CN103524533B - A kind of cefprozil compound, its dispersible tablet, dry suspensoid and preparation method - Google Patents
A kind of cefprozil compound, its dispersible tablet, dry suspensoid and preparation method Download PDFInfo
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Abstract
The present invention relates to field of medicaments, specifically, relate to a kind of cefprozil compound, its dispersible tablet, dry suspensoid and preparation method.Cefprozil compound of the present invention is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains as shown in Figure 1.Detect through experiment, Cefprozil dispersible table of the present invention, dry suspensoid stability are superior, and smell and mouthfeel very well, are very applicable to clinical application.
Description
Technical field
The present invention relates to field of medicaments, specifically, relate to a kind of cefprozil compound, its dispersible tablet, dry suspensoid and preparation method.
Background technology
Prozef (cefprozil) molecular formula is: C
18h
19n
3o
5sH
2o, chemical name: (6R, 7R)-7-L (R)-2-amino-2-(is to hydroxy-pheny) kharophen 1-8-oxo-3-propylene-5-thia-1-azabicyclo-(4,2,0) oct-2-ene-2-carboxylic acid monohydrate, its structural formula is:
Prozef belong to the IIth generation semi-synthetic cephalosporins microbiotic, be suitable, trans isomer mixture, wherein cis-isomeride accounts for 90%(>=87%).Nineteen eighty-three by Bristol-Myers Tokyo institute develop, 1991 in the U.S. with the Initial Public Offering of Cefzil trade(brand)name, go on the market successively in more than 20 countries such as Canada, Mexico, Sweden subsequently.Drug Administration department of China ratifies Sino-U.S.'s Shanghai Shi Guibao pharmaceutical Co. Ltd production and selling Prozef tablet and suspensoid in October, 1999.Its mechanism of action is by combining with the penicillin-binding protein (PBPs) on bacterial cell membrane, hinders bacteria cell wall synthesis, thus causes bacterolysis, death.
Cefprozil dispersible table has has a broad antifungal spectrum, highly effective and safe, easy administration, come into force fast, to features such as β-lactamase are extremely stable.It has good clinical efficacy to various light, the moderate disease that gram-positive microorganism, Gram-negative bacteria and anerobe etc. cause.In the treat-and-release of the diseases such as the upper and lower respiratory tract infection for the treatment of, otorhinolaryngology infection, soft tissue infection and acute gonococcal urethritis, there is excellent clinical efficacy.Prozef is applicable to responsive microbial light, the upper and lower respiratory tract infection of moderate (as pharyngitis, laryngitis, tonsillitis, pneumonia, bronchitis etc.) Respiratory infections (as otitis media, sinusitis paranasal sinusitis etc.), skin and skin soft-tissue infection's (as furuncle arsine, cellulitis, dermapostasis, folliculitis, trauma infection contamination etc.).Bibliographical information, experimenter is oral Prozef on an empty stomach, and about 95% dosage can be absorbed.Be 1.3 hours at the mean plasma half-life of healthy person, Vdss is about 0.23L/kg.Total body clearance and renal clearance are respectively about 3ml/min/kg and 2.3ml/min/kg.
Current European Pharmacopoeia has recorded a hydration Prozef, Chinese Pharmacopoeia and American Pharmacopeia have then all recorded 3 kinds of medicines such as Prozef, cefprozil suspension agent and cefprozil tablet, China is the consumption big country of cynnematin similar drug, and the exploitation of cephalosporins can meet the clinical demand of domestic extensive patients.About the preparation of the purification of Prozef and crystallization and dispersible tablet, dry suspensoid, a lot of patent is disclosed:
Disclose a kind of method of Prozef being carried out to purifying, crystallization in patent application 200910014981 " a kind of cefprozil compound and method for making thereof ", but the character such as the stability of the product prepared are not detected.
Also disclose a kind of Prozef crystalline compounds in patent application 201110261377.9 " a kind of Cefprozil compound crystal and pharmaceutical composition thereof ", and disclose the dispersible tablet adopting this crystalline compounds to prepare.But the stability of said preparation still has much room for improvement.
Comprise in the dispersible tablet of patent ZL200610024464.1 " Cefprozil dispersible table and preparation method thereof ": the polyvinylpyrrolidone of 260 ± 50 weight part Prozefs, 30 ± 5 weight part Microcrystalline Celluloses, 15 ± 2.5 part by weight of disintegrant cross-linked polyvinylpyrrolidones, 3 ± 0.5 weight parts, 3 ± 0.5 weight part micropowder silica gels, 3 ± 0.5 weight part Magnesium Stearates, 0.5 ± 0.02 weight part correctives.
Weight proportion in patent application 201210583508.X " a kind of Cefprozil dispersible table and preparation method thereof " is as follows: Prozef 250 ± 5 weight part, Microcrystalline Cellulose 180g ± 20 weight part, Micronised lactose or pregelatinized Starch 100 ± 10 weight part, hydroxypropylcellulose 30 ± 3 weight part, sodium lauryl sulphate 5 ± 2 weight part, Magnesium Stearate 2.5 ± 1 weight part, stevioside 2.5 ± 1 weight part.
Patent ZL201010603490.6 " cefprozil suspension pharmaceutical composition " relates to a kind of suspended drug composition containing Prozef and xanthan gum.Add appropriate disintegrating agent, thinner, correctives after the two mixing in certain proportion, rectify and smell the pharmaceutical excipient such as agent or lubricant, then make the dry suspensoid of appropriate size by the mode that dry granulation or powder are directly filled.
Patent ZL201010123539.8 " Cefprozil medicinal composition " relates to the pharmaceutical composition containing Prozef and cellulose derivative, it is obtained by the method for dry type granulation, after Prozef and cellulose derivative Homogeneous phase mixing, flap is made at the pressure of 0.1 ~ 25MPa, combine closely to be formed, make tablet, pulvis, granule or capsule.Also flap can be pulverized, be mixed and made into tablet, pulvis, granule, dry suspensoid or capsule with thinner, disintegrating agent, lubricant, tackiness agent and/or other auxiliary material.
Patent ZL201010606202.2 " a kind of sugar-free cefprozil dry suspension and preparation method thereof " discloses a kind of sugar-free cefprozil dry suspension and preparation method thereof, comprise active constituents of medicine 0.1% ~ 35%, sugar-free type thinner 40% ~ 90%, suspending agent and disintegrating agent 0.01 ~ 20%, sugar-free type correctives 0.01% ~ 10%, tackiness agent 0.01% ~ 1%.
Patent application 201110168945.0 " a kind of Cefprozil dry suspension and method for making thereof " discloses a kind of Prozef and does
Suspensoid and preparation method thereof.By carrying out micropill parcel to it thus increasing its stability, raising compressibility, hide head
The peculiar smell of spore propylene itself coordinates sweeting agent and improves mouthfeel well adding of essence.
Prozef is a kind of microbiotic of indissoluble, because it is easy to dissolve in gastric acid environment, is therefore prepared into oral solid formulation clinically, thus is conducive to absorption and the utilization of medicine.But because Prozef is to water, thermally labile, its oral solid formulation is storing improperly in situation, can occur to decompose and rotten, thus reduce the result for the treatment of affecting Prozef.In order to improve the stability of Prozef further, the present invention proposes a kind of cefprozil compound, cefprozil compound of the present invention has good stability, and the stability of the solid orally ingestible of the Prozef adopting this compound to prepare is good, is applicable to clinical application.
Summary of the invention
Primary goal of the invention of the present invention is to provide a kind of cefprozil compound.
Second goal of the invention of the present invention is the preparation providing this cefprozil compound.
In order to realize object of the present invention, the technical scheme of employing is:
The present invention relates to a kind of cefprozil compound, described cefprozil compound is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains as shown in Figure 1.The main granularity of described cefprozil compound is 288 ~ 465 μm, and Tile Width is 190 ~ 658 μm; Preferred main granularity is 365 ~ 402 μm, and Tile Width is 242 ~ 535 μm.
The invention still further relates to the preparation method of this cefprozil compound, comprise the following steps:
(1) Prozef crude product is prepared at the saturated aqueous solution of 50 ~ 60 DEG C;
(2) prepare the mixed organic solvents of ethanol, ether and ethyl acetate, the volume of mixed organic solvents is 3 ~ 9 times of Prozef crude product saturated aqueous solution, preferably 4 ~ 6 times;
(3) organic solvent is cooled to 0 ~ 5 DEG C, frequency be 20 ~ 25KHz, under output rating is the sound field of 40 ~ 80W, Prozef crude product saturated aqueous solution is at the uniform velocity added while stirring in organic solvent, add rear continuation stir and lower the temperature, stop after being cooled to 0 ~ 5 DEG C stirring, leave standstill growing the grain 2 ~ 8 hours; Filter after obtaining crystal, with absolute ethanol washing, vacuum-drying 2 ~ 8 hours, obtains cefprozil compound.
Wherein, in step (2), in mixed organic solvents, the volume ratio of ethanol, ether and ethyl acetate is 3 ~ 5:1 ~ 2:1, preferably 4 ~ 5:1:1;
In step (3), the stirring velocity adding Prozef crude product saturated aqueous solution in organic solvent is 600 ~ 1200 revs/min; Stirring velocity after Prozef crude product saturated aqueous solution adds is 60 ~ 360 revs/min;
In step (3), the speed that adds of Prozef crude product saturated aqueous solution is: v=M/20 ~ M/10, and wherein M is the volume of organic mixed solvent, and unit is for rising, and the unit of speed v is l/h;
In step (3), the cooling rate after Prozef crude product saturated aqueous solution adds is 0.5 ~ 3.5 DEG C/h, preferably 1.5 ~ 2.5 DEG C/h.
The invention still further relates to the preparation containing the invention still further relates to containing cefprozil compound, preparation can be selected from many kinds of solids oral preparations, as conventional tablet, capsule, dispersible tablet, disintegrating tablet, dry suspensoid etc.
Contain in dispersible tablet of the present invention: cefprozil compound 125 ~ 250 weight part, lactose 26.65 ~ 53.3 weight part; Low-substituted hydroxypropyl cellulose 25 ~ 50 weight part; Sodium starch glycolate 2.7 ~ 5.4 weight part; Silica 1 .65 ~ 3.3 weight part; Magnesium Stearate 1.65 ~ 3.3 weight part; Sweet 0.35 ~ 0.7 weight part of knob, essence 2.0 ~ 4.0 weight part.
The preparation method of dispersible tablet of the present invention is: comprise the following steps:
1. take each component by weight;
2. sieve: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, lactose are crossed 100 mesh sieves respectively;
3. mix: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, knob are mixed 10 ~ 30 minutes sweet adding in mixing machine, add essence again, silicon-dioxide, lactose continue mixing 10 ~ 30 minutes, finally add Magnesium Stearate mixing 5 ~ 15 minutes;
4. compressing tablet, packaging, to obtain final product.
Contain in dry suspensoid of the present invention: cefprozil compound 125 ~ 250 weight part, sucrose 1000 ~ 2000 weight part, xanthan gum 15 ~ 30 weight part, aspartame 5 ~ 10 weight part, essence 4 ~ 8 weight part, Magnesium Stearate 1 ~ 2 weight part, Citric Acid 0.5 ~ 1 weight part, Polysorbate 80 10 ~ 20 weight part.
The preparation method of dry suspensoid of the present invention is: comprise the following steps:
(1) each component is taken by weight;
(2) added mixing machine with cefprozil compound, xanthan gum, aspartame after sucrose being pulverized 100 mesh sieves, mixed, for subsequent use; Added by Polysorbate 80 (Polysorbate 80 and purified water weight ratio are 1:3.5) in appropriate purified water, stirring and dissolving, adds Citric Acid, and stirring and dissolving is for subsequent use;
(3) solution in step (2) to be added in step (2) softwood processed in mixed powder, granulation of sieving, puts into oven drying, whole grain, after the Magnesium Stearate adding recipe quantity and essence, mixes; Wherein, dry temperature is 45 ~ 55 DEG C, and dried particles to moisture is 0.50 ~ 1.50%;
(4) inspection, packing, packaging, to obtain final product.
Below content of the present invention is made further explanation:
The present invention, by changing the crystallization condition of Prozef, prepares a kind of new Prozef crystalline compounds, and the X-ray powder diffraction pattern obtained by using the measurement of Cu-K alpha-ray as shown in Figure 1.Measuring its fusing point is 218 ~ 220 DEG C, and proterties is off-white color crystalline powder.Cefprozil compound of the present invention detects through high performance liquid chromatography, and its purity can reach 99.96% ~ 99.99%, total impurities 0.01 ~ 0.03%, and purity, higher than prior art, is very suitable for clinical application.And after testing, organic solvent does not detect in Prozef, illustrate that cefprozil compound of the present invention is safer.After dissolution with solvents, the change of crystal formation can not be there is in this crystal formation.The present invention is by additional sound field, and the precise controlling of the condition such as volume, temperature to solvent, obtain a kind of new crystal.Particle diameter and the X-ray powder diffraction pattern of this crystal are different from disclosed in prior art, and, detect according to the stability test of crystal, show Prozef crystal of the present invention and there is very satisfactory stability, it all can keep stable components under high temperature, super-humid conditions, is much higher than prior art.Further, by known to the stability test of Cefprozil dispersible table and dry suspensoid, having good stability of Cefprozil dispersible table of the present invention and dry suspensoid, is very applicable to clinical application.
Measure through sem observation and particle size analyzer, the main granularity of Prozef of the present invention is 288 ~ 465 μm, and Tile Width is 190 ~ 658 μm; Preferred main granularity is 365 ~ 402 μm, and Tile Width is 242 ~ 535 μm.Found by simultaneous test, in crystallisation process, the size distribution of the Prozef that additional ultrasonic wave obtains is more concentrated, namely the particle of crystal is more even, this may be owing to have impact on crystallisation process in hyperacoustic cavatition, facilitate the formation of nucleus, and make the speed uniformity of crystallization, thus define evengranular crystallization.Due to the centralized particle diameter of cefprozil compound of the present invention, be of moderate size, facilitate production operation, thus yield is high, can 96.7% be reached.
Dispersible tablet is can the homodisperse tablet of disintegration rapidly in water.Relative to the solid preparation such as conventional tablet, capsule, dispersible tablet has easy administration, disintegration is rapid, absorption is fast and bioavailability high.It has, and preparation is simple, easy administration, can reduce the untoward reaction of medicine, improve the advantages such as drug bioavailability.Therefore, the present invention proposes a kind of dispersible tablet of Prozef, and selection is optimized to the auxiliary material in dispersible tablet.Such as spray-dried lactose selected by the weighting agent of dispersible tablet of the present invention, because of its mobility better and there is the similar sweet taste of sucrose, therefore be used for improving powder flowbility and mouthfeel; The present invention, in order to ensure the disintegration effect of dispersible tablet, has selected the good sodium starch glycolate of disintegration effect and low-substituted hydroxypropyl cellulose coupling to cook disintegrating agent; Meanwhile, low-substituted hydroxypropylcellulopowder powder also has certain dry adhesive effect, therefore also can serve as the dry adhesives of direct powder compression; Because direct powder compression requires higher to powder flowbility, therefore the present invention also adds silicon-dioxide improves powder flowbility further; For making the sheet of extrusion bright and clean, add appropriate Magnesium Stearate; Due to Prozef bitter, add sweet orange powdered flavor and knob is sweet in the smell improving dispersible tablet and mouthfeel.After testing, dispersible tablet of the present invention not only has good disintegration effect, and smell and mouthfeel are very well, improve the compliance of patient.The specification of dispersible tablet of the present invention is preferably 0.125g and 0.25g.
Dry suspensoid is easily molten because of it, and flavoring, easily takes, stable, easy to carry, and being convenient to the advantages such as children taking is that domestic and international pharmacy work person and patient welcome; And preparation is simple, be easy to preserve, validity period is not long, perishable and easily grasp dosage, and absorbing comparatively conventional tablet or capsule will get well, and the comparatively applicable child of taste, can improve the compliance that it is taken medicine.Therefore, the invention allows for a kind of dry suspensoid of Prozef, and selection is optimized to the auxiliary material in dry suspensoid.Select Polysorbate 80 as tackiness agent in the present invention, contributed to the shaping of preparation on the one hand, also can play the effect of hydrotropy on the other hand, the degree of scatter of dry suspensoid in water can be improved, improve the dissolution rate of medicine.The present invention has selected xanthan gum as suspending agent, after the dry suspensoid prepared is disperseed in water, occurs in 3 hours without obvious settling.Dry suspensoid of the present invention fully can meet the actual needs used, and decreases kind and the consumption of auxiliary material, further increases the security of preparation.Dry suspensoid of the present invention, fragrant odour taste is sweet, and mouthfeel is good, and dispersion is fast, deposit-free, and uses easy to carry, is applicable to each age group patient.The specification of dry suspensoid of the present invention is preferably 0.125g and 0.25g.
Accompanying drawing illustrates:
Fig. 1 is the X-ray powder diffraction figure of compound prepared by embodiment 1.
Below in conjunction with example, the present invention is further described.The specific embodiment of the present invention is only limitted to make further explanation content of the present invention, does not limit Composition of contents of the present invention.Reagent used in preparation process of the present invention is commercial reagent.
Embodiment
Embodiment 1: the preparation of cefprozil compound
1. prepare Prozef crude product at the saturated aqueous solution 5L of 55 DEG C;
2. prepare the mixed organic solvents 30L of ethanol, ether and ethyl acetate; In mixed organic solvents, the volume ratio of ethanol, ether and ethyl acetate is 4:1:1;
3. organic solvent is cooled to 5 DEG C, frequency be 25KHz, under output rating is the sound field of 40W, Prozef crude product saturated aqueous solution is at the uniform velocity added while stirring in organic solvent, adding speed is 3 ls/h, stirring velocity is 1200 revs/min, add rear continuation stir and lower the temperature, stirring velocity is 360 revs/min, and cooling rate is 1.5 DEG C/h; Stop after being cooled to 0 DEG C stirring, leave standstill growing the grain 8 hours; Filter after obtaining crystal, with absolute ethanol washing, vacuum-drying 4 hours, obtains cefprozil compound.
The X-ray powder diffraction pattern that the cefprozil compound prepared adopts the measurement of Cu-K alpha-ray to obtain as shown in Figure 1; Measure through sem observation and particle size analyzer, the main particle diameter of Prozef of the present invention is 365 ~ 402 μm, and Tile Width is 242 ~ 535 μm; Detect through high performance liquid chromatography, its purity is 99.98%; First method through " Chinese Pharmacopoeia " 2010 editions two annex VIC melting point determinations measures, and its fusing point is 219 DEG C.
Embodiment 2: the preparation of cefprozil compound
1. prepare Prozef crude product at the saturated aqueous solution 5L of 60 DEG C;
2. prepare the mixed organic solvents 20L of ethanol, ether and ethyl acetate; In mixed organic solvents, the volume ratio of ethanol, ether and ethyl acetate is 5:1:1;
3. organic solvent is cooled to 0 DEG C, frequency be 25KHz, under output rating is the sound field of 40W, Prozef crude product saturated aqueous solution is at the uniform velocity added while stirring in organic solvent, adding speed is 3 ls/h, stirring velocity is 600 revs/min, add rear continuation stir and lower the temperature, stirring velocity is 60 revs/min, and cooling rate is 0.5 DEG C/h; Stop after being cooled to 0 DEG C stirring, leave standstill growing the grain 6 hours; Filter after obtaining crystal, with absolute ethanol washing, vacuum-drying 6 hours, obtains cefprozil compound.
The X-ray powder diffraction pattern that the cefprozil compound prepared adopts the measurement of Cu-K alpha-ray to obtain as shown in Figure 1; Measure through sem observation and particle size analyzer, the main granularity of Prozef of the present invention is 365 ~ 402 μm, and Tile Width is 242 ~ 535 μm; Detect through high performance liquid chromatography, its purity is 99.98%; First method through " Chinese Pharmacopoeia " 2010 editions two annex VIC melting point determinations measures, and its fusing point is 219 DEG C.
Embodiment 3: Cefprozil dispersible table (specification 0.125g/ sheet)
It consists of:
Preparation method is:
1. weigh cefprozil compound and excipient substance according to formula; Cefprozil compound is prepared by embodiment 1 or 2;
2. sieve: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, lactose are crossed 100 mesh sieves respectively;
3. mix: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, knob are mixed 20 minutes sweet adding in mixing machine, add the Powdered essence of sweet orange taste again, silicon-dioxide, spray-dried lactose continue mixing 20 minutes, finally add Magnesium Stearate and mix 10 minutes;
4. compressing tablet, packaging, to obtain final product.
Embodiment 4: Cefprozil dispersible table (specification: 0.25g/ sheet)
It consists of:
Preparation method is:
1. weigh cefprozil compound and excipient substance according to formula; Cefprozil compound is prepared by embodiment 1 or 2;
2. sieve: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, spray-dried lactose are crossed 100 mesh sieves respectively;
3. mix: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, knob are mixed 20 minutes sweet adding in mixing machine, add the Powdered essence of sweet orange taste again, silicon-dioxide, spray-dried lactose continue mixing 20 minutes, finally add Magnesium Stearate and mix 10 minutes;
4. compressing tablet, packaging, to obtain final product.
Embodiment 5: Cefprozil dry suspension (specification 0.125g/ bag)
It consists of:
Preparation method is:
1. take each component by weight; Cefprozil compound is prepared by embodiment 1 or 2;
2. added mixing machine with cefprozil compound, xanthan gum, aspartame after sucrose being pulverized 100 mesh sieves, mixed, for subsequent use; Added by Polysorbate 80 in appropriate purified water, Polysorbate 80 and purified water weight ratio are 1:3.5; Stirring and dissolving, adds Citric Acid, and stirring and dissolving is for subsequent use;
3. solution in step (2) to be added in step (2) softwood processed in mixed powder, granulation of sieving, puts into oven drying, whole grain, after the Magnesium Stearate adding recipe quantity and flavoring orange essence, mixes; Wherein, dry temperature is 45 ~ 55 DEG C, and dried particles to moisture is 0.50 ~ 1.50%;
4. inspection, packing, packaging, to obtain final product.
Embodiment 6: Cefprozil dry suspension (specification: 0.25g/ bag)
It consists of:
Preparation method is:
1. take each component by weight; Cefprozil compound is prepared by embodiment 1 or 2;
2. added mixing machine with cefprozil compound, xanthan gum, aspartame after sucrose being pulverized 100 mesh sieves, mixed, for subsequent use; Added by Polysorbate 80 in appropriate purified water, Polysorbate 80 and purified water weight ratio are 1:3.5; Stirring and dissolving, adds Citric Acid, and stirring and dissolving is for subsequent use;
3. solution in step 2 to be added in step 2 softwood processed in mixed powder, granulation of sieving, puts into oven drying, whole grain, after the Magnesium Stearate adding recipe quantity and essence, mixes; Wherein, dry temperature is 45 ~ 55 DEG C, and dried particles to moisture is 0.50 ~ 1.50%;
4. inspection, packing, packaging, to obtain final product.
Experimental example 1: Prozef influence factor is tested
Three batches 101,102,103 of the cefprozil compound embodiment of the present invention 1 prepared, simulation listing packaging, carries out study on the stability.
1. high temperature test
By cefprozil compound, put in sealing clean container, place 10 days at 40 DEG C, sample respectively in the 5th day and the 10th day, detect by stability high spot reviews project, result compared with 0 day.
2. high humidity experiment
By cefprozil compound, put in sealing clean container, in temperature 25 ± 2 DEG C, place 10 days under the condition of relative humidity 90 ± 5%, sample respectively in the 5th day and the 10th day, detect by stability high spot reviews project, result compared with 0 day.
3. strong illumination test
By cefprozil compound, put in sealing clean container, be place 10 days under the condition of 4500lx in illumination, sample respectively in the 5th day and the 10th day, detect by stability high spot reviews project, result compared with 0 day.
Test-results is as shown in table 1.
Table 1:
Result shows: cefprozil compound prepared by the present invention, and under the condition of simulation listing packaging, place 10 days under the condition of high temperature, high humidity, illumination, indices is without considerable change.
Identical test is also carried out to the cefprozil compound that other embodiment of the present invention prepares, has obtained similar result.
Experimental example 2: Prozef Acceleration study
Three batches 101,102,103 of the cefprozil compound that the embodiment of the present invention 1 is prepared, simulation listing packaging, carry out following stability test: in 40 ± 2 DEG C, place 6 months under the condition of 75 ± 5%RH, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.Experimental result is as shown in table 2.
Table 2:
From accelerated test result, cefprozil compound of the present invention, within 6 months, investigating through accelerated test, there is not considerable change in indices.Confirm that cefprozil compound of the present invention has good stability.
Also carried out identical test to the cefprozil compound that other embodiment of the present invention prepares, its result obtained is similar.
Implement experimental example 3: dispersible tablet influence factor is tested
Three batches 101,102,103 of the cefprozil compound embodiment of the present invention 1 prepared, prepare dispersible tablet according to embodiment 3, and simulation listing packaging, carries out stability test.
1. high temperature test
By the dispersible tablet prepared, put in sealing clean container, place 10 days at 40 DEG C, sample respectively in the 5th day and the 10th day, detect by stability high spot reviews project, result compared with 0 day.
2. high humidity experiment
By the dispersible tablet prepared, put in sealing clean container, in temperature 25 ± 2 DEG C, place 10 days under the condition of relative humidity 90 ± 5%, sample respectively in the 5th day and the 10th day, detect by stability high spot reviews project, result compared with 0 day.3. strong illumination test
By the dispersible tablet prepared, put in sealing clean container, be place 10 days under the condition of 4500lx in illumination, sample respectively in the 5th day and the 10th day, detect by stability high spot reviews project, result compared with 0 day.
Test-results is as shown in table 3.
Table 3:
Result shows: dispersible tablet prepared by the cefprozil compound prepared by the present invention, and under the condition of simulation listing packaging, place 10 days under the condition of high temperature, high humidity, illumination, indices is without considerable change.
Identical test is also carried out to the Cefprozil dispersible table that other embodiment of the present invention prepares, has obtained similar result.
Experimental example 4: the Acceleration study of dispersible tablet
Three batches 101,102,103 of the cefprozil compound that the embodiment of the present invention 1 is prepared, dispersible tablet is prepared according to the method for embodiment 3, simulation listing packaging, carry out stability test: in 40 ± 2 DEG C, place 6 months under the condition of 75 ± 5%RH, respectively sample once respectively at 1,2,3,6 the end of month at duration of test, each stability high spot reviews project is tested.Experimental result is as shown in table 4.
Table 4:
From accelerated test result, Cefprozil dispersible table of the present invention is investigated through accelerated test for 6 months, and considerable change does not occur indices.Confirm that the stability of Cefprozil dispersible table of the present invention is good.
The cefprozil compound adopting other embodiment to prepare, the dispersible tablet prepared according to the pharmaceutical formulation of other embodiments, have similar result.
Experimental example 5: the test of long duration of dispersible tablet
3 batches 101,102,103 of the cefprozil compound that the embodiment of the present invention 1 is prepared, dispersible tablet is prepared according to the method for embodiment 3, simulation listing packaging, carry out stability test: put in sealing clean container, at 30 ± 2 DEG C, place 24 months under 60 ± 5%RH part, at duration of test respectively at the 3rd, 6,9,12,18,24 sampling at the end of month once, each stability high spot reviews project is tested.Test-results is as shown in table 5:
Table 5:
From long-term test results, Cefprozil dispersible table of the present invention is investigated through test of long duration for 24 months, and indices all considerable change does not occur.Confirm that the stability of Cefprozil dispersible table of the present invention is good.
The cefprozil compound adopting other embodiment to prepare, the dispersible tablet prepared according to the pharmaceutical formulation of other embodiments, have similar result.
Implement experimental example 6: stability contrast experiment
The preparation of drugs compared:
Comparative example 1: adopt commercially available Prozef bulk drug (Qilu Antibiotics Pharmaceutical Co., Ltd.), prepare dispersible tablet according to the method for embodiment 3;
Comparative example 2: the Prozef crystal adopting patent application 200910014981 embodiment 2 to prepare, prepares dispersible tablet according to the method for embodiment 3;
Comparative example 3: the Prozef crystal adopting patent application 200910014981 embodiment 7 to prepare, prepares dispersible tablet according to the method for embodiment 3;
Comparative example 4: the Prozef crystal adopting patent application 201110261377.9 embodiment 1 to prepare, prepares dispersible tablet according to the method for embodiment 3;
The Prozef crystal that the present invention adopts embodiment 1 to prepare, prepares dispersible tablet according to the method for embodiment 3.
By above-mentioned medicine simulation listing packaging, carry out following stability test: in 40 ± 2 DEG C, place 6 months under the condition of 75 ± 5%RH, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.Experimental result is as shown in table 6.
Table 6:
Implement experimental example 7: dry suspensoid influence factor is tested
Three batches 201,202,203 of the cefprozil compound embodiment of the present invention 2 prepared, prepare dry suspensoid according to the method for embodiment 5, and simulation listing packaging, carries out stability test.
1. high temperature test
By the dry suspensoid prepared, put in sealing clean container, place 10 days at 40 DEG C, sample respectively in the 5th day and the 10th day, detect by stability high spot reviews project, result compared with 0 day.
2. high humidity experiment
By the dry suspensoid prepared, put in sealing clean container, in temperature 25 ± 2 DEG C, place 10 days under the condition of relative humidity 90 ± 5%, sample respectively in the 5th day and the 10th day, detect by stability high spot reviews project, result compared with 0 day.
3. strong illumination test
By the dry suspensoid prepared, put in sealing clean container, be place 10 days under the condition of 4500lx in illumination, sample respectively in the 5th day and the 10th day, detect by stability high spot reviews project, result compared with 0 day.
Test-results is as shown in table 7.
Table 7:
Result shows: dry suspensoid prepared by the cefprozil compound prepared by the present invention, and under the condition of simulation listing packaging, place 10 days under the condition of high temperature, high humidity, illumination, indices is without considerable change.
Prozef crystal prepared by other embodiment of the employing prepared other embodiment of the present invention, the dry suspensoid prepared according to the pharmaceutical formulation of other embodiments, have similar result.
Experimental example 8: the Acceleration study of dry suspensoid
The just embodiment of the present invention 2 three batches 201,202,203 of cefprozil compound of preparing, dry suspensoid is prepared according to the method for embodiment 5, simulation listing packaging, carry out stability test: in 40 ± 2 DEG C, place 6 months under the condition of 75 ± 5%RH, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.Experimental result is as shown in table 8.
Table 8:
From accelerated test result, Cefprozil dry suspension of the present invention is investigated through accelerated test for 6 months, and considerable change does not occur indices.Confirm having good stability of Cefprozil dry suspension of the present invention.
The cefprozil compound adopting other embodiment to prepare, the preparation prepared according to the pharmaceutical formulation of other embodiments, have similar result.
Experimental example 9: the test of long duration of dry suspensoid
3 batches 201,202,203 of the cefprozil compound that the embodiment of the present invention 2 is prepared, dry suspensoid is prepared according to the preparation method of embodiment 5, simulation listing packaging, carry out stability test: put in sealing clean container, at 30 ± 2 DEG C, place 24 months under 60 ± 5%RH part, at duration of test respectively at the 3rd, 6,9,12,18,24 sampling at the end of month once, each stability high spot reviews project is tested.Test-results is as shown in table 9:
Table 9:
From long-term test results, Cefprozil dry suspension of the present invention is investigated through test of long duration for 24 months, and indices all considerable change does not occur.Confirm having good stability of Cefprozil dry suspension of the present invention.
The cefprozil compound adopting other embodiment to prepare, the dry suspensoid prepared according to the pharmaceutical formulation of other embodiments, have similar result.
Implement experimental example 10: the stability simultaneous test of compound formulation
The preparation of drugs compared:
Comparative example 5: adopt commercially available Prozef bulk drug (Qilu Antibiotics Pharmaceutical Co., Ltd.), prepare dry suspensoid according to the method for the embodiment of the present invention 6;
Comparative example 6: the Prozef crystal adopting patent application 200910014981 embodiment 2 to prepare, prepares dry suspensoid according to the method for the embodiment of the present invention 6;
Comparative example 7: the Prozef crystal adopting patent application 200910014981 embodiment 7 to prepare, prepares dry suspensoid according to the method for the embodiment of the present invention 6;
Comparative example 8: the Prozef crystal adopting patent application 201110261377.9 embodiment 1 to prepare, prepares dry suspensoid according to the method for the embodiment of the present invention 6;
The cefprozil compound that the present invention adopts embodiment 1 to prepare, prepares dry suspensoid according to the method for embodiment 6.
By above-mentioned medicine simulation listing packaging, carry out following stability test: in 40 ± 2 DEG C, place 6 months under the condition of 75 ± 5%RH, at duration of test respectively at 1,2,3,6 sampling at the end of month once, each stability high spot reviews project is tested.Experimental result is as shown in table 10.
Table 10:
From comparative test result, the stability of Cefprozil dry suspension of the present invention is better than prior art.
Implement experimental example 11: mobility comparative experiments
The mobility of this experimental example to the Prozef of the embodiment of the present invention 1 and comparative example detects, adopt fixed funnel method, funnel is placed in the suitable height on graph paper, Prozef is freely flowed down from flare opening, until the cone top formed contacts with flare opening, measure hypotenuse and the horizontal angle (slope of repose θ) of Prozef accumulation horizon.
Comparative example 1: adopt commercially available Prozef bulk drug (Qilu Antibiotics Pharmaceutical Co., Ltd.);
Comparative example 2: adopt the Prozef crystal that patent application 200910014981 embodiment 2 prepares;
Comparative example 3: adopt the Prozef crystal that patent application 200910014981 embodiment 7 prepares;
Comparative example 4: adopt the Prozef crystal that patent application 201110261377.9 embodiment 1 prepares;
Measure 10 times, average, experiment knot is as shown in table 11:
Table 11: Prozef mobility experimental result
| Batch | Embodiment 1 | Comparative example 1 | Comparative example 2 | Comparative example 3 | Comparative example 4 |
| θ（°） | 30.4 | 35.5 | 34.2 | 34.3 | 34.3 |
From the experimental result of table 11, the mobility that the present invention prepares Prozef is fine, is better than prior art.Thus the preparation of its preparation more convenient.
Claims (15)
1. a cefprozil compound, is characterized in that, described cefprozil compound is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha-ray obtains as shown in Figure 1.
2. cefprozil compound according to claim 1, is characterized in that, the main granularity of described cefprozil compound is 288 ~ 465 μm, and Tile Width is 190 ~ 658 μm.
3. cefprozil compound according to claim 2, is characterized in that, the main granularity of described cefprozil compound is main granularity is 365 ~ 402 μm, and Tile Width is 242 ~ 535 μm.
4. a preparation method for cefprozil compound as claimed in claim 1, is characterized in that, comprises the following steps:
(1) Prozef crude product is prepared at the saturated aqueous solution of 50 ~ 60 DEG C;
(2) prepare the mixed organic solvents of ethanol, ether and ethyl acetate, the volume of mixed organic solvents is 3 ~ 9 times of Prozef crude product saturated aqueous solution; In mixed organic solvents, the volume ratio of ethanol, ether and ethyl acetate is 3 ~ 5:1 ~ 2:1;
(3) organic solvent is cooled to 0 ~ 5 DEG C, frequency be 20 ~ 25KHz, under output rating is the sound field of 40 ~ 80W, Prozef crude product saturated aqueous solution is at the uniform velocity added while stirring in organic solvent, add rear continuation stir and lower the temperature, stop after being cooled to 0 ~ 5 DEG C stirring, leave standstill growing the grain 2 ~ 8 hours; Filter after obtaining crystal, with absolute ethanol washing, vacuum-drying 2 ~ 8 hours, obtains cefprozil compound.
5. the preparation method of cefprozil compound according to claim 4, is characterized in that, in step (2), the volume of mixed organic solvents is 4 ~ 6 times of Prozef crude product saturated aqueous solution.
6. the preparation method of cefprozil compound according to claim 4, is characterized in that, in step (2), in mixed organic solvents, the volume ratio of ethanol, ether and ethyl acetate is 4 ~ 5:1:1.
7. the preparation method of the cefprozil compound stated according to claim 4, it is characterized in that, in step (3), the stirring velocity adding Prozef crude product saturated aqueous solution in organic solvent is 600 ~ 1200 revs/min; Stirring velocity after Prozef crude product saturated aqueous solution adds is 60 ~ 360 revs/min.
8. the preparation method of cefprozil compound according to claim 4, it is characterized in that, in step (3), the speed that adds of Prozef crude product saturated aqueous solution is: v=M/20 ~ M/10, wherein M is the volume of organic mixed solvent, unit is for rising, and the unit of speed v is l/h.
9. the preparation method of cefprozil compound according to claim 4, is characterized in that, in step (3), the cooling rate after Prozef crude product saturated aqueous solution adds is 0.5 ~ 3.5 DEG C/h.
10. the preparation method of cefprozil compound according to claim 9, is characterized in that, in step (3), the cooling rate after Prozef crude product saturated aqueous solution adds is 1.5 ~ 2.5 DEG C/h.
11. 1 kinds of preparations containing cefprozil compound described in claim 1, it is characterized in that, described preparation is dispersible tablet or dry suspensoid.
12. preparations according to claim 11, is characterized in that, contain in described dispersible tablet: cefprozil compound 125 ~ 250 weight part, lactose 26.65 ~ 53.3 weight part; Low-substituted hydroxypropyl cellulose 25 ~ 50 weight part; Sodium starch glycolate 2.7 ~ 5.4 weight part; Silica 1 .65 ~ 3.3 weight part; Magnesium Stearate 1.65 ~ 3.3 weight part; Sweet 0.35 ~ 0.7 weight part of knob, essence 2.0 ~ 4.0 weight part.
13. preparations according to claim 12, is characterized in that, the preparation method of described dispersible tablet comprises the following steps:
(1) each component is taken by weight;
(2) sieve: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, lactose are crossed 100 mesh sieves respectively;
(3) mix: cefprozil compound, sodium starch glycolate, low-substituted hydroxypropyl cellulose, knob are mixed 10 ~ 30 minutes sweet adding in mixing machine, add essence again, silicon-dioxide, lactose continue mixing 10 ~ 30 minutes, finally add Magnesium Stearate mixing 5 ~ 15 minutes;
(4) compressing tablet, packaging, to obtain final product.
14. preparations according to claim 11, it is characterized in that, contain in described dry suspensoid: cefprozil compound 125 ~ 250 weight part, sucrose 1000 ~ 2000 weight part, xanthan gum 15 ~ 30 weight part, aspartame 5 ~ 10 weight part, essence 4 ~ 8 weight part, Magnesium Stearate 1 ~ 2 weight part, Citric Acid 0.5 ~ 1 weight part, Polysorbate 80 10 ~ 20 weight part.
15. preparations according to claim 14, is characterized in that, the preparation method of described dry suspensoid comprises the following steps:
(1) each component is taken by weight;
(2) added mixing machine with cefprozil compound, xanthan gum, aspartame after sucrose being pulverized 100 mesh sieves, mixed, for subsequent use; Added by Polysorbate 80 in appropriate purified water, stirring and dissolving, adds Citric Acid, and stirring and dissolving is for subsequent use;
(3) solution in step (2) to be added in step (2) softwood processed in mixed powder, granulation of sieving, puts into oven drying, whole grain, after the Magnesium Stearate adding recipe quantity and essence, mixes; Wherein, dry temperature is 45 ~ 55 DEG C, and dried particles to moisture is 0.50 ~ 1.50%;
(4) inspection, packing, packaging, to obtain final product.
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| CN106220505A (en) * | 2015-04-30 | 2016-12-14 | 苗怡文 | A kind of prepare antipyretic, analgesia, the method for anti-inflammatory drug compound |
| CN104983690A (en) * | 2015-08-18 | 2015-10-21 | 青岛蓝盛洋医药生物科技有限责任公司 | Medicine atorvastatin calcium composition dry suspension for treating coronary heart disease |
| CN105055334A (en) * | 2015-09-18 | 2015-11-18 | 青岛华之草医药科技有限公司 | Postoperative antiemetic tropisetron hydrochloride composition granule |
| CN108299468B (en) * | 2017-12-29 | 2020-06-16 | 山东裕欣药业有限公司 | Refining method of cefprozil |
| CN109010297A (en) * | 2018-10-25 | 2018-12-18 | 苏州东瑞制药有限公司 | A kind of cefprozil tablet and preparation method thereof |
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Address after: 519041 Guangdong Province, Zhuhai City Industrial Zone, Jinwan District biological Patentee after: Jin Hong pharmaceutical Limited by Share Ltd Address before: 519041 Guangdong Province, Zhuhai City Industrial Zone, Jinwan District biological Patentee before: Zhuhai Kinhoo Pharmaceutical Co., Ltd. |