CN104069072A - Tebipenam pivoxil composite granule - Google Patents
Tebipenam pivoxil composite granule Download PDFInfo
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- CN104069072A CN104069072A CN201410319910.6A CN201410319910A CN104069072A CN 104069072 A CN104069072 A CN 104069072A CN 201410319910 A CN201410319910 A CN 201410319910A CN 104069072 A CN104069072 A CN 104069072A
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Abstract
The invention relates to the field of chemical synthesis, and discloses a tebipenam pivoxil composite granule. The granule is prepared from the following medicinal components in parts by weight: 40 parts of tebipenam pivoxil, 198.7-219.7 parts of cane sugar, 5-10 parts of hydroxyethyl methylcellulose, 3-6 parts of croscarmellose sodium, 2-5 parts of phosphatidyl ethanolamine, 10-20 parts of inositol, 0.1-0.2 part of ascorbyl palmitate and 0.2-0.5 part of aspartame. The novel granule is prepared by adopting a plurality of proper medicinal components, including tebipenam pivoxil; performances of the prepared granule in acceleration tests, long-term tests and antibacterial effect tests are higher than those of existing patent products, and the granule disclosed by the invention has high quality and can be widely applied to clinical treatment.
Description
Technical field
The present invention relates to field of medicine preparations, be specifically related to a kind of L-084 composition granule.
Background technology
L-084, chemistry (+)-(4R by name, 5S, 6S)-6-[(1R)-hydroxyethyl]-4-methyl-7-oxo-3[[1-(2-thiazoline-2-yl)-3-azetidinyl] sulfur]-1-azabicyclo [3.2.0] hept-2-ene"-2-formic acid (2,2-dimethyl-1-oxopropoxy) methyl ester, belong to carbapenem antibiotic, structural formula is as follows:
L-084 is researched and developed by Pfizer Inc. the earliest, and L-084 granula subtilis is developed by Japanese Mingzhi company, obtains Japan's approval in February, 2009, and in April, 2009 listing, but does not domesticly have listing producer and a relevant report.L-084 granula subtilis is for the treatment of pediatric patient otorhinolaryngology and upper respiratory tract infection, and it is first treatment of infecting for streptococcus pneumoniae drug resistance strain, comprises the penem-like pharmaceutical of persistence otitis media and bacterial pneumonia.L-084 has a broad antifungal spectrum, to the bacterial strain of most of clinical separation, tebipenem all shows than penicillin series and the stronger antibiotic property of cephalo series, and compared with the carbapenem antibiotic of other injections, tebipenem also shows same degree or stronger antibacterial effect.Particularly for causing in recent years that the penicillin resistance pneumococcus of childhood infection main cause, resistance to erythromycin streptococcus pneumoniae and hemophilus influenza showed extremely strong antibacterial effect.
Due to L-084 less stable, under hot and humid condition, related substance increase is very large, so it is particularly important that the selection of ingredient and consumption become, ingredient chooses at random and likely makes L-084 granule dissolution variation, related substance increase, content minimizing, polymer increase, moisture rising etc., even cannot granulating.Application number is that 201310493646.3 Chinese patent discloses a kind of L-084 composition granule, it is made taking L-084, pregelatinized Starch, mannitol, sucrose and stevioside as component, although long term test and accelerated test result that this patent is recorded show that this granule has certain quality, but aspect L-084 granule quality, still need further to be improved.Simultaneously, the selection of ingredient also affects the fungistatic effect of L-084, how by selecting appropriate ingredient to make a kind of stability and fungistatic effect is medical research staff's research emphasis higher than the L-084 granule of existing product.
Summary of the invention
In view of this, the object of the present invention is to provide a kind of L-084 composition granule, make described granule there is higher stability at extreme environment;
Another object of the present invention is to provide a kind of L-084 composition granule, and the fungistatic effect of described granule is improved.
For achieving the above object, the invention provides following technical scheme:
A kind of L-084 composition granule, in weight portion, formed by the L-084 of ingredient 40 weight portions, sucrose, 5-10 weight portion hydroxyethylmethyl-cellulose, 3-6 weight portion cross-linking sodium carboxymethyl cellulose, 2-5 weight portion PHOSPHATIDYL ETHANOLAMINE, 10-20 weight portion inositol, 0.1-0.2 weight portion sodium ascorbate cetylate and the 0.2-0.5 weight portion aspartame of 198.7-219.7 weight portion.
The present patent application people furthers investigate physicochemical property, stability feature and the granule formulation characteristic of L-084, selects the collaborative L-084 of suitable ingredient to make novel particle agent according to these features.
Wherein, as preferably, granule of the present invention, in weight portion, is made up of the L-084 of 40 weight portions, sucrose, 7.5 weight portion hydroxyethylmethyl-celluloses, 4.5 weight portion cross-linking sodium carboxymethyl celluloses, 3.5 weight portion PHOSPHATIDYL ETHANOLAMINE, 15 weight portion inositols, 0.15 weight portion sodium ascorbate cetylate and the 0.35 weight portion aspartame of 209 weight portions.
As preferably, granule of the present invention makes by dry granulation, and further preferably, described dry granulation is specially:
Pulverize respectively ingredient L-084, sucrose, hydroxyethylmethyl-cellulose, cross-linking sodium carboxymethyl cellulose, PHOSPHATIDYL ETHANOLAMINE, inositol, sodium ascorbate cetylate and aspartame; mix homogeneously is sent in dry granulating machine and is granulated; then screening, obtains L-084 granule.
As preferably, the ambient humidity of described dry granulation is below 60%.
As preferably, the powder particle diameter of described each ingredient is 80 orders.
As preferably, described dry granulating machine adopts 16 order mesh screens.
As preferably, described screening be with shaking screen sieve out between 16 orders and 60 orders tiny evenly, without the granule of bulk.
The accelerated test of granule of the present invention and long-term test results demonstration, the patent that is all 201310493646.3 than application number on the total impurities content in same stage is less, has significant difference.Meanwhile, in the detection of antibacterial activity, the antibacterial effect of granule of the present invention is improved, its MIC
50and MIC
90the data that (suppressing the minimum inhibitory concentration of 50% and 90% bacterial strain) all recorded lower than 201310493646.3 patents.
From above technical scheme, granule of the present invention adopts the multiple suitable drugs composition including L-084 to prepare a kind of new granule, prepared granule all shows the effect higher than existing patented product in accelerated test, long term test and fungistatic effect test, there is very high quality, can be widely used in clinical treatment.
Detailed description of the invention
The invention discloses a kind of L-084 composition granule, those skilled in the art can use for reference content herein, suitably improve technological parameter and realize.Special needs to be pointed out is, all similar replacements and change apparent to those skilled in the artly, they are all deemed to be included in the present invention.Product of the present invention is described by preferred embodiment, related personnel obviously can, not departing from content of the present invention, spirit and scope compound as herein described and preparation method is changed or suitably change and combination, realize and apply the technology of the present invention.
Below in conjunction with embodiment, further set forth the present invention.
Embodiment 1: prepare L-084 composition granule of the present invention
L-084, the sucrose of 209 weight portions, 7.5 weight portion hydroxyethylmethyl-celluloses, 4.5 weight portion cross-linking sodium carboxymethyl celluloses, 3.5 weight portion PHOSPHATIDYL ETHANOLAMINE, 15 weight portion inositols, 0.15 weight portion sodium ascorbate cetylate, the 0.35 weight portion A Sipa material of pulverizing respectively ingredient 40 weight portions, mix homogeneously is sent in dry granulating machine and is granulated;
Dry granulation processing step:
Be under the environment below 60% at relative humidity; above-mentioned supplementary material was pulverized to 80 mesh sieves; by supplementary material mix homogeneously in SYH-15 three-dimensional mixer; then put granulation (being furnished with 16 order mesh screens) in GL-5 dry granulating machine; with shaking screen sieve out between 16 orders and 60 orders tiny evenly, without the granule of bulk; then carry out intermediate detection, particle detection content and moisture, be sub-packed in aluminum-plastic composite membrane bag sealing, packaging, Quan Jian, storage by standard compliant by specification.
Embodiment 2: prepare L-084 composition granule of the present invention
L-084, the sucrose of 219.7 weight portions, 5 weight portion hydroxyethylmethyl-celluloses, 3 weight portion cross-linking sodium carboxymethyl celluloses, 2 weight portion PHOSPHATIDYL ETHANOLAMINE, 10 weight portion inositols, 0.1 weight portion sodium ascorbate cetylate, the 0.2 weight portion aspartame material of pulverizing respectively ingredient 40 weight portions, mix homogeneously is sent in dry granulating machine and is granulated;
Dry granulation processing step:
Be under the environment below 60% at relative humidity; above-mentioned supplementary material was pulverized to 80 mesh sieves; by supplementary material mix homogeneously in SYH-15 three-dimensional mixer; then put in GL-5 dry granulating machine and to granulate (being furnished with 16 order mesh screens), with shaking screen sieve out between 16 orders and 60 orders tiny evenly, without the granule of bulk.Then carry out intermediate detection, particle detection content and moisture, be sub-packed in aluminum-plastic composite membrane bag sealing, packaging, Quan Jian, storage by standard compliant by specification.
Embodiment 3: prepare L-084 composition granule of the present invention
L-084, the sucrose of 198.7 weight portions, 10 weight portion hydroxyethylmethyl-celluloses, 6 weight portion cross-linking sodium carboxymethyl celluloses, 5 weight portion PHOSPHATIDYL ETHANOLAMINE, 20 weight portion inositols, 0.2 weight portion sodium ascorbate cetylate, the 0.5 weight portion aspartame material of pulverizing respectively ingredient 40 weight portions, mix homogeneously is sent in dry granulating machine and is granulated;
Dry granulation processing step:
Be under the environment below 60% at relative humidity; above-mentioned supplementary material was pulverized to 80 mesh sieves; by supplementary material mix homogeneously in SYH-15 three-dimensional mixer; then put granulation (being furnished with 16 order mesh screens) in GL-5 dry granulating machine; with shaking screen sieve out between 16 orders and 60 orders tiny evenly, without the granule of bulk; then carry out intermediate detection, particle detection content and moisture, be sub-packed in aluminum-plastic composite membrane bag sealing, packaging, Quan Jian, storage by standard compliant by specification.
Embodiment 4: accelerated test
L-084 composition granule prepared by the embodiment of the present invention 1 is known the relevant regulations of principle according to Chinese Pharmacopoeia version medicine stability test in 2005, under being 40 DEG C ± 2 DEG C, the condition of relative humidity 75% ± 5%, temperature carries out accelerated test, time is 6 months, duration of test is respectively at sampling once the 1st, 2,3,6 the end of month, measure by stability high spot reviews project, the results are shown in Table 1.
Table 1 accelerated test result
The testing result of table in reference, and the Data Comparison recorded of application number patent working example 4 tables 5 that are 201310493646.3, can obviously find out, aspect impurity content, the present invention has reduced by 0.15% left and right, has further improved the stability of product.
Embodiment 5: long term test
L-084 composition granule prepared by the embodiment of the present invention 1 is known the relevant regulations of principle according to Chinese Pharmacopoeia version medicine stability test in 2005, under being 25 DEG C ± 2 DEG C, the condition of relative humidity 60% ± 10%, temperature carries out accelerated test, time is 36 months, duration of test is respectively at sampling once the 0th, 3,6,9,12,18,24,36 the end of month, measure by stability high spot reviews project, the results are shown in Table 2.
Table 2 long-term test results
The testing result of table in reference, and the Data Comparison recorded of application number patent working example 4 tables 6 that are 201310493646.3, can obviously find out, aspect impurity content, the present invention has reduced by 0.15% left and right, has further improved the stability of product.
Embodiment 6: fungistatic effect test
Adopt agar dilution to measure the minimum inhibitory concentration of the embodiment of the present invention 1 L-084 composition granule, with the inoculation of multiple spot dibbler, each point is approximately containing 10
4cFU, cultivates 24h, the results are shown in Table 3 for 37 DEG C.
The test of table 3 fungistatic effect
As seen from the above table, L-084 composition granule of the present invention is owing to selecting suitable excipients, can bring into play to greatest extent the fungistatic effect of L-084, contrast granule (the patent working example 3 that data are 201310493646.3 with reference to application number is recorded) is apparently higher than MIC of the present invention
50and MIC
90, fungistatic effect is not as granule of the present invention.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the premise without departing from the principles of the invention; can also make some improvements and modifications, these improvements and modifications also should be considered as protection scope of the present invention.
Claims (8)
1. a L-084 composition granule, it is characterized in that, in weight portion, formed by the L-084 of ingredient 40 weight portions, sucrose, 5-10 weight portion hydroxyethylmethyl-cellulose, 3-6 weight portion cross-linking sodium carboxymethyl cellulose, 2-5 weight portion PHOSPHATIDYL ETHANOLAMINE, 10-20 weight portion inositol, 0.1-0.2 weight portion sodium ascorbate cetylate and the 0.2-0.5 weight portion aspartame of 198.7-219.7 weight portion.
2. granule according to claim 1, it is characterized in that, in weight portion, formed by the L-084 of ingredient 40 weight portions, sucrose, 7.5 weight portion hydroxyethylmethyl-celluloses, 4.5 weight portion cross-linking sodium carboxymethyl celluloses, 3.5 weight portion PHOSPHATIDYL ETHANOLAMINE, 15 weight portion inositols, 0.15 weight portion sodium ascorbate cetylate and the 0.35 weight portion aspartame of 209 weight portions.
3. granule according to claim 1, is characterized in that, makes by dry granulation.
4. granule according to claim 3, is characterized in that, described dry granulation is specially:
Pulverize respectively ingredient L-084, sucrose, hydroxyethylmethyl-cellulose, cross-linking sodium carboxymethyl cellulose, PHOSPHATIDYL ETHANOLAMINE, inositol, sodium ascorbate cetylate and aspartame; mix homogeneously is sent in dry granulating machine and is granulated; then screening, obtains L-084 granule.
5. granule according to claim 4, is characterized in that, the ambient humidity of described dry granulation is below 60%.
6. granule according to claim 4, is characterized in that, the powder particle diameter of described each ingredient is 80 orders.
7. granule according to claim 4, is characterized in that, described dry granulating machine adopts 16 order mesh screens.
8. granule according to claim 4, is characterized in that, described screening be with shaking screen sieve out between 16 orders and 60 orders tiny evenly, without the granule of bulk.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410319910.6A CN104069072B (en) | 2014-07-07 | 2014-07-07 | A kind of L-084 composition granule |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410319910.6A CN104069072B (en) | 2014-07-07 | 2014-07-07 | A kind of L-084 composition granule |
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| CN104069072A true CN104069072A (en) | 2014-10-01 |
| CN104069072B CN104069072B (en) | 2016-09-07 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004035517A (en) * | 2002-07-08 | 2004-02-05 | Wyeth Lederle Japan Ltd | Carbapenem antibiotic-containing oral preparation |
| CN102836130A (en) * | 2012-09-19 | 2012-12-26 | 山东罗欣药业股份有限公司 | Tebipenem pivoxil granules |
| CN102860985A (en) * | 2011-07-06 | 2013-01-09 | 石药集团中奇制药技术（石家庄）有限公司 | Tebipenem pivoxil oral preparation and preparation method thereof |
-
2014
- 2014-07-07 CN CN201410319910.6A patent/CN104069072B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2004035517A (en) * | 2002-07-08 | 2004-02-05 | Wyeth Lederle Japan Ltd | Carbapenem antibiotic-containing oral preparation |
| CN102860985A (en) * | 2011-07-06 | 2013-01-09 | 石药集团中奇制药技术（石家庄）有限公司 | Tebipenem pivoxil oral preparation and preparation method thereof |
| CN102836130A (en) * | 2012-09-19 | 2012-12-26 | 山东罗欣药业股份有限公司 | Tebipenem pivoxil granules |
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| CN104069072B (en) | 2016-09-07 |
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