CN1850089A - Methylprednisolone sodium succinate lyophilized composition and its preparing method - Google Patents
Methylprednisolone sodium succinate lyophilized composition and its preparing method Download PDFInfo
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Abstract
The present invention provides a freeze-dried medicine composition containing methylprednisolone sodium succinate and its preparation method. Said medicine composition includes 1-3000 mg of methylprednisolone sodium succinate as main component and auxiliary component including 1-1000 mg of sodium hydrogen carbonate or other alkaline medicinal auxiliary material 1-500 mg of lactose or other stabilizing agent. 1-50 mg of sodium dihydrogen phosphate or acid component of other pH buffering agent, 1-500 mg of disodium hydrogen phosphate or alkaline component of other pH buffering agent and 1-50 ml of injection water.
Description
One, technical field
The present invention relates to field of pharmaceutical preparations, say exactly, the present invention relates to a kind of freeze-dried composition that contains methylprednisolone succinum sodium and preparation method thereof.
Two, background technology
Urbason Solubile, chemical name are 11 β, 17 α, 21-trihydroxy-6 Alpha-Methyl pregnant steroid-1,4-diene-3,20-diketone-21-sodium succinate.Structural formula is as follows:
Molecular formula: C
26H
33O
8Na
Molecular weight: 496.53
This product is the injection steroid manually synthetic, that antiinflammatory action is strong.Except pharmacological action with glucocorticoid, compare with prednisolone, stronger antiinflammatory action and more weak water, sodium retention effect are arranged.This product has pharmacological actions such as stronger antiinflammatory, immunosuppressant, antiallergic, shock, is specially adapted to use under the critical illness situation.When carrying out " flooding " (pulse dosing) rescue life, promptly use methylprednisolone sodium succinate for inj as the critical patient.
Oral methylprednisolone succinic acid absorption of human body is bad, and bioavailability is low, easily by stomach acids destroy, thereby the suitable drug administration by injection of this product.Because the succinic acid methylprednisolone is almost insoluble in water, therefore when producing injection, this product must be made sodium salt, potassium salt or the calcium salt of methylprednisolone succinic acid, to increase its dissolubility.In order to ensure clinical drug safety, it is better that this product is made Urbason Solubile.Urbason Solubile is the prodrug of methylprednisolone, and meeting is hydrolyzed to free methylprednisolone rapidly and bring into play drug effect in blood plasma.Because Urbason Solubile is unstable in aqueous solution, can not store for a long time, therefore is necessary this product is made injectable powder.
Injectable powder has two kinds of preparation methoies usually, and a kind of is aseptic subpackaged method, is about to aseptic Urbason Solubile raw material direct packaging in control injection bottle, presses tight plug, rolls aluminium-plastic cap and makes.Another kind is succinic acid methylprednisolone and basic medicinally adjuvant to be reacted into salt make aqueous solution, and fill is in control injection bottle, and the false add plug carries out lyophilization, press tight in plug, roll aluminium-plastic cap and make.When utilizing aseptic subpackaged legal system to be equipped with the Urbason Solubile injectable powder, because the Urbason Solubile moisture absorption very easily, very strict to the requirement of production environment, the cost of production cost is higher.Simultaneously, owing to when aseptic subpackaged, can't add the pH buffer agent, therefore when clinical use dosing, must use the dedicated solvent dissolving that adds the pH buffer agent.For this reason, manufacturer is carrying out when aseptic subpackaged, and the pH buffer agent solution must form a complete production network.
The present invention adopts Freeze Drying Technique, succinic acid methylprednisolone and basic medicinally adjuvant is reacted into salt makes aqueous solution, obtains freeze dried pharmaceutical preparation after the lyophilization.
For this reason, the invention provides a kind of methylprednisolone sodium succinate lyophilized injectable powder and its preparation method, said preparation has stronger antiinflammatory, immunosuppressant, antiallergic, antishock pharmacological action.
Three, summary of the invention
Methylprednisolone sodium succinate lyophilized injectable powder of the present invention is made up of succinic acid methylprednisolone and basic medicinally adjuvant and an amount of pH buffer agent and stabilizer element.In every methylprednisolone sodium succinate lyophilized injectable powder, the weight range of contained active component succinic acid methylprednisolone is 1-3000mg.
In the methylprednisolone sodium succinate lyophilized injectable powder of the present invention, used basic auxiliary is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, sodium lactate, sodium citrate, potassium citrate, sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, calcium oxide, Soluble tartar., sodium tartrate, potassium metaphosphate, Polymeric sodium metaphosphate., sodium hydrogen phosphate, dipotassium hydrogen phosphate, arginine, lysine, in the alkaline matters such as meglumine any or any two kinds combination, preferred sodium bicarbonate, sodium carbonate, sodium hydroxide, most preferably sodium bicarbonate.In every Urbason Solubile compositions, the weight range that contains sodium bicarbonate is 1-1000mg.
In the methylprednisolone sodium succinate lyophilized injectable powder of the present invention, used stabilizing agent can be selected from glucides such as low molecular dextran, mannitol, lactose, glucose, maltose, poloxamer, chloride, cyclodextrin, cellulose substances.Preferred lactose and poloxamer, most preferably lactose.In every Urbason Solubile compositions, lactinated weight range is 0-500mg, and when the concentration of succinic acid methylprednisolone in the injection is 125mg/2ml when above, lactose can not add yet, the concentration of succinic acid methylprednisolone is 125mg/2ml when following in the injection, and lactose must add.
In the methylprednisolone sodium succinate lyophilized injectable powder of the present invention, the acid ingredient of used pH buffer agent can be acetic acid, citric acid, tartaric acid, sodium dihydrogen phosphate, sodium bicarbonate, most preferably sodium dihydrogen phosphate.In every Urbason Solubile compositions, the weight range of phosphoric acid sodium dihydrogen is 1-50mg.
In the methylprednisolone sodium succinate lyophilized injectable powder of the present invention, the alkaline components of used pH buffer agent can be sodium acetate, sodium citrate, sodium tartrate, sodium hydrogen phosphate, sodium carbonate, most preferably sodium hydrogen phosphate.In every Urbason Solubile compositions, the weight range of phosphoric acid disodium hydrogen is 1-500mg.
In the methylprednisolone sodium succinate lyophilized powder pin of the present invention, used solvent is sterilized water for injection, water for injection, preferred water for injection.The compositions of dissolving every Urbason Solubile need be 1-50ml with the volume scope of water for injection.Methylprednisolone sodium succinate lyophilized injectable powder of the present invention, the prescription of every lyophilized injectable powder is: succinic acid methylprednisolone 1-3000mg; Basic medicinally adjuvant 1-1000mg; Stabilizing agent 1-500mg; The acidic moiety 1-50mg of pH buffer agent, the basic moiety 1-500mg of pH buffer agent; Water for injection 1-50ml; With the check of American Pharmacopeia (USP25) method, every middle sodium content should be 1-500mg; By weight calculating, the weight that the sodium in every accounts for compositions should be 1-10%.
Methylprednisolone sodium succinate lyophilized injectable powder of the present invention, preparation specification are 1-2000mg (in methylprednisolone), preferred 10mg, 20mg, 40mg, 125mg, 250mg, 500mg, 1000mg, 2000mg.
Methylprednisolone sodium succinate lyophilized injectable powder of the present invention, its preparation method is as follows:
The succinic acid methylprednisolone, basic auxiliary, the pH buffer agent solution, the stabilizing agent mixed dissolution after the aseptic filtration, is sub-packed in the cillin bottle, and the lyophilized injectable powder of Urbason Solubile is made in lyophilization again.This product can use with mixed liquor dissolving, the dilution back of 5% glucose solution, normal saline or 5% glucose and 0.45% sodium chloride clinically.
Preferred manufacturing procedure is as follows:
1) the alkalescent medicine adjuvant dissolves in water, and it is standby to get alkaline solution,
2) preparation pH buffer agent is standby,
3) in case of necessity, stabilizing agent is dissolved in the water, standby,
4) succinic acid methylprednisolone water furnishing pasty state,
5) alkaline solution of the pastel of step 4 adding step 1) makes dissolving,
6) adding step 2 in the solution of step 5)) solution of step 3) adds water to full dose,
7) add medicinal charcoal, filter adjust pH, micro-pore-film filtration, fill, vacuum lyophilization.
Preferred preparation method is as follows:
1) the alkalescent medicine adjuvant of getting recipe quantity dissolves with water for injection,
2) the pH buffer agent of getting recipe quantity dissolves with water for injection,
3) stabilizing agent of getting recipe quantity adds the dissolving of injection water,
4) get the succinic acid methylprednisolone of recipe quantity, with water for injection furnishing pasty state,
5) slowly add alkaline solution, the limit edged stirs, dissolve fully up to the succinic acid methylprednisolone,
6) add pH buffer agent solution and stabiliser solution again, add the injection water and add to full dose,
8) add medicinal charcoal, stir evenly, placed about 20 minutes, the coarse filtration decarburization, and fine straining is qualified to medicinal liquid clarity, sampling, measuring and regulating the medicinal liquid pH value is 7-8, with Φ 0.22 μ m microporous membrane filter aseptic filtration, sampling and measuring, the character of medicinal liquid, pH value, drug content and bacterial endotoxin should be up to specification, press drug content and calculate fill volume, fill, cillin bottle false add plug, vacuum lyophilization, the final moisture of freeze-dried composition is controlled at below 2%, press tight interior plug, roll aluminium-plastic cap, be packaged to be finished product.
The most preferred preparation method of the present invention is seen embodiment.
Methylprednisolone sodium succinate lyophilized injectable powder of the present invention, every lyophilized injectable powder is preferably filled a prescription composed as follows:
| The succinic acid methylprednisolone | 1-3000mg |
| Sodium bicarbonate | 1-1000mg |
| Sodium dihydrogen phosphate | 1-50mg |
| Sodium hydrogen phosphate | 1-500mg |
| Lactose | 0-500mg. |
Every preferred prescription of lyophilized injectable powder is composed as follows:
| The succinic acid methylprednisolone | 10-3000mg |
| Sodium bicarbonate | 2-500mg |
| Sodium dihydrogen phosphate | 1-25mg |
| Sodium hydrogen phosphate | 10-300mg |
| Lactose | 0-100mg |
The most preferred prescription of the lyophilized injectable powder of different size is listed in the embodiment of the invention table 8.
More than prescription is formed, and needs to add water for injection in the preparation, and concrete grammar is seen embodiment.
The screening process of the preferred prescription of methylprednisolone sodium succinate lyophilized injectable powder of the present invention (is example with the 20mg specification) is as follows:
＜one 〉, the selection of adjuvant
1, the selection of basic medicinally adjuvant sodium bicarbonate
The succinic acid methylprednisolone is almost insoluble in water, utilizes itself and reaction of sodium bicarbonate to generate Urbason Solubile, increases its dissolubility, and carries out prescription at 1: 1 according to the mole molecular proportion.Select sodium hydroxide, sodium carbonate, or potassium hydroxide equally also can salify, increases dissolubility, but sodium hydroxide, sodium carbonate are too violent with the reaction of succinic acid methylprednisolone, easily cause the succinic acid methylprednisolone to decompose, and make the relative substance rising; Potassium hydroxide and the reaction of succinic acid methylprednisolone generate methylprednisolone succinic acid potassium salt, and high potassium easily works the mischief to the safety of human body, therefore select basic medicinally adjuvant sodium bicarbonate and succinic acid methylprednisolone salify.
2, the selection of PH buffer agent
The pH value of solution has tangible influence to its stability, is 7-8 according to the stationary value of Urbason Solubile solution.By test, more stable than acetic acid-sodium acetate, citric acid-sodium citrate by the pH value buffer that sodium dihydrogen phosphate-sodium hydrogen phosphate is formed.Thereby selection sodium dihydrogen phosphate-sodium hydrogen phosphate is the PH buffer agent.
3, the selection of stabilizing agent lactose
The Urbason Solubile solution of low concentration prevents to have in the solution floccule to produce because the big facile hydrolysis of the water yield adds an amount of stabilizing agent lactose and can suppress hydrolysis.By test glucose, poloxamer Stabilization is arranged also, but its stability is all not as lactose, thereby selection lactose used as stabilizers.
＜two 〉, adjuvant is selected test
1, the basic medicinally adjuvant is selected
The prescription of table 1. design
| Prescription | (1) | (2) | (3) |
| The succinic acid methylprednisolone | 25.35g | 25.35g | 25.35g |
| Sodium bicarbonate | 4.49g | - | - |
| Sodium hydroxide | - | 2.1g | - |
| Sodium carbonate | - | - | 2.8g |
| Water for injection | Add to 1000ml | Add to 1000ml | Add to 1000ml |
Method for making: respectively recipe quantity basic medicinally adjuvant is added stirring and dissolving in the water for injection.Precision takes by weighing recipe quantity succinic acid methylprednisolone, adds an amount of water for injection furnishing pasty state, slowly adds the basic medicinally adjuvant, and the limit edged stirs until the solution clarification, adds to the full amount of water for injection, and observes the solution character; Room temperature condition was placed down after 24 hours, the character of observing solution again.Result of the test sees Table 2.
Table 2. basic medicinally adjuvant is selected result of the test
| Prescription | (1) | (2) | (3) |
| The character of solution | Achromaticity and clarification | Little yellow clarification | Little yellow clarification |
| Room temperature condition is placed 24 hours character down | Achromaticity and clarification | Little yellow has floccule to produce in the solution | Little yellow has floccule to produce in the solution |
Conclusion (of pressure testing): three kinds of basic medicinally adjuvants, with the solution appearance character optimum that sodium bicarbonate is made, character is more stable.Select the sodium bicarbonate salify for this reason.
2, the selection of PH buffer agent
The prescription of table 3. design
| Prescription | (1) | (2) | (3) |
| The succinic acid methylprednisolone | 25.35g | 25.35g | 25.35g |
| Sodium bicarbonate | 4.49g | 4.49g | 4.49g |
| Sodium dihydrogen phosphate | 1.385g | - | - |
| Sodium hydrogen phosphate | 17.4g | - | - |
| Acetic acid | - | 2.4g | - |
| Sodium acetate | - | 5.8g | - |
| Citric acid | - | - | 3.0g |
| Sodium citrate | - | - | 6.0g |
| Water for injection | Add to 1000ml | Add to 1000ml | Add to 1000ml |
Method for making: the sodium bicarbonate of recipe quantity is added stirring and dissolving in the water for injection.Precision takes by weighing recipe quantity succinic acid methylprednisolone, adds an amount of water for injection furnishing pasty state, slowly adds sodium bicarbonate solution, and the limit edged is stirred to the solution clarification.The PH buffer agent that takes by weighing recipe quantity adds an amount of water for injection dissolving back and adds, and adds to the full amount of water for injection, and observes the solution character; Room temperature condition was placed down after 24 hours, the character of observing solution again.Result of the test sees Table 4.
The selection result of the test of table 4.PH buffer agent
| Prescription | (1) | (2) | (3) |
| The character of solution | Achromaticity and clarification | Achromaticity and clarification | Achromaticity and clarification |
| Room temperature condition is placed 24 hours character down | Achromaticity and clarification | Little yellow has floccule to produce in the solution | Little yellow has floccule to produce in the solution |
Conclusion (of pressure testing): three kinds of PH buffer agent result of the tests, the stability of the solution made from sodium dihydrogen phosphate-sodium hydrogen phosphate better.Select sodium dihydrogen phosphate-sodium hydrogen phosphate is the PH buffer agent of solution for this reason.
3, selection of stabilizers
The prescription of table 5. design
| Prescription | (1) | (2) | (3) |
| The succinic acid methylprednisolone | 25.35g | 25.35g | 25.35g |
| Sodium bicarbonate | 4.49g | 4.49g | 4.49g |
| Sodium dihydrogen phosphate | 1.385g | 1.385g | 1.385g |
| Sodium hydrogen phosphate | 17.4g | 17.4g | 17.4g |
| Lactose | 100g | - | - |
| Glucose | - | 50g | - |
| Poloxamer | - | - | 5g |
| Water for injection | Add to 1000ml | Add to 1000ml | Add to 1000ml |
Method for making: the sodium bicarbonate of recipe quantity is added stirring and dissolving in the water for injection.Precision takes by weighing recipe quantity succinic acid methylprednisolone, adds an amount of water for injection furnishing pasty state, slowly adds sodium bicarbonate solution, and the limit edged is stirred to the solution clarification.The PH buffer agent that takes by weighing recipe quantity adds an amount of water for injection dissolving back and adds.The stabilizing agent that takes by weighing recipe quantity adds an amount of water for injection dissolving back and adds.Add to the full amount of water for injection, observe the solution character; Room temperature condition was placed down after 48 hours, the character of observing solution again.Result of the test sees Table 6.
Table 6. selection of stabilizers result of the test
| Prescription | (1) | (2) | (3) |
| The character of solution | Achromaticity and clarification | Achromaticity and clarification | Achromaticity and clarification |
| Room temperature condition is placed 48 hours character down | Achromaticity and clarification | Little yellow has floccule to produce in the solution | Little yellow has floccule to produce in the solution |
Conclusion (of pressure testing): three kinds of stabilizing agent result of the tests, better with the stability of lactose.Select lactose is stabilizing agent for this reason.
＜three 〉, the prescription and the technology of establishing through experimental study
Prescription:
| Prescription | (1) |
| The succinic acid methylprednisolone | 25.35g |
| Sodium bicarbonate | 4.49g |
| Sodium dihydrogen phosphate | 1.385g |
| Sodium hydrogen phosphate | 17.4g |
| Lactose | 100g |
| Water for injection | Add to 1000ml |
Method for making: it is standby that the alkalescent medicine adjuvant of getting recipe quantity is put in the water for injection dissolving; The pH buffer agent of getting recipe quantity is standby with the water for injection dissolving; Getting the recipe quantity stabilizing agent, to add injection water dissolving standby; Precision takes by weighing the succinic acid methylprednisolone of recipe quantity, with water for injection furnishing pasty state, slowly adds alkaline solution, the limit edged stirs, and dissolves fully up to the succinic acid methylprednisolone, adds pH buffer agent solution and stabiliser solution again, stir evenly, add the injection water and add to full dose.Add medicinal charcoal, stir evenly, placed about 20 minutes, the coarse filtration decarburization, and fine straining is qualified to medicinal liquid clarity.Sampling, measuring and regulating the medicinal liquid pH value is 7-8.With Φ 0.22 μ m microporous membrane filter aseptic filtration.Sampling and measuring, the character of medicinal liquid, pH value, drug content and bacterial endotoxin should be up to specification.Press drug content and calculate fill volume, fill, cillin bottle false add plug, vacuum lyophilization is controlled at the final moisture of freeze-dried composition below 2%, press tight in plug, roll aluminium-plastic cap, be packaged to be finished product.
＜four 〉, key property evaluation
The key property evaluation test the results are shown in Table 7.The key property evaluation test is the result show, can produce the methylprednisolone sodium succinate for inj that conformance with standard requires according to prescription of establishing and technology.
Table 7. key property evaluation test result
| Assessment item | Standard code | Evaluation result |
| Character | The white loose block | The white loose block |
| Differentiate | Be positive reaction | Be positive reaction |
| The clarity of solution and color | Up to specification | Up to specification |
| Basicity | 7-8 | 7.4 |
| Free first Po Nilong | ≤6％ | 1.5 |
| Loss on drying | ∠2％ | 1.4 |
| Content uniformity | Up to specification | Up to specification |
| Clarity | Up to specification | Up to specification |
| Bacterial endotoxin | Up to specification | Up to specification |
| Aseptic | Up to specification | Up to specification |
| Content | 90-110％ | 100.4％ |
Five, estimation of stability
The estimation of stability result of the test sees Table 8, table 9.The estimation of stability result of the test shows, according to the prescription of establishing and the constant product quality of explained hereafter, can guarantee product quality in effect duration.
Table 8. accelerated test result
| Production number | Period of storage (moon) | The investigation project | Conclusion | ||||||||
| Character | The clarity of solution and color | Clarity | Basicity | Loss on drying (%) | Bacterial endotoxin | Content (%) | Free methylprednisolone (%) | Aseptic | |||
| 030525 | 0 | The white loose block | Up to specification | Up to specification | 7.3 | 0.2 | Up to specification | 102.2 | 1.2 | Up to specification | Qualified |
| 030527 | The white loose block | Up to specification | Up to specification | 7.4 | 0.4 | Up to specification | 100.0 | 1.2 | Up to specification | Qualified | |
| 030529 | The white loose block | Up to specification | Up to specification | 7.4 | 0.3 | Up to specification | 101.1 | 1.2 | Up to specification | Qualified | |
| 030525 | 1 | The white loose block | Up to specification | Up to specification | 7.3 | 0.3 | Up to specification | 99.5 | 1.3 | Up to specification | Qualified |
| 030527 | The white loose block | Up to specification | Up to specification | 7.4 | 0.4 | Up to specification | 98.7 | 1.3 | Up to specification | Qualified | |
| 030529 | The white loose block | Up to specification | Up to specification | 7.4 | 0.4 | Up to specification | 100.4 | 1.4 | Up to specification | Qualified | |
| 030525 | 2 | The white loose block | Up to specification | Up to specification | 7.3 | 0.3 | Up to specification | 100.5 | 1.9 | Up to specification | Qualified |
| 030527 | The white loose block | Up to specification | Up to specification | 7.4 | 0.4 | Up to specification | 99.4 | 2.0 | Up to specification | Qualified | |
| 030529 | The white loose block | Up to specification | Up to specification | 7.4 | 0.3 | Up to specification | 99.9 | 2.4 | Up to specification | Qualified | |
| 030525 | 3 | The white loose block | Up to specification | Up to specification | 7.3 | 0.4 | Up to specification | 98.4 | 2.6 | Up to specification | Qualified |
| 030527 | The white loose block | Up to specification | Up to specification | 7.3 | 0.3 | Up to specification | 97.6 | 3.1 | Up to specification | Qualified | |
| 030529 | The white loose block | Up to specification | Up to specification | 7.4 | 0.4 | Up to specification | 98.6 | 3.5 | Up to specification | Qualified | |
| 030525 | 6 | The white loose block | Up to specification | Up to specification | 7.2 | 0..3 | Up to specification | 98.9 | 4.2 | Up to specification | Qualified |
| 030527 | The white loose block | Up to specification | Up to specification | 7.3 | 0..5 | Up to specification | 98.3 | 3.9 | Up to specification | Qualified | |
| 030529 | The white loose block | Up to specification | Up to specification | 7.3 | 0.4 | Up to specification | 98.3 | 4.5 | Up to specification | Qualified | |
Table 9. long-term test results
| Batch number | Period of storage (moon) | The investigation project | Conclusion | ||||||||
| Character | The clarity of solution and color | Clarity/visible foreign matters | Basicity | Loss on drying (%) | Bacterial endotoxin | Content (%) | Free methylprednisolone (%) | Aseptic | |||
| 030525 | 0 | The white loose block | Up to specification | Up to specification | 7.3 | 0.2 | Up to specification | 102.2 | 1.2 | Up to specification | Qualified |
| 030527 | The white loose block | Up to specification | Up to specification | 7.4 | 0.4 | Up to specification | 100.0 | 1.2 | Up to specification | Qualified | |
| 030529 | The white loose block | Up to specification | Up to specification | 7.4 | 0.3 | Up to specification | 101.1 | 1.2 | Up to specification | Qualified | |
| 030525 | 3 | The white loose block | Up to specification | Up to specification | 7.3 | 0.3 | Up to specification | 101.3 | 1.3 | Up to specification | Qualified |
| 030527 | The white loose block | Up to specification | Up to specification | 7.4 | 0.4 | Up to specification | 100.3 | 1.3 | Up to specification | Qualified | |
| 030529 | The white loose block | Up to specification | Up to specification | 7.4 | 0.4 | Up to specification | 99.9 | 1.3 | Up to specification | Qualified | |
| 030525 | 6 | The white loose block | Up to specification | Up to specification | 7.3 | 0.2 | Up to specification | 100.8 | 1.5 | Up to specification | Qualified |
| 030527 | The white loose block | Up to specification | Up to specification | 7.4 | 0.4 | Up to specification | 100.5 | 1.4 | Up to specification | Qualified | |
| 030529 | The white loose block | Up to specification | Up to specification | 7.4 | 0.4 | Up to specification | 100.6 | 1.5 | Up to specification | Qualified | |
| 030525 | 9 | The white loose block | Up to specification | Up to specification | 7..3 | 0.3 | Up to specification | 100.1 | 2..3 | Up to specification | Qualified |
| 030527 | The white loose block | Up to specification | Up to specification | 7..3 | 0.4 | Up to specification | 99.8 | 2.8 | Up to specification | Qualified | |
| 030529 | The white loose block | Up to specification | Up to specification | 7..3 | 0.4 | Up to specification | 99.9 | 2.2 | Up to specification | Qualified | |
| 030525 | 12 | The white loose block | Up to specification | Up to specification | 7..3 | 0..3 | Up to specification | 99.4 | 3.2 | Up to specification | Qualified |
| 030527 | The white loose block | Up to specification | Up to specification | 7..3 | 0..4 | Up to specification | 99.3 | 3.6 | Up to specification | Qualified | |
| 030529 | The white loose block | Up to specification | Up to specification | 7..3 | 0..2 | Up to specification | 98.9 | 2.9 | Up to specification | Qualified | |
| 030525 | 18 | The white loose block | Up to specification | Up to specification | 7.2 | 0..4 | Up to specification | 98.8 | 4.0 | Up to specification | Qualified |
| 030527 | The white loose block | Up to specification | Up to specification | 7..3 | 0..3 | Up to specification | 99.1 | 2.8 | Up to specification | Qualified | |
| 030529 | The white loose block | Up to specification | Up to specification | 7..3 | 0..2 | Up to specification | 98.2 | 3.1 | Up to specification | Qualified | |
| 030525 | 24 | The white loose block | Up to specification | Up to specification | 7..2 | 0..4 | Up to specification | 98.1 | 4.2 | Up to specification | Qualified |
| 030527 | The white loose block | Up to specification | Up to specification | 7..3 | 0..4 | Up to specification | 98.3 | 3.8 | Up to specification | Qualified | |
| 030529 | The white loose block | Up to specification | Up to specification | 7..3 | 0..4 | Up to specification | 97.3 | 3.1 | Up to specification | Qualified |
The freeze-dried powder agent prescription The selection result of other specifications is identical.
The present invention, particularly preferred and preferred prescription has good stability, few side effects, the active raising, quality controllable, the storage life is long, is fit to large-scale production.
Four, the specific embodiment
Further specify the present invention by the following examples, but not as limitation of the present invention.
Embodiment 1
Prescription:
| Prescription | (1) |
| The succinic acid methylprednisolone | 25.35g |
| Sodium bicarbonate | 4.49g |
| Sodium dihydrogen phosphate | 1.385g |
| Sodium hydrogen phosphate | 17.4g |
| Lactose | 100g |
| Water for injection | Add to 1000ml |
1. preparating liquid: the alkalescent medicine adjuvant of getting recipe quantity dissolves with water for injection, the pH buffer agent of getting recipe quantity dissolves with water for injection, get stabilizing agent and add the dissolving of injection water, precision takes by weighing the succinic acid methylprednisolone of recipe quantity, with water for injection furnishing pasty state, slowly adds alkaline solution, the limit edged stirs, dissolve fully up to the succinic acid methylprednisolone, add pH buffer agent solution and stabiliser solution again, add the injection water and add to full dose.Add medicinal charcoal, stir evenly, placed about 20 minutes, the coarse filtration decarburization, and fine straining is qualified to medicinal liquid clarity.Sampling, measuring and regulating the medicinal liquid pH value is 7-8.With Φ 0.22 μ m microporous membrane filter aseptic filtration.Sampling and measuring, the character of medicinal liquid should be that colourless clear liquid, pH value should be 7-8, drug content should be the amount that contains bacterial endotoxin among the 90%-110% of labelled amount, the every ml should be less than 0.17EU.
2. liquid medicine filling: the processing of A. control cillin bottle: control cillin bottle specification is 2-50ml, earlier carry out ultrasonic cleaning with purified water, it is qualified that reuse is washed till clarity eventually through the filtering water for injection of 0.22 μ m, with clean qualified cillin bottle send into the tunnel baking oven carry out 350 ℃, dry and remove pyrogen more than 7 minutes, reduce to below 40 ℃, it is standby to enter sterilizing room.
B. the medicinal liquid of aseptic filtration is pressed the perfusion volume that drug content calculates every cillin bottle, carried out sterile filling 100 grades of laminar flow ultra-clean workplaces, first presses interior plug the cillin bottle after the fill.
3. lyophilization: in freeze drying box, pre-freeze below-38 ℃ 4 hours, under-38 ℃-0 ℃, 1.33Pa vacuum, distil then, remove after 90% at free moisture, after heat drying (maximum temperature must not be crossed 38 ℃) treats that temperature curve and vacuum curve overlap respectively, freeze-day with constant temperature promptly can be considered lyophilizing in 4 hours to be finished, and the final moisture content of freeze-dried composition is controlled at below 2%, and vacuum presses down and fills in tight in freeze drying box.
Other embodiment:
The weight and the weight range of main ingredient see Table 10 in the methylprednisolone sodium succinate for inj freeze-dried powder of different size of preparation, every bottle of freeze-dried composition.Its preparation method is with embodiment 1
Methylprednisolone sodium succinate lyophilized powder pin prepared according to the methods of the invention shows that through accelerated test and long-term test results it is qualified that freeze-dried powder of the present invention is stablized, and the results are shown in Table 8-table 9.
Table 10: the weight of main ingredient and contain the sodium amount in the methylprednisolone sodium succinate lyophilized powder pin
| The preparation specification | The 10mg/ bottle | The 20mg/ bottle | The 40mg/ bottle | The 125mg/ bottle | The 250mg/ bottle | The 500mg/ bottle | The 1000mg/ bottle | The 2000mg/ bottle |
| Succinic acid methylprednisolone weight (mg) | 12.67 | 25.35 | 50.69 | 158.42 | 316.85 | 633.70 | 1267.40 | 2534.80 |
| Sodium bicarbonate (mg) | 2.25 | 4.49 | 8.98 | 28.10 | 56.20 | 112.00 | 224.00 | 449.00 |
| Lactose (mg) | 100 | 100 | 100 | / | / | / | / | / |
| Sodium dihydrogen phosphate (mg) | 1.385 | 1.385 | 1.385 | 1.385 | 1.385 | 5.538 | 11.0765 | 22.1530 |
| Sodium hydrogen phosphate (mg) | 17.4 | 17.4 | 17.4 | 17.4 | 17.4 | 69.3 | 138.6 | 277.2 |
| Water for injection (ml) | 1.0 | 1.0 | 1.0 | 2.0 | 2.5 | 5.0 | 10.0 | 20.0 |
| Urbason Solubile dress (mg) | 13.26 | 26.52 | 53.04 | 165.77 | 331.56 | 663.11 | 1326.22 | 2652.45 |
| The sodium amount that contains (mg) in the Urbason Solubile | 0.6149 | 1.2297 | 2.4595 | 7.6868 | 15.3744 | 30.7484 | 61.4968 | 122.9941 |
| The sodium amount that contains (mg) in the sodium dihydrogen phosphate | 0.2655 | 0.2655 | 0.2655 | 0.2655 | 0.2655 | 1.0614 | 2.1229 | 4.2459 |
| The sodium amount that contains (mg) in the sodium hydrogen phosphate | 5.6366 | 5.6366 | 5.6366 | 5.6366 | 5.6366 | 22.4493 | 44.8986 | 89.7972 |
| The sodium amount that contains (mg) in every bottle | 6.5170 | 7.1318 | 8.3616 | 13.5889 | 21.2765 | 54.2591 | 108.5183 | 217.0372 |
| The weight of solid content (mg) in every bottle | 132.45 | 145.305 | 171.825 | 284.555 | 450.345 | 737.948 | 1475.8965 | 2951.803 |
| Sodium in every bottle accounts for the content (%) of solid content | 4.935 | 4.908 | 4.866 | 4.775 | 4.720 | 7.3526 | 7.3527 | 7.3526 |
| The content of sodium (%) in the Urbason Solubile | 4.637 | |||||||
Claims (10)
1. a lyophilized injectable powder that contains Urbason Solubile is characterized in that, is active ingredient with the succinic acid methylprednisolone, contains basic medicinally adjuvant, pH buffer agent and/or stabilizing agent.
2. according to the lyophilized injectable powder of claim 1, it is characterized in that,
Described basic medicinally adjuvant is selected from: any in sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, sodium lactate, sodium citrate, sodium sulfite, sodium sulfite, sodium pyrosulfite, sodium thiosulfate, potassium citrate, sodium acetate, sodium hydrogen phosphate, dipotassium hydrogen phosphate, Polymeric sodium metaphosphate., potassium metaphosphate, Soluble tartar., sodium tartrate, arginine, lysine, the meglumine or wantonly combination more than two kinds;
Described pH buffer agent is selected from: acetate buffer agent, citric acid buffer agent, tartaric acid buffer agent, phosphoric acid buffer agent, carbonic acid buffer agent,
Described stabilizing agent is selected from: glucide, poloxamer, sodium chloride, cyclodextrin, cellulose substances such as low molecular dextran, mannitol, lactose, glucose, maltose.
3. according to the lyophilized injectable powder of claim 1, it is characterized in that described basic medicinally adjuvant is a sodium bicarbonate; Described pH buffer agent is a phosphoric acid buffer agent; Described stabilizing agent is a lactose.
4. according to the lyophilized injectable powder of claim 3, it is characterized in that described phosphoric acid buffer agent is made up of acidic moiety sodium dihydrogen phosphate and basic moiety sodium hydrogen phosphate.
5. according to the lyophilized injectable powder of claim 1, it is characterized in that the prescription of every lyophilized injectable powder is: succinic acid methylprednisolone 1-3000mg; Basic medicinally adjuvant 1-1000mg; Stabilizing agent 1-500mg; The acidic moiety 1-50mg of pH buffer agent, the basic moiety 1-500mg of pH buffer agent; Water for injection 1-50ml; Every sodium content is 1-500mg.
6. according to the lyophilized injectable powder of claim 1, it is characterized in that the prescription of every lyophilized injectable powder is:
The succinic acid methylprednisolone 1-3000mg
Sodium bicarbonate 1-1000mg
Sodium dihydrogen phosphate 1-50mg
Sodium hydrogen phosphate 1-500mg
Lactose 0-500mg.
7. according to the lyophilized injectable powder of claim 1, it is characterized in that the prescription of every lyophilized injectable powder is:
The succinic acid methylprednisolone 10-3000mg
Sodium bicarbonate 2-500mg
Sodium dihydrogen phosphate 1-25mg
Sodium hydrogen phosphate 10-300mg
Lactose 0-100mg.
8. according to the lyophilized injectable powder of claim 1, it is characterized in that the prescription of different size lyophilized injectable powder is:
The preparation specification The 10mg/ bottle The 20mg/ bottle The 40mg/ bottle The 125mg/ bottle The 250mg/ bottle The 500mg/ bottle The 1000mg/ bottle The 2000mg/ bottle
Succinic acid methylprednisolone (mg) 12.67 25.35 50.69 158.42 316.85 633.70 1267.40 2534.80
Sodium bicarbonate (mg) 2.25 4.49 8.98 28.10 56.20 112.00 224.00 449.00
Lactose (mg) 100 100 100 / / / / /
Sodium dihydrogen phosphate (mg) 1.385 1.385 1.385 1.385 1.385 5.538 11.0765 22.1530
Sodium hydrogen phosphate (mg) 17.4 17.4 17.4 17.4 17.4 69.3 138.6 277.2
9. the preparation method of lyophilized injectable powder according to claim 1: through following steps:
1) the alkalescent medicine adjuvant dissolves in water, and it is standby to get alkaline solution,
2) preparation pH buffer agent is standby,
3) in case of necessity, stabilizing agent is dissolved in the water, standby,
4) succinic acid methylprednisolone water furnishing pasty state,
5) alkaline solution of the pastel of step 4 adding step 1) makes dissolving,
6) adding step 2 in the solution of step 5)) solution of step 3) adds water to full dose,
7) add medicinal charcoal, filter adjust pH, micro-pore-film filtration, fill, vacuum lyophilization.
10. the preparation method of lyophilized injectable powder according to claim 1: through following steps:
1) the alkalescent medicine adjuvant of getting recipe quantity dissolves with water for injection,
2) the pH buffer agent of getting recipe quantity dissolves with water for injection,
3) stabilizing agent of getting recipe quantity adds the dissolving of injection water,
4) get the succinic acid methylprednisolone of recipe quantity, with water for injection furnishing pasty state,
5) slowly add alkaline solution, the limit edged stirs, dissolve fully up to the succinic acid methylprednisolone,
6) add pH buffer agent solution and stabiliser solution again, add the injection water and add to full dose,
7) add medicinal charcoal, stir evenly, placed about 20 minutes, the coarse filtration decarburization, and fine straining is qualified to medicinal liquid clarity, sampling, measuring and regulating the medicinal liquid pH value is 7-8, with Ф 0.22 μ m microporous membrane filter aseptic filtration, sampling and measuring, the character of medicinal liquid, pH value, drug content and bacterial endotoxin should be up to specification, press drug content and calculate fill volume, fill, cillin bottle false add plug, vacuum lyophilization, the final moisture of freeze-dried composition is controlled at below 2%, press tight interior plug, roll aluminium-plastic cap, be packaged to be finished product.
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