CN105106136A - Cefetamet pivoxil hydrochloride dry suspension for treating diseases infected by sensitive bacteria - Google Patents
Cefetamet pivoxil hydrochloride dry suspension for treating diseases infected by sensitive bacteria Download PDFInfo
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- CN105106136A CN105106136A CN201510622649.1A CN201510622649A CN105106136A CN 105106136 A CN105106136 A CN 105106136A CN 201510622649 A CN201510622649 A CN 201510622649A CN 105106136 A CN105106136 A CN 105106136A
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- pivoxil hydrochloride
- cefetamet pivoxil
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Abstract
The invention relates to cefetamet pivoxil hydrochloride dry suspension for treating diseases infected by sensitive bacteria and belongs to the technical field of medicine. The dry suspension comprises cefetamet pivoxil hydrochloride, sorbitol, propyl gallate, xanthan gum, hydroxypropyl methylcellulose and apple essence. The cefetamet pivoxil hydrochloride is a new crystal compound, the X-ray powder diffraction diagram, obtained by using Cu-K alpha rays for measuring, of the cefetamet pivoxil hydrochloride is shown in figure 1, and the cefetamet pivoxil hydrochloride is different from cefetamet pivoxil hydrochloride reported in the prior art. Experiments show that the dry suspension prepared by the cefetamet pivoxil hydrochloride is low in high-molecular polymer content and good in stability, and the high-molecular polymer content increasing, along with storage time, of the dry suspension is low; meanwhile, the cefetamet pivoxil hydrochloride has evident antibacterial activity on pneumococcus and hemophilus influenzae and is high in antibacterial activity on enterococcus and staphylococcus.
Description
Technical field
The invention belongs to medical art, relate to a kind of medicine Cefetamet Pivoxil Hydrochloride dry suspension for the treatment of sensitive organism infectious disease.
Background technology
Cefetamet Pivoxil Hydrochloride is third generation broad-spectrum cephalosporin class antibiotic.The cefetamet being hydrolyzed to rapidly antibacterial activity after oral in vivo plays bactericidal action.Cefetamet Pivoxil Hydrochloride is to gram positive bacterias such as Streptococcus (except streptococcus faecalis), streptococcus pneumoniae, and have very strong antibacterial activity to escherichia coli, Klebsiella, hemophilus influenza, Diplococcus gonorrhoeae, especially obvious to the antibacterial activity of the low Serratia of cephalosporin sensitivity, indole-positive Bacillus proteus, Enterobacter and citric acid Pseudomonas.Bacteriogenic beta-lactamase is stablized.Cefetamet Pivoxil Hydrochloride is invalid to Pseudomonas, mycoplasma, chlamydia, enterococcus and drug resistance staphylococcus.
But because its basic structure is the same with antibiotic in the many semisynthetic beta-lactam gone on the market, Cefetamet Pivoxil Hydrochloride also can form high molecular polymer, also can cause type Ⅰ hypersensitivity reaction in Clinical practice, very harmful to patient.Prior art improves its stability from aspects such as raising content, reduction impurity mostly.
Research proves, the anaphylactogen causing beta-lactam antibiotic type Ⅰ hypersensitivity reaction is relevant with the high molecular polymer content wherein existed.Reduce the high molecular polymer content existed in Cefetamet Pivoxil Hydrochloride crude drug, improve stability, make it can ensure the lower effective way being the reaction of reduction anaphylactic shock and occurring of the content of its high molecular polymer existed in long term storage.Therefore, be necessary to provide the cefetamet pivoxil hydrochloride compound that a kind of high molecular polymer content is low, performance is more superior.
Summary of the invention
Goal of the invention of the present invention is to provide a kind of medicine Cefetamet Pivoxil Hydrochloride dry suspension for the treatment of sensitive organism infectious disease.
In order to complete object of the present invention, the technical scheme of employing is:
A kind of medicine Cefetamet Pivoxil Hydrochloride dry suspension for the treatment of sensitive organism infectious disease of the present invention, described dry suspension is made up of Cefetamet Pivoxil Hydrochloride, sorbitol, propyl gallate, xanthan gum, hypromellose, apple essence; Described Cefetamet Pivoxil Hydrochloride is crystal, and the X-ray powder diffraction pattern that the measurement of use Cu-K alpha ray obtains as shown in Figure 1.
First optimal technical scheme of the present invention is: with parts by weight, and described dry suspension is made up of the Cefetamet Pivoxil Hydrochloride of 1.25 weight portions, the sorbitol of 1.8-2.0 weight portion, the propyl gallate of 0.08-0.12 weight portion, the xanthan gum of 0.4-0.6 weight portion, the hypromellose of 0.4-0.6 weight portion, the apple essence of 0.04-0.06 weight portion.
Second optimal technical scheme of the present invention is: with parts by weight, and described dry suspension is made up of the Cefetamet Pivoxil Hydrochloride of 1.25 weight portions, the sorbitol of 1.9 weight portions, the propyl gallate of 0.1 weight portion, the xanthan gum of 0.5 weight portion, the hypromellose of 0.5 weight portion, the apple essence of 0.05 weight portion.
3rd optimal technical scheme of the present invention is: the preparation method of described dry suspension comprises the following steps:
(1) supplementary material process: sieve Cefetamet Pivoxil Hydrochloride, sorbitol, propyl gallate, xanthan gum, hypromellose, apple essence 80 orders;
(2) weigh: weigh according to prescription;
(3) mix: Cefetamet Pivoxil Hydrochloride, sorbitol, propyl gallate, xanthan gum, hypromellose, apple essence are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 50 minutes are set;
(4) pack: by mixed granule particles packing machine subpackage.
4th optimal technical scheme of the present invention is: the preparation method of described Cefetamet Pivoxil Hydrochloride crystal comprises the following steps:
(1) propanol, N, N-dimethyl formamide are mixed with mixed solvent, the volume ratio of propanol, N, N-dimethyl formamide is 1:1;
(2) get Cefetamet Pivoxil Hydrochloride crude drug, the volume being dissolved in step (1) is in the mixed solvent of the propanol of 6 times of Cefetamet Pivoxil Hydrochloride weight, N, N-dimethyl formamide, is warming up to 40 DEG C, is stirred to whole dissolving, obtain Cefetamet Pivoxil Hydrochloride solution;
(3) under the condition of low whipping speed 340r/min, the Cefetamet Pivoxil Hydrochloride solution of step (2) being joined volume is in the isobutanol of 5 times of Cefetamet Pivoxil Hydrochloride weight, mixing, forms suspension, is cooled to-10 DEG C with the speed of 10 DEG C/min;
(4) carry out sucking filtration, washing leaching cake, then by filter cake vacuum drying, obtain crystalline powder, be described cefetamet pivoxil hydrochloride compound.
The polymorphism of solid chemical is the natural phenomena that a kind of general material exists, this phenomenon refers to that a kind of solid chemical can exist 2 kinds or two or more crystal form state, be also called the polymorphic state of material, the polymorphic state of material is also referred to as " allomorphism " phenomenon.Although its chemical nature of allomorphous solid matter is identical, its physicochemical property may be different.For " allomorphism medicine " that physicochemical property is different, also can show the curative effect of different disease preventing and treating clinically, directly affect application and the clinical effectiveness of medicine.
Because the basic structure of Cefetamet Pivoxil Hydrochloride is the same with antibiotic in the many semisynthetic beta-lactam gone on the market, also type Ⅰ hypersensitivity reaction can be caused in Clinical practice, very harmful to patient.Research proves, the anaphylactogen causing beta-lactam antibiotic type Ⅰ hypersensitivity reaction is relevant with the high molecular polymer content wherein existed.But prior art improves its stability from aspects such as raising content, reduction impurity mostly, does not propose any improvement to high molecular polymer content wherein.
The present inventor obtains a kind of Cefetamet Pivoxil Hydrochloride novel crystal forms structure being different from prior art through a large amount of tests, and by test, show that this novel crystal forms structure not only has lower high molecular polymer content, and increase seldom along with its high molecular polymer content of prolongation of period of storage.
Simultaneously, the present inventor passes through In vitro Bactericidal Experiments, find that cefetamet pivoxil hydrochloride compound provided by the present invention has more significant antibacterial activity to streptococcus pneumoniae, hemophilus influenza, and without the enterococcus of antibacterial activity, staphylococcus, also there is stronger antibacterial activity to the Cefetamet Pivoxil Hydrochloride of prior art report.
Compared with prior art, tool of the present invention has the following advantages:
(1) cefetamet pivoxil hydrochloride compound provided by the present invention is crystal compound, it is a kind of cefetamet pivoxil hydrochloride compound being different from prior art report, find through test, this Cefetamet Pivoxil Hydrochloride crystal compound is compared compared with the cefetamet pivoxil hydrochloride compound of prior art, not only there is lower high molecular polymer content, and increase seldom along with its high molecular polymer content of prolongation of period of storage, obtained dry suspension has good stability, the advantages such as impurity content is low;
(2) cefetamet pivoxil hydrochloride compound provided by the present invention has more significant antibacterial activity to streptococcus pneumoniae, hemophilus influenza, and also has stronger antibacterial activity to the Cefetamet Pivoxil Hydrochloride of prior art report without the enterococcus of antibacterial activity, staphylococcus.
Accompanying drawing explanation
Fig. 1 is the X-ray powder diffraction of Cefetamet Pivoxil Hydrochloride crystal prepared by the embodiment of the present invention 1.
Detailed description of the invention
Below by specific embodiment, summary of the invention of the present invention is described in further detail, but does not therefore limit content of the present invention.
embodiment 1:the preparation of Cefetamet Pivoxil Hydrochloride crystal
(1) propanol, N, N-dimethyl formamide are mixed with mixed solvent, the volume ratio of propanol, N, N-dimethyl formamide is 1:1;
(2) get Cefetamet Pivoxil Hydrochloride crude drug, the volume being dissolved in step (1) is in the mixed solvent of the propanol of 6 times of Cefetamet Pivoxil Hydrochloride weight, N, N-dimethyl formamide, is warming up to 40 DEG C, is stirred to whole dissolving, obtain Cefetamet Pivoxil Hydrochloride solution;
(3) under the condition of low whipping speed 340r/min, the Cefetamet Pivoxil Hydrochloride solution of step (2) being joined volume is in the isobutanol of 5 times of Cefetamet Pivoxil Hydrochloride weight, mixing, forms suspension, is cooled to-10 DEG C with the speed of 10 DEG C/min;
(4) carry out sucking filtration, washing leaching cake, then by filter cake vacuum drying, obtain crystalline powder, be described cefetamet pivoxil hydrochloride compound.
The X-ray powder diffraction pattern that the Cefetamet Pivoxil Hydrochloride crystal prepared uses the measurement of Cu-K alpha ray to obtain as shown in Figure 1.
embodiment 2:the preparation of Cefetamet Pivoxil Hydrochloride dry suspension
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: Cefetamet Pivoxil Hydrochloride, sorbitol, propyl gallate, xanthan gum, hypromellose, apple essence are crossed 80 mesh sieves;
(2) weigh: weigh according to prescription;
(3) mix: Cefetamet Pivoxil Hydrochloride, sorbitol, propyl gallate, xanthan gum, hypromellose, apple essence are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 50 minutes are set;
(4) pack: by mixed granule particles packing machine subpackage.
embodiment 3:the preparation of Cefetamet Pivoxil Hydrochloride dry suspension
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: Cefetamet Pivoxil Hydrochloride, sorbitol, propyl gallate, xanthan gum, hypromellose, apple essence are crossed 80 mesh sieves;
(2) weigh: weigh according to prescription;
(3) mix: Cefetamet Pivoxil Hydrochloride, sorbitol, propyl gallate, xanthan gum, hypromellose, apple essence are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 50 minutes are set;
(4) pack: by mixed granule particles packing machine subpackage.
embodiment 4:the preparation of Cefetamet Pivoxil Hydrochloride dry suspension
Prescription: with parts by weight
Preparation method:
(1) supplementary material process: sieve Cefetamet Pivoxil Hydrochloride, sorbitol, propyl gallate, xanthan gum, hypromellose, apple essence 80 orders;
(2) weigh: weigh according to prescription;
(3) mix: Cefetamet Pivoxil Hydrochloride, sorbitol, propyl gallate, xanthan gum, hypromellose, apple essence are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 50 minutes are set;
(4) pack: by mixed granule particles packing machine subpackage.
test example 1:high molecular polymer comparision contents is tested
(1) accelerated test
By following each sample temperature 40 DEG C, place 6 months under relative humidity 75% condition, respectively at the 1st, 2,3, sampling in June, according to " HPLC method measures related substance in Cefetamet Pivoxil Hydrochloride and polymer ", [king builds, and wangdan is red, related substance in flood sharp Ya .HPLC method mensuration Cefetamet Pivoxil Hydrochloride and polymer (J), pharmaceutical analysis magazine, 2015, (2)] measure the content of polymer in each sample, and with 0 day results contrast, result of the test is shown in Table 1.
Trial target: the Cefetamet Pivoxil Hydrochloride crystal that the embodiment of the present invention 1 is obtained;
Reference substance: commercially available Cefetamet Pivoxil Hydrochloride raw material, is provided by Zhuhai United Laboratories Ltd.
The content of high molecular polymer in table 1, accelerated test each sample
(2) long term test
Each sample at room temperature, respectively at the 3rd, sampling in 6,9,12 months, according to " related substance in HPLC method mensuration Cefetamet Pivoxil Hydrochloride and polymer ", [king builds, wangdan is red, the related substance in big vast sharp Ya .HPLC method mensuration Cefetamet Pivoxil Hydrochloride and polymer (J), pharmaceutical analysis magazine, 2015, (2)] measure the content of polymer in each sample, and with 0 day results contrast, result of the test is shown in Table 2.
The assay result of polymer in table 2, long term test each sample
Find out from above-mentioned result of the test, compared with commercially available prod, the polymer content of cefetamet pivoxil hydrochloride compound crystal of the present invention is lower, good stability, and the content of polymer is along with the prolongation of period of storage, and it increases seldom.
test example 2:antibacterial activity is tested
1, materials and methods
1.1 antibacterial
Certain clinical laboratory of institute is collected in the blood of clinical patient, expectorant, secretions, Urine specimens and isolates 92 strain clinical bacterias, through the qualification of VITEK-AMS microbiological analysis instrument, has 22 strain streptococcus pneumoniae, 25 influenzae strain bacillus, 25 strain enterococcus, 20 strain staphylococcuses.Quality-control strains is provided by Ministry of Public Health Clinical Laboratory center.
1.2 culture medium
Isolation medium is 5% blood plate, and drug test MH agar is purchased from Oxoid company.
1.3 antibacterials
Trial target: the Cefetamet Pivoxil Hydrochloride crystal that the embodiment of the present invention 1 is obtained;
Reference substance: commercially available Cefetamet Pivoxil Hydrochloride raw material, is provided by Zhuhai United Laboratories Ltd.
1.4 criterion
Standard bacteria and tested bacterium drug sensitivity tests judge by NCCLS standard in 2000.
1.5 statistical method
Calculate Sensitivity rate, medium sensitivity rate, the resistant rate of various antibacterials to different bacterium, and use χ
2check the Sensitivity rate of more each Cefetamet Pivoxil Hydrochloride.
2, result
Table 3, antibacterials are to the pneumococcal antibacterial activity in vitro of 22 strain
Table 4, antibacterials are to the antibacterial activity in vitro of 25 influenzae strain bacillus
Table 5, antibacterials are to the enterococcal antibacterial activity in vitro of 25 strain
Table 6, antibacterials are to the staphylococcic antibacterial activity in vitro of 20 strain
As can be seen from above-mentioned result of the test, the cefetamet pivoxil hydrochloride compound prepared by the present invention has more significant antibacterial activity to streptococcus pneumoniae, hemophilus influenza; Commercially available Cefetamet Pivoxil Hydrochloride is to enterococcus, staphylococcus without antibacterial activity, and Cefetamet Pivoxil Hydrochloride provided by the invention has stronger antibacterial activity to enterococcus, staphylococcus.
Claims (5)
1. treat a medicine Cefetamet Pivoxil Hydrochloride dry suspension for sensitive organism infectious disease, it is characterized in that: described dry suspension is made up of Cefetamet Pivoxil Hydrochloride, sorbitol, propyl gallate, xanthan gum, hypromellose, apple essence; Described Cefetamet Pivoxil Hydrochloride 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. the medicine Cefetamet Pivoxil Hydrochloride dry suspension for the treatment of sensitive organism infectious disease according to claim 1, it is characterized in that: with parts by weight, described dry suspension is made up of the Cefetamet Pivoxil Hydrochloride of 1.25 weight portions, the sorbitol of 1.8-2.0 weight portion, the propyl gallate of 0.08-0.12 weight portion, the xanthan gum of 0.4-0.6 weight portion, the hypromellose of 0.4-0.6 weight portion, the apple essence of 0.04-0.06 weight portion.
3. the medicine Cefetamet Pivoxil Hydrochloride dry suspension for the treatment of sensitive organism infectious disease according to claim 2, it is characterized in that: with parts by weight, described dry suspension is made up of the Cefetamet Pivoxil Hydrochloride of 1.25 weight portions, the sorbitol of 1.9 weight portions, the propyl gallate of 0.1 weight portion, the xanthan gum of 0.5 weight portion, the hypromellose of 0.5 weight portion, the apple essence of 0.05 weight portion.
4. prepare a method for the medicine Cefetamet Pivoxil Hydrochloride dry suspension according to the arbitrary described treatment sensitive organism infectious disease of claim 1-3, it is characterized in that comprising the following steps:
(1) supplementary material process: Cefetamet Pivoxil Hydrochloride, sorbitol, propyl gallate, xanthan gum, hypromellose, apple essence are crossed 80 mesh sieves;
(2) weigh: weigh according to prescription;
(3) mix: Cefetamet Pivoxil Hydrochloride, sorbitol, propyl gallate, xanthan gum, hypromellose, apple essence are dropped into three-dimensional motion mixer, premixing speed 15 revs/min, incorporation time 50 minutes are set;
(4) pack: by mixed granule particles packing machine subpackage.
5. the medicine Cefetamet Pivoxil Hydrochloride dry suspension for the treatment of sensitive organism infectious disease according to claim 1, it is characterized in that, the preparation method of described Cefetamet Pivoxil Hydrochloride crystal comprises the following steps:
(1) propanol, N, N-dimethyl formamide are mixed with mixed solvent, the volume ratio of propanol, N, N-dimethyl formamide is 1:1;
(2) get Cefetamet Pivoxil Hydrochloride crude drug, the volume being dissolved in step (1) is in the mixed solvent of the propanol of 6 times of Cefetamet Pivoxil Hydrochloride weight, N, N-dimethyl formamide, is warming up to 40 DEG C, is stirred to whole dissolving, obtain Cefetamet Pivoxil Hydrochloride solution;
(3) under the condition of low whipping speed 340r/min, the Cefetamet Pivoxil Hydrochloride solution of step (2) being joined volume is in the isobutanol of 5 times of Cefetamet Pivoxil Hydrochloride weight, mixing, forms suspension, is cooled to-10 DEG C with the speed of 10 DEG C/min;
(4) carry out sucking filtration, washing leaching cake, then by filter cake vacuum drying, obtain crystalline powder, be described cefetamet pivoxil hydrochloride compound.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510622649.1A CN105106136A (en) | 2015-09-28 | 2015-09-28 | Cefetamet pivoxil hydrochloride dry suspension for treating diseases infected by sensitive bacteria |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510622649.1A CN105106136A (en) | 2015-09-28 | 2015-09-28 | Cefetamet pivoxil hydrochloride dry suspension for treating diseases infected by sensitive bacteria |
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Application publication date: 20151202 |