic wound dressing contacting aldehyde-modified Hemostatic dressing" discloses Hemostatic wound dressings comprising a substrate for contacting a wound, the substrate comprising a wound contacting surface, and a biocompatible, aldehyde-modified polysaccharide, wherein the wound dressing is a Hemostatic agent.

European publication EP1493451 entitled "Hemostatic devices and methods of manufacturing same" discloses compositions comprising biocompatible oxidized cellulose particles having an average specified nominal particle size of about 0.035mm to about 4.35mm, and a biocompatible porous water-soluble or water-swellable polysaccharide binder component, wherein the composition is suitable for use in a Hemostatic device.

Us patent 3,328,259 entitled "Dressing for a wound containing a static agent and method of treating a wound" discloses dressings for wounds comprising a flexible body sufficiently large to cover an open lesion as a Dressing, said body 40 containing a water-soluble plasma-soluble cellulose derivative having haemostatic and film-forming properties and having properties to bind with plasma in a wound to form an artificial water-insoluble eschar with said plasma, said cellulose derivative being present in said body in an overall non-discrete form and being proportioned such that said body effectively coagulates plasma exuding from a moist lesion to which the Dressing is applied.

U.S. patent publication No. 2007/0207180 entitled "Synthetic polypeptide-associating biological application material and film-forming material" discloses biological application-type materials containing polypeptides including Synthetic polypeptides having at least amino acid sequences represented by the formula Pro-Y-Gly, wherein Y represents Pro or Hyp, and forming a collagen-like structure.

U.S. patent publication 2012/0070470 entitled "Hemostatic compositions, devices, and methods" discloses blood clotting agents comprising a composition comprising clay dispersed in a liquid medium, wherein the clay is less than about 10% by weight of the composition, and wherein the composition comprising the liquid medium and the clay has a viscosity of about 1000cP or less.

U.S. patent publication 2002/0197302 entitled "Hemostatic polymer useful for rapid blood clotting and clot formation" discloses methods for hemostasis that include applying to a bleeding site a dry dressing comprising a matrix containing a Hemostatic-promoting amount of a Hemostatic agent that promotes blood clotting and clot formation at the interface between the wound surface and the Hemostatic region for a period of time sufficient to cause rapid blood clotting at the site, and removing the dressing after blood at the bleeding site has coagulated.

U.S. patent publication 2005/0226916 entitled "Hemostatic polymer useful for Rapid blood coagulation and hemostatis" discloses methods for promoting blood clotting at a bleeding site in a mammal, the method comprising administering to the bleeding site a composition comprising porous polymer spheres, and allowing the blood clotting to occur at the bleeding site.

Chinese patent publication CN101001649A entitled "haemostasis composition comprising hyaluronic acid" discloses Haemostatic compositions comprising a bioabsorbable material and Hyaluronic Acid (HA) or a derivative thereof.

U.S. Pat. No. 4,002,173 entitled "A Diester crosslinked polyglucans hydrogels and particulate polysaccharides thermoof" relates to hydrogel compositions of Diester crosslinked polyglucans and methods of making the same.

Chinese patent application publication CN102379827A entitled "tooth contacting teeth and preparation method of" relates to toothpastes having CMC as of its components.

U.S. patent publication 2005/0037088 entitled "processing of flowable pharmaceutical compositions and devicescontinging compositions" discloses a Process for preparing a flowable hemostatic composition comprising introducing volumes of a biocompatible liquid into a mixing vessel equipped with means for mixing the liquid, introducing volumes of a biocompatible gas into the volumes of liquid while the means for mixing operates under conditions effective to mix the liquid and the gas at to form a foam comprising a discontinuous gas phase comprising the gas substantially uniformly dispersed throughout a continuous liquid phase comprising the liquid, introducing amounts of solid particles suitable for hemostasis and substantially insoluble in the liquid into the foam, and mixing the foam and the solid particles at under conditions effective to form a substantially uniform composition comprising the substantially uniformly dispersed throughout the continuous liquid phase and the discontinuous gas phase, wherein the ratio of the discontinuous gas phase to the solid particles is effective to provide a uniform hemostatic composition having the properties and the flowable volume of the liquid and the hemostatic composition.

U.S. patent publication 2005/0284809 entitled "dynamic compositions and devices" discloses a plurality of filled particles that include interstitial pores as compared to a plurality of unfilled particles of the same material: the mesopores having a pore volume and a median pore diameter effective to improve absorption of physiological fluid or aqueous medium into said mesopores upon contact therewith, said particles comprising a biocompatible material and having a median diameter suitable for providing hemostasis to a body site of a mammal in need thereof.

Us patent 7,083,806 entitled "Wound gels" discloses hydrogels comprising pre-crosslinked gelling agents, water and a poloxamer, wherein the poloxamer concentration is between 10 and 25% by weight of the hydrogel and the gelling agent comprises at least crosslinked superabsorbent polysaccharides, the hydrogels exhibiting heat-induced viscosification at a temperature between ambient and 35 ℃, and wherein the hydrogels have the ability to absorb at least 50% additional water in addition to already present water, thereby indicating the presence of water in the hydrogel.

European publication 1942117A1, entitled "Derivatives of acid polysaccharides", discloses acidic polysaccharides, characterized in that, due to the formation of cross-links between the polysaccharide chains, partial esters with non-polysaccharide carboxylic acids are present simultaneously with the esters formed between the acid groups of the starting polysaccharide and the alcohol groups of the repeating units.

U.S. Pat. No. 9,353,191 entitled "Method for producing hydrogels" discloses polymeric hydrogels consisting essentially of carboxymethylcellulose crosslinked with citric acid, characterized in that (a) has a tap density of at least 0.5g/cm³(ii) a And (b) a media uptake rate in simulated gastric fluid/water (1: 8) of at least about 50 at 37 ℃.

U.S. patent 8,658,14782 entitled "polymers and methods of preparation of thermal of" (also European patent publication EP2532685A1) discloses methods of treating obesity in a subject in need thereof, the method comprising the step of orally administering to the subject a therapeutically effective amount of a Polymer hydrogel comprising carboxymethylcellulose covalently crosslinked with citric acid.

U.S. patent No. 5,905,092 entitled "Topical anti-inflammatory composition providing a moist environment for a wound, the composition comprising a Topical semisolid capable of providing a moist environment for a wound by promoting drying of an elevated content of water in the wound and promoting a reduced content of water in the wound with excess exudate, and a carrier capable of incorporating water to at least about 30% of its initial applied weight while also maintaining at least about 70% of its applied weight over two hours when placed on a non-absorbent surface, an antibiotic formulation, and at least 60% by weight water, wherein the Topical semisolid comprises from about 10% to about 20% by weight of a polyol and from about 0.5% to about 10% by weight of each of two or more gelling agents selected from hydroxyethylcellulose, a polyvinyl pyrrolidone/ammonium phosphate cross-linked polymer, and a polyvinyl pyrrolidone/ammonium phosphate cross-linking agent.

U.S. patent publication 2013/0108682 entitled "round car Product Comprising a Cathelicidin Polypeptide" discloses Wound Care products Comprising a Wound Care material and a Polypeptide having Wound healing properties, wherein the Polypeptide having Wound healing properties is an antimicrobial peptide or a fragment, variant or fusion thereof that at least partially retains the Wound healing activity of the antimicrobial peptide.

U.S. patent 8,829,053 entitled "Biocidal compositions and methods of using the same" discloses antimicrobial compositions comprising at least amounts of polymeric biguanides in at least 0.05% by weight, a chelating agent in a concentration of 0.01% to 1% by weight, and an vicinal diol component comprising at least monoalkyl diols and at least monoalkyl glycerols, wherein the weight ratio of the at least polymeric biguanides to the vicinal diol component is in the range of 1: 0.05 to 1: 500, wherein the antimicrobial composition kills at least 99.99% of organisms in a biofilm during ten minutes of treatment with the antimicrobial composition.

U.S. patent publication 2014/0105950 entitled "Haemostatic Material" discloses hemostatic materials comprising a hemostatic agent selected from the group consisting of oxidized regenerated cellulose, kaolin, gelatin, calcium ions, zeolites, collagen, chitosan, and chitosan derivatives, and a bioadhesive.

The article "Novel superabsorbent cellulose-Based Hydrogels Crosslinked with Citric Acid" ("Novel superabsorbent cellulose-Based Hydrogels Crosslinked with Citric Acid", Christian Demitri, et al, "Journal of Applied Polymer Science, Vol.110, 2453 and 2460(2008)) discloses the preparation of Novel environmentally friendly Hydrogels derived from cellulose and thus derived from renewable resources and characterized by biodegradability, two cellulose derivatives sodium carboxymethylcellulose (CMCNa) and Hydroxyethylcellulose (HEC) were used for the preparation of superabsorbent Hydrogels.

There is a need for improved hemostatic forms and materials that facilitate administration and rapid onset of hemostasis.

Disclosure of Invention

The present invention relates to flowable hemostatic pastes comprising cross-linked carboxymethylcellulose (CMC) and at least non-toxic dispersing agents for the purposes of this application, non-toxic means, i.e., materials generally regarded as safe according to or more food and/or drug related regulatory bodies, are now or in the future not limited to such GRAS materials only, but may also include other materials having similar safety characteristics and suitable for human consumption.

In some embodiments , the hemostatic paste comprises 35% to 65% by weight citric acid crosslinked CMC suspended or dispersed as a powder in a mixture of a nontoxic hygroscopic dispersant comprising glycerin, pharmaceutical grade in a thick liquid form, preferably substantially pure 100% glycerin, and a second nontoxic dispersant comprising propylene glycol, 1, 3-butylene glycol, or mixtures thereof, preferably a nontoxic hygroscopic dispersant.

In embodiments, the crosslinked CMC comprises a powder having an average particle size of less than 100 microns, and the paste is substantially free of water or substantially anhydrous in embodiments, the paste further comprises a basic neutralizing agent.

According to embodiments of the present invention, there is provided methods of preparing a flowable hemostatic paste comprising the steps of cross-linking CMC by mixing CMC with citric acid in the presence of water and reacting the CMC and citric acid at an elevated temperature, drying the cross-linked CMC, grinding the cross-linked CMC to a powder having an average particle size of less than 100 microns, adding glycerol to the CMC powder and mixing until a homogeneous dough-like material is formed, adding propylene glycol to the dough-like material and mixing thoroughly, thereby forming the flowable hemostatic paste.

According to embodiments of the invention, there is provided methods of using a hemostatic paste comprising the step of applying a hemostatic paste, optionally carried on a flexible absorbent sheet substrate, onto/into a bleeding tissue or wound.

Drawings

Fig. 1 shows a schematic route for the synthesis of cross-linked carboxymethylcellulose (CMC).

Fig. 2 is a photograph showing the hemostatic paste as it is delivered from the tube onto the substrate.

Fig. 3 shows the swelling of CMC-CA xerogel after 1min and 2.5min soaking in plasma, saline and water.

Fig. 4 shows the swelling of CMC-based xerogels crosslinked by different carboxylic acids after soaking for 1min and 2.5min when exposed to water.

Fig. 5 shows the swelling of xerogels prepared by cross-linking different polysaccharides with citric acid in a graph comparing the swelling in DI water, saline or porcine plasma.

Fig. 6 shows hygroscopic or anhydrous pastes relative to pastes containing 10% and 20% water.

Figure 7 shows hydrogel pastes containing 5% and 10% water in a slit dispensing tube.

Figure 8 shows a graph representing viscosity as a function of shear rate for different formulations of instant hemostatic pastes.

Figure 9 shows CMC-CA powder on bleeding sites (including puncture wounds) in animal models.

Fig. 10 shows the hemostatic paste being delivered accurately to the wound site.

Fig. 11 shows CMC-CA powder applied on a puncture model.

FIG. 12 shows an SEM micrograph of a CMC-CA powder-formed hydrogel

FIG. 13 shows a hemostatic paste of the present invention applied to a liver puncture model

Figure 14 shows a delivered hemostatic paste having a particle size of 100 μm to 300 μm.

FIG. 15 shows micrographs of CMC-CA xerogel powders with particle size < 100 μm.

Fig. 16 shows the test results for a hemostatic paste containing non-crosslinked CMC (comparative example).

Figure 17 shows the test results for a hemostatic paste containing CMC-CA (example of the invention).

Fig. 18 shows the test results of a hemostatic paste containing CA cross-linked carboxymethyl starch (comparative example).

Fig. 19 shows the test for tissue adhesion.

Figure 20 shows CMC-CA based hemostatic pastes of the present invention before, during, and after administration to a liver perforation model.

Fig. 21 shows the CMC-CA based hemostatic paste of the present invention applied to a commercially available Oxidized Regenerated Cellulose (ORC) based nonwoven mat.

Fig. 22 shows a CMC-CA based hemostatic paste applied to a commercially available Oxidized Regenerated Cellulose (ORC) based nonwoven pad and the resulting composite prior to testing for adhesion to a liver tissue coupon and after contact with the liver tissue coupon.

Detailed Description

The present invention relates generally to agents and materials for promoting hemostasis and tissue sealing, and more particularly, to fast-swelling, highly absorbent hemostatic compositions in the form of a paste comprising a mixture of cross-linked carboxymethylcellulose and or more dispersing agents, and to methods for making and using such hemostatic compositions.

component includes a xerogel powder synthesized by cross-linking carboxymethylcellulose (CMC) using a polyfunctional carboxylic acid such as citric acid (or malic acid, tartaric acid, citric acid, malonic acid, succinic acid, glutaric acid, adipic acid, and the like.) a xerogel is obtained when the liquid phase of the gel is removed by evaporation.

The crosslinked CMC may form a hydrogel when the xerogel is contacted with body fluids. Hydrogels are networks of hydrophilic polymer chains, which are sometimes found as colloidal gels, where water is the dispersion medium. The concentration of cross-linked CMC in the hemostatic paste is in the range of about 35% to 65% by weight. The second component comprises 10 to 30 wt% of a glycerol-containing dispersant. The third component comprises 10% to about 30% by weight of an alcohol functionalized dispersant, such as propylene glycol or 1, 3-butanediol. Hemostatic pastes are biocompatible to treat mild or moderate bleeding.

According to embodiments, the fast swelling, superabsorbent, biodegradable hemostatic paste comprises carboxymethyl cellulose cross-linked by citric acid (or similar polyfunctional carboxylic acid, e.g., malic acid, tartaric acid, citric acid, malonic acid, succinic acid, glutaric acid, adipic acid), as shown in the examples 35% to 65% as a fine powder suspended or dispersed in a mixture of a glycerin-containing nontoxic hygroscopic dispersant and a second nontoxic alcohol functionalized dispersant preferably comprising propylene glycol or 1, 3-butylene glycol for purposes of this application, paste means a flowable material having sufficient viscosity and cohesion to maintain a continuous single form at room temperature when placed on a flat, unrestricted flat surface aggregate of sand or similar particles is not a paste because the individual particles lack sufficient strength to each other.

The dried crosslinked CMC xerogel has a three-dimensional crosslinked polymer network that is capable of absorbing large amounts of water, saline, or physiological fluids to form a hydrogel. The strong osmotic action upon contact dehydrates and gels the blood and swells to more than 20 times the volume of the dry xerogel to fill the wound and create a "back pressure" in the confined wound space to simulate the packing effect and promote the natural clotting process. The fluidity and flexibility of the paste of the present invention also ensure that it enters narrow spaces and is applied to uneven surfaces, making it a material that can be used to address bleeding or oozing during surgery. The instant pastes are particularly useful in wounds that are difficult to access, such as tissue cracks or bleeding from cavities.

In alternative embodiments, the pastes of the present invention may also be used in combination with a backing, pad, scaffold or matrix to provide mechanical strength to cover the wound surface. In this case, the instant paste is carried on a pad for ease of application or padding.

In another embodiments, the immediate hemostatic paste can be used for sustained or delayed release of an active agent, for example, as a drug delivery vehicle the composition can incorporate growth factors, antibiotics, local anesthetics, and any agent useful for improving wound healing, preventing infection, or reducing pain the hemostatic effect of the paste can be further improved by incorporating blood coagulation activators, platelet activators or vasoconstrictors, inhibitors of fibrinolytic function, and the like (including thrombin, fibrinogen, and the like).

According to an embodiment of the present invention, the instant hemostatic paste is anhydrous and hygroscopic. It can absorb liquids such as water, blood, etc., and swell to form a hydrogel within seconds such as within 5 seconds, 20 seconds, 30 seconds, 50 seconds, 120 seconds, 300 seconds, more preferably within 5 seconds to 30 seconds.

The xerogel powder particles are suspended in the dispersant component of the hemostatic paste. The resulting paste is flowable and can be deposited into/on uneven surfaces or into narrow spaces.

The main component of the paste forming the xerogel is carboxymethyl cellulose, which is crosslinked by citric acid resulting in increased mechanical stability. Several polysaccharides exhibit high absorption capacity in an unmodified state, but these polysaccharides have the disadvantage that swelling and possibly dissolution only occurs in warm water. Such unmodified/uncrosslinked polysaccharides have low mechanical stability and may be subject to degradation and/or retrogradation and/or syneresis (gel shrinkage with separation of the liquid).

The inventors have observed that, although glycerol and propylene glycol are hydrophilic, the advantageously cross-linked CMC particles do not absorb anhydrous but hydrophilic glycerol and propylene glycol dispersants, while the particles are still able to rapidly absorb blood, plasma, water, body fluids.

Without wishing to be bound by any theory, the non-aqueous solvent/carrier/dispersant is external to the cross-linked network particle and should not affect its ability to absorb liquid. Absorption appears to be maximized by eliminating pre-swelling or pre-loading. The particles do not swell or absorb the selected solvent/carrier/dispersant, but can rapidly swell and absorb a maximum percentage of the plasma component when provided with plasma. The presence of compounds such as sorbitol in the crosslinking reaction solution may result in sorbitol being trapped within the crosslinked network. The entrapped sorbitol will then help to prevent excessive cross-linking by occupying network link spaces, and may also alter the hydrophilicity of the overall particle by absorbing water into the cross-linked particles. Thus, it is preferred that the present system be free of sorbitol or similar chemical moieties and/or excipients. The selected solvent/carrier/dispersant should not occlude the cross-linked network particles from the plasma components intended to be absorbed.