+

WO2018005145A1 - Composition de gel hémostatique fluide et ses méthodes d'utilisation - Google Patents

Composition de gel hémostatique fluide et ses méthodes d'utilisation Download PDF

Info

Publication number
WO2018005145A1
WO2018005145A1 PCT/US2017/038113 US2017038113W WO2018005145A1 WO 2018005145 A1 WO2018005145 A1 WO 2018005145A1 US 2017038113 W US2017038113 W US 2017038113W WO 2018005145 A1 WO2018005145 A1 WO 2018005145A1
Authority
WO
WIPO (PCT)
Prior art keywords
flowable
gel composition
solution
chitosan
applying
Prior art date
Application number
PCT/US2017/038113
Other languages
English (en)
Inventor
Victor Matthew Phillips
John Garner
Original Assignee
Victor Matthew Phillips
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US15/195,087 external-priority patent/US10660945B2/en
Application filed by Victor Matthew Phillips filed Critical Victor Matthew Phillips
Publication of WO2018005145A1 publication Critical patent/WO2018005145A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/36—Blood coagulation or fibrinolysis factors
    • A61K38/363—Fibrinogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/482—Serine endopeptidases (3.4.21)
    • A61K38/4833—Thrombin (3.4.21.5)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/06—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/106—Fibrin; Fibrinogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/10—Polypeptides; Proteins
    • A61L24/108—Specific proteins or polypeptides not covered by groups A61L24/102 - A61L24/106
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/04—Materials for stopping bleeding
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2400/00—Materials characterised by their function or physical properties
    • A61L2400/06—Flowable or injectable implant compositions

Definitions

  • the subject matter described herein relates generally to hemostatic compositions and, more particularly, to flowable hemostatic gel compositions configured for introduction to a site of a surgical incision or other defect within a biological tissue.
  • a method of inhibiting bleeding from a site of a defect within a biological tissue includes applying a flowable hemostatic gel composition to the site such that a biopolymer of the flowable hemostatic gel composition cross-links with red blood cells at the site to facilitate clot formation at the site.
  • the flowable hemostatic gel composition includes a flowable gel solution that includes the biopolymer dissolved in a first solvent, and at least one additional active agent.
  • a flowable hemostatic gel composition for use at a site of a defect within a biological tissue.
  • the flowable hemostatic gel composition includes a flowable gel solution that includes a biopolymer dissolved in a first solvent.
  • the biopolymer is configured to cross-link with red blood cells at the site to facilitate clot formation at the site.
  • the flowable hemostatic gel composition also includes at least one additional active agent.
  • FIG. 1 is a graph summarizing a gel strength as a function of sodium tripolyphosphatexhitosan mass ratio for various hemostatic gel compositions
  • FIG. 2 is a graph summarizing absorbance spectra of a buffered positive control sample including thrombin and a substrate, and a buffered negative control sample including the substrate only, using the buffer solution alone as a blank;
  • FIG. 3 is a graph summarizing absorbance spectra of the buffered positive control sample of FIG. 2 using the buffered negative control sample of FIG. 2 as a blank;
  • FIG. 4 is a graph summarizing a release of enzymatically active thrombin from a hemostatic gel composition as a function of thrombin loading of the hemostatic gel composition
  • FIG. 5 is a flow diagram of an exemplary embodiment of a method of inhibiting bleeding from a site of a defect within a biological tissue.
  • the compositions and methods described herein relate to the inhibition of blood loss from a surgical incision or other defect within biological tissue of a subject and, more particularly, to a flowable hemostatic gel composition and methods of inhibiting blood flow from a subject using the flowable hemostatic gel composition.
  • the flowable hemostatic gel composition includes a gel solution formed from a hemostatic biopolymer dissolved in a first solvent.
  • the flowable hemostatic gel composition further includes at least one additional active agent.
  • the at least one additional active agent is provided by pre- dissolving it into the gel solution.
  • the at least one additional active agent includes a clotting agent, such as, but not limited to, thrombin.
  • the at least one additional active agent includes a bioadhesive additive, such as, but not limited to, poly(acrylic acid).
  • the flowable hemostatic gel composition further includes a flowable hardener solution that interacts with the gel solution to facilitate an improved occlusion and/or strength of the gel after application.
  • the hardener solution includes sodium tripolyphosphate (NaTPP) dissolved in a second solvent.
  • the defect within biological tissue is associated with a medical procedure, such as, but not limited to, general surgery, thoracic/pulmonary surgery, colon resection, hepatobiliary surgery, pancreatic surgery, gynecologic surgery, orthopedic surgery, trauma surgery, ear-nose-throat (ENT) surgery, cosmetic surgery, urological procedures, neurosurgery, and cardiovascular surgery.
  • a medical procedure such as, but not limited to, general surgery, thoracic/pulmonary surgery, colon resection, hepatobiliary surgery, pancreatic surgery, gynecologic surgery, orthopedic surgery, trauma surgery, ear-nose-throat (ENT) surgery, cosmetic surgery, urological procedures, neurosurgery, and cardiovascular surgery.
  • the defect is suture lines created in one of aortic root repair, aortic arch repair, aortotomy, aortic reconstruction, CABG, LVAD implantation, carotid endarterectomy, abdominal aortic aneurysm repair, and femoral bypass (fem-fem bypass or fem-pop bypass).
  • the flowable nature of the flowable hemostatic gel composition facilitates application of the biopolymer and the at least one additional active agent directly to all portions of the site of the surgical incision or other defect, and the surrounding biological tissues.
  • the composition inhibits blood loss from the incision or other defect.
  • the biopolymer of the flowable hemostatic gel composition rapidly cross-links with red blood cells at the site to facilitate clot formation at the site.
  • the at least one incorporated active agent is released in active form to further facilitate inhibition of blood loss from the site by, for example, enhancing blood clotting and/or adhesion of the gel to the tissues surrounding the site.
  • the at least one active agent is selected to provide an additional benefit, such as to prevent infection or otherwise accelerate healing.
  • the flowable hemostatic gel composition safely biodegrades in vivo, eliminating a need for any secondary removal process.
  • the flowable hemostatic gel composition includes a gel solution formed from the biopolymer dissolved in a first solvent.
  • the gel solution includes chitosan dissolved in a dilute acid selected from a lactic acid solution or an acetic acid solution.
  • the biopolymer and first solvent of the gel solution are selected to be any suitable materials, as described in detail below.
  • the gel solution is formulated to enable at least one property such as, but not limited to, viscosity or injectability of the gel solution; hemostatic properties of the gel solution; suitability of the flowable hemostatic gel composition for certain surgical methods and/or injection devices; and any other relevant property.
  • the properties of the flowable hemostatic gel composition are governed by at least one of the composition of the gel solution; the selection of the at least one additional active agent in the flowable hemostatic gel composition; the method of introducing the flowable hemostatic gel composition to the incision site; and any other relevant property.
  • the biopolymer includes at least one polycationic polymer.
  • the charges distributed within the polycationic polymer impart bioadhesive properties to enable the binding of a hemostatic gel containing the polycationic polymers to negatively charged surfaces including, but not limited to, biological tissues in the vicinity of a site of a biological defect.
  • the polycationic biopolymers cross-link with negatively charged red blood cells at the site to facilitate clot formation at the site, and further link the clot to the biological tissues proximate the site to facilitate clot retention at the site.
  • Non- limiting examples of polycationic polymers suitable for inclusion in the gel solution include: chitosan, chitin, diethylaminoethyl-dextran, diethylaminoethyl-cellulose, diethylaminoethyl- agarose, diethylaminoethyl-alginate, any other polymer modified with a diethylaminoethyl group, any polymer containing a plurality of protonated amino groups, any polypeptide having an average residue isoelectric point above about 7, and any combination thereof.
  • chitosan is selected as the polycationic polymer.
  • Chitosan describes a naturally occurring linear polysaccharide composed of randomly distributed P-(l-4)-2-amino-2-D-glucosamine (deacetylated) and ⁇ -(1-4)-2- acetamido- 2-D-glucoseamine (acetylated) units.
  • Chitosan may be derived from chitin, a naturally occurring polymer isolated from fungi, mollusks, or from the exoskeletons of arthropods (e.g., crustaceans and insects).
  • Chitosan is produced by subjecting chitin to a process of alkaline deacetylation. As described more generally above, without being limited to any particular theory, positive charges along the backbone of chitosan cause it to interact electrostatically with negatively charged blood cells, thus creating a sticky interface between the chitosan within the hemostatic hydrogel composition and red blood cells proximate the site. In addition, chitosan is also known to possess inherent anti-microbial properties.
  • the chitosan is produced using an alkaline deacetylation of chitin using a strong alkaline solution according to suitable methods.
  • any chitin-based biopolymer with a degree of deacetylation greater than about 50% is referred to as chitosan.
  • the degree of deacetylation of the chitosan may influence the characteristics of the hemostatic gel in which the chitosan is included.
  • characteristics of the hemostatic gel that may be influenced by the degree of acetylation of the chitosan include bioadhesive properties, and resistance to premature degradation in vivo at the surgical site.
  • the chitosan is provided in any suitable form including, but not limited to, powder, coarse ground flakes, or dissolved in a weak acid solvent.
  • the molecular weight of the chitosan is in a range from about 60 kDaltons to about 375 kDaltons (viscosity-average molecular weight M v ).
  • the inclusion of chitosan of relatively higher molecular weight, such as at least 150 kDaltons results in relatively slower degradation in vivo.
  • Chitosan is degraded in vivo by, for example, lysozyme, N-acetyl-o- glucosaminidase, and lipases, and the byproducts of chitosan degradation are saccharides and glucosamines that are gradually absorbed by the body. Therefore, no secondary process for removal from the body is required.
  • Chitosan compositions having a 50% degree of deacetylation are highly degradable in vivo. As the degree of deacetylation increases, chitosan becomes increasingly resistant to degradation. Chitosan compositions having a degree of deacetylation that is higher than 95% degrade slowly over weeks or months.
  • the degree of deacetylation of the chitosan in the gel solution is in a range from about 50%) to about 100%>. Moreover, in some embodiments, the degree of deacetylation is in a range from about 50% to about 80%>. Moreover, in certain embodiments, the degree of deacetylation is in a range from about 65%> to about 80%>. In particular embodiments, the degree of deacetylation of the chitosan in the gel solution is about 75%.
  • the first solvent is selected to be a dilute acid solution, such as an aqueous solution that includes at least one of acetic, citric, oxalic, proprionic, ascorbic, hydrochloric, formic, lactic, or any other suitable organic or inorganic acid, in a range from about 0.1%> to about 5% (v/v).
  • a dilute acid solution such as an aqueous solution that includes at least one of acetic, citric, oxalic, proprionic, ascorbic, hydrochloric, formic, lactic, or any other suitable organic or inorganic acid, in a range from about 0.1%> to about 5% (v/v).
  • at least one polycationic polymer selected as the biopolymer is substantially insoluble in water and organic solvents, but is fairly soluble in dilute acid solutions.
  • the dilute acid is selected to influence at least one property of the gel solution including, but not limited to, susceptibility to degradation in vivo.
  • a concentration of the dilute acid and/or a time period over which the chitosan is dissolved in the dilute acid is selected to influence at least one property of the gel solution, including, but not limited to, susceptibility to degradation in vivo.
  • the dilute acid is 1%> L-lactic acid (v/v).
  • the dilute acid is 1%> acetic acid (v/v).
  • the concentration of the biopolymer dissolved in the first solvent is selected to enable delivery of an effective amount of the biopolymer while maintaining a flowable viscosity of the gel solution or flowable hemostatic gel composition.
  • the gel solution includes 1%> w/v chitosan dissolved in 1%> acetic acid, and has a viscosity in a range from about 200 centipoise (cP) to about 2000 cP.
  • the gel solution includes 1% w/v chitosan of a relatively high molecular weight, as described above, dissolved in 1% acetic acid, and the gel solution has a viscosity in a range from about 800 cP to about 2000 cP.
  • the gel solution includes within a range of 2- 3% w/v chitosan of a relatively high molecular weight dissolved in 1% L-lactic acid, and the gel solution has a viscosity of about 1500 cP.
  • a strength of the acid is selected to result in a pH of at least about 4. In particular embodiments, the strength of the acid is selected to result in a pH of at least about 2.
  • the at least one additional active agent is selected to include at least one clotting agent.
  • the at least one additional active agent is incorporated into the hemostatic gel composition such that it is released from the resulting clot in a predetermined release profile.
  • Non-limiting examples of clotting agents suitable for inclusion in the hemostatic gel composition include thrombin, fibrinogen, and any combination thereof.
  • "U” refers to an NIH-defined activity unit that corresponds to about 0.324 ⁇ g of enzymatically active thrombin.
  • the gel solution includes an amount of thrombin in a range from about 0.5 U to about 200 U per gram of chitosan in the gel solution.
  • the gel solution includes an amount of thrombin in a range from about 2 U to about 160 U per gram of chitosan in the gel solution.
  • a given amount of thrombin combined with chitosan results in greater thrombin enzymatic activity than does the given amount of thrombin in an absence of chitosan.
  • higher amounts of chitosan result in increased activity of the thrombin.
  • an amount of thrombin included in the flowable hemostatic gel composition is selected by a physician depending on factors associated with the patient.
  • the at least one clotting agent is incorporated into the flowable hemostatic gel composition in any suitable fashion.
  • the at least one clotting agent is dissolved into the gel solution at any suitable time prior to injection at the site.
  • Certain clotting agents such as, but not limited to, thrombin, include protein-based enzymes subject to denaturing or damage that reduce a capability to perform enzymatic activity.
  • the gel solution is formulated to maintain the clotting agent in an enzymatically active state.
  • the ingredients of the gel solution may be selected to maintain parameters within suitable ranges to facilitate maintaining the clotting agent in an enzymatically active state.
  • solution conditions selected to maintain the clotting agent in an enzymatically active condition include pH, ionic concentrations, temperature, and any other relevant solution parameter.
  • the gel solution includes 2% w/v chitosan dissolved in a 1% (v/v) aqueous solution of L-lactic acid. Dissolving active thrombin in the gel solution and storing the thrombin-loaded gel solution at room temperature does not substantially reduce enzymatic activity of the thrombin. Moreover, maintaining the resulting flowable gel composition at 37 degrees C for a period of time ranging from about 30 minutes to several hours does not substantially reduce the enzymatic activity of the thrombin.
  • a predetermined release profile of each clotting agent from the flowable hemostatic gel composition after flowable introduction to the site is any suitable release profile.
  • the predetermined release profile is influenced by at least one factor such as, but not limited to, an amount of the clotting agent loaded in the flowable hemostatic gel composition, an incubation time of the clotting agent added to the gel solution, if any, with the biopolymer in the gel solution, and the manner and/or timing of mixing the gel solution.
  • the clotting agent is released at a relatively steady (zero- order) rate.
  • the release profile is characterized by an initial release of the clotting agent at a relatively high rate, followed by an extended release at a relatively lower steady rate.
  • the clotting agent is thrombin
  • the release profile is selected based on at least one factor such as, but not limited to, the type and size of a surgical incision creating the defect in the tissue, the method of application of the flowable hemostatic gel composition, and/or the amount of gel applied to the site.
  • the gel solution includes 2% w/v chitosan dissolved in a 1% (v/v) aqueous solution of L-lactic acid, and thrombin is dissolved in the gel solution.
  • the gel solution is incubated at room temperature for a period of time ranging from about 30 minutes to overnight prior to use in the hemostatic gel composition to enable the thrombin to form complexes with, or otherwise adhere to, the biopolymer in the gel solution, thereby forming a depot from which the thrombin may be released from the applied composition according to the predefined release profile.
  • the at least one additional active agent is selected to include at least one bioadhesive agent
  • the flowable hemostatic gel composition further includes a flowable hardener solution that includes a cross-linking agent dissolved in a second solvent.
  • the cross-linking agent in the hardener solution Upon interaction with the cross-linking agent in the hardener solution, the biopolymers within the gel solution cross-link to form a bioadhesive layer adhered robustly over the defect and surrounding biological tissues.
  • the defect may include a wound, an incision or other defect associated with a surgical procedure, or any other defect within one or more biological tissues of a subject.
  • the flowable hemostatic gel composition is formed at least partially by mixing the gel solution, which contains the hemostatic biopolymer dissolved in the first solvent, with a bioadhesive solution that contains the at least one additional bioadhesive agent dissolved in a third solvent.
  • additional bioadhesive agents include a high molecular weight polymer selected from poly(acrylic acid), poly(vinylpyrrolidinone), and poly(aciylamide-co-acrylic acid).
  • the at least one additional bioadhesive agent is dissolved in water at a concentration ranging from about 10% (w/v) to about 40% (w/v).
  • the at least one additional bioadhesive agent is dissolved in water at a concentration ranging from about 10%> (w/v) to about 20% (w/v), from about 15% (w/v) to about 25% (w/v), from about 20% (w/v) to about 30%) (w/v), from about 25% (w/v) to about 35% (w/v), and from about 30%> (w/v) to about 40% (w/v).
  • the at least one bioadhesive agent is incorporated into the flowable hemostatic gel composition in any suitable fashion.
  • at least one bioadhesive agent is dissolved directly into one or both of the gel solution and the hardener solution prior to mixture of the gel solution and the hardener solution proximate the site.
  • the flowable hemostatic gel composition includes 2% chitosan (w/v) dissolved in 1% L-lactic acid as the gel solution, mixed with 25% w/v poly(acrylic acid) dissolved in water as the bioadhesive solution.
  • the gel solution and the bioadhesive solution are mixed at a volume ratio (volume of gel solution: volume of bioadhesive solution) ranging from about 0.33 to about 3.
  • the volume ratio ranges from about 0.33 to about 1.0, from about 0.5 to about 1.5, from about 1.0 to about 2.0, from about 1.5 to about 2.5, and from about 2.0 to about 3.
  • the flowable hemostatic gel composition includes a mixture ratio of about 25% (v/v) of the bioadhesive solution (25% w/v poly(acrylic acid) dissolved in water) and about 75% (v/v) of the gel solution (2% (w/v) chitosan dissolved inl% L-lactic acid).
  • the cross-linking agent of the flowable hardener solution is selected for its capability to cross-link the biopolymer of the gel solution.
  • the cross- linking agent links chains of the biopolymer together to form a three-dimensional matrix of interconnected, linear, polymeric chains.
  • the linking of the chains of the biopolymer causes the flowable hemostatic gel composition to rapidly cure into the solid bioadhesive layer over the defect within the biological tissue.
  • the cross-linking agent is selected based upon at least one of the type of the polycationic polymer in the gel solution, the desired degree or extent of cross-linking, biocompatibility, and any other suitable factor.
  • Non-limiting examples of suitable crosslinking agents include sodium tripolyphosphate (NaTPP), ethylene glycol diglycidyl ether, ethylene oxide, glutaraldehyde, epichlorohydrin, diisocyanate, calcium chloride, and genipin.
  • NaTPP sodium tripolyphosphate
  • ethylene glycol diglycidyl ether ethylene glycol diglycidyl ether
  • ethylene oxide glutaraldehyde
  • epichlorohydrin diisocyanate
  • calcium chloride and genipin.
  • the cross-linking agent is selected to result in a cure time of less than about 10 seconds after the gel solution and flowable hardener solution are mixed together.
  • the cross-linking agent is selected to result in a cure time of less than about one of 7, 6, 5, 4, 3, or 2 seconds.
  • the biopolymer of the gel solution is chitosan
  • the cross-linking agent of the hardener solution is NaTPP.
  • the hardener solution includes NaTPP dissolved in water in a range from about 0.1% w/v to about 20% w/v.
  • the hardener solution includes NaTPP dissolved in water in a range from about 0.3% w/v to about 10% w/v.
  • the hardener solution includes NaTPP dissolved in water in a range from about 1% w/v to about 2% w/v.
  • the hardener solution includes NaTPP dissolved in water at about 2% w/v.
  • the volume of the hardener solution ranges from about 50% to about 200% of the volume of the gel solution. In various other embodiments, the volume of the hardener solution ranges from about 50% to about 100%, from about 75% to about 125%, from about 100% to about 150%, from about 125% to about 175%), and from about 150%) to about 200%> of the volume of the gel solution.
  • the flowable hemostatic gel composition includes the hardener solution and gel solution at a volume ratio of about 1 : 1 to form the bioadhesive layer over the defect within the biological tissue. Alternatively, the hardener solution is not used, and the cross-linking of the biopolymer with red blood cells at the site and/or the action of the at least one clotting factor at the site facilitates sufficient clotting at the site.
  • FIG. 5 is a flow diagram of an exemplary embodiment of a method 500 of inhibiting bleeding from a site of a defect within a biological tissue.
  • method 500 includes applying 510 a flowable hemostatic gel composition to the site such that a biopolymer of the flowable hemostatic gel composition cross-links with red blood cells at the site to facilitate clot formation at the site.
  • the flowable hemostatic gel composition includes a flowable gel solution that includes the biopolymer dissolved in a first solvent.
  • the flowable hemostatic gel composition also includes at least one additional active agent.
  • the step of applying 510 the flowable hemostatic gel composition includes flowing 515 the flowable hemostatic gel composition out of a lumen of an injection device.
  • the site includes an internal incision, and an outlet of the lumen of the injection device is positioned adjacent the internal incision to enable the flowable hemostatic gel composition to flow directly onto the site.
  • the biopolymer cross-links with red blood cells at the site to facilitate clot formation at the site, and/or links the clot to biological tissues proximate the site to facilitate clot retention at the surgical site.
  • an ability to apply the hemostatic gel composition in flowable form facilitates achieving hemostasis even for, but not only for, incisions that are difficult to access using traditional methods.
  • the step of applying 510 the flowable hemostatic gel composition includes applying 520 the biopolymer that is substantially polycationic dissolved in the first solvent that is a dilute acid.
  • the biopolymer is substantially chitosan and the first solvent is lactic acid, as described above.
  • the step of applying 510 the flowable hemostatic gel composition includes applying 525 the at least one additional active agent that includes at least one clotting agent.
  • the at least one clotting agent is at least one of thrombin and fibrinogen.
  • the biopolymer includes chitosan and the at least one clotting agent includes thrombin, such that a mass ratio of thrombin to chitosan (U:grams of chitosan) in the flowable hemostatic gel composition is in a range from about 0.5: 1 to about 200: 1, each U corresponding to about 0.324 ⁇ g of enzymatically active thrombin, as described above.
  • the step of applying 510 the flowable hemostatic gel composition further includes applying 530 the at least one additional active agent that is at least one bioadhesive agent, and applying 535 a flowable hardener solution that includes a cross-linking agent dissolved in a second solvent.
  • the at least one bioadhesive agent includes at least one of poly(acrylic acid), poly(vinylpyrrolidinone), and poly(aciylamide-co-acrylic acid), as described above.
  • the bioadhesive agent includes poly(acrylic acid) having a molecular weight of about 1800 Da.
  • the flowable hemostatic gel composition includes a mixture ratio of about 25% (v/v) of a bioadhesive solution and about 75% (v/v) of the gel solution, in which the bioadhesive solution is about 25% w/v poly(acrylic acid) dissolved in water, and the gel solution is about 2% (w/v) chitosan dissolved inl% L-lactic acid, as described above.
  • the flowable hardener solution includes sodium tripolyphosphate (NaTPP) dissolved in water.
  • NaTPP sodium tripolyphosphate
  • the flowable hardener solution includes about 2% w/v of sodium tripolyphosphate (NaTPP) dissolved in water, as described above.
  • the flowable gel solution and the flowable hardener solution are applied at a volume ratio of about 1 : 1, as described above.
  • the flowable gel solution and the flowable hardener solution are mixed together to form the flowable hemostatic gel composition immediately prior to and/or during their common introduction into a lumen of an injection device, and the flowable hemostatic gel composition is applied out of the lumen of the injection device directly to the site for rapid curing in situ.
  • the flowable gel solution and the flowable hardener solution are applied separately to the site, such as simultaneously or in sequence through a dual lumen injection device, and are allowed to mix at the site to form the flowable hemostatic gel composition for rapid curing in situ.
  • the flowable gel solution and the flowable hardener solution are applied to the site in any suitable fashion.
  • the method or sequence of introduction of the gel solution and the hardener solution to the surgical site influences one or more characteristics of the resulting hemostatic gel composition including, but not limited to, hardening time, gel strength, gel resistance to degradation, release rate of thrombin and/or other active agent included in the gel, and combinations thereof.
  • the hardener solution is not used, and the cross-linking of the biopolymer with red blood cells and/or the action of the at least one clotting factor at the site facilitates sufficient clotting at the site.
  • Example 1 Mechanical Strength of Solid Hemostatic Gel Formed from the Flowable
  • Chitosan (Aldrich Cat# 419419, Sigma-Aldrich, St. Louis, MO) was dissolved at 2% w/v in a first solvent solution of 1% v/v L-lactic acid to form a gel solution.
  • Sodium tripolyphosphate NaTPP, Aldrich Cat# 238503 was dissolved in a second solvent of de-ionized water (DiH 2 0) to form a series of hardener solutions in the respective amounts of 0.3% w/v, 0.5% w/v, 0.7% w/v, 1% w/v, 2% w/v, and 10% w/v NaTPP.
  • FIG. 1 is a graph summarizing the maximum gel force obtained for each sample as a function of the NaTPPxhitosan mass ratio. The gel strength was observed to increase as the NaTPP content of the gel samples increased, up to a maximum gel strength at a NaTPP hitosan mass ratio of 0.5: 1. NaTPPxhitosan mass ratios above 0.5 resulted in successively decreasing gel strengths, although the gel strengths remained substantial. Table 1. Mechanical Strength of Hemostatic Gel Compositions.
  • thrombin substrate includes a cleavably linked beta-Ala-Gly-Arg para- nitroanilide. Upon contact with enzymatically active thrombin, release of the p-nitroanilide from the peptide linkage generates a UV absorbance around 405 nm.
  • the solution used for dissolving all enzymes and substrates was phosphate buffered saline (PBS) (10X concentrated, Aldrich Cat#P5493, Sigma-Aldrich, St. Louis, MO), aseptically diluted to IX using BPC grade water (Aldrich Cat#W3513, Sigma-Aldrich, St. Louis, MO).
  • PBS phosphate buffered saline
  • the PBS solution was 0.2 ⁇ filtered (Nalgene Cat#190-2520, Thermo Fisher Scientific Inc., USA) prior to use to maintain sterility.
  • the solutions were produced in a labconco purifier class II hood that had been sprayed down with 70% ethanol solution and UV light exposed for 20 minutes prior to initiating work to reduce bacterial contamination.
  • Thrombin from human plasma lyophilized powder (Aldrich Cat# T8885, Sigma-Aldrich, St. Louis, MO) was diluted in 5 ml of PBS thus forming a 3.2 U/ml thrombin solution.
  • the thrombin substrate was also dissolved in 5 ml of PBS forming a 5 mg/ml substrate solution.
  • a positive control (thrombin-positive) sample was generated by combining 0.1 ml of the substrate solution along with 0.1 ml of the thrombin solution and 1.8 ml of PBS.
  • a negative control (thrombin-negative) sample was generated by combining 0.1 ml of the substrate solution in 1.9 ml of PBS. Both samples were incubated at 37°C overnight. The next day the positive sample was visibly observed to be yellow in color while the negative sample was still clear.
  • FIG. 2 is a graph summarizing the UV/Vis absorption spectra of the positive and negative control samples scanned against a blank of 2 ml of PBS.
  • a UV/Vis absorption spectrum of the positive control samples was obtained using the negative control sample as the blank; the obtained spectrum is summarized in FIG. 3. Referring to FIG. 2 and FIG. 3, the peak difference in absorbance between the positive and negative control samples was observed at 385 nm.
  • the results of this experiment validated the assay for enzymatically active thrombin using the chromogenic thrombin substrate described above.
  • the assay exhibited peak sensitivity at an assay wavelength of 385 nm. Based on this finding, an assay wavelength of 385 nm, as well as an assay wavelength of 405 nm suggested by the manufacturer, were selected for use in subsequent thrombin release experiments described below. Further, due to the relatively low UV absorption exhibited in the results of this experiment, the amount of thrombin substrate solution was doubled to 0.2 mL for use in subsequent thrombin release experiments.
  • the negative control sample had very low absorbance (0.071) and there was relatively low indication of interference from chitosan alone, NaTPP alone, or the mixture of chitosan and NaTPP (absorbance ⁇ 0.2 for all corresponding samples) which indicates that the substrate solution is suitably selective so as to be cleaved by enzymatically active thrombin, rather than by other non-specific agents such as pH changes or ionicity.
  • Thrombin activity was observed in the sample of thrombin mixed with PBS but, interestingly, the measured thrombin activity was relatively low as compared to the thrombin-loaded chitosan gel solution samples.
  • each thrombin/chitosan solution was split into two 0.5 ml aliquots.
  • the first aliquot from each solution was put in the bottom of a vial and 0.5 ml of 2% NaTPP hardener solution was added on top to form "chitosan first" compositions.
  • the second aliquot from each solution was pipetted into a vial which already contained 0.5 ml of 2% NaTPP hardener solution to form "NaTPP first" compositions.
  • These compositions were incubated at 37°C/100RPM for 2 hours, and then 0.2 ml of supernatant was pulled from each sample and tested for thrombin activity as described in Example 3.
  • the samples tested for thrombin activity are summarized in Table 4 below.
  • FIG. 4 summarizes the relative changes in thrombin activity, measured as absorbance at 405 nm, as a function of thrombin loading for the gel compositions tested.
  • These relative curves for the chitosan-first compositions and the NaTPP -first compositions generally indicate a dose-dependent relationship with respect to thrombin loading of the gel solution, in which higher quantities of thrombin cleave more of the substrate used to assay thrombin activity.
  • the thrombin content of the test solutions analyzed in this experiment ranged from 0.0032 U to 0.32 U, whereas the thrombin content of the positive control from Ex. 3 contained 0.64 U.
  • the two part mixture gels included ionic gels formed by combining 2% NaTPP with a polycationic polymer, in this case 2% chitosan, a polysaccharide as described above.
  • the two-part mixture gels further included polyelectrolyte complexes (PEC) formed by combining 2% w/v chitosan in acid solution and 2% sodium alginate in alkaline solution.
  • PEC polyelectrolyte complexes
  • the sodium alginate is another polysaccharide, and an anionic copolymer, such that the combination of the chitosan and alginate solutions yielded a near pH neutral solution and the alginate and chitosan were attracted to each other by their respective ionic interactions.
  • chitosan For all solutions other than chitosan, the material was dissolved in water. For chitosan, the solution was done in either 0.1M HC1 or 1% v/v acetic acid.
  • the following polysaccharides were obtained from Aldrich: Chitosan medium molecular weight (“MMW”) - 75-85% deacetylation, viscosity 200-800 cP, 1 wt. % in 1% acetic acid (25 °C, Brookfield); Chitosan low molecular weight (“LMW”) - > 75% deacetylation, viscosity 20-300 cP, 1 wt.
  • MMW Chitosan medium molecular weight
  • LMW Chitosan low molecular weight
  • the solidified gel was subjected to an occlusion test in order to determine its capability to retain fluids.
  • the gel was set up by mixing 1ml each of gel and hardener in the bottom of a 12ml syringe with a standard Leur tip and a Leur cap.
  • the gel was set up in the syringe either by mixing or by heating to 37°C followed by addition of water and removal of cap. Table 5 summarizes the result properties observed using videotaped gelling of each mixture.
  • occlusion was not just a test of gel strength but capacity to stop flow, which relates to overall gel properties. In these experiments, occlusion was assessed as the ability to prevent flow through an orifice of approximately 2mm diameter.
  • Video Speed Testing Due to the speed at which the two part mixes set up relative to the sampling rate associated with rheological detection, the set-up rate of the two-part mixes was qualitatively recorded by video recording a mixture of the two materials.
  • An injection system was generated by combining two 1-ml syringes with rubber tubing and a Y-shaped adaptor for simultaneous injection. Video records were obtained of each mixed system during injection, with red dye added to enhance visualization, as summarized in Table 7. For the purposes of visualization, red dye was added. Table 7: Video Speed Testing Results
  • chitosan/NaTPP and polyelectrolyte gels are very biocompatible as each of NaTPP, calcium chloride, chitosan, and alginate is assigned status "generally regarded as safe” (GRAS) by the FDA for food usage, indicating low toxicity for these compounds.
  • GRAS generally regarded as safe
  • Example 6 Effect of Ingredient Proportions of Gel Properties
  • the gels used were NaTPP with chitosan compositions.
  • a series of chitosans were utilized, including: Chitosan medium molecular weight (“MMW”) - 75-85% deacetylation, viscosity 200-800 cP, 1 wt. % in 1% acetic acid(25 °C, Brookfield) (Aldrich Cat# 448877); Chitosan low molecular weight (“LMW”) - > 75% deacetylation, viscosity 20- 300 cP, 1 wt.
  • MMW Chitosan medium molecular weight
  • LMW Chitosan low molecular weight
  • the polysaccharide chitosan
  • the polyvalent counterion NaTPPP
  • the solidified gels were mechanically tested by the method described in Example 5. Table 8 below summarizes results of this testing.
  • the chitosan solutions were dissolved in 1% (v/v) L-lactic acid, because lactic acid is non-volatile (longer shelf-life), is a natural metabolic product found inside the human body (increased biocompatibility), and has an established USP monograph.
  • the primary testing was performed using 2% w/v chitosan, but additional solutions containing chitosan types CGF and MMW were formed at 3% w/v and 4% w/v concentrations in 1% L-lactic acid.
  • a bioadhesion probe fixture assay was developed for the TA.XTplus.
  • a commercial gel mucoadhesion probe (Texture Technologies part number: A/GMP) was purchased and mounted onto a custom built bracket constructed of 0.5 inch thick acrylic mounted onto the current TA-90 stage by #10-24 bolts and thumbscrews.
  • Traditional mucoadhesion testing was performed using pork loin to represent typical human muscle tissue.
  • Bioadhesion was tested using the TA.XTplus instrument by dropping the probe down onto the adhesion surface at 0.5mm/sec, applying 500 grams of force for 10 seconds, and then retracting the probe at 0.5mm/sec while measuring the downward pulling reaction force on the probe upon retraction due to adhesion.
  • the mucoadhesion probe was prepared by adding 0.5 ml of 2% chitosan in 0.1M acetic acid and 0.5 ml of 2% NaTPP sequentially into a plastic collar surrounding the probe to create the formulated chitosan- NaTPP gel.
  • Phosphate buffered saline was generated by dissolution of Aldrich tablets per manufacturer directions, as described above. Additionally, sodium azide was added to the solution to yield a final concentration of 0.1% sodium azide (w/v) in the PBS, to prevent microbial growth.
  • Freshly purchased and refrigerator-stored pork-loin was cut into squares approximately 1.5 inch in distance along the sides. A series of 10-oz plastic dishes was prepared by affixing a single thumbtack using two-part epoxy to the bottom middle of the dish, point side up, and by cleaning with 70% ethanol. For each test, the pork piece was pushed down onto the thumbtack point to affix the pork piece to the plate.
  • a one-inch long stir bar was placed in each dish to provide agitation during testing.
  • the dishes were placed on a Fisher Isotemp stirring hotplate with magnetic stirring at 100 RPM and gentle surface warming at 40°C from the bottom of the plates.
  • a Logitech Pro 9000 webcam was placed directly overhead in order to record movies and images from two dishes, which were tested at the same time.
  • 0.5 ml of the mixed gel solution as summarized in Table 15 was pipetted onto the middle of the pork piece and then 0.5 ml of 2% (w/v) NaTPP was added.
  • poly(acrylic acid) mixed with chitosan separately formed into a viscous, partially gelled mixture even prior to combining with the NaTPP. This interaction is likely due to hydrogen bonding between poly(acrylic acid) and chitosan. This property may be beneficial for usage as a bioadhesive, as a partially gelled substance tends to remain at the location where it is applied.
  • a volume of 0.5mL of PBS with 0.1% sodium azide was added to the pork to moisten it, and a solution to be tested was then applied to the pork.
  • the pork adhesion probe was lowered until the top pork piece met the pork mounted to the TA instrument platform, and approximately a 1 N compressive force was held on the pork adhesion probe for 10 seconds. Afterwards, the pork adhesion probe was retracted at a speed of 0.5mm/sec, while measuring the downward pulling force on the probe upon retraction due to pork-to-pork adhesion.
  • the sample solutions tested, and corresponding maximum adhesion force (N) values, are summarized in Table 16.
  • the chitosan solution used for these tests was MMW chitosan 2% w/v in 1% v/v L-lactic acid solution.
  • the poly(acrylic acid) solution used was poly(acrylic acid) (MW 1800Da, Aldrich Cat# 323667) 25% w/v in distilled water.
  • a hemostatic gel composition and methods of use are described above in detail.
  • the methods and compositions are not limited to the specific embodiments described herein, but rather, operations of the methods and components of the systems may be utilized independently and separately from other operations and/or components described herein.
  • the methods and compositions described herein may have other industrial and/or consumer applications and are not limited to practice in medical applications as described herein. Rather, one or more embodiments may be implemented and utilized in connection with other industries.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Surgery (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Zoology (AREA)
  • Materials For Medical Uses (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une composition de gel hémostatique fluide destinée à être utilisée sur le site d'un défaut à l'intérieur d'un tissu biologique. La composition de gel hémostatique fluide comprend une solution de gel fluide qui inclut un biopolymère dissous dans un premier solvant. Le biopolymère est conçu pour se réticuler avec les globules rouges au niveau du site pour faciliter la formation de caillots sur le site. La composition de gel hémostatique fluide comprend également au moins un agent actif supplémentaire.
PCT/US2017/038113 2016-06-28 2017-06-19 Composition de gel hémostatique fluide et ses méthodes d'utilisation WO2018005145A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US15/195,087 2016-06-28
US15/195,087 US10660945B2 (en) 2015-08-07 2016-06-28 Flowable hemostatic gel composition and its methods of use

Publications (1)

Publication Number Publication Date
WO2018005145A1 true WO2018005145A1 (fr) 2018-01-04

Family

ID=60787813

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/038113 WO2018005145A1 (fr) 2016-06-28 2017-06-19 Composition de gel hémostatique fluide et ses méthodes d'utilisation

Country Status (1)

Country Link
WO (1) WO2018005145A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10517988B1 (en) 2018-11-19 2019-12-31 Endomedix, Inc. Methods and compositions for achieving hemostasis and stable blood clot formation
US12091471B2 (en) 2018-11-19 2024-09-17 Endomedix, Inc. Methods and compositions for achieving hemostasis and stable blood clot formation

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060018973A1 (en) * 2002-09-30 2006-01-26 In-San Kim Composition for stimulating bone-formation and bone consolidation
US20070071728A1 (en) * 2004-12-16 2007-03-29 Ching-Chang Ko Biomimetic nanocomposite
US20100316739A1 (en) * 2008-01-18 2010-12-16 Ariel Shaul Hasson Nisis Chitosan gel for dermatological use, production method therefor and use of same
WO2011084326A2 (fr) * 2009-12-21 2011-07-14 Resodyn Corporation Agents hémostatiques et pansements de plaies
US20140187492A1 (en) * 2012-12-31 2014-07-03 George David Falus Single Component Fibrin Hemostat
US20140369991A1 (en) * 2011-07-06 2014-12-18 Profibrix Bv Formulations for Wound Therapy

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060018973A1 (en) * 2002-09-30 2006-01-26 In-San Kim Composition for stimulating bone-formation and bone consolidation
US20070071728A1 (en) * 2004-12-16 2007-03-29 Ching-Chang Ko Biomimetic nanocomposite
US20100316739A1 (en) * 2008-01-18 2010-12-16 Ariel Shaul Hasson Nisis Chitosan gel for dermatological use, production method therefor and use of same
WO2011084326A2 (fr) * 2009-12-21 2011-07-14 Resodyn Corporation Agents hémostatiques et pansements de plaies
US20140369991A1 (en) * 2011-07-06 2014-12-18 Profibrix Bv Formulations for Wound Therapy
US20140187492A1 (en) * 2012-12-31 2014-07-03 George David Falus Single Component Fibrin Hemostat

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GAFFNEY, PJ ET AL.: "The International and ''NIH'' units for thrombin--how do they compare?", THROMBOSIS AND HAEMOSTASIS, vol. 74, no. 3, September 1995 (1995-09-01) *
SIONKOWSKA, A ET AL.: "Molecular interactions in collagen and chitosan blends", BIOMATERIALS, vol. 25, no. 5, 29 February 2004 (2004-02-29), pages 795 - 801, XP004472538 *
ZHAO, Y ET AL.: "Pluronic-poly (acrylic acid)-cysteine/Pluronic L121 mixed micelles improve the oral bioavailability of paclitaxel", DRUG DEVELOPMENT AND INDUSTRIAL PHARMACY, vol. 40, no. 11, 1 November 2014 (2014-11-01), pages 1484, 1492 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10517988B1 (en) 2018-11-19 2019-12-31 Endomedix, Inc. Methods and compositions for achieving hemostasis and stable blood clot formation
US11033654B2 (en) 2018-11-19 2021-06-15 Endomedix, Inc. Methods and compositions for achieving hemostasis and stable blood clot formation
US12091471B2 (en) 2018-11-19 2024-09-17 Endomedix, Inc. Methods and compositions for achieving hemostasis and stable blood clot formation

Similar Documents

Publication Publication Date Title
Balakrishnan et al. A novel injectable tissue adhesive based on oxidized dextran and chitosan
US20230348699A1 (en) Hydrophobically modified chitosan compositions
JP7504473B2 (ja) 多様な湿潤表面用の生体から着想を得た分解性の強靭な接着剤
US10322170B2 (en) Hemostatic compositions
EP2821087B1 (fr) Composition de polymère antiadhésive pouvant servir de support à un facteur de croissance
Serban et al. Silk fibroin and polyethylene glycol‐based biocompatible tissue adhesives
CN110025821A (zh) 使用生物相容性止血剂和组织封闭剂的组合物处理活动性出血的方法
EP4137165A1 (fr) Compositions hémostatiques
WO2006080523A1 (fr) Adhesif reactif autodegradable a deux composants destine a un usage medical et resine destinee a un usage medical
WO2017072755A1 (fr) Produit de scellement bioadhésif composite
US10751444B2 (en) Flowable hemostatic gel composition and its methods of use
EP4186536A1 (fr) Composition à base de polymères anti-adhésive
CN110801528A (zh) 一种硬脊膜封合水凝胶及其制备方法与应用
US10660945B2 (en) Flowable hemostatic gel composition and its methods of use
US20100260845A1 (en) Biocompatible and Biodegradable Biopolymer Matrix
WO2018005145A1 (fr) Composition de gel hémostatique fluide et ses méthodes d'utilisation
Shi et al. A biguanide chitosan-based hydrogel adhesive accelerates the healing of bacterial-infected wounds
CN110740761A (zh) 含有海藻酸或其药学上允许使用的盐和胶体多糖类的液体组合物
US10953130B2 (en) Solid hemostatic composition and methods of making the same
WO2024064820A1 (fr) Films pectine
Lih et al. Search Docs

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17820922

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17820922

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载