CN101669916A - Method for preparing nifedipine freeze-dried powder injection - Google Patents
Method for preparing nifedipine freeze-dried powder injection Download PDFInfo
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- CN101669916A CN101669916A CN200910085567A CN200910085567A CN101669916A CN 101669916 A CN101669916 A CN 101669916A CN 200910085567 A CN200910085567 A CN 200910085567A CN 200910085567 A CN200910085567 A CN 200910085567A CN 101669916 A CN101669916 A CN 101669916A
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Abstract
The invention provides a nifedipine freeze-dried composition and a preparation method thereof, and the obtained product has good dissolubility and stability. The invention is applicable to being usedas safe and stable injection formulation.
Description
Technical field
The present invention relates to comprise the pharmaceutical composition of water-insoluble nifedipine, specifically, relate to contain the lyophilized medication composition and method of making the same of nifedipine.
Background technology
(molecular formula is C to nifedipine
17H
18N
2O
2Molecular weight is 346.34), it is dihydropyridine calcium channel antagonist, the energy selectively acting is in cerebrovascular, effect with expansion cerebral arteries, increase brain blood flow, be mainly used in intractable angina pectoris, the obstinate hypertension continuous intravenous is dripped, and is applicable to that more hypertensive patients has quiet of patients with coronary heart disease.
The bioavailability of nifedipine oral tablet is 60-70%, has first pass effect, and rapid inactivation after the metabolism, and pharmacological action descends thereupon.Therefore, for the intractable angina pectoris patient, there is irreplaceable advantage in injection type than peroral dosage form.
The chemical property of nifedipine is as follows, is yellow crystalline powder, odorless, tasteless.Be dissolved in chloroform, acetone, slightly be dissolved in methanol, ethanol, ether, water-soluble hardly, meet photo-labile, 171.5～173.5 ℃ of fusing points.Therefore, for the injection dosage form, the problem of the poorly water-soluble of nifedipine is perplexing everybody always.In commonly used hydrotropy of injection type and stable method, for example, need to add cosolvent (for example polyvidone etc.) in the transfusion usually, form complex with nifedipine, increase the dissolubility of nifedipine.But the effectiveness of these measures is limited.Usually, contain the above ethanol of 20% (V/V) in the transfusion as solvent, the amount of alcohol in the little liquid drugs injection is then bigger.Like this a large amount of ethanol can not join in the same infusion bottle in the lump in use to patient's zest and side effect big (for example, pain, vasculitis etc.), and with the inconsistent medicine of ethanol, uses extremely inconvenience.
In addition, nifedipine is to light very unstable (especially obvious under solution state), and commercially available injection adopts the packaging material (for example, adopting brown Packaging Bottle, bottle to add the froth bed of cover sun-proof) of lucifuge mostly, this not only increases cost, and uses also inconvenient.Usually, need to add antioxidant (for example sodium sulfite) in the solution to increase the stability of solution.There are some researches show that the conventional little liquid drugs injection that contains nifedipine was placed under the natural lighting condition about 6 minutes, it is about 10% that its content promptly descends, and illustrates that little liquid drugs injection is extremely unstable to illumination.Therefore, this area is starved of nifedipine is made the preparation with good solubility and stability.Lyophilized formulations can well solve the unstability of nifedipine solution, and good hydrotropy means among the present invention and preparation technology can make product redissolve and clarify rapidly.
Summary of the invention
Adopt freeze drying process to carry out the preparation of injectable powder,
Discover, though conventional freeze-dried formulation can solve the stability problem of system chaste tree, but in the product solubility property of nifedipine not be improved significantly, also need add other additives, or surfactant, can make stable freeze-dried products through lyophilization, add medicinal aqueous diluent in use, can be reconstructed into aqueous colloidal dispersion or solution rapidly.
An object of the present invention is to provide the nifedipine freeze-dried composition of closing phospholipid.Phospholipid has amphipathic, makes it be particularly suitable for preparing water-insoluble nifedipine of the present invention, and this is very useful for action time in dissolubility that improves nifedipine and the body.Adopt this area conventional method, for example membrane process, reverse phase evaporation or freeze-drying, and the consumption of phospholipid adjusted, can make the liposome or the lipid complex that contain nifedipine, be preferably lipid complex, and then make stable powder through lyophilization, the obtained freeze-drying goods can be reconstructed into aqueous colloidal dispersion rapidly after an amount of medicinal aqueous diluent.
Another object of the present invention provides the nifedipine freeze-dried composition that contains cyclodextrin.The insoluble drug nifedipine can significantly improve its physicochemical characteristic behind cyclodextrin clathrate, for example: will can improve its stability after the drug powderization, increase its dissolubility.Conditions such as enclose temperature wherein, dispersion force size and mixing speed can adopt conventional method to come design alternative.
Another object of the present invention provides the nifedipine freeze-dried composition that contains surfactant.The present invention has promoted its quick dissolving by using surfactant (for example tween) solubilising nifedipine, and the zest solvent of having avoided again simultaneously uses.In the technology, be preferably tween 80, Polyethylene Glycol, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini or their mixed system.Can determine the consumption of surfactant by normal experiment, to guarantee obtaining clear solutions after the reconstruction.Advantageously, the part by weight of nifedipine and surfactant about 1: 30-1: 500, be preferably 1: 150-1: 300.
Randomly, also can add medicinal freeze drying excipient in the pharmaceutical composition of the present invention.Preferably, described excipient is selected from mannitol, sorbitol, sodium chloride, glucose, fructose, sucrose, xylitol, lactose and their mixture.Be preferably: mannitol.The weight ratio of nifedipine and excipient is 1: 100-1: 800, be preferably 1: 100-1: 300.
In the gross weight of compositions, the consumption of active substance nifedipine is about 0.5mg-50mg, is preferably 2mg-10mg.
Those skilled in the art can be concrete according to the demand parallel port of clinical preparation production equipment, adjust the freeze dried cycle.Usually, uniform preparation can be placed 10 to 50ml cillin bottle, pre-freeze temperature-20 ℃ is preferably-30 ℃ extremely to-60 ℃--40 ℃, 2 hours to 8 hours pre-freeze time, be preferably 3-4 hour.Freeze temperature-5 ℃ is preferably-20 ℃ to-25 ℃ to-30 ℃, and freeze-drying time 15 hours to 40 hours is preferably 20 hours to 25 hours.Baking temperature is 0 ℃-40 ℃ again, and the time is 10-15 hour.The final moisture content of freeze-dried composition generally is lower than 5%, is preferably 1% to 2%.
Nifedipine freeze-dried composition of the present invention is suitable for using clinically.Before use, an amount of aseptic medicinal aqueous diluent (for example, water for injection, normal saline, G/W and other known aqueous carriers) be can add, aqueous colloidal dispersion or pharmaceutical solutions are reconstructed into for intramuscular injection or intravenous drip (intravenous administration) usefulness.
The specific embodiment
Following examples are intended to further specify the present invention, scope of the present invention are not limited.
Embodiment 1 preparation contains the injectable powder of phospholipid
Get nifedipine 2mg, phosphatidase 11 0mg and cholesterol 2mg, add dehydrated alcohol 5ml, be stirred to dissolving fully, on Rotary Evaporators, carry out drying under reduced pressure, remove and desolvate, add phosphate buffer 5ml, be stirred to evenly, adopt sonic oscillation, filter, add mannitol 100mg, put in the aseptic cillin bottle, put and carry out lyophilization in the freezer dryer, seal.Promptly get lurid nifedipine injectable powder.
Embodiment 2 preparations contain the injectable powder of cyclodextrin
Get nifedipine 2mg, use the 2ml dehydrated alcohol, be stirred to dissolving fully, other gets hydroxypropyl-D-cyclodextrin 20mg, adds the 7ml water dissolution, stirs down nifedipine solution is joined in the solution of hydroxypropyl-D-cyclodextrin, is prepared into uniform cyclodextrin clathrate.On Rotary Evaporators, carry out drying under reduced pressure, fling to ethanol.Under stirring condition, add mannitol 300mg, solution filters with the sintered filter funnel of handling through the mattress that goes out in advance, and filtrate is put in the aseptic cillin bottle, puts and carries out lyophilization in the freezer dryer, seals.Promptly get light yellow. flaxen nifedipine injectable powder.
Thank to the line diffraction approach through X and confirm that the pharmaceutical composition that embodiment 2 makes is the clathrate form.
Embodiment 3: preparation contains the injectable powder of surfactant
Get nifedipine 2mg, 15mg tween 80,0.2g Polyethylene Glycol-400, polyoxyethylene castor oil 20mg and mannitol 0.3g, add water 5ml, be stirred to dissolving fully. with the filtering with microporous membrane of 0.22um, put in the aseptic cillin bottle, get little yellow settled solution, put and carry out lyophilization in the freezer dryer, seal.Promptly get light yellow. flaxen nifedipine injectable powder.
The nifedipine powder pin of Sheng Chaning predicts that with classical thermostatic valve be 2.4 years the storage period of this preparation according to the method described above; Place under the 2000LX condition rayed and room temperature to keep sample cillin bottle and placed 2 years, every indexs such as its medicament contg, pH value, color do not note abnormalities.
Zoopery is the result show; Mouse mainline LD50 is 4.6mg/kg, and can resist the mouse cardiac muscle ischemia due to the pituitrin.Protective rate to cardiac muscle when 0.1mg/kg is 100%, P＜0.01; 0.025mg/kg the time can reduce anaesthetized dog blood pressure 62%, total periphery pressure 33.5%, increase coronary flow 51.9%, cardiac output 25.9%, cardiac index 34.5%, heart rate is not had obvious influence.
Claims (10)
1, a kind of injection freeze-drying medicinal composition, comprising nifedipine and the pharmaceutic adjuvant that is selected from phospholipid, cyclodextrin and derivant thereof or surfactant, described surfactant is selected from the mixed system of tween 20, tween 80, Polyethylene Glycol, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, polyvinylpyrrolidone, poloxamer and their compositions, and when pharmaceutic adjuvant was phospholipid, described compositions was liposome or lipid complex.
2, the described compositions of claim 1, the method for its preparation be, nifedipine and pharmaceutic adjuvant mixed dissolution add needle-use activated carbon and stir and placed 15-20 minute, filter decarburization, standardize solution, filtration sterilization, fill, lyophilization, roll cover finished product.
3, compositions as claimed in claim 1, wherein phospholipid is selected from: lecithin, soybean phospholipid, cephalin, phosphatidic acid, two Palmic acid phosphatidylcholines, hydrogen phosphatidyl ethanol ammonia, Phosphatidylserine and their mixture.
4, as the compositions of claim 1 or 3, the part by weight 1 of nifedipine and phospholipid: 1-1: 100 wherein.
5, compositions as claimed in claim 1, wherein cyclodextrin and derivant thereof are selected from beta-schardinger dextrin-, 2-HP-, 3-HP-and their derivant.
6, as the compositions of claim 1 or 5, wherein the ratio of nifedipine and cyclodextrin and derivant thereof is 1: 1 to 1: 20.
7, compositions as claimed in claim 1, wherein surfactant is selected from the mixed system of tween 20, tween 80, Polyethylene Glycol, polyoxyethylene castor oil, polyoxyethylene hydrogenated Oleum Ricini, poloxamer and their compositions.
8, as the compositions of claim 1 or 7, wherein the part by weight of nifedipine and surfactant is 1: 30-1: 500.
9, as the compositions of one of claim 1-8, also comprise pharmaceutically acceptable freeze drying excipient, described mannitol, sorbitol, sodium chloride, glucose, fructose, sucrose, xylitol, lactose and their mixture of being selected from.
10, in the described preparation method of claim 2, pre-freeze temperature during lyophilization is-20 ℃--60 ℃, the pre-freeze time is 2 hours-8 hours, the sublimation drying temperature is-5 ℃--30 ℃, the sublimation drying time is 15 hours-40 hours, baking temperature is 0 ℃-40 ℃ again, and be 10 hours-40 hours drying time again.
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| Application Number | Priority Date | Filing Date | Title |
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| CN200910085567A CN101669916A (en) | 2009-05-25 | 2009-05-25 | Method for preparing nifedipine freeze-dried powder injection |
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| CN200910085567A CN101669916A (en) | 2009-05-25 | 2009-05-25 | Method for preparing nifedipine freeze-dried powder injection |
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| CN101669916A true CN101669916A (en) | 2010-03-17 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105497909A (en) * | 2014-09-25 | 2016-04-20 | 蚌埠丰原涂山制药有限公司 | Composition containing clevidipine butyrate and hydroxypropyl-beta-cyclodextrin |
-
2009
- 2009-05-25 CN CN200910085567A patent/CN101669916A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105497909A (en) * | 2014-09-25 | 2016-04-20 | 蚌埠丰原涂山制药有限公司 | Composition containing clevidipine butyrate and hydroxypropyl-beta-cyclodextrin |
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Open date: 20100317 |