CN104876947A - Cefetamet pivoxil hydrochloride hydrate crystals and dispersible tablet thereof - Google Patents
Cefetamet pivoxil hydrochloride hydrate crystals and dispersible tablet thereof Download PDFInfo
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- CN104876947A CN104876947A CN201510227083.2A CN201510227083A CN104876947A CN 104876947 A CN104876947 A CN 104876947A CN 201510227083 A CN201510227083 A CN 201510227083A CN 104876947 A CN104876947 A CN 104876947A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/12—Separation; Purification
Abstract
The invention provides a cefetamet pivoxil hydrochloride hydrate, wherein an X-ray powder diffraction spectrogram obtained by measurement by using Cu-Kalpha rays is represented by the figure 1. Cefetamet pivoxil hydrochloride hydrate crystals disclosed by the invention are good in stability, difficult to absorb moisture and good in mobility and can be uniformly mixed with other accessories; and a prepared cefetamet pivoxil hydrochloride dispersible table is rapid in absorption speed and high in bioavailability.
Description
Technical field
The invention belongs to field of medicaments, especially relate to a kind of Ro 15-8075 hydrate crystal and dispersible tablet thereof.
Background technology
In prior art, β-lactam antibitics is that Clinical practice amount is maximum, most widely used, kind is maximum, the class microbiotic that curative effect is preferably the highest with evaluation, wherein, cynnematin series product account for 70%, in various cynnematin, Ro 15-8075 is oral third generation broad-spectrum cephalosporin class microbiotic, there is wide spectrum, efficiently, resistance to enzyme, the features such as low toxicity, comparatively with veriety Cephalexin Monohydrate Micro/Compacted, it is stronger that cefradines etc. have anti-microbial activity, the advantages such as dosage is less, overcome the shortcoming of pioneer's series product to β-lactamase instability, it is Cephalexin Monohydrate Micro/Compacted, the substitute that cefradine is desirable.
Ro 15-8075 is developed by Roche Holding Ag, the development of Japanese Takeda Pharmaceutical Company Limited, and organizes nationwide research in 1987 in Japan.Since listing in 1992, apply in countries in the world.As anti-infective oral pharmaceutical, the unique advantage of this product be oral after be that the cefetamet with anti-microbial activity plays a role by esterase hydrolyzed in intestines wall and liver rapidly in vivo.Its chemical name is: (6R, 7R)-3-methyl-7-((Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-kharophen)-8-oxo-5-thia-1-azabicyclo (4,2,0) oct-2-ene-2-formic acid pivalyl oxygen methyl ester hydrochloride.Every Western Europe country is studied from nineteen eighty-three, and 1986 start clinical trial, and 1984-1990 has done report in a lot of international academic conference.Japan starts to carry out Section 1 clinical trial for 1986, and nationwide clinical test results comes from 1989.
Cefetamet pivoxil in-vitro antibacterial vigor is more weak, not and parent compound cefetamet active strong.Cefetamet pivoxil is entering by the Viability compound cefetamet of esterase hydrolyzed in intestines wall and liver, and its anti-microbial activity improves greatly.Cefetamet pivoxil is the strongest to pneumococcal effect, all has certain anti-microbial effect to staphylococcus aureus, table Portugal coccus, streptococcus pyogenes, streptococcus agalactiae, tetrads etc.All have stronger anti-microbial activity to the escherichia coli in gram-negative bacteria, Bacillus proteus, Klebsiella Pneumoniae, Corynebacterium diphtheriae, dysentery bacterium, curative effect is obviously better than Cephaloridine, Kefzol, cefaclor 2 ~ 64 times.The Resistant strain of generation β-lactamase is comprised also very effectively (MIC≤0.125mg/L) to neisseria gonorrhoeae.Also certain anti-microbial activity is had to mycetozoan, Providence, Yersinia enterocolitica, acinetobacter calcoaceticus, bacillus cloacae, Hough Buddhist nun bacterium.And it is still responsive to produce β-lactamase bacterial strain to 80%.His U.S. free acid of active body to the main pathogenic fungi of respiratory tract infection as streptococcus pneumoniae, hemophilus influenzae, streptococcus pyogenes, mucositis Branhamella, Klebsiella Pneumoniae have fabulous anti-microbial effect.Be 72.7% to chronic bronchitis and the efficient of bacterial pneumonia.
CN101550146A discloses a kind of cefetamet pivoxil hydrochloride compound and method for making thereof, and Ro 15-8075 crude product prior art prepared prepares relatively pure cefetamet pivoxil hydrochloride compound through following steps.Ro 15-8075 crude product is dissolved in methyl alcohol or ethanol, adds sodium hydroxide or potassium hydroxide solution, stirring reaction, be hydrolyzed to obtain Ro 15-8074/001 or sylvite; Add charcoal absorption, filter, then add iodo-ester, react under organic solvent existent condition, obtain cefetamet pivoxil, cefetamet pivoxil is dissolved in Virahol, drips hydrochloric acid, adds hexanaphthene and stirs, crystallization, filter, washing, dry, obtain Ro 15-8075.
Ro 15-8075 stability and poor fluidity, the easy moisture absorption goes bad and occurs content uniformity.In view of this, special proposition the present invention.
Summary of the invention
The object of this invention is to provide a kind of Ro 15-8075 hydrate crystal.
A kind of Ro 15-8075 hydrate, it is characterized in that, each Ro 15-8075 hydrate contains 1 crystal water, and its X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
Researchist of the present invention is surprised to find that when Ro 15-8075 forms 1 hydrate crystal under study for action, and its stability significantly increases and has good mobility.
Described Ro 15-8075 hydrate crystal powder x-ray diffraction assay method measures, and the X-ray powder diffraction pattern represented with 2 θ ± 0.2 ° diffraction angle demonstrates characteristic diffraction peak at 7.4 °, 9.9 °, 12.8 °, 13.2 °, 17.3 °, 19.6 °, 20.8 °, 23.8 °, 24.4 °, 26.3 °, 29.0 °, 33.5 °, 36.6 °, 39.0 ° places.
Described Ro 15-8075 hydrate is analyzed by hot poor-thermogravimetric TG-DTA, weightless 3.1wt%-3.4wt% within the scope of 80-150 DEG C.
A preparation method for described Ro 15-8075 hydrate, described method comprises the steps:
(1) by Ro 15-8075 dissolving crude product in the ethanol of 5-10 DEG C, the volume of described ethanol be the 3-8 of Ro 15-8075 crude product quality doubly;
(2) add the activated carbon decolorizing 20-30 minute of Ro 15-8075 crude product quality 0.02-0.1, filter, a small amount of dissolve with ethanol liquid washing, obtains Ro 15-8075 ethanolic soln;
(3) Ro 15-8075 ethanolic soln is warmed up to 20-30 DEG C, in Ro 15-8075 ethanolic soln, the sodium chloride saturated solution of-15 DEG C-5 DEG C is dripped under the condition stirred, the volume of sodium chloride saturated solution is 5-8 times of Ro 15-8075 volumes of aqueous ethanol, at the uniform velocity dropwise in 0.5h, described stir speed (S.S.) is 20-25rmp;
(4) be cooled to-15 DEG C-5 DEG C after being added dropwise to complete to continue to stir 0.5-2h under the stir speed (S.S.) of 10-15rmp, leave standstill 2-4h and separate out light yellow crystal, filter;
(5) wash final vacuum drying successively by distilled water, ethyl acetate and obtain Ro 15-8075 hydrate crystal.
The sodium chloride saturated solution volume dripped to Ro 15-8075 ethanolic soln under the condition stirred in described step (3) is 7 times of Ro 15-8075 volumes of aqueous ethanol; Described stir speed (S.S.) when adding sodium chloride saturated solution is 23rmp.
Described in described step (3), the temperature of sodium chloride saturated solution is-10 DEG C.
Be cooled to-10 DEG C after being added dropwise to complete in described step (4) to continue to stir 1h under the stir speed (S.S.) of 12rmp.
A pharmaceutical composition containing described Ro 15-8075 hydrate, described pharmaceutical composition is dispersible tablet, tablet, capsule, lyophilized injectable powder, sterile powder injection.
Dispersible tablet component containing described Ro 15-8075 hydrate comprises:
A kind of preparation method of described Ro 15-8075 hydrate dispersible tablet, it is characterized in that, described preparation method comprises: by raw material Ro 15-8075 hydrate and supplementary product starch, Microcrystalline Cellulose, hydroxypropylcellulose, acesulfame potassium and carboxymethylstach sodium are pulverized respectively, sieve, wet granular processed, make dry particle, compressing tablet and packaging, described wet granular processed be take recipe quantity Ro 15-8075 hydrate, starch, Microcrystalline Cellulose, acesulfame potassium and hydroxypropylcellulose, insert in high-speed mixing granulating machine, sealing is dry mixed 5-15 minute at a high speed, then appropriate amount of ethanol wet mixing 1-5 minute is added, after wet mixing, wet mixing cutting 1-3 minute, release particle, obtain wet granular.
The preparation method of described Ro 15-8075 hydrate dispersible tablet comprises the steps:
1) get the raw materials ready
Ro 15-8075 hydrate is pulverized, crosses 100 mesh sieves, starch, Microcrystalline Cellulose, hydroxypropylcellulose, acesulfame potassium and carboxymethylstach sodium are pulverized respectively, cross 120 mesh sieves, obtain former, auxiliary material for subsequent use;
2) wet granular processed
Take Ro 15-8075 hydrate, starch, Microcrystalline Cellulose, acesulfame potassium and the hydroxypropylcellulose above-mentioned for subsequent use of recipe quantity, insert in high-speed mixing granulating machine, sealing is dry mixed 5-15 minute at a high speed, then appropriate amount of ethanol wet mixing 1-3 minute is added, after wet mixing, wet mixing cuts 2 minutes, releases particle, obtains wet granular;
3) dry particle is made
The wet granular that upper step is obtained proceeds in ebullated dryer, and temperature controls to dry 17-20 minute at 60-70 DEG C, and shut down, clear filter bag, blowing, obtains dry particle;
4) compressing tablet, packaging
Dry particle obtained by upper step is added pelletizing machine, start button, carries out whole grain, then add the carboxymethylstach sodium of recipe quantity and appropriate Magnesium Stearate, add three-dimensional mixer mixing with suction feeding, compressing tablet, packs and obtains hydrochloric acid cefetamet pivoxil dispersible tablet.
The advantage that the present invention has and positively effect are: Ro 15-8075 hydrate crystal good stability of the present invention, not easily moisture absorption, has good mobility, can with other auxiliary material Homogeneous phase mixing, prepared hydrochloric acid cefetamet pivoxil dispersible tablet agent absorption rate is fast, and bioavailability is high.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffractogram of Ro 15-8075 hydrate of the present invention
Fig. 2 is the thermogravimetric analysis figure of Ro 15-8075 hydrate of the present invention
Embodiment
By embodiment, technical scheme of the present invention is described in detail below; the advantage contributed to technical scheme of the present invention, effect are had and further understands; embodiment does not limit protection scope of the present invention, and protection scope of the present invention is decided by claim.
Embodiment 1
Getting Ro 15-8075 crude material medicine 10g, to be dissolved into 30ml temperature be in the ethanol of 5 DEG C, add the activated carbon decolorizing 20-30 minute of Ro 15-8075 crude product quality 0.1, filter, a small amount of dissolve with ethanol liquid washing, obtain Ro 15-8075 ethanolic soln activated carbon decolorizing 20 minutes, filter, a small amount of dissolve with ethanol liquid washing, obtain Ro 15-8075 ethanolic soln, Ro 15-8075 ethanolic soln is warmed up to 20 DEG C, stir speed (S.S.) is in Ro 15-8075 ethanolic soln, at the uniform velocity drip the sodium chloride saturated solution that 200ml temperature is-15 DEG C under the condition of 20rmp, at the uniform velocity dropwise in 0.5h, be cooled to-15 DEG C after being added dropwise to complete to continue to stir 0.5h under the stir speed (S.S.) of 10rmp, leave standstill 4h and separate out light yellow crystal, filter, with distilled water, ethyl acetate is washed final vacuum drying successively and is obtained Ro 15-8075 hydrate crystal 9.78g.
Measure by powder x-ray diffraction assay method, the X-ray powder diffraction pattern represented with 2 θ ± 0.2 ° diffraction angle demonstrates characteristic diffraction peak at 7.4 °, 9.9 °, 12.8 °, 13.2 °, 17.3 °, 19.6 °, 20.8 °, 23.8 °, 24.4 °, 26.3 °, 29.0 °, 33.5 °, 36.6 °, 39.0 ° places.
Ultimate analysis:
Measured value: C 42.48%, H 5.03%, N 12.32%, O 22.68%, S11.41%, Cl 6.22%
Theoretical value: C 42.43%, H 4.99%, N 12.38%, O 22.61%, S11.33%, Cl 6.26%.
Results of elemental analyses and theoretical value basically identical.
Adopting Ka Shi aquametry to measure moisture content is 3.4wt%, substantially identical with theoretical value.
Employing thermogravimetric analysis measures, and as shown in Figure 2, crystal water content is 3.2wt% to result, substantially identical with theoretical value.
Embodiment 2
Getting Ro 15-8075 crude material medicine 10g, to be dissolved into 50ml temperature be in the ethanol of 10 DEG C, add the activated carbon decolorizing 30 minutes of Ro 15-8075 crude product quality 0.02, filter, a small amount of dissolve with ethanol liquid washing, obtain Ro 15-8075 ethanolic soln, Ro 15-8075 ethanolic soln is warmed up to 30 DEG C, stir speed (S.S.) is in Ro 15-8075 ethanolic soln, at the uniform velocity drip the sodium chloride saturated solution that 350ml temperature is-10 DEG C under the condition of 23rmp, at the uniform velocity dropwise in 0.5h, be cooled to-10 DEG C after being added dropwise to complete to continue to stir 1h under the stir speed (S.S.) of 12rmp, leave standstill 2h and separate out light yellow crystal, filter, with distilled water, ethyl acetate is washed final vacuum drying successively and is obtained Ro 15-8075 hydrate crystal 9.89g.
Measure by powder x-ray diffraction assay method, the X-ray powder diffraction pattern represented with 2 θ ± 0.2 ° diffraction angle demonstrates characteristic diffraction peak at 7.4 °, 9.9 °, 12.8 °, 13.2 °, 17.3 °, 19.6 °, 20.8 °, 23.8 °, 24.4 °, 26.3 °, 29.0 °, 33.5 °, 36.6 °, 39.0 ° places.
Results of elemental analyses and embodiment 1 basically identical.
Adopt Ka Shi aquametry to measure moisture content and embodiment 1 basically identical.
Embodiment 3
Getting Ro 15-8075 crude material medicine 10g, to be dissolved into 80ml temperature be in the ethanol of 8 DEG C, add the activated carbon decolorizing 25 minutes of Ro 15-8075 crude product quality 0.1, filter, a small amount of dissolve with ethanol liquid washing, obtain Ro 15-8075 ethanolic soln, Ro 15-8075 ethanolic soln is warmed up to 25 DEG C, stir speed (S.S.) is in Ro 15-8075 ethanolic soln, at the uniform velocity drip the sodium chloride saturated solution that 500ml temperature is-5 DEG C under the condition of 25rmp, at the uniform velocity dropwise in 0.5h, be cooled to-10 DEG C after being added dropwise to complete to continue to stir 2h under the stir speed (S.S.) of 15rmp, leave standstill 4h and separate out light yellow crystal, filter, with distilled water, ethyl acetate is washed final vacuum drying successively and is obtained Ro 15-8075 hydrate crystal 9.83g.
Measure by powder x-ray diffraction assay method, the X-ray powder diffraction pattern represented with 2 θ ± 0.2 ° diffraction angle demonstrates characteristic diffraction peak at 7.4 °, 9.9 °, 12.8 °, 13.2 °, 17.3 °, 19.6 °, 20.8 °, 23.8 °, 24.4 °, 26.3 °, 29.0 °, 33.5 °, 36.6 °, 39.0 ° places.
Results of elemental analyses and embodiment 1 basically identical.
Adopt Ka Shi aquametry to measure moisture content and embodiment 1 basically identical.
Embodiment 4
Getting Ro 15-8075 crude material medicine 10g, to be dissolved into 50ml temperature be in the ethanol of 5 DEG C, add the activated carbon decolorizing 30 minutes of Ro 15-8075 crude product quality 0.05, filter, a small amount of dissolve with ethanol liquid washing, obtain Ro 15-8075 ethanolic soln, Ro 15-8075 ethanolic soln is warmed up to 25 DEG C, stir speed (S.S.) is in Ro 15-8075 ethanolic soln, at the uniform velocity drip the sodium chloride saturated solution that 300ml temperature is-5 DEG C under the condition of 23rmp, at the uniform velocity dropwise in 0.5h, be cooled to-5 DEG C after being added dropwise to complete to continue to stir 1h under the stir speed (S.S.) of 12rmp, leave standstill 3h and separate out light yellow crystal, filter, with distilled water, ethyl acetate is washed final vacuum drying successively and is obtained Ro 15-8075 hydrate crystal 9.96g.
Measure by powder x-ray diffraction assay method, the X-ray powder diffraction pattern represented with 2 θ ± 0.2 ° diffraction angle demonstrates characteristic diffraction peak at 7.4 °, 9.9 °, 12.8 °, 13.2 °, 17.3 °, 19.6 °, 20.8 °, 23.8 °, 24.4 °, 26.3 °, 29.0 °, 33.5 °, 36.6 °, 39.0 ° places.
Results of elemental analyses and embodiment 1 basically identical.
Adopt Ka Shi aquametry to measure moisture content and embodiment 1 basically identical.
Embodiment 5
Getting Ro 15-8075 crude material medicine 10g, to be dissolved into 60ml temperature be in the ethanol of 5 DEG C, add the activated carbon decolorizing 30 minutes of Ro 15-8075 crude product quality 0.08, filter, a small amount of dissolve with ethanol liquid washing, obtain Ro 15-8075 ethanolic soln, Ro 15-8075 ethanolic soln is warmed up to 25 DEG C, stir speed (S.S.) is in Ro 15-8075 ethanolic soln, at the uniform velocity drip the sodium chloride saturated solution that 360ml temperature is-15 DEG C under the condition of 23rmp, at the uniform velocity dropwise in 0.5h, be cooled to-15 DEG C after being added dropwise to complete to continue to stir 0.5h under the stir speed (S.S.) of 12rmp, leave standstill 3h and separate out light yellow crystal, filter, with distilled water, ethyl acetate is washed final vacuum drying successively and is obtained Ro 15-8075 hydrate crystal 9.87g.
Measure by powder x-ray diffraction assay method, the X-ray powder diffraction pattern represented with 2 θ ± 0.2 ° diffraction angle demonstrates characteristic diffraction peak at 7.4 °, 9.9 °, 12.8 °, 13.2 °, 17.3 °, 19.6 °, 20.8 °, 23.8 °, 24.4 °, 26.3 °, 29.0 °, 33.5 °, 36.6 °, 39.0 ° places.
Results of elemental analyses and embodiment 1 basically identical.
Adopt Ka Shi aquametry to measure moisture content and embodiment 1 basically identical.
The formula ratio of each raw material in table 1 embodiment 6 to embodiment 10
Table 1
Embodiment 6
Preparation technology:
1) get the raw materials ready
Ro 15-8075 hydrate is pulverized, crosses 100 mesh sieves, starch, Microcrystalline Cellulose, hydroxypropylcellulose, acesulfame potassium and carboxymethylstach sodium are pulverized respectively, cross 120 mesh sieves, obtain former, auxiliary material for subsequent use;
2) wet granular processed
Take Ro 15-8075 hydrate, starch, Microcrystalline Cellulose, acesulfame potassium and the hydroxypropylcellulose above-mentioned for subsequent use of recipe quantity, insert in high-speed mixing granulating machine, sealing is dry mixed 10 minutes at a high speed, then appropriate amount of ethanol wet mixing is added 3 minutes, after wet mixing, wet mixing cuts 2 minutes, releases particle, obtains wet granular;
3) dry particle is made
The wet granular that upper step is obtained proceeds in ebullated dryer, and temperature controls to dry 17 minutes at 65 DEG C, and shut down, clear filter bag, blowing, obtains dry particle;
4) compressing tablet, packaging
Dry particle obtained by upper step is added pelletizing machine, start button, carries out whole grain; add the carboxymethylstach sodium of recipe quantity and appropriate Magnesium Stearate again; add three-dimensional mixer mixing with suction feeding, compressing tablet, packs and obtains 1000 hydrochloric acid cefetamet pivoxil dispersible tablets.
Embodiment 7
Preparation technology:
1) get the raw materials ready
Ro 15-8075 hydrate is pulverized, crosses 100 mesh sieves, starch, Microcrystalline Cellulose, hydroxypropylcellulose, acesulfame potassium and carboxymethylstach sodium are pulverized respectively, cross 120 mesh sieves, obtain former, auxiliary material for subsequent use;
2) wet granular processed
Take Ro 15-8075 hydrate, starch, Microcrystalline Cellulose, acesulfame potassium and the hydroxypropylcellulose above-mentioned for subsequent use of recipe quantity, insert in high-speed mixing granulating machine, sealing is dry mixed 5 minutes at a high speed, then appropriate amount of ethanol wet mixing is added 1 minute, after wet mixing, wet mixing cuts 3 minutes, releases particle, obtains wet granular;
3) dry particle is made
The wet granular that upper step is obtained proceeds in ebullated dryer, and temperature controls to dry 17 minutes at 60 DEG C, and shut down, clear filter bag, blowing, obtains dry particle;
4) compressing tablet, packaging
Dry particle obtained by upper step is added pelletizing machine, start button, carries out whole grain; add the carboxymethylstach sodium of recipe quantity and appropriate Magnesium Stearate again; add three-dimensional mixer mixing with suction feeding, compressing tablet, packs and obtains 1000 hydrochloric acid cefetamet pivoxil dispersible tablets.
Embodiment 8
Preparation technology:
1) get the raw materials ready
Ro 15-8075 hydrate is pulverized, crosses 100 mesh sieves, starch, Microcrystalline Cellulose, hydroxypropylcellulose, acesulfame potassium and carboxymethylstach sodium are pulverized respectively, cross 120 mesh sieves, obtain former, auxiliary material for subsequent use;
2) wet granular processed
Take Ro 15-8075 hydrate, starch, Microcrystalline Cellulose, acesulfame potassium and the hydroxypropylcellulose above-mentioned for subsequent use of recipe quantity, insert in high-speed mixing granulating machine, sealing is dry mixed 15 minutes at a high speed, then appropriate amount of ethanol wet mixing is added 5 minutes, after wet mixing, wet mixing cuts 1 minute, releases particle, obtains wet granular;
3) dry particle is made
The wet granular that upper step is obtained proceeds in ebullated dryer, and temperature controls to dry 17 minutes at 70 DEG C, and shut down, clear filter bag, blowing, obtains dry particle;
4) compressing tablet, packaging
Dry particle obtained by upper step is added pelletizing machine, start button, carries out whole grain; add the carboxymethylstach sodium of recipe quantity and appropriate Magnesium Stearate again; add three-dimensional mixer mixing with suction feeding, compressing tablet, packs and obtains 1000 hydrochloric acid cefetamet pivoxil dispersible tablets.
Embodiment 9,10
Preparation technology is with embodiment 1.
Present invention also offers following experimental example, to further illustrate product of the present invention.
Experimental example 1
This experimental example detects the related substance in the Ro 15-8075 hydrate crystal prepared by embodiment 1-4, this experiment is carried out according to Chinese Pharmacopoeia 2010 editions second annex VIII P residual solvent assay method, annex Ⅺ Ⅹ F medicine impurity analysis governing principle, and it the results are shown in Table 2:
Table 2
The detected result of related substance
Experimental example 2
It is moist that this experimental example has investigated drawing of Ro 15-8075 hydrate crystal provided by the invention, and this experiment is drawn moist test direction principle according to Chinese Pharmacopoeia 2010 editions second annex Ⅺ Ⅹ J medicine and carried out, and the results are shown in Table 3.
Table 3
| Sample 1 | Sample 2 | Sample 3 | Sample 4 | Sample 5 | Sample 6 | Sample 7 | |
| Draw wet percentage weight increase | 3.8％ | 3.6％ | 3.9％ | 4.2％ | 3.8％ | 13.5％ | 13.2％ |
Wherein, sample 1 is embodiment 1 product;
Sample 2 is embodiment 2 products;
Sample 3 is embodiment 3 products;
Sample 4 is embodiment 4 products;
Sample 5 is embodiment 5 products;
Sample 6 is the Ro 15-8075s prepared with reference to patent CN101550146A embodiment 1;
Sample 7 is commercially available Ro 15-8075 bulk drugs, originates from HARBIN PHARMACEUTICAL GROUP CO., LTD. General Pharm. Factory.
As seen from Table 2, compared with the Ro 15-8075 of prior art, Ro 15-8075 hydrate crystal of the present invention to draw wet percentage weight increase little, water absorbability is little.
Experimental example 3
This experimental example has investigated the mobility of Ro 15-8075 hydrate crystal provided by the invention.
This experimental example carrys out the mobility of assess sample by the slope of repose of working sample, concrete grammar is as follows: sample thief particle, flow into from fixing little funnel in circular watch-glass, know and obtain the highest cone, measure cone height H and radius R, calculate slope of repose α by tan α=H/R, the results are shown in Table 3, slope of repose is larger, and mobility is poorer.Refer to table 4.
Table 4
| Sample 1 | Sample 2 | Sample 3 | Sample 4 | Sample 5 | Sample 6 | Sample 7 | |
| H | 2.11cm | 2.18cm | 2.11cm | 2.03cm | 2.10 | 3.21cm | 3.11cm |
| R | 3cm | 3cm | 3cm | 3cm | 3cm | 3cm | 3cm |
| α | 35° | 36° | 35° | 34° | 35° | 47° | 46° |
Wherein, wherein, sample 1 is embodiment 1 product;
Sample 2 is embodiment 2 products;
Sample 3 is embodiment 3 products;
Sample 4 is embodiment 4 products;
Sample 5 is embodiment 5 products;
Sample 6 is the Ro 15-8075s prepared with reference to patent CN101550146A embodiment 1;
Sample 7 is commercially available Ro 15-8075 bulk drugs, originates from HARBIN PHARMACEUTICAL GROUP CO., LTD. General Pharm. Factory.
As seen from Table 4, compared with the Ro 15-8075 of prior art, Ro 15-8075 hydrate crystal of the present invention has excellent mobility, is conducive to the accuracy improving packing, and is easy to mix when mixing with other compositions.
Experimental example 4
This experimental example has investigated the relative bioavailability of the hydrochloric acid cefetamet pivoxil dispersible tablet prepared by Ro 15-8075 hydrate crystal of the present invention in human body and bioequivalence.
1 materials and methods
1.1 medicines and reagent
For test preparation: the hydrochloric acid cefetamet pivoxil dispersible tablet prepared by the embodiment of the present invention 6;
Reference preparation: the hydrochloric acid cefetamet pivoxil dispersible tablet obtained according to prescription and the preparation method of the embodiment of the present invention 6, difference is Ro 15-8075 used is commercially available bulk drug; Acetonitrile, methyl alcohol are chromatographically pure, and perchloric acid is analytical pure.
1.2 instrument
Japan Shimadzu LC-10A type high performance liquid chromatograph, LC-10AD type constant flow pump, SIL-10AD type automatic sampler, SPD-10A type UV-detector.
1.3 study subjects and test design
18 experimenters are healthy male, age 21-24 year, body weight 52-70kg, without habits of smoking and alcohol drinking, no abnormal through inquiry medical history, physical examination and laboratory examination before test, not taking in two weeks anyly may affect that this product absorbs, the medicine of metabolism.Tested period unifies light diet, does not use other drug, does not accept cigarette, wine and the beverage containing coffee.Experimenter signs Informed Consent Form before the test, tests and ratifies through Ethics Committee of Xiangye No. 2 Hospital of Central South University.
Adopt random self cross-reference test design of intersecting, experimenter is divided into two groups at random, fasting 12h before taking medicine, in 8:00 in morning two groups of difference oral hydrochloride cefetamet pivoxils for test preparation or reference preparation 500mg, unification warm water 200mL takes, before taking medicine and after taking medicine 0.15,0.175,1.10,1.15,2.10,2.15,3.10,3.15,4.10,6.10,8.10,10,12h extracting vein blood 4mL, the 2nd cycle got the blood time with the 1st cycle.Blood sample is put in the centrifuge tube containing heparin, centrifugal immediately, isolates blood plasma, puts in-70 DEG C of refrigerators and is saved to mensuration.
1.4 blood samples measure
1.4.1 chromatographic condition
Chromatographic column is Phenomenex C
18post (250mm × 46mm, 5 μm), column temperature is 40 DEG C, and moving phase is the high chloro acid solution (20:80) of acetonitrile-4mmol/L, and flow velocity is 0.8mL/min.Determined wavelength is 263nm.
1.4.2 sample preparation
The centrifugal 5min of jolting 0.5min, 10000r/min after blood plasma unfreezing, then gets 400 μ L blood plasma and inserts in 1.5mL centrifuge tube, add the perchloric acid solution 400 μ L of 6%, the centrifugal 10min of vortex mixing 1min, 10000r/min, gets supernatant liquor 100 μ L sample introduction 20 μ L and analyzes.
1.5 data processing
The blood concentration-time data of 18 experimenters are carried out relevant pharmacokinetic parameter and asks calculation, calculate lower area of blood concentration-time curve (AUC) with trapezoidal faces area method, the straight slope returned to eliminate the logarithm of phase time to concentration calculates transformation period (t
1/2), peak concentration (C
max) and peak time (t
max) be measured value.Single dose administration pharmacokinetic parameter AUC
0-12and C
max, after Logarithm conversion, adopt 3 analysis of variance that SPSS statistics program is carried out between medicine, during week, between individuality, then carry out Doubled haploid population and 90% credibility interval calculates.T
maxmeasured value is adopted to carry out rank test.
2 results
After 18 health volunteers take medicine in blood plasma hydrochloric acid cefetamet main pharmacokinetic parameter in table 5.
The pharmacokinetic parameter (x ± s, n=18) of table 518 health volunteer's single oral dose 500mg hydrochloric acid cefetamet pivoxil dispersible tablet
As can be seen from Table 5, when prescription is identical with preparation method, the highest Plasma Concentration of the hydrochloric acid cefetamet pivoxil dispersible tablet adopting Ro 15-8075 hydrate crystal of the present invention to obtain obviously is greater than the highest Plasma Concentration of the hydrochloric acid cefetamet pivoxil dispersible tablet adopting commercially available Ro 15-8075 bulk drug to obtain, and the Ro 15-8075 of bioavailability higher than prior art of Ro 15-8075 hydrate crystal of the present invention is described; T of the present invention
maxalso there is notable difference with prior art, the Ro 15-8075 of the absorption rate of Ro 15-8075 hydrate crystal of the present invention in human body faster than prior art is described.
The hydrochloric acid cefetamet pivoxil dispersible tablet obtained to other embodiment of the present invention has also carried out above-mentioned test, and its result obtained is similar.
Claims (10)
1. a Ro 15-8075 hydrate, is characterized in that, each Ro 15-8075 hydrate contains 1 crystal water, and its X-ray powder diffractogram using the measurement of Cu-K alpha-ray to obtain as shown in Figure 1.
2. Ro 15-8075 hydrate according to claim 1, is characterized in that, is analyzed, weightless 3.1-3.4wt% within the scope of 80-150 DEG C by heat difference-thermogravimetric TG-DTA.
3. a preparation method for the Ro 15-8075 hydrate described in claim 1 or 2, is characterized in that, described method comprises the steps:
(1) by Ro 15-8075 dissolving crude product in the ethanol of 5-10 DEG C, the volume of described ethanol be the 3-8 of Ro 15-8075 crude product quality doubly;
(2) add the activated carbon decolorizing 20-30 minute of Ro 15-8075 crude product quality 0.02-0.1, filter, a small amount of dissolve with ethanol liquid washing, obtains Ro 15-8075 ethanolic soln;
(3) Ro 15-8075 ethanolic soln is warmed up to 20-30 DEG C, in Ro 15-8075 ethanolic soln, the sodium chloride saturated solution of-15 DEG C-5 DEG C is dripped under the condition stirred, the volume of sodium chloride saturated solution is 5-8 times of Ro 15-8075 volumes of aqueous ethanol, at the uniform velocity dropwise in 0.5h, described stir speed (S.S.) is 20-25rmp;
(4) be cooled to-15 DEG C-5 DEG C after being added dropwise to complete to continue to stir 0.5-2h under the stir speed (S.S.) of 10-15rmp, leave standstill 2-4h and separate out light yellow crystal, filter;
(5) wash final vacuum drying successively by distilled water, ethyl acetate and obtain Ro 15-8075 hydrate crystal.
4. the preparation method of Ro 15-8075 hydrate according to claim 3, it is characterized in that, the sodium chloride saturated solution volume dripped to Ro 15-8075 ethanolic soln under the condition stirred in described step (3) is 7 times of Ro 15-8075 volumes of aqueous ethanol; Described stir speed (S.S.) when adding sodium chloride saturated solution is 23rmp.
5. the preparation method of Ro 15-8075 hydrate according to claim 3, is characterized in that, described in described step (3), the temperature of sodium chloride saturated solution is-10 DEG C.
6. the preparation method of Ro 15-8075 hydrate according to claim 3, is characterized in that, is cooled to-10 DEG C and continues to stir 1h under the stir speed (S.S.) of 12rmp in described step (4) after being added dropwise to complete.
7. the pharmaceutical composition containing Ro 15-8075 hydrate according to claim 1, described pharmaceutical composition is dispersible tablet, tablet, capsule, lyophilized injectable powder or sterile powder injection.
8. pharmaceutical composition according to claim 7, is characterized in that: described dispersible tablet component comprises:
9. the preparation method of pharmaceutical composition described in a claim 8, it is characterized in that, described preparation method comprises: by raw material Ro 15-8075 hydrate and supplementary product starch, Microcrystalline Cellulose, hydroxypropylcellulose, acesulfame potassium, Magnesium Stearate and carboxymethylstach sodium are pulverized respectively, sieve, wet granular processed, make dry particle, compressing tablet and packaging, described wet granular processed be take recipe quantity Ro 15-8075 hydrate, starch, Microcrystalline Cellulose, acesulfame potassium and hydroxypropylcellulose, insert in high-speed mixing granulating machine, sealing is dry mixed 5-15 minute at a high speed, then appropriate amount of ethanol wet mixing 1-5 minute is added, after wet mixing, wet mixing cutting 1-3 minute, release particle, obtain wet granular.
10. preparation method according to claim 9, is characterized in that described method comprises the steps:
1) get the raw materials ready
Ro 15-8075 hydrate is pulverized, crosses 100 mesh sieves, starch, Microcrystalline Cellulose, hydroxypropylcellulose, acesulfame potassium and carboxymethylstach sodium are pulverized respectively, cross 120 mesh sieves, obtain former, auxiliary material for subsequent use;
2) wet granular processed
Take Ro 15-8075 hydrate, starch, Microcrystalline Cellulose, acesulfame potassium and the hydroxypropylcellulose above-mentioned for subsequent use of recipe quantity, insert in high-speed mixing granulating machine, sealing is dry mixed 5-15 minute at a high speed, then appropriate amount of ethanol wet mixing 1-3 minute is added, after wet mixing, wet mixing cuts 2 minutes, releases particle, obtains wet granular;
3) dry particle is made
The wet granular that upper step is obtained proceeds in ebullated dryer, and temperature controls to dry 17-20 minute at 60-70 DEG C, and shut down, clear filter bag, blowing, obtains dry particle;
4) compressing tablet, packaging
Dry particle obtained by upper step is added pelletizing machine, start button, carries out whole grain, then add the carboxymethylstach sodium of recipe quantity and appropriate Magnesium Stearate, add three-dimensional mixer mixing with suction feeding, compressing tablet, packs and obtains hydrochloric acid cefetamet pivoxil dispersible tablet.
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