CN111840583B - 血管内皮损伤治疗的药物制剂 - Google Patents
血管内皮损伤治疗的药物制剂 Download PDFInfo
- Publication number
- CN111840583B CN111840583B CN202010816881.XA CN202010816881A CN111840583B CN 111840583 B CN111840583 B CN 111840583B CN 202010816881 A CN202010816881 A CN 202010816881A CN 111840583 B CN111840583 B CN 111840583B
- Authority
- CN
- China
- Prior art keywords
- vascular endothelial
- nitric oxide
- endothelial injury
- pharmaceutical preparation
- preparation
- 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
- 230000002792 vascular Effects 0.000 title claims abstract description 53
- 230000006378 damage Effects 0.000 title claims abstract description 50
- 208000027418 Wounds and injury Diseases 0.000 title claims abstract description 48
- 230000003511 endothelial effect Effects 0.000 title claims abstract description 48
- 208000014674 injury Diseases 0.000 title claims abstract description 48
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 22
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims abstract description 126
- 238000002360 preparation method Methods 0.000 claims abstract description 26
- 229920001612 Hydroxyethyl starch Polymers 0.000 claims abstract description 22
- 229940050526 hydroxyethylstarch Drugs 0.000 claims abstract description 22
- 229960000502 poloxamer Drugs 0.000 claims abstract description 20
- 229920001983 poloxamer Polymers 0.000 claims abstract description 20
- 108010020346 Polyglutamic Acid Proteins 0.000 claims abstract description 13
- 229920002643 polyglutamic acid Polymers 0.000 claims abstract description 13
- 210000003556 vascular endothelial cell Anatomy 0.000 claims abstract description 13
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical class CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims abstract description 10
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003637 basic solution Substances 0.000 claims abstract description 9
- 230000010261 cell growth Effects 0.000 claims abstract description 6
- 239000003102 growth factor Substances 0.000 claims abstract description 6
- 239000000463 material Substances 0.000 claims abstract description 4
- 239000012528 membrane Substances 0.000 claims abstract description 4
- 239000002245 particle Substances 0.000 claims abstract description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 238000000034 method Methods 0.000 claims description 7
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 230000009471 action Effects 0.000 claims description 4
- 238000005516 engineering process Methods 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 239000000243 solution Substances 0.000 claims description 4
- 108090000386 Fibroblast Growth Factor 1 Proteins 0.000 claims description 3
- 102100031706 Fibroblast growth factor 1 Human genes 0.000 claims description 3
- 210000004369 blood Anatomy 0.000 claims description 3
- 239000008280 blood Substances 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 3
- 238000004108 freeze drying Methods 0.000 claims description 3
- 229920006395 saturated elastomer Polymers 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- TVEXGJYMHHTVKP-UHFFFAOYSA-N 6-oxabicyclo[3.2.1]oct-3-en-7-one Chemical compound C1C2C(=O)OC1C=CC2 TVEXGJYMHHTVKP-UHFFFAOYSA-N 0.000 claims description 2
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- 229920002307 Dextran Polymers 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 238000010253 intravenous injection Methods 0.000 claims description 2
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 230000003204 osmotic effect Effects 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 description 15
- 210000004204 blood vessel Anatomy 0.000 description 10
- 239000007789 gas Substances 0.000 description 9
- 206010020772 Hypertension Diseases 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 8
- 241000700159 Rattus Species 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000002840 nitric oxide donor Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 4
- 230000004064 dysfunction Effects 0.000 description 4
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 3
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 3
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 3
- 230000017531 blood circulation Effects 0.000 description 3
- 210000002889 endothelial cell Anatomy 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 210000002254 renal artery Anatomy 0.000 description 3
- ZOOGRGPOEVQQDX-UUOKFMHZSA-N 3',5'-cyclic GMP Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=C(NC2=O)N)=C2N=C1 ZOOGRGPOEVQQDX-UUOKFMHZSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 208000031481 Pathologic Constriction Diseases 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- 208000011775 arteriosclerosis disease Diseases 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- ZOOGRGPOEVQQDX-UHFFFAOYSA-N cyclic GMP Natural products O1C2COP(O)(=O)OC2C(O)C1N1C=NC2=C1NC(N)=NC2=O ZOOGRGPOEVQQDX-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 210000003989 endothelium vascular Anatomy 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 230000036262 stenosis Effects 0.000 description 2
- 208000037804 stenosis Diseases 0.000 description 2
- 230000001502 supplementing effect Effects 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 1
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 description 1
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000004531 Renal Artery Obstruction Diseases 0.000 description 1
- 206010038378 Renal artery stenosis Diseases 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 208000024248 Vascular System injury Diseases 0.000 description 1
- 208000012339 Vascular injury Diseases 0.000 description 1
- 206010057469 Vascular stenosis Diseases 0.000 description 1
- 206010047141 Vasodilatation Diseases 0.000 description 1
- 206010047163 Vasospasm Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960000796 barbital sodium Drugs 0.000 description 1
- FTOAOBMCPZCFFF-UHFFFAOYSA-N barbitone sodium Natural products CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000005422 blasting Methods 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000036770 blood supply Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000005978 brain dysfunction Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000005986 heart dysfunction Effects 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000005977 kidney dysfunction Effects 0.000 description 1
- 230000023404 leukocyte cell-cell adhesion Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000004768 organ dysfunction Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 210000004303 peritoneum Anatomy 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- RGHFKWPGWBFQLN-UHFFFAOYSA-M sodium;5,5-diethylpyrimidin-3-ide-2,4,6-trione Chemical compound [Na+].CCC1(CC)C([O-])=NC(=O)NC1=O RGHFKWPGWBFQLN-UHFFFAOYSA-M 0.000 description 1
- 230000001148 spastic effect Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000004218 vascular function Effects 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1858—Platelet-derived growth factor [PDGF]
- A61K38/1866—Vascular endothelial growth factor [VEGF]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- Acoustics & Sound (AREA)
- Radiology & Medical Imaging (AREA)
- Vascular Medicine (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Immunology (AREA)
- Dispersion Chemistry (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明的血管内皮损伤治疗的药物制剂是由基础溶液和一氧化氮微泡组成。基础溶液的组分包括聚谷氨酸、羟乙基淀粉和血管内皮细胞生长因子组成,聚谷氨酸和羟乙基淀粉的质量比为1∶10,血管内皮细胞生长因子10mg/L。一氧化氮微泡是由氢化大豆磷脂、肝素‑泊洛沙姆和泊洛沙姆为泡膜材料包裹一氧化氮气体形成的泡囊组成,氢化大豆磷脂、肝素‑泊洛沙姆和泊洛沙姆的质量比为1∶2∶10,粒径范围为2~5μm。本发明的药物制剂用于血管内皮损伤的治疗。
Description
技术领域
本发明涉及一种一氧化氮的制剂,特别涉及一种血管内皮损伤治疗的药物制剂。
背景技术
血管内皮细胞是一切血管内侧的单层上皮细胞,在血管功能调节中发挥至关重要的作用。血管遍布全身几乎所有器官和组织,对组织器官功能的发挥具有重要作用。因此,血管内皮细胞功能异常也就成为许多疾病发生发展的关键因素。
糖尿病、动脉硬化、高血压、肿瘤、脑血管疾病、内分泌功能障碍和心肝肾脑等器官功能障碍,都会引起血管内皮细胞的损伤和功能的异常。例如,长时间的高血压会引起血管内皮的损伤,导致血管变脆、变硬,活动能力下降,反过来血管(特别是动脉)的硬化又会进一步升高血压,形成恶性循环。此外,机体血管内皮受损,血管弹性变差,有时还会出现血管痉挛,痉挛的血管同样可以影响心脏和大脑的血液供应,导致心脑血管病的发生。因此高血压引起的血管内皮损伤已成为危害人们生命健康的一类严重疾病。
研究发现,一氧化氮(NO)对于血管内皮损伤具有很好的治疗潜力。一氧化氮作为内皮依赖性舒血管因子,在血管损伤性疾病中发挥重要的调控作用。一般情况下,血管内皮细胞功能障碍的特征之一是合成一氧化氮的能力不足。及时补充一氧化氮,可以进入血管平滑肌细胞内,启动细胞内环GMP(cGMP)合成,导致血管扩张,同时调节机体生理保护功能,如:血小板聚集、白细胞黏附。因此,一氧化氮在血管稳态保护中发挥了不可替代的重要作用。
已有报道的用于补充体内一氧化氮的方法多是应用一氧化氮供体化合物,例如他汀类药物、精氨酸等。这些一氧化氮供体化合物通过体内复杂的生物酶等作用才能产生出一氧化氮分子。但是这些一氧化氮供体化合物给药剂量较高,产生的一氧化氮分子无法迅速浓集于血管内皮损伤病灶部位起效,全身副作用较大,存在潜在安全性问题。
直接应用一氧化氮分子进行血管内皮损伤的治疗,其作用发挥的最好,安全性也最高。但是一氧化氮分子是气体形态,一氧化氮气体(NO)微溶于水,在20℃的水中溶解度仅为5.6×10-3g/L(相当于0.186μmol/L),无法直接制成普通药物制剂。
因此,虽然一氧化氮对血管内皮损伤具有很好的治疗潜力,但是一氧化氮作为气体,目前尚未见到能将一氧化氮气体高效携载于药物制剂并进行血管内皮损伤治疗的研究报道。因此,制备高效携载一氧化氮气体的血管内皮损伤治疗制剂是实现一氧化氮对于血管内皮损伤的高效治疗的限制性瓶颈。
发明内容
本发明的目的在于克服现有技术的缺点(即:缺乏高效携载一氧化氮气体的血管内皮损伤治疗制剂)提供一种血管内皮损伤治疗的药物制剂,为保证一氧化氮有效治疗血管内皮损伤提供充分的保障,同时满足临床治疗的安全、有效、便捷、经济的要求。
本发明人发现氢化大豆磷脂、肝素-泊洛沙姆和泊洛沙姆为泡膜材料包裹一氧化氮气体形成的2~5μm微泡同时具有良好的超声造影、空化爆破和防止血管狭窄作用,一氧化氮微泡在声场中爆破后产生的空化效应,有利于开放可逆性通道,促使一氧化氮气体快速进入血管内皮损伤部位组织内部。而聚谷氨酸和羟乙基淀粉的混合溶液同时具有血管黏附性和血液容积保持性,对于一氧化氮微泡具有很好的亲和力,可以更好促进一氧化氮微泡在受损血管壁上发挥治疗作用。此外,血管内皮细胞生长因子(VEGF)与一氧化氮微泡之间可以发挥协同作用。
通过大量实验发现,最终形成本发明的一种血管内皮损伤治疗的药物制剂,该制剂是由基础溶液和一氧化氮微泡组成。
上述的基础溶液的组分包括聚谷氨酸、羟乙基淀粉和血管内皮细胞生长因子组成,聚谷氨酸和羟乙基淀粉的质量比为1∶10,血管内皮细胞生长因子10mg/L。
上述的羟乙基淀粉的分子量范围为9000-600000,取代度为0.2~0.7,包括:低分子羟乙基淀粉、中分子羟乙基淀粉和高分子量高取代级的羟乙基淀粉。
上述的基础溶液中进一步加入指药学中公认的用于调节血液渗透压的物质,包括氯化钠、硫酸盐、磷酸盐、枸橼酸盐、硼酸盐、葡萄糖、右旋糖酐、甘露醇。
上述的一氧化氮微泡是由氢化大豆磷脂、肝素-泊洛沙姆和泊洛沙姆为泡膜材料包裹一氧化氮气体形成的泡囊组成。
上述的氢化大豆磷脂、肝素-泊洛沙姆和泊洛沙姆的质量比为1∶2∶10。
上述的一氧化氮微泡的粒径范围为2~5μm。
上述的一氧化氮微泡在药物制剂中的浓度为1×107~5×107个/mL。
一种上述的血管内皮损伤治疗的药物制剂的制备方法,包括以下步骤:
(1)一氧化氮微泡的制备:取质量比为1∶2∶10的氢化大豆磷脂、肝素-泊洛沙姆和泊洛沙姆,混合,溶解于65℃10倍质量的无水叔丁醇中,缓慢降温至溶液凝固,-10℃静置过夜,冷冻干燥得到疏松的冻干粉,转入具塞瓶中,充入一氧化氮气体至饱和,加入5倍冻干粉质量的注射用水中,混匀,即得一氧化氮微泡。
(2)取质量比为1∶10的聚谷氨酸与羟乙基淀粉130/0.4,溶解于15倍质量(即:聚谷氨酸与羟乙基淀粉130/0.4总质量的15倍)的注射用水中,加入血管内皮细胞生长因子至10mg/L,搅拌作用下分别加入上述步骤(1)制得的一氧化氮微泡,形成治疗血管内皮损伤的药物制剂,15~20℃环境中密封避光保存。
上述的药物制剂静脉注射后通过超声介导技术,实现一氧化氮的精准定位和治疗,用于血管内皮损伤的治疗。
本发明的血管内皮损伤治疗的药物制剂具有以下优点:①聚谷氨酸和羟乙基淀粉组成的基础溶液与氢化大豆磷脂、肝素-泊洛沙姆和泊洛沙姆为泡膜的一氧化氮微泡之间发挥协同作用;②对于机体组织有良好的亲和性和生物相容性;③不使用任何一氧化氮供体化合物,不会因为一氧化氮供体化合物对机体组织产生不良反应和毒副作用;④可以结合超声介导技术,实现血管内皮损伤部位的精准定位、治疗和治疗;⑤储存和运输便捷。
具体实施方式
下文将详细描述本发明具体实施例。应当注意的是,下述实施例中描述的技术特征或者技术特征的组合不应当被认为是孤立的,它们可以被相互组合从而达到更好的技术效果。
实施例1血管内皮损伤治疗的药物制剂的制备
实验组治疗血管内皮损伤的药物制剂制备:按照表1的组分比例,具体步骤如下:
(1)一氧化氮微泡的制备:取质量比为1∶2∶10的氢化大豆磷脂、肝素-泊洛沙姆和泊洛沙姆,混合,溶解于65℃10倍质量的无水叔丁醇中,缓慢降温至溶液凝固,-10℃静置过夜,冷冻干燥得到疏松的冻干粉,转入具塞瓶中,充入一氧化氮气体至饱和,加入5倍冻干粉质量的注射用水中,混匀,即得一氧化氮微泡。
(2)取质量比为1∶10的聚谷氨酸与羟乙基淀粉130/0.4,溶解于15倍质量(即:聚谷氨酸与羟乙基淀粉130/0.4总质量的15倍)的注射用水中,加入血管内皮细胞生长因子(VEGF)至10mg/L,搅拌作用下分别加入上述步骤(1)制得的一氧化氮微泡,按照表1设计调整一氧化氮微泡的浓度,形成实验组的治疗血管内皮损伤的药物制剂,15~20℃环境中密封避光保存。
对照组制剂的制备:按照表1的组分比例,参照实验组的方法进行。各个实验组是根据本申请权利要求项保护范围内的组分和比例配置的,而各个对照组是某项组分缺失或组分质量百分含量超出本申请权利要求项保护的范围。
表1实验组和对照组的制剂组成
注:“√”代表该项为实施例1实验组的浓度和方法制备;“/”代表该项不存在;*代表该项组分被括号内的组分替代;IGF-1代表胰岛素样生长因子-1;NO代表一氧化氮气体;O2代表氧气;N2代表氮气。
实施例2药物制剂对于血管内皮损伤模型动物的应用效果
(1)高血压型血管内皮损伤模型动物的建立
以SD大鼠为对象,参考文献【中国药理学通报,2003,19(3):270-273】,建立高血压型血管内皮损伤模型动物,方法简述为:180-200g雄性SD大鼠,按30mg/kg体重的剂量经腹腔注射成巴比妥钠麻醉,麻醉后将大鼠仰卧固定于手术台上,于腹部正中偏左1cm处切开皮肤和腹膜,用直径0.2mm的银夹缩窄左肾动脉,使左肾动脉部分狭窄,对侧肾和肾动脉不触及。术后4至6周高血压趋于平稳,收缩压在150mmHg以上者为建模成功动物。
(2)各组制剂治疗高血压型血管内皮损伤模型动物的效果
选取建模成功的大鼠,按照表1设计平均分成若干组,每天进行给药实验,连续10天,具体为:大鼠麻醉后,通过超声成像将超声探头定位于肾动脉狭窄部位,尾静脉注射0.5mL各组制剂,即刻观察到血管内皮损伤部位血管的影像增强后,提高声压爆破一氧化氮微泡即完成给药。第14天进行超声检查,观察血管壁状态和血流情况,处死动物后分离获取目标血管,显微观察血管内皮细胞形态等指标,给出各组制剂应用效果的总评分。
表2实验组和对照组制剂对于高血压型血管内皮损伤模型动物的应用效果
由表2实验结果可见,实验组对于血管内皮损伤的治疗效果较好,特别是实验组6,受损血管恢复较好,血管壁均匀,无狭窄,血流正常,内皮细胞完整,排列整齐。相比实验组,对照组对于血管内皮损伤的治疗效果明显较差,特别是对照组1、2、10、11、15和16,对于血管内皮损伤的治疗效果很差,血管壁不均匀,狭窄明显,血流紊乱,内皮细胞缺损,排列不整齐。
表2的实验结果证明,本发明技术保护方案中的任一组分和条件都是相互协同、缺一不可的,缺乏本发明技术保护方案中的任一组分和条件,都会对血管内皮损伤的治疗效果产生明显的影响。本发明的药物制剂对于血管内皮损伤的治疗效果好,具有良好的应用前景。
上述详细说明是针对发明的可行实施例的具体说明,该实施例并非用以限制本发明的专利范围,凡未脱离本发明的等效实施或变更,均应当包含于本发明的专利范围内。另外,本领域技术人员还可在本发明权利要求公开的范围和精神内做其它形式和细节上的各种修改、添加和替换。当然,这些依据本发明精神所做的各种修改、添加和替换等变化,都应包含在本发明所要求保护的范围之内。
Claims (7)
1.血管内皮损伤治疗的药物制剂,其主要特征在于:所述的药物制剂是由基础溶液和一氧化氮微泡组成;所述的基础溶液的组分包括聚谷氨酸、羟乙基淀粉和血管内皮细胞生长因子,聚谷氨酸和羟乙基淀粉的质量比为1∶10,血管内皮细胞生长因子10mg/L;所述的羟乙基淀粉的分子量范围为9000~600000,取代度为0.2~0.7;所述的一氧化氮微泡是由质量比为1∶2∶10的氢化大豆磷脂、肝素-泊洛沙姆和泊洛沙姆为泡膜材料包裹一氧化氮气体形成的泡囊组成;所述的一氧化氮微泡的粒径范围为2~5μm;所述的一氧化氮微泡在药物制剂中的浓度为1×107~5×107个/mL;所述的药物制剂静脉注射后通过超声介导技术,实现血管内皮损伤部位的治疗。
2.根据权利要求1的血管内皮损伤治疗的药物制剂,其特征是:所述的羟乙基淀粉包括低分子羟乙基淀粉、中分子羟乙基淀粉、高分子量高取代级的羟乙基淀粉的一种或几种组合。
3.根据权利要求1的血管内皮损伤治疗的药物制剂,其特征是:所述的基础溶液中加入调节血液渗透压的物质,包括氯化钠、硫酸盐、磷酸盐、枸橼酸盐、硼酸盐、葡萄糖、右旋糖酐、甘露醇的一种或几种组合。
4.根据权利要求1的血管内皮损伤治疗的药物制剂,其特征是:所述的一氧化氮微泡的粒径为3.5μm。
5.根据权利要求1的血管内皮损伤治疗的药物制剂,其特征是:所述的一氧化氮微泡在药物制剂中的浓度为3×107个/mL。
6.一种权利要求1~5任一项血管内皮损伤治疗的药物制剂的制备方法,其特征是:制备方法包括以下步骤:
(1)一氧化氮微泡的制备:取质量比为1∶2∶10的氢化大豆磷脂、肝素-泊洛沙姆和泊洛沙姆,混合,溶解于65℃ 10倍质量的无水叔丁醇中,缓慢降温至溶液凝固,-10℃静置过夜,冷冻干燥得到疏松的冻干粉,转入具塞瓶中,充入一氧化氮气体至饱和,加入5倍冻干粉质量的注射用水中,混匀,即得一氧化氮微泡;
(2)取质量比为1∶10的聚谷氨酸与羟乙基淀粉130/0.4,溶解于15倍质量的注射用水中,加入血管内皮细胞生长因子至10mg/L,搅拌作用下分别加入上述步骤(1)制得的一氧化氮微泡,形成治疗血管内皮损伤的药物制剂,15~20℃环境中密封避光保存。
7.根据权利要求6所述的血管内皮损伤治疗的药物制剂的制备方法,其特征是:所述的治疗血管内皮损伤的药物制剂静脉注射后通过超声介导技术,实现血管内皮损伤部位的治疗。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010816881.XA CN111840583B (zh) | 2020-08-06 | 2020-08-06 | 血管内皮损伤治疗的药物制剂 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202010816881.XA CN111840583B (zh) | 2020-08-06 | 2020-08-06 | 血管内皮损伤治疗的药物制剂 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN111840583A CN111840583A (zh) | 2020-10-30 |
CN111840583B true CN111840583B (zh) | 2023-03-28 |
Family
ID=72968862
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202010816881.XA Active CN111840583B (zh) | 2020-08-06 | 2020-08-06 | 血管内皮损伤治疗的药物制剂 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN111840583B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114558114B (zh) * | 2022-03-31 | 2023-10-20 | 温州医科大学 | 治疗压疮的乳剂型喷雾剂 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5670177A (en) * | 1995-10-20 | 1997-09-23 | L'air Liquide, Societe Anonyme Pour L'etude Et L'exploitation Des Procedes Georges Claude | Injectable NO/CO2 gaseous mixture |
CN104353088A (zh) * | 2014-09-30 | 2015-02-18 | 东南大学 | 一种脂质气泡的制备方法 |
CN111228466A (zh) * | 2020-02-27 | 2020-06-05 | 温州医科大学 | 治疗糖尿病足的含氧气微泡的水凝胶及其制备方法和用途 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8871257B2 (en) * | 2012-09-19 | 2014-10-28 | Transdermal Biotechnology, Inc. | Prevention and treatment of cardiovascular diseases using systems and methods for transdermal nitric oxide delivery |
-
2020
- 2020-08-06 CN CN202010816881.XA patent/CN111840583B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5670177A (en) * | 1995-10-20 | 1997-09-23 | L'air Liquide, Societe Anonyme Pour L'etude Et L'exploitation Des Procedes Georges Claude | Injectable NO/CO2 gaseous mixture |
CN104353088A (zh) * | 2014-09-30 | 2015-02-18 | 东南大学 | 一种脂质气泡的制备方法 |
CN111228466A (zh) * | 2020-02-27 | 2020-06-05 | 温州医科大学 | 治疗糖尿病足的含氧气微泡的水凝胶及其制备方法和用途 |
Non-Patent Citations (2)
Title |
---|
Nitricoxidedeliverybyultrasoniccracking:Somelimitations;MichielPostema等;《Ultrasonics》;20061231;全文 * |
Ultrasound-targeted microbubble cavitation with sodium nitrite synergistically enhances nitric oxide production and microvascular perfusion;Gary Z. Yu等;《Ultrasound Med Biol》;20191231;全文 * |
Also Published As
Publication number | Publication date |
---|---|
CN111840583A (zh) | 2020-10-30 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20100136140A1 (en) | A use of hypertonic solution composition in manufacturing medicaments for promoting wound healing | |
CN106699896B (zh) | 一种可自组装成水凝胶的肿瘤杀伤性多肽及其应用 | |
EA010948B1 (ru) | Фармацевтическая композиция, содержащая лактат, и ее применение | |
JPH06500130A (ja) | 循環器系ショックに対する高浸透圧等塩素性製剤 | |
CN111840583B (zh) | 血管内皮损伤治疗的药物制剂 | |
CN102579340A (zh) | 青藤碱囊泡及其制剂及制备方法 | |
CN101850124B (zh) | 白蛋白纳米-超声微泡载组织型纤溶酶原激活物基因靶向体系及其制备方法 | |
CN1997383A (zh) | 含水母发光蛋白的组合物及使用它的方法 | |
Salim et al. | Smart biomaterials for enhancing cancer therapy by overcoming tumor hypoxia: a review | |
Li et al. | Multiple delivery strategies of nanocarriers for myocardial ischemia-reperfusion injury: Current strategies and future prospective | |
CN111939122B (zh) | 肺动脉高压靶向治疗的速效制剂 | |
EP3453390B1 (en) | Polymerized drug-containing pharmaceutical composition | |
WO2021158937A1 (en) | Bortezomib-loaded nanoparticles | |
CN111973731B (zh) | 冠心病靶向定位和递释的一氧化氮制剂 | |
JP5298028B2 (ja) | 脳虚血障害治療剤 | |
CN111991416B (zh) | 肿瘤靶向定位和递释的一氧化氮制剂 | |
CN106606783A (zh) | 一种靶向共递释光敏剂与化疗药物的药物递释系统 | |
CN111840512B (zh) | 治疗软骨修复和/或骨关节炎的组合物 | |
CN110870918A (zh) | 包含氨基酸类营养素和抗肿瘤化疗药物的药物组合物及其应用 | |
CN110302389B (zh) | 一种抗血管生成的水凝胶缓释制剂及其应用 | |
CN109498547B (zh) | 一种平阳霉素局部注射制剂及其制备方法 | |
CN114181286A (zh) | 一种纳米蛋白复合物、药物递送系统及应用 | |
CN113908276A (zh) | 一种光控释药纳米粒子及其制备方法和应用 | |
CN104324032A (zh) | 抗结核药物三联复方微球血管靶向栓塞缓释剂及其制备方法和用途 | |
CN114732789B (zh) | 一种用于治疗肺动脉高压的复方长效递药系统及其制备 |
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 |