CN105640879A - Heparin nasal drop preparation and preparation method thereof - Google Patents
Heparin nasal drop preparation and preparation method thereof Download PDFInfo
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- CN105640879A CN105640879A CN201610101458.5A CN201610101458A CN105640879A CN 105640879 A CN105640879 A CN 105640879A CN 201610101458 A CN201610101458 A CN 201610101458A CN 105640879 A CN105640879 A CN 105640879A
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- Prior art keywords
- heparin
- sea water
- collunarium
- sodium
- water
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- 229920000669 heparin Polymers 0.000 title claims abstract description 79
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 title claims abstract description 32
- 229960002897 heparin Drugs 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 239000007923 nasal drop Substances 0.000 title abstract description 5
- 239000013535 sea water Substances 0.000 claims abstract description 62
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 claims abstract description 46
- 229960001008 heparin sodium Drugs 0.000 claims abstract description 46
- 239000003755 preservative agent Substances 0.000 claims abstract description 30
- 230000002335 preservative effect Effects 0.000 claims abstract description 30
- 239000000853 adhesive Substances 0.000 claims abstract description 28
- 230000003204 osmotic effect Effects 0.000 claims abstract description 28
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 28
- 238000003756 stirring Methods 0.000 claims description 27
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- 229940097572 chloromycetin Drugs 0.000 claims description 21
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerol group Chemical group OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 8
- 239000001488 sodium phosphate Substances 0.000 claims description 8
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 8
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 7
- 210000004347 intestinal mucosa Anatomy 0.000 claims description 7
- 239000012153 distilled water Substances 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000000463 material Substances 0.000 claims description 6
- 239000012264 purified product Substances 0.000 claims description 6
- 230000001954 sterilising effect Effects 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 5
- 238000009360 aquaculture Methods 0.000 claims description 5
- 244000144974 aquaculture Species 0.000 claims description 5
- XIWFQDBQMCDYJT-UHFFFAOYSA-M benzyl-dimethyl-tridecylazanium;chloride Chemical group [Cl-].CCCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 XIWFQDBQMCDYJT-UHFFFAOYSA-M 0.000 claims description 5
- 238000010790 dilution Methods 0.000 claims description 5
- 239000012895 dilution Substances 0.000 claims description 5
- 230000008030 elimination Effects 0.000 claims description 5
- 238000003379 elimination reaction Methods 0.000 claims description 5
- 230000029142 excretion Effects 0.000 claims description 5
- 238000001556 precipitation Methods 0.000 claims description 5
- 230000005855 radiation Effects 0.000 claims description 5
- 239000011780 sodium chloride Substances 0.000 claims description 5
- 230000003068 static effect Effects 0.000 claims description 5
- 229920002125 Sokalan® Polymers 0.000 claims description 4
- 229960001631 carbomer Drugs 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 229960002233 benzalkonium bromide Drugs 0.000 claims description 3
- KHSLHYAUZSPBIU-UHFFFAOYSA-M benzododecinium bromide Chemical compound [Br-].CCCCCCCCCCCC[N+](C)(C)CC1=CC=CC=C1 KHSLHYAUZSPBIU-UHFFFAOYSA-M 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 239000011630 iodine Substances 0.000 claims description 3
- 229920000609 methyl cellulose Polymers 0.000 claims description 3
- 239000001923 methylcellulose Substances 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 229920002101 Chitin Polymers 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 235000010981 methylcellulose Nutrition 0.000 claims 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims 1
- 210000004369 blood Anatomy 0.000 abstract description 16
- 239000008280 blood Substances 0.000 abstract description 16
- 230000000694 effects Effects 0.000 abstract description 14
- 210000004204 blood vessel Anatomy 0.000 abstract description 7
- 230000008901 benefit Effects 0.000 abstract description 3
- 238000010521 absorption reaction Methods 0.000 abstract description 2
- 230000001070 adhesive effect Effects 0.000 abstract 2
- 229960005091 chloramphenicol Drugs 0.000 abstract 2
- 238000012360 testing method Methods 0.000 description 37
- 239000000203 mixture Substances 0.000 description 17
- 239000003814 drug Substances 0.000 description 16
- 229940079593 drug Drugs 0.000 description 10
- 210000003928 nasal cavity Anatomy 0.000 description 10
- 210000002381 plasma Anatomy 0.000 description 10
- 230000008014 freezing Effects 0.000 description 9
- 238000007710 freezing Methods 0.000 description 9
- 238000010255 intramuscular injection Methods 0.000 description 9
- 239000007927 intramuscular injection Substances 0.000 description 9
- 241001494479 Pecora Species 0.000 description 8
- 238000010253 intravenous injection Methods 0.000 description 7
- 238000001990 intravenous administration Methods 0.000 description 6
- 230000017531 blood circulation Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 210000000492 nasalseptum Anatomy 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000002951 street drug Substances 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- 230000010100 anticoagulation Effects 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 210000004877 mucosa Anatomy 0.000 description 3
- HJXMNVQARNZTEE-UHFFFAOYSA-N Butylphthalide Chemical compound C1=CC=C2C(CCCC)OC(=O)C2=C1 HJXMNVQARNZTEE-UHFFFAOYSA-N 0.000 description 2
- 206010028748 Nasal obstruction Diseases 0.000 description 2
- 241000283898 Ovis Species 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000000845 cartilage Anatomy 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000008058 pain sensation Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- ATVJXMYDOSMEPO-UHFFFAOYSA-N 3-prop-2-enoxyprop-1-ene Chemical compound C=CCOCC=C ATVJXMYDOSMEPO-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 206010053567 Coagulopathies Diseases 0.000 description 1
- 241001269238 Data Species 0.000 description 1
- 229920002683 Glycosaminoglycan Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 229940086737 allyl sucrose Drugs 0.000 description 1
- 230000002429 anti-coagulating effect Effects 0.000 description 1
- 230000001139 anti-pruritic effect Effects 0.000 description 1
- 239000003908 antipruritic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000005252 bulbus oculi Anatomy 0.000 description 1
- 229950005197 butylphthalide Drugs 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 230000035602 clotting Effects 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 229960000610 enoxaparin Drugs 0.000 description 1
- 208000001780 epistaxis Diseases 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000004379 myopia Effects 0.000 description 1
- 208000001491 myopia Diseases 0.000 description 1
- 210000002850 nasal mucosa Anatomy 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 229940059574 pentaerithrityl Drugs 0.000 description 1
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical compound OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000004436 pseudomyopia Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 206010039083 rhinitis Diseases 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012086 standard solution Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 210000001614 vomer Anatomy 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
Classifications
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/727—Heparin; Heparan
-
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/08—Solutions
-
- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F9/00—Multistage treatment of water, waste water or sewage
-
- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F1/00—Treatment of water, waste water, or sewage
- C02F1/001—Processes for the treatment of water whereby the filtration technique is of importance
-
- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F1/00—Treatment of water, waste water, or sewage
- C02F1/30—Treatment of water, waste water, or sewage by irradiation
- C02F1/32—Treatment of water, waste water, or sewage by irradiation with ultraviolet light
-
- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F1/00—Treatment of water, waste water, or sewage
- C02F1/52—Treatment of water, waste water, or sewage by flocculation or precipitation of suspended impurities
-
- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F1/00—Treatment of water, waste water, or sewage
- C02F1/66—Treatment of water, waste water, or sewage by neutralisation; pH adjustment
-
- C—CHEMISTRY; METALLURGY
- C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
- C02F2301/00—General aspects of water treatment
- C02F2301/08—Multistage treatments, e.g. repetition of the same process step under different conditions
Abstract
The invention discloses a heparin nasal drop preparation and a preparation method thereof. The heparin nasal drop preparation comprises heparin sodium, chloramphenicol, an osmotic pressure regulator, an adhesive, a preservative and alkaline purified seawater, wherein every 1,000 ml of the preparation contains 1-20 g of heparin sodium, 0-10.5 g of chloramphenicol, 1-50 g of the osmotic pressure regulator, 1-50 g of the adhesive, 0.1-1.0 g of the preservative and the balance of the alkaline purified seawater. The heparin nasal drop preparation can reduce the viscosity of blood in a human body and recover the blood vessel elasticity and has the advantages of convenience in use, safety, no pain, high absorption efficiency, capability of taking effect rapidly and the like.
Description
Technical field
The present invention relates to pharmaceutical technology field, particularly relate to a kind of heparin Collunarium and preparation method thereof.
Background technology
The nasal cavity of people is based on bone and cartilage, and inner face is coated with mucosa. Nasal cavity is divided into two chambeies, left and right by nasal septum, and nasal septum is made up of lamina mediana, vomer and nasal septal cartilage, lining mucosa. There is an easy hemorrhage district (Little district or Kiesselbach district) in the front lower district of nasal septum, this district's rich blood vessel and location tables is shallow, stimulated by wound or dry air, blood vessel is easily rupturable and hemorrhage. Hypertensive patient's a large amount of epistaxiss for several times are the omens of cerebral thrombosis to have lot of documents to prove, it is seen that the abundant blood vessel of nasal septum has with cerebrovascular and very contacts closely.
The local diseases such as treatment rhinitis it are used for before nasal-cavity administration, the mode of nasal-cavity administration progressively obtained the accreditation of people in recent years, the disease of Whole Body can be treated, this is relevant with easy the to be hemorrhage district in the front lower district of nasal septum (Little district or Kiesselbach district) rich blood vessel--and medicine directly can be absorbed by nasal mucosa medium vessels and enter body circulation, this administering mode pain compared with intramuscular injection and intravenous injection is substantially reduced, and do not need the doctor of specialty and the help of nurse, can medication voluntarily at any time, therefore be prone to be accepted by patients. It is a good route of administration for long-term care, low dose, oral invalid or poor efficiency drug medication.
Heparin is derived from the mucopolysaccharide in mammal body, there is (a set of pig intestinal mucosa can extract 0.5 gram) in a large number in animal intestine mucosa, there is anticoagulation and reduce the effect of blood viscosity blood circulation promoting, having had the history of last 100 years clinically--its biogenetic derivation determines it gentleness and good characteristic. Heparin has certain electronegativity, can overcome the electron impeding layer between plastidogenetic horny layer, granular layer, it is easy to entered blood circulation by capillary wall.
Heparin is more stable in neutral and alkaline conditions, shows its anticoagulation and reduces the activity of blood viscosity blood circulation promoting. But easily decompose rotten in acid condition and lose activity, owing in human body, gastric acid is strong, therefore the oral administration poor effect of heparin, it is all intramuscular injection and intravenous injection clinically.
The intramuscular injection of heparin and intravenous injection except pain is strong, need medical practitioner or nurse complete except, intravenous injection there is likely to be bigger security risk, owing to transfusion is directly entered blood vessel, having many additional problems--too many link is likely to problem to be occurred: off quality such as injection, containing thermal source;Containing particulate matter in medicinal liquid, it was reported that if transfusion can form thrombosis containing a large amount of microgranules more than 12um, cause blood capillary blocking or form phlebitis; Contaminated syringe, infusion set or medicine are contaminated; Transfusion speed is too fast, and short time local inputs substantial amounts of liquid; Air enters blood vessel etc. At CFDA2011, (www.sda.gov.cn) prompting " intravenous administration approach risk is higher " specially in national drug adverse reaction monitoring annual reports in 2013, its untoward reaction report reaches nearly 60%, and the ratio of matters of aggravation report is up to 73.4% (74.3%). These events still occurred frequently under professional medical mechanism and human users, point out the high risk of its existence more.
It is main with chloromycetin for primary raw material that patent " CN103316030A " discloses " a kind of medicine of nasal obstruction when treating flu ", adds buffer, antibacterial, water, surfactant etc., for treating the administration new way of cold stuffy nasal obstruction.
Patent " CN103505414A " discloses " butylphthalide nasal drop and preparation method thereof " with butyphthalide for primary raw material, ejection preparation etc. is transformed into the administration new way of nasal cavity, before overcoming, the nasal-cavity administration idea that simply treatment topical intranasal is scorching, develops the new approaches of nasal cavity systemic administration.
It is calciparine that patent CN102366398A discloses one " Multifunctional eye drops " its effective ingredient, and with chloromycetin as diluent, " can be antipruritic to eyes in the short time, eliminate eyeball congestion; to treatment pseudomyopia, control myopia degree and deepen there is characteristic ". Its core concept is to make use of the attenuating blood viscosity of heparin, the effect of blood circulation promoting.
At present, market has intramuscular injection and intravenous formulations. Intramuscular injection is many based on calciparine, and intravenous injection is many based on low molecular weight sodium (Enoxaparin). Oral and other preparations have no production because of poor effect.
Heparin powder sealing, dry, low (room) temperature when can long storage time deposit; but easily decompose under aqueous solution state; produce little molecule aminopolysaccharide, acetyl group (N-sulfate) polysaccharide and glycuronic acid etc., thus losing anticoagulant active.
The history of the existing last 100 years of application of heparin, its good biocompatibility, safety are verified. The main feature of heparin is exactly excellent anticoagulant property, can be substantially reduced the viscosity of blood. Owing to human body is the ecosystem maintained by blood, therefore the benefit to health extended out therefrom is full of the imagination. But heparin must just show its anticoagulation in neutral and alkaline conditions and reduce the activity of blood viscosity blood circulation promoting. Heparin sodium easily decomposes rotten and loses activity in acid condition, owing to containing strong acid in human stomach, therefore is all intramuscular injection and intravenous injection clinically.
Intramuscular injection not only pain is strong but also needs medical practitioner or nurse to complete, it addition, intravenous injection there is likely to be bigger security risk.
Summary of the invention
In order to overcome Lipo-Hepin clinic to be all intramuscular injection and intravenous shortcoming, the invention provides a kind of heparin Collunarium and preparation method thereof, the present invention adopts the method for nasal cavity applied medicine, alleviates the professional requirement of operation, and intravenous control unknown risks, alleviate pain sensation; Adopt simultaneously and add preservative, it is possible to prevent the decomposition to heparin sodium of antibacterial and thermal source.
The present invention adopts the following technical scheme that
The heparin sodium Collunarium of the present invention is made up of heparin sodium, chloromycetin, osmotic pressure regulator, adhesive agent, preservative and alkalescence purifying sea water, wherein contains in every 1000ml preparation: heparin sodium 1-20g, chloromycetin 0-10.5g, osmotic pressure regulator 1-50g, adhesive agent 1-50g, preservative 0.1-1.0g, surplus are alkalescence purifying sea water.The nasal cavity applied medicine mode being main drug with heparin.
Preferred: every 1000ml preparation contains: heparin sodium 10g, chloromycetin 5g, osmotic pressure regulator 25g, adhesive agent 25g, preservative 0.5g, surplus are alkalescence purifying sea water.
Described heparin sodium adopts the purified product deriving from mammal intestinal mucosa, and molecular weight is below 100,000.
Described chloromycetin adopts street drug level product.
Described osmotic pressure regulator is glycerol or propylene glycol.
Described adhesive agent is cellulose family (such as methylcellulose, sodium carboxymethyl cellulose etc.), polyvinyl alcohol (polyvinyl alcohol, polyvinylpyrrolidone), chitin, carbomer (polymer of acrylic acid bonding allyl sucrose or tetramethylolmethane allyl ether).
Described preservative is Benzalkonii Chloridum or benzalkonium bromide.
Described alkaline purifying sea water PH=7-9, preparation method is as follows:
Away from the mouth of the river, city dirty (under) the water excretion region such as mouth, aquaculture area, obtain clean sea water, pour in clean container, sea water is through static, precipitation, filtration, after Organic substance in elimination water, ultraviolet radiation was more than 2 hours, due to the salinity of sea water higher (3.0-3.5%), need to adding 2.3-2.8 times of pure water dilution of sea water amount, the Adjust and use disodium hydrogen phosphate of basicity or sodium phosphate or sodium hydroxide realize.
Described alkaline purifying sea water PH=7-9, can be selected for normal saline and replace purifying sea water, the commercially available pure salt without iodine should be selected, water then to select pure water or distilled water, takes 0.9% gram of sodium chloride in container, adds distilled water 100% milliliter, stirring is to being completely dissolved, in 121 DEG C of sterilizings of high-pressure steam sterilizing pan 30 minutes, obtaining normal saline, the Adjust and use disodium hydrogen phosphate of basicity or sodium phosphate or sodium hydroxide realize.
Specifically comprising the following steps that of the method for the heparin sodium Collunarium of the present invention
(1) take the pure sea water of alkalescence of half amount, the heparin sodium of formula ratio is added, stirring, dissolve completely;
(2) taking the pure sea water of surplus, be sequentially added into adhesive agent, stirring, dissolving completely, add osmotic pressure regulator, stirring; Adding preservative, stirring, dissolving are completely;
(3) above-mentioned two parts are mixed, obtain material liquid, subpackage after standing 24 hours.
The positive effect of the present invention is as follows:
At present, the medication of heparin sodium has intramuscular injection and intravenous formulations, and it is directly entered blood, acts on antithrombase, stops the formation of antithrombase. Owing to the acidifying problem of gastric acid, oral medication poor effect, and the intestinal absorption of heparin also destroy its activity. The present invention overcomes disadvantages mentioned above, the method adopting nasal cavity applied medicine, alleviates the professional requirement of operation and intravenous control unknown risks, alleviates pain sensation; Adopt simultaneously and add preservative, it is possible to prevent the decomposition to heparin sodium of antibacterial and thermal source.
The heparin sodium Collunarium of the present invention can reduce the viscosity of blood of human body, recover blood vessel elasticity. Have easy to use, safe, painless, absorption efficiency is high, acts on the advantages such as rapid.
Detailed description of the invention
The following examples are describing in further detail the present invention.
Embodiment 1
The heparin sodium Collunarium of the present invention is made up of heparin sodium, chloromycetin, osmotic pressure regulator, adhesive agent, preservative and alkalescence purifying sea water, wherein contains in every 1000ml preparation: heparin sodium 1g, chloromycetin 0.5g, osmotic pressure regulator 1g, adhesive agent 50g, preservative 0.1g, surplus are alkalescence purifying sea water.
Described heparin sodium adopts the purified product deriving from mammal intestinal mucosa, and molecular weight is below 100,000.
Described chloromycetin adopts street drug level product.
Described osmotic pressure regulator is glycerol.
Described adhesive agent is methylcellulose.
Described preservative is Benzalkonii Chloridum.
Described alkaline purifying sea water PH=7-9, preparation method is as follows:
Away from the mouth of the river, city dirty (under) the water excretion region such as mouth, aquaculture area, obtain clean sea water, pour in clean container, sea water is through static, precipitation, filtration, after Organic substance in elimination water, ultraviolet radiation was more than 2 hours, due to the salinity of sea water higher (3.0-3.5%), need to adding 2.3-2.8 times of pure water dilution of sea water amount, the Adjust and use disodium hydrogen phosphate of basicity or sodium phosphate or sodium hydroxide realize.
Specifically comprising the following steps that of the method for the heparin sodium Collunarium of the present invention
(1) take the pure sea water of alkalescence of half amount, the heparin sodium of formula ratio is added, stirring, dissolve completely;
(2) taking the pure sea water of surplus, be sequentially added into adhesive agent, stirring, dissolving completely, add osmotic pressure regulator, stirring; Adding preservative, stirring, dissolving are completely;
(3) above-mentioned two parts are mixed, obtain material liquid, subpackage after standing 24 hours.
Embodiment 2
The heparin sodium Collunarium of the present invention is made up of heparin sodium, chloromycetin, osmotic pressure regulator, adhesive agent, preservative and alkalescence purifying sea water, wherein contains in every 1000ml preparation: heparin sodium 20g, chloromycetin 0.1g, osmotic pressure regulator 50g, adhesive agent 1g, preservative 1.0g, surplus are alkalescence purifying sea water.
Described heparin sodium adopts the purified product deriving from mammal intestinal mucosa, and molecular weight is below 100,000.
Described chloromycetin adopts street drug level product.
Described osmotic pressure regulator is propylene glycol.
Described adhesive agent is polyvinylpyrrolidone.
Described preservative is benzalkonium bromide.
Described alkaline purifying sea water PH=7-9, can be selected for normal saline and replace purifying sea water, the commercially available pure salt without iodine should be selected, water then to select pure water or distilled water, takes 0.9% gram of sodium chloride in container, adds distilled water 100% milliliter, stirring is to being completely dissolved, in 121 DEG C of sterilizings of high-pressure steam sterilizing pan 30 minutes, obtaining normal saline, the Adjust and use disodium hydrogen phosphate of basicity or sodium phosphate or sodium hydroxide realize.
Specifically comprising the following steps that of the method for the heparin sodium Collunarium of the present invention
(1) take the pure sea water of alkalescence of half amount, the heparin sodium of formula ratio is added, stirring, dissolve completely;
(2) taking the pure sea water of surplus, be sequentially added into adhesive agent, stirring, dissolving completely, add osmotic pressure regulator, stirring; Adding preservative, stirring, dissolving are completely;
(3) above-mentioned two parts are mixed, obtain material liquid, subpackage after standing 24 hours.
Embodiment 3
The heparin sodium Collunarium of the present invention is made up of heparin sodium, chloromycetin, osmotic pressure regulator, adhesive agent, preservative and alkalescence purifying sea water, wherein contains in every 1000ml preparation: heparin sodium 10g, chloromycetin 5g, osmotic pressure regulator 25g, adhesive agent 25g, preservative 0.5g, surplus are alkalescence purifying sea water.
Described heparin sodium adopts the purified product deriving from mammal intestinal mucosa, and molecular weight is below 100,000.
Described chloromycetin adopts street drug level product.
Described osmotic pressure regulator is glycerol.
Described adhesive agent is carbomer.
Described preservative is Benzalkonii Chloridum.
Described alkaline purifying sea water PH=7-9, preparation method is as follows:
Away from the mouth of the river, city dirty (under) the water excretion region such as mouth, aquaculture area, obtain clean sea water, pour in clean container, sea water is through static, precipitation, filtration, after Organic substance in elimination water, ultraviolet radiation was more than 2 hours, due to the salinity of sea water higher (3.0-3.5%), need to adding 2.3-2.8 times of pure water dilution of sea water amount, the Adjust and use disodium hydrogen phosphate of basicity or sodium phosphate or sodium hydroxide realize.
Specifically comprising the following steps that of the method for the heparin sodium Collunarium of the present invention
(1) take the pure sea water of alkalescence of half amount, the heparin sodium of formula ratio is added, stirring, dissolve completely;
(2) taking the pure sea water of surplus, be sequentially added into adhesive agent, stirring, dissolving completely, add osmotic pressure regulator, stirring; Adding preservative, stirring, dissolving are completely;
(3) above-mentioned two parts are mixed, obtain material liquid, subpackage after standing 24 hours.
Embodiment 4
The heparin sodium Collunarium of the present invention is made up of heparin sodium, chloromycetin, osmotic pressure regulator, adhesive agent, preservative and alkalescence purifying sea water, wherein contains in every 1000ml preparation: heparin sodium 15g, chloromycetin 10.5g, osmotic pressure regulator 30g, adhesive agent 35g, preservative 0.5g, surplus are alkalescence purifying sea water.
Described heparin sodium adopts the purified product deriving from mammal intestinal mucosa, and molecular weight is below 100,000.
Described chloromycetin adopts street drug level product.
Described osmotic pressure regulator is glycerol.
Described adhesive agent is carbomer.
Described preservative is Benzalkonii Chloridum.
Described alkaline purifying sea water PH=7-9, preparation method is as follows:
Away from the mouth of the river, city dirty (under) the water excretion region such as mouth, aquaculture area, obtain clean sea water, pour in clean container, sea water is through static, precipitation, filtration, after Organic substance in elimination water, ultraviolet radiation was more than 2 hours, due to the salinity of sea water higher (3.0-3.5%), need to adding 2.3-2.8 times of pure water dilution of sea water amount, the Adjust and use disodium hydrogen phosphate of basicity or sodium phosphate or sodium hydroxide realize.
Specifically comprising the following steps that of the method for the heparin sodium Collunarium of the present invention
(1) take the pure sea water of alkalescence of half amount, the heparin sodium of formula ratio is added, stirring, dissolve completely;
(2) taking the pure sea water of surplus, be sequentially added into adhesive agent, stirring, dissolving completely, add osmotic pressure regulator, stirring; Adding preservative, stirring, dissolving are completely;
(3) above-mentioned two parts are mixed, obtain material liquid, subpackage after standing 24 hours.
One, biological activity test:
Method (seeing appendix) the design biological activity determination experiment of " Sanguis caprae seu ovis slurry processes measures titer of heparin sodium " that reference heparin sodium industry is commonly used:
Formula A:
Alkalescence purifying sea water (PH=7--9) surplus. 1000ml in addition
Formula B (comparison):
Alkalescence purifying sea water (PH=7--9) surplus. 1000ml in addition
Formula C (blank):
Alkalescence purifying sea water (PH=7--9) 1000ml in addition
1. sheep blood plasma suitability experiment:
Take one, test tube, the sheep blood plasma 1ml after adding 0.8ml0.25%CaCl2 and filtering, builds pipe lid, reverse 34 mixings, make inwall moisten, vertically put into 37 DEG C of waters 5min, check after 5min whether blood plasma solidifies, and as the clotting of plasma then can use, does not solidify, can not use.
2. formula determination of activity:
Take formula A, formula B, formula C each 10ul, 20ul, 20ul, 40ul, adds in tool plug test tube, adds sheep blood plasma 1ml respectively, then be separately added into 0.25% calcium chloride solution 0.8ml, cover stopper in every test tube, mix immediately, it is to avoid produce bubble, and at 37 �� 1 DEG C of water-bath inside holding, every 2n* within 30 minutes, observing sheep blood plasma curdled appearance, record data are in Table 1. (parallel laboratory test 3 times, average)
Table 1: formula sheep blood plasma activity assay data
Active testing shows: formula A has obvious anticoagulant functions, and effective time is up to a couple of days, and increasing along with addition, and anticoagulation time substantially increases, and illustrates that this formula is highly effective.
Two, clinical effectiveness experiment:
Follow the tracks of continuously 5 people, before medication after 3 weeks and medication 3 weeks (medication 2-3 time every day) whole blood viscosity determination datas in Table 2. (capillary viscosimeter detection method: normal value: male 3.84��4.66 (mPa s); Women 3.33��3.97 (mPa s). )
The forward and backward whole blood viscosity determination data of table 2 clinical application (unit mPa s)
Clinical experiment shows: this formula has the effect reducing blood viscosity, and little range test effective percentage is 100%, and obvious effective rate is 75%, particularly middle age example, has that whole blood viscosity is higher returns to normal value after medication. There is good biocompatibility (actually all containing heparin at mammiferous lungs and little enteral), there is the Clinical practice experience of nearly 100 years due to heparin, can speculate and in this scope of experiment, have no the case that after using this formula, whole blood viscosity is fallen below normal value by normal value and produce.
Adnexa: Sanguis caprae seu ovis slurry processes measures the titer of heparin sodium:
1. the configuration of need testing solution
From the stock solution dissolved, accurately measure 1.0ml, estimate titer by test sample, calculate 0.9% sodium chloride solution addition, make the need testing solution of 8 units/ml.
0.9% sodium chloride solution addition (ml)=test sample estimates titer/8-1.
2. detection
According to sheep blood plasma half freezing point, by 10ul dosage escalation, draw standard solution and the need testing solution of above-mentioned 8 units/ml respectively with liquid rifle, in parallel injection five tool plug test tube. Standard substance, test sample add support after, in the every test tube often organize sample, laterally add sheep blood plasma 1ml respectively, longitudinally it is separately added into 0.25% calcium chloride solution 0.8ml again, cover stopper, mix immediately, it is to avoid produce bubble, and at 37 �� 1 DEG C of water-bath inside holding 1h, according to sheep blood plasma half curdled appearance, by rule for read data reading. Rule is such as following table:
Table 3 half curdled appearance rule for read data table (10 �� l) is incremented by
| 1-0.25<X<0.5 | 1-0.25 | 1-0<X<0.25 | 0.75-0.25 | 0.5-0 |
| +8(a) | +6.6(b) | +6(c) | +5(d) | +0(e) |
| 1-0 | 0.75-0<X<0.25 | 0.8-0 | 0.75-0 | 0.5<X<0.75-0 |
| +5(f) | +4(g) | +4(h) | +3.3(i) | +3(j) |
(1). tube contents solidifies reading " 1 " completely; Solidifying reading " 0 "; Tube contents solidifies completely but can entirety come off, and reads " 0.8 "; Grumeleuse accounts for the four/third reading " 0.75 " of entire mixture; Grumeleuse accounts for the half of entire mixture and reads " 0.5 "; Grumeleuse accounts for 1/4 reading " 0.25 " of entire mixture.
(2). grumeleuse is be more than or equal to the half of entire mixture, not solidify sample size added by test tube completely for radix; Grumeleuse less than the half of entire mixture, with solidify test tube completely previous test tube added by sample size for radix; If having grumeleuse in two test tubes, then with sample size added by the big test tube of grumeleuse for radix, the test tube such as rule (a) 170 �� l coagulates entirely, and in 180 �� l test tubes, grumeleuse accounts for the volume of entire mixture between 0.25 and 0.5, then half freezing point is 178;The test tube of rule (b) 170 �� l coagulates entirely, and in 180 �� l test tubes, grumeleuse accounts for the 0.25 of entire mixture volume, then half freezing point is 176.6; The test tube of rule (c) 170 �� l coagulates entirely, and in 180 �� l test tubes, grumeleuse accounts for the volume of entire mixture between 0 and 0.25, then half condensation point is 176; The test tube grumeleuse of rule (d) 170 �� l accounts for grumeleuse in 0.75,180 �� l test tube of entire mixture and accounts for the 0.25 of entire mixture, then half freezing point is 175; The test tube grumeleuse of rule (e) 170 �� l accounts for 0.5,180 �� l test tube of entire mixture and does not coagulate, then half freezing point is 170; The test tube of rule (f) 170 �� l coagulates entirely, and 180 �� l test tubes do not coagulate, then half freezing point is 175; Rule (h) 170 �� l test tube solidifies completely but can entirety come off, and 180 �� l test tubes do not coagulate, then half freezing point is 174; In rule (i) 170 �� l test tube, grumeleuse accounts for 0.75,180 �� l test tube of entire mixture and does not coagulate, then half freezing point is 173.3; In rule (j) 170 �� l test tube, grumeleuse accounts for the volume of entire mixture between 0.5 to 0.75, and the test tube of 180 �� l does not coagulate, then half freezing point is 173.
Although an embodiment of the present invention has been shown and described, for the ordinary skill in the art, being appreciated that and these embodiments can be carried out multiple change, amendment, replacement and modification without departing from the principles and spirit of the present invention, the scope of the present invention be defined by the appended.
Claims (9)
1. a heparin Collunarium, it is characterized in that: described Collunarium is made up of heparin sodium, chloromycetin, osmotic pressure regulator, adhesive agent, preservative and alkalescence purifying sea water, wherein every 1000ml preparation contains: heparin sodium 1-20g, chloromycetin 0-10.5g, osmotic pressure regulator 1-50g, adhesive agent 1-50g, preservative 0.1-1.0g, surplus are alkalescence purifying sea water.
2. heparin Collunarium as claimed in claim 1, it is characterised in that: every 1000ml preparation contains: heparin sodium 10g, chloromycetin 5g, osmotic pressure regulator 25g, adhesive agent 25g, preservative 0.5g, surplus are alkalescence purifying sea water.
3. heparin Collunarium as claimed in claim 1 or 2, it is characterised in that: described heparin sodium adopts the purified product deriving from mammal intestinal mucosa, and molecular weight is below 100,000.
4. heparin Collunarium as claimed in claim 1 or 2, it is characterised in that: described osmotic pressure regulator is glycerol or propylene glycol.
5. heparin Collunarium as claimed in claim 1 or 2, it is characterised in that: described adhesive agent is the one in methylcellulose, sodium carboxymethyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, chitin or carbomer.
6. heparin Collunarium as claimed in claim 1 or 2, it is characterised in that: described preservative is Benzalkonii Chloridum or benzalkonium bromide.
7. heparin Collunarium as claimed in claim 1 or 2, it is characterised in that: described alkaline purifying sea water PH=7-9, preparation method is as follows:
Away from the mouth of the river, city dirty (under) the water excretion region such as mouth, aquaculture area, obtain clean sea water, pour in clean container, sea water is through static, precipitation, filtration, after Organic substance in elimination water, ultraviolet radiation was more than 2 hours, due to the salinity of sea water higher (3.0-3.5%), need to adding 2.3-2.8 times of pure water dilution of sea water amount, the Adjust and use disodium hydrogen phosphate of basicity or sodium phosphate or sodium hydroxide realize.
8. heparin Collunarium as claimed in claim 1 or 2, it is characterized in that: described alkaline purifying sea water PH=7-9, normal saline is selected to replace purifying sea water, the commercially available pure salt without iodine should be selected, water then to select pure water or distilled water, take 0.9% gram of sodium chloride in container, add distilled water 100% milliliter, stirring is to being completely dissolved, in 121 DEG C of sterilizings of high-pressure steam sterilizing pan 30 minutes, obtaining normal saline, the Adjust and use disodium hydrogen phosphate of basicity or sodium phosphate or sodium hydroxide realize.
9. the method preparing heparin Collunarium as claimed in claim 1 or 2, it is characterised in that: specifically comprising the following steps that of described method
(1) take the pure sea water of alkalescence of half amount, the heparin sodium of formula ratio is added, stirring, dissolve completely;
(2) taking the pure sea water of surplus, be sequentially added into adhesive agent, stirring, dissolving completely, add osmotic pressure regulator, stirring; Adding preservative, stirring, dissolving are completely;
(3) above-mentioned two parts are mixed, obtain material liquid, subpackage after standing 24 hours.
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| US20110238003A1 (en) * | 2002-02-12 | 2011-09-29 | Alfredo Emilio Bruno-Raimondi | Method for systemic drug delivery through the nail |
| CN1394610A (en) * | 2002-07-12 | 2003-02-05 | 黄建林 | Herapin calcium eye drops |
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