CN101647776B - Doxofylline venous injection with small volume as well as preparation method and quality control method thereof - Google Patents

Doxofylline venous injection with small volume as well as preparation method and quality control method thereof Download PDF

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Publication number
CN101647776B
CN101647776B CN200910306505XA CN200910306505A CN101647776B CN 101647776 B CN101647776 B CN 101647776B CN 200910306505X A CN200910306505X A CN 200910306505XA CN 200910306505 A CN200910306505 A CN 200910306505A CN 101647776 B CN101647776 B CN 101647776B
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doxofylline
intravenous fluid
injection
low capacity
osmotic pressure
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CN200910306505XA
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Chinese (zh)
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CN101647776A (en
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吴光彦
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吴光彦
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Abstract

The invention discloses Doxofylline venous injection with a small volume and a preparation method thereof. The preparation unit of the isotonic small volume of doxofylline venous injection is 1-20ml, the weight percentage concentration of doxofylline is01-4 percent, and the isotonic value of the venous injection is 257-340mosmol/kg. The invention enlarges the optional range of clinical application of doxofylline and provides the isotonic doxofylline venous injection with favorable security.

Description

Doxofylline low capacity intravenous fluid and preparation method thereof and method of quality control
Technical field the present invention relates to a kind of doxofylline low capacity intravenous fluid, particularly a kind of isoosmotic doxofylline injection with small volume and preparation method thereof.
The background technology doxofylline is a kind of antasthmatic of xanthine.Gone on the market by Italian company ABC in the eighties, the dosage form of external listing has injection with small volume, sheet and syrup, and wherein the using method of injection with small volume does not have the mode of intravenous injection administration for the dilution posterior vein instils.
In China, 2000 by the exploitation of Heilungkiang China star pharmacy Group Plc gone on the market doxofylline injection (high capacity and low capacity), tablet, multiple dosage forms such as slow releasing capsule, granule and oral administration solution had been developed afterwards again successively, the clinical administration form of doxofylline has been enriched in the listing of above-mentioned dosage form greatly.But,, the still drug administration by injection of clinical meaning is arranged most for the treatment of asthma.The acute attack of asthma is very general, and clinical alternative the most effective theophylline class that is of asthmatic medicament that is used for first aid, wherein the therapeutic index of aminophylline and theophylline and safety index are approaching, and what the safety range of doxofylline injection will be big is many.Though drug administration by injection has very big advantage, existing doxofylline injection still exists osmotic pressure problem on the low side, operation instructions according to this medicine, when in the sodium chloride injection of 5% the glucose injection of 100ml or 0.9%, adding the doxofylline injection of 3 10ml, osmotic pressure drops to 207mOsmol/kg with minimum meeting, because of the scope of human body fluid and colloidal osmotic pressure is 280--310mOsmol/kg, so the osmotic pressure of doxofylline injection solution when clinical use and the osmotic pressure of blood of human body fall far short at present,, can bring very big potential safety hazard clinically.
Averaging out of the inside and outside osmotic pressure of human body cell, be rely on cell inside and outside between the moving of moisture.When extracellular fluid was higher than the osmotic pressure of intracellular fluid, moisture was by flowing to the extracellular in the cell, on the contrary then by cell drain in cell.If the osmotic pressure of extracellular fluid is during less than the osmotic pressure of intracellular fluid, ICW outflows thereupon, makes cell generation shrinkage and distortion, and this solution belongs to high sepage; If the osmotic pressure of extracellular fluid is during greater than the osmotic pressure of intracellular fluid, part moisture is inhaled in the erythrocyte, makes it swelling, and this solution belongs to hypotonic medium.No matter osmotic pressure reduces and causes haemolysis, or increasing of osmotic pressure will cause the atrophy of patient's erythrocyte, all is the health that seriously jeopardizes the patient.
Though, the osmotic pressure of regulating injection by materials such as sodium chloride, glucoses is conventionally known to one of skill in the art, jumbo doxofylline sodium chloride or glucose injection such as commercially available 100ml, the osmotic pressure problem has obtained a little improvement clinically, but because non-grade is oozed a large amount of doxofylline solution (20--30 milliliters, osmotic pressure is 20mOsmol/kg) adding after, the volume that this solution can become hypisotonic solution and injection is big (130 milliliters).If inject hypisotonic solution clinically in a large number, can make the people feel hemoglobin to occur in feeling of fullness in the head, uncomfortable in chest, serious taken place numbness, shiver with cold, hyperpyrexia even the urine.So the low excessively problem of osmotic pressure when solving the administration of low capacity doxofylline injection is very urgent and necessary clinically, also can increase safety clinically greatly.
Summary of the invention the object of the invention has provided a kind of isoosmotic doxofylline injection with small volume.
Another one purpose of the present invention has provided the preparation method of above-mentioned injection with small volume.
The present invention also provides a kind of method of quality control of doxofylline injection with small volume.
Doxofylline low capacity intravenous fluid of the present invention, wherein the preparation unit of intravenous fluid is 1-20ml, and the concentration expressed in percentage by weight of doxofylline is 1-4%, and intravenous fluid is an isosmotic solution, and the grade of intravenous fluid is oozed value at 257~340mOsmol/kg.
Isoosmotic doxofylline low capacity intravenous fluid of the present invention, wherein to ooze value be 265~331mOsmol/kg to the grade of intravenous fluid.
Isoosmotic doxofylline low capacity intravenous fluid of the present invention, wherein the isoosmotic adjusting agent of isosmotic solution is selected from a kind of separately or mixing use of sodium chloride, glucose, xylitol, mannitol, dextran.
Doxofylline low capacity intravenous fluid of the present invention, wherein isoosmotic adjusting agent is selected from sodium chloride, glucose, and preparation unit is 10ml and 20ml, and the concentration expressed in percentage by weight of doxofylline is 1% and 1.5%.
The low capacity intravenous fluid of doxofylline of the present invention also need add the pH regulator agent, the pH regulator agent be selected from hydrochloric acid, sodium hydroxide, wherein the concentration of hydrochloric acid is that 1mol/L, concentration sodium hydroxide are 0.1mol/L.
The preparation method of isoosmotic doxofylline low capacity intravenous fluid of the present invention is: the dense step of joining that contains doxofylline and osmotic pressure regulator with the water for injection preparation, with the adjusting pH value step of pH regulator agent, decarburization filtration step, intermediate controlled step, packing step, and sterilization steps.
The preparation method of isoosmotic doxofylline low capacity intravenous fluid of the present invention, wherein in the intermediate controlled step, 95-105%, pH value that doxofylline content should be labelled amount should be 4.5-6.5, and in the sterilization steps, sterilising conditions is 115 ℃, steam sterilization 30min.
The method of quality control of doxofylline low capacity intravenous fluid of the present invention, comprise that determination of related substances, assay, pH value are measured, bacterial endotoxin is measured, differentiate, also comprise osmometry: get described doxofylline low capacity intravenous fluid, osmotic pressure molar density algoscopy according to version Chinese Pharmacopoeia in 2005 is measured, and should be 268.2~327.8mOsmol/kg.
Below the present invention is further described:
The specification of injection with small volume of the present invention is the defined specification of Chinese Pharmacopoeia; comprise 1ml, 2ml, 5ml, 10ml, 20ml; certainly can not be interpreted as that the inventor is confined to above-mentioned specification, as long as all belong within the protection domain of the present invention in the specification within the 1-20ml.
The concentration expressed in percentage by weight of doxofylline of the present invention is interpreted as the gram number of the doxofylline that every 100ml contains.
The invention has the beneficial effects as follows the clinical application selectable range that enriches doxofylline, provide a kind of safety good isoosmotic doxofylline injection.In clinical, injection with small volume added to instil in the transfusion uses or carry out the intravenous injection administration, be common practise, though the human body osmotic pressure can change because self regulating power of human body influences less to health.Yet after joining in mixed solution (120-130ml) the input body that obtains behind 100 milliliters in the sodium chloride of 100 milliliters of 5% glucoses or 0.9% for a large amount of doxofylline injection, the change that osmotic pressure causes, influence for the patient is very big really, malpractice in various degree often appears, limited the application of doxofylline intravenous route administration, this is that those skilled in the art are unexpected, the present invention is directed to above-mentioned situation, provide the grade that is more suitable for accordingly injecting to ooze injection with small volume.
Further the present invention will be described below by the specific embodiment.
Specific embodiment embodiment 1 every 10ml: contain the 0.1g doxofylline, ooze with sodium chloride adjusting etc.
Indicate prescription:
Doxofylline 100g
Sodium chloride 81g
Add water to 10000ml
--------------------------
Make 1000
Get water for injection 6000ml, heat temperature raising, (doxofylline is 15% by the activated carbon adsorption amount, so add 15 grams than recipe quantity under agitation to add doxofylline 115g, hereinafter for sake of convenience, note no longer) and sodium chloride 81g, treat that medicated powder all dissolves the back and adds active carbon 5g about liquid temperature rise to 80 ℃, continue to stir 10 minutes, treat that temperature reduces to 40 ℃, filter carbon removal, concentrated wiring liquid.Get concentrated wiring liquid add the injection water mend to 10000ml, stir, filtering with microporous membrane to clarity qualified after, the content of taking a sample to check, pH value.Content should be the 95-105% of labelled amount, and pH value should be 5.0-6.5.Be sub-packed in the 10ml ampoule at clean area, holding is honored as a queen puts in the autoclave, in 115 ℃ of steam sterilization 30min, and through product inspection, lettering, packing, promptly.The finished product osmotic pressure is 298mOsmol/kg, and it is 99.7% that doxofylline indicates content.
Embodiment 2 every 10ml: contain the 0.1g doxofylline, ooze with glucose adjusting etc.
Indicate prescription:
Doxofylline 100g
Glucose 450g
Add water to 10000ml
------------------------
Make 1000
Get water for injection 6000ml, heat temperature raising under agitation adds doxofylline 115g and glucose 450g, treats about liquid temperature rise to 80 ℃, and medicated powder all dissolves the back and adds active carbon 5g, continues to stir 10 minutes, treats that temperature reduces to 40 ℃, filters carbon removal, concentrated wiring liquid.Get concentrated wiring liquid add the injection water mend to 10000ml, stir, filtering with microporous membrane to clarity qualified after, the content of taking a sample to check, pH value.Content should be the 95-105% of labelled amount, and pH value should be 4.5-5.5.Be sub-packed in the 10ml ampoule at clean area, holding is honored as a queen puts in the autoclave, in 115 ℃ of steam sterilization 30min, and through product inspection, lettering, packing, promptly.The finished product osmotic pressure is 295mOsmol/k, and it is 99.4% that doxofylline indicates content.
Embodiment 3-11 preparation method is with embodiment 1 or 2, be not both doxofylline consumption, etc. ooze and adjust consumption and kind
Embodiment 3 Embodiment 4 Embodiment 5 Embodiment 6
Doxofylline 115g 115g 115g 115g
Isoosmotic adjusting agent Sodium chloride 72.95g Sodium chloride 89.1g Glucose 405g Glucose 495g
Loading amount 10ml 10ml 10ml 10ml
Make total amount 1000 1000 1000 1000
Osmotic pressure mOsmol/kg 265 317 269 331
Embodiment 7 Embodiment 8 Embodiment 9 Embodiment 10
Doxofylline ?230g ?360g ?360g ?400g
Isoosmotic adjusting agent Sodium chloride 72g Sodium chloride 88g Mannitol 2kg Xylitol 1kg
Loading amount ?20ml ?20ml ?20ml ?10ml
Make total amount 1000 1000 1000 1000
Osmotic pressure mOsmol/kg ?265 ?317 ?340 ?257
Further specify beneficial effect of the present invention below by the test example.
The 1 osmotic pressure comparative test of test example
It is that full-automatic freezing-point osmometer FM-8P by Instrument Factory of Shanghai Medical Univ. measures that grade of the present invention is oozed value.
Experimental technique:
Get of the description requirement of the isoosmotic doxofylline injection of not accent (hereinafter to be referred as reference substance) of isoosmotic doxofylline injection (hereinafter to be referred as test sample) that embodiment makes for 1,8 times and commercially available our factory according to the listing product, get respectively among the sodium chloride solution 100ml and 5% glucose solution 100ml of 3 addings 0.9%, measure osmotic pressure, the results are shown in Table (unit of osmotic pressure is mOsmol/kg in the table):
(1), 0.9% sodium chloride injection adds 3 (10 milliliters /) etc. respectively and blends anisosmotic doxofylline injection
(2), 5% glucose injection adds 3 (10 milliliters /) etc. respectively and blends anisosmotic doxofylline injection
(3), 0.9% sodium chloride injection adds 20ml embodiment 8 samples and anisosmotic doxofylline injection respectively;
(4), 5% glucose injection adds 20ml embodiment 8 samples and anisosmotic doxofylline injection respectively;
Conclusion: do not cause that almost osmotic pressure changes after joining isoosmotic doxofylline injection of the present invention in 0.9% sodium chloride injection of 100ml or 5% glucose injection, and the osmotic pressure that anisosmotic doxofylline injection uses by same way as reduces very obvious.

Claims (7)

1. doxofylline low capacity intravenous fluid, it is characterized in that the preparation unit of described intravenous fluid is 1-20ml, the concentration expressed in percentage by weight of described doxofylline is 1-4%, described intravenous fluid is an isosmotic solution, and the grade of described intravenous fluid is oozed value at 265~331mOsmol/kg.
2, doxofylline low capacity intravenous fluid as claimed in claim 1 is characterized in that, the isoosmotic adjusting agent of described isosmotic solution is selected from a kind of separately or mixing use of sodium chloride, glucose, xylitol, mannitol, dextran.
3, doxofylline low capacity intravenous fluid as claimed in claim 2 is characterized in that described isoosmotic adjusting agent is selected from sodium chloride, glucose, and described preparation unit is 10ml, and the concentration expressed in percentage by weight of described doxofylline is 1%.
4, doxofylline low capacity intravenous fluid as claimed in claim 2 is characterized in that described isoosmotic adjusting agent is selected from sodium chloride, glucose, and described preparation unit is 20ml, and the concentration expressed in percentage by weight of described doxofylline is 1.5%.
5, the low capacity intravenous fluid of doxofylline as claimed in claim 1 is characterized in that, also need add the pH regulator agent, described pH regulator agent be selected from hydrochloric acid, sodium hydroxide, wherein the concentration of hydrochloric acid is that 1mol/L, concentration sodium hydroxide are 0.1mol/L.
6, the preparation method of doxofylline low capacity intravenous fluid as claimed in claim 1 is: the dense step of joining that contains doxofylline and osmotic pressure regulator with the water for injection preparation, regulate the pH value step with the pH regulator agent, the decarburization filtration step, the intermediate controlled step, packing step, and sterilization steps.
7, the preparation method of doxofylline low capacity intravenous fluid as claimed in claim 6, in the described intermediate controlled step, doxofylline content should be labelled amount 95-105%, pH value should be 4.5-6.5, in the described sterilization steps, sterilising conditions is 115 ℃, steam sterilization 30min.
CN200910306505XA 2009-09-02 2009-09-02 Doxofylline venous injection with small volume as well as preparation method and quality control method thereof CN101647776B (en)

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CN101953803B (en) * 2010-09-02 2012-05-09 天津市铭泰医药科技有限公司 Preparation method of small-volume doxofylline freeze-dried powder injection and device thereof
CN103487517B (en) * 2013-09-02 2015-07-15 成都百裕科技制药有限公司 Determination method for theophylline in doxofylline injection preparation
CN103837612B (en) * 2013-11-03 2016-10-05 黑龙江福和华星制药集团股份有限公司 Doxofylline injection relevant substance-measuring method
CN104688673B (en) * 2013-12-04 2017-09-29 长春海悦药业股份有限公司 A kind of pharmaceutical composition containing doxofylline

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4187308A (en) * 1978-04-06 1980-02-05 Istituto Biologico Chemioterapico "Abc" S.P.A. Pharmaceutical composition with anti-bronchospasmodic and anti-tussive activity
CN1468600A (en) * 2002-07-18 2004-01-21 挺 赵 Prepn process of glucose injection of Doxofylline

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4187308A (en) * 1978-04-06 1980-02-05 Istituto Biologico Chemioterapico "Abc" S.P.A. Pharmaceutical composition with anti-bronchospasmodic and anti-tussive activity
CN1468600A (en) * 2002-07-18 2004-01-21 挺 赵 Prepn process of glucose injection of Doxofylline

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