WO2022234963A1 - 혈액 응고 활성을 갖는 펩타이드와 이의 용도 - Google Patents
혈액 응고 활성을 갖는 펩타이드와 이의 용도 Download PDFInfo
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- WO2022234963A1 WO2022234963A1 PCT/KR2022/005090 KR2022005090W WO2022234963A1 WO 2022234963 A1 WO2022234963 A1 WO 2022234963A1 KR 2022005090 W KR2022005090 W KR 2022005090W WO 2022234963 A1 WO2022234963 A1 WO 2022234963A1
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
Definitions
- the present invention relates to a novel peptide capable of inducing blood coagulation and a use thereof.
- the vascular system plays an important role in transporting various nutrients and transporting oxygen or carbon dioxide in animals, and blood and body fluids are exchanged between blood vessels and tissues.
- blood and body fluids may leak to the outside. If such bleeding is excessive, oxygen transport, etc. may not be performed normally, leading to death. has been developed
- the living body there is a system that induces blood clotting by itself, and blood cells are agglomerated by thrombin formed through an enzymatic reaction and fibrin fibers made therefrom to form a thrombus or blood clot while inhibiting the outflow of blood or body fluid components This may cause bleeding.
- the coagulation system of the living body alone may not be sufficient to stop hemostasis. It can be said that the demand for substances having hyperhemostatic activity is always high.
- chitosan, collagen, starch, beeswax, etc. have been used, and these are manufactured and applied in the form of powder, sponge, sheet, or gel.
- Korean Patent Application Laid-Open No. 2018-0027126 a hemostatic effect was induced by using a composition comprising a cross-linked hyaluronic acid derivative matrix.
- the agents for hemostasis are basically applied to the damaged or wounded area, they should be harmless to the living body and should not cause side effects such as hemolysis.
- Hemostatic products using chitosan, polymer, etc. which have been developed as conventional medical devices, have insignificant hemostatic efficacy, have a problem in that the residue must be decomposed or discharged from the body after application to the living body, and the residue may cause an inflammatory reaction. .
- a conventional biological drug product having a blood coagulation mechanism since it is a bio-derived component, it is not easy to manufacture and transport/storage. It takes a long time to apply, so it has the disadvantage that it is not usable well. Therefore, there is a need for the development of a peptide formulation for promoting blood coagulation synthesized using an amino acid component, which is a biological component, while having excellent manufacturing and storage stability and hemostatic efficacy.
- An object of the present invention is to provide a peptide that can be used to induce blood clotting by being gelled under specific conditions.
- Another object of the present invention is to provide a composition capable of effectively inducing hemostasis by using the peptide as described above.
- Another object of the present invention is to provide a method for hemostasis using the composition.
- one aspect of the present invention provides a peptide comprising the amino acid sequence of SEQ ID NO: 1, having a pH-dependent gelation property.
- Another aspect of the present invention provides a composition for inducing hemostasis, including the peptide.
- Another aspect of the present invention provides a method of hemostasis comprising the step of applying the composition to a bleeding site of an animal in which bleeding has occurred.
- the peptides provided in the present invention have the property of self-gelling under neutral pH conditions.
- the peptide may be gelled under a specific pH condition to form an aggregate, and thus, when the peptide or a composition comprising the same is treated in blood or body fluid, the peptide may be gelated by the pH condition in the blood. .
- the peptide aggregates together with blood cells or the nanofiber structure formed by the gelation of the peptide surrounds and confines blood components other than blood cells and blood cells to form a lump, thereby precipitating or interfering with blood flow or outflow to induce hemostasis has the effect of making it happen.
- the peptide of the present invention and a composition comprising the same have a similar level of blood coagulation-inducing activity compared to conventionally marketed hemostatic agents, have an excellent effect of shortening the hemostasis time, and do not cause hemolysis, so hemostasis It can be usefully used for the purpose of inducing
- gelation does not proceed under acidic conditions and can be in the form of liquids or sols, so the peptides and compositions of the present invention have fluidity by maintaining acidic pH conditions before being applied to actual blood or body fluids. It may exhibit properties more suitable for storage or application. And when applied to blood or body fluid, gelation proceeds according to its neutral pH, which has the advantage that it can effectively exhibit a hemostatic effect at the actual bleeding site.
- the peptide of the present invention and the composition comprising the same are prepared from amino acid components constituting the living body, there is an advantage that side effects or problems of decomposition/discharge are less likely to occur when applied to the living body, and the resulting inflammatory reaction is reduced. less likely to occur And compared with the conventional hemostatic preparation, there is an effect of being easy to manufacture and excellent in storage stability.
- 1 is a graph showing the light scattering intensity kcps value and particle size measured by the peptide of the present invention according to the change in pH.
- FIG. 2 is a graph showing the optical density value (OD 600) of a solution containing the peptide of the present invention according to a change in salt (NaCl) concentration, and a photograph showing the shape of the solution according to the salt concentration.
- FIG. 3 is a photograph showing a comparison of the difference in the degree of gelation that appears according to the difference in the concentration of the peptide of the present invention.
- FIG. 4 is a result of a hemagglutination test observed by mixing a composition containing the peptide of the present invention with a suspension of red blood cells collected from mice at different concentrations.
- the circled part represents the experimental result of the concentration at which blood cells started to form thrombus without precipitation.
- FIG. 5 is a photograph showing that blood coagulation occurred after 13 seconds as a result of performing a blood coagulation test using a composition containing the peptide of the present invention.
- FIG. 6 is a result of performing a blood coagulation test using a composition containing the peptide of the present invention, and is a result of measuring and comparing the optical density of the supernatant of the centrifuged sample. Relative values were shown based on the values of the negative control group (DW) treated with distilled water, and the group treated with GreenplastQ and RADA16 peptide preparations was used as a control group.
- DW negative control group
- FIG. 7 is an animal test result on the hemostatic effect of the composition containing the peptide of the present invention, a control untreated (No Treatment), a control treated with greenplast (Greenplast Q), and the peptide of the present invention
- No Treatment a control untreated
- Greenplast Q a control treated with greenplast
- the amount of bleeding was measured 90 seconds after the start of bleeding.
- FIG. 8 is an animal test result for the hemostatic effect of the composition containing the peptide of the present invention, a control group untreated (NC), a control group treated with greenplast (Greenplast Q), and the peptide of the present invention, respectively. It is a graph showing the comparison of bleeding time values of the groups treated with concentrations of 1% and 2.5%. In the case of the control group without any treatment, the experiment was stopped about 90 seconds after the start of bleeding.
- FIG. 9 is an animal test result on the hemostatic effect of the composition containing the peptide of the present invention, a control untreated (NC), a control treated with greenplast (Greenplast Q), and the peptide of the present invention, respectively. It is a graph showing the comparison of the bleeding amount of the group treated with the concentration of 1% and 2.5%. In the case of the control group without any treatment, the amount of bleeding was measured approximately 90 seconds after the start of bleeding.
- FIG. 10 is a photograph and graph showing comparison of the hemolysis test results using the composition containing the peptide of the present invention, and as a control, 1% SDS and PBS were treated instead of the composition of the present invention to confirm the results.
- One aspect of the present invention provides a novel peptide having a pH-dependent gelation property.
- peptide refers to a polymer composed of two or more amino acids linked by a peptide bond.
- a gel refers to a phenomenon that changes to a gel form (shape), and the colloidal particles in the solution lose fluidity and have a solid or semi-solid state.
- a gel may be a gel in which solid particles are dispersed in a liquid while forming a chemical bond.
- the peptide includes the amino acid sequence of SEQ ID NO: 1.
- the peptide may include a mutant peptide having a different sequence by deletion, insertion, substitution or a combination of amino acid residues within a range that does not affect the properties or activity of the peptide, or a protein having the same function It may be in the form of a fragment.
- Amino acid modification at the protein and peptide level which does not entirely change the properties or activity according to the inclusion of the amino acid sequence of SEQ ID NO: 1, is known in the art, and in some cases phosphorylation, sulfurization ( sulfation), acrylation, glycosylation, methylation, farnesylation, and the like.
- the peptide includes not only the amino acid sequence of SEQ ID NO: 1, but also a peptide having substantially the same amino acid sequence or a variant thereof.
- the peptide having the substantially identical amino acid sequence is 90% or more, 91% or more, 92% or more, 93% or more, 94% or more, 95% or more, 96% or more, 97% or more of the amino acid sequence of SEQ ID NO: 1 , 98% or more, 99% or more, or may be a peptide comprising an amino acid sequence having a homology of 99.5% or more, but is not limited thereto, and a sequence having a homology of 90% or more with the amino acid sequence of SEQ ID NO: 1 If it is a peptide having the same activity while including, it is included in the scope of the present invention.
- the peptide of the present invention may be composed of 20 or less amino acids, including the amino acid sequence of SEQ ID NO: 1, exhibiting pH-dependent gelation properties. Specifically, the peptide may be composed of 20 or less, 18 or less, 15 or less, or 12 amino acids.
- the peptide of the present invention can be obtained by various methods well known in the art. As an example, it may be prepared using polynucleotide recombination and protein expression systems, or synthesized in vitro through chemical synthesis such as peptide synthesis, and cell-free protein synthesis, but is limited by the manufacturing method thereof. not.
- the N-terminal or A protecting group may be bound to the C-terminus.
- the protecting group may be an acetyl group, a fluorenyl methoxycarbonyl group, a formyl group, a palmitoyl group, a myristyl group, a stearyl group, or polyethylene glycol (PEG). If there is an ingredient, it may be included without limitation.
- the 'stability' refers to storage stability (eg, room temperature storage stability) as well as in vivo stability that protects the peptide of the present invention from attack by proteolytic enzymes in vivo.
- the peptide of the present invention may be gelled at neutral pH. Specifically, the peptide may be gelled at pH conditions ranging from pH 4 to pH 8, pH 4 to pH 7, pH 4.5 to pH 7, or pH 5 to pH 7, but is not limited thereto. The peptide may be gelled in a pH range that can be represented by human or non-human blood or body fluids.
- the peptide of the present invention may exhibit a sol or liquid form at acidic pH.
- the solution containing the peptide may be in a sol or liquid form at an acidic pH, for example, in the range of pH 0 to pH 3.9, and the peptide of the present invention, as the pH is changed and neutral pH conditions are given, It may be one having a property of losing fluidity due to gelation and forming a solid or semi-solid gel.
- the light scattering intensity kcps value and size of the peptide were measured while changing the pH, and it was confirmed that the size of the particles in the solution increases and the kcps value gradually increases under the condition of pH 4 or higher, and gelation proceeds. was confirmed.
- aggregation of the peptide was observed with the naked eye under the conditions of pH 6 or higher, and it was confirmed that the peptide of the present invention has a characteristic of being pH-dependent, more specifically, gelling under neutral pH conditions.
- the peptide may have a property of gelling in the presence of a salt, for example, the salt may be sodium chloride (NaCl), but is not limited thereto.
- the peptide may be gelled under conditions in which the salt concentration is 50 mM or more, 60 mM or more, 70 mM or more, or 100 mM or more, and the degree of gelation may increase as the concentration of the salt increases.
- the peptide may be gelled within a salt concentration range that can be expressed in human or non-human blood or body fluids.
- the degree of aggregation of the peptide was measured by measuring the optical density while changing the concentration of the salt and visually confirmed.
- concentration of sodium chloride (NaCl) is 100 mM or more, the turbidity gradually increases and the viscosity increases Thus, it was confirmed that gelation occurred.
- the peptide may induce blood clotting.
- the blood coagulation means that blood solidifies, and the peptide may induce a reaction in which liquid blood is solidified into a solid blood clot, blood clot, or the like.
- the nanofiber-like structure formed by the gelation of the peptide can be induced to aggregate by surrounding blood cells and other blood components in the blood.
- the blood cells aggregated together with the peptide of the present invention may form a lump, which may result in an increase in volume and thus may precipitate or interfere with blood flow or outflow. Therefore, since the peptide of the present invention has an activity to induce blood clotting when bleeding occurs, the peptide of the present invention or a composition comprising the same can be usefully used for hemostasis.
- Another aspect of the present invention provides a composition for inducing hemostasis, comprising the peptide.
- the peptide is to include the amino acid sequence of SEQ ID NO: 1, and the description thereof is '1. It is the same as the peptide described in the section 'Peptides having pH-dependent gelation properties', and detailed descriptions thereof are incorporated herein by reference.
- the term 'hemostasis' refers to reducing bleeding, which may mean reducing both the outflow of blood and the outflow of body fluids other than blood.
- the hemostasis includes all of inducing or promoting coagulation of blood or body fluid, reducing the amount of bleeding, reducing bleeding time, stopping bleeding, and promoting the formation of a thrombus or blood clot.
- a composition comprising the same may also be gelled by aggregation depending on pH conditions, and may be used for inducing hemostasis as it aggregates with blood cells.
- gelation of the peptides included in the composition may occur at the site where bleeding occurs, and thus the formed gel or nanofiber may aggregate while surrounding blood cells and other blood components. Agglomerates formed in this way may form large lumps and may precipitate or obstruct blood flow or outflow. Therefore, the composition of the present invention can be usefully used to induce hemostasis at a bleeding site.
- the composition may exhibit an acidic pH.
- the composition may exhibit a range of pH 0 to pH 3.9, and thus may be in the form of a liquid or sol without gelation.
- the peptide may be included in the composition at a concentration of 0.5 mg/ml to 50 mg/ml. Specifically, the peptide is contained at a concentration of 0.5 mg/ml to 50 mg/ml, 1 mg/ml to 40 mg/ml, 10 mg/ml to 35 mg/ml or 20 mg/ml to 30 mg/ml may be, but is not limited thereto.
- concentration of the peptide contained in the composition of the present invention is within the above range, gelation by the peptide can occur sufficiently, thereby induced blood coagulation and has the advantage that the hemostatic effect can be sufficiently exhibited.
- the composition may further include calcium ions.
- the calcium ion may be added to the composition of the present invention in the form of, for example, calcium chloride (CaCl 2 ).
- Calcium ions are known to induce and promote a blood clotting reaction in the blood, and more specifically, may help a thrombin formation reaction by an enzyme such as thrombokinase involved in the blood clotting reaction. Accordingly, the calcium ion may help the blood clotting or hemostatic effect exhibited by the composition of the present invention, and may also be included to form an appropriate salt concentration.
- the composition may be to coagulate blood at neutral pH, and more specifically, to coagulate blood at pH conditions in the range of pH 4 to pH 8, pH 4 to pH 7, pH 4.5 to pH 7, or pH 5 to pH 7. It may be possible, but is not limited thereto.
- the composition may coagulate blood in a pH range that can be expressed by human or non-human animal blood or body fluids.
- the composition may be one capable of coagulating blood under a condition of a salt concentration of 50 mM or more, and more specifically, one capable of coagulating blood under a condition of a salt concentration of 50 mM or more, 60 mM or more, 70 mM or more, or 100 mM or more.
- the present invention is not limited thereto.
- the composition may coagulate blood within a salt concentration range that can be expressed in human or non-human animal blood or body fluids.
- the composition may not cause hemolysis.
- the hemolysis refers to a phenomenon in which blood cells are destroyed, and specifically, it may be a phenomenon in which red blood cells are destroyed. Since the composition of the present invention does not cause hemolysis, it is suitable for application to blood or bleeding sites.
- the composition of the present invention did not induce blood hemolysis.
- the composition can be made into various types of agents to induce hemostasis.
- the composition may be in at least one form selected from the group consisting of powder formulations, patches, gauze, sprays and injections, but is not limited thereto, and the peptides included in the composition are gelled to form blood cells and It may be provided in any form as long as it can aggregate with other blood components.
- Another aspect of the present invention provides a method of hemostasis using the composition.
- the hemostasis method of the present invention comprises the step of applying the composition of claim 4 to a bleeding site of an animal in which bleeding has occurred.
- the animal includes both humans and non-human animals, wherein the non-human animal includes, for example, cattle, pigs, sheep, goats, deer, horses, rats, or poultry (chickens, ducks, geese, turkeys, ostriches, turkeys). , pheasant), but is not limited thereto, and may be applied without limitation if the animal has a vascular system.
- the bleeding site includes all sites from which blood or body fluids other than blood flow, for example, a site where blood or body fluid leaks due to damage to the surface of the skin, a site where blood or body fluid leaks due to damage or cut in blood vessels It may include both sites, intestinal bleeding sites, and the like.
- the method of treating the composition may vary depending on the type of the composition, for example, if the composition is a powder formulation, a spray, etc., it may be treated by spraying or applying to the bleeding site, and in the case of a patch, gauze, etc., the bleeding site It can be treated by adhering to the surface.
- the composition when the composition is an injection, it may be treated by injecting a syringe into the bleeding site, but is not limited thereto.
- the hemostasis method may further include applying physical pressure to the bleeding site after the step of treating the composition.
- the hemostatic method of the present invention is not limited thereto, and any hemostatic method commonly used to suppress bleeding may be applied together with the treatment step of the composition of the present invention without limitation.
- the change in the degree of gelation was confirmed by measuring the change in the physical properties of the peptide of the present invention while controlling the pH. Specifically, the peptide of the present invention was dissolved at a concentration of 1 mg/ml using 10 mM acetic acid buffer (pH 3.4 to pH 5.5) and 10 mM phosphate buffer (pH 6.0 to pH 7.4).
- the change in the kcps value of the light scattering intensity was not large at pH 3.4 and 4, but it was measured that the kcps value increased significantly when the pH was increased to 4.5, so that the gelation of the peptide of the present invention started.
- the gelling point which is the pH to be used, was confirmed to be between pH 4 and pH 4.5.
- the kcps value also gradually increased, and it was measured to be the highest at pH 5.5. It is expected that this is because the structural change of the peptide of the present invention is induced as the pH increases, and thus the peptide has gelation properties due to the arrangement of the particles.
- the peptide of the present invention gelation does not proceed under acidic pH conditions, so aggregation phenomenon is not observed, but when the pH is gradually increased and the pH is 4 to 4.5, gelation starts and aggregates to a neutral pH. It was confirmed that there is a characteristic of forming a gel shape. Therefore, the peptide can form aggregates depending on its pH conditions and has the potential to be used for inducing blood coagulation.
- the peptide of the present invention in which gelation occurs in a pH range similar to that of animal blood and body fluids. Considering the characteristics of this, it was confirmed that it is suitable for application to the living body.
- the turbidity of the mixture started to increase when the concentration of NaCl was 100 mM, and the turbidity of the mixture continued to increase until the concentration of NaCl reached 200 mM. It is expected that this is because aggregation is promoted according to an increase in the interaction between the peptide molecules of the present invention. In addition, it was confirmed that the viscosity tends to increase up to a concentration of 150 mM NaCl.
- the concentration of the peptide of the present invention having the amino acid sequence of SEQ ID NO: 1 it was confirmed how the degree of gelation of the peptide changes. Specifically, the peptide is mixed with distilled water at a concentration of 5, 10 and 25 mg/ml, respectively, and dissolved in a 1.5 ml microtube, and then 5N NaOH is added thereto to gradually increase the pH of the mixture containing the peptide. The phase transition was observed with the naked eye.
- the peptides of the present invention generally exhibit sol properties under the initial acidic pH condition, but gelation proceeded as the pH increased.
- the concentration of the peptide was 0.5 mg/ml, gelation did not occur even when the pH reached 7.5, but as the concentration of the peptide increased, the gelation of the peptide was further promoted, and the peptide was included at a concentration of 25 mg/ml. In the tube, it was confirmed that gelation proceeded from pH 4.2.
- a RADA16 peptide sample (3D Matrix) for research that is known to have hemostatic activity and is commercially available was used.
- the preparation example peptide and the control peptide of the present invention were dissolved in purified water and treated with 10 ⁇ l at a concentration of 0, 62.5, 125, 250, 500 and 1,000 ⁇ g/ml, respectively, and then 90 ⁇ l of sodium chloride aqueous solution was added.
- 10 ⁇ l of the red blood cell suspension was added thereto, mixed at 300 rpm for 10 minutes, and reacted at 4° C. for 2 hours or more. And by visually confirming the degree of precipitation of the red blood cell suspension, the degree of aggregation of blood cells by the formation of nanofibers in each sample was evaluated.
- the red blood cell suspension could not be precipitated at a concentration of the present invention peptide of 500 ⁇ g/ml or more, and a thrombus was formed.
- This is the effect of aggregation of red blood cells due to the nanofiber formed by the peptide of the present invention, and it was confirmed that the blood coagulation promoting effect appeared at a level similar to that of the control peptide sample, which is known to have an aggregation effect on blood cells. Therefore, it was confirmed that the peptide of the present invention or a composition comprising the same can be usefully used for hemostasis by inducing aggregation of blood cells.
- the clotting time of blood according to the peptide treatment of the present invention was evaluated.
- 300 ⁇ l of blood was transferred to an EP tube, and 150 ⁇ l of a solution in which the peptide of the present invention was dissolved in purified water was treated.
- the clotting time was measured by visually evaluating the blood flow by inverting the tube at 10-second intervals.
- the RADA16 peptide sample and Greenplast Greenplast Q, GC Green Cross
- the optical density thereof was measured after the peptide of Preparation Example was treated in the blood of a rat. Specifically, 300 ⁇ l of blood was transferred to a 15 ml conical tube in a state in which the blood coagulation reaction of mice collected in a heparin vacuum collection vessel was suppressed, and then 300 ⁇ l of the peptide solution of the present invention was added and lightly mixed. Then, 30 ⁇ l of 0.2 M CaCl 2 solution was added and incubated at 37° C. for 10 minutes to accelerate the coagulation reaction.
- the optical density measured when the peptide of the present invention was treated was at a level of 0.41 based on the blood coagulation degree of the negative control treated with distilled water, and the amount of blood cells in the supernatant was significantly increased. was measured to decrease. This indicates that the blood coagulation effect is better than the effect (0.7) when the RADA16 peptide preparation, which is a commercially available hemostatic agent, is treated. It was confirmed that it could be used.
- a bleeding model was constructed by exposing the artery by excising the femur of an 8-week-old female rat (SD-rat), and then damaging the exposed artery with a 21 G needle. Then, immediately after bleeding, samples prepared by dissolving the peptides of the present invention in purified water at concentrations of 1% and 2.5%, respectively, were treated at 200 ⁇ l bleeding sites, respectively, and then the bleeding blood was absorbed with gauze weighed in advance. Then, the time taken until the bleeding stopped was measured, and the weight of the gauze in which the blood was absorbed was measured to determine the amount of bleeding. Greenplast preparation was used as a positive control group, and in the case of a negative control group without any treatment, the experiment was stopped 90 seconds after the bleeding started, and the amount of bleeding up to that time was checked.
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Abstract
Description
서열번호 | 펩타이드 서열 |
1 | SASQAYLAGNIT |
혈액 응고 시간 | |
증류수 | - |
Greenplast Q | < 20초 |
RADA16 2.5% | < 30초 |
본 발명 펩타이드 2.5% | 13초 |
Claims (11)
- 서열번호 1의 아미노산 서열을 포함하는, pH 의존적 겔화 특성을 갖는 펩타이드.
- 청구항 1에 있어서,상기 펩타이드는 pH 4 내지 pH 8에서 겔화되는 것인, 펩타이드.
- 청구항 1에 있어서,상기 펩타이드는 혈액 응고를 유도할 수 있는 것인, 펩타이드.
- 청구항 1의 펩타이드를 포함하는, 지혈 유도용 조성물.
- 청구항 4에 있어서,상기 펩타이드는 상기 조성물 내에 0.5 ㎎/㎖ 내지 50 ㎎/㎖의 농도로 포함되는 것인, 지혈 유도용 조성물.
- 청구항 4에 있어서,상기 조성물은 칼슘 이온을 더 포함하는 것인, 지혈 유도용 조성물.
- 청구항 4에 있어서,상기 조성물은 pH 4 내지 pH 8에서 혈액을 응고시키는 것인, 지혈 유도용 조성물.
- 청구항 4에 있어서,상기 조성물은 염 농도가 50 mM 이상인 조건에서 혈액을 응고시키는 것인, 지혈 유도용 조성물.
- 청구항 4에 있어서,상기 조성물은 용혈 현상을 일으키지 않는 것인, 지혈 유도용 조성물.
- 청구항 4에 있어서,상기 조성물은 분말형 제제, 패치제, 거즈, 스프레이제 및 주사제로 이루어진 군으로부터 선택되는 적어도 하나의 형태인 것인, 지혈 유도용 조성물.
- 출혈이 발생한 동물의 출혈 부위에 청구항 4의 조성물을 처리하는 단계를 포함하는, 지혈 방법.
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CN202280031584.1A CN117255796A (zh) | 2021-05-04 | 2022-04-08 | 具有凝血活性的肽及其用途 |
JP2023560412A JP2024514093A (ja) | 2021-05-04 | 2022-04-08 | 血液凝固活性を有するペプチドとこの用途 |
EP22799008.2A EP4335860A1 (en) | 2021-05-04 | 2022-04-08 | Peptide having blood coagulation activity, and use thereof |
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KR1020210058155A KR102647642B1 (ko) | 2021-05-04 | 2021-05-04 | 혈액 응고 활성을 갖는 펩타이드와 이의 용도 |
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KR20180027126A (ko) | 2016-09-06 | 2018-03-14 | (주)한국비엠아이 | 가교화 히알루론산 유도체 매트릭스가 포함된 지혈 조성물 |
KR20190052027A (ko) * | 2016-09-23 | 2019-05-15 | 씨에스엘 리미티드 | 응고 인자 결합 단백질 및 이의 용도 |
KR20190073576A (ko) * | 2016-11-11 | 2019-06-26 | 체에스엘 베링 렝나우 아게 | 혈액 응고 장애의 치료 또는 예방에서 혈관외 투여를 위한 절단된 폰 빌레브란트 인자 폴리펩타이드 |
KR20190102101A (ko) * | 2013-03-06 | 2019-09-02 | 가부시끼가이샤 쓰리디 매트릭스 | 정제된 양친매성 펩타이드 조성물을 이용하는 수술 방법 |
JP2020533023A (ja) * | 2017-09-08 | 2020-11-19 | ネオペプ ファーマ ゲーエムベーハー ウント コンパニー カーゲー | 病気の治療のためのポリペプチド |
US20200399310A1 (en) * | 2014-03-10 | 2020-12-24 | 3-D Matrix, Ltd. | Self-assembling peptide compositions |
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KR20020081601A (ko) * | 1999-06-29 | 2002-10-30 | 정광회 | Factor Xa 억제 단백질 및 그의 제조방법 |
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- 2022-04-08 JP JP2023560412A patent/JP2024514093A/ja active Pending
- 2022-04-08 CN CN202280031584.1A patent/CN117255796A/zh active Pending
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Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
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KR20190102101A (ko) * | 2013-03-06 | 2019-09-02 | 가부시끼가이샤 쓰리디 매트릭스 | 정제된 양친매성 펩타이드 조성물을 이용하는 수술 방법 |
US20200399310A1 (en) * | 2014-03-10 | 2020-12-24 | 3-D Matrix, Ltd. | Self-assembling peptide compositions |
KR20180027126A (ko) | 2016-09-06 | 2018-03-14 | (주)한국비엠아이 | 가교화 히알루론산 유도체 매트릭스가 포함된 지혈 조성물 |
KR20190052027A (ko) * | 2016-09-23 | 2019-05-15 | 씨에스엘 리미티드 | 응고 인자 결합 단백질 및 이의 용도 |
KR20190073576A (ko) * | 2016-11-11 | 2019-06-26 | 체에스엘 베링 렝나우 아게 | 혈액 응고 장애의 치료 또는 예방에서 혈관외 투여를 위한 절단된 폰 빌레브란트 인자 폴리펩타이드 |
JP2020533023A (ja) * | 2017-09-08 | 2020-11-19 | ネオペプ ファーマ ゲーエムベーハー ウント コンパニー カーゲー | 病気の治療のためのポリペプチド |
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EP4335860A1 (en) | 2024-03-13 |
KR20220150776A (ko) | 2022-11-11 |
CN117255796A (zh) | 2023-12-19 |
KR102647642B1 (ko) | 2024-03-15 |
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