CN103239411B - Cefdinir, citric acid and sodium citrate dry suspension composition - Google Patents
Cefdinir, citric acid and sodium citrate dry suspension composition Download PDFInfo
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- CN103239411B CN103239411B CN201310169647.2A CN201310169647A CN103239411B CN 103239411 B CN103239411 B CN 103239411B CN 201310169647 A CN201310169647 A CN 201310169647A CN 103239411 B CN103239411 B CN 103239411B
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Abstract
The invention provides a cefdinir (C14H13N5O5S2), citric acid and sodium citrate dry suspension composition and a preparation method thereof. The cefdinir, citric acid and sodium citrate dry suspension composition comprises the following components in parts by weight: 100 parts of cefdinir, 1900-2100 parts of a diluent, 120-200 parts of a flocculant, 28-35 parts of a corrigent, 185-195 parts of an adhesive, 15-30 parts of a suspending aid, 8-12 parts of a flow aid and 1.5-2.5 parts of a lubricant. The cefdinir, citric acid and sodium citrate dry suspension composition disclosed by the invention is convenient for being taken by patients, and has high bioavailability and stability.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of cefdinir (C
14h
13n
5o
5s
2) and citric acid and sodium citrate dry suspension compositions.
Background technology
Cefdinir is cephalo the 3rd generation oral antibiotic of a new generation, and within 1988, synthesize first, 1991 start to be applied to Japan, and in December, 1997 obtains U.S. FDA approval, starts to use in the U.S..Due to Cefdinir oral good absorbing, untoward reaction is little, has a broad antifungal spectrum, not only effective to gram-negative bacteria (G-), and also has higher antibacterial activity to gram-positive bacteria (G+), is therefore used widely clinically.About cefdinir quasi drugs, " CFDN capsule " that " the multiple capsule in full pool " that have Xi'an Yang Sen to produce of domestic listing and Tianjin central authorities Pharmaceutical are produced etc.
At present, the cefdinir quasi drugs of domestic production mostly is capsule and dispersible tablet, is not easy to patient and takes, especially for the patient of the dysphagia such as old man, child.In addition because cefdinir raw material is comparatively insoluble in water, make the bioavailability of cefdinir quasi drugs and stability lower, therefore, how to develop and a kind ofly there is higher bioavailability and stability and the cefdinir medicament facilitated patients becomes this area problem urgently to be resolved hurrily.
Summary of the invention
For the problems referred to above, one object of the present invention is to provide a kind of cefdinir (C
14h
13n
5o
5s
2) and citric acid and sodium citrate dry suspension compositions, this cefdinir (C
14h
13n
5o
5s
2) and citric acid and sodium citrate dry suspension compositions facilitate patients, and there is higher bioavailability and stability.
Another object of the present invention is to provide a kind of cefdinir (C1
4h
13n
5o
5s
2) and the preparation method of citric acid and sodium citrate dry suspension compositions.
Above-mentioned purpose of the present invention realizes by following technical scheme:
The invention provides a kind of cefdinir (C
14h
13n
5o
5s
2) and citric acid and sodium citrate dry suspension compositions, with the Weight computation of each component, comprising:
Cefdinir 100 parts of diluent 1900-2100 parts
Flocculating agent 120-200 part correctives 28-35 part
Binding agent 185-195 part suspending agent 15-30 part
Fluidizer 8-12 part lubricant 1.5-2.5 part.
Further, described flocculating agent is the mixture of citric acid and sodium citrate;
Preferably, described diluent is lactose, glucose, sucrose or maltose, preferably sucrose;
Preferably, described suspending agent is xanthan gum, Sodium Tvlose, hypromellose or polyvidone, is preferably xanthan gum;
Preferably, described correctives is aspartame or strawberry essence, preferred strawberry essence;
Preferably, described lubricant is Pulvis Talci or magnesium stearate, is preferably magnesium stearate;
Preferably, described fluidizer is silica gel or Pulvis Talci, preferred silica gel, more preferably micropowder silica gel;
Preferably, described binding agent is ethanol water, be preferably 50%(wt) ethanol water.
Further, described flocculating agent comprises the citric acid and sodium citrate that weight ratio is 1:0.6-2.5, preferably comprises citric acid and sodium citrate that weight ratio is 1:1;
Preferably, described cefdinir (C
14h
13n
5o
5s
2) and citric acid and sodium citrate dry suspension compositions comprise the binding agent of 190 parts;
Preferably, the weight ratio of described xanthan gum and cefdinir is 0.15-0.30, is more preferably 0.2.
Further, by described cefdinir (C
14h
13n
5o
5s
2) and the add water pH value of the suspension made containing cefdinir 2.5mg in every 1ml of citric acid and sodium citrate dry suspension compositions be 3.5-4.5, preferable ph is 4.
The present invention further provides a kind of above-mentioned cefdinir (C
14h
13n
5o
5s
2) and the preparation method of citric acid and sodium citrate dry suspension compositions, this preparation method comprises the following steps:
Step a: diluent and flocculating agent are pulverized, and respectively cefdinir, diluent, flocculating agent, lubricant, correctives, suspending agent and fluidizer is sieved;
Step b: each component raw material taking formula ratio, mixes diluent, flocculating agent, correctives and cefdinir, then adds binding agent, soft material processed, discharging, the material obtained is added in granulator granulation of sieving;
Step c: by the particle drying obtained in step b, obtains dry granule;
Steps d: by the dry granule granulate obtained in step c, then suspending agent, fluidizer and lubricant are added premix in mixer, then add in mixer by the dry granule after granulate, mixing, obtains dry suspension.
Further, in described step a, diluent and flocculating agent are pulverized, cefdinir is crossed 200 mesh sieves, diluent, flocculating agent and lubricant are crossed 100 mesh sieves, correctives, suspending agent and fluidizer are crossed 80 mesh sieves.
Further, in described step b, take each component raw material of formula ratio, diluent, flocculating agent, correctives and cefdinir are added in high-speed mixing granulating machine, open granulating cutter and cutter, be dry mixed 3min, mixing velocity is 400rpm, cutting speed is 3000rpm, then adds binding agent, soft material 2min processed, discharging, adds the material obtained in oscillating granulator and crosses 24 mesh sieves granulations;
Preferably, when described flocculating agent be citric acid and sodium citrate time, in described step b, take each component raw material of formula ratio, diluent is added in high-speed mixing granulating machine with citric acid and mixes 1min, mixing velocity is 400rpm, cutting speed is 3000rpm, again by sodium citrate, correctives and cefdinir add in mixer-granulator, open granulating cutter and cutter, be dry mixed 3min, mixing velocity is 400rpm, cutting speed is 3000rpm, add binding agent again, soft material 2min processed, discharging, the material obtained is added in oscillating granulator and cross 24 mesh sieves granulations.
Further, in described step c, add in Fluidbedgranulatingdrier by the granule obtained in step b, at 38-42 DEG C, preferably dry 20min at 40 DEG C, obtains dry granule.
Further; in described steps d; by the dry granule pelletizing machine that obtains in step c with 30 mesh sieve granulate; again suspending agent, fluidizer and lubricant are added premix 2min in three-dimensional mixer; then the dry granule after granulate is added in three-dimensional mixer and mix 15min; granulation speed is 150kg/h, obtains cefdinir (C
14h
13n
5o
5s
2) and citric acid and sodium citrate dry suspension compositions.
Compared with prior art, cefdinir (C provided by the invention
14h
13n
5o
5s
2) and citric acid and sodium citrate dry suspension and preparation method thereof at least have the following advantages:
One, compare with the cefdinir class medicament adopting capsule and tablet formulation to prepare in prior art, the Cefdinir dry suspension agent that the present invention adopts dry suspension dosage form to prepare has that particle diameter is little, dispersion is large, the feature that mouthfeel is good, faster than common oral preparation stripping, can the short time reaches higher blood drug level in vivo, absorb fully, thus improve bioavailability and the stability of insoluble drug cefdinir;
Two, compared with the cefdinir class medicament of other dosage forms in prior art, Cefdinir dry suspension agent of the present invention is easy to carry, and is convenient to take, and is particularly suitable for swallowing inconvenient patient, as child, old man etc.; In addition, the present invention selects glucide (as sucrose) as diluent, relative to conventional dextrin, has both reduced the risk of untoward reaction, and has turn improved the taste of medicine, be more suitable for children; And Cefdinir dry suspension agent of the present invention adds correctives (as strawberry essence) further, Cefdinir dry suspension agent is dispersed into evenly and the suspension of good mouthfeel in water, facilitates patients, enhance the compliance of medication;
Three, add flocculating agent and lubricant in Cefdinir dry suspension agent of the present invention, and regulate the proportioning of each component, make Cefdinir dry suspension agent grain dissolution of the present invention very fast, good fluidity, is more suitable for large-scale production, and has higher stability;
Four, the present invention adopts the additional legal system of suspending agent, fluidizer and lubricant for Cefdinir dry suspension agent, to avoid in wet granulation step the situations such as granulating difficulty, is conducive to suitability for industrialized production;
Five, at cefdinir (C of the present invention
14h
13n
5o
5s
2) and citric acid and sodium citrate dry suspension preparation method in, for the different qualities of each component raw material, adopting each component raw material of diverse ways process (as crossed the sieve of different meshes), reducing the loss of each raw material, improve the utilization rate of each raw material, and improve the quality of product; Adopt high-speed mixing granulating machine to granulate in addition, drastically increase work efficiency, reduce the risk that impurity produces, improve quality and the safety of product; The present invention's dried particles under preference temperature (40 DEG C ± 2 DEG C, preferably 40 DEG C), while enhancing productivity, ensure that the quality of product in addition;
Six, the present invention adopts the method for control ph to prepare cefdinir (C
14h
13n
5o
5s
2) and citric acid and sodium citrate dry suspension, improve the quality of Cefdinir dry suspension agent.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in detail.It will be appreciated by those skilled in the art that these embodiments are only for illustration of the present invention, its scope do not limited the present invention in any way.
preparation embodiment 1
The Cefdinir dry suspension agent of the present embodiment is prepared according to following component proportion:
Cefdinir 100g sucrose 2000g
Sodium citrate 80g citric acid 80g
Fructus Fragariae Ananssae powdered flavor 32g 50%(wt) ethanol water 190g
Xanthan gum 20g micropowder silica gel 10g
Magnesium stearate 2g
Step 1, pulverizes sucrose, citric acid and sodium citrate;
Step 2, crosses 200 mesh sieves by cefdinir, sucrose, citric acid, sodium citrate and magnesium stearate cross 100 mesh sieves, and 80 mesh sieves are crossed in Fructus Fragariae Ananssae powdered flavor, xanthan gum and micropowder silica gel;
Step 3, takes each component by above-mentioned content, is first added in high-speed mixing granulating machine with citric acid by sucrose and mixes 1min; mixing velocity is 400rpm, and cutting speed is 3000rpm, then sodium citrate, Fructus Fragariae Ananssae powdered flavor and cefdinir is added; open granulating cutter and cutter; top gear is dry mixed 3min, and mixing velocity is 400rpm, and cutting speed is 3000rpm; then the ethanol water of 50wt% is added; soft material 2min processed, discharging, then adds oscillating granulator and crosses 24 mesh sieves granulations by material.
Step 4, adds in Fluidbedgranulatingdrier by granule obtained in step 3, design temperature 40 DEG C, and the dry 20min of starting device, obtains dry granule;
Step 5; first by dry granule pelletizing machine with 30 mesh sieve granulate; again xanthan gum, micropowder silica gel and magnesium stearate are added premix 2min in three-dimensional mixer; and then the dry granule after above-mentioned granulate added in three-dimensional mixer mix 15min; granulation speed is 150kg/h, obtains Cefdinir dry suspension agent.
preparation embodiment 2
The Cefdinir dry suspension agent of the present embodiment is prepared according to following component proportion:
Cefdinir 100g sucrose 2100g
Sodium citrate 60g citric acid 60g
Fructus Fragariae Ananssae powdered flavor 35g 50%(wt) ethanol water 185g
Xanthan gum 30g micropowder silica gel 8g
Magnesium stearate 1.5g
Step 1, pulverizes sucrose, citric acid and sodium citrate;
Step 2, crosses 200 mesh sieves by cefdinir, sucrose, citric acid, sodium citrate and magnesium stearate cross 100 mesh sieves, and 80 mesh sieves are crossed in Fructus Fragariae Ananssae powdered flavor, xanthan gum and micropowder silica gel;
Step 3, takes each component by above-mentioned content, is first added in high-speed mixing granulating machine with citric acid by sucrose and mixes 1min; mixing velocity is 400rpm, and cutting speed is 3000rpm, then sodium citrate, Fructus Fragariae Ananssae powdered flavor and cefdinir is added; open granulating cutter and cutter; top gear is dry mixed 3min, and mixing velocity is 400rpm, and cutting speed is 3000rpm; then the ethanol water of 50wt% is added; soft material 2min processed, discharging, then adds oscillating granulator and crosses 24 mesh sieves granulations by material.
Step 4, adds in Fluidbedgranulatingdrier by granule obtained in step 3, design temperature 40 DEG C, and the dry 20min of starting device, obtains dry granule;
Step 5; first by dry granule pelletizing machine with 30 mesh sieve granulate; again xanthan gum, micropowder silica gel and magnesium stearate are added premix 2min in three-dimensional mixer; and then the dry granule after above-mentioned granulate added in three-dimensional mixer mix 15min; granulation speed is 150kg/h, obtains Cefdinir dry suspension agent.
preparation embodiment 3
The Cefdinir dry suspension agent of the present embodiment is prepared according to following component proportion:
Cefdinir 100g sucrose 2100g
Sodium citrate 90g citric acid 90g
Fructus Fragariae Ananssae powdered flavor 28g 50%(wt) ethanol water 190g
Xanthan gum 20g micropowder silica gel 10g
Magnesium stearate 2g
Step 1, pulverizes sucrose, citric acid and sodium citrate;
Step 2, crosses 200 mesh sieves by cefdinir, sucrose, citric acid, sodium citrate and magnesium stearate cross 100 mesh sieves, and 80 mesh sieves are crossed in Fructus Fragariae Ananssae powdered flavor, xanthan gum and micropowder silica gel;
Step 3, takes each component by above-mentioned content, is first added in high-speed mixing granulating machine with citric acid by sucrose and mixes 1min; mixing velocity is 400rpm, and cutting speed is 3000rpm, then sodium citrate, Fructus Fragariae Ananssae powdered flavor and cefdinir is added; open granulating cutter and cutter; top gear is dry mixed 3min, and mixing velocity is 400rpm, and cutting speed is 3000rpm; then the ethanol water of 50wt% is added; soft material 2min processed, discharging, then adds oscillating granulator and crosses 24 mesh sieves granulations by material.
Step 4, adds in Fluidbedgranulatingdrier by granule obtained in step 3, design temperature 40 DEG C, and the dry 20min of starting device, obtains dry granule;
Step 5; first by dry granule pelletizing machine with 30 mesh sieve granulate; again xanthan gum, micropowder silica gel and magnesium stearate are added premix 2min in three-dimensional mixer; and then the dry granule after above-mentioned granulate added in three-dimensional mixer mix 15min; granulation speed is 150kg/h, obtains Cefdinir dry suspension agent.
preparation embodiment 4
The Cefdinir dry suspension agent of the present embodiment is prepared according to following component proportion:
Cefdinir 100g sucrose 1900g
Sodium citrate 100g citric acid 100g
Fructus Fragariae Ananssae powdered flavor 35g 50%(wt) ethanol water 195g
Xanthan gum 15g micropowder silica gel 12g
Magnesium stearate 2.5g
Step 1, pulverizes sucrose, citric acid and sodium citrate;
Step 2, crosses 200 mesh sieves by cefdinir, sucrose, citric acid, sodium citrate and magnesium stearate cross 100 mesh sieves, and 80 mesh sieves are crossed in Fructus Fragariae Ananssae powdered flavor, xanthan gum and micropowder silica gel;
Step 3, takes each component by above-mentioned content, is first added in high-speed mixing granulating machine with citric acid by sucrose and mixes 1min; mixing velocity is 400rpm, and cutting speed is 3000rpm, then sodium citrate, Fructus Fragariae Ananssae powdered flavor and cefdinir is added; open granulating cutter and cutter; top gear is dry mixed 3min, and mixing velocity is 400rpm, and cutting speed is 3000rpm; then the ethanol water of 50wt% is added; soft material 2min processed, discharging, then adds oscillating granulator and crosses 24 mesh sieves granulations by material.
Step 4, adds in Fluidbedgranulatingdrier by granule obtained in step 3, design temperature 40 DEG C, and the dry 20min of starting device, obtains dry granule;
Step 5; first by dry granule pelletizing machine with 30 mesh sieve granulate; again xanthan gum, micropowder silica gel and magnesium stearate are added premix 2min in three-dimensional mixer; and then the dry granule after above-mentioned granulate added in three-dimensional mixer mix 15min; granulation speed is 150kg/h, obtains Cefdinir dry suspension agent.
preparation embodiment 5
The Cefdinir dry suspension agent of the present embodiment is prepared according to following component proportion:
Cefdinir 100g sucrose 1900g
Sodium citrate 70g citric acid 70g
Fructus Fragariae Ananssae powdered flavor 35g 50%(wt) ethanol water 195g
Hypromellose 20g micropowder silica gel 12g
Magnesium stearate 2.5g
Step 1, pulverizes sucrose, sodium citrate and citric acid;
Step 2, crosses 200 mesh sieves by cefdinir, sucrose, sodium citrate, citric acid and magnesium stearate cross 100 mesh sieves, and 80 mesh sieves are crossed in Fructus Fragariae Ananssae powdered flavor, hypromellose and micropowder silica gel;
Step 3, takes each component by above-mentioned content, is first added in high-speed mixing granulating machine with citric acid by sucrose and mixes 1min; mixing velocity is 400rpm, and cutting speed is 3000rpm, then sodium citrate, Fructus Fragariae Ananssae powdered flavor and cefdinir is added; open granulating cutter and cutter; top gear is dry mixed 3min, and mixing velocity is 400rpm, and cutting speed is 3000rpm; then the ethanol water of 50wt% is added; soft material 2min processed, discharging, then adds oscillating granulator and crosses 24 mesh sieves granulations by material.
Step 4, adds in Fluidbedgranulatingdrier by granule obtained in step 3, design temperature 40 DEG C, and the dry 20min of starting device, obtains dry granule;
Step 5; first by dry granule pelletizing machine with 30 mesh sieve granulate; again hypromellose, micropowder silica gel and magnesium stearate are added premix 2min in three-dimensional mixer; and then the dry granule after above-mentioned granulate added in three-dimensional mixer mix 15min; granulation speed is 150kg/h, obtains Cefdinir dry suspension agent.
method of testing
The present invention, with reference to related quality criterion requirement in USP34, CP2010, adopts following methods to test impurity in Cefdinir dry suspension agent of the present invention and polymer content:
1. the locate mode of impurity
With reference to Chinese Pharmacopoeia and USP34 version cefdinir related substance standard, following manner is adopted to position impurity.
(1) relative retention time location: the model of stationary chromatographic post, comprises length, diameter, filling kind, filler granularity etc., by experiment, substantially can accurately locate;
(2) impurity reference substance location: related substance A reference substance can locate 4 impurity peaks; 1 impurity peaks located by related substances B reference substance;
(3) main constituent destroy method location: adopt the experimental condition under Chinese Pharmacopoeia version cefdinir raw material related substance item in 2010, destroy cefdinir, for impurity VII(E-isomer) location.
2. the ownership of impurity and limit
(1) impurity ownership: in order to prove the accuracy that impurity belongs to further, structural identification test is carried out to impurity, result shows, all impurity all derives from raw material, wherein by strength tests such as water-bath, oxidation, high temperature, cefdinir is degraded, be S1, S2, S4, S5, S6, S7a, S8, S9, S9a, S14 by the known principal degradation impurity of structural identification, the structure of impurity is identical with USP34 version.
Known by study on the stability data, sample is cefdinir related substances A(and S5, S6, S7a, S8 in storage process), impurity XI(and S4) and impurity VII(and S14) be principal degradation impurity, but consider impurity XIV(and S2), impurity I(and S9) and impurity VI(and S9a) may degrade under intense conditions, cefdinir related substances B has the probability of degraded, above-mentioned known impurities is controlled all separately.
(2) limit of impurity
Known by stability study data, continue to use the limit of the cefdinir suspensoid related substance that USP32 version is recorded, can control effectively to impurity, illustrate that limit is formulated rationally, the present invention is strict in the control of USP32 version to impurity to the limit of impurity in cefdinir suspensoid, and impurity is limited, product quality can be controlled better.
3. polymeric detection
The present invention, with reference to CP2010 version like product polymeric detection method, by experiment sieving detection method, and carries out system methodology checking, finally determines the detection method of polymer in cefdinir suspensoid of the present invention.
Method one: according to the assay method of polymer most of in Chinese Pharmacopoeia, adopts sephadex column to test
Adopt sephadex G-10(40 ~ 120 μm) be filler, glass column internal diameter 1.3 ~ 1.6cm, post height 30 ~ 40cm.With the 0.01mol/L phosphate buffered solution of pH7.0 (0.01mol/L disodium phosphate soln-0.01mol/L sodium dihydrogen phosphate (61:39)) for mobile phase A, take water as Mobile phase B, flow velocity is about 0.8ml per minute; Determined wavelength is 254nm.
According to result of the test, the mensuration of polymer in the adjuvant disturbed specimen adopted in the method, is therefore unsuitable for the detection of polymer in cefdinir suspensoid of the present invention.
Method two: with reference to Cefodizime Sodium polymeric detection method
Measure according to molecular exclusion chromatography (annex VH), adopt globular protein chromatograph and use hydrophilic silica gels as filler; With phosphate buffered solution (pH7.0) (0.005mol/L sodium hydrogen phosphate and 0.005mol/L sodium dihydrogen phosphate (61:39)) ,-acetonitrile (95:5) is for mobile phase, and flow velocity is 0.8ml per minute, and determined wavelength is 231nm.
According to result of the test, the method can be used for the mensuration of polymer in cefdinir suspensoid of the present invention, and therefore, the present invention adopts method two to detect the content of polymer in cefdinir suspensoid.
contrast test
Respectively the Shandeshi company of the cefdinir suspensoid A(U.S. that the U.S. goes on the market is produced) and the Cefdinir capsule B(Tianjin Jin Kang pharmaceutical Co. Ltd of domestic listing produce) compare with cefdinir suspensoid of the present invention.
Adopt the performance of above-mentioned method of testing to cefdinir suspensoid of the present invention and existing cefdinir suspensoid A and Cefdinir capsule B to test respectively, result is as shown in table 1.
The performance comparison of table 1 cefdinir suspensoid of the present invention and existing product
As seen from Table 1, cefdinir suspensoid drug content prepared by the embodiment of the present invention is 98.7%-100.5%, polymer content is 0.76%-0.84%, dissolution is 85.9%-100.1%, and total impurities is 0.73%-0.86%, and wherein polymer and total impurities content are all less than polymer and the total impurities content of existing like product, illustrate thus, relative to existing cefdinir medicament, cefdinir suspensoid of the present invention has higher safety, thus improves quality and the stability of product.
influence factor tests 1temperature is on the impact of impurity in suspensoid and polymer
Under different baking temperatures, prepare Cefdinir dry suspension agent according to the method in embodiment 1, test the content of impurity and polymer in each Cefdinir dry suspension agent respectively.Test result is as shown in table 2.
The content (%) of impurity and polymer in the dry suspension prepared under table 2 different temperatures
Cephalo-type material belongs to high sensitive materials, the impurity itself contained and polymer more, the increase of baking temperature can make its impurity and polymer increase.As seen from Table 2, along with the increase of baking temperature, in Cefdinir dry suspension agent, the content of impurity and polymer is in rising trend, and baking temperature is too low, can drying time be extended, improve the probability that impurity produces, be unfavorable for enhancing productivity, and affect the quality of product.The preferred baking temperature of the present invention is 38-42 DEG C (more preferably 40 DEG C), and under this baking temperature, in Cefdinir dry suspension agent, the content of impurity and polymer is less, while enhancing productivity, ensure that product quality.
influence factor tests 2flocculating agent is on the impact of suspensoid character
Adopt citric acid and sodium citrate as flocculating agent, in test flocculating agent, the content of citric acid and sodium citrate is on the impact of Cefdinir dry suspension agent character, method wherein in employing embodiment 1 is (except citric acid is different from the content of sodium citrate, other materials and technological parameter are all with reference to the method for embodiment 1) prepare Cefdinir dry suspension agent, test result is as shown in table 3.
The nature parameters of the suspensoid that table 3 adopts the citric acid of different ratio and sodium citrate to prepare
As shown in Table 3, pH value 3.5-4.5(get Cefdinir dry suspension agent add water make the pH value of suspension of every 1ml containing cefdinir 2.5mg) between the related substance of sample substantially identical, but be significantly less than the sample of pH value 5.0, therefore be greater than the quality of the sample of 4.5 than pH value more stable for the sample of pH value within the scope of 3.5-4.5, the stability of simultaneously placing for a long time from the viewpoint of sample, preferable ph of the present invention about 4.0 prescription, namely the weight ratio of citric acid and sodium citrate is the prescription of 1:1, every Testing index of the Cefdinir dry suspension agent of this formula preparation is adopted to meet USP32 standard.
influence factor tests 3suspending agent is on the impact of Cefdinir dry suspension agent
1, suspending agent material is on the impact of Cefdinir dry suspension agent
Adopt xanthan gum, Sodium Tvlose (CMC-Na), hypromellose (HPMC) and polyvidone (PVP) to make Cefdinir dry suspension agent as suspending agent respectively and (prepare Cefdinir dry suspension agent with reference to the method in embodiment 1, and the Cefdinir dry suspension agent of preparation is pressed different content subpackage by particle packaging machine paper using aluminum composite membrane), detect the sedimentation volume ratio of each suspending agent according to the regulation in Chinese Pharmacopoeia version annex in 2000, test result is as shown in table 4:
The sedimentation volume ratio of dry suspension prepared by table 4 variety classes suspending agent
As seen from Table 4, compared with other suspending agents, the settling volume of the dry suspension adopting xanthan gum to prepare is larger, and suspending effect is better, and therefore the present invention preferably adopts xanthan gum to prepare Cefdinir dry suspension agent as suspending agent.
2, the amount of suspending agent is on the impact of dry suspension
Adopt not commensurability suspending agent to prepare Cefdinir dry suspension agent (except suspending agent, other materials are all identical with the method for embodiment 1) respectively, compare the impact of suspending agent content on the settling character of Cefdinir dry suspension agent, test result is as shown in table 5.
The settling character of Cefdinir dry suspension agent prepared by table 5 different content suspending agent
As seen from Table 5, when the amount of the xanthan gum (relative to cefdinir) added is greater than 0.3, suspensoid in 3h almost without sedimentation; Xanthan gum, within the scope of aforementioned proportion, does not produce obvious impact to the pH value of suspensoid; The consumption of xanthan gum is non-linear relation on the rate of settling of suspensoid, the impact of sedimentation volume ratio, consider based on clinical drug safety, according to reaching the minimum addition of suspendible effect as the standard selected, the weight ratio of the preferred xanthan gum of the present invention and cefdinir is 0.15-0.30, is more preferably 0.2.
high light and hot test
The Cefdinir dry suspension agent embodiment of the present invention 1 prepared is placed 5,10 days respectively under high light and high temperature (40 DEG C, 60 DEG C) condition, and each nature parameters of test Cefdinir dry suspension agent, result of the test is as shown in table 6.Table 6 Cefdinir dry suspension agent is test data under High temperature condition
As seen from Table 6, Cefdinir dry suspension agent of the present invention is placed after 5,10 days under high light (4500LX) and high temperature (40 DEG C, 60 DEG C), and character all remains faint yellow granule, and sedimentation volume ratio all conforms with the regulations.Strong illumination is after 10 days, and related substance is 0.56%, and total impurities is 1.58, and polymer is 0.82%, and drug content is 99.3%, all meets bound requirements; Place after 10 days under high temperature, related substance is 0.1% to the maximum, and total impurities is 1.57 to the maximum, polymer is 0.84% to the maximum, and drug content is 99.3% to the maximum, all meets bound requirements, illustrate thus, Cefdinir dry suspension agent of the present invention still keeps higher stability after high light and hot test.
accelerated test
Cefdinir dry suspension agent prepared by embodiment 1,2,3 is carried out subpackage by particle packaging machine, and carries out accelerated test further, experimental condition is as follows:
Subpackage specification: 100mg/ bag
Packaging: paper/aluminum/polyvinyl medicine composite packing film bag
Test condition: temperature: 30 DEG C ± 2 DEG C, humidity: RH65% ± 5%
Test result is as shown in table 7, as seen from Table 7, after Cefdinir dry suspension agent of the present invention places 1,2,3,6 month under test conditions, character all keeps faint yellow granule, acidity is 3.94-4.06, settling volume when microbial limit all conforms with the regulations requirement, polymer content is 0.78-0.83%, and drug content is 99.1-100.0%, and related substance is 0.77-1.40%, all in bound requirements, show that Cefdinir dry suspension agent of the present invention has good stability.
Table 7 Cefdinir dry suspension agent accelerated test test data
long term test 1
Cefdinir dry suspension agent prepared by embodiment 1,2,3 is carried out subpackage by particle packaging machine, and carries out long term test further, experimental condition is as follows:
Subpackage specification: 100mg/ bag
Packaging: paper/aluminum/polyvinyl medicine composite packing film bag
Investigation condition: temperature: 25 ± 2 DEG C, humidity: 60% ± 10%
It is as shown in the table 8 for test result, as seen from Table 8, after Cefdinir dry suspension agent of the present invention places 3,6,9,12 months under test conditions, character all keeps faint yellow granule, acidity is 3.93-4.06, settling volume when microbial limit all conforms with the regulations requirement, polymer content is 0.78-0.83%, and drug content is 99.0-100.0%, and related substance is 0.77-1.42%, all in bound requirements, show that Cefdinir dry suspension agent of the present invention has good stability.
Table 8 Cefdinir dry suspension agent long term test test data
long term test 2
Cefdinir dry suspension agent prepared by embodiment 1,2,3 is carried out subpackage by particle packaging machine, and carries out long term test further, experimental condition is as follows:
Subpackage specification: 100mg/ bag
Packaging: paper/aluminum/polyvinyl medicine composite packing film bag
Investigation condition: temperature: 20 DEG C, humidity: 60% ± 10%
Test result is as shown in table 9, as seen from Table 9, after Cefdinir dry suspension agent of the present invention places 3,6,9,12 months under test conditions, character all keeps faint yellow granule, acidity is 3.93-4.07, settling volume when microbial limit all conforms with the regulations requirement, polymer content is 0.78-0.84%, and drug content is 98.9-100.0%, and related substance is 0.77-1.04%, all in bound requirements, show that Cefdinir dry suspension agent of the present invention has good stability.
Table 9 Cefdinir dry suspension agent long term test test data
Specific description of embodiments of the present invention does not above limit the present invention, and those skilled in the art can make various change or distortion according to the present invention, only otherwise depart from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (24)
1. a molecular formula C
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, with the Weight computation of each component, comprising:
Wherein, described flocculating agent is the mixture of citric acid and sodium citrate, and the weight ratio of citric acid and sodium citrate is 1:0.6-2.5;
Described suspending agent is xanthan gum, and the weight ratio of described xanthan gum and cefdinir is 0.15-0.30;
Described diluent is sucrose;
Described lubricant is magnesium stearate;
Described fluidizer is micropowder silica gel;
Described binding agent is the ethanol water of concentration expressed in percentage by weight 50%;
The pH value of the suspension made containing cefdinir 2.5mg in every 1ml of described cefdinir and citric acid and sodium citrate dry suspension compositions being added water is 3.5-4.5.
2. molecular formula C according to claim 1
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, described correctives is aspartame or strawberry essence.
3. molecular formula C according to claim 1
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, described correctives is strawberry essence.
4. molecular formula C according to any one of claim 1 to 3
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, described flocculating agent is weight ratio is the citric acid of 1:1 and the mixture of sodium citrate.
5. molecular formula C according to any one of claim 1 to 3
14h
13n
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5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, described molecular formula C
14h
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5s
2cefdinir and citric acid and sodium citrate dry suspension compositions comprise the binding agent of 190 parts.
6. molecular formula C according to claim 4
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, described molecular formula C
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions comprise the binding agent of 190 parts.
7. molecular formula C according to any one of claims 1 to 3
14h
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5s
2cefdinir (C
14h
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5s
2) and citric acid and sodium citrate dry suspension compositions, it is characterized in that, the weight ratio of described xanthan gum and cefdinir is 0.2.
8. molecular formula C according to claim 4
14h
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5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, the weight ratio of described xanthan gum and cefdinir is 0.2.
9. molecular formula C according to claim 5
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, the weight ratio of described xanthan gum and cefdinir is 0.2.
10. molecular formula C according to claim 6
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, the weight ratio of described xanthan gum and cefdinir is 0.2.
11. according to any one of claims 1 to 3 molecular formula C
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, the pH value of the suspension made containing cefdinir 2.5mg in every 1ml that described cefdinir and citric acid and sodium citrate dry suspension compositions added water is 4.
12. molecular formula C according to claim 4
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, the pH value of the suspension made containing cefdinir 2.5mg in every 1ml that described cefdinir and citric acid and sodium citrate dry suspension compositions added water is 4.
13. molecular formula C according to claim 5
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, the pH value of the suspension made containing cefdinir 2.5mg in every 1ml that described cefdinir and citric acid and sodium citrate dry suspension compositions added water is 4.
14. molecular formula C according to claim 6
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, the pH value of the suspension made containing cefdinir 2.5mg in every 1ml that described cefdinir and citric acid and sodium citrate dry suspension compositions added water is 4.
15. molecular formula C according to claim 7
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, the pH value of the suspension made containing cefdinir 2.5mg in every 1ml that described cefdinir and citric acid and sodium citrate dry suspension compositions added water is 4.
16. molecular formula C according to claim 8
14h
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5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, the pH value of the suspension made containing cefdinir 2.5mg in every 1ml that described cefdinir and citric acid and sodium citrate dry suspension compositions added water is 4.
17. molecular formula C according to claim 9
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, the pH value of the suspension made containing cefdinir 2.5mg in every 1ml that described cefdinir and citric acid and sodium citrate dry suspension compositions added water is 4.
18. molecular formula C according to claim 10
14h
13n
5o
5s
2cefdinir and citric acid and sodium citrate dry suspension compositions, it is characterized in that, the pH value of the suspension made containing cefdinir 2.5mg in every 1ml that described cefdinir and citric acid and sodium citrate dry suspension compositions added water is 4.
19. according to any one of claim 1-18 molecular formula C
14h
13n
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5s
2cefdinir and the preparation method of citric acid and sodium citrate dry suspension compositions, this preparation method comprises the following steps:
Step a: diluent and flocculating agent are pulverized, cefdinir is crossed 200 mesh sieves, diluent, flocculating agent and lubricant are crossed 100 mesh sieves, correctives, suspending agent and fluidizer are crossed 80 mesh sieves;
Step b: each component raw material taking formula ratio, mixes diluent, flocculating agent, correctives and cefdinir, then adds binding agent, soft material processed, discharging, the material obtained is added in granulator granulation of sieving;
Step c: the granule obtained in step b is added in Fluidbedgranulatingdrier, dry 20min at 38-42 DEG C, obtains dry granule;
Steps d: by the dry granule granulate obtained in step c, then suspending agent, fluidizer and lubricant are added premix in mixer, then add in mixer by the dry granule after granulate, mixing, obtains dry suspension.
20. preparation methoies according to claim 19; it is characterized in that, in described step b, take each component raw material of formula ratio; diluent, flocculating agent, correctives and cefdinir are added in high-speed mixing granulating machine; open granulating cutter and cutter, be dry mixed 3min, mixing velocity is 400rpm, cutting speed is 3000rpm; add binding agent again; soft material 2min processed, discharging, adds the material obtained in oscillating granulator and crosses 24 mesh sieves granulations.
21. preparation methoies according to claim 20, it is characterized in that, in described step b, take each component raw material of formula ratio, diluent is added in high-speed mixing granulating machine with citric acid and mixes 1min, mixing velocity is 400rpm, cutting speed is 3000rpm, again by sodium citrate, correctives and cefdinir add in mixer-granulator, open granulating cutter and cutter, be dry mixed 3min, mixing velocity is 400rpm, cutting speed is 3000rpm, add binding agent again, soft material 2min processed, discharging, the material obtained is added in oscillating granulator and cross 24 mesh sieves granulations.
22., according to claim 19 to the preparation method according to any one of 21, is characterized in that, in described step c, add in Fluidbedgranulatingdrier by the granule obtained in step b, and dry 20min at 40 DEG C, obtains dry granule.
23. according to claim 19 to the preparation method according to any one of 21; it is characterized in that; in described steps d; by the dry granule pelletizing machine that obtains in step c with 30 mesh sieve granulate; again suspending agent, fluidizer and lubricant are added premix 2min in three-dimensional mixer; then added in three-dimensional mixer by the dry granule after granulate and mix 15min, granulation speed is 150kg/h, obtains molecular formula C
14h
13n
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2cefdinir and citric acid and sodium citrate dry suspension compositions.
24. preparation methoies according to claim 22; it is characterized in that; in described steps d; by the dry granule pelletizing machine that obtains in step c with 30 mesh sieve granulate; again suspending agent, fluidizer and lubricant are added premix 2min in three-dimensional mixer; then added in three-dimensional mixer by the dry granule after granulate and mix 15min, granulation speed is 150kg/h, obtains molecular formula C
14h
13n
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2cefdinir and citric acid and sodium citrate dry suspension compositions.
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|---|---|---|---|---|
| CN101018543A (en) * | 2003-12-10 | 2007-08-15 | 艾博特公司 | Cefdinir oral suspension |
| CN101468020A (en) * | 2007-12-29 | 2009-07-01 | 北京琥珀光华医药科技开发有限公司 | Cefdinir dry suspension agent |
| CN101816635A (en) * | 2010-05-17 | 2010-09-01 | 广东恒健制药有限公司 | Cephalosporin suspension granule and preparation method thereof |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101018543A (en) * | 2003-12-10 | 2007-08-15 | 艾博特公司 | Cefdinir oral suspension |
| CN101468020A (en) * | 2007-12-29 | 2009-07-01 | 北京琥珀光华医药科技开发有限公司 | Cefdinir dry suspension agent |
| CN101816635A (en) * | 2010-05-17 | 2010-09-01 | 广东恒健制药有限公司 | Cephalosporin suspension granule and preparation method thereof |
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| Title |
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| 头孢地尼的抗菌活性和药动学概述;张明发等;《上海医药》;20051231;第26卷(第6期);第266－270页 * |
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