CN1552327A - Oral ofloxacin control-sustained releasing medicinal composition - Google Patents
Oral ofloxacin control-sustained releasing medicinal composition Download PDFInfo
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- CN1552327A CN1552327A CNA031372406A CN03137240A CN1552327A CN 1552327 A CN1552327 A CN 1552327A CN A031372406 A CNA031372406 A CN A031372406A CN 03137240 A CN03137240 A CN 03137240A CN 1552327 A CN1552327 A CN 1552327A
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Abstract
A release-controlled composite levo-ofloxacin medicine for oral application contains levo-ofloxacin, the cellulose ester or esters chosen from hydroxypropyl methylcellulose, carboxymethyl cellulose and polyvinyl pyrrolidone, and stearic acid or emtrol.
Description
Invention field
The present invention is one and is used to reduce every day relevant for levofloxacin hydrochloride a kind of and takes peroral dosage form number of times, control drug release, is drug prescription once-a-day.
Background of invention
(Levofloxacin is the optical activity L-type isomer of ofloxacin (OFLX) LVFX) to levofloxacin, and its antibacterial activity is about 2 times of OFLX, is 8～128 times of dextrorotation OFLX.This product dosage is little, and indication is wide, good effect.The clinical infection symptoms that is widely used in each section field such as respiratory system, gastrointestinal tract, urinary tract, ophthalmology, department of otorhinolaryngology, the department of stomatology and gynecological, general clinical effective rate reaches 75～95%.
The domestic Duo Jia pharmaceutical factory that gone through of levofloxacin hydrochloride ordinary tablet produces, and be curative effect antibiotics medicine preferably, but its ordinary preparation needs take every day 3 times, and adult's oral dose is 0.3g/d, and the half-life is grown (4.0h).Therefore, must medicine time is spaced apart regularly, could guarantee that antibiotic concentration keeps treatment level.
Slow releasing tablet is a kind of novel form that development in recent years is got up.Weigh antimicrobial drug and whether play therapeutical effect, one of standard is to see whether infection focus is eliminated in the body.Medicine enters in the body back and reaches in blood and other body fluid and tissue and kill and when suppressing the concentration of bacterial multiplication, promptly be considered to reach active drug concentration.Tissue is in close relations with the concentration and the blood drug level of body fluid.In most cases, always require blood drug level to reach as early as possible and maintain a suitable treatment level, this can realize by repeat administration.Antibiotics begin to throw with after, medicine reaches effective blood concentration in the short time and will play a decisive role to the lapsing to of patient infection, prognosis.Slow releasing tablet can be kept levofloxacin hydrochloride blood drug level for a long time than ordinary tablet, has prolonged the time of contact of medicine and antibacterial thus, promotes directly treatment pathogenic bacteria.The antibacterial that retains continues breeding in vivo, when antibacterial produces variation in a different manner antibiotic is produced drug resistance, reduces or eliminated the curative effect of Drug therapy and prevention, may cause more injuries.The external slow release antibacterial activity of levofloxacin slow-releasing granules and slow releasing tablet is measured research, the result shows, the antibacterial that levofloxacin slow-releasing granules and slow releasing tablet suppress to retain continues breeding and reaches 18～40 hours in culture fluid, slow releasing agent constantly discharges medicine, kill the antibacterial of a small amount of survival, antibacterial is difficult to continue breeding, avoid antibacterial to produce variation in a different manner antibiotic is produced drug resistance, improved the curative effect of Drug therapy and prevention, therefore, the hydrochloric acid levofloxacin can be made the slow releasing tablet that only need take every day once.This product is the slow releasing agent of levofloxacin hydrochloride, adopt unique slow release method, the medicine of Shi Fanging reaches treatment treatment concentration (snap action with ordinary tablet) in the short period of time, utilize the imbibition of high viscosity macromolecular material to form gel, utilize it at the gastrointestinal adhesive attraction, delay the medicine holdup time in vivo, levofloxacin hydrochloride is slowly discharged in vivo, make blood concentration fluctuation little, more steady, the half-life prolongs, make valid density keep the longer time, have more long-lasting, the antibacterial activity extra-heavy, thus reduced the dosage and the number of times of medication.Both make things convenient for patient to take, can reduce toxic and side effects again.
Summary of the invention
The purpose of this invention is to provide a kind of controlled release pharmaceutical compositions, the levofloxacin hydrochloride medicine can continue to discharge by gastrointestinal tract the time in the said composition.
Another special aspects of the present invention is that this pharmaceutical composition is a kind of oral solid controlled-release once a day that is applicable to, which comprises at least:
About 50～300mg levofloxacin; With cellulose esters or esters, wherein cellulose esters or esters are selected from about 5～200mg hydroxypropyl emthylcellulose (HPMC), about 5～200mg carboxymethyl cellulose (CMC) and about 5～200mg polyvinylpyrrolidone (PVP); With about 5～150mg stearic acid, aliphatic alcohol.
This pharmaceutical composition can also comprise: about 10～60mg acrylic resin; About 5～150mg sucrose; About 5～200mg dextrin; About 5～200mg 1-hyprolose; Pharmaceutically acceptable carriers such as about 5～200mg carboxymethyl starch sodium.
Cellulose esters or esters can be selected HPMC, CMC, MC, PVP, HPC for use, preferably HPMC, CMC or PVP.
Levofloxacin of the present invention comprises levofloxacin hydrochloride, levofloxacin lactate.The part by weight of levofloxacin and fatty acid/alcohol preferably can be preferably in 100 between 100: 2 to 100: 50: 5-100: between 20.
The part by weight of levofloxacin and cellulose esters or esters preferably can be preferably in 100: 10-100: between 50 a variation in 100: 2 to 100: 150.
Also comprise in the prescription and well known to a person skilled in the art other adjuvants, as: binding agent, lubricant etc.This prescription is suitable for making peroral dosage form, as tablet, capsule, granule etc.Tablet also can be made into Film coated tablets.
The method that is used to improve the controlling slow release solid preparation refers to that pharmaceutical composition comprises the improved formulations that a kind of and water form gel.Be typically, this water soluble polymer such as HPMC, PVP, CMC, acrylic resin etc., it can slowly be dissolved in body fluid, gastrointestinal fluid for example, they form gel by reaction and water.For these preparation compositions, different and different with consumption with its molecular weight, viscosity.
Prepare pharmaceutical preparation of the present invention, must finish by those skilled in the art.Adopt technology well known in the art and method, for example, prepare preparation of the present invention, must earlier supplementary material be sieved, with suitable mixer mixing, make granule then then, these granules that prepare can be used as:
A, direct compression: select oval-shaped drift for use, the tablet that is pressed into can directly be taken.
B, be pressed into sheet with abnormity or round punch after, sieve, the granule of acquisition can be used as all kinds of preparations of preparation.
Under the A condition, the powder that is used for tabletting can contain the 0.3g levofloxacin, thereby must optimize the tabletting condition, and to obtain pressure at 7-20kg, sheet focuses on the tablet about 1g.Tablet needs to carry out film coating with the aqueous suspension of HPMC, titanium dioxide, PEG4000, PEG6000.
Under the B condition, granule makes and is used for preparing another kind of oral formulations, and granule must be pressed into sheet with abnormity or round punch, with thereby also need to optimize process conditions, make its hardness reach the 8-12 kilogram, the granule that is obtained after prepared sheet sieves can be used for preparing other dosage form.Pharmaceutical formulation of the present invention can make the levofloxacin hydrochloride concentration in the blood maintain on the treatment level in 24 hours, thereby only need take 1 every day.In addition, during administration, the levofloxacin hydrochloride concentration in the blood can be kept constant, the phenomenon of the levofloxacin hydrochloride fluctuation of concentration in the blood of having avoided causing because of repeat administration.
The invention provides the dosage regimen of taking medicine once in a day, have the levofloxacin hydrochloride medicine in the said composition at least, for the patient of needs, this solid controlled-release is suitable for oral.Preferred this pharmaceutical composition tablet form.
The present invention has used the medicine levofloxacin hydrochloride of high-dissolvability.
This pharmaceutical composition Chinese medicine levofloxacin can account for about 30～50 weight % of total composition or tablet.
The rate of release of said preparation is by with the water soluble polymer being the erosion type control drug release that make on the basis.
Dissolve when the amount of required organic acid or alcohol is used to control levofloxacin through gastrointestinal tract in the controlled release preparation of the present invention.How much deciding of its amount by selected organic acid carboxylic acid or aliphatic alcohol (acid or alcohol) character.The weight ratio of levofloxacin and organic acid or alcohol is between 100: 2 to 100: 50, preferably 100: 5-100: between 20.
The used organic acid of the present invention comprises any organic acid carboxylic acid or aliphatic alcohol, preferred C
3～C
20Aliphatic carboxylic acid or aliphatic alcohol, for example, preferred stearic acid, octadecanol.Stearic acid most preferably.
Pharmaceutical composition of the present invention is preferred tablet aspect dosage form, also optional capsule, pill or granule.
Other composition generally includes pharmaceutical excipient in the preparation according to the present invention, as diluent; For example, starch, the fine Starch Sodium of carboxymethyl, dextrin or microcrystalline Cellulose; Binding agent such as starch, hypromellose, acrylic resin, polyvinylpyrrolidone (Povidone), sodium carboxymethyl cellulose; Fluidizer or lubricant are as Pulvis Talci, micropowder silica gel, stearic acid and magnesium stearate; Filler such as lactose, sucrose etc.; Coloring agent.But preparation is coating also, and coating material is not in particular the control of drug release and improvement and designs.
This medicine can be made into tablet, suppository or be used for filled capsules.Said preparation may be in requisition for by coating, for example in order to cover a kind of bitterness preparation.
According to the present invention, for a kind of successful instructions of taking is preparation once-a-day, contain the present invention of 300mg levofloxacin and represent the bioavailability of preparation to reach acceptable standard.This means its area under curve AUC
0-24At least be equivalent to three times on the one (tid) instructions about how to take medicine of 100mg area under curve 1 ± 20%, three times on the one (tid) instructions about how to take medicine of 24 hours plasma concentration and 100mg of levofloxacin hydrochloride are similar.
The rate of release of pharmaceutical composition of the present invention is that 1～3 hour release is that 10～60%, 2～8 hours release of labelled amount is that 30～80%,＞6 hours release of labelled amount is 70% of a labelled amount.
Specific embodiments
Following embodiment only is for technical scheme of the present invention is described, and non-limiting the present invention, in conjunction with the method for prior art, can finish following some and technology or embodiment for describing in detail.
Embodiment 1 preparation tablets
Controlled release granule
Preparation technology: all tablets are all pressed following conventional preparation method preparation.By prescription get levofloxacin hydrochloride and corresponding adjuvant such as hypromellose, sodium carboxymethyl cellulose, stearic acid, etc. put into fully mixing of blender, sieve, it is an amount of to add corresponding binding agent, make and do wet moderate soft material, granulate oven dry, granulate, add the abundant mixing of tablet lubricants, tabletting promptly.
Tabletting
Use the rotary tablet machine tabletting, sheet is fit to different/round punch.Preparation is compressed and reaches the tablet crushing strength that can produce suitable thickness and friability.The composition of tablet composition sees the following form 1.
Fill a prescription 1 per 1000 contain following material
Levofloxacin hydrochloride 50g (by levofloxacin)
Stearic acid 150g
Embodiment 2
Finish present embodiment according to embodiment 1 described method step, different is prescription 2 per 1000 contain following material:
Levofloxacin hydrochloride 300g (by levofloxacin)
Octadecanol 5g
Hypromellose K100MCR 200g
Low-substituted hydroxypropyl cellulose 200g
Polyvinylpyrrolidone (binding agent) 60g
Magnesium stearate 7.8g
Embodiment 3
Finish present embodiment according to embodiment 1 described method step, different is prescription 3 per 1000 contain following material:
Levofloxacin hydrochloride 300g (by levofloxacin)
Sodium carboxymethyl cellulose 5g
Hypromellose K15MCR 200g
Sucrose 150g
Micropowder silica gel 5g
Acrylic resin II number (binding agent) 60g
Magnesium stearate 7.8g
Embodiment 4
Finish present embodiment according to embodiment 1 described method step, different is prescription 4 per 1000 contain following material:
Levofloxacin hydrochloride 300g (by levofloxacin)
Sucrose 5g
Polyvinylpyrrolidone 200g
Hypromellose K15MCR 5g
Ethyl cellulose 5g
Low-substituted hydroxypropyl cellulose 5g
Acrylic resin IV number (binding agent) 60g
Magnesium stearate 7.3g
Embodiment 5
Finish present embodiment according to embodiment 1 described method step, different is prescription 5 per 1000 contain following material:
Levofloxacin hydrochloride 300g (by levofloxacin)
Hypromellose K100MCR 5g
Hypromellose K4MCR 200g
Carboxymethyl starch sodium 200g
Acrylic resin IV number (binding agent) 60g
Stearic acid 7.8g
Embodiment 6
Finish present embodiment according to embodiment 1 described method step, different is prescription 6 per 1000 contain following material:
Levofloxacin hydrochloride 300g (by levofloxacin)
Polyvinylpyrrolidone 5g
Hypromellose K4MCR 5g
Ethyl cellulose 100g
Polyvinylpyrrolidone (binding agent) 60g
Magnesium stearate 4.6g
Embodiment 7
Finish present embodiment according to embodiment 1 described method step, different is prescription 7 per 1000 contain following material
Levofloxacin hydrochloride 300g (by levofloxacin)
Sodium carboxymethyl cellulose 200g
Octadecanol 200g
Polyvinylpyrrolidone 20g
Citric acid 20g
Acrylic resin II 10g
Acrylic resin IV number (binding agent) 60g
Magnesium stearate 7.8g
Embodiment 8
Finish present embodiment according to embodiment 1 described method step, different is prescription 8 per 1000 contain following material:
Hydrochloric acid levofloxacin 300g (by levofloxacin)
Hypromellose K
100MCR50g
Carboxymethyl starch sodium 5g
Dextrin 200g
Polyvinylpyrrolidone (binding agent) 60g
Magnesium stearate 6.1g
Embodiment 9
Finish present embodiment according to embodiment 1 described method step, different is prescription 9 per 1000 contain following material:
Hydrochloric acid levofloxacin 300g (by levofloxacin)
Hypromellose K
100MCR50g
Icing Sugar 20g
Stearic acid 30g
Acrylic resin II number (binding agent) 40g
Magnesium stearate 4.8g
Embodiment 10
Finish present embodiment according to embodiment 1 described method step, different is prescription 10 per 1000 contain following material:
Hydrochloric acid levofloxacin 300g (by levofloxacin)
Hypromellose K
100MCR50g
Icing Sugar 20g
Dextrin 5g
Stearic acid 30g
Acrylic resin IV number (binding agent) 40g
Magnesium stearate 4.8g
Embodiment 11
Finish present embodiment according to embodiment 1 described method step, different is prescription 11 per 1000 contain following material:
Levofloxacin hydrochloride 300g (by levofloxacin)
Hypromellose K
100MCR50g
Icing Sugar 20g
Stearic acid 30g
Dextrin 30g
1-hyprolose 20g
Acrylic resin IV number (binding agent) 40g
Magnesium stearate 6g
Embodiment 12 drug release determination results:
The drug release determination method is: according to drug release determination method (two appendix XD first methods of Chinese Pharmacopoeia version in 2000), be dissolution medium with 0.1mol/L hydrochloric acid solution 1000ml, adopt the basket method of changeing, rotating speed is that per minute 100 changes, operation in accordance with the law.The result is as follows:
The drug release determination result
The drug release determination result
CoatingOpadry adds 40～80% ethanol, 2～8% suspensions.
Tablet is prepared by the prescription method for making, then with mentioned component bag film-coat.
Above-mentioned to explanation of the present invention and in conjunction with the embodiments, experimental data or the like provides the present composition complete preparation method and purposes.Because the many specific embodiments among the present invention can be revised under character of the present invention and the scope situation not violating, thereby protection domain of the present invention is seen claim of the present invention.
Claims (10)
1. oral levofloxacin controlled release pharmaceutical compositions is characterized in that comprising following composition: 50～300mg levofloxacin; With cellulose esters or esters, wherein cellulose esters or esters are selected from 5～200mg hydroxypropyl emthylcellulose (HPMC), 5～200mg carboxymethyl cellulose (CMC) and 5～200mg polyvinylpyrrolidone (PVP); With 5～150mg stearic acid, aliphatic alcohol.
2. according to the pharmaceutical composition of claim 1, it is characterized in that this pharmaceutical composition also comprises 5～200mg carboxymethyl starch sodium, 5～60mg acrylic resin.
3. according to the pharmaceutical composition of claim 1, it is characterized in that described levofloxacin comprises levofloxacin hydrochloride, levofloxacin lactate.
4. according to the pharmaceutical composition of claim 1 or 2, it is characterized in that comprising 5～150mg sucrose, 5～200mg dextrin.
5. according to the pharmaceutical composition of claim 1 or 2, it is characterized in that this pharmaceutical composition is tablet or capsule, pill or granule.
6. according to the pharmaceutical composition of claim 5, it is characterized in that said composition is the dosage form of instructions about how to take medicine once-a-day.
7. according to the pharmaceutical composition of claim 1, it is characterized in that this pharmaceutical composition rate of release is by with the water soluble polymer being the erosion type control drug release that make on the basis.
8. according to the pharmaceutical composition of claim 6, the rate of release that it is characterized in that this pharmaceutical composition is that 1～3 hour release is that 10～60%, 2～8 hours release of labelled amount is that 30～80%,＞6 hours release of labelled amount is 70% of a labelled amount.
9. according to the pharmaceutical composition of claim 1, the ratio that it is characterized in that levofloxacin and stearic acid or aliphatic alcohol in this pharmaceutical composition was preferably 100: 5-100: between 20 between 100: 2 to 100: 50.
10. according to the pharmaceutical composition of claim 1, it is characterized in that the ratio of levofloxacin and cellulose esters or esters can be preferably 100: 10-100: between 50 at 100: 2 to 100: 150 in this pharmaceutical composition.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031372406A CN1552327A (en) | 2003-06-03 | 2003-06-03 | Oral ofloxacin control-sustained releasing medicinal composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA031372406A CN1552327A (en) | 2003-06-03 | 2003-06-03 | Oral ofloxacin control-sustained releasing medicinal composition |
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| Publication Number | Publication Date |
|---|---|
| CN1552327A true CN1552327A (en) | 2004-12-08 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA031372406A Pending CN1552327A (en) | 2003-06-03 | 2003-06-03 | Oral ofloxacin control-sustained releasing medicinal composition |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102106842A (en) * | 2009-12-24 | 2011-06-29 | 杭州赛利药物研究所有限公司 | Levofloxacin hydrochloride micropill capsule and preparation method thereof |
| CN102048704B (en) * | 2009-11-06 | 2012-02-29 | 华北制药股份有限公司 | Levofloxacin lactate dispersible tablet and preparation method thereof |
| CN102697788A (en) * | 2012-06-27 | 2012-10-03 | 苏州科牧动物药品有限公司 | Compound lactic acid levofloxacin oral liquid and preparation process thereof |
| CN114917197A (en) * | 2022-06-16 | 2022-08-19 | 南京正科医药股份有限公司 | Levofloxacin hydrochloride tablet |
-
2003
- 2003-06-03 CN CNA031372406A patent/CN1552327A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102048704B (en) * | 2009-11-06 | 2012-02-29 | 华北制药股份有限公司 | Levofloxacin lactate dispersible tablet and preparation method thereof |
| CN102106842A (en) * | 2009-12-24 | 2011-06-29 | 杭州赛利药物研究所有限公司 | Levofloxacin hydrochloride micropill capsule and preparation method thereof |
| CN102106842B (en) * | 2009-12-24 | 2014-03-05 | 杭州赛利药物研究所有限公司 | Levofloxacin hydrochloride micropill capsule and preparation method thereof |
| CN102697788A (en) * | 2012-06-27 | 2012-10-03 | 苏州科牧动物药品有限公司 | Compound lactic acid levofloxacin oral liquid and preparation process thereof |
| CN102697788B (en) * | 2012-06-27 | 2013-09-04 | 苏州科牧动物药品有限公司 | Compound lactic acid levofloxacin oral liquid and preparation process thereof |
| CN114917197A (en) * | 2022-06-16 | 2022-08-19 | 南京正科医药股份有限公司 | Levofloxacin hydrochloride tablet |
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