CN1903180A - Freeze-dried powder injection of frusemide and its prepn. method - Google Patents
Freeze-dried powder injection of frusemide and its prepn. method Download PDFInfo
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Abstract
A powder injection of frusemide is prepared from frusemide, mannitol or saccharide, NaOH (or meglumine) solution and hydrochloric acid through freeze drying. Its preparing process is also disclosed.
Description
Technical field
The present invention relates to potent diuretic lyophilized formulations and preparation method.
Background technology
Diuretic is that a class acts on kidney, the urinary function, the power and water that influence kidney separated the matter process thereby causes the medicine of urine quantitative changeization.Be divided into high, medium and low three classes according to its diuresis function, furosemide belongs to high-ceiling diuretic; All belong to sulfonamides class diuretic with thiazide diuretic.This product has been the one line medication of diuresis class since the seventies always, and sales volume is very big, is a diuretic that clinical efficacy is definite, untoward reaction is clear and definite.
Furosemide (furosemide is a kind of potent diuretic FD), mainly suppresses the heavily absorption of renal tubules medullary loop ascending branch portion to Na+, Cl-, and the performance diuresis.Because a large amount of Na+ arrives Distal convoluted tubule and collecting tubule, the Na+-K+ exchange is active, increases the discharge of urine K+, causes losing of K+.In addition, the expansible kidney blood vessel of this product, renal blood flow increasing is adjusted blood flow distribution in the kidney.Renal tubules capable of blocking increases the discharge of Ca2+, Mg2+ to the heavily absorption of Ca2+, Mg2+, reduces the discharge of uric acid.
This product oral absorption is rapid but incomplete.Bioavailability about 50～75%; Vd0.1L/kg; Plasma protein binding rate is up to 95%～99%; T1/2 is 30～70 minutes (being reported as 1.5～3.5 hours in addition); Renal insufficiency patient's t1/2 can be extended for 10 hours; About 10% metabolism is in vivo mainly got rid of with original shape through kidney; Take care, during renal insufficiency, then remove through kidney, as coming across in the feces through bile based on non-; Plasma treatment concentration is about 0.2～0.3 μ g/ml (0.6～0.9 μ mol/L).But plasma drug level and diuresis effect relation are non-constant, because of significantly individual variation is arranged.This product nothing in tissue obviously stores after 24 hours.
Summary of the invention
Furosemide inj is for many years the kind of going on the market, and its standard is by " Chinese pharmacopoeia two ones of versions in 2000 are recorded.Because this injection is aqueous injection, transportation is inconvenient, in the storage than solid-state stability difference.
The inventor is very big according to the clinical consumption of existing furosemide inj, but ampoule bottle breakage in the process of circulation is more serious, and furosemide inj is stable not ideal enough, so the injectable powder that the inventor researchs and develops it is to address the above problem.For the demand that satisfies clinical treatment and from market prospect so exploitation furosemide freeze-dried powder.
According to the actual requirement of domestic dosage form with kind, specification and the clinical use of going on the market, we think that furosemide inj is changed agent makes freeze-dried powder, and are not only safe and effective, and good stability, and transportation, storage all make things convenient for.
The inventor adopts multiple excipient and furosemide to test, excipient such as mannitol, lactose, lactose and mannitol equal amount of mixture, glucose, fructose, glucose and fructose equal amount of mixture, Dextran 40 (having another name called glucosan); Prescription is furosemide 20g, mannitol, lactose, lactose and mannitol equal amount of mixture and Dextran 40 (having another name called glucosan), 40-400g, glucose, fructose, glucose and fructose equal amount of mixture 40-200g, an amount of at hydro-oxidation sodium, hydrochloric acid is an amount of, and water for injection adds to 2000ml, make 1000 bottles altogether, every bottle contains furosemide 20mg.
The inventor optimizes furosemide freeze-dried powder agent prescription through further studying: furosemide 20g, and mannitol 80g, sodium hydroxide is an amount of, and hydrochloric acid is an amount of, and water for injection adds to 2000ml, makes 1000 bottles altogether, and every bottle contains furosemide 20mg.
Lyophilized injectable powder preparation method: 1, get formula ratio furosemide crude drug, it is an amount of to add 0.4%NaOH solution, stirring makes dissolving, constant temperature in 40 ℃ of water-baths, dripping hydrochloric acid solution is regulated pH value between 8.5-9.5 when stirring, put coldly, add formula ratio mannitol or lactose, lactose and mannitol equal amount of mixture, glucose, fructose, glucose and fructose equal amount of mixture, Dextran 40 (having another name called glucosan); After the stirring and dissolving, add to the full amount of water for injection.2, with above-mentioned solution coarse filtration, add the active carbon of 0.1% (w/v), stirred 15 minutes, filter, remove active carbon.3, with above-mentioned filtrate aseptic filtration, filtrate is surveyed its pH value should be in the 8.5-9.5 scope.4, filtrate censorship qualified after, according to crude drug cubage loading amount.5, aseptic subpackagedly go into the aseptic glass tube vial of 10ml, every bottle of about 2ml of fill.6, butyl rubber plug half lid in putting in the freeze dryer, freezing, drying and moulding.7, close plug, gland also adds the bundle aluminium lid.8, sampling observation qualified after, label packing warehouse-in.
Description of drawings
Fig. 1 process chart
Fig. 2 furosemide eutectic point curve chart
Fig. 3 freeze-drying curve figure
Fig. 4 sucting wet curve figure
The specific embodiment
The inventor further describes the present invention in detail by embodiment.
The preparation method 1 of embodiment 1 lyophilized formulations
Prescription:
Furosemide 20g
Mannitol 80g
Sodium hydroxide is an amount of
Hydrochloric acid is an amount of
Water for injection 2000ml
Make 1000 bottles altogether, every bottle contains furosemide 20mg.
Preparation method:
1, get formula ratio furosemide crude drug, it is an amount of to add 0.4%NaOH solution, stirs to make dissolving, constant temperature in 40 ℃ of water-baths, dripping hydrochloric acid solution is regulated pH value between 8.5-9.5 in the time of stirring, puts cold, after adding formula ratio mannitol stirring and dissolving, add to the full amount of water for injection.
2, with above-mentioned solution coarse filtration, add the active carbon of 0.1% (w/v), stirred 15 minutes, filter, remove active carbon.
3, with above-mentioned filtrate aseptic filtration, filtrate is surveyed its pH value should be in the 8.5-9.5 scope.
4, filtrate censorship qualified after, according to crude drug cubage loading amount.
5, aseptic subpackagedly go into the aseptic glass tube vial of 10ml, every bottle of about 2ml of fill.
6, butyl rubber plug half lid in putting in the freeze dryer, freezing, drying and moulding.
7, close plug, gland also adds the bundle aluminium lid.
8, sampling observation qualified after, label packing warehouse-in.
Process chart is seen Fig. 1
The preparation method 2 of embodiment 2 lyophilized formulations
Prescription:
Furosemide 20g
Lactose 40-400g
Sodium hydroxide is an amount of
Hydrochloric acid is an amount of
Water for injection 2000ml
Make 1000 bottles altogether, every bottle contains furosemide 20mg.
Preparation method:
1, get formula ratio furosemide crude drug, it is an amount of to add 0.4%NaOH solution, stirs to make dissolving, constant temperature in 40 ℃ of water-baths, dripping hydrochloric acid solution is regulated pH value between 8.5-9.5 in the time of stirring, puts cold, after adding formula ratio lactose stirring and dissolving, add to the full amount of water for injection.
The subsequent preparation method is with the method for embodiment 1.
The preparation method 3 of embodiment 3 lyophilized formulations
Prescription:
Furosemide 20g
Lactose and mannitol equal amount of mixture 40-400g
Sodium hydroxide is an amount of
Hydrochloric acid is an amount of
Water for injection 2000ml
Make 1000 bottles altogether, every bottle contains furosemide 20mg.
Preparation method:
1, gets formula ratio furosemide crude drug, it is an amount of to add 0.4%NaOH solution, stirring makes dissolving, constant temperature in 40 ℃ of water-baths, dripping hydrochloric acid solution is regulated pH value between 8.5-9.5 when stirring, put cold, add formula ratio lactose and mannitol equal amount of mixture stirring and dissolving after, add to the full amount of water for injection.
The subsequent preparation method is with the method for embodiment 1.
The preparation method 4 of embodiment 4 lyophilized formulations
Prescription:
Furosemide 20g
Glucose 40-200g
Sodium hydroxide is an amount of
Hydrochloric acid is an amount of
Water for injection 2000ml
Make 1000 bottles altogether, every bottle contains furosemide 20mg.
Preparation method:
1, get formula ratio furosemide crude drug, it is an amount of to add 0.4%NaOH solution, stirs to make dissolving, constant temperature in 40 ℃ of water-baths, dripping hydrochloric acid solution is regulated pH value between 8.5-9.5 in the time of stirring, puts cold, after adding formula ratio glucose stirring and dissolving, add to the full amount of water for injection.
The subsequent preparation method is with the method for embodiment 1.
The preparation method 5 of embodiment 5 lyophilized formulations
Prescription:
Furosemide 20g
Fructose 40-200g
Sodium hydroxide is an amount of
Hydrochloric acid is an amount of
Water for injection 2000ml
Make 1000 bottles altogether, every bottle contains furosemide 20mg.
Preparation method:
1, get formula ratio furosemide crude drug, it is an amount of to add 0.4%NaOH solution, stirs to make dissolving, constant temperature in 40 ℃ of water-baths, dripping hydrochloric acid solution is regulated pH value between 8.5-9.5 in the time of stirring, puts cold, after adding formula ratio fructose stirring and dissolving, add to the full amount of water for injection.
The subsequent preparation method is with the method for embodiment 1.
The preparation method 6 of embodiment 6 lyophilized formulations
Prescription:
Furosemide 20g
Glucose and fructose equal amount of mixture 40-200g
Sodium hydroxide is an amount of
Hydrochloric acid is an amount of
Water for injection 2000ml
Make 1000 bottles altogether, every bottle contains furosemide 20mg.
Preparation method:
1, gets formula ratio furosemide crude drug, it is an amount of to add 0.4%NaOH solution, stirring makes dissolving, constant temperature in 40 ℃ of water-baths, dripping hydrochloric acid solution is regulated pH value between 8.5-9.5 when stirring, put cold, add formula ratio glucose and fructose equal amount of mixture stirring and dissolving after, add to the full amount of water for injection.
The subsequent preparation method is with the method for embodiment 1.
The preparation method 7 of embodiment 7 lyophilized formulations
Prescription:
Furosemide 20g
Dextran 40 (having another name called glucosan) 40-400g
Sodium hydroxide is an amount of
Hydrochloric acid is an amount of
Water for injection 2000ml
Make 1000 bottles altogether, every bottle contains furosemide 20mg.
Preparation method:
1, gets formula ratio furosemide crude drug, it is an amount of to add 0.4%NaOH solution, stirring makes dissolving, constant temperature in 40 ℃ of water-baths, dripping hydrochloric acid solution is regulated pH value between 8.5-9.5 when stirring, put cold, add formula ratio Dextran 40 (having another name called glucosan) stirring and dissolving after, add to the full amount of water for injection.
The subsequent preparation method is with the method for embodiment 1.
Experimental example 1 prescription screening
The pH span of control:
Furosemide dissolves in acetone, and is molten in the ethanol part omitted, insoluble in water.By the discrimination test of its crude drug as can be known, furosemide is easily molten in 0.4% sodium hydroxide solution.And sodium hydroxide alkalescence is strong excessively, can cause the zest of injection, so when preparation injection furosemide solution, it is particularly important to select suitable pH regulator agent to regulate suitable pH value.According to the requirement of the relevant pH value of furosemide inj, the pH value of this product should be controlled in the 8.5-9.5 scope.
The screening of pH regulator agent:
Select multiple pH regulator agent respectively: NaOH, NaHCO3, meglumine are that measurement index is selected suitable pH regulator agent with sample dissolution behavior, pH value.Take by weighing furosemide 1.0g respectively, add water 100ml, add above three kinds of pH regulator agent again and dissolve fully until furosemide.See Table 1.
Table 1 pH regulator agent screening
| Regulator | The sample dissolution behavior | PH value |
| NaOH | Yi Rong | 11.21 |
| NaHCO3 | Insoluble | |
| Meglumine | Yi Rong | 11.68 |
The result shows that NaOH is optimum pH regulator agent.
The screening of pH regulator agent concentration:
Carry out the screening test of its concentration with the NaOH of variable concentrations as the pH regulator agent, the results are shown in following table 2.
The screening of table 2 pH regulator agent concentration
| Concentration (%) | The sample dissolution behavior | PH value |
| 0.4 | Yi Rong | 11.28 |
| 0.3 | Be partly dissolved | / |
| 0.2 | Be partly dissolved | / |
The result shows: furosemide can dissolve in 0.4% NaOH solution fully, and the NaOH solution concentration reduces furosemide can't dissolve fully, so determine that 0.4% NaOH solution is the concentration of pH regulator agent.
According to the quality standard of furosemide inj as can be known, the solution pH value should be controlled in 8.5～9.5 scopes, so also need to regulate solution pH value before the lyophilizing with acid.Consider to regulate acid-base value, generate sodium chloride in the adjustment process, reduced the introducing of impurity with the 1mol/L hydrochloric acid solution.In adding the hydrochloric acid process, there is cotton-shaped white precipitate to generate, so solution should be placed 40 ℃ of water-bath constant temperature, add hydrochloric acid solution in the time of stirring slowly.For having avoided dissolved precipitation to separate out, should avoid pH value low excessively.
The selection of pH value of solution before the lyophilizing:
Take by weighing six parts of furosemide, every part of 1.0g adds 0.4%NaOH 50ml it is dissolved fully, 40 ℃ of constant temperature of water-bath, and dripping hydrochloric acid solution regulator solution adds water and is settled to 100ml, packing 2ml/ bottle, lyophilizing to different pH value.With the pH value of sample is pH value before the measurement index lyophilizing selecting to be fit to.The results are shown in following table 3.
The selection of pH value of solution before table 3 lyophilizing
| PH value of solution before the lyophilizing | PH value * |
| 10.02 | 10.35 |
| 9.52 | 9.36 |
| 9.31 9.20 8.91 | 9.01 8.78 8.52 |
The result shows: when pH value of solution was in 8.5～9.5 scopes before the lyophilizing, the sample pH value was all up to specification.
* the assay method of pH value: sample thief adds water 10ml respectively for 5 bottles, is equivalent to 2mg/ml, measures pH value.
The screening of excipient
Because of principal agent amount in the sample is little, so also need to select for use suitable excipient to obtain good sample appearance.Select mannitol and lactose for use, with its solvability and sample appearance as the index screening excipient.With formula ratio configuration sample solution, add mannitol and lactose 5.0g respectively, the dissolving back is fixed molten to 100ml fully.Packing 2ml/ bottle, lyophilizing.The results are shown in following table 4.
The screening of table 4 excipient
| Excipient | Solvability | Stability of solution before the lyophilizing | PH value | Sample appearance |
| Mannitol | Yi Rong | Stable | 9.32 | White lyophilizing block |
| Lactose | Can be molten | Stable | 9.37 | White lyophilizing block |
The result shows: mannitol is the excipient that is more suitable for.The inventor also tests lactose and mannitol equal amount of mixture, glucose, fructose, glucose and fructose equal amount of mixture, Dextran 40 (having another name called glucosan), and result's proof also can reach the basic demand of medication preparation.
The screening of excipient concentration:
Select the mannitol of variable concentrations, with the concentration of sample appearance as the index screening excipient.The results are shown in following table 5.
The screening of table 5 excipient concentration
| Excipient concentration | Sample appearance | Dissolution time (second) |
| 1％ | The loose shape that drying layer is white in color, poor morphology | 45 |
| 2％ | 45 | |
| 3％ | The looser shape that drying layer is white in color, poor morphology | 38 |
| 4％ | The drying layer hole is moderate, and form is full, loose block, appearance looks elegant | 26 |
| 6％ | The drying layer hole is little, and the distillation resistance is big, compact structure | 30 |
| 8％ | 32 | |
| 10％ | 35 |
The result shows: 4% mannitol is optimum excipient concentration.
So determine that the prescription of this product is as follows:
Prescription
Furosemide 20.0g
Mannitol 80.0g
0.4% sodium hydroxide solution is an amount of
The 1mol/L hydrochloric acid solution is an amount of
Water for injection is made 1000 bottles to 2000ml.
The inventor is also to furosemide 20g, lactose, lactose and mannitol equal amount of mixture and Dextran 40 (having another name called glucosan), and 40-400g, glucose, fructose, glucose and fructose equal amount of mixture 40-200g also can reach the basic demand of pharmaceutical preparation substantially.
Experimental example 2 preparation method researchs
The screening of active carbon addition
When preparing the injection furosemide, add a certain amount of active carbon and remove pyrogen with crude drug.Whether the adding of this The effects active carbon has adsorption to crude drug.Concrete test operation sees Table 6.
Table 6 activated-carbon test
| Sample number into spectrum | 1 | 2 | 3 |
| Furosemide weighing (g) | 1.0124 | 1.0098 | 1.0021 |
| Sample solution amount (ml) | 100 | 100 | 100 |
| Add active carbon (%) | 0.2 | 0.1 | - |
| Mixing time (branch) | 15 | 15 | - |
| Filter number of | 2 | 2 | 2 |
| Content (%) | 92.11 | 92.41 | 97.58 |
| Bacterial endotoxin is checked | Up to specification | Up to specification | Against regulation |
Conclusion: three samples are measured concentration results from the UV method, and with sample 3 in contrast, sample 1 and 2 concentration have reducing in various degree.Illustrate that adding active carbon in this solution has absorption to crude drug.So we select its solution to add 0.1% active carbon depyrogenation and the absorption of crude drug are increased the addition of crude drug according to active carbon in preparation technology.Sample 1 and 2 is the bacterial endotoxin conformance with standard after testing.
Eutectic point is measured:
Measuring principle: utilize resistance to the significant change of phase transformation and measure.But because temperature is easy to generate supercooled state when descending, obscure easily with real eutectic point, so the resistance variations during by intensification is measured eutectic point.
Need testing solution preparation: press formula proportion preparation injection furosemide liquid 50ml, as need testing solution.
Assay method: with above-mentioned need testing solution,, insert cryogenic thermometer and electrode and carry out quick-freezing, make need testing solution be frozen into solid fully to going in the container.To pop one's head in and insert on the conductivity meter, this moment the resistance value infinity, conductivity value is zero.Solid phase begins fusing when heating up, and the every rising of temperature was once being counted once, measures the temperature that this moment, resistance descended suddenly and is eutectic point.See Table 7.Be abscissa then with the temperature, conductivity value (Δ US) is the vertical coordinate mapping.See Fig. 2.
The result: this product eutectic point is-18 ℃, in prepared, be preferably lower than carry out under-25 ℃ of conditions freezing.
Table 7 eutectic point measurement result
| Temperature (℃) | -50 | -21 | -20 | -19 | -18 | -17 |
| Conductivity value (Δ US) | 0 | 0.14 | 0.24 | 0.34 | 0.23 | 0.58 |
| Temperature (℃) | -16 | -15 | -14 | -13 | -12 | -11 |
| Conductivity value (Δ US) | 1.51 | 3.09 | 5.78 | 9.04 | 13.08 | 16.85 |
Freeze-drying curve
The experimental record that sample liquid enters behind the freeze dryer sees Table 8.
Relation according to the temperature and time among the table 8-4.Draw freeze-drying curve and see Fig. 3.
Table 8
| Time (hr) | 0 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 |
| Temperature (℃) | 18 | -50 | -50 | -50 | -50 | -16 | -12 | -10 | -8 | -5 | -4 | -3 |
| Time (hr) | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | 24 |
| Temperature (℃) | -1 | 0 | 3 | 5 | 6 | 10 | 20 | 30 | 40 | 40 | 40 | 40 |
The moisture equilibrium at dry side test
It is an amount of that precision takes by weighing this product, places 8 uncovered flat bottles in 60 ℃ of drying under reduced pressure to constant weight respectively, spreads out＜thin layer of 5mm, and accurate the title decide weight, places the exsiccator of 8 different humidity more respectively, places after 10 days for 25 ℃, and moisture absorption is increased weight constant relatively.Accurate then title is fixed, is vertical coordinate with the moisture absorption weightening finish, is the abscissa mapping with the relative humidity.Obtaining critical relative humidity is 78.0%.Illustrate that this product hygroscopicity is not strong, the production environment relative humidity should be controlled at below 75%, and temperature is between 20-25 ℃.The results are shown in Table 9, Fig. 4.
Table 9 moisture equilibrium at dry side result of the test
| Relative humidity (%) | 31 | 40 | 58 | 66 | 75 | 84 | 92.5 | 95 |
| Rate of body weight gain (%) | 0.71 | -0.32 | 1.78 | 1.95 | 5.82 | 9.88 | 26.07 | 39.46 |
The research of experimental example 3 stability experiments
The pilot project of this research is by " two appendix XIC of Chinese pharmacopoeia version in 2000 medicine stability test guideline design: the regulation that meets guideline for test agent.It is 2000 bottles that the sample pilot scale is amplified every batch.Lot number is 040301,040302,040303 all to meet this product drug standard (draft) regulation after testing; Detect by outward appearance, color and luster, loss on drying, pH value, content project; The described every method of detection method is carried out; The influence factor that this product has been undertaken 10 days by listing packing (control injection vial lead extrusion is moulded lid) tests investigation; Under 40 ℃, 75%RH condition, carried out 6 months accelerated tests,, carried out 12 months the test that keeps sample for a long time under the 60%RH condition at 25 ℃.Result of the test shows: the injection furosemide is pressed commercially available back to light less stable (illumination 10 days), to thermally-stabilised (40 ℃, 60 ℃ ° 10 days), to wet stable (92.5%RH10 days); 40 ℃ of accelerated tests 6 months are basicly stable; 25 ℃ of long term tests were stablized in 12 months.
Table 10 injection furosemide light durability result of the test
| Time (my god) | Outward appearance | Solution colour | Clarity | pH | Loss on drying (%) | Indicate content (%) | Percentage ratio (%) with 0 day content |
| 0 | The loose block of white lyophilizing | Colourless | Clarification | 9.2 6 | 1.04 | 102.7 6 | 100 |
| 5 | The off-white color lyophilizing block that loosens | With yellow No. 3 quite | Clarification | 9.2 5 | 1.16 | 102.2 4 | 99.49 |
| 10 | The light yellow lyophilizing block that loosens | With yellow No. 8 quite | Clarification | 9.1 9 | 1.18 | 101.7 2 | 98.99 |
40 ℃ of heat stabilization test results of table 11 injection furosemide
| Time (my god) | Outward appearance | Solution colour | Clarity | pH | Loss on drying (%) | Indicate content (%) | Percentage ratio (%) with 0 day content |
| 0 | The loose block of white lyophilizing | Colourless | Clarification | 9.26 | 1.04 | 102.76 | 100 |
| 5 | The loose block of white lyophilizing | Colourless | Clarification | 9.27 | 1.06 | 103.10 | 100.33 |
| 10 | The loose block of white lyophilizing | Colourless | Clarification | 9.25 | 0.92 | 102.75 | 99.99 |
60 ℃ of heat stabilization test results of table 12 injection furosemide
| Time (my god) | Outward appearance | Solution colour | Clarity | pH | Loss on drying (%) | Indicate content (%) | Percentage ratio (%) with 0 day content |
| 0 | The loose block of white lyophilizing | Colourless | Clarification | 9.26 | 1.04 | 102.76 | 100 |
| 5 | The loose block of white lyophilizing | Colourless | Clarification | 9.31 | 1.07 | 100.34 | 97.64 |
| 10 | The loose block of white lyophilizing | Colourless | Clarification | 9.38 | 0.96 | 100.69 | 97.99 |
Stability test result under table 13 injection furosemide 92.5% relative humidity
| Time (my god) | Outward appearance | Solution colour | Clarity | pH | Loss on drying (%) | Indicate content (%) | Percentage ratio (%) with 0 day content |
| 0 | The loose block of white lyophilizing | Colourless | Clarification | 9.26 | 1.04 | 102.76 | 100 |
| 5 | The loose block of white lyophilizing | Colourless | Clarification | 9.20 | 1.02 | 102.41 | 99.66 |
| 10 | The loose block of white lyophilizing | Colourless | Clarification | 9.29 | 1.12 | 102.58 | 99.82 |
40 ℃ of table 14 injection furosemide (0.75g), 75%RH accelerated test result
| 040301 batch | |||||||
| Time (moon) | Outward appearance | Solution colour | Clarity | pH | Loss on drying (%) | Indicate content (%) | Percentage ratio (%) with 0 day content |
| 0 | The loose block of white lyophilizing | Colourless | Clarification | 9.30 | 1.34 | 105.4 | 100.0 |
| 1 | The loose block of white lyophilizing | Colourless | Clarification | 9.32 | 1.28 | 105.0 | 99.6 |
| 2 | The loose block of white lyophilizing | Colourless | Clarification | 9.27 | 1.40 | 105.2 | 99.8 |
| 3 | The loose block of white lyophilizing | Colourless | Clarification | 9.32 | 1.39 | 105.3 | 99.8 |
| 6 | The loose block of white lyophilizing | Colourless | Clarification | 9.29 | 1.19 | 105.2 | 99.8 |
| 40302 batches | |||||||
| 0 | The loose block of white lyophilizing | Colourless | Clarification | 9.16 | 1.27 | 101.7 | 100.0 |
| 1 | The loose block of white lyophilizing | Colourless | Clarification | 9.24 | 1.20 | 101.4 | 99.7 |
| 2 | The loose block of white lyophilizing | Colourless | Clarification | 9.16 | 1.23 | 101.3 | 99.6 |
| 3 | The loose block of white lyophilizing | Colourless | Clarification | 9.23 | 1.28 | 102.8 | 101.1 |
| 6 | The loose block of white lyophilizing | Colourless | Clarification | 9.17 | 1.28 | 102.9 | 101.2 |
| 040303 batch | |||||||
| 0 | The loose block of white lyophilizing | Colourless | Clarification | 9.22 | 1.32 | 104.3 | 100.0 |
| 1 | The loose block of white lyophilizing | Colourless | Clarification | 9.22 | 1.27 | 104.2 | 99.9 |
| 2 | The loose block of white lyophilizing | Colourless | Clarification | 9.21 | 1.25 | 104.2 | 99.9 |
| 3 | The loose block of white lyophilizing | Colourless | Clarification | 9.17 | 1.32 | 104.8 | 100.5 |
| 6 | The loose block of white lyophilizing | Colourless | Clarification | 9.28 | 1.27 | 104.0 | 99.7 |
25 ℃ of table 15 injection furosemide, the 60%RH long-term test results
| 040301 batch | |||||||
| Time (moon) | Outward appearance | Solution colour | Clarity | pH | Loss on drying (%) | Indicate content (%) | Percentage ratio (%) with 0 day content |
| 0 | The loose block of white lyophilizing | Colourless | Clarification | 9.30 | 1.34 | 105.4 | 100.0 |
| 3 | The loose block of white lyophilizing | Colourless | Clarification | 9.27 | 1.29 | 104.7 | 99.3 |
| 6 | The loose block of white lyophilizing | Colourless | Clarification | 9.32 | 1.27 | 105.0 | 99.6 |
| 9 | The loose block of white lyophilizing | Colourless | Clarification | 9.31 | 1.38 | 104.9 | 99.5 |
| 12 | The loose block of white lyophilizing | Colourless | Clarification | 9.29 | 1.39 | 104.7 | 99.3 |
| 040302 batch | |||||||
| Time (moon) | Outward appearance | Solution colour | Clarity | pH | Loss on drying %) | Indicate content (%) | Percentage ratio (%) with 0 day content |
| 0 | The loose block of white lyophilizing | Colourless | Clarification | 9.16 | 1.27 | 101.7 | 100.0 |
| 3 | The loose block of white lyophilizing | Colourless | Clarification | 9.19 | 1.23 | 102.9 | 101.1 |
| 6 | The loose block of white lyophilizing | Colourless | Clarification | 9.20 | 1.27 | 102.7 | 101.0 |
| 9 | The loose block of white lyophilizing | Colourless | Clarification | 9.19 | 1.31 | 101.6 | 99.9 |
| 12 | The loose block of white lyophilizing | Colourless | Clarification | 9.17 | 1.31 | 100.6 | 98.9 |
| 040303 batch | |||||||
| Time (moon) | Outward appearance | Solution colour | Clarity | pH | Loss on drying (%) | Indicate content (%) | Percentage ratio (%) with 0 day content |
| 0 | The loose block of white lyophilizing | Colourless | Clarification | 9.22 | 1.32 | 104.3 | 100.0 |
| 3 | The loose block of white lyophilizing | Colourless | Clarification | 9.23 | 1.32 | 104.3 | 100.0 |
| 6 | The loose block of white lyophilizing | Colourless | Clarification | 9.26 | 1.28 | 104.1 | 99.8 |
| 9 | The loose block of white lyophilizing | Colourless | Clarification | 9.17 | 1.31 | 104.0 | 99.7 |
| 12 | The loose block of white lyophilizing | Colourless | Clarification | 9.26 | 1.37 | 103.5 | 99.2 |
The injection furosemide is pressed commercially available back to light less stable (illumination 10 days), to thermally-stabilised (40 ℃, 60 ℃ ° 10 days), to wet stable (92.5%RH10 days); Accelerated test 6 months is basicly stable; Long term test was stablized in 12 months.
Claims (8)
1, a kind of furosemide lyophilized formulations, by the active component furosemide, excipient, the pH regulator agent is made through lyophilizing in right amount.
2, lyophilized formulations as claimed in claim 1, excipient are mannitol or saccharide.
3, lyophilized formulations as claimed in claim 2 is characterized in that saccharide is lactose or lactose and mannitol equal amount of mixture or glucose or fructose or glucose and fructose equal amount of mixture or Dextran 40.
4, lyophilized formulations as claimed in claim 1, pH regulator agent are NaOH or meglumine or hydrochloric acid.
5, lyophilized formulations as claimed in claim 4, the concentration of pH regulator agent NaOH is 0.4% solution.
6, it is 8.5～9.5 that lyophilized formulations as claimed in claim 1, hydrochloric acid solution are regulated its pH value.
7, the preparation method of lyophilized formulations as claimed in claim 1:
1) prescription:
Furosemide 20.0g
Lactose or lactose and mannitol equal amount of mixture or Dextran 40 40-400g
Or glucose or fructose or glucose and fructose equal amount of mixture 40-200g
0.4% sodium hydroxide solution is an amount of
The 1mol/L hydrochloric acid solution is an amount of
Water for injection is made 1000 bottles to 2000ml.
2)
(1) gets formula ratio furosemide crude drug, it is an amount of to add 0.4%NaOH solution, stirring makes dissolving, constant temperature in 40 ℃ of water-baths, dripping hydrochloric acid solution is regulated pH value between 8.5-9.5 when stirring, put cold, add formula ratio lactose or lactose and mannitol equal amount of mixture or dextran or glucose or fructose or glucose and fructose equal amount of mixture stirring and dissolving after, add to the full amount of water for injection.
(2) with above-mentioned solution coarse filtration, add the active carbon of 0.1% (w/v), stirred 15 minutes, filter, remove active carbon.
(3) with above-mentioned filtrate aseptic filtration, filtrate is surveyed its pH value should be in the 8.5-9.5 scope.
(4) filtrate censorship qualified after, according to crude drug cubage loading amount.
(5) aseptic subpackagedly go into the aseptic glass tube vial of 10ml, every bottle of about 2ml of fill.
(6) butyl rubber plug half lid in putting in the freeze dryer, freezing, drying and moulding.
(7) close plug, gland also adds the bundle aluminium lid.
(8) sampling observation qualified after, label packing warehouse-in.
8, the preparation method of lyophilized formulations as claimed in claim 1:
1) prescription:
Furosemide 20.0g
Mannitol 80.0g
0.4% sodium hydroxide solution is an amount of
The 1mol/L hydrochloric acid solution is an amount of
Water for injection is made 1000 bottles to 2000ml.
2)
(1) get formula ratio furosemide crude drug, it is an amount of to add 0.4%NaOH solution, stirs to make dissolving, constant temperature in 40 ℃ of water-baths, dripping hydrochloric acid solution is regulated pH value between 8.5-9.5 in the time of stirring, puts cold, after adding formula ratio mannitol stirring and dissolving, add to the full amount of water for injection.
(2) with above-mentioned solution coarse filtration, add the active carbon of 0.1% (w/v), stirred 15 minutes, filter, remove active carbon.
(3) with above-mentioned filtrate aseptic filtration, filtrate is surveyed its pH value should be in the 8.5-9.5 scope.
(4) filtrate censorship qualified after, according to crude drug cubage loading amount.
(5) aseptic subpackagedly go into the aseptic glass tube vial of 10ml, every bottle of about 2ml of fill.
(6) butyl rubber plug half lid in putting in the freeze dryer, freezing, drying and moulding.
(7) close plug, gland also adds the bundle aluminium lid.
(8) sampling observation qualified after, label packing warehouse-in.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200610082346 CN1903180A (en) | 2005-05-25 | 2006-05-25 | Freeze-dried powder injection of frusemide and its prepn. method |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200510020949 | 2005-05-25 | ||
| CN200510020949.9 | 2005-05-25 | ||
| CN 200610082346 CN1903180A (en) | 2005-05-25 | 2006-05-25 | Freeze-dried powder injection of frusemide and its prepn. method |
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|---|---|
| CN1903180A true CN1903180A (en) | 2007-01-31 |
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|---|---|---|---|
| CN 200610082346 Pending CN1903180A (en) | 2005-05-25 | 2006-05-25 | Freeze-dried powder injection of frusemide and its prepn. method |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030700A (en) * | 2015-06-29 | 2015-11-11 | 湖南科伦制药有限公司 | Preparation method of furosemide freeze-dried powder injection |
| CN109303765A (en) * | 2018-11-21 | 2019-02-05 | 南京泽恒医药技术开发有限公司 | A kind of Frusemide oral solution and preparation method thereof |
| CN110954629A (en) * | 2019-12-24 | 2020-04-03 | 南京科宁检测科技有限公司 | Control method for measuring content of furfuryl amine in furosemide |
-
2006
- 2006-05-25 CN CN 200610082346 patent/CN1903180A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105030700A (en) * | 2015-06-29 | 2015-11-11 | 湖南科伦制药有限公司 | Preparation method of furosemide freeze-dried powder injection |
| CN109303765A (en) * | 2018-11-21 | 2019-02-05 | 南京泽恒医药技术开发有限公司 | A kind of Frusemide oral solution and preparation method thereof |
| CN110954629A (en) * | 2019-12-24 | 2020-04-03 | 南京科宁检测科技有限公司 | Control method for measuring content of furfuryl amine in furosemide |
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