CN101167730B - Compound betamethasone suspension injection - Google Patents
Compound betamethasone suspension injection Download PDFInfo
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- CN101167730B CN101167730B CN2007101642994A CN200710164299A CN101167730B CN 101167730 B CN101167730 B CN 101167730B CN 2007101642994 A CN2007101642994 A CN 2007101642994A CN 200710164299 A CN200710164299 A CN 200710164299A CN 101167730 B CN101167730 B CN 101167730B
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Abstract
The invention provides a compound suspending injection of betadexamethasone, which is a compound preparation containing betamethasone dipropionate with low dissolving degree, and betamethasone sodium phosphate with high dissolving degree. The invention has the advantages of quick effect, and long actuation duration, and is applicable for the treatment of diseases on muscle skeleton, and cartilage tissue, allergic disease, dermatopathy, collagenosis, neoplastic disease and other clinical diseases.
Description
Technical field
The present invention relates to pharmaceutical preparation, particularly a kind of compound betamethasone suspension injection.This injection is made up of low-solubility betamethasone dipropionate and highly dissoluble betamethasone sodium phosphate.
Background technology
Anaphylactic disease and allergic disease are clinical commonly encountered diseases and frequently-occurring diseases.Can involve each internal organs organ of human body, as joint, skin, kidney, respiratory tract and digestive tract etc.The lighter such as allergic rhinitis only are the property crossed symptoms such as nasal obstruction, sneeze; Weight person is as allergic asthma, lupus nephritis entail dangers to people's life then.At present, along with the continual renovation and the development of antibiotics and antiviral drugs, bacterial disease and viral disease have obtained better controlled, and anaphylactic disease and allergic disease then become the main killer who threatens human health.According to statistics, China's lupus erythematosus has 1,000,000 patients approximately, and sickness rate is up to 0.1%, and China rheumatoid disease patient Ze Yue has 3,600,000 more than.In addition, as allergic asthma, the harm broad masses of the people's that diseases such as urticaria, hypertrophic lichen planus, keloid, osteoarthritis are also all serious is healthy, has caused white elephant also for simultaneously family and society.
For these anaphylactic diseases and allergic disease, mainly be to rely on glucocorticoid to treat clinically, to stop the progress of the state of an illness.Glucocorticoid can be divided into fugitive, middle effect and long lasting several, though the kind onset of fugitive and middle effect is rapid, but action time is short, water-sodium retention is more serious, need every day in addition every several hours with regard to administration, compound betamethasone then can address this problem effectively, its wherein contained betamethasone sodium phosphate is soluble in water, onset rapidly after the injection reaches the purpose of rapid relief of symptoms; And betamethasone dipropionate is slightly soluble in water, is difficult for being organized absorption, can slowly and enduringly play a role, and can keep more than 4 weeks after the injection once.
At first by development of Schering Plough (Schering-Plough) company and production, name is called " Diprospan " to the compound betamethasone injection.But use benzyl alcohol in this formula for a product as local analgesia agent and antiseptic.Because its degraded of benzyl alcohol is produced and the metabolite benzaldehyde exists toxicity to the central nervous system.The intercalating agent of using in " Diprospan " prescription is a disodium edetate.Because it does not decompose in vivo, the interior calcium of energy consubstantiality and other ions (trace element) combine and excrete, so can cause hypocalcemia.In " Diprospan " prescription, use Polyethylene Glycol 3350, because the Polyethylene Glycol of macromolecule is many as the substrate of using in ointment and the suppository, as the easy triggered degradation of the solubilizing agent of injecting and administering preparations as surfactant.
For overcoming above defective, particularly reduce the generation of untoward reaction.The invention provides the compound betamethasone injection that a kind of new prescription is formed, the curative effect that this medicine is definite, indication widely, few untoward reaction, good stability, injection pain alleviates, good absorbing.
Summary of the invention
The invention provides a kind of new compound betamethasone injection prescription.
Its main component is: betamethasone sodium phosphate and betamethasone dipropionate, all the other are the medicine acceptable carrier.
Betamethasone sodium phosphate in the prescription is soluble in water, and onset rapidly after the injection reaches the purpose of rapid relief of symptoms; And betamethasone dipropionate is slightly soluble in water, is difficult for being organized absorption, can slowly and enduringly play a role, and can keep more than 4 weeks after the injection once.
We have studied the medicine acceptable carrier, and it is screened, and medicine acceptable carrier of the present invention comprises:
Surfactant: for example polyoxyethylene sorbitan monoleate, PEG400, Polyethylene Glycol 3350, propylene glycol
Metal-chelate mixture: calcium disodium edetate for example
Isoosmotic adjusting agent: sodium chloride for example
Antibacterial: for example methyl parahydroxybenzoate, propyl p-hydroxybenzoate sodium hydrogen phosphate
Protecting colloid: methylcellulose, sodium carboxymethyl cellulose, hydroxypropyl emthylcellulose surfactant wherein for example, consumption is preferably 0.0001-0.5%, 0.001-0.3% more preferably,
Antibacterial uses methyl parahydroxybenzoate, both mixture of propyl p-hydroxybenzoate; Both mix application and use more effectively more separately, mix to use preferable range at 0.001-0.1%.Methyl parahydroxybenzoate more preferably scope at 0.05-0.1%, propyl p-hydroxybenzoate more preferably scope at 0.01-0.1%.
Protecting colloid preferably carboxymethyl cellulose (sodium salt), consumption is preferably 0.001-0.5%, more preferably 0.005-0.4%.
All percentage ratios among the present invention are percent weight in volume W/V (%).
Therefore, prescription of the present invention is composed as follows:
Betamethasone sodium phosphate 0.01-0.22%
Betamethasone dipropionate 0.01-0.55%
Surfactant 0.001-0.3%
Metal-chelate mixture 0.0001-0.2%
Isoosmotic adjusting agent 0.001-0.5%
Antibacterial 0.001-0.1%
Sodium hydrogen phosphate 0.001-0.01%
Protecting colloid 0.001-0.5%
All the other are water for injection
Preferably as follows:
The micronized 0.45-0.55% of betamethasone dipropionate (in betamethasone)
Betamethasone sodium phosphate (in betamethasone) 0.18-0.22%
Polyoxyethylene sorbitan monoleate 0.01-0.2%
Sodium chloride 0.01-0.5%
Ca-EDTA is received 0.01-0.2%
PEG400 0.01-0.1%
Methyl parahydroxybenzoate 0.01-0.1%
Propyl p-hydroxybenzoate 0.01-0.1%
Sodium hydrogen phosphate 0.001-0.01%
Sodium carboxymethylcellulose pyce 0.005-0.4%
All the other are water for injection
The most preferred prescription of the present invention is listed in the embodiment of the invention.
The present invention also provides the preparation method of injection of the present invention, and this method is as follows:
Prepare: ampoule, handle according to a conventional method.Betamethasone dipropionate makes its particle diameter less than 15 μ m through micronizing.
1, the preparation of suspension
(1) gets the water for injection (temperature: 75-85 ℃) of recipe quantity 60%, after the sodium carboxymethyl cellulose that adds recipe quantity is treated stirring and dissolving, put into 0-10 ℃ of cold closet cooling back immediately and take out; Polyoxyethylene sorbitan monoleate, PEG400 are added with an amount of water for injection (80-90 ℃) dissolving back; Add through the betamethasone dipropionate of micronizing and fully stirring, reuse 300-350 purpose filter screen filters and promptly gets solution (A) again.
(1) water for injection (temperature: 80-90 ℃) adding methyl parahydroxybenzoate, the propyl p-hydroxybenzoate of getting recipe quantity 30% fully stirs and makes its dissolving, cool the temperature to 40-50 ℃, add again sodium hydrogen phosphate, sodium chloride, calcium disodium edetate and betamethasone sodium phosphate be stirred to after the dissolving solution (B).
Solution (B) is added in the prepared solution (A) at the state that stirs, and reuse 300-350 purpose filter screen filters.Suspension promptly.
2, use 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution adjust pH to the scope of 6.7-7.7 prepared suspension, sampling and measuring intermediate content.
3, water is penetrated in after-teeming according to intermediate content.
4, will make solution with 300-350 purpose strainer filtering, and make it become uniform suspension.
5, with suspension logical nitrogen fill under stirring, seal.
6, sterilization: 100 ℃ of steam sterilizations 30 minutes.
7, clarity test.
8, check.
9, packing, warehouse-in.
Prescription of the present invention and preparation method obtain through screening, and screening process is as follows:
In the prescription screening process, on the basis of our non-active ingredient recipe quantity in the prescription of reference and analysis " Diprospan ", simultaneously it is optimized.
(1) Chu Fang optimization
1, uses benzyl alcohol in " Diprospan " as local analgesia agent and antiseptic.Because its degraded of benzyl alcohol is produced and the metabolite benzaldehyde exists toxicity to the central nervous system.Consider that this product illustrates in usage and dosage, can share with procaine hydrochloride or lignocaine in case of necessity, play analgesic effect, thus we in the process of prescription screening, benzyl alcohol is not considered, benzyl alcohol is left out in prescription.
2, suitably add chelating agen in order to increase stability of formulation in the injection, what use in " Diprospan " prescription is disodium edetate.Because it does not decompose in vivo, the interior calcium of energy consubstantiality and other ions (trace element) combine and excrete, so can cause hypocalcemia.We substitute with edetic acid acid calcium sodium, to avoid occurring hypocalcemia.Recipe quantity is that usual amounts is 0.02%.
3, in " Diprospan " prescription, use Polyethylene Glycol 3350 as surfactant, because it is the Polyethylene Glycol of macromolecule is many as the substrate of using in ointment and the suppository, general not as the solubilizing agent of injecting and administering preparations; So substitute with PEG400.
(2) consumption of various nonactive compositions determines
1, methyl parahydroxybenzoate, propyl p-hydroxybenzoate recipe quantity determines
Both mix methyl parahydroxybenzoate, propyl p-hydroxybenzoate application and use more effectively more separately, mix range of application at 0.05-0.1%.Get according to both corresponding calculated by peak area in high-efficient liquid phase chromatogram in the Diprospan product that Schering-Plough company is produced, the consumption of methyl parahydroxybenzoate is 0.78mg/ml, the consumption of methyl parahydroxybenzoate is 0.11mg/ml, is lower than its usual amounts.So the recipe quantity of methyl parahydroxybenzoate is 0.78mg/ml, the consumption of methyl parahydroxybenzoate is 0.11mg/ml.
2, the sodium chloride consumption determines
When the osmotic pressure of injection surpassed the tolerance range of human body, injection tended to produce the absorption that stimulates and have influence on medicine.Sodium chloride is then used in injection as isoosmotic adjusting agent.By the Diprospan product potentiometric determination sodium chloride content that Schering-Plough company is produced, its result is about sodium chloride-containing 5mg in every 1ml solution, so with the recipe quantity of this consumption as us.
3, the screening of surfactant and protecting colloid consumption
We will be prepared into suspension through the protecting colloid and the surfactant of micronizing betamethasone dipropionate adding different amounts, compare.(betamethasone sodium phosphate with bsp represent, betamethasone dipropionate represents with bet) prescription is as follows:
The screening of table 1 surfactant and protecting colloid consumption
| The prescription number | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 |
| Bet bsp sodium carboxymethyl cellulose polyoxyethylene sorbitan monoleate PEG400 sodium chloride methyl parahydroxybenzoate propyl p-hydroxybenzoate | 5g 2g 5 3g 2g 5g 0.78g 0.11g | 5g 2g 5 2g 1g 5g 0.78g 0.11g | 5g 2g 4g 3g 2g 5g 0.78g 0.11g | 5g 2g 4g 2g 1g 5g 0.78g 0.11g | 5g 2g 3g 3g 2g 5g 0.78g 0.11g | 5g 2g 3g 2g 1g 5g 0.78g 0.11g |
| Edetic acid acid calcium sodium sodium hydrogen phosphate water | 0.2g 0.1g adds to 1L | 0.2g 0.1g adds to 1L | 0.2g0.1g add to 1L | 0.2g 0.1g adds to 1L | 0.2g 0.1g adds to 1L | 0.2g 0.1g adds to 1L |
With the prescription suspension of 1-6 and commercially available product (lot number: ABBKA03A) in the calorstat of 4500LX ± 500LX illumination condition and 40 ℃ ± 2 ℃, placed 10 days respectively, detect its character, pH value, clarity, easily injectivity (quality standard with reference to Diprospan is measured with No. 41/2 syringe needle), and the related substance of bet, bsp in sampling in 0,10 day.The results are shown in Table 2 and table 3:
Influence factor's result of the test that table 2 is placed under illumination condition:
| The prescription number | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 | Commercially available product | ||
| 0 day | The easy injectivity of character pH value clarity | White suspension 7.2 is qualified | White suspension 7.1 is qualified | White suspension 7.2 is qualified | White suspension 7.2 is qualified | White suspension 7.1 is qualified | White suspension 7.2 is qualified | White suspension 7.2 is qualified | |
| Impurity (%) | bet | 1.83 | 1.79 | 1.74 | 1.82 | 1.75 | 1.92 | 1.84 | |
| bsp | 0.91 | 0.85 | 0.79 | 0.86 | 0.85 | 0.84 | 0.97 | ||
| 10 days | The easy injectivity of character pH value clarity | White suspension 7.3 is qualified | White suspension 7.2 is qualified | White suspension 7.3 is qualified | White suspension 7.3 is qualified | White suspension 7.2 is qualified defective | White suspension 7.2 is qualified defective | White suspension 7.2 is qualified | |
| Impurity (%) | bet | 2.07 | 2.08 | 2.01 | 2.08 | 2.04 | 2.14 | 2.09 | |
| bsp | 1.06 | 1.05 | 1.01 | 1.08 | 1.06 | 1.07 | 1.13 | ||
Influence factor's result of the test that table 3 is placed in 40 ℃ ± 2 ℃ calorstat:
| The prescription number | Prescription 1 | Prescription 2 | Prescription 3 | Prescription 4 | Prescription 5 | Prescription 6 | Commercially available product | ||
| 0 day | The easy injectivity of character pH value clarity | White suspension 7.2 is qualified | White suspension 7.1 is qualified | White suspension 7.2 is qualified | White suspension 7.2 is qualified | White suspension 7.1 is qualified | White suspension 7.2 is qualified | White suspension 7.2 is qualified | |
| Impurity (%) | bet | 1.83 | 1.79 | 1.74 | 1.82 | 1.75 | 1.92 | 1.84 | |
| bsp | 0.91 | 0.85 | 0.79 | 0.86 | 0.85 | 0.84 | 0.97 | ||
| 10 days | The easy injectivity of character pH value clarity | White suspension 7.2 is qualified | White suspension 7.2 is qualified | White suspension 7.2 is qualified | White suspension 7.2 is qualified | White suspension 7.2 is qualified defective | White suspension 7.2 is qualified defective | White suspension 7.2 is qualified | |
| Impurity (%) | bet | 2.11 | 2.07 | 2.09 | 2.15 | 2.13 | 2.15 | 2.23 | |
| bsp | 1.13 | 1.08 | 1.05 | 1.11 | 1.08 | 1.07 | 1.24 | ||
Shown by above result of the test: prescription 1～4 was placed 10 days under high temperature and illumination condition with commercially available product, and the related substance of its character, pH value, clarity, easy injectivity and two principal agents has no significant change; And the 5 easy injectivities when placing 10 days with prescription 6 under these two kinds of conditions of writing out a prescription are defective; the consumption that protecting colloid is described has a direct impact the easy injectivity of suspension; prescription 1～4 is placed 10 days its each test items under illumination and hot conditions do not have significant change, illustrates that protecting colloid and the applied amount of surfactant in the prescription 1～4 all can.Optimizing prescriptions 4.
The present invention also provides method of quality control, and this method is as follows:
[character] this product is the suspension of subparticle, leaves standstill the back subparticle and sinks, and becomes uniform white suspension after the jolting.
In the chromatogram that [discriminating] writes down under the assay item, the betamethasone dipropionate peak should be consistent with the retention time at corresponding reference substance peak with the retention time at betamethasone sodium phosphate peak in the need testing solution.
[inspection] pH value should be 6.7-7.7 (two appendix VI of Chinese Pharmacopoeia version in 2000 H).
Easily injectivity is got this product, with No. 41/2 syringe needle test, should easily pass through.
Aseptic 11 of this product of getting all add 0.5% tween 80 in THIOGLYCOLLIC ACID salt and mycete soup culture medium, check (two appendix XI of Chinese Pharmacopoeia version in 2000 H direct inoculation) in accordance with the law, should be up to specification.
Other should meet every regulation (except the pyrogen) relevant under the injection item (two appendix IB of Chinese Pharmacopoeia version in 2000).
[assay] measured according to high performance liquid chromatography (two appendix VD of Chinese Pharmacopoeia version in 2000).
Betamethasone dipropionate chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, with methanol-0.05mol/L potassium dihydrogen phosphate (70: 30) is mobile phase, the detection wavelength is 254nm, number of theoretical plate calculates by the betamethasone dipropionate peak should be not less than 2000, and the separating degree at betamethasone dipropionate main peak and adjacent impurity peaks and betamethasone sodium phosphate peak should meet the requirements.
Algoscopy is got 20 of this product, the jolting mixing, and precision is measured 5ml, puts in the 50ml measuring bottle, adds mobile phase and is diluted to scale, shakes up, and filters, and precision is measured 20 μ l, injects chromatograph of liquid, the record chromatogram; It is an amount of that other gets the betamethasone dipropionate reference substance, and accurate title is fixed, adds the mobile phase dissolving and quantitatively be diluted to the solution that every 1ml contains betamethasone 0.5mg, measures with method, presses external standard method with calculated by peak area, promptly.
Betamethasone sodium phosphate chromatographic condition and system suitability test are filler with octadecylsilane chemically bonded silica, with methanol-0.05mol/L potassium dihydrogen phosphate (70: 55) is mobile phase, the detection wavelength is 254nm, number of theoretical plate calculates by the betamethasone sodium phosphate peak should be not less than 2000, and the separating degree at betamethasone sodium phosphate main peak and adjacent impurity peaks and betamethasone dipropionate peak should meet the requirements.
Algoscopy is got 20 bottles of this product, the jolting mixing, and precision is measured 5ml, puts in the 50ml measuring bottle, adds mobile phase and is diluted to scale, shakes up, and filters, and precision is measured in the 20 μ l injecting chromatographs, the record chromatogram; It is an amount of that other gets the betamethasone sodium phosphate reference substance of once measuring moisture, accurate claim fixed, add the mobile phase dissolving and quantitatively dilution make the solution that contains betamethasone 0.2mg among every 1ml approximately, measure with method, by external standard method with calculated by peak area, promptly.
[classification] Aeroseb-Dex.
[specification] 1ml: betamethasone dipropionate 5mg and betamethasone sodium phosphate 2mg (all in betamethasone).
[storage] uses preceding shake well, 2～25 ℃ of preservations, notes lucifuge and antifreeze.
Suspension of the present invention has multiple advantage, be included in long term storage after, the easy injectivity that jolting does not occur " piece " yet and greatly improves when using compositions.And compositions is stable, for example the stability up to 3 years.
The specific embodiment
Below in conjunction with embodiment the present invention is described further.
Embodiment 1: the preparation of compound betamethasone injection
Prepare: ampoule, handle according to a conventional method.Betamethasone dipropionate makes its particle diameter less than 15 μ m through micronizing.
1, the preparation of suspension
(1) gets the water for injection (temperature: 75-85 ℃) of recipe quantity 60%, after the sodium carboxymethyl cellulose that adds recipe quantity is treated stirring and dissolving, put into 0-10 ℃ of cold closet cooling back immediately and take out; Polyoxyethylene sorbitan monoleate, PEG400 are added with an amount of water for injection (80-90 ℃) dissolving back; Add through the betamethasone dipropionate of micronizing and fully stirring, reuse 300-350 purpose filter screen filters and promptly gets solution (A) again.
(2) water for injection (temperature: 80-90 ℃) adding methyl parahydroxybenzoate, the propyl p-hydroxybenzoate of getting recipe quantity 30% fully stirs and makes its dissolving, cool the temperature to 40-50 ℃, add again sodium hydrogen phosphate, sodium chloride, calcium disodium edetate and betamethasone sodium phosphate be stirred to after the dissolving solution (B).
Solution (B) is added in the prepared solution (A) at the state that stirs, and reuse 300-350 purpose filter screen filters.Suspension promptly.
Use 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution adjust pH to the scope of 6.7-7.7 prepared suspension, sampling and measuring intermediate content.Water is penetrated in after-teeming according to intermediate content.To make solution with 300-350 purpose strainer filtering, and make it become uniform suspension.With suspension logical nitrogen fill under stirring, seal.100 ℃ of steam sterilizations 30 minutes.Sterilization back sample carries out clarity test.
Embodiment 2: the composition of compound betamethasone injection
| Betamethasone dipropionate (in betamethasone) is micronized | 5g |
| Betamethasone sodium phosphate (in betamethasone) polyoxyethylene sorbitan monoleate sodium chloride Ca-EDTA is received PEG400 methyl parahydroxybenzoate propyl p-hydroxybenzoate sodium hydrogen phosphate sodium carboxymethyl cellulose | 2g 2g 5g 0.2g 1g 0.78g 0.11g 0.1g 4g |
Water for injection adds to 1000ml
Embodiment 3: the composition of compound betamethasone injection
| The micronized betamethasone sodium phosphate of betamethasone dipropionate (in betamethasone) (in betamethasone) polyoxyethylene sorbitan monoleate sodium chloride Ca-EDTA is received PEG400 methyl parahydroxybenzoate propyl p-hydroxybenzoate sodium hydrogen phosphate methylcellulose | 5g 2g 2g 5g 0.2g 1g 0.78g 0.11g 0.1g 4g |
Water for injection adds to 1000ml
Test: compound betamethasone injection stability test
1, sample source and lot number
Sample source: Tianjin Hankang Medicine Bioisystech Co., Ltd
Lot number: 040424,040226,040428
2, the method for inspection and investigation project
Test according to quality research and quality standard prescriptive procedure, mainly investigate appearance character, clarity, pH value, easy injectivity, related substance, the aseptic and content of this product.
3, stability test project and result
Accelerated test: with lot number is 040424,040426,040428 sample simulation listing packing, under 30 ± 2 ℃ of temperature, RH60% ± 5% condition, carry out accelerated test, respectively at 0,1,2,3, sampling in 6 months with quality standard (draft), is investigated appearance character, clarity, pH value, easy injectivity, related substance, aseptic and content by clinical.Project, and with 0 day data relatively, the results are shown in Table 1.
Result of the test shows, accelerated test 6 months, and the every index of three batch samples has no significant change.Illustrate that this product is stable with this understanding.
Keep sample for a long time: with lot number is 040424,040426,040428 sample simulation listing packing, preserve at room temperature condition, respectively at sampling in the 3rd, 6,9,12,18,24 month, investigate appearance character, clarity, pH value, easy injectivity, related substance, aseptic and content.Project, and with 0 day data relatively, the results are shown in Table 2.
Result of the test shows: kept sample for a long time 24 months, every detection index of three batch samples has no significant change.
4 conclusions
1) the accelerated test result shows: accelerated test 6 months, the every index of three batch samples has no significant change.Illustrate that this product is stable with this understanding.
2) result of the test that keeps sample for a long time shows: kept sample for a long time 24 months, every detection index of three batch samples has no significant change.
Table 1 compound betamethasone injection accelerated test result
| Lot number | Time (moon) | Character | pH | Clarity | Easy injectivity | Related substance (%) | Aseptic | Content (%) | ||
| Betamethasone dipropionate | Betamethasone sodium phosphate | Betamethasone dipropionate | Betamethasone sodium phosphate | |||||||
| 040424 | 0 1 2 3 6 | Up to specification up to specification | 7.2 7.1 7.1 7.0 7.1 | Qualified qualified | Qualified qualified | 1.83 2.04 2.10 2.27 2.36 | 0.71 0.71 0.74 0.76 0.77 | Up to specification up to specification | 101.2 99.4 99.2 100.6 99.8 | 105.0 102.8 103.5 102.2 102.9 |
| 040426 | 0 1 2 3 6 | Up to specification up to specification | 7.3 7.2 7.2 7.1 7.1 | Qualified qualified | Qualified qualified | 2.07 2.14 2.17 2.29 2.41 | 0.71 0.70 0.76 0.75 0.79 | Up to specification up to specification | 100.6 99.5 99.4 101.0 99.7 | 103.8 103.0 103.3 102.7 102.6 |
| 040428 | 0 1 2 3 6 | Up to specification up to specification | 7.2 7.2 7.1 7.1 7.0 | Qualified qualified | Qualified qualified | 1.82 2.05 2.13 2.26 2.34 | 0.72 0.74 0.78 0.83 0.76 | Up to specification up to specification | 100.8 99.4 99.6 100.9 99.6 | 104.0 103.0 103.5 103.1 102.1 |
Table 2 compound betamethasone injection long-term test results
| Lot number | Time (moon) | Character | pH | Clarity | Easy injectivity | Related substance (%) | Aseptic | Content (%) | ||
| Betamethasone dipropionate | Betamethasone sodium phosphate | Betamethasone dipropionate | Betamethasone sodium phosphate | |||||||
| 040424 | 0 3 6 9 12 18 24 | Up to specification up to specification up to specification | 7.2 7.1 7.2 7.1 7.0 7.1 7.1 | Qualified qualified qualified | Qualified qualified qualified | 1.83 1.92 2.07 2.14 2.20 2.25 2.29 | 0.71 0.73 0.70 0.81 0.75 0.79 0.85 | Up to specification up to specification up to specification | 101.2 100.6 99.5 99.9 99.3 99.2 99.1 | 105.0 102.9 103.0 101.9 102.7 101.9 101.6 |
| 040426 | 0 3 6 9 12 18 24 | Up to specification up to specification up to specification | 7.3 7.2 7.2 7.1 7.0 7.0 7.0 | Qualified qualified qualified | Qualified qualified qualified | 2.07 2.02 2.13 2.15 2.19 2.21 2.24 | 0.71 0.76 0.74 0.79 0.81 0.88 0.91 | Up to specification up to specification up to specification | 100.6 100.8 99.9 99.3 99.1 99.0 99.0 | 103.8 102.8 103.2 101.9 102.1 102.0 101.8 |
| 040428 | 0 3 6 9 12 18 24 | Up to specification up to specification up to specification | 7.2 7.1 7.0 7.0 7.1 7.1 7.0 | Qualified qualified qualified | Qualified qualified qualified | 1.82 1.96 2.15 2.09 2.14 2.19 2.23 | 0.72 0.79 0.78 0.72 0.92 0.94 0.96 | Up to specification up to specification up to specification | 100.8 100.9 99.9 99.5 99.1 99.0 99.0 | 104.0 102.6 103.1 102.2 101.7 101.5 101.2 |
Claims (3)
1. an injection medicine preparation that contains betamethasone dipropionate and betamethasone sodium phosphate is characterized in that, described preparation consists of:
Micronized betamethasone dipropionate is in betamethasone 5g
Betamethasone sodium phosphate is in betamethasone 2g
Polyoxyethylene sorbitan monoleate 2g
Sodium chloride 5g
Ca-EDTA is received 0.2g
PEG400 1g
Methyl parahydroxybenzoate 0.78g
Propyl p-hydroxybenzoate 0.11g
Sodium hydrogen phosphate 0.1g
Sodium carboxymethyl cellulose 4g
Water for injection adds to 1000ml.
2. the preparation method of the described preparation of claim 1, step is as follows:
Prepare: ampoule, to handle according to a conventional method, betamethasone dipropionate makes its particle diameter less than 15 μ m through micronizing,
1) preparation of suspension
(1) gets the water for injection of recipe quantity 60%, temperature: 75-85 ℃, after the sodium carboxymethyl cellulose that adds recipe quantity is treated stirring and dissolving, put into 0-10 ℃ of cold closet cooling back immediately and take out; With an amount of water for injection of polyoxyethylene sorbitan monoleate, PEG400, add after the 80-90 ℃ of dissolving; Add through the betamethasone dipropionate of micronizing and fully stirring, reuse 300-350 purpose filter screen filters and promptly gets solution A again,
(2) get the water for injection of recipe quantity 30%, temperature: 80-90 ℃ of adding methyl parahydroxybenzoate, propyl p-hydroxybenzoate fully stir and make its dissolving, cool the temperature to 40-50 ℃, add again and get solution B after sodium hydrogen phosphate, sodium chloride, calcium disodium edetate and betamethasone sodium phosphate are stirred to dissolving
Solution B is added in the prepared solution A at the state that stirs, and reuse 300-350 purpose filter screen filters, and promptly gets suspension,
2) use 1mol/L hydrochloric acid solution or 1mol/L sodium hydroxide solution adjust pH to the scope of 6.7-7.7 prepared suspension, sampling and measuring intermediate content,
3) water is penetrated in after-teeming according to intermediate content,
4) will make solution with 300-350 purpose strainer filtering, and make it become uniform suspension,
5) with suspension logical nitrogen fill under stirring, seal,
6) sterilization: 100 ℃ of steam sterilizations 30 minutes,
7) clarity test,
8) check,
9) packing, warehouse-in.
3. the detection method of the described preparation of claim 1, step is as follows:
Character: this product is the suspension of subparticle, leaves standstill the back subparticle and sinks, and becomes uniform white suspension after the jolting,
Differentiate: in the chromatogram that writes down under the assay item, the betamethasone dipropionate peak should be consistent with the retention time at corresponding reference substance peak with the retention time at betamethasone sodium phosphate peak in the need testing solution,
Check: should meet the regulation of two appendix VIH of Chinese Pharmacopoeia version in 2000, pH value should be 6.7-7.7,
Easy injectivity: get this product,, should easily pass through with No. 41/2 syringe needle test,
Aseptic: get 11 of this product, in THIOGLYCOLLIC ACID salt and mycete soup culture medium, all add 0.5% tween 80, press two appendix XIH of Chinese Pharmacopoeia version in 2000 direct inoculation, check in accordance with the law, should be up to specification,
Other: outside the depyrogenation, should meet the regulation of two appendix I of Chinese Pharmacopoeia version in 2000 B,
Assay: according to two appendix VD of Chinese Pharmacopoeia version in 2000 high effective liquid chromatography for measuring,
Betamethasone dipropionate: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, with 70: 30 methanol-0.05mol/L potassium dihydrogen phosphates of volume ratio is mobile phase, the detection wavelength is 254nm, number of theoretical plate calculates by the betamethasone dipropionate peak should be not less than 2000, the separating degree at betamethasone dipropionate main peak and adjacent impurity peaks and betamethasone sodium phosphate peak should meet the requirements
Algoscopy: get 20 of this product, the jolting mixing, precision is measured 5ml, puts in the 50ml measuring bottle, adds mobile phase and is diluted to scale, shakes up, and filters, and precision is measured 20 μ l, injects chromatograph of liquid, the record chromatogram; It is an amount of that other gets the betamethasone dipropionate reference substance, and accurate title is fixed, adds the mobile phase dissolving and quantitatively be diluted to the solution that every 1ml contains betamethasone 0.5mg, measures with method, presses external standard method with calculated by peak area, that is,
Betamethasone sodium phosphate: chromatographic condition and system suitability test: with octadecylsilane chemically bonded silica is filler, with 70: 55 methanol of volume ratio-0.05mol/L potassium dihydrogen phosphate is mobile phase, the detection wavelength is 254nm, number of theoretical plate calculates by the betamethasone sodium phosphate peak should be not less than 2000, the separating degree at betamethasone sodium phosphate main peak and adjacent impurity peaks and betamethasone dipropionate peak should meet the requirements
Algoscopy: get 20 bottles of this product, the jolting mixing, precision is measured 5ml, puts in the 50ml measuring bottle, adds mobile phase and is diluted to scale, shakes up, and filters, and precision is measured in the 20 μ l injecting chromatographs, the record chromatogram; It is an amount of that other gets the betamethasone sodium phosphate reference substance of once measuring moisture, accurate claim fixed, add the mobile phase dissolving and quantitatively dilution make the solution that contains betamethasone 0.2mg among every 1ml approximately, measure with method, by external standard method with calculated by peak area, promptly.
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| CN2007101642994A CN101167730B (en) | 2007-10-24 | 2007-10-24 | Compound betamethasone suspension injection |
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| CN2007101642994A CN101167730B (en) | 2007-10-24 | 2007-10-24 | Compound betamethasone suspension injection |
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| CN101167730A CN101167730A (en) | 2008-04-30 |
| CN101167730B true CN101167730B (en) | 2010-11-24 |
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| CN101791313B (en) * | 2010-03-17 | 2012-06-06 | 天津金耀集团有限公司 | Application of calcium disodium edentate and corticosteroid compound preparation in preparing medicine capable of inhibiting connective tissue growth factors and monoamine oxidase |
| CN103705922B (en) * | 2012-10-08 | 2018-07-17 | 天津金耀集团有限公司 | Using glucocorticoid as the externally-applied medicinal composition of active constituent |
| CN105997866B (en) * | 2016-07-13 | 2019-08-20 | 成都明慈医药科技有限公司 | A kind of suspension and preparation method thereof containing dexamethasone |
| CN110548005B (en) * | 2018-05-30 | 2021-08-31 | 南京诺瑞特医药科技有限公司 | Sustained-release injection preparation containing donepezil derivative |
| CN113030281B (en) * | 2019-12-24 | 2024-03-12 | 重庆华邦制药有限公司 | Method for separating compounds D and/or J |
| CN112807314A (en) * | 2020-09-17 | 2021-05-18 | 四川大学 | Gargle solution and preparation method thereof |
| CN112924633B (en) * | 2021-05-10 | 2021-08-10 | 天津瑞普生物技术股份有限公司 | Sterility detection method for ceftiofur oil suspension injection |
| CN113855630A (en) * | 2021-11-19 | 2021-12-31 | 莱默(北京)药业科技有限公司 | Betamethasone sodium phosphate and betamethasone acetate suspension injection and preparation method thereof |
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