CN103301068B - Cefixime dry suspension and preparation method thereof - Google Patents
Cefixime dry suspension and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a cefixime dry suspension and a preparation method thereof. The preparation comprises the following components in parts by weight: 1 part of cefixime, 0.8-4 parts of polyoxyethylated castor oil, 3-6 parts of medium-chain fatty acid glyceride, 2-6 parts of a suspending agent and 8-15 parts of a filler; the preparation method comprises the flowing steps of: dissolving cefixime in the medium-chain fatty acid glyceride with the polyoxyethylated castor oil, and subsequently absorbing by using a mixture of the suspending agent and the filler. The preparation is good in stability, rapid to dissolve, simple in process and applicable to industrial large-scale production.
Description
Technical field
The invention belongs to medical technical field, be specifically related to a kind of Cefixime suspension agent and preparation method thereof.
Background technology
Cefixime (Cefixime) is a kind of oral third generation cephalosporin antibiotic, chemical name: (6R, 7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-(carboxylic methoxyimino) acetylamino]-8-oxo-3-ethylene-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid trihydrate, chemical structural formula is as follows:
Cefixime be white to light yellow crystalline powder, tasteless, tool is slight special smelly, is soluble in methanol, dimethyl sulfoxine, is slightly dissolved in acetone, is insoluble in ethanol, in several water insoluble, ethyl acetates, ether, hexane.Cefixime is as third generation oral cephalosporin class antibiotic, there is has a broad antifungal spectrum, antibacterial activity is strong, gram-positive microorganism, gram-negative micro-organism, moraxelle catarrhalis (comprise and produce enzyme strain), escherichia coli, proteus mirabilis, gonococcus (comprise and produce enzyme strain) are all had to good antibacterial activity, the advantage such as stable and side effect is little to most beta lactamases.Be applicable to the following bacterial infection disease that the Streptococcus of cefixime sensitive organism (except enterococcus), streptococcus pneumoniae, gonococcus, branhamella catarrhalis, escherichia coli, Klebsiella, Serratia, Proteus and hemophilus influenza etc. are caused: bronchitis, bronchiectasis, the secondary infection that chronic respiratory system catches, pneumonia; Pyelonephritis, cystitis, gonococcal urethritis; Cholecystitis, cholangitis; Scarlet fever; Otitis media, nasal sinusitis etc.
At present, the cefixime preparation of listing has capsule, tablet, dispersible tablet, chewable tablet, granule and dry suspension, is traditional oral administered dosage form.Less stable due to cefixime, and bioavailability is also relatively low, medicine absorption and distribution is in vivo slower, has affected onset speed and the final curative effect of medicine, and ordinary preparation technology is difficult to solve the instability problem of cefixime in preparation and storage process simultaneously.
Chinese patent CN101889987A discloses the preparation method of a kind of new Cefixime tablets and capsule, and the method comprises cefixime, solubilizing agent and water soluble adjuvant micronization, then dry granulation after mixing with all the other adjuvants.Chinese patent CN101721363A discloses a kind of cefixime oral administration mixed suspension and preparation method thereof, the every 100ml of this oral administration mixed suspension consists of the following composition: cefixime 0.5～4.0g, thickening suspending agent is greater than 0 to 20.0g, cosolvent, correctives, antiseptic, all the other are non-aqueous liquid media.Chinese patent CN101606913A discloses a kind of cefixime dispersible tablet and preparation method thereof, and every containing cefixime 40～420mg, starch 0～100mg, pregelatinized Starch 0～250mg, mannitol 10～80mg, microcrystalline Cellulose 0～150mg, carboxymethylstach sodium 10～60mg, PVP K30 2～20mg, magnesium stearate 0.4～10mg, steviosin 0～10mg, orange flavor 0～10mg.Chinese patent CN101496791A discloses a kind of cefixime sustained-release tablets and preparation method thereof, this slow releasing tablet is comprised of the supplementary material of following weight proportioning: 200 parts of cefiximes (in anhydride), at least one pharmaceutically acceptable slow-release material that the scalable sustained drug of 20～200 parts slowly discharges completely, at least one pharmaceutically acceptable excipient of 20～400 parts, at least one of 5～100 parts can effectively improve the solubilizing agent of drug release rate.Chinese patent CN1803138A discloses a kind of cefixime oral disintegration tablet and preparation method thereof, and the weight ratio ingredient comprising is: cefixime 10.0%～35.0%, microcrystalline Cellulose 0%～10.0%, lactose starch 0%～35.0%, mannitol 35.0%～59.0%, cross-linking sodium carboxymethyl cellulose 4.0%～15.0%, copolyvidone 1.0%～5.0%, sodium lauryl sulphate 0.01%～1.0%, micropowder silica gel 0.01%～0.5%.The cefixime preparation that above-mentioned patented technology the relates to problem that all existence and stability is poor, bioavailability is relatively low.
Chinese patent CN101972231A, CN101966166A, CN101966160A, CN101966159A and CN101966154A disclose respectively dry suspension, capsule, dispersible tablet, tablet and the granule containing cefixime liposome, and the Liposomal formulation stability of these cefiximes needs further to be improved.Chinese patent CN101711741A discloses a kind of cefixime submicro-emulsion solid preparation, owing to there is no oil phase, therefore during dissolution determination, surfactant is soluble in the aqueous phase rapidly, causes drug crystallization to be separated out, so drug-eluting unhappy.CN102327235B discloses a kind of solid cefixime lipid nanoparticle preparation and method for making thereof, the solid lipid nano-particle preparation drug loading that provides is high, particle diameter evenly, medicine retention time in blood circulation is long, there is better slow release and controlled-release effect, yet liposome technology preparation is complicated, does not utilize in production and applies.
Summary of the invention
In view of the deficiencies in the prior art, the object of the present invention is to provide that a kind of good stability, stripping are rapid, the simple Cefixime suspension agent of technique and preparation method thereof.
Particularly, the object of the invention is to be achieved through the following technical solutions:
A Cefixime suspension, the component that comprises following weight portion:
Preferably, above-mentioned Cefixime suspension, is prepared from by the component of following weight portion:
Further preferably, above-mentioned Cefixime suspension, wherein said medium chain length fatty acid triglyceride is selected from as follows: saturated Trivent OCG, saturated tricaprin, saturated sad-triglyceride that capric acid mixes.
Cefixime suspension of the present invention, wherein said suspending agent is selected from following one or more: sodium carboxymethyl cellulose, polyvidone, hydroxypropyl cellulose, hypromellose and xanthan gum.Preferably described suspending agent is hydroxypropyl cellulose.
Cefixime suspension of the present invention, wherein said filler is selected from following one or more: pregelatinized Starch, cyclodextrin, lactose, starch, sucrose, mannitol, calcium hydrogen phosphate and calcium sulfate.Preferably described filler is pregelatinized Starch.
Another object of the present invention is to provide the preparation method of above-mentioned Cefixime suspension, comprises the steps:
(1) get cefixime, under stirring condition, add in Trivent OCG, make to dissolve, and then add polyoxyethylene castor oil, stir, obtain solution;
(2) suspending agent is mixed homogeneously with filler, obtain mixture, adopt the solution of described mixture adsorption step (1), stir, on particles packing machine, carry out subpackage, obtain Cefixime suspension.
The preparation method of Cefixime suspension of the present invention, wherein said suspending agent is selected from following one or more: sodium carboxymethyl cellulose, polyvidone, hydroxypropyl cellulose, hypromellose and xanthan gum; Described filler is selected from following one or more: pregelatinized Starch, cyclodextrin, lactose, starch, sucrose, mannitol, calcium hydrogen phosphate and calcium sulfate.
The preparation method of Cefixime suspension of the present invention, wherein said suspending agent is preferably hydroxypropyl cellulose; Described filler is preferably pregelatinized Starch.
The present invention in containing the oil phase of surfactant, utilizes the hydrophobic property of oil phase by material dissolution, has avoided the impact of extraneous moisture on medicine; Itself has anti-oxidant action oil phase, has further improved medicine stability; Meanwhile, owing to having added surfactant polyoxyethylene Oleum Ricini, the oil phase of preparation is Emulsion concentrated solution, and while carrying out stripping mensuration, rapid dispersion becomes emulsion, and stripping is rapid.Compared with prior art, Cefixime suspension agent the present invention relates to and preparation method thereof tool has the following advantages and is significant progressive: (1) technique is simple, is applicable to industrialized great production; (2) better stability of preparation, stripping is rapid, has improved bioavailability.
Specific embodiment
In completing process of the present invention, inventor considers, in order to improve medicine stability, should protect medicine to avoid moisture effects.In prior art, powder coating operation easier is large; Add water-insoluble lipid material, as stearic acid etc., no doubt can protect medicine, but that the unfavorable factor of bringing is drug-eluting is slack-off; Prepare liposome, the complex process such as microsphere, industrialization difficulty is high.In order to overcome the problems referred to above, inventor creatively proposes following imagination: if by medicine dissolution in the low viscous oil that contains surfactant, then with adjuvant, adsorb this oil-phase solution, will have following effect: protection medicine, avoid moisture effects; In stripping mensuration process, oil phase moment can be dispersed in dissolution medium, forms microemulsion solution, the rapid stripping of medicine; Measure settling volume than time, because oil phase is similar Emulsion concentrated solution, thus can be well dispersed in water, can layering, suspendible is respond well.Based on this, inventor selects from a large amount of oil phases, has finally selected medium chain length fatty acid triglyceride as oil phase, and its character is a kind of colorless and odorless, low viscous lipophile isostearyl glyceryl pentaerythrityl ether, has high non-oxidizability; Surfactant is selected polyoxyethylene castor oil, because itself and medium chain length fatty acid triglyceride dissolve each other.Inventor in containing the medium chain length fatty acid triglyceride of polyoxyethylene castor oil, obtains settled solution by cefixime material dissolution, then with pharmaceutically conventional adjuvant, adsorbs this solution, obtains Cefixime suspension.
Following examples further describe preparation process of the present invention and beneficial effect, embodiment is only for the object of illustration, do not limit the scope of the invention, within the apparent change that those of ordinary skills make according to the present invention simultaneously and modification are also contained in the scope of the invention.
Embodiment 1
Preparation technology:
(1) recipe quantity takes cefixime, under stirring condition, adds in saturated Trivent OCG, makes to dissolve, and then in this oil solution, adds polyoxyethylene castor oil, stirs, and obtains settled solution;
(2) recipe quantity takes polyvidone and pregelatinized Starch, and mix homogeneously obtains mixture;
(3) use the solution of the mixture adsorption step (1) of step (2), stir;
(4) on particles packing machine, carry out subpackage, obtain Cefixime suspension.
Embodiment 2
Preparation technology:
(1) recipe quantity takes cefixime, under stirring condition, adds in saturated tricaprin, makes to dissolve, and then in this oil solution, adds polyoxyethylene castor oil, stirs, and obtains settled solution;
(2) recipe quantity takes lactose and sodium carboxymethyl cellulose, and mix homogeneously obtains mixture;
(3) use the solution of the mixture adsorption step (1) of step (2), stir;
(4) on particles packing machine, carry out subpackage, obtain Cefixime suspension.
Embodiment 3
Preparation technology:
(1) recipe quantity takes cefixime, under stirring condition, in to add sad and capric acid mol ratio be 1:1 saturated sad-capric acid mixed triglyceride, makes to dissolve, and then in this oil solution, adds polyoxyethylene castor oil, stirs, and obtains settled solution;
(2) recipe quantity takes pregelatinized Starch and hydroxypropyl cellulose, and mix homogeneously obtains mixture;
(3) use the solution of the mixture adsorption step (1) of step (2), stir;
(4) on particles packing machine, carry out subpackage, obtain Cefixime suspension.
Comparative example 1
Preparation technology:
(1) recipe quantity takes cefixime, under stirring condition, in to add sad and capric acid mol ratio be 1:1 saturated sad-capric acid mixed triglyceride, makes to dissolve, and obtains settled solution;
(2) recipe quantity takes pregelatinized Starch and hydroxypropyl cellulose, and mix homogeneously obtains mixture;
(3) use the solution of the mixture adsorption step (1) of step (2), stir;
(4) on particles packing machine, carry out subpackage, obtain Cefixime suspension.
Comparative example 2
Preparation technology:
(1) recipe quantity takes cefixime, under stirring condition, in to add sad and capric acid mol ratio be 1:1 saturated sad-capric acid mixed triglyceride, makes to dissolve, and then in this oil solution, adds Tween 80, stirs, and obtains muddy oil solution;
(2) recipe quantity takes pregelatinized Starch and hydroxypropyl cellulose, and mix homogeneously obtains mixture;
(3) use the solution of the mixture adsorption step (1) of step (2), stir;
(4) on particles packing machine, carry out subpackage, obtain Cefixime suspension.
Comparative example 3
Cefixime 50g
Pregelatinized Starch 470g
Preparation technology:
Cefixime is crossed 100 mesh sieves, mixs homogeneously with pregelatinized Starch, and subpackage, obtains Cefixime suspension.
Embodiment 4
1, dissolution test
Get respectively sample prepared by embodiment 1 and comparative example 1-3, according to dissolution method (two appendix X C first methods of Chinese Pharmacopoeia version in 2010), test, phosphate buffer (pH7.2) 900ml of take is solvent, and rotating speed is per minute 100 to turn, in accordance with the law operation, in the time of 5 minutes, get solution appropriate, filter, it is appropriate that precision measures subsequent filtrate, with above-mentioned solvent dilution, become the solution that approximately contains cefixime 12 μ g in every 1ml, as need testing solution; It is appropriate that another precision takes this product, adding methanol appropriate (every 5mg cefixime adds methanol 2ml) makes to dissolve, by labelled amount, with above-mentioned solvent dilution, make the solution that approximately contains cefixime 250 μ g in every 1ml, filter, it is appropriate that precision measures subsequent filtrate, with above-mentioned solvent dilution, make the solution that approximately contains cefixime 12 μ g in every 1ml, in contrast solution.Get above-mentioned two kinds of solution, according to spectrophotography (two appendix IV A of Chinese Pharmacopoeia version in 2010), at the wavelength place of 288nm, measure respectively trap, by the ratio of the two trap, calculate the stripping quantity of every.The results are shown in Table 1.
2, related substance inspection
Get respectively sample prepared by embodiment 1 and comparative example 1-3 appropriate, accurately weighed, with phosphate buffer, dissolve and dilute the solution of making 1mg/ml, as need testing solution; Precision measures in right amount, makes the solution of 0.01mg/ml, in contrast solution with phosphate dilution.According to the chromatographic condition under assay item, injection liquid chromatography, single impurity must not be crossed 0.2 times (0.5%) of contrast solution main peak area.The results are shown in Table 2.
3, settling volume is than measuring
Get respectively each bag, sample prepared by embodiment 1 and comparative example 1-3, add water 50ml, jolting 1min, standing 3h, measures.The results are shown in Table 3.
Table 15min dissolution determination result
| Embodiment | 0 day (%) | 40 ℃, 75%RH accelerates 6 months (%) |
| Embodiment 1 | 99.8 | 97.9 |
| Embodiment 2 | 95.7 | 94.8 |
| Embodiment 3 | 99.4 | 98.2 |
| Comparative example 1 | 45.5 | 32.1 |
| Comparative example 2 | 50.2 | 30.2 |
| Comparative example 3 | 32.1 | 20.2 |
From the result of the test of table 1, can find out: embodiments of the invention 1-3 stripping is rapid, under 40 ℃, the condition of 75%RH, accelerate after 6 months, it is complete that 5min still can stripping; Although comparative example 1 in oil phase, does not add surfactant by medicine dissolution, when stripping is measured, the bad dispersion of oil phase, so stripping is bad; Comparative example 2 uses Tween 80 instead as surfactant, does not form Emulsion pre-concentration liquid, therefore dissolubility is bad; Comparative example's 3 use oil phase and surfactants, stripping is the poorest; And the sample of comparative example 1-3 is after accelerating, and stripping all obviously declines.
The maximum single assorted measurement result of table 2 related substance
| Embodiment | 0 day (%) | 40 ℃, 75%RH accelerates 6 months (%) |
| Embodiment 1 | 0.21 | 0.34 |
| Embodiment 2 | 0.22 | 0.35 |
| Embodiment 3 | 0.20 | 0.33 |
| Comparative example 1 | 0.23 | 0.37 |
| Comparative example 2 | 0.24 | 0.39 |
| Comparative example 3 | 0.23 | 3.56 |
From the result of the test of table 2, can find out, owing to having added oil phase, therefore the related substance of embodiment 1-3 and comparative example 1-2 is all better, after accelerated test, also change little; Comparative example 3 does not add oil phase, after related substance accelerates, increases obviously.
Table 3 settling volume compares measurement result
| Embodiment | Measurement result |
| Embodiment 1 | 0.95 |
| Embodiment 2 | 0.96 |
| Embodiment 3 | 0.97 |
| Comparative example 1 | 0.94 |
| Comparative example 2 | 0.94 |
| Comparative example 3 | 0.65 |
From the result of the test of table 3, can find out, sample prepared by embodiment 1-3 and comparative example 1-2 all can meet the regulation of dry suspension; Comparative example 3 settling volume is than against regulation.
Claims (7)
1. a Cefixime suspension, is characterized in that: the component that comprises following weight portion:
Described medium chain length fatty acid triglyceride be saturated Trivent OCG, saturated tricaprin, saturated sad-triglyceride that capric acid mixes, preparation method comprises the steps:
(1) get cefixime, under stirring condition, add in medium chain length fatty acid triglyceride, make to dissolve, and then add polyoxyethylene castor oil, stir, obtain solution;
(2) suspending agent is mixed homogeneously with filler, obtain mixture, adopt the solution of described mixture adsorption step (1), stir, on particles packing machine, carry out subpackage, obtain Cefixime suspension.
2. Cefixime suspension according to claim 1, is characterized in that: the component by following weight portion is prepared from:
3. Cefixime suspension according to claim 1, is characterized in that: described suspending agent is selected from following one or more: sodium carboxymethyl cellulose, polyvidone, hydroxypropyl cellulose, hypromellose and xanthan gum.
4. Cefixime suspension according to claim 3, is characterized in that: described suspending agent is hydroxypropyl cellulose.
5. Cefixime suspension according to claim 1, is characterized in that: described filler is selected from following one or more: pregelatinized Starch, cyclodextrin, lactose, starch, sucrose, mannitol, calcium hydrogen phosphate and calcium sulfate.
6. Cefixime suspension according to claim 5, is characterized in that: described filler is pregelatinized Starch.
7. Cefixime suspension according to claim 1, is characterized in that: described medium chain length fatty acid triglyceride is saturated Trivent OCG.
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| JPS56100712A (en) * | 1980-01-18 | 1981-08-12 | Sankyo Co Ltd | Preparation of pharmaceutical of 7-methoxycephalosporin for rectal administration |
| DE4418957A1 (en) * | 1994-05-31 | 1995-12-07 | Merck Patent Gmbh | Cefixime preparation |
| RU2178293C2 (en) * | 1998-08-18 | 2002-01-20 | Панацея Биотек Лимитед | Cyclosporin-containing pharmaceutical composition, method of soft gelatin capsule preparing |
| CN1981741A (en) * | 2005-11-23 | 2007-06-20 | 兰贝克赛实验室有限公司 | Method of improving biological utilization degree of precursor medicament using self-emulsification delivering system |
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