CN101327194A - Hydrochloric acid diltiazem freeze-dried powder injection for injections and preparation method thereof - Google Patents
Hydrochloric acid diltiazem freeze-dried powder injection for injections and preparation method thereof Download PDFInfo
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- CN101327194A CN101327194A CNA2008101267508A CN200810126750A CN101327194A CN 101327194 A CN101327194 A CN 101327194A CN A2008101267508 A CNA2008101267508 A CN A2008101267508A CN 200810126750 A CN200810126750 A CN 200810126750A CN 101327194 A CN101327194 A CN 101327194A
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Abstract
The invention provides a diltiazem hydrochloride freeze-dried powder injection for injection and a preparation method thereof. The freeze-dried powder injection comprises diltiazem hydrochloride and mannite, the proportion by weight of diltiazem hydrochloride and mannite is 1: 1 to 8. The freeze-dried powder injection has favorable clarity and stability and high content of main drug, thereby being freeze-dried powder injection with good quality.
Description
Technical field
The invention belongs to the pharmaceutical technology field, particularly a kind of hydrochloric acid diltiazem freeze-dried powder injection for injections and preparation method thereof.
Background technology
Diltiazem hydrochloride, chemistry is called suitable-(+)-5-[(2-dimethylamino) ethyl]-2-(4-methoxyphenyl)-3-acetoxyl group-2,3-dihydro-1,5-benzothiazepines-4 (5H)-keto hydrochloride, molecular formula is: C
22H
26N
2O
4S; Molecular weight is 450.98, and its chemical structural formula is:
Diltiazem hydrochloride is the calcium channel blocade, can expand visceral pericardium and subendocardial coronary artery effectively, alleviates spontaneous angina pectoris or brings out angina pectoris due to the coronary vasospasm by ergometrine; By decreased heart rate and bringing high blood pressure down, reduce myocardium requirementing keto quantity, increase exercise tolerance and also alleviate exertional angina pectoris; Can make vascular smooth muscle relaxation, peripheral vascular resistance descends, and blood pressure reduces; The amplitude of its blood pressure lowering is relevant with hypertensive degree, and the normotensive only makes blood pressure slightly descend; Negative inotropic action is arranged, and the conduction of can slow down sinuatrial node and atrioventricular node.Be used for angina pectoris and exertional angina pectoris that coronary vasospasm causes clinically.Also can be used for hypertension and source of manure cardiomyopathy.
Patent application CN200510061398.0, name is called " diltiazem hydrochloride and preparation method thereof ", a kind of diltiazem hydrochloride and preparation method thereof is disclosed in this patent application, diltiazem hydrochloride and drop pill substrate are become diltiazem hydrochloride according to certain ratio preparation, the diltiazem hydrochloride raw material is water insoluble, and the absorption rate of medicine improves with the increase of dispersion.Diltiazem hydrochloride system adopts the preparation of solid-state physics dispersion principle preparation, will be in water fusion behind the medicine of indissoluble and the drop pill substrate mixing, solidify by system of dripping and quenching, making medicine be molecule, colloid or microcrystalline state is scattered in the substrate, because the gross area of medicine increases, medicine disengages with crystallite or unformed microgranule, so medicine dissolution and absorption quickening, and bioavailability is improved.
Patent application CN200310112634.8, name is called " diltiazem hydrochloride postpone spacetabs type pellet and preparation method thereof ", is filled in the hard capsule after this pellet is mixed by a certain percentage by the diltiazem hydrochloride micropill of two or more different drug release behaviors or compacting makes in flakes.The application's preparation is after administration, and hysteresis release through 4-6 hour the time reaches and keeps this level behind the peak and reach 10-16 hour, then slowly discharges medicine until taking medicine back 24 hours.Pass through preparation in this application to different micropills, resulting pellet release longer duration, but its preparation method is too complicated.
Patent application CN200510002112.1, name is called " purposes of diltiazem hydrochloride in the preparation antidote ", diltiazem hydrochloride is disclosed in this patent application in the new purposes aspect antidote, specifically, drug induced hepatitis such as carbon tetrachloride poisoning hepatitis and analeptic drugs cocaine poisoning hepatitis can be effectively treated, and the neural excitation that cocaine brings out can be suppressed effectively.
Prior art shows, relevant patent and the document both at home and abroad that also do not have at present hydrochloric acid diltiazem freeze-dried powder injection for injections, although existing on the market now hydrochloric acid diltiazem freeze-dried powder injection for injections is sold, but the preparation method of not mentioned this product, and commercially available prod clarity and stable bad, wherein drug content is low, the content of related substance is then high, research worker of the present invention is in order to improve the above-mentioned performance of diltiazem hydrochloride, by long-term experiment research, find to prepare some changes of method again by changing prescription and freeze-dry process, can overcome above-mentioned defective, obtain clarity and good stability, and the drug content height, the lyophilized injectable powder on its related substances ground, therefore, special proposition the present invention.
Summary of the invention
One of purpose of the present invention is to provide a kind of hydrochloric acid diltiazem freeze-dried powder injection for injections, and described lyophilized injectable powder clarity is good, good stability, drug content height wherein.
A kind of hydrochloric acid diltiazem freeze-dried powder injection for injections, comprise diltiazem hydrochloride and mannitol, it is characterized in that, the weight ratio of described diltiazem hydrochloride and mannitol is 1: 1-8, the weight ratio of preferred described diltiazem hydrochloride and mannitol is 1: 3-8, the weight ratio of more preferably described diltiazem hydrochloride and mannitol is 1: 5-7.
Hydrochloric acid diltiazem freeze-dried powder injection for injections of the present invention comprises:
Diltiazem hydrochloride 10.2g
Mannitol 70.0g
Water for injection adds to 2000ml
Lyophilizing is made 1000 bottles
Described lyophilizing is: earlier be under-40 ℃ the condition pre-freeze 2-4 hour in temperature, through being warming up in 10-16 hour-5-5 ℃, be incubated 12-18 hour more then, be warming up to 25-30 ℃ more gradually afterwards, kept 3-5 hour.
Hydrochloric acid diltiazem freeze-dried powder injection for injections of the present invention comprises:
Diltiazem hydrochloride 51.0g
Mannitol 75.0g
Water for injection adds to 2000ml
Lyophilizing is made 1000 bottles
Described lyophilizing is: earlier be under-40 ℃ the condition pre-freeze 2-4 hour in temperature, through being warming up in 10-16 hour-5-5 ℃, be incubated 12-18 hour more then, be warming up to 25-30 ℃ more gradually afterwards, kept 3-5 hour.
In the hydrochloric acid diltiazem freeze-dried powder injection for injections of the present invention, described water for injection is 50-70 ℃ water, and the temperature of preferred described water for injection is 50-60 ℃ a water.
In the prior art, exist diltiazem hydrochloride and diltiazem hydrochloride and postpone slow-release micro-pill, but do not have hydrochloric acid diltiazem freeze-dried powder injection for injections, its reason may be that present technology can't become freeze-dried powder injection with its preparation, or prepared hydrochloric acid diltiazem freeze-dried powder injection for injections clarity and stable bad, wherein drug content is low, and the content of related substance is then high.Among the present invention, by the principal agent raw material is mixed with a certain amount of mannitol, add water for injection then, the water for injection that particularly adds temperature and be 50-70 ℃ dissolves it, cooperate appropriate freeze-dry process again, making prepared hydrochloride for injection diltiazem can overcome above-mentioned defective, is the high lyophilized injectable powder of a kind of quality.
Another object of the present invention is to provide a kind of preparation method of hydrochloric acid diltiazem freeze-dried powder injection for injections.
To achieve these goals, the technical solution used in the present invention is:
A kind of preparation method for preparing hydrochloric acid diltiazem freeze-dried powder injection for injections is characterized in that, described method may further comprise the steps:
(1) take by weighing the diltiazem hydrochloride and the mannitol of recipe quantity, place Agitation Tank, the water for injection that adds the 1/2-2/3 that accounts for whole water for injection consumptions again dissolves it fully, obtains mixed solution;
(2) in above-mentioned mixed solution, add sodium hydroxide solution and regulate its pH value to 5.0 ± 0.05;
(3) in the solution of step (2) gained, add medicinal carbon, leave standstill after stirring, refilter and take off charcoal, obtain taking off the filtrate behind the charcoal;
(4) filtrate that will take off behind the charcoal is diluted to configuration amount with adding water for injection, and the back that stirs is by 0.22 μ m filtering with microporous membrane, and the filtrate that obtains is packed in the bottle and kept the gas outlet;
(5) filtrate that step (4) is loaded on call in the bottle is carried out lyophilization: earlier be under-40 ℃ the condition pre-freeze 2-4 hour in temperature, then through being warming up in 10-16 hour-5-5 ℃, be incubated 12-18 hour again, be warming up to 25-30 ℃ more gradually afterwards, kept 3-5 hour.
The consumption of medicinal carbon of the present invention is 0.05% of step (a 2) gained solution weight.
The time of stirring in the step of the present invention (3) is 20-40 minute.
The concentration of sodium hydroxide solution of the present invention is 0.05-0.15mol/l.
The concentration of sodium hydroxide solution of the present invention is 0.1mol/l.
Lyophilization of the present invention comprises:
First pre-freeze 4 hours under-40 ℃ temperature conditions through being warming up under-5 ℃～5 ℃ conditions reduced vacuum in 12-14 hour dry 14-16 hour, was warming up to 28 ℃ of high temperature dryings 4 hours then at last, obtained described lyophilized injectable powder.
The temperature of the water for injection described in the step of the present invention (1) is 50-70 ℃, and the temperature of preferred described water for injection is 50-60 ℃.
Specifically, preparation method of the present invention comprises:
1., the cleaning of cillin bottle, sterilization
Bottle (low Pyrex control injection bottle) is removed through outer package, bottle is put into the wash bottle transfer dish, power-on, bottle is reached in the bottle washer, be delivered to Drying tunnel with 50 ℃～60 ℃ purified water, water for injection after cleaning cleaning, through the preheating zone drying, the 350 ℃ of sterilizations in high-temperature region, sterilization in 15 minutes, the low-temperature space cooling, it is standby to enter the fill chamber.
2., the cleaning of butyl rubber bung, sterilization
Plug is put into rubber cork rinsing machine, extremely clean with the water for injection rinsing; Move in the efficient plug sterilizing oven of clamshell doors, carry out 120 ℃, 2 hours drying, sterilization, cooling, it is standby to enter the fill chamber.
3., the cleaning of plastic-aluminum composite cover, sterilization
Aluminium-plastic cap is removed through outer package, and after being conveyed into the aluminium-plastic cap cleaning machine and cleaning, baking is 120 minutes in 120 ℃ of baking ovens, and cooling is standby.
4., precision takes by weighing the diltiazem hydrochloride and the mannitol of recipe quantity, places Agitation Tank, add proper amount of water for injection and stir it is dissolved fully; Sodium hydroxide solution with 0.1mol/l is regulated pH value to 5.0 ± 0.05; Medicinal carbon stirring and adsorbing with 0.05% 30 minutes, through the carbon removal of 0.45um filtering with microporous membrane, filtrate adds to the full amount of water for injection in pipeline input dilute preparing tank, fully stirs and makes the solution mix homogeneously in 20 minutes, the solution for preparing carries out the end-filtration degerming through the microporous filter membrane of 0.22um, filtrate is fed through in the basin standby through pipeline, quality inspection personnel extracts solution, carries out clarity, content, pH value, bacterial endotoxin mensuration, filtrate after qualified changes canned over to, and is standby.
5., fill
The operator will detect qualified solution and insert, and adjust loading amount and false add plug quality by detecting intermediate amounts, and fill is in low Pyrex control injection bottle, every loading amount of self check in 15 minutes and false add plug quality situation respectively.
6., lyophilization
The fill certified products are put into material disc in time put on the dividing plate of freeze drying box pre-freeze: the temperature inside the box is reduced to about-40 ℃, is incubated 2-4 hour; Distillation: the temperature of condenser is reached below-40 ℃,, slowly be warming up to-5-5 ℃ through 10-16 hour slow intensification temperature to the whole system evacuation, be incubated 12-18 hour, control temperature and vacuum, redrying: temperature is risen to 25-30 ℃, be incubated 3-5 hour, press plug entirely, go out the railway carriage or compartment.
7., roll lid
The operator inserts the good semi-finished product of lyophilizing and carries out gland, observes at any time to prick to cover situation, chooses defective work, certified products is put into the handing-over bucket put to the handing-over window.
8., lamp inspection
The operator inserts to roll and builds semi-finished product, chooses to detect defective works such as rolling lid scratches, distortion, spray bottle tomography, atrophy, and certified products are put to the handing-over window.
9. labeling, packing and warehouse-in
Qualified semi-finished product are inserted, carry out labeling and packing after audit semi-finished product, label, packing box are errorless, packaged finished product is warehousing after passing after testing.
Freezing described in the present invention may further comprise the steps specifically:
1, pre-freeze
It is freezing medicine to be put into the freeze drying box that is cooled to-40 ℃, and the time is 2-4 hour;
The purpose of pre-freeze is for fixed product, so that distil under vacuum.If do not freeze reality, then product can emit bottle outlet external during evacuation, causes the spray bottle, does not have certain shape; If temperature is low excessively, then wasted the energy and time, in addition, the pre-freeze process has also determined the quality of the speed and the freeze-drying prods of dry run to a great extent.
Because the eutectic point of this product is-10.5 ℃, the design cryogenic temperature is-40 ℃, and why freeze drying box will be cooled in advance-40 ℃, is in order to strengthen the temperature difference of shelf in medicine and the freeze dryer.In practical operation, the medicine of bottling mainly with freeze dryer in shelf finish exchange heat.Shelf temperature is low, and the temperature difference of shelf is big in medicine and the freeze dryer, and rate of temperature fall is fast more, and the degree of supercooling of solution and degree of supersaturation are bigger, and critical crystalline granularity is then little, and nucleation rate is fast more, can form the less thin ice crystal of the more size of granule easily.After these thin ice crystal distillations, the pore-size that forms in the material is less, though dry rate afterwards is low, it is good to do the back solubility.Otherwise, not cooling in advance, rate of temperature fall is slow, forms oarse-grained ice crystal, and the aqueous vapor discharge channel size that ice crystal distillation back forms is bigger, though help improving dry rate, it is poor to do the back solubility.
The freeze drying box resulting product solubility of lowering the temperature in advance is good, and product appearance is also qualified substantially, but the slightly atrophy of product of minority bottle is arranged, and this is because the present invention is a freeze drying process that adopts bottle to freeze, and is heated and can not accomplishes fully evenly.In when cooling, the medicinal liquid in the bottle up and down two parts can to produce thermograde poor, in the propulsive from bottom to top process in ice interface, upwards migration of solute causes the solute of upper epidermis often more in the solution, density is higher, and bottom density is less down, short texture.Though because the design cryogenic temperature is lower, shortened crystallization time to a great extent, shorten the solute migration time equally, improved the atrophy situation that causes owing to density variation greatly, but in order to reach better effect, the present invention preferably adopts three-step approach pre-freeze, be about to medicinal liquid and be cooled to eutectic point earlier from room temperature and be about-18.6 ℃, be incubated, the time of insulation is 20-40 minute, make temperature autobalance in the medicinal liquid, eliminate the thermograde in it; Then medicinal liquid is put into the freeze drying box that is cooled to-40 ℃, freezing 2-4 hour, can reduce like this in the bottle medicinal liquid up and down two parts can to produce thermograde poor, and it is supercool to make that easily medicinal liquid forms, when energy accumulation is enough, whole crystallizations of moment, prepared product solubility is splendid, and outward appearance is full, color even, hole densification, and is better than the outward appearance that adopts direct pre-freeze method product, clarity and stability.
2, distillation
After medicine freezes, start the vacuum machine and be evacuated to about 10Pa, close fridge, heat up to make to medicine and freeze the product temperature and rise to-5-5 ℃; Be incubated 12-18 hour then, the needed time of heating up is 10-16 hour.The distillation phase can be removed the moisture about 90%.
The choice relation of sublimation temperature is to the speed of distillation, why select-5 to 5 ℃, rather than more near the temperature of eutectic point, be because when distillation, the upper materials drying that will take the lead in, if it is too fast that its temperature rises, might reach the temperature of caving in (or being referred to as the disintegrate temperature), porous skeleton rigidity reduces, and coming off appears in the granule in the drying layer, can seal the micro channel of drying nest, stop the carrying out of distillation, rate of sublimation is slowed down, even make underclad portion atrophy slightly, influence the content of goods residual moisture, cause solubility, stability and clarity is variation simultaneously.
In addition, temperature retention time is unsuitable long, this is because the small crystals that medicinal liquid quick freezing of the present invention produces has very high surface energy, when heating recrystallize might take place; mutually combining between the little ice crystal forms big ice crystal; make its surface to volume ratio reach minimum, and big ice crystal makes the dried frozen aquatic products outward appearance bad, solubility is poor.
Pressure during the distillation is 10Pa, though this is because the low distillation that helps ice in the product of pressure, because pressure is unfavorable to conducting heat when too low, product is difficult for the acquisition heat, and rate of sublimation reduces on the contrary.But when pressure was too high, the rate of sublimation of ice slowed down in the product, and minimizing falls in the product caloric receptivity.So the temperature of product self rises, when being higher than temperature of eutectic point, product will melt, and cause the lyophilizing failure.Therefore, pressure is set at 10-12Pa, not only has been beneficial to the transmission of heat but also has been beneficial to the carrying out of distillation.
3, drying
In case the ice distillation finishes in the product, can enter drying stage.Do not freeze ice though do not exist in this stage product, also have the moisture content about 10% in the product, remaining water content meets the requirements in the product in order to make, must be further dry to product.
Exsiccant process is gradually to 25-30 ℃ of insulation vacuum drying 3-5h with medicine.
The present invention adopts above-mentioned freeze drying process, makes the lyophilized injectable powder good stability, and water content is low, and the products obtained therefrom quality is loose, adds during use can dissolve rapidly behind the water for injection and recover the primary characteristic of medicinal liquid; The products obtained therefrom dose controlled, good appearance.
Hydrochloric acid diltiazem freeze-dried powder injection for injections provided by the present invention, its good stability, drug content is low, and water content is also very low, makes the product storage long period also undergo no deterioration like this, thereby can not influence the performance of drug effect.And lyophilized injectable powder quality of the present invention is loose, adds during use can dissolve rapidly behind the water for injection and recover the primary characteristic of medicinal liquid, and stability is very good.The preparation method of lyophilized injectable powder provided by the invention, simple to operate, adopt pyritous water for injection (50-70 ℃) that it is dissolved, again at the freeze-dry process that concrete characteristics provided of diltiazem hydrochloride among the present invention, make resulting end product quality height, good stability, water content is low.
The specific embodiment
Embodiment 1
Hydrochloric acid diltiazem freeze-dried powder injection for injections is formed
Prescription 1:(specification: 50mg)
Constituent content
Diltiazem hydrochloride 51.0g (50mg)
Mannitol 75.0g
Water for injection 2000mL
Make 1000 bottles
The preparation method of hydrochloric acid diltiazem freeze-dried powder injection for injections is as follows:
(1) takes by weighing the diltiazem hydrochloride and the mannitol of recipe quantity, place Agitation Tank, add 1/2 the 50 ℃ of waters for injection that account for whole water for injection consumptions again it is dissolved fully, obtain mixed solution;
(2) in above-mentioned mixed solution, add the 0.15mol/l sodium hydroxide solution and regulate its pH value to 5.00;
(3) add medicinal carbon in the solution of step (2) gained, the addition of medicinal carbon is 0.05% of a solution weight, stirs to leave standstill after evenly to solution in 20 minutes, refilters and takes off charcoal, obtains taking off the filtrate behind the charcoal;
(4) filtrate that will take off behind the charcoal is diluted to configuration amount with adding water for injection, and the back that stirs is by 0.22 μ m filtering with microporous membrane, and the filtrate that obtains is packed in the bottle and kept the gas outlet;
(5) filtrate that step (4) is loaded on call in the bottle is carried out lyophilization: first pre-freeze 4 hours under-40 ℃ temperature conditions, be warming up to-5 ℃ through 10 hours then, the dry insulation of reduced vacuum is 18 hours again, is warming up to 25 ℃ of high temperature dryings at last 5 hours, obtains described lyophilized injectable powder.
Embodiment 2
Hydrochloric acid diltiazem freeze-dried powder injection for injections is formed
Prescription 1:(specification: 10mg)
Constituent content
Diltiazem hydrochloride 10.2g
Mannitol 70.0g
Water for injection 2000ml
Make 1000 bottles
The preparation method of hydrochloric acid diltiazem freeze-dried powder injection for injections is as follows:
(1) takes by weighing the diltiazem hydrochloride and the mannitol of recipe quantity, place Agitation Tank, add 2/3 the 60 ℃ of waters for injection that account for whole water for injection consumptions again it is dissolved fully, obtain mixed solution;
(2) in above-mentioned mixed solution, add the 0.05mol/l sodium hydroxide solution and regulate its pH value to 4.95;
(3) add medicinal carbon in the solution of step (2) gained, the addition of medicinal carbon is 0.05% of a solution weight, stirs to leave standstill after evenly to solution in 30 minutes, refilters and takes off charcoal, obtains taking off the filtrate behind the charcoal;
(4) filtrate that will take off behind the charcoal is diluted to configuration amount with adding water for injection, and the back that stirs is by 0.22 μ m filtering with microporous membrane, and the filtrate that obtains is packed in the bottle and kept the gas outlet;
(5) filtrate that step (4) is loaded on call in the bottle is carried out lyophilization: first pre-freeze 3 hours under-40 ℃ temperature conditions, be warming up to 5 ℃ through 16 hours then, the dry insulation of reduced vacuum is 12 hours again, is warming up to 30 ℃ of high temperature dryings at last 3 hours, obtains described lyophilized injectable powder.
Embodiment 3
Hydrochloric acid diltiazem freeze-dried powder injection for injections is formed
Prescription 1:(specification: 10mg)
Constituent content
Diltiazem hydrochloride 10.2g
Mannitol 70.0g
Water for injection 2000ml
0.1mol/l sodium hydroxide solution an amount of (pH regulator agent)
Make 1000 bottles 1000 bottles
The preparation method of hydrochloric acid diltiazem freeze-dried powder injection for injections is as follows:
(1) takes by weighing the diltiazem hydrochloride and the mannitol of recipe quantity, place Agitation Tank, add 1/2 the 70 ℃ of waters for injection that account for whole water for injection consumptions again it is dissolved fully, obtain mixed solution;
(2) in above-mentioned mixed solution, add the 0.1mol/l sodium hydroxide solution and regulate its pH value to 4.95;
(3) add medicinal carbon in the solution of step (2) gained, the addition of medicinal carbon is 0.05% of a solution weight, stirs to leave standstill after evenly to solution in 30 minutes, refilters and takes off charcoal, obtains taking off the filtrate behind the charcoal;
(4) filtrate that will take off behind the charcoal is diluted to configuration amount with adding water for injection, and the back that stirs is by 0.22 μ m filtering with microporous membrane, and the filtrate that obtains is packed in the bottle and kept the gas outlet;
(5) filtrate that step (4) is loaded on call in the bottle is carried out lyophilization: first pre-freeze 2 hours under-40 ℃ temperature conditions, be warming up to-2 ℃ through 13 hours then, the dry insulation of reduced vacuum is 15 hours again, is warming up to 28 ℃ of high temperature dryings at last 4 hours, obtains described lyophilized injectable powder.
Outside the amount of embodiment 4-10 demineralizing acid diltiazem and mannitol was different, other specifically saw the following form as embodiment 2:
| Embodiment | Diltiazem hydrochloride (g) | Mannitol (g) |
| Embodiment 4 | 10 | 80 |
| Embodiment 5 | 10 | 65 |
| Embodiment 6 | 10 | 50 |
| Embodiment 7 | 10 | 40 |
| Embodiment 8 | 10 | 30 |
| Embodiment 9 | 10 | 20 |
| Embodiment 10 | 10 | 10 |
Test example 1
This test example relates to the investigation of pH value, color and clarity
Get the prepared hydrochloric acid diltiazem freeze-dried powder injection for injections of 1 embodiment 1,2,3 respectively, add the aqueous solution that water is mixed with per 1 milliliter of hydrochloric diltiazem 0.0051g, investigate its pH value, color and clarity respectively by labelled amount.
PH value is measured: sample thief is measured (2000 editions two appendix VI H of Chinese Pharmacopoeia) pH value in accordance with the law.
Colour measurement: sample thief and yellow standard color solution (two appendix IX of Chinese Pharmacopoeia version in 2000 A, first method) are relatively.
Clarity is measured: sample thief compares with No. 1 turbidity standard (two appendix IX of Chinese Pharmacopoeia version in 2000 B) as showing muddy.
Result of the test such as following table 1:
The testing result of table 1 sample appearance, pH value, color and clarity
Test example 2
This test example relates to study on the stability
(1) influence factor's test
Get 1 embodiment, 1 prepared hydrochloric acid diltiazem freeze-dried powder injection for injections and carry out illumination (airtight vial, illumination 4000lx), high temperature (60 ℃), low temperature (4 ℃) test respectively, placed 10 days, in the 0th, 5, the every index of sampling and measuring in the time of 10 days.The results are shown in Table 2:
Table 2. influence factor result of the test
(2) accelerated test
It is 75% thermostatic container that the sample of embodiment 1,2,3 (being respectively sample A, B, C) is placed relative humidity (RH), and constant temperature was placed 6 months in 40 ℃ of baking ovens, takes a sample respectively at the 0th, 1,2,3, during June, measures every index.Each batch sample character is white powder, odorless as a result, and sterility test is all qualified, and other indexs see Table 3.
Table 3. accelerated test is investigated the result
(3) the room temperature investigation that keeps sample
Three groups of sample room temperatures of A, B, C are placed, respectively at the 0th, 3,6,9, the December sampling, measure every index.Each batch sample character is white powder, odorless as a result, and sterility test is all qualified, and other indexs see Table 4.
The table 4. room temperature investigation result that keeps sample
The above results shows, the having good stability of product hydrochloric acid diltiazem freeze-dried powder injection for injections of the present invention, and pH value can maintain about 5.06 for a long time.
Claims (10)
1, a kind of hydrochloric acid diltiazem freeze-dried powder injection for injections, comprise diltiazem hydrochloride and mannitol, it is characterized in that, the weight ratio of described diltiazem hydrochloride and mannitol is 1: 1-8, the weight ratio of preferred described diltiazem hydrochloride and mannitol is 1: 3-8, the weight ratio of more preferably described diltiazem hydrochloride and mannitol is 1: 5-7.
2, lyophilized injectable powder according to claim 1 is characterized in that, described hydrochloric acid diltiazem freeze-dried powder injection for injections comprises:
Diltiazem hydrochloride 10.2g
Mannitol 70.0g
Water for injection adds to 2000ml
Lyophilizing is made 1000 bottles
Described lyophilizing is: earlier be under-40 ℃ the condition pre-freeze 2-4 hour in temperature, through being warming up in 10-16 hour-5-5 ℃, be incubated 12-18 hour more then, be warming up to 25-30 ℃ more gradually afterwards, kept 3-5 hour.
3, lyophilized injectable powder according to claim 1 is characterized in that, described hydrochloric acid diltiazem freeze-dried powder injection for injections comprises:
Diltiazem hydrochloride 51.0g
Mannitol 75.0g
Water for injection adds to 2000ml
Lyophilizing is made 1000 bottles
Described lyophilizing is: earlier be under-40 ℃ the condition pre-freeze 2-4 hour in temperature, through being warming up in 10-16 hour-5-5 ℃, be incubated 12-18 hour more then, be warming up to 25-30 ℃ more gradually afterwards, kept 3-5 hour.
4, a kind of preparation method for preparing claim 1 or 2 or 3 described hydrochloric acid diltiazem freeze-dried powder injection for injections is characterized in that described method may further comprise the steps:
(1) take by weighing the diltiazem hydrochloride and the mannitol of recipe quantity, place Agitation Tank, the water for injection that adds the 1/2-2/3 that accounts for whole water for injection consumptions again dissolves it fully, obtains mixed solution;
(2) in above-mentioned mixed solution, add sodium hydroxide solution and regulate its pH value to 5.0 ± 0.05;
(3) in the solution of step (2) gained, add medicinal carbon, leave standstill after stirring, refilter and take off charcoal, obtain taking off the filtrate behind the charcoal;
(4) filtrate that will take off behind the charcoal is diluted to configuration amount with adding water for injection, and the back that stirs is by 0.22 μ m filtering with microporous membrane, and the filtrate that obtains is packed in the bottle and kept the gas outlet;
(5) filtrate that step (4) is loaded on call in the bottle is carried out lyophilization: earlier be under-40 ℃ the condition pre-freeze 2-4 hour in temperature, then through being warming up in 10-16 hour-5-5 ℃, be incubated 12-18 hour again, be warming up to 25-30 ℃ more gradually afterwards, kept 3-5 hour.
5, preparation method according to claim 4 is characterized in that, the consumption of described medicinal carbon is 0.05% of step (a 2) gained solution weight.
6, preparation method according to claim 4 is characterized in that, the time of stirring in the described step (3) is 20-40 minute.
7, preparation method according to claim 4 is characterized in that, the concentration of described sodium hydroxide solution is 0.05-0.15mol/l.
8, preparation method according to claim 4 is characterized in that, the concentration of described sodium hydroxide solution is 0.1mol/l.
9, preparation method according to claim 4 is characterized in that, described lyophilization comprises:
First pre-freeze 4 hours under-40 ℃ temperature conditions through being warming up under-5 ℃～5 ℃ conditions reduced vacuum in 12-14 hour dry 14-16 hour, was warming up to 28 ℃ of high temperature dryings 4 hours then at last, obtained described lyophilized injectable powder.
10, preparation method according to claim 4 is characterized in that, the temperature of the water for injection described in the step (1) is 50-70 ℃, and the temperature of preferred described water for injection is 50-60 ℃.
Priority Applications (1)
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| CN102091045A (en) * | 2010-12-30 | 2011-06-15 | 江苏奥赛康药业有限公司 | Hydrochloride diltiazem composition for injection and preparation method thereof |
| CN102106833A (en) * | 2011-02-12 | 2011-06-29 | 海南锦瑞制药股份有限公司 | Pemetrexed disodium freeze-dried powder injection and preparation method thereof |
| CN102657621A (en) * | 2012-04-28 | 2012-09-12 | 天津金耀集团有限公司 | Diltiazem hydrochloride freeze-dry powder injection for injection |
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| CN103371978B (en) * | 2012-04-28 | 2018-10-16 | 天津金耀集团有限公司 | Using the freeze drying powder injection prepared containing alcohol solvent |
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| CN113476411A (en) * | 2021-06-22 | 2021-10-08 | 海南锦瑞制药有限公司 | Diltiazem hydrochloride freeze-dried powder injection for injection and preparation method thereof |
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| CN102091045A (en) * | 2010-12-30 | 2011-06-15 | 江苏奥赛康药业有限公司 | Hydrochloride diltiazem composition for injection and preparation method thereof |
| CN102091045B (en) * | 2010-12-30 | 2012-12-19 | 江苏奥赛康药业股份有限公司 | Hydrochloride diltiazem composition for injection and preparation method thereof |
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| CN102657621A (en) * | 2012-04-28 | 2012-09-12 | 天津金耀集团有限公司 | Diltiazem hydrochloride freeze-dry powder injection for injection |
| CN102657621B (en) * | 2012-04-28 | 2013-11-13 | 天津金耀集团有限公司 | Diltiazem hydrochloride freeze-dry powder injection for injection |
| CN103371978B (en) * | 2012-04-28 | 2018-10-16 | 天津金耀集团有限公司 | Using the freeze drying powder injection prepared containing alcohol solvent |
| CN103304514A (en) * | 2013-06-28 | 2013-09-18 | 天津梅花医药有限公司 | Acid diltiazem compound with good stability, and pharmaceutical composition |
| CN103304514B (en) * | 2013-06-28 | 2014-09-17 | 天津梅花医药有限公司 | Acid diltiazem compound with good stability, and pharmaceutical composition |
| CN112294767A (en) * | 2020-11-17 | 2021-02-02 | 海南锦瑞制药有限公司 | Diltiazem hydrochloride freeze-dried powder injection for injection and preparation method thereof |
| CN113476411A (en) * | 2021-06-22 | 2021-10-08 | 海南锦瑞制药有限公司 | Diltiazem hydrochloride freeze-dried powder injection for injection and preparation method thereof |
| WO2022267237A1 (en) * | 2021-06-22 | 2022-12-29 | 海南锦瑞制药有限公司 | Freeze-dried diltiazem hydrochloride powder injection for injection and preparation method therefor |
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| CN100563633C (en) | 2009-12-02 |
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Address after: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee after: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. Address before: 570216 No. 8 factory building, Haikou Free Trade Zone, Nanhai Avenue, Hainan, Haikou Patentee before: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. |
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Denomination of invention: Diltiazem hydrochloride freeze-dried powder injection and its preparation method Effective date of registration: 20230920 Granted publication date: 20091202 Pledgee: Qingdao Qishun Investment Management Co.,Ltd. Pledgor: HAINAN JINRUI PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980057940 |