CN102258521B - Cefodizime Sodium composition and method of making the same - Google Patents
Cefodizime Sodium composition and method of making the same Download PDFInfo
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- CN102258521B CN102258521B CN201110149456.0A CN201110149456A CN102258521B CN 102258521 B CN102258521 B CN 102258521B CN 201110149456 A CN201110149456 A CN 201110149456A CN 102258521 B CN102258521 B CN 102258521B
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- cefodizime sodium
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Abstract
The present invention relates to belong to medicine and synthesize and formulation art, relate to a kind of preparation method of antibacterials, relate in particular to a kind of stable Cefodizime Sodium composite preparation and formulation method thereof. The present invention is directly dissolved in the water aseptic Cefodizime Sodium, add aseptic potassium clavulanate, it is all dissolved, obtain the aqueous solution of Cefodizime Sodium/potassium clavulanate, in this aqueous solution, add HP-β-CD (HP-β-CD) to carry out inclusion, through packing, freeze drying obtains cefodizime sodium for injection/potassium clavulanate. The preparation method that this invention provides is simple, and Cefodizime Sodium/clavulanic acid sylvite, after HP-β-CD inclusion, increases the stability of aseptic Cefodizime sodium medicament, reduce its toxic and side effect, improved drug utilization degree, and preparation technology is simple, is applicable to suitability for industrialized production.
Description
Technical field
The present invention relates to a kind of antibacterials and preparation method thereof, relate in particular to a kind of stable Cefodizime composition of sodium and system thereofPreparation Method.
Background technology
Cefodizime Sodium belongs to third generation cephalosporin for injections class antibiotic, is opened by German Hirst company and Japanese roc companySend out, go on the market in Japan with trade name " Neucef " May nineteen ninety. German Hirst-Ruse that company injection head in 1994Spore ground piperazine sodium (not enemy) obtains registration in China.
Cefodizime is that first has the third generation cephalosporin of immune enhancing function in the world, has antimicrobial spectrum widely, facesBed is mainly used in pneumonia, bronchitis, sphagitis, tonsillitis, the renal plevis due to the sensitive bacteria such as streptococcus, pneumococcusEphritis, urinary tract infections, gonococcal urethritis, cholecystitis, cholangitis, gynecological infection, septicemia and tympanitis etc., but cephaloGround piperazine has different sensitiveness to solidifying Bacillus, Enterobacter, epidermis glucose, Bacterium prodigiosum, to pseudomonas, non-leverPseudomonas, enterococcus faecalis, monocytogenes Li Site Salmonella, mycoplasma and Chlamydia etc. are insensitive.
The preparation of Cefodizime Sodium is in the market mainly cefodizime sodium for injection aseptic powder injection, and said preparation exists stableProperty poor, very unstable to light and heat, be placed with for a long time related substance increase, and dissolve after there is turbid phenomenon, cause it to makeUse and run into a lot of difficulties.
For solving its antimicrobial spectrum to solidifying Bacillus, Enterobacter, epidermis glucose, Bacterium prodigiosum, pseudomonas, acinetobacter calcoaceticusGenus, enterococcus faecalis, monocytogenes Li Site Salmonella, mycoplasma and the insensitive weak point of Chlamydia, Chinese patent documentCefodizime Sodium and Sulbactam are mixed to get composition by CN101810621.A, but said composition is just simply by CefodizimeSodium mixes with Sulbactam, is difficult to obtain the uniform composite preparation of content.
For solving its stability problem, Chinese patent document 200910016147.9, the liposome that discloses a kind of Cefodizime freezesDry preparation and preparation method thereof, but its preparation process more complicated, and liposome to prepare yield very low, be not suitable for industryChange and produce.
Existing cefodizime sodium for injection is mainly the powder injection formulation of Cefodizime Sodium dilution crystallization aseptic powder in the market,In preparation production process, exist and be difficult to packing problem simultaneously, the less stable of current Cefodizime preparation of sodium, puts for a long time in additionBeing equipped with related substance increases a lot, the quality requirement that can not satisfy the prescriptive period in the time. Urgent need provides to have good stability and is suitable for clinical makingWith Cefodizime sodium medicament preparation.
Summary of the invention
The deficiency existing in order to overcome existing Cefodizime Sodium, solves prior art and prepares cefodizime sodium for injection antimicrobial spectrum notFoot, and the less stable of current cefodizime sodium for injection preparation, being placed with for a long time related substance increases, and causes expiringThe problems such as the quality requirement in the foot term of validity time, the invention provides a kind of stable Cefodizime Sodium and mix with potassium clavulanateComposite preparation and preparation method thereof, expanded the antimicrobial spectrum of Cefodizime Sodium, improved the stability of Cefodizime Sodium, forThe use of cefodizime sodium for injection provides technical support more reliably.
The present invention mainly contains two objects, and the one, solve the antibacterial weak point of Cefodizime, the one, solve preparation stability problem;Adopt with potassium clavulanate combination and solve antibacterial deficiency; Adopt cyclodextrin encapsulated solution stability, comprehensive above-mentioned 2 requirements, thisThe technical scheme that invention adopts is as follows:
This pharmaceutical composition only contains Cefodizime Sodium, potassium clavulanate and HP-β-CD (HP-β-CD); DescribedPreparation be ejection preparation, wherein the ejection preparation in the present invention comprises parenteral solution or freeze drying powder injection; No matter adopt which kind of formulation,In pharmaceutical composition of the present invention, the amount of active principle is following ranges:
The composition proportioning of specifically selecting is counted by weight:
Cefodizime Sodium 1～2
Potassium clavulanate 2～6
HP-β-CD (HP-β-CD) 1～4
The hydroxyl that one end opening part in beta-schardinger dextrin-(β-CD) molecule hole has C2 on glucose molecule, C3 to connect, anotherEnd opening be C6 connect hydroxyl, so the two ends of tubular structure are hydrophilic, and its hole have glucosyl group oxo bridge and-CH-Group, therefore be hydrophobic in hole. Some sizeable drug molecules are often by Van der Waals force, by its inclusion in hydrophobic regionForm inclusion complex. HP-β-CD (HP-β-CD) be beta-schardinger dextrin-(β-CD) in alkaline aqueous solution with 2-Chlorethanol condensation and polytype CD. HP-β-CD tool safe dose is large, good with blood compatibility, do not changeDrug effect, increase the feature such as water-soluble, stability of medicine, be considered to more promising drug carrier material. Of the present inventionIn pharmaceutical composition, adopt HP-β-CD to be coated active component Cefodizime composition of sodium, make Cefodizime Sodium combinationThing can be wrapped up by its hydrophobic region, finally prepares the stable Cefodizime sodium medicament preparation that formulation and technology is simplified.
Cefodizime Sodium ejection preparation as above comprises parenteral solution and freeze drying powder injection, therefore, and Cefodizime Sodium group of the present inventionCompound must use water for injection in preparation process, and the consumption of water for injection is not particularly limited, and determines phase according to product specificationThe water for injection use amount of answering. If freeze drying powder injection, the composition of above-mentioned composition refers to that said preparation is freeze drying powder injectionComposition content, now, due to factors such as techniques, it is also understandable in final preparation, existing pharmacy to allow the water of content,In preparation, may contain the water of final total formulation weight amount 0～6wt%; If said preparation is parenteral solution, Cefodizime Sodium and injectionThe weight ratio of water changes in 1: 5～50 scope, and preferably 1: 5～20, more preferably 1: 5-15, further preferably 1:5～10. If final preparation is freeze drying powder injection, the water for injection using in preparation process also changes in above-mentioned scope, onlyNeed water for injection content in final preparation to reach above-mentioned standard.
Cefodizime Sodium of the present invention is the product of directly buying on market or adopting prior art directly to obtain, employingBe aseptic Cefodizime Sodium, it has the characteristic identical with Cefodizime Sodium described in the prior art; The clavulanic acid adoptingPotassium is commercially available aseptic potassium clavulanate, why selects aseptic potassium clavulanate, be mainly due to potassium clavulanate can with majorityBeta-lactamase strong bonded, generate irreversible bond, make it have brute force and the inhibition beta-lactamase of wide spectrumEffect, not only has effect to staphylococcic enzyme, and the enzyme that multiple gram-negative bacteria is produced also has effect, for effectivelyβ-lactamase inhibitor, the present invention is potassium clavulanate and Cefodizime interworking, by adjusting the proportioning of above-mentioned two kinds of materials,Can strengthen Cefodizime to some because of produce beta lactamase to the antibacterial activity of gram negative bacilli of resistance, than existingHave compared with the Sulbactam of technology employing and the combination of Cefodizime Sodium, there is wider antimicrobial spectrum, and cost is lower.
On the component proportion basis of above-mentioned disclosed pharmaceutical composition, the present inventor further optimizes Cefodizime SodiumThe weight portion proportioning of pharmaceutical composition is as follows:
Cefodizime Sodium 1～1.5
Potassium clavulanate 2～4
HP-β-CD (HP-β-CD) 1～3
Further preferably, the component that Cefodizime sodium medicament composition of the present invention contains following weight proportion:
Cefodizime Sodium 1～1.2
Potassium clavulanate 2～3
HP-β-CD (HP-β-CD) 1～2
Most preferably, the component that Cefodizime sodium medicament composition of the present invention contains following weight proportion:
Cefodizime Sodium 1～1.2
Potassium clavulanate 2～2.4
HP-β-CD (HP-β-CD) 1～1.8
When adopting after above-mentioned proportioning, the Cefodizime sodium medicament composition obtaining can obtain more excellent effect.
Another object of the present invention is to provide a kind of preparation method of Cefodizime sodium medicament composition, and the method is directly by asepticβ-Cefodizime Sodium is dissolved in water for injection, adds aseptic potassium clavulanate, stirs it is all dissolved, and obtains Cefodizime SodiumWith the aqueous solution of potassium clavulanate mixture, in this aqueous solution, add HP-β-CD (HP-β-CD) to carry out inclusion,Through packing, obtain Cefodizime Sodium injecta composition of the present invention, if needed, parenteral solution freeze drying is obtained to injectionCefodizime sodium freeze-dried powder injection composition.
Concrete preparation method is as follows:
1) in room temperature downhill reaction still, add the aseptic Cefodizime Sodium of prescription amount to be dissolved in water for injection; Add afterwards prescriptionThe potassium clavulanate of amount, stirs it is all dissolved, and obtains the aqueous solution of Cefodizime Sodium and potassium clavulanate;
2) to the HP-β-CD (HP-β-CD) that adds prescription amount in above-mentioned reactor, stirring at room temperature inclusion 0.5～2.0 hour; Inject and be diluted with water to the required content of cefodizime sodium for injection preparation, then use the miillpore filter of 0.45 μ mFilter, finally, by the filtering with microporous membrane of 0.22 μ m, packing, obtains cefodizime sodium for injection freeze-drying through freeze dryingPowder pin.
Preferably, described step 2) stirring at room temperature inclusion 0.5～2.0 hour, most preferred selection 1.0～1.5 hours; AdoptWith above-mentioned comprising after the time, the composite preparation can the stable Cefodizime Sodium of maximized acquisition mixing with potassium clavulanate.
The composite preparation that adopts the Cefodizime Sodium prepared of said method to mix with potassium clavulanate, has expanded Cefodizime SodiumAntimicrobial spectrum, has improved the stability of Cefodizime Sodium, props up for the use of cefodizime sodium for injection provides technology more reliablyHold, the preparation method who adopts is simple, has reduced the toxic and side effect of medicine, is more applicable to applying widely.
Detailed description of the invention
Below in conjunction with embodiment, the present invention will be further described, and described is only several concrete forms of implementation of the present invention, noBe limitation of the present invention, to those skilled in the art, can also make many distortion and improvement. All not superGo out the distortion described in claim or improve and all should be considered as scope of the present invention.
Embodiment 1:
The proportioning of composition is:
Preparation technology:
In room temperature downhill reaction still, add aseptic Cefodizime Sodium to be dissolved in water for injection; Add aseptic potassium clavulanate, stirIt is all dissolved, obtain the aqueous solution of Cefodizime Sodium and potassium clavulanate mixture; In reactor, add hydroxy propyl-Beta-ring to stick with pasteEssence (HP-β-CD), stirs inclusion 1.0 hours; Inject and be diluted with water to the required content of cefodizime sodium for injection preparation,Use the filtering with microporous membrane of 0.45 μ m, finally by the filtering with microporous membrane of 0.22 μ m, packing, through freeze drying and get final product againCefodizime sodium for injection/potassium clavulanate freeze-dried powder.
Embodiment 2:
Preparation technology:
In room temperature downhill reaction still, add aseptic Cefodizime Sodium to be dissolved in water for injection; Add aseptic L-potassium clavulanate, stirMix it is all dissolved, obtain the aqueous solution of Cefodizime Sodium and potassium clavulanate mixture; To add in reactor hydroxy propyl-Beta-Cyclodextrin (HP-β-CD), stirs inclusion 1.5 hours; Use again the filtering with microporous membrane of 0.45 μ m, finally by 0.22 μ m'sFiltering with microporous membrane, packing, obtains Cefodizime sodium injection.
Embodiment 3:
Preparation technology:
In room temperature downhill reaction still, add aseptic Cefodizime Sodium to be dissolved in water for injection; Add aseptic potassium clavulanate, stirIt is all dissolved, obtain the aqueous solution of Cefodizime Sodium and potassium clavulanate mixture; In reactor, add hydroxy propyl-Beta-ring to stick with pasteEssence (HP-β-CD), stirs inclusion 0.5 hour; Inject and be diluted with water to the required content of cefodizime sodium for injection preparation,Use the filtering with microporous membrane of 0.45 μ m, finally by the filtering with microporous membrane of 0.22 μ m, packing, through freeze drying and get final product againCefodizime sodium for injection/potassium clavulanate freeze-dried powder.
Embodiment 4:
Preparation technology:
In room temperature downhill reaction still, add aseptic Cefodizime Sodium to be dissolved in water for injection; Add aseptic potassium clavulanate, stirIt is all dissolved, obtain the aqueous solution of Cefodizime Sodium and potassium clavulanate mixture; In reactor, add hydroxy propyl-Beta-ring to stick with pasteEssence (HP-β-CD), stirs inclusion 1.0 hours; Inject and be diluted with water to required mass concentration, then use the micropore of 0.45 μ mMembrane filtration, finally by the filtering with microporous membrane of 0.22 μ m, packing, through freeze drying obtain cefodizime sodium for injection/Potassium clavulanate freeze-dried powder.
Embodiment 5:
Preparation technology:
In room temperature downhill reaction still, add aseptic Cefodizime Sodium to be dissolved in water for injection; Add aseptic potassium clavulanate, stirIt is all dissolved, obtain the aqueous solution of Cefodizime Sodium and potassium clavulanate mixture; In reactor, add hydroxy propyl-Beta-ring to stick with pasteEssence (HP-β-CD), stirs inclusion 2.0 hours; Inject and be diluted with water to the required content of cefodizime sodium for injection preparation,Use the filtering with microporous membrane of 0.45 μ m, finally by the filtering with microporous membrane of 0.22 μ m, packing, through freeze drying and get final product againCefodizime sodium for injection/potassium clavulanate freeze-dried powder.
Embodiment 6:
Preparation technology:
In room temperature downhill reaction still, add aseptic Cefodizime Sodium to be dissolved in water for injection; Add aseptic potassium clavulanate, stirIt is all dissolved, obtain the aqueous solution of Cefodizime Sodium and potassium clavulanate mixture; In reactor, add hydroxy propyl-Beta-ring to stick with pasteEssence (HP-β-CD), stirs inclusion 1.5 hours; Inject and be diluted with water to the required content of cefodizime sodium for injection preparation,Use the filtering with microporous membrane of 0.45 μ m, finally by the filtering with microporous membrane of 0.22 μ m, packing, through freeze drying and get final product againCefodizime sodium for injection/potassium clavulanate freeze-dried powder.
Test example: (stability experiment)
1, sample preparation: be prepared according to the method for embodiment 6 respectively; Control sample is commercially available sample injection CefodizimeSodium (Shandong Lu Ya pharmaceutical Co. Ltd produces, lot number 20101006)
2, influence factor: sample is placed in respectively to room temperature (25 DEG C), high temperature (60 DEG C), relative humidity 75%, relative humidity 92.5%Under six kinds of conditions of illumination 4500Lx.
3, investigate result: investigate indices in sampling in the 5th day, 10 days, and taking 0 day result as contrast, the results are shown in following table 1:Factors influencing result
As seen from the above table, the sample of embodiment 6 and control sample contrast are known, in 25 DEG C of room temperatures, 60 DEG C of high temperature, relative humidity75%, under the condition of relative humidity 92.5% and illumination 4500Lx, place 5 days, 10 days, the sample indices of embodiment 6 withoutSignificant change; Control sample related substance slightly raises, and under under 60 DEG C of high temperature and illumination (4500Lx) condition, relevantMaterial raises very fast, and therefore Cefodizime sodium and clavulanate potassium salt of the present invention, after HP-β-CD inclusion, increasesAdds the stability of Cefodizime sodium medicament, reduced its toxic and side effect, improved drug utilization degree, and preparation technology is simple,Be applicable to suitability for industrialized production.
Claims (4)
1. a Cefodizime composition of sodium, is characterized in that: said composition proportioning is counted by weight:
1～1.2 part of Cefodizime Sodium
2～2.4 parts of potassium clavulanates
1～1.8 part of HP-β-CD;
Its preparation method:
Step is as follows:
1) in room temperature downhill reaction still, add the aseptic Cefodizime Sodium of prescription amount to be dissolved in water for injection; Add afterwards the potassium clavulanate of prescription amount, stir it is all dissolved, obtain the aqueous solution of Cefodizime Sodium and potassium clavulanate;
2) to the HP-β-CD that adds prescription amount in above-mentioned reactor, stirring at room temperature inclusion 0.5～2.0 hour; Inject and be diluted with water to the required content of cefodizime sodium for injection preparation, then use the filtering with microporous membrane of 0.45 μ m, finally, by the filtering with microporous membrane of 0.22 μ m, packing, obtains Cefodizime Sodium composite injection.
2. a preparation method for Cefodizime composition of sodium as claimed in claim 1, is characterized in that: its step is as follows:
1) in room temperature downhill reaction still, add the aseptic Cefodizime Sodium of prescription amount to be dissolved in water for injection; Add afterwards the potassium clavulanate of prescription amount, stir it is all dissolved, obtain the aqueous solution of Cefodizime Sodium and potassium clavulanate;
2) to the HP-β-CD (HP-β-CD) that adds prescription amount in above-mentioned reactor, stirring at room temperature inclusion 0.5～2.0 hour; Inject and be diluted with water to the required content of cefodizime sodium for injection preparation, then use the filtering with microporous membrane of 0.45 μ m, finally, by the filtering with microporous membrane of 0.22 μ m, packing, obtains Cefodizime Sodium composite injection.
3. method according to claim 2, is characterized in that: described step 2) in Cefodizime Sodium composite injection obtain cefodizime sodium for injection freeze-dried powder through freeze drying.
4. it is characterized in that according to the method in claim 2 or 3: described step 2) in stirring at room temperature inclusion 1.0～1.5 hours.
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| CN103908673A (en) * | 2014-01-22 | 2014-07-09 | 邓学峰 | Ceftriaxone combinatorial drug |
| CN106309449A (en) * | 2016-08-24 | 2017-01-11 | 南昌立健药业有限公司 | Preparing method of cefodizime sodium for injection |
| CN107445978B (en) * | 2017-08-24 | 2019-06-18 | 艾美科健（中国）生物医药有限公司 | A kind of synthesis of cefalonium and purification process |
| CN109893663A (en) * | 2019-04-22 | 2019-06-18 | 苏州东瑞制药有限公司 | A kind of cefmetazole for injection composition and preparation method thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5608052A (en) * | 1992-07-08 | 1997-03-04 | Lek, Tovarna Farmacevtskih In Kemicnih | Inclusioin complexes of clavulanic acid and of alkali salts thereof with hydrophilic and hydrophobic beta-cyclodextrin derivatives, a process for the preparation thereof and the use thereof |
| US20040072798A1 (en) * | 2000-12-29 | 2004-04-15 | Annamaria Naggi | Compositions comprising cyclodextrins and no-releasing drugs |
| CN1565457A (en) * | 2003-06-21 | 2005-01-19 | 张哲峰 | Beta- lactamase suppressing antibacterial compound drugs |
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2011
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5608052A (en) * | 1992-07-08 | 1997-03-04 | Lek, Tovarna Farmacevtskih In Kemicnih | Inclusioin complexes of clavulanic acid and of alkali salts thereof with hydrophilic and hydrophobic beta-cyclodextrin derivatives, a process for the preparation thereof and the use thereof |
| US20040072798A1 (en) * | 2000-12-29 | 2004-04-15 | Annamaria Naggi | Compositions comprising cyclodextrins and no-releasing drugs |
| CN1565457A (en) * | 2003-06-21 | 2005-01-19 | 张哲峰 | Beta- lactamase suppressing antibacterial compound drugs |
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