CN103239411A - 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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- CN103239411A CN103239411A CN2013101696472A CN201310169647A CN103239411A CN 103239411 A CN103239411 A CN 103239411A CN 2013101696472 A CN2013101696472 A CN 2013101696472A CN 201310169647 A CN201310169647 A CN 201310169647A CN 103239411 A CN103239411 A CN 103239411A
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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 1988 synthetic first, and 1991 begin to be applied to Japan, and in December, 1997 obtains drugs approved by FDA, and beginning is used in the U.S..Because the Cefdinir oral good absorbing, untoward reaction is little, and has a broad antifungal spectrum is not only effective to gram-negative bacteria (G-), and gram-positive bacteria (G+) is also had higher antibacterial activity, therefore is used widely clinically.About the cefdinir quasi drugs, " generation is held up Buddhist nun's capsule " that the central Pharmaceutical of " full pool is capsule again " and Tianjin that has Xi'an Yang Sen to produce of domestic listing is produced etc.
At present, the cefdinir quasi drugs of domestic production mostly is capsule and dispersible tablet, is not easy to the patient and takes, especially for the patient of dysphagias such as old man, child.In addition because the cefdinir raw material is insoluble in water, make that bioavailability and the stability of cefdinir quasi drugs are lower, therefore, how to develop and a kind ofly have higher bioavailability and stability and the cefdinir medicament that facilitates patients and become the problem that this area needs to be resolved hurrily.
Summary of the invention
At 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 have high bioavailability and stability.
Another object of the present invention is to provide a kind of cefdinir (C1
4H
13N
5O
5S
2) and citric acid and sodium citrate dry suspension preparation of compositions method.
Above-mentioned purpose of the present invention can be achieved through the following technical solutions:
The invention provides a kind of cefdinir (C
14H
13N
5O
5S
2) and citric acid and sodium citrate dry suspension compositions, calculate with the weight of each component, comprising:
100 parts of diluent 1900-2100 of cefdinir part
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, is preferably 50%(wt) ethanol water.
Further, described flocculating agent comprises citric acid and the 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 190 parts binding agent;
Preferably, the weight ratio of described xanthan gum and cefdinir is 0.15-0.30, more preferably 0.2.
Further, with described cefdinir (C
14H
13N
5O
5S
2) and citric acid and sodium citrate dry suspension compositions add water to make the pH value of the suspension that contains cefdinir 2.5mg among every 1ml be 3.5-4.5, preferred pH value is 4.
The present invention further provides a kind of above-mentioned cefdinir (C
14H
13N
5O
5S
2) and citric acid and sodium citrate dry suspension preparation of compositions method, this preparation method may further comprise the steps:
Step a: diluent and flocculating agent are pulverized, and respectively cefdinir, diluent, flocculating agent, lubricant, correctives, suspending agent and fluidizer are sieved;
Step b: take by weighing each component raw material of formula ratio, diluent, flocculating agent, correctives and cefdinir are mixed, add binding agent again, soft material processed, discharging adds the granulation of sieving in the granulator with the material that obtains;
Step c: with the particle drying that obtains among the step b, obtain dried granule;
Steps d: with the dried granule granulate that obtains among the step c, again suspending agent, fluidizer and lubricant are added premix in the mixer, then the dried granule behind the granulate is added in the mixer, mix, obtain dry suspension.
Further, among the 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, among the described step b, take by weighing each component raw material of formula ratio, diluent, flocculating agent, correctives and cefdinir are added in the high-speed mixing granulating machine, open granulating cutter and cutter, do and mix 3min, mixing velocity is that 400rpm, cutting speed are 3000rpm, adds binding agent again, soft material 2min processed, discharging is waved 24 mesh sieves granulation excessively in the granulator with the material adding that obtains;
Preferably; when described flocculating agent is citric acid and sodium citrate; among the described step b; take by weighing each component raw material of formula ratio; diluent and citric acid added in the high-speed mixing granulating machine mix 1min; mixing velocity is 400rpm, and cutting speed is 3000rpm, sodium citrate, correctives and cefdinir is added in the mixer-granulator again; open granulating cutter and cutter; do and mix 3min, mixing velocity is 400rpm, and cutting speed is 3000rpm; add binding agent again; soft material 2min processed, discharging is waved 24 mesh sieves granulation excessively in the granulator with the material adding that obtains.
Further, among the described step c, the granule that obtains among the step b is added in the Fluidbedgranulatingdrier, at 38-42 ℃, preferred 40 ℃ of following dry 20min obtain dried granule.
Further; in the described steps d; use pelletizing machine with 30 mesh sieve granulate the dried granule that obtains among the step c; again suspending agent, fluidizer and lubricant are added premix 2min in the three-dimensional mixer; then the dried granule behind the granulate is added in the 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 have the following advantages at least:
One, compares with the cefdinir class medicament of tablet formulation preparation with the available technology adopting capsule, the present invention adopts the Cefdinir dry suspension agent of dry suspension dosage form preparation to have that particle diameter is little, dispersion is big, the characteristics that mouthfeel is good, faster than common oral preparation stripping, short time reaches higher blood drug level in vivo, absorption is abundant, thereby has improved bioavailability and the stability of insoluble drug cefdinir;
Two, compare with the cefdinir class medicament of other dosage forms in the 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 for use glucide (as sucrose) as diluent, with respect to dextrin commonly used, has both reduced the risk of untoward reaction, has improved the taste of medicine again, more be applicable to children; And Cefdinir dry suspension agent of the present invention further adds correctives (as strawberry essence), and Cefdinir dry suspension agent is dispersed in water evenly and the suspension of good mouthfeel, facilitates patients, and has strengthened the compliance of medication;
Three, added flocculating agent and lubricant in the Cefdinir dry suspension agent of the present invention, and regulated the proportioning of each component, made that Cefdinir dry suspension agent granule dissolving of the present invention is very fast, good fluidity is more suitable for large-scale production, and has advantages of higher stability;
Four, the present invention adopts suspending agent, fluidizer and lubricant to add legal system to be equipped with Cefdinir dry suspension agent, to have avoided situation such as granulating difficulty in the wet granulation step, be conducive to suitability for industrialized production;
Five, at cefdinir (C of the present invention
14H
13N
5O
5S
2) and the preparation method of citric acid and sodium citrate dry suspension in, at the different qualities of each component raw material, adopt diverse ways to handle each component raw material (as crossing the sieve of different meshes), reduced the loss of each raw material, improve each utilization ratio of raw materials, and improved the quality of product; Adopt high-speed mixing granulating machine to granulate in addition, greatly improved work efficiency, reduced the risk that impurity produces, the quality and the safety that have improved product; The present invention's dried particles under preference temperature (40 ℃ ± 2 ℃, preferred 40 ℃) when enhancing productivity, has guaranteed the quality of product in addition;
Six, the present invention adopts the method for control pH value to prepare cefdinir (C
14H
13N
5O
5S
2) and citric acid and sodium citrate dry suspension, improved the quality of Cefdinir dry suspension agent.
The specific embodiment
The present invention is described in detail below in conjunction with specific embodiment.It will be appreciated by those skilled in the art that these embodiment only are used for explanation the present invention, the scope that it does not limit the present invention in any way.
Preparation embodiment 1
Cefdinir dry suspension agent according to following set of dispense ratio preparation present embodiment:
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 is pulverized sucrose, citric acid and sodium citrate;
Step 2 is crossed 200 mesh sieves with cefdinir, and sucrose, citric acid, sodium citrate and magnesium stearate are crossed 100 mesh sieves, and 80 mesh sieves are crossed in Fructus Fragariae Ananssae powdered flavor, xanthan gum and micropowder silica gel;
Step 3 takes by weighing each component by above-mentioned content, sucrose is added in the high-speed mixing granulating machine with citric acid mix 1min earlier; mixing velocity is 400rpm, and cutting speed is 3000rpm, sodium citrate, Fructus Fragariae Ananssae powdered flavor and cefdinir is added again; open granulating cutter and cutter; top gear is done and is mixed 3min, and mixing velocity is 400rpm, and cutting speed is 3000rpm; the ethanol water that adds 50wt% then; soft material 2min processed, discharging is waved granulator with the material adding then and is crossed the granulation of 24 mesh sieves.
Step 4 adds the granule that makes in the step 3 in the Fluidbedgranulatingdrier, 40 ℃ of design temperatures, and the dry 20min of starting device obtains dried granule;
Step 5; use pelletizing machine with 30 mesh sieve granulate dried granule earlier; again xanthan gum, micropowder silica gel and magnesium stearate are added premix 2min in the three-dimensional mixer; and then will mix 15min in the dried granule adding three-dimensional mixer behind the above-mentioned granulate; granulation speed is 150kg/h, obtains Cefdinir dry suspension agent.
Preparation embodiment 2
Cefdinir dry suspension agent according to following set of dispense ratio preparation present embodiment:
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 is pulverized sucrose, citric acid and sodium citrate;
Step 2 is crossed 200 mesh sieves with cefdinir, and sucrose, citric acid, sodium citrate and magnesium stearate are crossed 100 mesh sieves, and 80 mesh sieves are crossed in Fructus Fragariae Ananssae powdered flavor, xanthan gum and micropowder silica gel;
Step 3 takes by weighing each component by above-mentioned content, sucrose is added in the high-speed mixing granulating machine with citric acid mix 1min earlier; mixing velocity is 400rpm, and cutting speed is 3000rpm, sodium citrate, Fructus Fragariae Ananssae powdered flavor and cefdinir is added again; open granulating cutter and cutter; top gear is done and is mixed 3min, and mixing velocity is 400rpm, and cutting speed is 3000rpm; the ethanol water that adds 50wt% then; soft material 2min processed, discharging is waved granulator with the material adding then and is crossed the granulation of 24 mesh sieves.
Step 4 adds the granule that makes in the step 3 in the Fluidbedgranulatingdrier, 40 ℃ of design temperatures, and the dry 20min of starting device obtains dried granule;
Step 5; use pelletizing machine with 30 mesh sieve granulate dried granule earlier; again xanthan gum, micropowder silica gel and magnesium stearate are added premix 2min in the three-dimensional mixer; and then will mix 15min in the dried granule adding three-dimensional mixer behind the above-mentioned granulate; granulation speed is 150kg/h, obtains Cefdinir dry suspension agent.
Preparation embodiment 3
Cefdinir dry suspension agent according to following set of dispense ratio preparation present embodiment:
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 is pulverized sucrose, citric acid and sodium citrate;
Step 2 is crossed 200 mesh sieves with cefdinir, and sucrose, citric acid, sodium citrate and magnesium stearate are crossed 100 mesh sieves, and 80 mesh sieves are crossed in Fructus Fragariae Ananssae powdered flavor, xanthan gum and micropowder silica gel;
Step 3 takes by weighing each component by above-mentioned content, sucrose is added in the high-speed mixing granulating machine with citric acid mix 1min earlier; mixing velocity is 400rpm, and cutting speed is 3000rpm, sodium citrate, Fructus Fragariae Ananssae powdered flavor and cefdinir is added again; open granulating cutter and cutter; top gear is done and is mixed 3min, and mixing velocity is 400rpm, and cutting speed is 3000rpm; the ethanol water that adds 50wt% then; soft material 2min processed, discharging is waved granulator with the material adding then and is crossed the granulation of 24 mesh sieves.
Step 4 adds the granule that makes in the step 3 in the Fluidbedgranulatingdrier, 40 ℃ of design temperatures, and the dry 20min of starting device obtains dried granule;
Step 5; use pelletizing machine with 30 mesh sieve granulate dried granule earlier; again xanthan gum, micropowder silica gel and magnesium stearate are added premix 2min in the three-dimensional mixer; and then will mix 15min in the dried granule adding three-dimensional mixer behind the above-mentioned granulate; granulation speed is 150kg/h, obtains Cefdinir dry suspension agent.
Preparation embodiment 4
Cefdinir dry suspension agent according to following set of dispense ratio preparation present embodiment:
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 is pulverized sucrose, citric acid and sodium citrate;
Step 2 is crossed 200 mesh sieves with cefdinir, and sucrose, citric acid, sodium citrate and magnesium stearate are crossed 100 mesh sieves, and 80 mesh sieves are crossed in Fructus Fragariae Ananssae powdered flavor, xanthan gum and micropowder silica gel;
Step 3 takes by weighing each component by above-mentioned content, sucrose is added in the high-speed mixing granulating machine with citric acid mix 1min earlier; mixing velocity is 400rpm, and cutting speed is 3000rpm, sodium citrate, Fructus Fragariae Ananssae powdered flavor and cefdinir is added again; open granulating cutter and cutter; top gear is done and is mixed 3min, and mixing velocity is 400rpm, and cutting speed is 3000rpm; the ethanol water that adds 50wt% then; soft material 2min processed, discharging is waved granulator with the material adding then and is crossed the granulation of 24 mesh sieves.
Step 4 adds the granule that makes in the step 3 in the Fluidbedgranulatingdrier, 40 ℃ of design temperatures, and the dry 20min of starting device obtains dried granule;
Step 5; use pelletizing machine with 30 mesh sieve granulate dried granule earlier; again xanthan gum, micropowder silica gel and magnesium stearate are added premix 2min in the three-dimensional mixer; and then will mix 15min in the dried granule adding three-dimensional mixer behind the above-mentioned granulate; granulation speed is 150kg/h, obtains Cefdinir dry suspension agent.
Preparation embodiment 5
Cefdinir dry suspension agent according to following set of dispense ratio preparation present embodiment:
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 is pulverized sucrose, sodium citrate and citric acid;
Step 2 is crossed 200 mesh sieves with cefdinir, and sucrose, sodium citrate, citric acid and magnesium stearate are crossed 100 mesh sieves, and 80 mesh sieves are crossed in Fructus Fragariae Ananssae powdered flavor, hypromellose and micropowder silica gel;
Step 3 takes by weighing each component by above-mentioned content, sucrose is added in the high-speed mixing granulating machine with citric acid mix 1min earlier; mixing velocity is 400rpm, and cutting speed is 3000rpm, sodium citrate, Fructus Fragariae Ananssae powdered flavor and cefdinir is added again; open granulating cutter and cutter; top gear is done and is mixed 3min, and mixing velocity is 400rpm, and cutting speed is 3000rpm; the ethanol water that adds 50wt% then; soft material 2min processed, discharging is waved granulator with the material adding then and is crossed the granulation of 24 mesh sieves.
Step 4 adds the granule that makes in the step 3 in the Fluidbedgranulatingdrier, 40 ℃ of design temperatures, and the dry 20min of starting device obtains dried granule;
Step 5; use pelletizing machine with 30 mesh sieve granulate dried granule earlier; again hypromellose, micropowder silica gel and magnesium stearate are added premix 2min in the three-dimensional mixer; and then will mix 15min in the dried granule adding three-dimensional mixer behind the above-mentioned granulate; granulation speed is 150kg/h, obtains Cefdinir dry suspension agent.
Method of testing
The present invention adopts impurity and polymer content in the following method test Cefdinir dry suspension agent of the present invention with reference to correlated quality standard-required among USP34, the CP2010:
1. the locate mode of impurity
With reference to Chinese Pharmacopoeia and USP34 version cefdinir related substance standard, adopt following manner that impurity is positioned.
(1) relative retention time location: the model of stationary chromatographic post, comprise length, diameter, filling kind, filler granularity etc., by experiment, can accurately locate substantially;
(2) impurity reference substance location: related substance A reference substance can be located 4 impurity peaks; 1 impurity peaks in related substances B reference substance location;
(3) main constituent destroy method location: adopt the experimental condition under Chinese Pharmacopoeia version cefdinir in 2010 the raw material related substance item, cefdinir is destroyed, be used for impurity VII(E-isomer) location.
2. the ownership of impurity and limit
(1) impurity ownership: in order further to prove the accuracy of impurity ownership, impurity is carried out the structural identification test, the result shows, all impurity all derive from raw material, wherein make the cefdinir degraded by strength tests such as water-bath, oxidation, high temperature, by structural identification as can be known main degradation impurity be S1, S2, S4, S5, S6, S7a, S8, S9, S9a, S14, the structure of impurity is identical with the USP34 version.
By the study on the stability data as can be known, sample cefdinir related substances A(in storage process is S5, S6, S7a, S8), impurity XI(is S4) and impurity VII(be S14) be main degradation impurity, but consider that impurity XIV(is S2), impurity I(is S9) and impurity VI(be S9a) under strong condition, may degrade, cefdinir related substances B has the probability of degraded, and above-mentioned known impurities is all controlled separately.
(2) limit of impurity
By the stability study data as can be known, continue to use the limit of the cefdinir suspensoid related substance of USP32 version record, can control effectively to impurity, the limit formulation is described rationally, the present invention is strict in the USP32 version to the control of impurity to the limit of impurity in the cefdinir suspensoid, and impurity limited, can control product quality better.
3. polymeric detection
The present invention by the experiment sieving detection method, and carries out the system approach checking with reference to CP2010 version like product polymeric detection method, finally determines the detection method of polymer in the cefdinir suspensoid of the present invention.
Method one: according to the assay method of most of polymer in the Chinese Pharmacopoeia, adopt sephadex column to test
Adopt sephadex G-10(40～120 μ m) be filler, glass column internal diameter 1.3～1.6cm, post height 30～40cm.0.01mol/L phosphate buffered solution (0.01mol/L disodium phosphate soln-0.01mol/L sodium dihydrogen phosphate (61:39)) with pH7.0 is mobile phase A, is Mobile phase B with water, and flow velocity is about per minute 0.8ml; The detection wavelength is 254nm.
According to result of the test, therefore the mensuration of polymer in the adjuvant disturbed specimen that adopts in this method be unsuitable for the detection of polymer in the cefdinir suspensoid of the present invention.
Method two: with reference to Cefodizime Sodium polymeric detection method
Measure according to molecular exclusion chromatography (appendix VH), adopt the globular protein chromatograph and with hydrophilic silica gel as filler; (0.005mol/L sodium hydrogen phosphate and 0.005mol/L sodium dihydrogen phosphate (61:39))-acetonitrile (95:5) is mobile phase with phosphate buffered solution (pH7.0), and flow velocity is per minute 0.8ml, and the detection wavelength is 231nm.
According to result of the test, this method can be used for the mensuration of polymer in the cefdinir suspensoid of the present invention, and therefore, the present invention adopts method two to detect the content of polymer in the cefdinir suspensoid.
Contrast test
Cefdinir suspensoid A(U.S. Shandeshi company with U.S. listing produces respectively) and the Cefdinir capsule B(Tianjin Jin Kang pharmaceutical Co. Ltd of domestic listing produce) contrast with cefdinir suspensoid of the present invention.
Adopt above-mentioned method of testing that the performance of cefdinir suspensoid of the present invention and existing cefdinir suspensoid A and Cefdinir capsule B is tested respectively, the 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, the cefdinir suspensoid drug content of embodiment of the invention preparation 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, explanation thus, with respect to existing cefdinir medicament, cefdinir suspensoid of the present invention has higher safety, thereby has improved quality and the stability of product.
The influence factor tests 1Temperature is to the influence of impurity in the suspensoid and polymer
Under different baking temperatures, prepare Cefdinir dry suspension agent according to the method among the 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 for preparing under table 2 different temperatures
The cephalo-type material belongs to high sensitive materials, and the impurity and the polymer that itself contain are more, and the increase of baking temperature can make its impurity and polymer increase.As seen from Table 2, along with the increase of baking temperature, the content of impurity and polymer is in rising trend in the Cefdinir dry suspension agent, and baking temperature is low excessively, can prolong drying time, improves the probability that impurity produces, be unfavorable for enhancing productivity, and influence the quality of product.The preferred baking temperature of the present invention is 38-42 ℃ (more preferably 40 ℃), and under this baking temperature, the content of impurity and polymer is less in the Cefdinir dry suspension agent, when enhancing productivity, has guaranteed product quality.
The influence factor tests 2Flocculating agent is to the influence of suspensoid character
Adopt citric acid and sodium citrate as flocculating agent, the content of citric acid and sodium citrate is to the influence of Cefdinir dry suspension agent character in the test flocculating agent, wherein adopt method among the embodiment 1 (except citric acid is different with the content of sodium citrate, other materials and technological parameter are all with reference to the method for embodiment 1) the preparation Cefdinir dry suspension agent, test result is as shown in table 3.
Table 3 adopts the nature parameters of citric acid and the suspensoid that sodium citrate prepares of different proportionings
As shown in Table 3, pH value is got Cefdinir dry suspension agent at 3.5-4.5(and is added water and make the pH value that every 1ml contains the suspension of cefdinir 2.5mg) between the related substance of sample basic identical, but be significantly less than the sample of pH value 5.0, therefore the sample of pH value in the 3.5-4.5 scope is more stable greater than the quality of 4.5 sample than pH value, consider from the long-term stable aspect of placing of sample simultaneously, the prescription of the preferred pH value of the present invention about 4.0, the weight ratio that is citric acid and sodium citrate is the prescription of 1:1, adopts every detection index of the Cefdinir dry suspension agent of this prescription preparation to meet the USP32 standard.
The influence factor tests 3Suspending agent is to the influence of Cefdinir dry suspension agent
1, the suspending agent material is to the influence 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 among the embodiment 1, and the Cefdinir dry suspension agent for preparing is passed through the granule racking machine press the different content packing with the paper aluminum composite membrane), detect the settling volume ratio of each suspending agent according to the regulation in the Chinese Pharmacopoeia version appendix in 2000, test result is as shown in table 4:
The settling volume ratio of the dry suspension of table 4 variety classes suspending agent preparation
As seen from Table 4, compare with other suspending agents, the settling volume of the dry suspension of employing xanthan gum preparation is bigger, and the suspending effect is better, so the present invention preferably adopts xanthan gum to prepare Cefdinir dry suspension agent as suspending agent.
2, the amount of suspending agent is to the influence of dry suspension
Adopt not commensurability suspending agent to prepare Cefdinir dry suspension agent (except suspending agent, other materials all method with embodiment 1 are identical) respectively, relatively suspending agent content is to the influence of the settling character of Cefdinir dry suspension agent, and test result is as shown in table 5.
The settling character of the Cefdinir dry suspension agent of table 5 different content suspending agent preparation
As seen from Table 5, the amount of the xanthan gum of adding (with respect to cefdinir) was greater than 0.3 o'clock, and suspensoid does not almost have sedimentation in 3h; Xanthan gum does not produce obvious influence to the pH value of suspensoid in the aforementioned proportion scope; The consumption of xanthan gum is non-linear relation to the rate of settling of suspensoid, the influence of settling volume ratio, based on the clinical drug safety consideration, according to the standard of the minimum addition that can reach the suspendible effect as selection, the weight ratio of the preferred xanthan gum of the present invention and cefdinir is 0.15-0.30, more preferably 0.2.
High light and hot test
The Cefdinir dry suspension agent of the embodiment of the invention 1 preparation was placed 5,10 days under high light and high temperature (40 ℃, 60 ℃) condition respectively, 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 high light condition
As seen from Table 6, Cefdinir dry suspension agent of the present invention all remains faint yellow granule on the character after placing 5,10 days under high light (4500LX) and the high temperature (40 ℃, 60 ℃), and settling volume is more up to specification than all.Behind the strong illumination 10 days, related substance is 0.56%, and total impurities is 1.58, and polymer is 0.82%, and drug content is 99.3%, all meets the limit requirement; Place after 10 days under the 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 the limit requirement, explanation thus, Cefdinir dry suspension agent of the present invention still keeps advantages of higher stability after high light and hot test.
Accelerated test
The Cefdinir dry suspension agent of embodiment 1,2,3 preparations is carried out packing by the granule racking machine, and the step of going forward side by side is carried out accelerated test, and experimental condition is as follows:
Packing specification: 100mg/ bag
Packing: paper/aluminum/polyethylene drug packaging compound membrane bag
Test condition: temperature: 30 ℃ ± 2 ℃, humidity: RH65% ± 5%
Test result is as shown in table 7, as seen from Table 7, Cefdinir dry suspension agent of the present invention is placed 1,2,3,6 month under experimental condition after, all keep faint yellow granule on the character, acidity is 3.94-4.06, settling volume all requirements up to specification of microbial limit when, 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 limit requires, show that Cefdinir dry suspension agent of the present invention has stability preferably.
Table 7 Cefdinir dry suspension agent accelerated test test data
Long term test 1
The Cefdinir dry suspension agent of embodiment 1,2,3 preparations is carried out packing by the granule racking machine, and the step of going forward side by side is carried out long term test, and experimental condition is as follows:
Packing specification: 100mg/ bag
Packing: paper/aluminum/polyethylene drug packaging compound membrane bag
Investigation condition: temperature: 25 ± 2 ℃, humidity: 60% ± 10%
It is as shown in the table 8 for test result, as seen from Table 8, Cefdinir dry suspension agent of the present invention is placed 3,6,9,12 months under experimental condition after, all keep faint yellow granule on character, acidity is 3.93-4.06, settling volume all requirements up to specification of microbial limit when, 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 limit requires, show that Cefdinir dry suspension agent of the present invention has stability preferably.
Table 8 Cefdinir dry suspension agent long term test test data
Long term test 2
The Cefdinir dry suspension agent of embodiment 1,2,3 preparations is carried out packing by the granule racking machine, and the step of going forward side by side is carried out long term test, and experimental condition is as follows:
Packing specification: 100mg/ bag
Packing: paper/aluminum/polyethylene drug packaging compound membrane bag
Investigation condition: temperature: 20 ℃, humidity: 60% ± 10%
Test result is as shown in table 9, as seen from Table 9, Cefdinir dry suspension agent of the present invention is placed 3,6,9,12 months under experimental condition after, all keep faint yellow granule on character, acidity is 3.93-4.07, settling volume all requirements up to specification of microbial limit when, 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 limit requires, show that Cefdinir dry suspension agent of the present invention has stability preferably.
Table 9 Cefdinir dry suspension agent long term test test data
More than specific description of embodiments of the present invention does not limit the present invention, those skilled in the art can make various changes or distortion according to the present invention, only otherwise break away from spirit of the present invention, all should belong to the scope of claims of the present invention.
Claims (9)
1. cefdinir (C
14H
13N
5O
5S
2) and citric acid and sodium citrate dry suspension compositions, calculate with the weight of each component, comprising:
100 parts of diluent 1900-2100 of cefdinir part
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.
2. cefdinir (C according to claim 1
14H
13N
5O
5S
2) and citric acid and sodium citrate dry suspension compositions, it is characterized in that 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, is preferably 50%(wt) ethanol water.
3. cefdinir (C according to claim 1 and 2
14H
13N
5O
5S
2) and citric acid and sodium citrate dry suspension compositions, it is characterized in that described flocculating agent comprises citric acid and the sodium citrate that weight ratio is 1:0.6-2.5, preferably comprise 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 190 parts binding agent;
Preferably, the weight ratio of described xanthan gum and cefdinir is 0.15-0.30, more preferably 0.2.
4. according to each described cefdinir (C in the claim 1 to 3
14H
13N
5O
5S
2) and citric acid and sodium citrate dry suspension compositions, it is characterized in that described cefdinir and citric acid and sodium citrate dry suspension compositions are added water, and to make the pH value of the suspension that contains cefdinir 2.5mg among every 1ml be 3.5-4.5, preferred pH value is 4.
5. according to each described cefdinir (C among the claim 1-4
14H
13N
5O
5S
2) and citric acid and sodium citrate dry suspension preparation of compositions method, this preparation method may further comprise the steps:
Step a: diluent and flocculating agent are pulverized, and respectively cefdinir, diluent, flocculating agent, lubricant, correctives, suspending agent and fluidizer are sieved;
Step b: take by weighing each component raw material of formula ratio, diluent, flocculating agent, correctives and cefdinir are mixed, add binding agent again, soft material processed, discharging adds the granulation of sieving in the granulator with the material that obtains;
Step c: with the particle drying that obtains among the step b, obtain dried granule;
Steps d: with the dried granule granulate that obtains among the step c, again suspending agent, fluidizer and lubricant are added premix in the mixer, then the dried granule behind the granulate is added in the mixer, mix, obtain dry suspension.
6. preparation method according to claim 5 is characterized in that, among the 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.
7. according to claim 5 or 6 described preparation methoies, it is characterized in that, among the described step b, take by weighing each component raw material of formula ratio, diluent, flocculating agent, correctives and cefdinir are added in the high-speed mixing granulating machine, open granulating cutter and cutter, do and mix 3min, mixing velocity is that 400rpm, cutting speed are 3000rpm, add binding agent again, soft material 2min processed, discharging is waved 24 mesh sieves granulation excessively in the granulator with the material adding that obtains;
Preferably; when described flocculating agent is citric acid and sodium citrate; among the described step b; take by weighing each component raw material of formula ratio; diluent and citric acid added in the high-speed mixing granulating machine mix 1min; mixing velocity is 400rpm, and cutting speed is 3000rpm, sodium citrate, correctives and cefdinir is added in the mixer-granulator again; open granulating cutter and cutter; do and mix 3min, mixing velocity is 400rpm, and cutting speed is 3000rpm; add binding agent again; soft material 2min processed, discharging is waved 24 mesh sieves granulation excessively in the granulator with the material adding that obtains.
8. according to each described preparation method among the claim 5-7, it is characterized in that, among the described step c, the granule that obtains among the step b added in the Fluidbedgranulatingdrier that at 38-42 ℃, preferred 40 ℃ of following dry 20min obtain dried granule.
9. according to each described preparation method among the claim 5-8; it is characterized in that; in the described steps d; use pelletizing machine with 30 mesh sieve granulate the dried granule that obtains among the step c; again suspending agent, fluidizer and lubricant are added premix 2min in the three-dimensional mixer; then the dried granule behind the granulate is added in the 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.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104971041A (en) * | 2015-06-29 | 2015-10-14 | 浙江汇能动物药品有限公司 | Dinitolmide dry suspension and preparation method thereof |
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| CN103239411B (en) | 2015-01-21 |
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