CN1864684A - Lyophilized powder injection of doxofylline and preparation method thereof - Google Patents
Lyophilized powder injection of doxofylline and preparation method thereof Download PDFInfo
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- CN1864684A CN1864684A CNA2005100711184A CN200510071118A CN1864684A CN 1864684 A CN1864684 A CN 1864684A CN A2005100711184 A CNA2005100711184 A CN A2005100711184A CN 200510071118 A CN200510071118 A CN 200510071118A CN 1864684 A CN1864684 A CN 1864684A
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- doxofylline
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Abstract
The present invention relates to doxofylline for treating asthma and its freeze dried powder for injection and preparation process. The freeze dried doxofylline powder for injection with high stability contains doxofylline as the active component and pharmaceutically acceptable solubilizer and excipient. The solubilizer may be one or several of methanesulfonic acid, maleic acid, glycine, citric acid, arinine, etc. and is preferably citric acid. The excipient may be one or several of mannitol, dextran, cyclodextrin and soluble starch, and is preferably mannitol. The injection of the present invention may be in different specifications containing doxofylline of 1-1000 mg, preferably of 50 mg, 100 mg, 150 mg, 200 mg, 300 mg, etc. The preparation process includes compounding medicine liquid, eliminating pyrogen, sterilizing, pouring, freeze drying and other steps.
Description
Technical field
The invention belongs to medical technical field, be specifically related to medicine doxofylline and formulation art thereof, specifically, cough medicine doxofylline and freezing-dried powder injection thereof and preparation method thereof relate to relieving asthma.
Background technology
Doxofylline (doxofylline) is a kind of novel anti-asthmatic, and chemistry is called 1,3-dimethyl-7-(1,3-dioxy cyclopenta-2-methyl) methyl-3,7-dihydro-1H-purine-2,6-diketone.Molecular formula is C
11H
14N
4O
4Molecular weight is 266.3; Structural formula is as follows:
Many plain theophylline
Doxofylline is used for the treatment of bronchial asthma, the pulmonary disease of companion's bronchospasm, chronic obstructive pulmonary disease.By the exploitation of Italian company ABC, listing in 1988.Present commercially available doxofylline dosage form is liquid drugs injection and transfusion.Liquid drugs injection in use pollutes because of the peace bottle that fractures easily produces, and it is many that processes such as production lamp inspection take man-hour, cost height, transportation cracky; And the clinical use of infusing easily produces waste, and process of producing product is many lost time, and split run production output is little, and packaging volume is big, and transportation is damaged easily, transportation, packaging material cost height.Because doxofylline is poor at water stability, oxidation reaction takes place easily again, so there is short drawback of storage time in aqueous solution injection, use effect duration weak point has influenced the safety of this product and has effectively used.Powder injection formulation can address the above problem, but because the dissolubility of doxofylline in water is bad, make the powder pin certain degree of difficulty is arranged, so the present invention screens at aspects such as solubilizing agents, solved its above-mentioned defective, and adopt cryodesiccated method to make injectable sterile powder, and the freezing-dried powder injection of the present invention's preparation has good stability.
About 24 hours of freeze-dried powder production cycle, the workshop can continuous production, and small product size is little, easily packed and transported, not cracky; Clinical use preparation is convenient, is difficult for producing and pollutes, and can better serve extensive patients.
Goal of the invention
The purpose of this invention is to provide a kind of lyophilized powder injection of doxofylline; Another object of the present invention has provided a kind of method for preparing lyophilized powder injection of doxofylline; Another object of the present invention has provided a kind of purposes with lyophilized powder injection of doxofylline preparation treatment asthmatic medicament.
Summary of the invention
Lyophilized powder injection of doxofylline of the present invention is made up of active component doxofylline and the agent of medicine acceptable solubilizing and pharmaceutically-acceptable excipients, the agent of wherein said medicine acceptable solubilizing can be selected from one or more in methanesulfonic acid, maleic acid, glycine, citric acid, arginine, serine, threonine, glutamic acid, Macrogol 4000, the polyethylene glycol 6000, preferably citric acid; Wherein said pharmaceutically-acceptable excipients can be selected from one or more in mannitol, dextran, cyclodextrin, the soluble starch, preferred mannitol.Weight ratio between doxofylline and the solubilizing agent can be 0.5-10: 1, be preferably 1-2: 1; The preferred group of injection of the present invention becomes active component doxofylline and solubilizing agent citric acid, and wherein the weight ratio of doxofylline and citric acid is 1-3: 1, be preferably 1.4: 1.Weight ratio between doxofylline and the excipient can be 1: 0.5-5 is preferably 1: 0.5-2; Wherein the weight ratio of doxofylline and mannitol is 1: 0.5-1.5 is preferably 1: 1.17.
The specification of injection of the present invention is for containing reactive compound doxofylline 1-1000mg, and preferably containing the reactive compound doxofylline is 50mg, 100mg, 150mg, 200mg or 300mg.
Freezing-dried powder injection of the present invention prepares in order to the below method:
The preparation method of lyophilized powder injection of doxofylline of the present invention comprises the following steps:
A, weighing:, take by weighing supplementary material according to the prescription ratio according to inventory;
B, dosing process: citric acid, mannitol, the doxofylline that takes by weighing be added in an amount of hot water dissolve; Be adjusted to 4/5 of cumulative volume with water for injection, measure the solution pH value, and regulate pH value to 2.0-3.0, add to the full amount of water for injection after pH value is qualified with citric acid or sodium hydroxide solution;
C, depyrogenation
The active carbon of adding 0.5% mixes and stirs, and filters decarburization;
D, fine straining
Decarburization finishes, and medicinal liquid is through 0.22 μ m microporous filter membrane fine straining;
E, packing
Determine loading amount according to the intermediate measurement result, use the control cillin bottle;
F, lyophilization
Under cryogenic vacuum, carry out lyophilization.
To prepare 1000 lyophilized powder injection of doxofylline is example, and the weight of material scope that preparation doxofylline lyophilized injectable powder uses is:
Doxofylline 10-300g
Citric acid (or other solubilizing agents) 10-250mg
Mannitol (or other excipient) 50-400mg
Add the injection water to 3500ml
Make 1000 of dried frozen aquatic productses altogether
Concrete steps are as follows:
Preparating liquid
Take by weighing injection doxofylline raw material (doxofylline content must not be less than 98.5%, contains heavy metal and must not cross 15/1000000ths), citric acid, mannitol are added in an amount of injection hot water, make its dissolving; Add the injection water to 2800ml.Measure the pH value of solution, and regulate pH value to 2.0-3.0, add the injection water after pH value is qualified to prescribed volume 3500ml with citric acid or sodium hydroxide solution.
Depyrogenation:
Add injection in the above-mentioned medicinal liquid with active carbon (activated carbon dosage is the 0.3-0.5% of doxofylline raw material weight), filter, collect filtrate.
Degerming:
Above-mentioned filtrate is carried out the malleation degerming by aseptic manipulation with germ tight filter filter, pressure with 0.22 μ microporous filter membrane, should carry out the bubbling point test earlier before filtering below 0.1Mpa, and the filtrate sample presentation carries out pyrogen test and semi-finished product content is checked packing then.Fill: carry out fill, the false add plug 100 grades of cleanliness factor ultra-clean workplaces.
Lyophilizing:
In special-purpose freeze drying box, at pre-freeze 2-4 below-45 ℃ hour, per hour 3-4 ℃ of-45 ℃-0 ℃, programming rate, distil under the 13.33Pa vacuum then, remove after 90% at free moisture, heat drying, with per hour 4-5 ℃ of intensification (maximum temperature must not above 30 ℃), treat that temperature rises to 30 ℃, insulation was observed 4-5 hour, promptly can be considered lyophilizing and finish, jump a queue entirely automatically in the freeze drying box.
About 24 hours of lyophilizing required time, preparation appearance character are the loose block of off-white color, and sample redissolves good, and clarity is qualified, and technical process is easy to operate.
Seal: the control cillin bottle takes out from freeze drying box in batches, adds aluminium lid and gets final product.
Injection of the present invention joins during use among 5% glucose injection or the normal saline solution 100ml, slowly intravenous drip, once a day.
Injection of the present invention has good stability, and curative effect is good, characteristics easy to use, and have good stability.
The beneficial effect that uses solubilizing agents such as citric acid among the present invention below is described by experiment.
The dissolubility of doxofylline in water is bad, for increasing the dissolubility of principal agent in water, and can make its 4ml with the water of lower volume in the dissolving 150mg doxofylline, the water excess of sample dissolution makes freeze-drying time increase, cost raises, so must mainly study the influence of solubilizing agent to the principal agent dissolubility in the prescription screening process.
1, selects the organic acid solubilizing agent
Methanesulfonic acid, maleic acid, glycine, citric acid, arginine, serine, threonine, glutamic acid.Solubilizing agent and principal agent were with mol ratio 1: 1, and 1.5: 1,2: 1 ratio was tested.Raw materials weighing and organic acid, preparation principal agent specification is the solution of 4ml: 0.15g, heating for dissolving is cooled to room temperature gradually, observes.
Organic acid solubilising result
| Organic acid | Solubilising result (solubilizing agent and principal agent mol ratio) | ||
| 1∶1 | 1.5∶1 | 2∶1 | |
| Methanesulfonic acid | Crystallize | Dissolving | Dissolving |
| Maleic acid | Crystallize | Crystallize | Dissolving back crystallize |
| Glycine | Crystallize | Dissolving | Dissolving |
| Citric acid | Dissolving | Dissolving | Dissolving |
| Arginine | Crystallize | Crystallize | Dissolving |
| Serine | Crystallize | Dissolving back crystallize | Dissolving back crystallize |
| Threonine | Crystallize | Crystallize | Dissolving back crystallize |
| Glutamic acid | Crystallize | Crystallize | Dissolving back crystallize |
Result of the test: methanesulfonic acid, maleic acid, glycine, citric acid, arginine, serine, threonine, glutamic acid all have solubilizing effect in various degree, but citric acid soln is best, and various mol ratios are all dissolved, and crystallize does not appear in placement a period of time yet.Preferably citric acid.
2, polyethylene glycols solubilizing agent
Select Macrogol 4000, polyethylene glycol 6000, solubilizing agent and principal agent are tested with 1: 1,1: 2 ratio of mass ratio.Raw materials weighing and solubilizing agent, preparation principal agent specification is the solution of 4ml:0.15g, heating for dissolving is cooled to room temperature gradually, static observation.
Polyethylene glycols solubilising result
| Organic acid | Macrogol 4000 | Polyethylene glycol 6000 |
| The solubilising result | Dissolving back crystallize | Dissolving back crystallize |
Result of the test: Macrogol 4000, polyethylene glycol 6000 all have solubilizing effect, separate out crystallization.
The solubilizing agent result of the test is: methanesulfonic acid, maleic acid, glycine, citric acid, arginine, serine, threonine, glutamic acid, Macrogol 4000, polyethylene glycol 6000 solution all have solubilizing effect in various degree, but the best citric acid solubilizing effect of citric acid soln is best, is glycine secondly.
Further the citric acid optimum amount is determined in experimental study.
Experimental study is reaching on the basis of solubilizing effect the minimum amount of citric acid.Relatively citric acid and principal agent are determined the citric acid consumption with the principal agent solubilising result of 1: 1,1: 0.5,0.5: 1 ratio of mol ratio.
Preparation principal agent specification is the solution of 4ml:0.15g, heating for dissolving, static observation.
Citric acid and principal agent mol ratio 1: 0.5, the solution of 1: 1 ratio be crystallize not all, citric acid and principal agent mol ratio 1: 0.5; The solution crystallize.
Consider cost and solubilising result, the usage ratio of citric acid and principal agent is preferably among the present invention: citric acid and principal agent mol ratio 1: 1.
Further study the influence of the variation of solution pH value among the present invention to the principal agent dissolubility.
Get the solution of the solution (mol ratio 1: 1) of above-mentioned citric acid and principal agent, measuring pH value is 2.47.Solution is divided into several parts.Regulate principal agent solution with sodium hydroxide solution, solution is separated out crystallization at once when pH value reaches 3.2, so the present invention determines that the pH value of solution will be controlled at below 3.0.Regulate principal agent solution with citric acid soln, solution is not separated out crystallization when pH value reaches 1.0, and according to producing practical situation, the pH value of preferred solution of the present invention will be controlled at more than 2.0.
At definite citric acid is on the principal agent solubilizing agent experimental basis, study acceptable excipient, excipient can be selected from one or more in mannitol, dextran, cyclodextrin, the soluble starch, preferred mannitol, with excipient mannitol is the consumption that example begins to screen excipient, and consumption is determined according to the outward appearance of formulation samples.
The screening of excipient consumption
| Supplementary material | Prescription 1 | Prescription 2 | Prescription 3 |
| Doxofylline | 150g | 150g | 150g |
| Citric acid | 108g | 108g | 108g |
| Mannitol | 87.5g | 175g | 245g |
| Water for injection | To 3.5L | To 3.5L | To 3.5L |
| Make | 1000 | ||
Take by weighing mannitol, citric acid, doxofylline according to prescription, add in an amount of hot water and dissolve.Principal agent dissolving back solution is adjusted to 4/5 of cumulative volume with water for injection, and regulates pH value to 2.0-3.0, and water for injection adds to full dose.Fill, lyophilizing.
Result of the test:
Depression appears in 1 sample of writing out a prescription, and is not full, proves to lack excipient;
The 2 formulation samples outward appearances of writing out a prescription are the off-white color block;
The 3 formulation samples outward appearances of writing out a prescription are the off-white color block;
Consider the regulation of cost and lyophilized formulations quality standard appearance character, the ratio of optimizing prescriptions 2 of the present invention.
The present invention can adopt with 0.9% sodium chloride solution 100ml or the dissolving of 5% glucose solution, and intravenous drip, is used for the treatment of asthma, and said preparation is stable in 8 hours, can be used for patient very easily.
Get 1 of formulation samples of the present invention,, place with 0.9% sodium chloride solution 100ml, 5% glucose solution 100ml dissolving.Respectively at the 0th, 4,8 hour mensuration, with comparison in 0 hour.The results are shown in following table.
The compatibility experimental result
| Solution | Time | PH value | Content % | Clarity | Related substance % |
| 0.9% sodium chloride | 0 hour 4 hours 8 hours | 4.42 4.38 4.40 | 100.8 100.7 102.1 | Qualified qualified | 0.47 0.41 0.43 |
| 5% glucose | 0 hour 4 hours 8 hours | 5.32 5.36 5.35 | 98.2 100.2 102.3 | Qualified qualified | 0.54 0.55 0.51 |
Result of the test shows that significant change did not take place for the pH value of solution, content, clarity and related substance when injection doxofylline compatibility used, and shows that preparation can keep stable in use.
For further studying the stability of injection doxofylline of the present invention, it has been carried out influence factor's test, we press preparation prescription 2 processed samples, carry out influence factor's test.
1, hot test
Get this product and place 60 ℃ of conditions, placed 10 days, in 0,5,10 day working sample, comparative test data.The results are shown in following table.
Injection doxofylline high temperature is investigated the result
| Time | Appearance character | PH value | Moisture | Content % | Clarity | Related substance % |
| 0 day | The off-white color block that loosens | 2.48 | 1.78 | 100.0 | Qualified | 0.38 |
| 5 days | The off-white color block that loosens | 2.49 | 1.64 | 99.1 | Qualified | 0.23 |
| 10 days | The off-white color block that loosens | 2.46 | 1.72 | 98.1 | Qualified | 0.37 |
Conclusion: the appearance character of injection doxofylline of the present invention under 60 ℃ of conditions of high temperature, content, related substance, pH value, the basic no change of clarity.
2, high wet test
Get this product and place humidity 95% ± 5 condition, placed 10 days, in 0,5,10 day working sample, comparative test data.The results are shown in following table.
Injection doxofylline high humidity is investigated the result
| Time | Appearance character | PH value | Moisture | Content % | Clarity | Related substance % |
| 0 day | The off-white color block that loosens | 2.48 | 1.78 | 100.0 | Qualified | 0.38 |
| 5 days | The off-white color block that loosens | 2.47 | 1.73 | 99.9 | Qualified | 0.36 |
| 10 days | The off-white color block that loosens | 2.45 | 1.67 | 99.3 | Qualified | 0.44 |
Conclusion: the appearance character of injection doxofylline of the present invention under 60 ℃ of conditions, content, related substance, pH value, the basic no change of clarity.
3, strong illumination test
Get this product and place under light intensity 4500Lx ± 500Lx, placed 10 days, in 0,5,10 day working sample, comparative test data.Measurement result sees the following form.
Injection doxofylline high light is investigated the result
| Time | Appearance character | PH value | Moisture | Content % | Clarity | Related substance % |
| 0 day | The off-white color block that loosens | 2.48 | 1.78 | 100.0 | Qualified | 0.38 |
| 5 days | The off-white color block that loosens | 2.49 | 1.78 | 100.9 | Qualified | 0.25 |
| 10 days | The off-white color block that loosens | 2.50 | 1.76 | 100.7 | Qualified | 0.42 |
Conclusion: injection doxofylline of the present invention is at high light (appearance character under 4500 ± 500LX) conditions, pH value, clarity, content, the basic no change of related substance.
For further setting forth the stability of injection doxofylline of the present invention, the stability of this product is investigated.Carried out the research of accelerated test.
This product is pressed commercially available back, place under 40 ± 2 ℃ of temperature, RH75% ± 5% condition, placed 6 months, respectively at 1st month, 2 months, 3 months, 6 samplings at the end of month once at duration of test, detect by stable high spot reviews project, and with 0 month testing result relatively.
Accelerated test result
| Lot number | Time | Appearance character | Acidity | Moisture % | Clarity | Related substance % | Content % |
| 20000901 | 0 month | The off-white color block that loosens | 2.43 | 1.84 | Clear and bright | 0.38 | 102.7 |
| January | The off-white color block that loosens | 2.55 | 1.85 | Clear and bright | 0.49 | 100.4 | |
| February | The off-white color block that loosens | 2.47 | 1.76 | Clear and bright | 0.36 | 100.1 | |
| March | The off-white color block that loosens | 2.53 | 1.79 | Clear and bright | 0.37 | 100.1 | |
| June | The off-white color block that loosens | 2.49 | 1.82 | Clear and bright | 0.37 | 100.3 | |
| 20000902 | 0 month | The off-white color block that loosens | 2.51 | 1.96 | Clear and bright | 0.43 | 99.5 |
| January | The off-white color block that loosens | 2.55 | 1.89 | Clear and bright | 0.48 | 100.8 | |
| February | The off-white color block that loosens | 2.52 | 1.81 | Clear and bright | 0.26 | 100.0 | |
| March | The off-white color block that loosens | 2.61 | 1.82 | Clear and bright | 0.53 | 99.9 | |
| June | The off-white color block that loosens | 2.48 | 1.75 | Clear and bright | 0.45 | 100.1 | |
| 20000903 | 0 month | The off-white color block that loosens | 2.52 | 1.77 | Clear and bright | 0.23 | 101.3 |
| January | The off-white color block that loosens | 2.61 | 1.82 | Clear and bright | 0.44 | 100.5 | |
| February | The off-white color block that loosens | 2.52 | 2.03 | Clear and bright | 0.32 | 100.1 | |
| March | The off-white color block that loosens | 2.59 | 1.84 | Clear and bright | 0.49 | 99.4 | |
| June | The off-white color block that loosens | 2.48 | 2.01 | Clear and bright | 0.51 | 102.4 |
Experimental result: injection doxofylline of the present invention is placed under the accelerated tests condition and was stablized the basic no change of content and related substance in 6 months.
For further setting forth the stability of injection doxofylline of the present invention, the stability of this product is investigated.Carried out long-term stable experiment.This product is pressed commercially available back, under 25 ± 2 ℃ of temperature, RH60% ± 10% condition, placed 6 months, detect respectively at 12nd month, 24 samplings at the end of month at duration of test.
Long-term test results
| Lot number | Time | Appearance character | Acidity | Moisture % | Clarity | Related substance % | Content % |
| 20000901 | 0 month | The off-white color block that loosens | 2.43 | 1.84 | Clear and bright | 0.38 | 102.7 |
| December | The off-white color block that loosens | 2.46 | 1.93 | Clear and bright | 0.31 | 101.9 | |
| 24 months | The off-white color block that loosens | 2.42 | 1.69 | Clear and bright | 0.53 | 99.0 | |
| 20000902 | 0 month | The off-white color block that loosens | 2.51 | 1.96 | Clear and bright | 0.43 | 99.5 |
| December | The off-white color block that loosens | 2.59 | 1.92 | Clear and bright | 0.29 | 100.6 | |
| 24 months | The off-white color block that loosens | 2.47 | 1.76 | Clear and bright | 0.50 | 99.1 | |
| 20000903 | 0 month | The off-white color block that loosens | 2.52 | 1.77 | Clear and bright | 0.23 | 101.3 |
| December | The off-white color block that loosens | 2.56 | 1.82 | Clear and bright | 0.41 | 100.6 | |
| 24 months | The off-white color block that loosens | 2.59 | 1.81 | Clear and bright | 0.48 | 101.0 |
Experimental result: injection doxofylline of the present invention is placed under the long-term experiment condition and was stablized the basic no change of content and related substance in 24 months.
Injection doxofylline good stability of the present invention, easy to use.
Further specify the present invention below by embodiment.It should be understood that embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.Except as otherwise noted, the percent among the present invention is percetage by weight.
Embodiment 1: the preparation lyophilized powder injection of doxofylline
Doxofylline 150g
Citric acid 108g
Mannitol 175g
Water for injection is to 3.5L
Make 1000
Preparation technology:
Preparating liquid:
Take by weighing injection doxofylline raw material (doxofylline content must not be less than 98.5%, contains heavy metal and must not cross 15/1000000ths), citric acid, mannitol are added in an amount of aseptic apyrogeneity injection hot water, make its dissolving; Add the injection water to 2800ml.Measure the pH value of solution, and regulate pH value to 2.0-3.0, add the injection water after pH value is qualified to prescribed volume 3500ml with citric acid or sodium hydroxide solution.Depyrogenation:
Add injection in the above-mentioned medicinal liquid with active carbon (activated carbon dosage is the 0.3-0.5% of doxofylline raw material weight), filter, collect filtrate.
Degerming:
Above-mentioned filtrate is carried out the malleation degerming by aseptic manipulation with germ tight filter filter, pressure with 0.22 μ microporous filter membrane, should carry out the bubbling point test earlier before filtering below 0.1Mpa, and the filtrate sample presentation carries out pyrogen test and semi-finished product content is checked packing then.Fill: carry out fill, the false add plug 100 grades of cleanliness factor ultra-clean workplaces.
Lyophilizing:
In special-purpose freeze drying box, at pre-freeze 2-4 below-45 ℃ hour, per hour 3-4 ℃ of-45 ℃-0 ℃, programming rate, distil under the 13.33Pa vacuum then, remove after 90% at free moisture, heat drying, with per hour 4-5 ℃ of intensification (maximum temperature must not above 30 ℃), treat that temperature rises to 30 ℃, insulation was observed 4-5 hour, promptly can be considered lyophilizing and finish, jump a queue entirely automatically in the freeze drying box.
Seal: the control cillin bottle takes out from freeze drying box in batches, adds aluminium lid and gets final product.
Embodiment 2: the preparation lyophilized powder injection of doxofylline
Doxofylline 150g
Citric acid 150g
Mannitol 200g
Water for injection is to 4.0L
Make 1000
Preparation method is except that the amount of the adjuvant that adds and water for injection is different, and other are with embodiment 1
Embodiment 3: the preparation lyophilized powder injection of doxofylline
Doxofylline 150g
Glycine 150g
Mannitol 175g
Water for injection is to 3.5L
Make 1000
Preparation method is except that the varying in weight of the adjuvant that adds, and other are with embodiment 1
Embodiment 4: the preparation lyophilized powder injection of doxofylline
Doxofylline 150g
Citric acid 108g
Cyclodextrin 145g
Water for injection is to 3.5L
Make 1000
Preparation method is except that the adjuvant difference that adds, and other are with embodiment 1
Embodiment 5: the preparation lyophilized powder injection of doxofylline
Doxofylline 150g
Glycine 110g
Dextran 40 175g
Water for injection is to 3.5L
Make 1000
Preparation method is except that the adjuvant difference that adds, and other are with embodiment 1
Claims (8)
1. lyophilized powder injection of doxofylline for the treatment of asthma, it contains as the doxofylline chemical compound of active component and agent of medicine acceptable solubilizing and pharmaceutically-acceptable excipients composition, and the agent of wherein said medicine acceptable solubilizing can be selected from one or more in methanesulfonic acid, maleic acid, glycine, citric acid, arginine, serine, threonine, glutamic acid, Macrogol 4000, the polyethylene glycol 6000; Wherein said pharmaceutically-acceptable excipients can be selected from one or more in mannitol, dextran, cyclodextrin, the soluble starch, weight ratio between doxofylline and the solubilizing agent can be 0.5-10: 1, and the weight ratio between doxofylline and the excipient can be 1: 0.5-5.
2. freezing-dried powder injection according to claim 1, its Chinese medicine acceptable solubilizing agent is a citric acid; Wherein pharmaceutically-acceptable excipients is a mannitol.
3. freezing-dried powder injection according to claim 2, wherein the weight ratio of doxofylline and citric acid is 0.5-3: 1; Wherein the weight ratio of doxofylline and mannitol is 1: 0.5-1.5.
4. freezing-dried powder injection according to claim 3, wherein the weight ratio of doxofylline and citric acid is 1.4: 1; Wherein the weight ratio of doxofylline and mannitol is 1: 1.17.
5. freezing-dried powder injection according to claim 4, wherein the content specification of doxofylline chemical compound is 1-1000mg.
6. freezing-dried powder injection according to claim 5, wherein the content specification of doxofylline chemical compound is 50mg, 100mg, 150mg, 200mg or 300mg.
7. freezing-dried powder injection according to claim 6, wherein every injection contains the 150mg doxofylline, 108mg citric acid, 175mg mannitol.
8. according to the preparation method of the injection of one of claim 1-7, comprise the following steps:
A, weighing:, take by weighing supplementary material according to the prescription ratio according to inventory;
B, dosing process: citric acid, mannitol, the doxofylline that takes by weighing be added in an amount of hot water dissolve; Be adjusted to 4/5 of cumulative volume with water for injection, measure the solution pH value, and regulate pH value to 2.0-3.0, add to the full amount of water for injection after pH value is qualified with citric acid or sodium hydroxide solution;
C, depyrogenation
The active carbon of adding 0.5% mixes and stirs, and filters decarburization;
D, fine straining
Decarburization finishes, and medicinal liquid is through 0.22 μ m microporous filter membrane fine straining;
E, packing
Determine loading amount according to the intermediate measurement result, use the control cillin bottle;
F, lyophilization
Under cryogenic vacuum, carry out lyophilization.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2005100711184A CN1864684A (en) | 2005-05-20 | 2005-05-20 | Lyophilized powder injection of doxofylline and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2005100711184A CN1864684A (en) | 2005-05-20 | 2005-05-20 | Lyophilized powder injection of doxofylline and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
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| CN1864684A true CN1864684A (en) | 2006-11-22 |
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| CNA2005100711184A Pending CN1864684A (en) | 2005-05-20 | 2005-05-20 | Lyophilized powder injection of doxofylline and preparation method thereof |
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| CN (1) | CN1864684A (en) |
Cited By (11)
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| CN101953803A (en) * | 2010-09-02 | 2011-01-26 | 天津市铭泰医药科技有限公司 | Preparation method of small-volume doxofylline freeze-dried powder injection as well as product and device thereof |
| CN102133199A (en) * | 2011-03-15 | 2011-07-27 | 西南药业股份有限公司 | Doxofylline lyophilized preparation for injection and preparation method thereof |
| CN101544683B (en) * | 2008-03-28 | 2012-11-14 | 上海莱士血液制品股份有限公司 | Method and substance for keeping fibrinogen activity in thermal treatment |
| CN102846560A (en) * | 2012-09-25 | 2013-01-02 | 罗诚 | Medicinal composition containing doxofylline compound and preparation method thereof |
| CN104173298A (en) * | 2014-08-21 | 2014-12-03 | 四川兴科蓉药业有限责任公司 | Lincomycin freeze-dried injection and preparation method thereof |
| CN105250227A (en) * | 2015-09-30 | 2016-01-20 | 合肥华方医药科技有限公司 | Citric acid caffeine freeze-dried powder and preparation method thereof |
| CN106038495A (en) * | 2016-07-11 | 2016-10-26 | 山西普德药业有限公司 | Injection doxofylline freeze-dried powder injection and preparing method thereof |
| CN106943358A (en) * | 2016-01-06 | 2017-07-14 | 山东新时代药业有限公司 | Fosaprepitant dimeglumine freeze-dried powder and preparation method thereof |
| CN107184557A (en) * | 2017-07-31 | 2017-09-22 | 天津梅花生物医药科技有限公司 | A kind of doxofylline injection |
| CN109833293A (en) * | 2019-02-25 | 2019-06-04 | 浙江长典医药有限公司 | A kind of preparation method of Doxofylline injection |
| CN114272210A (en) * | 2021-12-29 | 2022-04-05 | 维生原(厦门)生物科技有限公司 | Doxofylline injection preparation and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101544683B (en) * | 2008-03-28 | 2012-11-14 | 上海莱士血液制品股份有限公司 | Method and substance for keeping fibrinogen activity in thermal treatment |
| CN101953803A (en) * | 2010-09-02 | 2011-01-26 | 天津市铭泰医药科技有限公司 | Preparation method of small-volume doxofylline freeze-dried powder injection as well as product and device thereof |
| CN102133199A (en) * | 2011-03-15 | 2011-07-27 | 西南药业股份有限公司 | Doxofylline lyophilized preparation for injection and preparation method thereof |
| CN102846560A (en) * | 2012-09-25 | 2013-01-02 | 罗诚 | Medicinal composition containing doxofylline compound and preparation method thereof |
| CN102846560B (en) * | 2012-09-25 | 2014-11-05 | 罗诚 | Medicinal composition containing doxofylline compound and preparation method thereof |
| CN104173298A (en) * | 2014-08-21 | 2014-12-03 | 四川兴科蓉药业有限责任公司 | Lincomycin freeze-dried injection and preparation method thereof |
| CN104173298B (en) * | 2014-08-21 | 2015-12-30 | 四川兴科蓉药业有限责任公司 | Lincomycin freeze-dried powder and preparation method thereof |
| CN105250227A (en) * | 2015-09-30 | 2016-01-20 | 合肥华方医药科技有限公司 | Citric acid caffeine freeze-dried powder and preparation method thereof |
| CN106943358B (en) * | 2016-01-06 | 2021-08-31 | 河南省肿瘤医院 | Fosaprepitant dimeglumine freeze-dried powder injection and preparation method thereof |
| CN106943358A (en) * | 2016-01-06 | 2017-07-14 | 山东新时代药业有限公司 | Fosaprepitant dimeglumine freeze-dried powder and preparation method thereof |
| CN106038495A (en) * | 2016-07-11 | 2016-10-26 | 山西普德药业有限公司 | Injection doxofylline freeze-dried powder injection and preparing method thereof |
| CN107184557B (en) * | 2017-07-31 | 2019-10-01 | 天津梅花生物医药科技有限公司 | A kind of doxofylline injection |
| CN107184557A (en) * | 2017-07-31 | 2017-09-22 | 天津梅花生物医药科技有限公司 | A kind of doxofylline injection |
| CN109833293A (en) * | 2019-02-25 | 2019-06-04 | 浙江长典医药有限公司 | A kind of preparation method of Doxofylline injection |
| CN109833293B (en) * | 2019-02-25 | 2021-12-21 | 浙江长典药物技术开发有限公司 | Preparation method of doxofylline injection |
| CN114272210A (en) * | 2021-12-29 | 2022-04-05 | 维生原(厦门)生物科技有限公司 | Doxofylline injection preparation and preparation method thereof |
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