CN101612138B - Cefetamet pivoxil hydrochloride capsule and preparation method thereof - Google Patents
Cefetamet pivoxil hydrochloride capsule and preparation method thereof Download PDFInfo
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- CN101612138B CN101612138B CN2009101008438A CN200910100843A CN101612138B CN 101612138 B CN101612138 B CN 101612138B CN 2009101008438 A CN2009101008438 A CN 2009101008438A CN 200910100843 A CN200910100843 A CN 200910100843A CN 101612138 B CN101612138 B CN 101612138B
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Abstract
The invention relates to a cefetamet pivoxil hydrochloride capsule which contains the raw materials by the weight percent: 59% of effective and active ingredient, 10-15% of disintegrant, 1-3% of solubilizer, 20-28% of bulking agent and 2-3% of lubricating agent; wherein the effective and active ingredient is cefetamet pivoxil hydrochloride; the disintegrant comprises sodium carboxymethyl starch and cross-linked sodium carboxyl cellulose; the solubilizer is lauryl sodium sulfate; the bulking agent is one or two of lactose and mannitol; and the lubricating agent includes superfine silica powder and magnesium stearate. The invention also discloses a preparation method of the cefetamet pivoxil hydrochloride capsule, which adopts dry pressing pelletization technique; therefore, the invention has the advantages of simple equipment and less investment; the prepared capsule is stable in quality, excellent in solubility property, rapid in absorption, convenient in taking and good in mouthfeel.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to a kind of cefetamet pivoxil hydrochloride capsule and preparation method thereof.
Background technology
Current society, living standards of the people improve constantly, and the common people pay close attention to more to health care, and beta-lactam antibiotic is as clinical consumption maximum, most widely used, kind is maximum, curative effect is a best class antibiotic, more and more be subjected to the common people's favor, consumption figure increases year by year.Wherein, the cephalosporin series products accounts for 70%.
Cefetamet Pivoxil Hydrochloride is put into China and Tenth Five-Year Plan Period recommends one of kind of research and development as the emphasis kind of cephalosporin series products, has very big market development potentiality.The tablet of Cefetamet Pivoxil Hydrochloride is developed by U.S. F.Hoffmann-La Roche company, and first in Mexico's listing, commodity were called Globocef in 1992, goes on the market in Japan in 1993.
The cefetamet pivoxil hydrochloride formal name used at school is called: (6R, 7R)-the 3-methyl-7[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)-acetylamino]-8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-formic acid pivaloyl oxygen methyl ester hydrochloride, it is third generation oral cephalosporin precursor medicine, belong to the product in advance of cephalosporin, be the C of cefetamet
2-carboxylic acid and the bonded ester of pivaloyl oxygen methyl, this ester is become reactive compound cefetamet (CEMT) by esterase hydrolyzed in entering intestinal wall and/or liver, be broad ectrum antibiotic, and its antibacterial activity is embodied in the synthetic inhibition to bacteria cell wall.Cefetamet all has bactericidal action to most of penicillinases and intravital Gram-positive, negative bacterium.Especially to very strong antimicrbial powers of tool such as Diplococcus pneumoniae, hemophilus influenza, klebsiellas, stable to beta-lactamase, the bacterium that beta-lactamase is produced also has antibacterial action, the treatment of infection that can be used for pharyngitis, laryngitis, tonsillitis, acute/chronic bronchitis, pneumonia etc. clinically, be safely, the broad ectrum antibiotic that is easy to take.
At present, the Cefetamet Pivoxil Hydrochloride preparation mostly is dosage forms such as tablet, capsule, be to disclose a kind of hydrochloric acid cefetamet pivoxil dispersible tablet and preparation method thereof in 03134097.0 the Chinese patent as: application number, the percentage by weight that this dispersible tablet contains raw material consists of: active component: 25-35%, filler: 55-70%, disintegrating agent: 2.0-5.0%, correctives: 1.0-2.0%, lubricant: 0.5-2.0%, binding agent: 0.2-0.4%.Preparation method adopts boiling granulating technology, adds adjuvant simultaneously and mixes compacting in flakes, and technology is simple, easy operating, constant product quality.Dispersible tablet can be dispersed in the water fast, and taking convenience, absorption are rapidly.Be particularly suitable for infant and swallow inconvenient patient's use.
Application number is to disclose a kind of hydrochloric acid cefetamet pivoxil dispersible tablet and preparation method thereof in 200810009181.9 the Chinese patent, under the prerequisite of Cefetamet Pivoxil Hydrochloride given activity composition, kind by disintegrating agent and consumption are selected and are united use, the suitable composition and the ratio of binding agent and other inserts, the selection of the micronization processes of supplementary material and corresponding optimized process conditions, prepare compared with prior art disintegrate, stripping is rapid, and stay-in-grade hydrochloric acid cefetamet pivoxil dispersible tablet.
But because Cefetamet Pivoxil Hydrochloride raw material flavour of a drug are extremely bitter, directly film-making influences mouthfeel, and medication person has the psychology of conflicting to taking medicine, and needs can take through coating or after adding correctives, and capsule is a kind of common formulations that can cover bitter taste of drug.In addition, Cefetamet Pivoxil Hydrochloride crude drug stickiness is stronger, and many at present employing wet granulations improve drug flow, but because its character instability under hot and humid condition adopts wet granulation bigger to the product quality influence, contained active component is easy to degraded.
Summary of the invention
The invention provides a kind of cefetamet pivoxil hydrochloride capsule, select flowability adjuvant preferably for use, effectively improved the stickiness of crude drug Cefetamet Pivoxil Hydrochloride, guaranteed the flowability of medicine in preparation process, overcome preparation process to the influence that drug quality produces, guaranteed the quality of cefetamet pivoxil hydrochloride capsule.
The present invention also provides a kind of preparation method of cefetamet pivoxil hydrochloride capsule, adopts the moisture in the strict control of the dry granulation capsule, has guaranteed the quality of cefetamet pivoxil hydrochloride capsule.This method equipment needed thereby is simple simultaneously, and cost is low, and energy savings, is suitable for suitability for industrialized production.
A kind of cefetamet pivoxil hydrochloride capsule, its content is made up of following raw materials by weight percent:
Effective active composition 59%
Disintegrating agent 10～15%
Solubilizing agent 1～3%
Filler 20～28%
Lubricant 2～3%;
Described effective active composition is a Cefetamet Pivoxil Hydrochloride;
Described disintegrating agent is carboxymethyl starch sodium and crosslinked carboxycellulose sodium (both can arbitrarily than using);
Described solubilizing agent is a sodium lauryl sulphate;
Described filler is one or both (two kinds when using simultaneously can arbitrarily than using) in lactose, the mannitol;
Described lubricant is micropowder silica gel and magnesium stearate (both can arbitrarily than using).
In view of Cefetamet Pivoxil Hydrochloride crude drug stickiness strong excessively, mobile poor, dissolubility in water is less, and capsule moisture needs strict control, so the present invention need be from improving the medicine stickiness, solving the research that stripping and control capsule moisture carry out the assembly of capsule adjuvant.
In the filler commonly used, starch is not suitable for direct dry-pressing owing to compressibility is relatively poor; Microcrystalline Cellulose is owing to have stickiness and certain draw moist be unfavorable for improving medicine stickiness and control capsule moisture; And lactose is not owing to no stickiness, have and to draw moist, chemical property and stablize, and can directly carry out tabletting, so the present invention selects for use lactose as filler.In addition, the mannitol that is fit to direct compression also can be separately or with the lactose coupling as filler of the present invention.
Carboxymethyl starch sodium and cross-linking sodium carboxymethyl cellulose all are good selections of disintegrating agent, with these two kinds of disintegrating agent use in conjunction, and adopt suitable consumption so that the cefetamet pivoxil hydrochloride capsule of preparation has good disintegrate effect.Weight ratio as preferred carboxymethyl starch sodium and cross-linking sodium carboxymethyl cellulose is (0.5～2): 1, have more superior disintegrate effect this moment.
Magnesium stearate is good lubricant, helps to increase the flowability of medicine; Micropowder silica gel can effectively improve the flowability of dry powder because its small particle diameter and bigger serface have good fluidizer.Anionic can improve the dissolution of insoluble medicine as solubilizing agent.As preferably, the weight ratio of micropowder silica gel and magnesium stearate is 4: 1, and this moment, the dissolution performance of medicine was better.
A kind of preparation method of cefetamet pivoxil hydrochloride capsule comprises:
(1) carboxymethyl starch sodium, lactose and mannitol are dried processing respectively in advance, be pre-mixed evenly with cross-linking sodium carboxymethyl cellulose, sodium lauryl sulphate and micropowder silica gel, add Cefetamet Pivoxil Hydrochloride again, mix homogeneously is after dry-pressing, sieving obtains drug particles;
(2) with said medicine granule and magnesium stearate mix homogeneously, carry out fill, promptly make cefetamet pivoxil hydrochloride capsule at sealing state.
In the described step (1), Cefetamet Pivoxil Hydrochloride can add several times, so that Cefetamet Pivoxil Hydrochloride and pharmaceutic adjuvant mix homogeneously.From saving man-hour, the aspect of enhancing productivity is considered, preferably adds at twice, and each addition is 1/2 of a Cefetamet Pivoxil Hydrochloride gross weight.
Because carboxymethyl starch sodium, the water content of lactose own are higher, and the weight percentage of capsule moisture must not surpass 3.0%, in order to control the moisture of capsule, so carboxymethyl starch sodium and lactose are dried processing in advance, preferably with carboxymethyl starch sodium 120 ℃ of dryings 4 hours, 80 ℃ of dryings 4 hours, make its moisture Control in ideal range lactose, reach the preparation requirement of capsule.
Except that above-mentioned adjuvant needs the oven dry processing in advance in order to control moisture, mannitol also needs to dry in advance processing.Because the mannitol powder is originally as crystalline powder, cohesiveness is arranged, thereby it has the in bulk of cohering phenomenon in storage process, so need it is dried processing in advance, can cross 80 mesh sieves after 4 hours 80 ℃ of dryings, get and tail over standbyly, the mannitol of handling through oven dry in advance is rarefaction, be convenient to and the other medicines mix homogeneously, can guarantee particulate flowability after the dry-pressing.
The adjuvant compatibility test:
Press Cefetamet Pivoxil Hydrochloride: carboxymethyl starch sodium: cross-linking sodium carboxymethyl cellulose: lactose: mannitol: micropowder silica gel: sodium lauryl sulphate: magnesium stearate=20: 100: 100: 100: 100: 1: 1: 1 weight ratio is with crude drug and adjuvant mix homogeneously, obtain mixture, at influence factor's experimental condition be: illumination (4500 ± 500Lx), high temperature (60 ℃), high humidity [25 ℃ place relative humidity 75% ± 1% (exsiccator that contains saturated NaCl solution)] is placed down, respectively at the 5th day, the character of getting an amount of mensuration mixture on the 10th day, content and related substance the results are shown in Table 1:
Table 1 adjuvant compatibility test result
Conclusion: test shows that selected adjuvant and the Cefetamet Pivoxil Hydrochloride compatibility are good, related substance (impurity) though have increases but all single assorted≤2.0%, in total prescribed limit of assorted≤5.0%, show that each selected adjuvant is stable, do not produce bad interaction with the principal agent Cefetamet Pivoxil Hydrochloride.
The present invention has following beneficial effect:
The present invention adopts the pharmaceutic adjuvant of suitable species and consumption, utilize dry granulation to prepare cefetamet pivoxil hydrochloride capsule, improved the stickiness of medicine effectively, controlled the moisture in the capsule, the cefetamet pivoxil hydrochloride capsule result of extraction that makes is good, steady quality, solubility property is excellent, absorption is rapid, taking convenience, mouthfeel are good.
The specific embodiment
Embodiment 1
120 ℃ of dryings 4 hours, it was standby to put into rustless steel week turning barrel with the sealing of double-layer plastic bag with carboxymethyl starch sodium; 80 ℃ of dryings 4 hours, it was standby to put into rustless steel week turning barrel with the sealing of double-layer plastic bag with lactose; After 80 ℃ of dryings were crossed 80 mesh sieves after 4 hours, it was standby to put into all turning barrels of rustless steel with the sealing of double-layer plastic bag with mannitol.
To be pre-mixed 10 minutes in above-mentioned dried carboxymethyl starch sodium, lactose and mannitol and cross-linking sodium carboxymethyl cellulose, sodium lauryl sulphate and the micropowder silica gel input mixer, added 1/2 recipe quantity Cefetamet Pivoxil Hydrochloride premix 10 minutes behind the mix homogeneously, add 1/2 recipe quantity Cefetamet Pivoxil Hydrochloride mix homogeneously again, obtain mixed material.
The said mixture material is pressed into hard sheet with the dry press granule-making machine, and pressure, rotating speed and mixing speed are adjusted according to molding thickness, hardness.Material after the dry-pressing is crossed 18 mesh sieve granulate with waving granulation machine, and the material behind the granulate is crossed 30 mesh sieves and 18 mesh sieves successively, sieve greater than 30 orders less than 18 purpose granules.
Said medicine granule and magnesium stearate dropped in the mixer mixed 25 minutes, mix homogeneously is after the Capsules fill makes 1000 cefetamet pivoxil hydrochloride capsules.
Embodiment 2
Preparation method is with embodiment 1.
Embodiment 3
Preparation method is with embodiment 1.
Embodiment 4
Preparation method is with embodiment 1.
Embodiment 5
Preparation method is with embodiment 1.
Comparative Examples 1
Preparation method is with embodiment 1.
Comparative Examples 2
Preparation method is with embodiment 1.
Comparative Examples 3
Preparation method is with embodiment 1.
Comparative Examples 4
Preparation method is with embodiment 1.
The cefetamet pivoxil hydrochloride capsule of Comparative Examples 1～3 preparation is carried out disintegrate, dissolution detection, and testing result sees Table 2:
Table 2
As shown in Table 3, the capsule disintegrate degree varies of preparation in Comparative Examples 1, the Comparative Examples 2, stripping is undesirable; The capsule disintegrate for preparing in the Comparative Examples 3 is complete, but the stripping result is on the low side, and the consumption that needs to increase solubilizing agent is described, to improve dissolution.
The cefetamet pivoxil hydrochloride capsule of Comparative Examples 4 and embodiment 1 preparation is carried out content uniformity, sticks and detect towards situation, dissolution, and testing result sees Table 3:
Table 3
| Project | Comparative Examples 4 | Embodiment 1 |
| Content uniformity | -7.08％～+13.65％ | -2.11％～+5.36％ |
| Glutinous towards situation | Do not improve | Have clear improvement not glutinous dashing |
| Average dissolution (%) | 93.2 | 97.6 |
Conclusion: increased the consumption of solubilizing agent in the Comparative Examples 4, reduced the consumption of magnesium stearate lubricant and micropowder silica gel,, do not changed particulate sticking, occurred the big phenomenon of content uniformity on the contrary towards problem though dissolution has clear improvement;
Suitably increased the consumption of magnesium stearate lubricant and micropowder silica gel among the embodiment 1, reduced the consumption of solubilizing agent, significantly improved sticking towards phenomenon, mobility of particle is good, and has guaranteed the stripping of medicine.
Cefetamet pivoxil hydrochloride capsule to embodiment 1 preparation is examined entirely, and content is 100.2%, and the related substance list is assorted to be 0.89%, always mixes 1.78%, moisture 1.7%, and check result is up to specification.
Cefetamet pivoxil hydrochloride capsule to embodiment 1～5 preparation carries out the stability test investigation
1. the design of stability study method sees Table 4:
Table 4
| Test type | Packing | The placement condition | Investigate time point | The investigation project |
| Influence factor's test | Remove unlap | Trisection put respectively high light (4500 ± 500Lx), place under the high temperature (60 ℃), high humidity [25 ℃ place relative humidity 75% ± 1% (exsiccator that contains saturated NaCl solution)] condition | The sampling respectively in the 5th day, the 10th day | Investigate content character, drug dissolution, content, related substance |
| Accelerated test | Aluminum-plastic packaged, add the aluminum composite membrane bag | 40 ℃ ± 2 ℃ of temperature, relative humidity 75% ± 5% | Quicken January, February, March, June | Investigate content character, moisture, drug dissolution, content, related substance |
| Long term test | Aluminum-plastic packaged, add the aluminum composite membrane bag | 25 ℃ ± 2 ℃ of temperature, relative humidity 60% ± 10% | Long-term March, June, JIUYUE, December, 18 months, 24 months | Investigate content character, moisture, drug dissolution, content, related substance |
2. the cefetamet pivoxil hydrochloride capsule influence factor result of the test of embodiment 1 preparation sees Table 5
Table 5 cefetamet pivoxil hydrochloride capsule influence factor test determination result
3. stability test the results are shown in Table 5～table 7
Table 6 cefetamet pivoxil hydrochloride capsule accelerated test measurement result
Table 7 cefetamet pivoxil hydrochloride capsule long term test measurement result
Conclusion:
Can find out from table 5～7, the cefetamet pivoxil hydrochloride capsule of the present invention's preparation has good stability, particularly adopt aluminum-plastic packaged, add aluminum composite membrane bag packing after, the every index of sample changes not obvious, all up to specification, adjuvant and supplementary product consumption that the present invention's employing is described are suitable, and preparation method is feasible.
Claims (2)
1. the preparation method of a cefetamet pivoxil hydrochloride capsule comprises:
120 ℃ of dryings 4 hours, it was standby to put into rustless steel week turning barrel with the sealing of double-layer plastic bag with the 11g carboxymethyl starch sodium; 80 ℃ of dryings 4 hours, it was standby to put into rustless steel week turning barrel with the sealing of double-layer plastic bag with the 25g lactose; After 80 ℃ of dryings were crossed 80 mesh sieves after 4 hours, it was standby to put into all turning barrels of rustless steel with the sealing of double-layer plastic bag with 25g mannitol;
To be pre-mixed 10 minutes in above-mentioned dried carboxymethyl starch sodium, lactose and mannitol and 15g cross-linking sodium carboxymethyl cellulose, 4g sodium lauryl sulphate and the 5g micropowder silica gel input mixer, added 62.5g Cefetamet Pivoxil Hydrochloride premix behind the mix homogeneously 10 minutes, add 62.5g Cefetamet Pivoxil Hydrochloride mix homogeneously again, obtain mixed material;
The said mixture material is pressed into hard sheet with the dry press granule-making machine, and pressure, rotating speed and mixing speed are adjusted according to molding thickness, hardness; Material after the dry-pressing is crossed 18 mesh sieve granulate with waving granulation machine, and the material behind the granulate is crossed 30 mesh sieves and 18 mesh sieves successively, sieve greater than 30 orders less than 18 purpose granules;
Said medicine granule and 1g magnesium stearate dropped in the mixer mixed 25 minutes, mix homogeneously is after the Capsules fill makes 1000 cefetamet pivoxil hydrochloride capsules.
2. the cefetamet pivoxil hydrochloride capsule that makes of the preparation method of a cefetamet pivoxil hydrochloride capsule as claimed in claim 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2566450A2 (en) * | 2010-05-04 | 2013-03-13 | Mahmut Bilgic | Pharmaceutical compositions comprising cefetamet |
| CN102397249B (en) * | 2011-07-14 | 2013-01-23 | 海南美大制药有限公司 | Cefetamet pivoxil hydrochloride liposome solid preparation |
| CN102335159A (en) * | 2011-09-30 | 2012-02-01 | 深圳市国源药业有限公司 | Cefetamet pivoxil hydrochloride capsule and preparation method thereof |
| CN106138052B (en) * | 2015-04-16 | 2020-02-21 | 欣凯医药化工中间体（上海）有限公司 | Thalidomide preparation and preparation method thereof |
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Non-Patent Citations (5)
| Title |
|---|
| 周建平.胶囊剂.药剂学.东南大学出版社,2007,第218页. * |
| 国家药典委员会.盐酸头孢他美酯胶囊.国家药品标准新药转正标准.2008,第67册第52页. * |
| 李华等.盐酸头孢他美酯胶囊溶出度方法的研究.山东医药工业.2001 vol.20(no.4) |
| 李华等.盐酸头孢他美酯胶囊溶出度方法的研究.山东医药工业.2001,vol.20(no.4),1-3. * |
| 陆彬.胶囊剂.药剂学.中国医药科技出版社,2003,149-183. * |
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