WO2016041443A1 - 一种生物相容性止血制品及其制备方法 - Google Patents
一种生物相容性止血制品及其制备方法 Download PDFInfo
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- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
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Definitions
- the invention relates to a biocompatible hemostatic product and a tissue blocking agent and a preparation method thereof, in particular, the invention relates to a person who can be directly applied to a person due to surgery (including minimally invasive surgery) and trauma Highly water-absorbent biocompatible hemostatic products and tissue sealers for damaged wounds of tissues and organs of other mammals, for hemostasis, sealing wounds, reducing tissue exudation, promoting tissue repair, protecting wound tissue, preventing infection, etc. And its preparation method.
- hemostasis products for treating wounds are generally classified into the following categories:
- Hemostatic dressings including bandages, hemostatic sponges and hemostatic gauze;
- Hemostatic products applied to tissues and organs in the body are usually those materials that can be degraded by enzymes in the human body or can be swallowed by phagocytic cells in the human body, so that this can be made for a period of time after administration.
- the hemostatic product is degraded or metabolized by the human body.
- Hemostatic products applied to the surface of human body or body cavity are usually those materials that do not need to be degraded by enzymes in the human body or are not engulfed by phagocytic cells. It can then be removed or excreted as the crust falls off.
- Polyethylene oxide also known as polyethylene oxide, is a commonly used medical polymer material, usually used as a pharmaceutical adjuvant or plasticizer for the preparation of medical adhesives or pharmaceutical tablets.
- the structural unit of PEO is -[CH 2 CH 2 O]-, the molecular weight can be varied within a wide range, and the PEO having a relative molecular weight of 200 to 20,000 is a viscous liquid or a waxy solid; the relative molecular weight is 1 x 10 5 to 1 x 10 6 PEO is a white flowable powder.
- the molecular weight of the synthesized high molecular polymer is generally polydisperse, and the molecular weight of the high molecular polymer in the usual sense is substantially the average molecular weight.
- the average molecular weight of the high molecular polymer can be further defined as a number average molecular weight, a weight average molecular weight, a Z average molecular weight, and a viscosity average molecular weight according to a statistical average molecular weight, wherein the viscosity average molecular weight refers to a molar mass of the polymer measured by a viscosity method. .
- linear polymers have a viscosity which is related to the molecular weight due to the viscosity of the solution, and therefore, the viscosity method is usually used to measure the molecular weight of the linear polymer, and the apparatus used for the viscosity method is used.
- the device is simple, easy to operate, has a large molecular weight range, and has quite good experimental precision.
- Measuring the viscosity average molecular weight of a high molecular polymer by a viscosity method is the most commonly used experimental technique by those skilled in the polymer field (see, for example, Li Jinsong et al., Determination of Viscosity Average Molecular Weight of Oxidized Polyethylene Wax), Shandong Chemical Industry, Volume 35, 2006; Yuan Jinying et al., Determination of the viscosity average molecular weight of polyethylene glycol, Polymer Materials Science and Engineering, Vol. 15, No. 4, 1999).
- CN86103931 discloses an adhesive bandage composed of a substrate coated with a pressure sensitive adhesive, an absorbent pad fixed thereto, and a porous plastic film wound release cover covering the absorbent pad, wherein The wound release cover has a polyoxyethylene coating having a molecular weight of at least 600,000.
- the bandage disclosed in the Chinese patent application contains low molecular weight polyoxyethylene, but the use of such a bandage form of hemostatic product has certain limitations, such as the inability to apply it to the human body and the internal cavity (for example, the endometrial surface of the digestive tract) ) bleeding wounds.
- hemostatic gels such as hydrogels and sealants
- polysaccharides or synthetic polymer materials are directly applied to surgically sutured skin wounds or wounds caused by trauma to protect the wound. Prevents tissue fluid from oozing out and prevents bacteria from infecting the wound.
- hemostatic gels are only convenient for use on wounds on the body surface, but such hemostatic gels cannot be conveniently applied to the bleeding wounds in the interior of the body (eg, the surface of the intima of the digestive tract).
- a biocompatible hemostatic article comprising polyoxyethylene (PEO) particles having a viscosity average molecular weight of from 100,000 Daltons to 7,000,000 Daltons.
- the polyoxyethylene particles have a particle diameter of from 0.5 ⁇ m to 2000 ⁇ m, and the polyoxyethylene particles have a water absorption ratio of from 1 to 500, wherein the hemostatic article forms a gel capable of blocking the blood wound after water absorption.
- a biocompatible tissue blocker comprising polyoxyethylene (PEO) particles having a viscosity average molecular weight of from 100,000 Daltons to 7,000,000 Daltons.
- the polyoxyethylene particles have a particle diameter of 0.5 ⁇ m to 2000 ⁇ m, and the polyoxyethylene particles have a water absorption ratio of 1 to 500, wherein the tissue blocking agent forms a closable after application to a wound surface having exudation of tissue fluid.
- the viscosity average molecular weight of the polyoxyethylene in the present invention is preferably from 500,000 Daltons to 7,000,000 Daltons, more preferably from 600,000 Daltons to 4,000,000 Daltons, even more preferably from 800,000 Daltons to 4,000,000 Daltons.
- the particle diameter of the polyoxyethylene particles in the present invention is preferably from 10 ⁇ m to 500 ⁇ m, more preferably from 10 ⁇ m to 300 ⁇ m, and most preferably from 30 ⁇ m to 250 ⁇ m.
- the water absorption ratio of the polyoxyethylene particles in the present invention is preferably from 2 to 100.
- the viscosity of the polyoxyethylene particles in the present invention is preferably not less than 30 kPa ⁇ s in an aqueous solution having a concentration of 6.67% at 37 °C.
- the viscosity of the polyoxyethylene particles in the present invention is further preferably such that the viscosity of the aqueous solution having a concentration of 1% at 37 ° C is not less than 30 kPa ⁇ sec.
- the biocompatible hemostatic product and tissue blocker comprise PEO and at least one of biocompatible modified starch and povidone (PVP);
- the biocompatible modified starch has an average molecular weight of 15,000 to 2,000,000 Daltons selected from the group consisting of: pregelatinized starch, acid modified starch, esterified starch, etherified starch, grafted starch, crosslinked starch, and composite modified starch.
- the etherified starch comprises carboxymethyl starch and hydroxyethyl starch;
- the crosslinked starch comprises crosslinked carboxymethyl starch; and
- the composite modified starch comprises pregelatinized Hydroxypropyl distarch phosphate;
- the esterified starch comprises hydroxypropyl distarch phosphate;
- the grafted starch comprises an acrylic acid-carboxymethyl starch graft copolymer and a propylene ester-carboxymethyl starch graft copolymerization
- the biocompatible modified starch is carboxymethyl starch.
- the mass ratio between the polyoxyethylene particles and the biocompatible modified starch and/or povidone can be adjusted by a person skilled in the art according to actual needs, for example, polyoxygen
- the mass ratio of the ethylene particles to the biocompatible modified starch may be from 9:1 to 1:9; preferably from 9:1 to 6:1; the mass ratio of the polyoxyethylene particles to the povidone is from 6:1 to 3:1. .
- the polyoxyethylene granules have a mass percentage of 99% to 5%; biocompatible denaturation The mass percentage of starch is 90% to 5%; the mass percentage of povidone is 90% to 1%.
- the biocompatible hemostatic product and tissue blocker comprises, in addition to the PEO particles, one of a pharmaceutically acceptable excipient, a blood coagulant, an anti-infective drug, and an anti-inflammatory drug.
- the pharmaceutically acceptable excipients include, but are not limited to, solvents, dispersion media, coating agents, surfactants, antioxidants, preservatives, isotonic agents, delayed absorption agents, Binders, lubricants, pigments, and combinations or analogs thereof, such pharmaceutically acceptable excipients are well known to those of ordinary skill in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Edition, Mack Printing Company, 1990, pp.
- the clotting agents include, but are not limited to, gelatin, collagen, oxidized cellulose, carboxymethylcellulose, chitosan , hyaluronic acid, sodium alginate, kaolin, thrombin, fibrin, calcium, protamine, polypeptide, peptide, amino acid, or a combination thereof;
- the anti-infective drug includes It is not limited to: antibiotics, antibacterial preparations, antiviral preparations, antifungal drugs, antiulcer drugs, traditional Chinese medicine preparations, one or a combination of propolis;
- the anti-inflammatory drugs include but are not limited to: non-steroidal and steroidal drugs, An anti-ulcer drug, a traditional Chinese medicine preparation, one or a combination of propolis.
- step (b) adding to the raw material placed in the granulator of step (a) a solvent commonly used in the field of granulation, such as purified water or distilled water;
- the method further comprises: in step (a), adding at least one of biocompatible modified starch and povidone to the raw material and/or pharmaceutically acceptable fu form At least one of a shape agent, a blood coagulant, an anti-infective drug, and an anti-inflammatory drug; preferably, the hemostatic article obtained in the step (c) can be rescreened to make the hemostatic product having a particle diameter of 50 ⁇ m to 250 ⁇ m account for total hemostasis More than 70% of the products.
- the method further comprises adding at least one of a biocompatible modified starch and a povidone-type polymer to the raw material after the step (b) and after the step (c). Or at least one of a pharmaceutically acceptable excipient, a blood coagulant, an anti-infective drug, and an anti-inflammatory drug; preferably, the hemostatic article obtained in the step (c) can be rescreened to have a particle size of 50 ⁇ m to The 250 ⁇ m hemostatic product accounts for more than 70% of the total hemostatic product.
- biocompatible hemostatic article and tissue blocker of the present invention can also be prepared using grafting methods commonly used in the art, including the following steps:
- step (c) adding at least one of biocompatible modified starch and PVP to the swollen or dissolved polyoxyethylene granule solution obtained in step (b) to biocompatibility by covalent bonding or ionic bonding At least one of modified starch and PVP is attached to the surface of the polyoxyethylene particles to obtain a composite particle;
- step (d) The compound particles obtained in the step (c) are dried and sieved to obtain a biocompatible hemostatic product having a particle diameter of 30 ⁇ m to 500 ⁇ m.
- biocompatible hemostatic product of the present invention in the form of a hemostatic aerosol, a hemostatic sponge, a hemostatic membrane, a hemostatic gel or a hemostatic patch by a conventional preparation method in the art.
- biocompatible tissue blockers of the present invention in the form of an aerosol, a closure film, a closed sponge, a sealant or a closure patch using conventional methods of preparation in the art.
- biocompatible hemostatic product of the present invention can also apply to other hemostatic materials and fabrics to form a hemostatic material with a PEO coating, such as with a PEO coating, using conventional preparation methods in the art.
- the method of preparing the above-mentioned hemostatic article with a PEO coating is preferably the following method, but is not limited to these methods:
- Method 1 The PEO particles are dissolved in a common solvent (such as water), and a PEO solution having a certain concentration is applied or sprayed on the surface of other hemostatic materials to be dried.
- a common solvent such as water
- Method 2 Other hemostatic materials are immersed in a water (or other solvent) solution of a certain concentration of PEO particles, taken out and dried to obtain.
- Method 3 After the PEO particles are dissolved in a solvent (such as water), the PEO molecules are bound to the molecules of other hemostatic materials by a covalent bond, a hydrogen bond or the like, and then other methods commonly used in the art (including lyophilization, Film formation, weaving, etc.) are obtained by preparation.
- a solvent such as water
- the object of the present invention is to provide a hemostatic wound of a biocompatible hemostatic product and a tissue blocking agent on the surface, tissues and tissues of an animal, blood stasis, anti-adhesion, tissue healing and/or closure.
- a biocompatible hemostatic product and a tissue blocking agent on the surface, tissues and tissues of an animal, blood stasis, anti-adhesion, tissue healing and/or closure.
- Such animals include, but are not limited to, primates, cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like.
- the animal is a mammal, more preferably a human.
- the biocompatible hemostatic article of the present invention can be applied directly to a blood wound in a clinical surgical and traumatic first aid procedure.
- the biocompatible hemostatic article of the present invention for hemostasis and/or closed tissue can be applied to a blood wound of a tissue or organ in a human body cavity by means of an endoscope to stop bleeding and seal the wound.
- the endoscope includes a nose, a laryngoscope, a gastroscope, a colonoscope, a laparoscope, a uroscope, a hysteroscope, and a thoracoscope.
- EndoClot TM hemostatic powder spray system manufactured by U.S. EndoClot Plus, Inc.
- the biocompatible hemostatic product of the present invention is directly applied to a blood-stained surface of a tissue or organ in a body cavity of a human body, for example, a blood wound is formed due to minimally invasive surgery or biopsy exploration by an endoscope.
- the system is used in conjunction with the GI endoscopy, so that the biocompatible hemostatic article of the present invention is applied directly as performing minimally invasive A blood wound on the body cavity formed by surgery or biopsy to stop bleeding and close the wound.
- the biocompatible hemostatic product of the invention can immediately absorb the moisture in the blood after contact with the blood to form a gel and a gel-like clot, the gel and the gel-like clot have good viscosity and can adhere to On the wound surface, the wound is closed and blood vessels are prevented from bleeding. Moreover, the gel is not easily degraded by the enzyme in the body, can adhere to the wound surface for a long time, and then falls off together with the scar.
- the biocompatible hemostatic product and the tissue blocking agent when directly sprayed into the digestive tract, in addition to the action of the blood on the wound surface, the biocompatible hemostatic product and the tissue blocking agent can also be administered with gastric juice and intestinal fluid or a doctor.
- the salt water or the like acts to form a hydrogel.
- the formed hydrogel and gel-like clot can also protect the wound, seal the wound, prevent the stimulation of the wound by the gastric juice and intestinal fluid, prevent the wound infection and facilitate the healing of the wound.
- the gel formed above can stay on the surface of the digestive tract for several hours and several days, and therefore, the ulcer surface of the inner wall of the digestive tract can be And inflammatory lesions, or wounds caused by minimally invasive surgery, surgery, and trauma, or wounds and injuries such as burns/burns/corrosion wounds caused by food, chemicals, and drugs are very important.
- Clinical significance including but not limited to hemostasis, partial closure of tissues, prevention of infection, and promotion of tissue healing.
- some medicinal ingredients are added to the above-mentioned products, the effects and purposes of local sustained release and local treatment of the digestive tract can be achieved.
- the biocompatible hemostatic product and the tissue blocking agent are directly sprayed on the wounds, wounds and lesions on the body surface and in the body, in addition to the action on the blood of the wound, the biocompatible hemostatic product and tissue closure of the present invention
- the agent may also react with body fluids including lymph and exudates, as well as physiological saline administered by a doctor, to form a hydrogel.
- the formed hydrogel and gel-like clot can also protect the wound, seal the wound, prevent the wound from being stimulated by local bile and intestinal fluid, prevent wound infection and facilitate wound healing.
- the gel formed above can stay on the surface of the wound or the lesion for several hours and several days, and therefore, can form a mechanical Isolation prevents postoperative adhesions, Helps with organizational repair.
- the sustained release and local treatment of the drug can be achieved, and the invention can be used for local anti-infection, anti-tumor and the like.
- the biocompatible hemostatic product and the tissue blocking agent are directly sprayed on the wounds and wounds on the body surface and the body, in addition to the action of the blood on the wound surface, the biocompatible hemostatic product and the tissue closure of the present invention.
- the agent may also react with body fluids including lymph, intestinal fluid, pleural fluid, wound exudate, and physiological saline administered by a doctor to form a hydrogel.
- the formed hydrogel or gel-like clot can also protect the wound, seal the wound, prevent intestinal fistula, biliary fistula, chest sputum, hydrocephalus, lymphatics, and tissue fluid leakage that reduces the wound.
- the biocompatible article of the present invention can be packaged and sterilized and used after conventional methods in the industry.
- the method of sterilization may be carried out by means of radiation, ethylene oxide and ozone, among which ethylene oxide sterilization is preferred.
- FIG. 1A through 1D show the operation steps of applying the biocompatible hemostatic article and tissue sealant of the present invention by a spray tool in an embodiment of the present invention.
- FIG 2 is a schematic view EndoClot TM hemostatic powder spray system.
- FIG. 2 shows an embodiment in the present invention, EndoClot TM hemostatic powder spray system shown in FIG. 2 and by means of endoscopy or colonoscopy biocompatible tissue sealant and hemostatic article of the present invention is administered to a gastrointestinal
- EndoClot TM hemostatic powder spray system shown in FIG. 2 and by means of endoscopy or colonoscopy biocompatible tissue sealant and hemostatic article of the present invention is administered to a gastrointestinal
- This embodiment provides a series of biocompatible hemostatic products #1 to #4 containing polyethylene oxide (PEO) particles having different viscosity average molecular weights, physical and chemical parameters of PEO particles contained in these biocompatible hemostatic products, and The particle size of the biocompatible hemostatic product is listed in Table 1 below:
- PEO polyethylene oxide
- the above biocompatible hemostatic products #1 to #4 were prepared by the following steps:
- step (b) adding distilled water to the raw material placed in the granulator of step (a);
- Granulation is carried out at 40 ° C to 50 ° C, followed by sieving to obtain a biocompatible hemostatic product having a particle diameter of 50 ⁇ m to 250 ⁇ m.
- the biocompatible hemostatic article of this example and the following examples can be sprayed onto a bleeding wound using a method commonly used in the art to detect its hemostatic effect.
- the biocompatible hemostatic article of the present invention can be sprayed according to the procedure shown in Figures 1A-1D. Specifically, the biocompatible hemostatic product of the present invention is first filled into a container and the lid of the container is removed (as shown in FIG. 1A), and then the container containing the biocompatible hemostatic product of the present invention is sprayed.
- the bleeding wound stopped bleeding within 15 seconds to 30 seconds after the application of sample #3 and sample #4, and the bleeding wound stopped bleeding within 45 seconds to 1 minute after the application of samples #1 and #2, and the control sample
- the 3-5 minute bleeding wound gradually stopped bleeding.
- the hemostatic product of the present invention and the clot formed after contact with blood are not degraded by amylase in the body (while the hemostatic material of the control group can be rapidly degraded by amylase), and can adhere to the wound surface for a long time. In the body can achieve very good effect of sealing the wound.
- This embodiment provides a series of biocompatible hemostatic products #5 to #8 comprising different mass ratios of polyoxyethylene (PEO) particles and carboxymethyl starch (CMS) particles, wherein the PEO particles have a viscosity average molecular weight of 2,000,000.
- PEO polyoxyethylene
- CMS carboxymethyl starch
- the present embodiment used in the control sample is Arista TM hemostatic powder (produced Medafor Inc. USA); molecular weight : 5,000 D to 200,000 D; particle diameter: 10 ⁇ m to 350 ⁇ m, average particle diameter: 100 ⁇ m, water absorption ratio: 5 to 10.
- step (b) adding distilled water to the raw material placed in the granulator of step (a);
- Granulation is carried out at 40 ° C to 50 ° C, followed by sieving to obtain a biocompatible hemostatic product having a particle diameter of 50 ⁇ m to 250 ⁇ m.
- the bleeding wound stopped bleeding within 15 seconds after the application of samples #5 to #8, and the hemostatic effect was achieved within 3 to 5 minutes of the control sample. It can be seen from the above observation of the hemostatic effect that the hemostatic product containing the PEO particles and the CMS particles rapidly concentrates the blood after forming contact with the blood to form a clot, and the formed clot is sticky and can be immediately adhered to the bleeding wound.
- the wound On the upper side, the wound is closed to prevent blood vessel bleeding, and the control sample is slower to concentrate blood after contact with blood than the experimental group, and the viscosity of the clot is lower than that of the experimental group, so it takes a long time. To stop bleeding.
- This embodiment provides a series of biocompatible hemostatic products #9 to #11 comprising polyoxyethylene (PEO) particles and povidone (PVP) particles of different mass ratios, wherein the PEO particles have a viscosity average molecular weight of 2,000,000D.
- the particle size is 0.5 ⁇ m to 2000 ⁇ m, the water absorption ratio is 5 to 15; the PVP particles have a viscosity average molecular weight of 90,000 D, a particle diameter of 0.5 ⁇ m to 1000 ⁇ m, and a water absorption ratio of 5 to 15, and the biocompatibility in the present embodiment
- the mass ratios of PEO particles and PVP particles in the hemostatic products #9 to #11 are listed in Table 3 below:
- step (b) adding distilled water to the raw material placed in the granulator of step (a);
- Granulation is carried out at 40 ° C to 50 ° C, followed by sieving to obtain a biocompatible hemostatic product having a particle diameter of 50 ⁇ m to 250 ⁇ m.
- the hemostatic effects of the samples #9 to #11 of the present example were also tested. After the samples #9 to #10 of the present example were applied, the bleeding occurred within 30 seconds of the wound wound, and the sample #11 took 3-5 minutes to achieve complete hemostasis, and the samples #9 to #10 concentrated the blood faster. The time to form a blood clot is fast, while the speed of sample #11 is obviously slowed down. It may be that the excessive PVP ratio affects the overall water absorption speed of the sample, thereby slowing down the time for the sample sample to concentrate blood, and affecting the hemostatic effect. The clots formed by samples #9 to #11 are more viscous and can adhere to the bleeding wound surface to prevent blood vessel bleeding.
- This embodiment provides a series of biocompatible hemostatic products #12 and #13 comprising different ratios of polyoxyethylene (PEO) particles and carboxymethyl starch (CMS) particles and povidone (PVP), wherein PEO
- PEO polyoxyethylene
- CMS carboxymethyl starch
- PVP povidone
- PEO polyoxyethylene
- CMS carboxymethyl starch
- PVP povidone
- the particles have a viscosity average molecular weight of 2,000,000 D, a particle diameter of 0.5 ⁇ m to 2000 ⁇ m, and a water absorption ratio of 5 to 15;
- the CMS particles have a molecular weight of 3,000 D to 200,000 D, a particle diameter of 0.5 ⁇ m to 1000 ⁇ m, and a water absorption ratio of 10 to 30,
- the PVP particles have a viscosity average molecular weight of 90,000 D, a particle diameter of 0.5 ⁇ m to 1000 ⁇ m, and a water absorption ratio of 5 to 15.
- Table 4 The mass ratios
- the above biocompatible hemostatic products #12 and #13 were prepared by the following steps:
- step (b) adding distilled water to the raw material placed in the granulator of step (a);
- Granulation is carried out at 40 ° C to 50 ° C, followed by sieving to obtain a biocompatible hemostatic product having a particle diameter of 50 ⁇ m to 250 ⁇ m.
- the hemostatic effects of the samples #12 and #13 of the present example were tested. After the administration of the samples #12 and #13 of the present example, the bleeding was stopped within 30 seconds of the bleeding wound. Samples #12 and #13 immediately concentrated blood after contact with blood to form a blood clot. Moreover, samples #12 and #13 and the clots formed by them were more viscous and could quickly adhere to the wound surface and seal the wound. Prevent blood vessels from bleeding.
- the hemostatic article of Examples 1-4 above can also be prepared using a coating method commonly used in the art, which includes the following steps:
- step (b) adding water to the raw material of step (a) to swell;
- step (c) adding a proportion of carboxymethyl starch granules and/or PVP granules to the swollen polyoxyethylene granules obtained in step (b);
- (d) Granulation is carried out at 40 ° C to 50 ° C, followed by sieving to obtain a biocompatible hemostatic product having a particle diameter of 50 ⁇ m to 250 ⁇ m.
- the hemostatic article of the above Examples 1-4 can also be prepared using a grafting method commonly used in the art, which comprises the following steps:
- step (c) adding at least one of biocompatible modified starch and PVP to the swollen or dissolved polyoxyethylene granule solution obtained in step (b) to biocompatibility by covalent bonding or ionic bonding At least one of modified starch and PVP is attached to the surface of the polyoxyethylene particles to obtain a composite particle;
- step (d) The compound particles obtained in the step (c) are washed, dried, and sieved to obtain a biocompatible hemostatic product having a particle diameter of 30 ⁇ m to 500 ⁇ m.
- the present invention provides a series of biocompatible hemostatic products including PEO particles having different physical and chemical properties (such as water absorption characteristics and viscosity), different viscosity average molecular weights, and other materials having certain physical and chemical properties (such as water absorption characteristics and viscosity, etc.) Polymers, for example, biocompatible modified starch and PVP. From the series of biocompatible hemostatic products prepared in the above Examples 1 to 4 and the hemostatic effect thereof, it can be seen that the biocompatible hemostatic product of the present invention can achieve the effect of rapidly stopping bleeding after application to a bleeding wound, which is relative to It has been recognized as an effective clinical use of commercially available Arista TM styptic powder (US Medafor Inc. production) has better hemostatic effect and the effect of closing the wound.
- PEO particles having different physical and chemical properties (such as water absorption characteristics and viscosity), different viscosity average molecular weights, and other materials having certain physical and chemical properties (such as water absorption characteristics and viscosity, etc.) Poly
- Example 5 In vivo cavity administration of the biocompatible hemostatic product of the present invention
- the biocompatible hemostatic product of the above embodiments of the present invention is passed through the EndoClotTM Hemostatic Powder Spraying System (provided by EndoClot Plus, Inc., USA ) during the minimally invasive surgery of the gastrointestinal tract.
- EndoClotTM Hemostatic Powder Spraying System provided by EndoClot Plus, Inc., USA
- the method of use please refer to J Patel et al, PTU-029 The Use of Endoclot TM Therapy in The Endoscopic Management of Gastrointestinal Bleeding, Gut, 201 463:..
- the hemostatic powder spray system comprising a gas filter may be connected to a gas source 5 (or pump) 1, the gas delivery tube 2, the gas / powder mixing chamber 3 And Annex 4.
- the operation of applying the biocompatible hemostatic article of the present invention by the hemostatic powder spraying system and by means of an endoscope such as a gastroscope and a colonoscope comprises the following steps:
- biocompatible hemostatic article (a) of the present invention is charged into a sterilized container (shown in FIG. 3A), the cap is removed and the container connected to EndoClot TM hemostatic powder spray system (FIG. 3B);
- the biocompatible hemostatic product of the present invention is directly sprayed through the above-mentioned catheter to the bleeding wound in the digestive tract (as shown in Fig. 3D), and the blood is rapidly concentrated to form a clot, a gel formed and a gel-like clot ( Gel-clot matrix) can seal the wound to prevent further bleeding of the wound;
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Abstract
Description
样品编号 | PEO颗粒与CMS颗粒的质量比 |
#5 | 6:1 |
#6 | 3:1 |
#7 | 1:3 |
#8 | 1:6 |
样品编号 | PEO颗粒与PVP颗粒的质量比 |
#9 | 6:1 |
#10 | 3:1 |
#11 | 1:3 |
样品编号 | PEO颗粒与CMS颗粒以及PVP颗粒的质量比 |
#12 | 1:3:1 |
#13 | 6:3:1 |
Claims (24)
- 一种生物相容性止血制品,其包含聚氧乙烯颗粒,所述聚氧乙烯的粘均分子量为100,000道尔顿至7,000,000道尔顿,所述聚氧乙烯颗粒的粒径为0.5μm至2000μm,所述聚氧乙烯颗粒的吸水倍率为1~500,其中,所述止血制品在吸水后形成可封闭有血创面的凝胶。
- 如权利要求1所述的生物相容性止血制品,其中,所述聚氧乙烯的粘均分子量为500,000道尔顿至7,000,000道尔顿,或600,000道尔顿至4,000,000道尔顿,或800,000道尔顿至4,000,000道尔顿。
- 如权利要求1所述的生物相容性止血制品,其中,所述聚氧乙烯颗粒的粒径为10μm至500μm,或10μm至300μm,或30μm至250μm。
- 如权利要求1所述的生物相容性止血制品,其中,所述聚氧乙烯颗粒的吸水倍率为2-100。
- 如权利要求1所述的生物相容性止血制品,其中,所述聚氧乙烯颗粒在37℃下,浓度为6.67%的水溶液的粘度不低于30豪帕·秒。
- 如权利要求1所述的生物相容性止血制品,其中,所述止血制品还包含生物相容性变性淀粉和聚维酮中的至少一种。
- 如权利要求6所述的生物相容性止血制品,其中,所述生物相容性变性淀粉的分子量为15,000~2,000,000道尔顿,吸水倍率为1-1000倍,其选自:预糊化淀粉、酸变性淀粉、酯化淀粉、醚化淀粉、接枝淀粉、交联淀粉、复合变性淀粉中的至少一种。
- 如权利要求7所述的生物相容性止血制品,其中:所述醚化淀粉包括羧甲基淀粉及羟乙基淀粉;所述交联淀粉包括交联羧甲基淀粉;所述复合变性淀粉包括预糊化的羟丙基二淀粉磷酸酯;所述酯化淀粉包括羟丙基二淀粉磷酸酯;所述接枝淀粉包括丙烯酸-羧甲基淀粉接枝共聚物和丙烯酯-羧甲基淀粉接枝共聚物。
- 如权利要求7所述的生物相容性止血制品,其中,所述生物相容性变性淀粉为羧甲基淀粉及其钠盐。
- 如权利要求6所述的生物相容性止血制品,其中,所述生物相容性变性淀粉与所述聚氧乙烯颗粒的质量比为9:1至1:9。
- 如权利要求6所述的生物相容性止血制品,其中,所述聚维酮与所述聚氧乙烯颗粒的质量比为1:9至9:1。
- 如权利要求6所述的生物相容性止血制品,其中,所述止血制品还包括生物相容性变性淀粉和聚维酮,所述生物相容变性淀粉的质量百分含量为5%至90%,所述聚维酮的质量百分含量为1%至90%,所述聚氧乙烯的质量百分含量为99%至10%。
- 如权利要求1至12中任一项所述的生物相容性止血制品,其中,所述止血制品还包含药学上可接受的赋形剂、凝血剂、抗感染药物和消炎药物中的至少一种。
- 如权利要求13所述的生物相容性止血制品,其中:所述药学上可接受的赋形剂选自:溶剂、分散介质、包被剂、表面活性剂、抗氧化剂、防腐剂、等渗剂、延迟吸收剂、粘合剂、润滑剂、颜料,以及它们的组合或类似物;所述凝血剂选自:明胶、胶原蛋白、氧化纤维素、羧甲基纤维素、壳聚糖、透明质酸、海藻酸钠、高岭土、凝血酶、纤维蛋白、钙剂、鱼精蛋白、 多肽、缩氨酸、氨基酸中的一种或其组合;所述抗感染药物选自:抗生素、抗菌制剂、抗病毒制剂、抗真菌药物、抗溃疡药物、中药制剂、蜂胶的一种或其组合;所述消炎药物选自:非甾体类和甾体类药物、抗溃疡药物、中药制剂、蜂胶的一种或其组合。
- 权利要求1至14中任一项所述的生物相容性止血制品在动物体表、组织器官及体腔内组织或器官的有血创面的止血、防粘连、防感染、促进组织愈合和/或封闭伤口中的应用。
- 如权利要求1至14中任一项所述的生物相容性止血制品,其中,所述止血制品为止血粉剂、止血颗粒、止血球、止血气雾剂、止血海绵、止血膜、止血胶或止血贴的形式。
- 一种制备生物相容性止血制品的方法,其中,所述方法包括以下步骤:(a)将作为原料的粘均分子量为100,000道尔顿至7,000,000道尔顿、颗粒的粒径为0.5μm至2000μm、吸水倍率为1~500的聚氧乙烯颗粒置于造粒机内,(b)向步骤(a)的置于造粒机内的原料中加入蒸馏水;(c)在40℃~50℃下进行造粒,得到颗粒粒径为30μm至500μm的生物相容性止血制品。
- 如权利要求17所述的方法,其中,所述方法还包括:在步骤(a)中,向原料中加入生物相容性变性淀粉和非离子型聚合物中的至少一种和/或药学上可接受的赋形剂、凝血剂、抗感染药物和消炎药物中的至少一种。
- 如权利要求17所述的方法,其中,所述方法还包括在步骤(b)之后,步骤(c)之前向原料中加入生物相容性变性淀粉和非离子型聚合物中的至少一种和/或药学上可接受的赋形剂、凝血剂、抗感染药物和消炎药物中的至少 一种。
- 如权利要求17至19中任一项所述的方法,其中,所述方法还包括:对步骤(c)得到的止血制品进行再次筛分以使颗粒粒径为50μm至250μm的生物相容性止血制品占总止血制品的70%以上。
- 一种生物相容性组织封闭剂,其包含聚氧乙烯颗粒,所述聚氧乙烯的粘均分子量为100,000道尔顿至7,000,000道尔顿,所述聚氧乙烯颗粒的粒径为0.5μm至2000μm,所述聚氧乙烯颗粒的吸水倍率为1~500,其中,所述组织封闭剂在施用于有组织液渗出的伤口及病变组织之后形成可封闭所述有组织液渗出的伤口及病变组织的凝胶。
- 如权利要求21所述的生物相容性组织封闭剂,其中,所述组织封闭剂还包含生物相容性变性淀粉和聚维酮中的至少一种。
- 如权利要求21或22所述的生物相容性组织封闭剂,其中,所述组织封闭剂还包含药学上可接受的赋形剂、凝血剂和抗感染药物及消炎药物中的至少一种。
- 一种制备生物相容性组织封闭剂的方法,其中,所述方法包括以下步骤:(a)将作为原料的粘均分子量为100,000道尔顿至7,000,000道尔顿、颗粒的粒径为0.5μm至2000μm、吸水倍率为1~500的聚氧乙烯颗粒置于造粒机内,(b)向步骤(a)的置于造粒机内的原料中加入蒸馏水;(c)在40℃~50℃下进行造粒,得到颗粒粒径为30μm至500μm的生物相容性组织封闭剂。
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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EP15841194.2A EP3228331B1 (en) | 2014-09-18 | 2015-09-02 | Biocompatible hemostatic product and preparation method thereof |
JP2017515844A JP2017527416A (ja) | 2014-09-18 | 2015-09-02 | 生体適合性止血製品及びその製造方法 |
KR1020177010072A KR20170060054A (ko) | 2014-09-18 | 2015-09-02 | 생체 적합성 지혈 제품 및 그 제조 방법 |
US15/511,300 US10314937B2 (en) | 2014-09-18 | 2015-09-02 | Biocompatible hemostatic product and preparation method thereof |
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CN201410478818.4A CN105412975B (zh) | 2014-09-18 | 2014-09-18 | 一种生物相容性止血制品及其制备方法 |
CN201410478818.4 | 2014-09-18 |
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EP (1) | EP3228331B1 (zh) |
JP (1) | JP2017527416A (zh) |
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CN105412975A (zh) | 2016-03-23 |
EP3228331A1 (en) | 2017-10-11 |
JP2017527416A (ja) | 2017-09-21 |
CN105412975B (zh) | 2019-05-31 |
EP3228331B1 (en) | 2020-05-27 |
US10314937B2 (en) | 2019-06-11 |
US20170252479A1 (en) | 2017-09-07 |
EP3228331A4 (en) | 2018-10-17 |
KR20170060054A (ko) | 2017-05-31 |
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