CN102579319A - Slow release composition with cefaclor - Google Patents
Slow release composition with cefaclor Download PDFInfo
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- CN102579319A CN102579319A CN2011100265812A CN201110026581A CN102579319A CN 102579319 A CN102579319 A CN 102579319A CN 2011100265812 A CN2011100265812 A CN 2011100265812A CN 201110026581 A CN201110026581 A CN 201110026581A CN 102579319 A CN102579319 A CN 102579319A
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Abstract
The invention relates to the technical field of medicine preparation, in particular to slow release composition with cefaclor, which comprises materials by weight: 60% to 90% of the cefaclor, 5% to 20% of hydroxypropyl methylcellulose, 0.5% to 5% of a potential of hydrogen (pH) adjusting agent and 3% to 18% of a porogen. The slow release composition with the cefaclor can be completely released in 4 to 7 hours, thereby being good in release characteristics.
Description
Technical field
The present invention relates to technical field of medicine, concrete relate to a kind of slow releasing composition that contains cefaclor
Background technology
Cefaclor is the semi-synthetic beta-Lactam antibiotic of a kind of wide spectrum.Medicine moves/demonstration of pharmacodynamics (PK/PD) result of study; Antibacterial effect depends on that drug level in the blood plasma is greater than time of minimal inhibitory concentration (MIC) (T＞MIC) in the body of beta-lactam antibiotic; When T＞MIC greater than 40% of dosing interval; Just can bring into play curative effect (the Craig WA.Pharmacokinetic/pharmacodynamic parameters:rationale for antibacterial dosing of mice and men.Clin Infect Dis of 80-90%; 1998,26:-10; Quiz11-2.).
The half-life of the beta-Lactam antibiotic of many orally-ingestible is very short, only has 0.6-0.9 hour like the half-life in the cefaclor body, and common cefaclor preparation is administered three times every day, just can reach therapeutic purposes.Administration number of times is too many, results in hand cramps to the patient, therefore is necessary to develop administration number of times preparation still less.
Chinese patent CN99806823.3 discloses a kind of effervescence type floating in stomach preparation of cefaclor, except that principal agent, comprises water-soluble bloated capable polymer and carbonate, can in 20 hours, discharge medicine.But effervescence type intragastric floating sustained-release preparation produces a large amount of gases under one's belt, makes stomach discomfort.
Chinese patent CN200610153069.3 also discloses a kind of floating in stomach preparation of cefaclor, except that principal agent, comprises the lightweight wax material, can in 24 hours, discharge medicine.Although overcome the shortcoming that produces a large amount of gases and make stomach discomfort, regrettably this patent is failed the technical scheme that discharges fully in open 4-7 hour.The overlong time that discharges fully, under same dose, be difficult to guarantee that patient takes medicine after, drug level promptly is difficult to guarantee the antibacterial effect of medicine greater than minimal inhibitory concentration (MIC) in its blood plasma.
Chinese patent 200810151325.4 discloses a kind of slow releasing preparation of cefaclor, and except that principal agent, it comprises acrylic resin and hypromellose, can in 12-24 hour, discharge medicine.Because the half-life of cefaclor only has 0.6-0.9 hour; As be designed to 12-24 hour slow release; Be difficult to guarantee the steady of whole release stage patient's blood drug level under the routine dose, the blood drug level in later stage is inevitable on the low side, so the shortcoming of this patent also is to be difficult to guarantee curative effect.
Summary of the invention
Technical problem to be solved by this invention is to overcome the prior art deficiency, and a kind of slow releasing composition that reduces the cefaclor that administration number of times, release behavior do not affect the treatment is provided.
Cefaclor slow releasing tablet in the market is the hydrogel matrix slow releasing tablet.As a kind of ideal slow releasing preparation, its in gastric juice with intestinal juice in release behavior should be consistent.Because cefaclor is amphion, promptly have acidic functionality and basic functionality, its dissolubility has the pH dependency, and promptly dissolubility is high in than the intestinal juice (pH5～7) at normal ph in the gastric juice (pH1～3) of low pH.As cefaclor being prepared into conventional hydrogel matrix tablet, the release ratio of pharmaceutical formulation of the present invention in simulated gastric fluid is fast in mimic intestinal juice.Therefore, guarantee that cefaclor release behavior in gastric juice and intestinal juice is consistent, can in prescription, add part PH regulator, like enteric polymer, organic acid.This type PH regulator does not dissolve in gastric juice, and in intestinal juice, dissolves, and on the one hand, the dissolving of adjuvant can make the aperture of framework material become big, is beneficial to the release of cefaclor; On the other hand,, be acid after the adjuvant dissolving, can keep the cefaclor part to be acid, increased the dissolubility of cefaclor, and improved the release degree of cefaclor in simulated intestinal fluid because cefaclor dissolubility under acid condition increases; The effect of two aspects makes in the release degree of cefaclor in simulated intestinal fluid and the simulated intestinal fluid consistent.
The inventor finds in research process, uses enteric polymer or stearic acid separately, is difficult to accomplish to make medicine consistent with the release behavior in the simulated intestinal fluid at simulated gastric fluid.The discovery that the inventor is pleasantly surprised is used enteric polymer and stearic acid, and uses hypromellose to do framework material, can solve aforesaid problem preferably, obtains continuing to discharge 4-7 hour cefaclor slow releasing tablet.
The present invention at first provides a kind of new sustained-release composition of cefaclor; It includes as the cefaclor of active component or its pharmaceutically acceptable salt at least; Hypromellose as hydrophilic gel type sustained-release matrix material; As the enteric polymer and the stearic mixture of PH regulator, as the water soluble excipient of porogen.
Cefaclor slow releasing tablet of the present invention, the 60-90% that accounts for the tablet total weight amount as cefaclor or its pharmaceutically acceptable salt of active component.
In the cefaclor slow releasing tablet of the present invention; Its sustained-release matrix is a hypromellose, is selected from hypromellose Methocel E3, E5, E6, E15, E50, E400, E10000, K3, K100, K4M, K15M, the K100M of the Dow Chemical Company or is equal to other company's corresponding products of viscosity grade.Wherein the hypromellose consumption accounts for the 5%-20% of tablet total weight amount.
Cefaclor slow releasing tablet of the present invention; Wherein the PH regulator is enteric polymer and organic acid; Enteric polymer is selected from acrylic resin; For example Eudragit L, Eudragit E, Eudragit L-100-55-RohmPharma, acrylic based emulsion dispersion such as Eudragit L30D-RohmPharma and, wherein Eudragit L-100-55 most preferably with the corresponding product of other other company of dissolubility level; Organic acid is selected from fumaric acid, succinic acid, sorbic acid, 1,3-propanedicarboxylic acid, stearic acid, citric acid, preferred stearic acid; Ratio between Eudragit L-100-55 and the stearic acid is 1: 5-1: 1, and the consumption sum of the two accounts for the 0.5-5% of tablet total weight amount.
Cefaclor slow releasing tablet of the present invention, wherein porogen is a water soluble excipient, for example glucose, fructose, xylose, galactose, sucrose, maltose, xylitol, sorbitol, and other pharmaceutically acceptable monosaccharide and disaccharidase.Other suitable excipient comprises inorganic compound, for example the chloride of potassium, sodium, magnesium and calcium, sulfate and phosphoric acid salt and citrate, phosphate, lactate and Fructus Vitis viniferae hydrochlorate and succinic acid salt, preferably lactose and mannitol, most preferably mannitol.The consumption of porogen accounts for the 3%-18% of tablet total amount.
Cefaclor slow releasing tablet of the present invention can also include acceptable filler, binding agent, lubricant on the pharmaceutics.
Above-mentioned filler can be selected from microcrystalline Cellulose, Powderd cellulose, starch, pregelatinized Starch, calcium hydrogen phosphate, calcium sulfate, and the gross weight of filler accounts for the 0-20% of tablet total weight amount.
Described lubricant is selected from magnesium stearate, sodium stearyl fumarate, and its consumption accounts for the 0.5-2% of total formulation weight amount.
Described binding agent is selected from polyvidone, hyprolose, hypromellose, preferred hyprolose (HPC-L-Japan SHIN-ETSU HANTOTAI), and the preparation of binding agent will will be dissolved with the ethanol that is not less than 50%.
According to cefaclor slow releasing tablet of the present invention, be preferably thin membrane coated tablet, preferred use stomach dissolution type thin film coating material coating, coating material accounts for tablet total weight amount 1%-6%.
The present invention also provides the method for preparing of aforementioned cefaclor slow releasing tablet, may further comprise the steps:
(1) binding agent of recipe quantity is dissolved in is mixed with adhesive solution in the alcoholic solution;
(2) with active component, hypromellose, PH regulator, porogen and optional filler mixing;
(3) binder solution of step (1) is joined in the mixture of step (2) prepare wet granular;
(4) wet grain drying and the arrangement with step (3) obtains dried granule;
(5) dried granule and the lubricant with step (4) is mixed together evenly;
(6) mixture with step (5) is pressed into tablet;
(7) optional, with the tablet of step (6) with stomach dissolution type thin film coating material coating, coating weightening finish 1%～6%.
Description of drawings
The release degree contrast of accompanying drawing 1: embodiment 5 medicines in 0.1M hydrochloric acid and phosphate buffer (pH6.8)
The release degree contrast of accompanying drawing 2: embodiment 6 medicines in 0.1M hydrochloric acid and phosphate buffer (pH6.8)
The release degree contrast of accompanying drawing 3: embodiment 7 medicines in 0.1M hydrochloric acid and phosphate buffer (pH6.8)
The release degree contrast of accompanying drawing 4: embodiment 8 medicines in 0.1M hydrochloric acid and phosphate buffer (pH6.8)
The specific embodiment
Through following specific embodiment, can help the reader better to understand the present invention, but following example can not be construed as limiting the present invention.
Embodiment 1
Present embodiment only is used for comparative illustration, is not content of the present invention.
Behind cefaclor and mannitol, hypromellose K4M, hypromellose K100M mix homogeneously, add 80% ethanol water granulation after drying of 5% hyprolose, arrangement adds the magnesium stearate mixing, tabletting.
Only adopt hypromellose to do framework material in this example prescription, do porogen, do not use any PH regulator with mannitol.
These article of getting; According to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2010 D, first method); Adopt the device of dissolution method first method; Be release medium with 0.1mol/L hydrochloric acid solution (replacement simulated gastric fluid, down together), phosphate buffer (pH6.8) (replacing simulated intestinal fluid, down together) respectively; Rotating speed is that per minute 100 changes; Operation in accordance with the law in 30min, 60min, 90min, 120min, 180min, 240min, 300min, 360min, 420min sampling, is measured absorbance according to ultraviolet-visible beam split light method (two appendix IV of Chinese Pharmacopoeia version in 2010 A) respectively in the wavelength of 265nm; Measure every burst size at different time, the result sees table 1: the accumulative total release degree (%)
of table 1 cefaclor in 0.1M hydrochloric acid and phosphate buffer (pH6.8)
Discharge degrees of data potential problems have been described, use conventional hydrophilic gel type framework material to prepare the cefaclor slow releasing tablet, the release degree of cefaclor in 0.1M hydrochloric acid is apparently higher than phosphate buffer (pH6.8).When clinical use, after medicine moves to small intestinal,, can cause the release of cefaclor slack-off along with the increase of pH value, bioavailability reduces, and therefore curative effect can be affected.
Embodiment 2
Present embodiment only is used for comparative illustration, is not content of the present invention.
Behind cefaclor and lactose, hypromellose K100M, acrylic resin (Eudragi tL-100-55) mixing, add 70% ethanol water granulation after drying of 6% 30 POVIDONE K 30 BP/USP 30, arrangement adds the magnesium stearate mixing, tabletting.
Adopt hypromellose to do that framework material, lactose are done porogen, acrylic resin (EudragitL-100-55) is made the PH regulator in this example prescription.
These article of getting; According to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2010 D, first method); Adopt the device of dissolution method first method; Be release medium with 0.1mol/L hydrochloric acid solution, phosphate buffer (pH6.8) respectively; Rotating speed is that per minute 100 changes; Operation in accordance with the law in 30min, 60min, 90min, 120min, 180min, 240min, 300min, 360min, 420min sampling, is measured absorbance according to ultraviolet-visible beam split light method (two appendix IV of Chinese Pharmacopoeia version in 2010 A) respectively in the wavelength of 265nm; Measure every burst size at different time, the result sees table 2: the accumulative total release degree (%)
of table 2 cefaclor in 0.1M hydrochloric acid and phosphate buffer (pH6.8)
The release degrees of data shows; Add in the prescription after acrylic resin (EudragitL-100-55) does the pH regulator agent; In phosphate buffer (pH6.8); The release degree of medicine in 8 hours brings up to 84% by 62% of embodiment 1, but the release degree of medicine in phosphate buffer (pH6.8) is still less than 0.1M hydrochloric acid.
Embodiment 3
Present embodiment only is used for comparative illustration, is not content of the present invention.
Behind cefaclor and lactose, hypromellose K100M, acrylic resin (EudragitL-100-55) mixing, add 70% ethanol water granulation after drying of 6% 30 POVIDONE K 30 BP/USP 30, arrangement adds the magnesium stearate mixing, tabletting.
Adopt hypromellose to do that framework material, lactose are done porogen, acrylic resin (EudragitL-100-55) is made the PH regulator in this example prescription.
These article of getting; According to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2010 D, first method); Adopt the device of dissolution method first method; Be release medium with 0.1mol/L hydrochloric acid solution, phosphate buffer (pH6.8) respectively; Rotating speed is that per minute 100 changes; Operation in accordance with the law in 30min, 60min, 90min, 120min, 180min, 240min, 300min, 360min, 420min sampling, is measured absorbance according to ultraviolet-visible beam split light method (two appendix IV of Chinese Pharmacopoeia version in 2010 A) respectively in the wavelength of 265nm; Measure every burst size at different time, the result sees table 3: the accumulative total release degree (%)
of table 3 cefaclor in 0.1M hydrochloric acid and phosphate buffer (pH6.8)
The release degrees of data shows, after the acrylic resin that adds in the prescription (EudragitL-100-55) ratio strengthens, in phosphate buffer (pH6.8); The release degree of medicine in 8 hours brings up to 90% by 84% of embodiment 2; But medicine is bigger than normal at one hour release degree, as increasing the acrylic resin (EudragitL-100-55) in the prescription again, no doubt can improve the release degree in the medicine 8 hours; But will certainly cause medicine prominent the releasing of first hour; So, use a kind of pH regulator agent separately, be difficult to realize medicine consistent target of release in 0.1M hydrochloric acid and phosphate buffer (pH6.8).
Embodiment 4
Present embodiment only is used for comparative illustration, is not content of the present invention.
Behind cefaclor and mannitol, hypromellose K100M, stearic acid mixing, add 85% ethanol water granulation after drying of 4% hyprolose, arrangement adds the magnesium stearate mixing, tabletting.
Adopt hypromellose to do that framework material, mannitol are done porogen, stearic acid is made the PH regulator in this example prescription.
These article of getting; According to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2010 D, first method); Adopt the device of dissolution method first method; Be release medium with 0.1mol/L hydrochloric acid solution, phosphate buffer (pH6.8) respectively; Rotating speed is that per minute 100 changes; Operation in accordance with the law in 30min, 60min, 90min, 120min, 180min, 240min, 300min, 360min, 420min sampling, is measured absorbance according to ultraviolet-visible beam split light method (two appendix IV of Chinese Pharmacopoeia version in 2010 A) respectively in the wavelength of 265nm; Measure every burst size at different time, the result sees table 4: the accumulative total release degree (%)
of table 4 cefaclor in 0.1M hydrochloric acid and phosphate buffer (pH6.8)
The release degrees of data shows; After the adding stearic acid is done the pH regulator agent in the prescription; Medicine does not have significant difference in the release number of degrees value in 8 hours and the 0.1M hydrochloric acid in phosphate buffer (pH6.8); But before 90 minutes, the release degree of phosphate buffer (pH6.8) Chinese medicine is starkly lower than 0.1M hydrochloric acid.So, use stearic acid can't make medicine represent ideal release profiles separately.
Embodiment 5
Behind cefaclor and mannitol, hypromellose K4M, hypromellose K100M, acrylic resin (EudragitL-100-55), stearic acid mixing; 85% ethanol water granulation after drying of the hyprolose of adding 2%; Arrangement adds the magnesium stearate mixing, tabletting.
These article of getting; According to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2010 D, first method); Adopt the device of dissolution method first method; Be release medium with 0.1mol/L hydrochloric acid solution, phosphate buffer (pH6.8) respectively; Rotating speed is that per minute 100 changes; Operation in accordance with the law in 30min, 60min, 90min, 120min, 180min, 240min, 300min, 360min, 420min sampling, is measured absorbance according to ultraviolet-visible beam split light method (two appendix IV of Chinese Pharmacopoeia version in 2010 A) respectively in the wavelength of 265nm; Measure every burst size at different time, the result sees table 5: the accumulative total release degree (%)
of table 5 cefaclor in 0.1M hydrochloric acid and phosphate buffer (pH6.8)
The release degree correlation curve figure of embodiment 5 medicines in 0.1M hydrochloric acid and phosphate buffer (pH6.8) sees accompanying drawing 1.
Embodiment 6
Behind cefaclor and lactose, hypromellose K4M, acrylic resin (EudragitL-100-55), stearic acid mixing, add 85% ethanol water granulation after drying of 5% hyprolose, arrangement adds the magnesium stearate mixing, tabletting.
These article of getting; According to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2010 D, first method); Adopt the device of dissolution method first method; Be release medium with 0.1mol/L hydrochloric acid solution, phosphate buffer (pH6.8) respectively; Rotating speed is that per minute 100 changes; Operation in accordance with the law in 30min, 60min, 90min, 120min, 180min, 240min, 300min, 360min, 420min sampling, is measured absorbance according to ultraviolet-visible beam split light method (two appendix IV of Chinese Pharmacopoeia version in 2010 A) respectively in the wavelength of 265nm; Measure every burst size at different time, the result sees table 6: the accumulative total release degree (%)
of table 6 cefaclor in 0.1M hydrochloric acid and phosphate buffer (pH6.8)
The release degree correlation curve figure of embodiment 6 medicines in 0.1M hydrochloric acid and phosphate buffer (pH6.8) sees accompanying drawing 2.
Embodiment 7
Behind cefaclor and sucrose, hypromellose E5, hypromellose E50, acrylic resin (EudragitL-100-55), stearic acid mixing; 85% ethanol water granulation after drying of the hyprolose of adding 3%; Arrangement adds the magnesium stearate mixing, tabletting.
These article of getting; According to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2010 D, first method); Adopt the device of dissolution method first method; Be release medium with 0.1mol/L hydrochloric acid solution, phosphate buffer (pH6.8) respectively; Rotating speed is that per minute 100 changes; Operation in accordance with the law in 30min, 60min, 90min, 120min, 180min, 240min, 300min, 360min, 420min sampling, is measured absorbance according to ultraviolet-visible beam split light method (two appendix IV of Chinese Pharmacopoeia version in 2010 A) respectively in the wavelength of 265nm; Measure every burst size at different time, the result sees table 7: the accumulative total release degree (%)
of table 7 cefaclor in 0.1M hydrochloric acid and phosphate buffer (pH6.8)
The release degree correlation curve figure of embodiment 7 medicines in 0.1M hydrochloric acid and phosphate buffer (pH6.8) sees accompanying drawing 3.
Embodiment 8
Behind cefaclor and sorbitol, hypromellose E5, hypromellose E400, acrylic resin (Eudragi tL-100-55), stearic acid mixing; The hyprolose 85% ethanol water granulation after drying of adding 3%; Arrangement adds the magnesium stearate mixing, tabletting.
These article of getting; According to drug release determination method (two appendix X of Chinese Pharmacopoeia version in 2010 D, first method); Adopt the device of dissolution method first method; Be release medium with 0.1mol/L hydrochloric acid solution, phosphate buffer (pH6.8) respectively; Rotating speed is that per minute 100 changes; Operation in accordance with the law in 30min, 60min, 90min, 120min, 180min, 240min, 300min, 360min, 420min sampling, is measured absorbance according to ultraviolet-visible beam split light method (two appendix IV of Chinese Pharmacopoeia version in 2010 A) respectively in the wavelength of 265nm; Measure every burst size at different time, the result sees table 8: the accumulative total release degree (%)
of table 8 cefaclor in 0.1M hydrochloric acid and phosphate buffer (pH6.8)
The release degree correlation curve figure of embodiment 8 medicines in 0.1M hydrochloric acid and phosphate buffer (pH6.8) sees accompanying drawing 4.
Claims (6)
1. slow releasing composition that contains cefaclor, in the gross weight of said composition, it comprises 60～90% cefaclor, 5%～20% hypromellose, 0.5%～5% pH regulator agent, 3～18% porogen.
2. sustained-release composition of cefaclor as claimed in claim 1, said hypromellose are HPMC E3 HPMC E5, HPMCE6, HPMC E15, HPMC E50, HPMC E400, HPMC E10000, HPMC K3, HPMC K100, HPMC K4M, HPMC K15M, HPMC K100M.
3. sustained-release composition of cefaclor as claimed in claim 1, said pH regulator agent are enteric polymer and organic acid mixture.
4. sustained-release composition of cefaclor as claimed in claim 3, said enteric polymer are Eudragit L-100-55, and said organic acid is a stearic acid, and the ratio between Eudragit L-100-55 and the stearic acid is 1: 5～1: 1.
5. sustained-release composition of cefaclor as claimed in claim 1, said porogen are water soluble excipient.
6. sustained-release composition of cefaclor as claimed in claim 5, said water soluble excipient are mannitol, lactose, sorbitol, glucose, sucrose.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111388428A (en) * | 2020-04-14 | 2020-07-10 | 上海奥科达生物医药科技有限公司 | Topiramate sustained-release preparation, preparation method and application thereof |
| CN113081986A (en) * | 2021-04-22 | 2021-07-09 | 杭州泓友医药科技有限公司 | Cefaclor sustained-release composition and preparation method thereof |
-
2011
- 2011-01-14 CN CN2011100265812A patent/CN102579319A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111388428A (en) * | 2020-04-14 | 2020-07-10 | 上海奥科达生物医药科技有限公司 | Topiramate sustained-release preparation, preparation method and application thereof |
| CN113081986A (en) * | 2021-04-22 | 2021-07-09 | 杭州泓友医药科技有限公司 | Cefaclor sustained-release composition and preparation method thereof |
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Application publication date: 20120718 |