CN113368098B - Application of icariin in preparation of medicine for preventing and treating hemophilia - Google Patents
Application of icariin in preparation of medicine for preventing and treating hemophilia Download PDFInfo
- Publication number
- CN113368098B CN113368098B CN202011623189.1A CN202011623189A CN113368098B CN 113368098 B CN113368098 B CN 113368098B CN 202011623189 A CN202011623189 A CN 202011623189A CN 113368098 B CN113368098 B CN 113368098B
- Authority
- CN
- China
- Prior art keywords
- hemophilia
- icariin
- use according
- treatment
- disease
- Prior art date
- Legal status (The legal status 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 status listed.)
- Active
Links
- TZJALUIVHRYQQB-XFDQAQKOSA-N Icariin Natural products O(C)c1ccc(C2=C(O[C@H]3[C@@H](O)[C@H](O)[C@@H](O)[C@H](C)O3)C(=O)c3c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O4)c(C/C=C(\C)/C)c3O2)cc1 TZJALUIVHRYQQB-XFDQAQKOSA-N 0.000 title claims abstract description 68
- TZJALUIVHRYQQB-XLRXWWTNSA-N icariin Chemical compound C1=CC(OC)=CC=C1C1=C(O[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)C(=O)C2=C(O)C=C(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-XLRXWWTNSA-N 0.000 title claims abstract description 68
- TZJALUIVHRYQQB-UHFFFAOYSA-N icariine Natural products C1=CC(OC)=CC=C1C1=C(OC2C(C(O)C(O)C(C)O2)O)C(=O)C2=C(O)C=C(OC3C(C(O)C(O)C(CO)O3)O)C(CC=C(C)C)=C2O1 TZJALUIVHRYQQB-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 208000009292 Hemophilia A Diseases 0.000 title claims abstract description 57
- 208000031220 Hemophilia Diseases 0.000 title claims abstract description 52
- 239000003814 drug Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title abstract description 28
- 238000011282 treatment Methods 0.000 claims abstract description 25
- 229940079593 drug Drugs 0.000 claims abstract description 6
- 201000010099 disease Diseases 0.000 claims description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 13
- 102100022641 Coagulation factor IX Human genes 0.000 claims description 9
- 208000009429 hemophilia B Diseases 0.000 claims description 5
- 239000006187 pill Substances 0.000 claims description 5
- 239000002775 capsule Substances 0.000 claims description 4
- 230000002068 genetic effect Effects 0.000 claims description 3
- 230000003902 lesion Effects 0.000 claims description 3
- 210000004185 liver Anatomy 0.000 claims description 3
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- 208000030507 AIDS Diseases 0.000 claims description 2
- 206010000830 Acute leukaemia Diseases 0.000 claims description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 2
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims description 2
- 206010008909 Chronic Hepatitis Diseases 0.000 claims description 2
- 208000004332 Evans syndrome Diseases 0.000 claims description 2
- 206010016654 Fibrosis Diseases 0.000 claims description 2
- 206010018910 Haemolysis Diseases 0.000 claims description 2
- 206010019759 Hepatitis chronic persistent Diseases 0.000 claims description 2
- 206010020850 Hyperthyroidism Diseases 0.000 claims description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 2
- 206010025323 Lymphomas Diseases 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000000443 aerosol Substances 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 230000000340 anti-metabolite Effects 0.000 claims description 2
- 229940100197 antimetabolite Drugs 0.000 claims description 2
- 239000002256 antimetabolite Substances 0.000 claims description 2
- 229960002155 chlorothiazide Drugs 0.000 claims description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 230000007882 cirrhosis Effects 0.000 claims description 2
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 2
- 208000011664 congenital factor XI deficiency Diseases 0.000 claims description 2
- 229940127089 cytotoxic agent Drugs 0.000 claims description 2
- 239000002254 cytotoxic agent Substances 0.000 claims description 2
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 201000007219 factor XI deficiency Diseases 0.000 claims description 2
- 230000008588 hemolysis Effects 0.000 claims description 2
- 208000006454 hepatitis Diseases 0.000 claims description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000000829 suppository Substances 0.000 claims description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 claims description 2
- 208000019423 liver disease Diseases 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 14
- 238000000034 method Methods 0.000 abstract description 9
- 238000011160 research Methods 0.000 abstract description 4
- 230000007547 defect Effects 0.000 abstract description 2
- 231100000956 nontoxicity Toxicity 0.000 abstract description 2
- 239000007924 injection Substances 0.000 description 19
- 238000002347 injection Methods 0.000 description 19
- 239000000203 mixture Substances 0.000 description 19
- 208000032843 Hemorrhage Diseases 0.000 description 18
- 208000034158 bleeding Diseases 0.000 description 18
- 230000000740 bleeding effect Effects 0.000 description 18
- 238000009472 formulation Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- 238000002156 mixing Methods 0.000 description 11
- 210000002381 plasma Anatomy 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 10
- 239000004530 micro-emulsion Substances 0.000 description 10
- 102100026735 Coagulation factor VIII Human genes 0.000 description 9
- 101000911390 Homo sapiens Coagulation factor VIII Proteins 0.000 description 9
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- 229940124531 pharmaceutical excipient Drugs 0.000 description 9
- 208000033316 Acquired hemophilia A Diseases 0.000 description 8
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 8
- 239000007901 soft capsule Substances 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 229910052799 carbon Inorganic materials 0.000 description 7
- TUUXBSASAQJECY-UHFFFAOYSA-N 3,5,7-trihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-enyl)chromen-4-one Chemical compound C1=CC(OC)=CC=C1C1=C(O)C(=O)C2=C(O)C=C(O)C(CC=C(C)C)=C2O1 TUUXBSASAQJECY-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- -1 flavonoid glycoside compounds Chemical class 0.000 description 6
- 239000002245 particle Substances 0.000 description 6
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 5
- 201000003542 Factor VIII deficiency Diseases 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 5
- 108010000499 Thromboplastin Proteins 0.000 description 5
- 102000002262 Thromboplastin Human genes 0.000 description 5
- 230000036961 partial effect Effects 0.000 description 5
- 229960004063 propylene glycol Drugs 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 241000893536 Epimedium Species 0.000 description 4
- 108010076282 Factor IX Proteins 0.000 description 4
- 101150108210 IX gene Proteins 0.000 description 4
- 241000283973 Oryctolagus cuniculus Species 0.000 description 4
- 229940105774 coagulation factor ix Drugs 0.000 description 4
- 230000004064 dysfunction Effects 0.000 description 4
- 235000018905 epimedium Nutrition 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 210000003462 vein Anatomy 0.000 description 4
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 3
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 3
- CTGVBHDTGZUEJZ-UHFFFAOYSA-N Noricaritin Natural products CC(C)(O)CCC1=C(O)C=C(O)C(C(C=2O)=O)=C1OC=2C1=CC=C(O)C=C1 CTGVBHDTGZUEJZ-UHFFFAOYSA-N 0.000 description 3
- 230000003213 activating effect Effects 0.000 description 3
- 239000003114 blood coagulation factor Substances 0.000 description 3
- 230000015271 coagulation Effects 0.000 description 3
- 238000005345 coagulation Methods 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003209 gene knockout Methods 0.000 description 3
- WEXRUCMBJFQVBZ-UHFFFAOYSA-N pentobarbital Chemical compound CCCC(C)C1(CC)C(=O)NC(=O)NC1=O WEXRUCMBJFQVBZ-UHFFFAOYSA-N 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000008213 purified water Substances 0.000 description 3
- 238000009210 therapy by ultrasound Methods 0.000 description 3
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 2
- 208000035473 Communicable disease Diseases 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 208000000059 Dyspnea Diseases 0.000 description 2
- 206010013975 Dyspnoeas Diseases 0.000 description 2
- 241000893531 Epimedium koreanum Species 0.000 description 2
- 108010054218 Factor VIII Proteins 0.000 description 2
- 102000001690 Factor VIII Human genes 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000283977 Oryctolagus Species 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000007963 capsule composition Substances 0.000 description 2
- 239000004359 castor oil Substances 0.000 description 2
- 235000019438 castor oil Nutrition 0.000 description 2
- 229940105778 coagulation factor viii Drugs 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000007812 deficiency Effects 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 125000005456 glyceride group Chemical group 0.000 description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 208000031169 hemorrhagic disease Diseases 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 229960001412 pentobarbital Drugs 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229940113116 polyethylene glycol 1000 Drugs 0.000 description 2
- 229940050929 polyethylene glycol 3350 Drugs 0.000 description 2
- 229940093429 polyethylene glycol 6000 Drugs 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 239000003549 soybean oil Substances 0.000 description 2
- 235000012424 soybean oil Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000007619 statistical method Methods 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- WOKDXPHSIQRTJF-UHFFFAOYSA-N 3-[3-[3-[3-[3-[3-[3-[3-[3-(2,3-dihydroxypropoxy)-2-hydroxypropoxy]-2-hydroxypropoxy]-2-hydroxypropoxy]-2-hydroxypropoxy]-2-hydroxypropoxy]-2-hydroxypropoxy]-2-hydroxypropoxy]-2-hydroxypropoxy]propane-1,2-diol Chemical compound OCC(O)COCC(O)COCC(O)COCC(O)COCC(O)COCC(O)COCC(O)COCC(O)COCC(O)COCC(O)CO WOKDXPHSIQRTJF-UHFFFAOYSA-N 0.000 description 1
- 241000133570 Berberidaceae Species 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 241001362421 Epimedium brevicornu Species 0.000 description 1
- 241001660849 Epimedium pubescens Species 0.000 description 1
- 241001362411 Epimedium sagittatum Species 0.000 description 1
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 1
- 206010018852 Haematoma Diseases 0.000 description 1
- 206010018985 Haemorrhage intracranial Diseases 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101001014213 Homo sapiens Morphogenetic neuropeptide Proteins 0.000 description 1
- 206010021118 Hypotonia Diseases 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 208000008574 Intracranial Hemorrhages Diseases 0.000 description 1
- 235000006662 Lansium Nutrition 0.000 description 1
- 241001156382 Lansium Species 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010062575 Muscle contracture Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002565 Polyethylene Glycol 400 Polymers 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 208000031975 Yang Deficiency Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000002929 anti-fatigue Effects 0.000 description 1
- 230000003262 anti-osteoporosis Effects 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000003149 assay kit Methods 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000010836 blood and blood product Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 229940125691 blood product Drugs 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 230000004097 bone metabolism Effects 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 208000006111 contracture Diseases 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 1
- 210000003191 femoral vein Anatomy 0.000 description 1
- 208000017561 flaccidity Diseases 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 229930182486 flavonoid glycoside Natural products 0.000 description 1
- 150000002215 flavonoids Chemical class 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000004023 fresh frozen plasma Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 230000009395 genetic defect Effects 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000011132 hemopoiesis Effects 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 201000001881 impotence Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 208000000509 infertility Diseases 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 231100000535 infertility Toxicity 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 230000027939 micturition Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 231100000862 numbness Toxicity 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 210000000963 osteoblast Anatomy 0.000 description 1
- 210000002997 osteoclast Anatomy 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 208000037920 primary disease Diseases 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000011265 semifinished product Substances 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000036962 time dependent Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/29—Berberidaceae (Barberry family), e.g. barberry, cohosh or mayapple
- A61K36/296—Epimedium
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Biotechnology (AREA)
- Diabetes (AREA)
- Microbiology (AREA)
- Medical Informatics (AREA)
- Botany (AREA)
- Alternative & Traditional Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Mycology (AREA)
- Hematology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of medicines, relates to medical application of icariin, and in particular relates to application of icariin in preparation of a medicine for preventing and treating hemophilia. In order to overcome the defects of the existing hemophilia treatment method, the invention researches the treatment effect of the icariin on hemophilia, and the research result shows that: the icariin has remarkable treatment effect on hereditary hemophilia and secondary hemophilia, has the advantages of safety, no toxicity, convenient administration and low price, and is expected to become an effective treatment medicine for hemophilia.
Description
Technical Field
The invention belongs to the field of medicines, relates to medical application of icariin, and in particular relates to application of icariin in preparation of a medicine for preventing and treating hemophilia.
Background
Hemophilia (hemophilia) is a group of X-linked recessive genetic diseases caused by mutations in genes encoding coagulation factor VIII (coagulation factor VIII, FVIII) and/or coagulation factor IX (coagulation factor IX, FIX). This genetic defect causes a deficiency or dysfunction of FVIII and/or FIX in the body, resulting in a coagulation dysfunction in the body, which is seriously threatening the life health of the patient. Diseases can be divided into Hemophilia A (HA) caused by FVIII dysfunction and Hemophilia B (HB) caused by FIX dysfunction, most hemophilia patients being men. Study data indicate that there are approximately 1 human HA patient in 5000 male infants. HA can be divided into hereditary and acquired, acquired hemophilia a is a rarely hemorrhagic disease, resulting from the production of anti-fviii: C antibodies in the circulation. The bleeding symptoms of the disease are heavy, the reaction to the conventional FVIII substitution treatment is poor, the life of patients is often endangered, and about 16 to 22 percent of acquired hemophilia A patients die from severe bleeding. Currently, there is no uniform and exact treatment regimen for acquired hemophilia a internationally. HB is lower in incidence compared to HA, with an incidence of about 1/25,000 in men. The clinical manifestations of hemophilia are mainly repeated bleeding and somatic deformity caused by hematoma compression, and when severe, the patient faces life crisis due to intracranial hemorrhage. There is no effective cure for this disease. Hemophilia treatment is followed by infusion of whole blood and fresh frozen plasma from the beginning of the second combat phase to cryoprecipitation, prothrombin complex and clotting factor preparation. However, long-term infusion of these blood products and the like has resulted in a great increase in the incidence of blood-borne infectious diseases and the like. Although the application of the plasma-derived coagulation factor or the gene recombination coagulation factor can reduce the occurrence probability of blood-derived infectious diseases, antibodies are easy to generate in vivo after long-term use, serious complications are caused, and the bleeding frequency of patients is further increased, the bleeding symptoms are obviously aggravated before, and the treatment is more difficult. On the other hand, the high cost makes it difficult to develop a lifetime prophylactic treatment widely. Thus, there is a great clinical need to find a new method of treating hemophilia that overcomes the above-mentioned drawbacks.
The herba Epimedii is dried stem and leaf of Epimedium (Epimedium brevicornum Maxim.), epimedium sagittatum Maxim.), epimedium lansium (Epimedium pubescens Maxim.), or Epimedium koreanum (Epimedium koreanum Nakai). Clinically, the Chinese medicinal composition is mainly used for treating kidney-yang deficiency, impotence, frequent urination and infertility; rheumatalgia, numbness and contracture of limbs, flaccidity of bones and muscles, and difficult walking; deficiency of kidney-yang, dyspnea and cough with shortness of breath. Icariin has effects of increasing cardiovascular and cerebrovascular blood flow, promoting hematopoiesis, immunity, and bone metabolism, invigorating kidney, supporting yang, resisting aging, and resisting tumor.
Icaritin (IT) is a polyhydroxy flavonoid monomer component in herba Epimedii of Epimedium of berberidaceae. Pharmacological studies have shown that: IT has stronger anti-osteoporosis effect than other flavonoid glycoside compounds in herba Epimedii, and has effects of promoting osteoblast activity and inhibiting osteoclast activity in vitro. Icariin and icariin, which are important active ingredients in epimedium, have been attracting attention from medical workers in recent years. For example, patent CN201310652615.8 discloses the use of icariin in the preparation of anti-fatigue drugs; patent CN201310373517.0 discloses the use of icariin in the preparation of a medicament for treating asthma.
There is no report of icariin in the aspect of hemophilia prevention and treatment in the literature.
Disclosure of Invention
In order to overcome the defects of the existing hemophilia treatment method, the invention provides the application of the icariin in preparing the hemophilia prevention drug.
The hemophilia is any one of hemophilia or secondary hemophilia caused by genetic factors.
The hemophilia is any one of hemophilia A, hemophilia B or hemophilia C.
Further, the secondary hemophilia is a disease caused by a drug or a disease itself.
Further, the disease caused by the self disease includes, but is not limited to, one of liver lesions, hemolysis, acquired immunodeficiency diseases, evans syndrome, chronic lymphocytic leukemia, various acute leukemia, lymphoma, systemic lupus erythematosus, rheumatoid arthritis, hyperthyroidism.
Further, the liver lesion is caused by chronic persistent hepatitis or cirrhosis.
Such agents include, but are not limited to, alkylating agents, antimetabolites, cytotoxic agents chlorothiazide and synergists thereof.
Specific example 1 influence of icariin on bleeding time of coagulation factor IX knockout hemophilia mice results indicate that: the result shows that the icariin can effectively shorten the bleeding time of IX gene knockout hemophilia mice, and the blood routine of each group of mice has no significant difference.
Specific example 2 effect of icariin on time to activate partial thromboplastin for acquired hemophilia a results demonstrate that:
the icariin can obviously shorten the time of activating partial thromboplastin of hemophilia patients and promote the coagulation of hemophilia patients.
The icariin not only has remarkable treatment effect on hemophilia caused by genetic factors, but also has remarkable treatment effect on secondary hemophilia.
The invention provides the application of the icariin in preparing the medicament for preventing and treating the hemorrhagic diseases, and also provides a pharmaceutical preparation used for treating the diseases, which comprises the icariin and pharmaceutically acceptable pharmaceutical excipients.
The pharmaceutical preparation comprises but is not limited to injection, powder injection, capsule, tablet, microemulsion, dripping pill and enteric soft capsule. Routes of administration include the gastrointestinal and parenteral routes.
The term "pharmaceutically acceptable pharmaceutical excipients" as used in the present invention refers to any substance which does not interfere with the physiological action of icariin and which is not toxic to subjects including humans.
The pharmaceutical excipients used in the preparation of the invention are common excipients known to those skilled in the art. Suitable pharmaceutical excipients are described in detail in "pharmaceutical excipients university" (page 123, published by Sichuan science and technology Press, 1993, main editions Luo Mingsheng and Gao Tianhui). For example: common pharmaceutical excipients for preparing microemulsion preparations include, but are not limited to, soybean oil, polyoxyethylene-23-lauryl ether, 1, 2-propanediol, hydrogenated coco glyceride, lauroyl polyethylene glycol-32-glyceride, polyethylene glycol 3350, safflower oil, cottonseed oil, decaglycerol monostearate; common pharmaceutical excipients for preparing the dripping pill preparation include, but are not limited to, polyethylene glycol 6000 and polyethylene glycol 1000; pharmaceutical excipients commonly used in the preparation of capsule formulations include, but are not limited to lactose and corn starch; pharmaceutically acceptable carriers commonly used in the preparation of soft capsule formulations include, but are not limited to, medium chain fatty acid glycerides, polyoxyethylated castor oil, 1, 2-propanediol, and the like.
The person skilled in the art can select suitable pharmaceutical excipients according to the actual need and formulate the formulation according to the invention by methods known in the art. Such formulations include, but are not limited to, solids, liquids, oils, emulsions, gels, aerosols, inhalants, sprays, capsules, pills, patches, suppositories, and the like.
In the treatment of the above diseases, icariin is administered at a dose of 0.03mg/kg to 400mg/kg, preferably at a dose of 0.3mg/kg to 40mg/kg.
Compared with the existing treatment method for hemophilia, the icariin has the following advantages when being used for treating hemophilia:
1. has obvious curative effect
The research shows that the icariin can obviously shorten the bleeding time of hereditary and secondary hemophilia model animals, and has obvious treatment effect on hemophilia.
2. Safe and nontoxic, and convenient for administration
The icariin is an extracted component of the traditional Chinese medicine, can be prepared into an oral preparation for treating hemophilia, does not cause complications in the treatment process, does not aggravate the primary disease condition, and has the characteristics of convenient administration, safety and no toxicity compared with the existing treatment method.
3. Low cost
Compared with the existing treatment method, the icariin has remarkable advantages in price, and can reduce the economic burden of hemophilia patients.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further described below by means of specific embodiments, to which the invention is not limited.
Formulation example 1 icariin injection
The preparation process comprises the following steps: mixing ethanol and tween-80, adding icariin, stirring to dissolve, adding injectable water to 10L, stirring, adding 0.5% of active carbon for injection, stirring, and removing carbon.
Formulation example 2 icariin injection
The preparation process comprises the following steps: adding icariin into PEG-400 with the prescription dosage, stirring for dissolving, adding 0.9% sodium chloride solution to 10L, stirring uniformly, adding 0.5% needle active carbon, stirring, and removing carbon to obtain the final product.
Formulation example 3 icariin injection
Icariin 1g
Ethanol 3.3L
Injection water is added to 10L
The preparation process comprises the following steps: adding icariin into ethanol with a prescription amount, stirring for dissolving, adding injectable water to 10L, stirring, adding 0.5% active carbon for injection, stirring, and removing carbon to obtain the final product.
Formulation example 4 icariin powder injection
The preparation process comprises the following steps: weighing the icariin raw materials for injection with the prescription dosage, and adding a proper amount of water for injection for dissolution. Then adding a prescribed amount of the sterilized and pyrogen-removed mixture, and adding water for injection to a prescribed volume of 1000ml; adding 5g of active carbon for injection into the above medicinal liquid, heating at 60-80deg.C for 30min, filtering with a filter membrane, and collecting filtrate. And (3) carrying out positive pressure sterilization filtration on the filtrate by using a sterilization filter according to a sterile operation method, filtering by using a 0.22 mu M microporous filter membrane, carrying out pyrogen examination and semi-finished product content examination on the filtrate, and then packaging in penicillin bottles. Pre-freezing at-40deg.C for 1.5-3.5 hr, sublimating under vacuum for 90% of free water, heating to dry (maximum temperature not exceeding 35deg.C), and lyophilizing to obtain icariin powder for injection.
Formulation example 5 icariin tablet
The preparation process comprises mixing icariin and microcrystalline cellulose as adjuvant, and sodium carboxymethyl starch, adding appropriate amount of starch slurry to make soft mass, and granulating with 16 mesh sieve. Drying the wet granules at 60 ℃, sieving the dry granules by a 20-mesh sieve, sieving out fine powder in the dry granules, uniformly mixing with magnesium stearate, then uniformly mixing with the dry granules, tabletting, and obtaining about 200mg of tablets. Formulation example 6 icariin capsule formulation
The preparation process comprises the following steps: mixing icariin 100g, lactose 120g and corn starch 130g in a mixer for 10-15 min, adding magnesium stearate 5g, mixing for 1-3 min, and packaging into 1000 capsule shells.
Formulation example 7 icariin microemulsion preparation
The preparation process comprises the following steps: weighing soybean oil, polyoxyethylene-23-lauryl ether and 1, 2-propylene glycol according to the prescription, mixing, stirring uniformly, adding icariin for dissolving, and optionally performing ultrasonic treatment to accelerate dissolving to obtain clear solution, namely the icariin microemulsion preparation. The particle size was measured by a laser particle size analyzer, and the average particle size was 15nm.
Formulation example 8 icariin microemulsion preparation
The preparation process comprises the following steps: weighing hydrogenated cocoglyceride, lauroyl polyethylene glycol-32-glyceride, 1, 2-propylene glycol and polyethylene glycol 3350, mixing, stirring, adding icariin for dissolving, and optionally performing ultrasonic treatment to accelerate dissolving to obtain clear solution, namely icariin microemulsion preparation. The particle size was measured by a laser particle size analyzer, and the average particle size was 40nm.
Formulation example 9 icariin enteric soft capsule formulation
Content prescription:
rubber formula:
gelatin 10g
Glycerol 5g
Purified water 10g
Enteric coating liquid prescription:
the preparation process comprises the following steps: weighing medium chain fatty glyceride, polyoxyethylene castor oil, 1, 2-propylene glycol and absolute ethanol, mixing, stirring, adding icariin for dissolving, and optionally performing ultrasonic treatment to accelerate dissolving to obtain clear concentrate, namely icariin microemulsion concentrate. Adding water to the obtained microemulsion concentrate according to the following ratio of 1: diluting to clear solution at weight ratio of 10-20 to obtain soft capsule microemulsion content. Weighing gelatin, glycerol and purified water according to the prescription, uniformly mixing, pressing into rubber, weighing Eudragit L30D-55, triethyl citrate, talcum powder and purified water according to the prescription, and uniformly mixing to obtain the enteric coating liquid. And wrapping the content of the micro emulsion of the soft capsule containing the icariin by using a rubber to prepare a soft capsule, and wrapping the soft capsule with a casing to prepare the enteric soft capsule.
Formulation example 10 icariin dripping pill
The preparation process comprises the following steps: weighing icariin with prescription amount passing through 100 mesh sieve, adding into mixed solution containing polyethylene glycol 6000 and polyethylene glycol 1000 with prescription amount heated and melted in water bath, stirring thoroughly, placing into dropping bottle, and dropping at 95+ -2deg.C; dropping into a glass condensation column containing 4-6mL of methyl silicone oil, taking out after molding, and sucking the adhered methyl silicone oil with water absorbing paper.
Example 1 Effect of icariin on bleeding time in coagulation factor IX knockout hemophilia mice
1. Test animals
IX Gene knockout hemophilia mice are offered by Beijing Bai-Sai Gene Biotechnology Co
2. Grouping and administration of animals
The 40 IX gene-deficient hemophilia mice were randomly divided into four groups of 10, and the low, medium and high dose groups (B, C, D) of icariin were administered with 3mg/kg, 6mg/kg and 18mg/kg of icariin by intragastric administration, respectively, 1 time per day for 11 days. The control group (A) was administered with an equal volume of physiological saline by lavage.
3. Detection index
3.1 bleeding time measurement
After 1 hour from the last administration, the bleeding time of each mouse was measured by cutting the tail.
3.2 blood routine determination
After the last time of detecting bleeding time, the mice are anesthetized with sodium pentobarbital, the main abdominal vein is sampled, and the blood routine is detected.
4. Test results
4.1 bleeding time measurement
The bleeding time of each group of mice is shown in the following table, and compared with the control group, the bleeding time of each dose group of icariin is obviously shortened, and the statistical significance is achieved # P<0.01 or ## P<0.01 The result shows that the icariin can effectively shorten the bleeding time of the IX gene knockout hemophilia mouse.
TABLE 1 influence of icariin on bleeding time in IX knockout hemophilia mice
| Group of | Number of animals | T(min) |
| Control group (A) | 16 | 37.8±12.4 |
| B | 16 | 25.5±8.9 # |
| C | 16 | 20.4±6.9 # |
| D | 16 | 16.5±9.7 ## |
In comparison with the control group, # P<0.01 or ## P<0.01。
4.2 blood Condition
The blood routine of the mice in each dose group of the icariin is not obviously different from that of the control group, which proves that the icariin does not influence the blood routine value while shortening the bleeding time of the hemophilia mice.
Example 2 Effect of icariin on time of activating partial thromboplastin in acquired hemophilia A
1. Test material and animal
Activated partial thromboplastin time (aPTT) assay kit was purchased from Shanghai solar biotechnology limited; the plasma of the acquired hemophilia A patient is provided by Yi market-free people hospitals; the experimental healthy New Zealand rabbits are provided by a cattle and sheep culture scientific research base in the Chinese iceberg pastoral industry.
2. Preparation and administration of an animal model for acquired hemophilia a
24 healthy New Zealand rabbits were selected and randomly divided into 8 control, model and treatment groups, each weighing about 1.5kg. Cage-feeding in stainless steel cages at 18-25deg.C, and feeding each group with normal diet without any special treatment. After 1 week, the marginal ear vein was anesthetized with 2% pentobarbital (1.5 ml/kg), and then the left femoral vein of the rabbit was isolated and exposed for injection. The plasma of the acquired hemophilia A patient (confirmed diagnosis of the blood department of the civil hospital in the Yi city) is injected into the rabbits of the model group and the treatment group according to the weight of 2ml/kg, and the treatment group immediately infuses the stomach according to 18mg/kg to administer icariin after the injection is completed, and the model group infuses the stomach to administer the same amount of physiological saline; the rabbit of the control group is injected with normal human plasma in an intravenous way, and blood is drawn from the auricular edge vein at the time points of 30min before plasma injection and 30min, 60min, 90min and 120min after plasma injection respectively, and the blood is taken from the auricular edge vein at the time point of 3.8 percent 1: sodium citrate 9 is anticoagulated, and plasma is separated after the anticoagulation is carried out by 3000r/m centrifugation.
aPTT assay and statistical method
Referring to the description of the kit, 0.1ml of rabbit plasma is taken, 0.1ml of aPTT reagent is added, the mixture is mixed, then the mixture is subjected to a warm bath at 37 ℃ for 2min, 0.1ml of 0.025M calcium chloride at 37 ℃ for preheating is added, a stopwatch is started immediately after the mixture is uniformly mixed, the aPTT value at each time point is measured, the aPTT at each time point is repeated twice, and the average value is obtained.
Statistical analysis of the data was performed using SPSS11.0 software. Data are expressed as mean ± standard deviation, and normal and variance alignment tests are performed. The comparison between groups uses t-test.
4. Test results
The comparison of the aPTT at each time point of each group is shown in Table 2, and as can be seen from the table, the control group has no obvious change before and after plasma injection, the model group has obviously prolonged aPTT at the time points of 30min, 60min, 90min and 120min after injection compared with the aPTT value before injection, and the aPTT prolonged is in a time-dependent trend, and the treatment group can obviously shorten the aPTT at each time point. The icariin can obviously shorten the time of activating partial thromboplastin of hemophilia patients and promote the coagulation of hemophilia patients.
Table 2 aPTT comparisons for each time point for each group
| Group of | Example number (n) | -30 | 0 | 60 | 90 | 120 |
| Control group | 8 | 39.3±3.76 | 38.7±1.09 | 36.6±2.98 | 38.3±4.87 | 39.6±5.98 |
| Model group | 8 | 37.6±1.23 | 48.3±2.09 # | 52.9±3.44 ## | 65.4±3.78 ## | 69.9±5.23 ## |
| Treatment group | 8 | 36.8±4.12 | 40.4±3.23 ﹩ | 39.9±4.09 ﹩﹩ | 40.4±5.67 ﹩﹩ | 41.3±6.21 ﹩﹩ |
In comparison with the control group, # P<0.05， ## P<0.01；
in contrast to the set of models, ﹩ P<0.05， ﹩﹩ P<0.01。
Claims (12)
1. the application of icariin as the only active ingredient in preparing medicine for preventing and treating hemophilia.
2. The use according to claim 1, wherein the hemophilia is a genetic factor-induced hemophilia or a secondary hemophilia.
3. The use according to claim 2, wherein the secondary hemophilia is a drug or a disease caused by a disease of its own.
4. The use according to claim 3, wherein the disease caused by the self-disease includes, but is not limited to, one of liver lesions, hemolysis, acquired immunodeficiency diseases, evans syndrome, chronic lymphocytic leukemia, various acute leukemias, lymphomas, systemic lupus erythematosus, rheumatoid arthritis, hyperthyroidism.
5. The use according to claim 4, wherein the liver disease is caused by chronic persistent hepatitis or cirrhosis.
6. The use according to claim 3, wherein the medicament is an antimetabolite, a cytotoxic agent, a chlorothiazide, and a synergist thereof.
7. The use according to claim 6, wherein the medicament is an alkylating agent.
8. The use according to claim 1, wherein the hemophilia is any one of hemophilia a, hemophilia B or hemophilia C.
9. The use according to claim 1, wherein the pharmaceutical preparation comprising icariin is an oil, emulsion, gel, inhalant, spray, capsule, pill, patch or suppository thereof.
10. The use according to claim 9, wherein the pharmaceutical formulation comprising icariin is an aerosol.
11. The use according to claim 1, wherein the medicament is administered in an amount of 0.03mg/kg to 400mg/kg for the treatment of hemophilia.
12. The use according to claim 5, wherein the medicament is administered in an amount of 0.3mg/kg to 40mg/kg for the treatment of hemophilia.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010163055X | 2020-03-10 | ||
| CN202010163055 | 2020-03-10 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113368098A CN113368098A (en) | 2021-09-10 |
| CN113368098B true CN113368098B (en) | 2024-03-29 |
Family
ID=77569143
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011623189.1A Active CN113368098B (en) | 2020-03-10 | 2020-12-31 | Application of icariin in preparation of medicine for preventing and treating hemophilia |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113368098B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104546823A (en) * | 2013-10-21 | 2015-04-29 | 鲁南制药集团股份有限公司 | Application of anhydroicaritin in preparing drug for treating or preventing thrombopenia |
| WO2016205010A1 (en) * | 2015-06-19 | 2016-12-22 | The Regents Of The University Of California | Treating vasculature related diseases or disorders using nanoparticles |
| WO2018181870A1 (en) * | 2017-03-31 | 2018-10-04 | 公立大学法人奈良県立医科大学 | Medicinal composition usable for preventing and/or treating blood coagulation factor ix abnormality, comprising multispecific antigen binding molecule replacing function of blood coagulation factor viii |
-
2020
- 2020-12-31 CN CN202011623189.1A patent/CN113368098B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104546823A (en) * | 2013-10-21 | 2015-04-29 | 鲁南制药集团股份有限公司 | Application of anhydroicaritin in preparing drug for treating or preventing thrombopenia |
| WO2016205010A1 (en) * | 2015-06-19 | 2016-12-22 | The Regents Of The University Of California | Treating vasculature related diseases or disorders using nanoparticles |
| WO2018181870A1 (en) * | 2017-03-31 | 2018-10-04 | 公立大学法人奈良県立医科大学 | Medicinal composition usable for preventing and/or treating blood coagulation factor ix abnormality, comprising multispecific antigen binding molecule replacing function of blood coagulation factor viii |
Also Published As
| Publication number | Publication date |
|---|---|
| CN113368098A (en) | 2021-09-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US10799521B2 (en) | Use of icaritin in preparing medicament for preventing or treating hematocytopenia | |
| JP5744213B2 (en) | Use of arctigenin in the manufacture of a drug for the prevention or treatment of diseases associated with erythropenia | |
| AU2014305430B2 (en) | Application of andrographolide in the preparation of a pharmaceutical for treatment of inflammatory bowel disease, andrographolide enteric targeting micropellet, and method for preparation thereof | |
| JP2016534074A5 (en) | ||
| CN104546823A (en) | Application of anhydroicaritin in preparing drug for treating or preventing thrombopenia | |
| CN113368098B (en) | Application of icariin in preparation of medicine for preventing and treating hemophilia | |
| CN101108230B (en) | Di'ao xinxuekang slow release formulated product and method of preparing the same and use thereof | |
| CN113546089A (en) | Application of 1-ethyl-3, 7-dimethyl xanthine in preparation of medicine for treating pneumonia | |
| CN101757443A (en) | Traditional Chinese medicine preparation for treating hemophilia | |
| CN113368099B (en) | Application of icariin in preparation of medicines for preventing and treating diseases related to platelet dysfunction | |
| JP3247381B2 (en) | Anticholeratoxin agent | |
| CN101007014B (en) | A compound puerarin preparation | |
| CN106511394B (en) | Application of aspongopus fatty oil extract | |
| RU2806093C1 (en) | Use of icaritin for obtaining medicinal products | |
| CN114191427B (en) | Medicine for inhibiting platelet activation and application thereof | |
| CN108815342B (en) | Traditional Chinese medicine composition for treating male infertility | |
| CN115175676A (en) | Medical application of icaritin | |
| CN113368095A (en) | Application of icaritin in preparation of medicines for thrombolysis of myocardial infarction and prevention and treatment of thrombosis hemorrhage complications | |
| JP2007051144A (en) | Medicine for preventing or treating irritable intestine syndrome or gastrointestinal tract infectious disease | |
| CN105687181B (en) | Application of phillygenin in preparation of medicine for treating viral hepatitis B | |
| CN106511290A (en) | Lamiophlomis rotata(Benth.) Kudo solid dispersion preparation and preparation method thereof | |
| CN112675162A (en) | Application of loganin aglycone in preparation of medicine for preventing and treating viral hepatitis B | |
| CN113368096A (en) | Application of icaritin in preparation of medicine for preventing and treating cerebral infarction hemorrhage conversion | |
| TW202245772A (en) | A pharmaceutical composition of a capsid protein inhibitor and preparation method thereof | |
| CN102697719B (en) | Oily drug composition containing vitamin K1 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |