CN102397290A - Hydroxyethyl starch injection and preparation method thereof - Google Patents
Hydroxyethyl starch injection and preparation method thereof Download PDFInfo
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- CN102397290A CN102397290A CN2011101748618A CN201110174861A CN102397290A CN 102397290 A CN102397290 A CN 102397290A CN 2011101748618 A CN2011101748618 A CN 2011101748618A CN 201110174861 A CN201110174861 A CN 201110174861A CN 102397290 A CN102397290 A CN 102397290A
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- Prior art keywords
- injection
- hetastarch
- hydroxyethyl starch
- chloride
- glucose
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Links
- 229920001612 Hydroxyethyl starch Polymers 0.000 title claims abstract description 87
- 238000002347 injection Methods 0.000 title claims abstract description 60
- 239000007924 injection Substances 0.000 title claims abstract description 60
- 229940050526 hydroxyethylstarch Drugs 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims description 5
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims abstract description 18
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 17
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims abstract description 12
- 239000001632 sodium acetate Substances 0.000 claims abstract description 12
- 235000017281 sodium acetate Nutrition 0.000 claims abstract description 12
- 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 abstract description 11
- 239000008103 glucose Substances 0.000 claims abstract description 11
- 239000011780 sodium chloride Substances 0.000 claims abstract description 10
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims abstract description 9
- 239000001110 calcium chloride Substances 0.000 claims abstract description 9
- 229910001628 calcium chloride Inorganic materials 0.000 claims abstract description 9
- 239000001103 potassium chloride Substances 0.000 claims abstract description 9
- 235000011164 potassium chloride Nutrition 0.000 claims abstract description 9
- 208000032456 Hemorrhagic Shock Diseases 0.000 claims abstract description 8
- 206010049771 Shock haemorrhagic Diseases 0.000 claims abstract description 8
- 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 abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 235000011148 calcium chloride Nutrition 0.000 claims abstract description 3
- 235000001727 glucose Nutrition 0.000 claims abstract description 3
- 235000002639 sodium chloride Nutrition 0.000 claims abstract description 3
- 229940027278 hetastarch Drugs 0.000 claims description 66
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- 239000003058 plasma substitute Substances 0.000 claims description 11
- 239000007788 liquid Substances 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 6
- 239000008215 water for injection Substances 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 238000006467 substitution reaction Methods 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 3
- 238000007689 inspection Methods 0.000 claims description 3
- 238000009413 insulation Methods 0.000 claims description 3
- 239000012528 membrane Substances 0.000 claims description 3
- 238000012856 packing Methods 0.000 claims description 3
- PVGBHEUCHKGFQP-UHFFFAOYSA-N sodium;n-[5-amino-2-(4-aminophenyl)sulfonylphenyl]sulfonylacetamide Chemical compound [Na+].CC(=O)NS(=O)(=O)C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=C1 PVGBHEUCHKGFQP-UHFFFAOYSA-N 0.000 claims description 3
- 238000001179 sorption measurement Methods 0.000 claims description 3
- 230000001954 sterilising effect Effects 0.000 claims description 3
- 238000004659 sterilization and disinfection Methods 0.000 claims description 3
- 238000005303 weighing Methods 0.000 claims description 3
- 230000000694 effects Effects 0.000 abstract description 9
- 241000282414 Homo sapiens Species 0.000 abstract description 8
- 239000003792 electrolyte Substances 0.000 abstract description 8
- 238000011282 treatment Methods 0.000 abstract description 7
- 210000004185 liver Anatomy 0.000 abstract description 5
- 210000001124 body fluid Anatomy 0.000 abstract description 4
- 239000010839 body fluid Substances 0.000 abstract description 4
- 238000001727 in vivo Methods 0.000 abstract description 4
- 230000003907 kidney function Effects 0.000 abstract description 4
- 239000008354 sodium chloride injection Substances 0.000 abstract description 4
- 230000006378 damage Effects 0.000 abstract description 3
- 238000004321 preservation Methods 0.000 abstract description 3
- 230000003908 liver function Effects 0.000 abstract 1
- 230000006641 stabilisation Effects 0.000 abstract 1
- 238000011105 stabilization Methods 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 description 16
- 239000008280 blood Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 238000013112 stability test Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000010257 thawing Methods 0.000 description 5
- 206010021138 Hypovolaemic shock Diseases 0.000 description 4
- 150000008065 acid anhydrides Chemical class 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 230000017531 blood circulation Effects 0.000 description 4
- 235000009508 confectionery Nutrition 0.000 description 4
- 206010040560 shock Diseases 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 3
- 208000032843 Hemorrhage Diseases 0.000 description 3
- 208000027418 Wounds and injury Diseases 0.000 description 3
- 230000004872 arterial blood pressure Effects 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000035939 shock Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 2
- 208000010444 Acidosis Diseases 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229920002527 Glycogen Polymers 0.000 description 2
- 206010027417 Metabolic acidosis Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940096919 glycogen Drugs 0.000 description 2
- DNZMDASEFMLYBU-RNBXVSKKSA-N hydroxyethyl starch Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O.OCCOC[C@H]1O[C@H](OCCO)[C@H](OCCO)[C@@H](OCCO)[C@@H]1OCCO DNZMDASEFMLYBU-RNBXVSKKSA-N 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 230000002085 persistent effect Effects 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920000945 Amylopectin Polymers 0.000 description 1
- 206010002198 Anaphylactic reaction Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- YZCKVEUIGOORGS-UHFFFAOYSA-N Hydrogen atom Chemical compound [H] YZCKVEUIGOORGS-UHFFFAOYSA-N 0.000 description 1
- 206010021137 Hypovolaemia 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
- 206010053159 Organ failure Diseases 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000008156 Ringer's lactate solution Substances 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 206010044541 Traumatic shock Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000036783 anaphylactic response Effects 0.000 description 1
- 208000003455 anaphylaxis Diseases 0.000 description 1
- 230000002364 anti-haemorrhagic effect Effects 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- -1 bicarbonate radical Chemical class 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- BMLSTPRTEKLIPM-UHFFFAOYSA-I calcium;potassium;disodium;hydrogen carbonate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].OC([O-])=O BMLSTPRTEKLIPM-UHFFFAOYSA-I 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 230000001627 detrimental effect Effects 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229940064366 hespan Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- VUZPPFZMUPKLLV-UHFFFAOYSA-N methane;hydrate Chemical compound C.O VUZPPFZMUPKLLV-UHFFFAOYSA-N 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 244000144977 poultry Species 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229940075601 voluven Drugs 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a hydroxyethyl starch 130/0.4 sodium chloride injection, wherein the injection uses hydroxyethyl starch 130/0.4 as the main raw material, and further contains sodium chloride, potassium chloride, calcium chloride, glucose and sodium acetate. (1) The injection has the reasonable formula, and the capacity expanding time of the hydroxyethyl starch 130/0.4 injection of the invention and the stay time in vivo is better than that of the hydroxyethyl starch injection of the prior art. (2) The injection has well stability, and the injection property, the clarity and the content and the stabilization of the molecular weight of the hydroxyethyl starch 130/0.4 can also be kept for long time preservation. (3) The injection has the short capacity expanding time and takes fast effect in the treatment of hemorrhagic shock. (4) The injection is more approaching to the human body internal environment, is propitious to regulate the body fluid, balance the electrolyte, and reduce the damage to the liver and kidney function.
Description
Technical field
The present invention relates to a kind of hydroxyethyl starch injection liquid as blood plasma substitute, a kind of hetastarch (130/0.4) injection especially is provided.Belong to field of medicaments.
Background technology
From the thirties in 20th century, since the gelatin gels plasma substitute comes out, existing so far nearly 80 years history.Invented the polyvinylpyrrolidone (PVP) of synthetic during the World War I; The synthetic dextrorotation candy of microorganism acid anhydride (Dextran) has appearred again in World War II; The mid-1970s U.S. develop hetastarch (HydroxyethylStarch, HES), China is by blood transfusion of China Concord Medical Science University, the Chinese Academy of Medical Sciences and Blood Research Institute; Studied successful dextrorotation candy acid anhydride and hetastarch respectively in 1958 and 1967; And forming industrialization at home rapidly, this has brought into play significant role to China prevention and treatment Hypovolemia and shock patients, has saved millions of life.Clinically; The hetastarch volume treatment of doing commonly used; Behind the intravenously administrable, the blood volume that can increase sharply is usually used in treatment because of massive hemorrhage; Burn or other wounds shock or the hemorrhage that cause can prevent each organic blood flow volume that circulatory disturbance that the backflow blood volume causes causes, the minimizing of oxygen confession amount and the organ failure of appearance.Experimentation and the clinical application practice of decades show, really estimate from clinical practice safety and blood plasma dilatation dose-effect, and hetastarch has become first-use drug--the blood plasma substitute that common people are used to treat the shock patient that losing blood property and a variety of causes cause.Abroad report in the period of 1978 to 1992 15, three kinds of blood plasma substitute quantity of clinical use gelatin, dextrorotation candy acid anhydride, hetastarch relatively, to hetastarch consumption in 1992 be that the first two plants more than 10 times; Aspect safety, see with the anaphylaxis of clinical worry the most, also be that hetastarch is minimum (0.054%), only be equivalent to 1/6 of gelatin, 1/4.7 of dextrorotation candy acid anhydride, even than also low one times of human albumin; Add raw material from natural corn, not only obtain easily but also good and cheap, and relatively letter of technology, be convenient to promote and produce.Because the chemical composition and the similar of hetastarch are former in the human body glycogen, be easy to metabolism at the blood vessel internal recycle in addition, the overwhelming majority is discharged from urine, thereby in organ, does not almost have savings, and vast clinical position person is happy to adopt.
Abroad, the hetastarch sodium chloride injection is at country variant, and its selected clinically kind is different; The hetastarch mean molecule quantity is 480KD ten thousand on American market; Mainly produced by du pont company (DuPont), commodity respectively are HESPan, and this product is widely used in the U.S.; Its blood volume expands big, and is lasting and effective.6% (480/0.7) average out to 24h action time, the defective on the performance is that it is influential and poultry is long-pending in vivo to blood coagulation system, and the ($43/500ml 6%480/0.7 that costs an arm and a leg) thereby limited its application clinically.On the European market, German Fresenius card has been succeeded in developing commodity He Si (HAES) 200/0.5 hetastarch product by name than company (Fresenius kabi) in nineteen eighty-two, and this product occupies the European market more than 70%; And in accurate Chinese market, this product mean molecule quantity 200KD, the substitution value 0.43-0.55 of getting into of quilt in 1999; Be used for blood plasma substitute, dilatation intensity is big, and it is 100% that the 6%HES dilatation is renderd a service; Dilatation effective time 4-8 hour, the half-life is 3-4 hour, irritated incidence rate is low; Be the leading products on the European blood plasma substitute market, it is 130KD that nearest Fresenius card is released its mean molecule quantity of hetastarch product Voluven of new generation again than company, and substitution value is 0.4; They think a lower molecular weight and a low mole degree of exchange can further improve Product Safety and effectiveness.Through the research that concerns between hetastarch chemical constitution characteristics and the physiological function is shown; Bigger its dilatation intensity of hetastarch mean molecule quantity is big more; Molecular weight size decision dilatation is renderd a service; Half-life length in its blood circulation of degree of exchange size decision is made a general survey of external hetastarch development and can be found out, hetastarch just from the high mole of HMW degree of exchange towards low-molecular-weight and low degree of exchange production development.Homemade hetastarch 40 or 20 products (706 plasma substitute); Because molecular weight is lower; And degree of exchange higher (0.8-1.2), blood plasma dilatation effect is relatively poor, and the half-life is shorter in the blood circulation; The anti-hemorrhagic shock function is lower, and clinical at home being mainly used in improved blood flow, treatment circulation or microcirculation disturbance patient.
Hetastarch is a third generation artificial colloid, is to be processed after degraded, hydroxyethylation and further processed by the HMW amylopectin.Press molecular weight and divide, low-molecular-weight hetastarch (Mw40000-7000D), middle molecular weight hydroxyethyl starch (Mw1300000-2000000D) and high molecular weight hydroxyethyl starch (Mw4500000-4800000D) are arranged.Divide by the replacement degree, low level hetastarch (Ms0.3-0.5) and the high level hetastarch (Ms0.6-0.7) that replaces of replacing arranged.What use always on the Chinese market at present mainly is hetastarch 200/0.5; The hetastarch of molecular weight in the genus; This article beginning of the nineties in last century is succeeded in developing (trade name: He Si HES), and successively in some country's listings, especially use the most extensive in Europe by German Fresenius company.He Si got into Chinese market in 1998, received clinician's welcome.Become the leading products on the present market.But single hetastarch 200/0.5 preparation still can not satisfy clinical demand.
Clinically, hetastarch is widely used in artificial plasm's succedaneum.Announced a kind of hydroxy ethyl starch for injection and preparation method thereof among the CN1650885A.CN1235833A, CN1195527A have announced the injection of hetastarch, be made up of hetastarch and sodium chloride, but there are the deficiency that causes high chlorine property metabolic acidosis easily in it when using.
Summary of the invention
Be safety and the effectiveness that improves clinical use, the present invention aims to provide a kind of human internal environment that more meets, and has reliable and stable capacity effect and persistent period, can fastly put in order effective dilatation and improve hypovolemic shock patient's the state of an illness.Hetastarch 130/0.4 injection of the present invention has good stable property, and clinical use is safer, effective.
Technical scheme of the present invention is following:
A kind of hetastarch 130/0.4 injection; Is to be 130 with weight average molecular weight with hetastarch as plasma expander; 000 dalton; The molar substitution level is that 0.4 (130/0.4) hetastarch is a primary raw material, and contains sodium chloride, potassium chloride, calcium chloride, glucose and sodium acetate composition.
The embodiment of hetastarch 130/0.4 injection according to the invention, described hydroxyethyl starch injection liquid contains in wherein every 100ml injection: hetastarch 130/0.48-10g; Sodium chloride 0.5-1.0g; Glucose 0.05-0.1g, potassium chloride 0.02-0.04g, calcium chloride 0.02-0.04g; Sodium acetate 0.01-0.02mg, surplus is a water for injection.
As the preferred embodiments of the invention, described hetastarch 130/0.4 injection contains in wherein every 100ml injection: hetastarch 130/0.4 8g; Sodium chloride 0.5g, glucose 0.1g, potassium chloride 0.02g; Calcium chloride 0.02g, sodium acetate 0.01mg, surplus is a water for injection.Hydroxyethyl starch injection liquid people pH value of the present invention is 5-7, preferably 6.5-7.
The method for preparing of hetastarch 130/0.4 injection according to the invention:
(1) takes by weighing hetastarch 130/0.4, sodium chloride, potassium chloride, calcium chloride, glucose and the sodium acetate of recipe quantity, mix, add water for injection and dissolve fully;
(2) activated carbon adsorption: the needle-use activated carbon decolouring of adding 0.1%, boil insulation 20 minutes, adjust pH is to 5.0-7.0;
(3) fine straining: with diameter 0.45um microporous filter membrane; Fill; In 115 ℃ of sterilizations 30 minutes; Lamp inspection, packing; Get injection.
Above-mentioned described hydroxyethyl starch injection liquid can be used as artificial plasm's succedaneum.As be used to treat hypovolemic shock, for example lose hemorrhagic shock, septic shock, burn and traumatic shock; Perhaps reduce operation blood consumption, like ANH, the property controlled blood property dilution etc.
Hetastarch 130/0.4 injection of the present invention contains sodium, potassium, the calcium that approaches the normal physiological level, more meets human internal environment's demand.In addition, also contain glucose in hetastarch 130/0.4 injection of the present invention, helping provides energy to patient, reduces protein depletion.In addition, also contain acetic acid in hetastarch 130/0.4 injection of the present invention.Sodium acetate is dissociated into Na in the water
+And C
3H
5O
3 -Acetate anion is an alkalescence, removes acetic acid and hydrion simultaneously through liver.In liver, acetic acid is metabolised to glycogen, and final oxidized metabolism changes into carbon dioxide and water.Produce and utilization when acetic acid is normal, can not cause that acetic Acid Metabolism is disorderly, acetate anion can be used as the alternate source of bicarbonate radical.
Hetastarch 130/0.4 injection of the present invention, its Cl-level more approaches the normal physiological scope than 0.9% sodium chloride injection, and contains near physiological level Ca
2+, K
+, Na+, C
3H
5O
3-, electrolyte such as glucose, dilatation is suitable with its sodium chloride injection, and more helps improving hypovolemic shock patient's water-electrolyte balance.
The hetastarch 130/0.4 that uses in the plasma substitute injection of the present invention; Belong to a kind of middle molecular weight hydroxyethyl starch; Its molecular weight is 130000 left and right sides dalton, and molecular distribution is more concentrated, further reduces than the existing molecular weight of 200/0.5 hetastarch of report that uses; The replacement level of ethoxy is reduced to 0.4 from 0.5, and can be with the mode of replacement from C
2With C
5(or C
6) ratio increased to 9: 1 by 5: 1, help obtaining better effect.On this basis, simultaneously again with sodium acetate and the common compound injection of forming of multiple electrolyte ingredient optimum organization, make it and can reach the target of " desirable colloid solution ".It not only can provide reliable and stable capacity effect and persistent period; And more meet the interior environment of human blood; Influence and the effect of expansion blood appearance to blood system also all are superior to plasma substitutes such as hetastarch 200/0.5 sodium acetate ringer's injection; More ideal comprehensive therapeutic effect can be arranged, also convenient clinical use.
Therefore, when adopting these article treatments hypovolemic shock patient, compare with existing expander, can replenishment of blood content and multiple electrolyte ingredient to regulate body fluid, electrolyte and acid-base balance.Simultaneously, less to the detrimental effect of renal function, can not produce high chlorine property metabolic acidosis, clinical use is safer, improves the safety and the effectiveness of clinical use.And can practice thrift blood used in clinic, and solved the nervous problem in blood source to a great extent, reduced the complication of allosome blood transfusion, the effectiveness and the safety that have also improved volume treatment greatly, and thus to the prognosis of disease with lapse to the generation wholesome effect.
The compared with prior art the most outstanding advantage of the present invention is: the prescription of (1) injection is reasonable, dilatation time of hetastarch 130/0.4 the injection of the present invention and time of staying is superior to the hydroxyethyl starch injection liquid of prior art in vivo; (2) good stability, long preservation still guarantee the stable of injection character, clarity, hetastarch 130/0.4 content and molecular weight; (3) the dilatation time short rapid-action, onset rapidly in treating hemorrhagic shock; (4) more approach human interior environment, help regulating body fluid, electrolyte balance, reduce liver, renal function injury.
Below again foregoing of the present invention is done further to specify through the specific embodiment of embodiment.But should this be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following instance.Do not breaking away under the above-mentioned technological thought situation of the present invention, various replacements or change according to ordinary skill knowledge and customary means are made all should comprise within the scope of the invention.
Inventive embodiments
Embodiment 1
Injection is formed (by every 100ml injection):
(1) takes by weighing hetastarch 130/0.4, sodium chloride, potassium chloride, calcium chloride, glucose and the sodium acetate of recipe quantity, mix, add water for injection and dissolve fully;
(2) activated carbon adsorption: the needle-use activated carbon decolouring of adding 0.1%, boil insulation 20 minutes, adjust pH is to 6.5-7.0;
(3) fine straining: with diameter 0.45um microporous filter membrane; Fill; In 115 ℃ of sterilizations 30 minutes; Lamp inspection, packing; Get injection.
Embodiment 2
Injection is formed (by every 100ml injection):
Method for preparing is with embodiment 1.
Embodiment 3
Injection is formed (by every 100ml injection):
Method for preparing is with embodiment 1.
Embodiment 4
Injection is formed (by every 100ml injection):
Method for preparing is with embodiment 1.
Galenic pharmacy is investigated
(1) freezing-thawing test
In the freezing-thawing test, the sample of selecting embodiment 1-4 was respectively placed two days respectively under-10 ℃ and 40 ℃ of acceleration environments, then checked clarity of solution, clarity and principal agent (hetastarch (130/0.4)) content, and the result sees table 1.
Table 1 freezing and thawing test result
Can know that by the result before and after the freezing-thawing test, clarity of solution, clarity and molecular weight be no change almost.After the freezing-thawing test, visible hetastarch 130/0.4 injection of the present invention.
(2) accelerated stability test
In the long-time stability examination; Select the sample of embodiment 1-4, carry out each sample with reference to Chinese Pharmacopoeia appendix XIXC crude drug pharmaceutical preparation stability test guideline; Get three batches; In temperature is 40 ℃ ± 2 ℃, and relative humidity is 75% ± 5% condition held 6 months, respectively at 1,2,3, the sampling in June investigates character, microorganism qualification, visible foreign matters, principal agent (hetastarch (130/0.4)) content, the pH value of sample.The result is following:
Table 2 accelerated stability test result (January)
Table 3 accelerated stability test result (February)
Table 4 accelerated stability test result (March)
Table 5 accelerated stability test result (June)
(3) pharmacodynamics and dilatation effect test
Hetastarch (130/0.4) injection of selecting embodiment 1-4 for use is as sample, evidence beneficial effect of the present invention in rat hemorrhagic shock model.After the administration 30 minutes, measure the mean arterial pressure lift-off value.
Hetastarch (130/0.4) injection of table 6 embodiment 1-4 is to the mean arterial pressure lift-off value
| Embodiment | 1 | 2 | 3 | 4 |
| Mean arterial pressure | 85 | 90 | 87 | 88 |
| Lift-off value mmHg |
It is thus clear that the hetastarch of embodiment 1-4 (130/0.4) injection is onset rapidly in treating hemorrhagic shock.
Infusion 500ml sample behind the hemorrhage 500ml of healthy volunteer, sample are selected from hetastarch (130/0.4) injection of embodiment 1-4, can produce the volume replacement effect to losing blood.Measure the time of staying in hetastarch (130/0.4) body, and dilatation is relaxed the notes time.
In sum, prior art of the present invention is compared the most outstanding advantage and is: the prescription of (1) injection is reasonable, dilatation time of hetastarch 130/0.4 the injection of the present invention and time of staying is superior to the hydroxyethyl starch injection liquid of prior art in vivo; (2) good stability, long preservation still guarantee the stable of injection character, clarity, hetastarch 130/0.4 content and molecular weight; (3) the dilatation time short rapid-action, onset rapidly in treating hemorrhagic shock; (4) more approach human interior environment, help regulating body fluid, electrolyte balance, reduce liver, renal function injury.
The present invention is described according to preferred embodiment.The description and the embodiment that should be understood that the front are just to illustrating the present invention.Under prerequisite without departing from the spirit and scope of the present invention, those skilled in the art can design multiple alternative of the present invention and improvement project, and it all should be understood to be within protection scope of the present invention.
Claims (4)
1. hetastarch 130/0.4 injection; Is to be 130 with weight average molecular weight with hetastarch as plasma expander; 000 dalton; The molar substitution level is that 0.4 (130/0.4) hetastarch is a primary raw material, and contains sodium chloride, potassium chloride, calcium chloride, glucose and sodium acetate composition.
2. described hetastarch 130/0.4 injection of claim 1, described hydroxyethyl starch injection liquid contains in wherein every 100ml injection: hetastarch 130/0.4 8-10g; Sodium chloride 0.5-1.0g; Glucose 0.05-0.1g, potassium chloride 0.02-0.04g, calcium chloride 0.02-0.04g; Sodium acetate 0.01-0.02mg, surplus is a water for injection.
3. the method for preparing of claim 1 and 2 hetastarch 130/0.4 injection; It is characterized in that: (1) takes by weighing hetastarch 130/0.4, sodium chloride, potassium chloride, calcium chloride, glucose and the sodium acetate of recipe quantity; Mix, add water for injection and dissolve fully;
(2) activated carbon adsorption: the needle-use activated carbon decolouring of adding 0.1%, boil insulation 20 minutes, adjust pH is to 6.5-7.0;
(3) fine straining: with diameter 0.45um microporous filter membrane; Fill; In 115 ℃ of sterilizations 30 minutes; Lamp inspection, packing; Get injection.
4. described hetastarch 130/0.4 injection of claim 1-3 has application at the medicine that preparation is used for treating hemorrhagic shock.
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