CN1420763A - Oral administration controlled release system for once daily administration of ciprofloxacin - Google Patents
Oral administration controlled release system for once daily administration of ciprofloxacin Download PDFInfo
- Publication number
- CN1420763A CN1420763A CN01805998A CN01805998A CN1420763A CN 1420763 A CN1420763 A CN 1420763A CN 01805998 A CN01805998 A CN 01805998A CN 01805998 A CN01805998 A CN 01805998A CN 1420763 A CN1420763 A CN 1420763A
- Authority
- CN
- China
- Prior art keywords
- ciprofloxacin
- preparation according
- xanthan gum
- tablet
- weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 title claims abstract description 233
- 229960003405 ciprofloxacin Drugs 0.000 title claims abstract description 117
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- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 50
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 210000001187 pylorus Anatomy 0.000 description 1
- 229940043230 sarcosine Drugs 0.000 description 1
- PPASLZSBLFJQEF-RKJRWTFHSA-M sodium ascorbate Substances [Na+].OC[C@@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RKJRWTFHSA-M 0.000 description 1
- 235000010378 sodium ascorbate Nutrition 0.000 description 1
- 229960005055 sodium ascorbate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- PPASLZSBLFJQEF-RXSVEWSESA-M sodium-L-ascorbate Chemical compound [Na+].OC[C@H](O)[C@H]1OC(=O)C(O)=C1[O-] PPASLZSBLFJQEF-RXSVEWSESA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960003080 taurine Drugs 0.000 description 1
- 235000013337 tricalcium citrate Nutrition 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract
A once daily tablet formulation for oral administration in humans for the controlled release of ciprofloxacin comprising a pharmaceutically effective amount of ciprofloxacin, from about 0.1% to about 8.0% of a viscolyzing agent and/or a gelling agent, about 5.0% to about 15% of a gas generating agent, and about 3.0% to about 15% of a swelling agent, said percentages being by weight of the composition.
Description
Background of invention
The present invention relates to the pharmaceutical composition of tablet or Capsule form.Controlled release drug, particularly ciprofloxacin (ciprofloxacin) that it provides room and time to control for patient are with the result that obtains the effective treatment.Pharmaceutical composition comprises ciprofloxacin, aerogenesis component, sweller, at least a sticking solvent (viscolyzing agent) or gellant.Sweller belongs to the high absorption compound class, often is called as superdisintegrant.This compounds comprises, as crosslinked polyvinyl pyrrolidone and crosslinked sodium carboxymethyl cellulose.Sticking solvent is a heavy viscous material, holds back the gas that is produced by the aerogenesis component when contacting with gastric juice.Sticking solvent comprises, as carbohydrate natural gum, as xanthan gum or cellulose ether, as hydroxypropyl emthylcellulose (methocel).The preferably crosslinkable gellant of gellant is as the water soluble salt of one or more polyuronic acids, as sodium alginate.
The improved controlled drug delivery system of the present invention is designed in the regular hour (time control) and discharges ciprofloxacin effectively from patient's gastrointestinal specific part (spatial control).This improved controlled drug delivery system avoids that dosage is prominent to be released, and is that ciprofloxacin is to the most effective administering mode of human body.
The present technique field is known, and some disease needs the certain drug multiple dose administration, and blood level need maintain more than the minimum effective dose and be lower than minimum toxic level, to obtain required curative effect, avoids bad toxic action and makes the side effect minimum.When the blood level of medicine was in this scope, medicine was discharged from body with particular rate.Controlled drug delivery system is designed to discharge medicine with this particular rate usually; As long as system discharges medicine with this speed continuously, just can in certain hour, keep blood level safely and effectively.Observed not control fluctuation is compared when giving patient with multiple dose rapid release regular dosage form, and controlled release drug obtains the basicly stable blood level of active component usually.Controlled release drug has produced best treatment, and it has not only reduced administration frequency, and has reduced the order of severity and the occurrence frequency of side effect.
The basic conception of above-mentioned controlled release drug is well-known in the art.People have made various effort and have developed upward effective controlled drug delivery system of novel pharmaceutically feasible and treatment in decades in the past.People very pay close attention to the oral drugs controlled release system, but because the easy administration of this by oral route, and can prepare peroral dosage form economically, as tablet and capsule.Developed a lot of different oral controlled-release drug systems according to different releasing mechanisms already.These oral drugs controlled release systems have various names based on different operator schemes, do not rely on preparation, swelling control system or the like as stripping control system, diffusion controlled system, ion exchange resin, infiltration control system, corrodible shell system, pH.
Various contingent conditions in an oral drugs controlled release system can run into very on a large scale, composition of gastrointestinal fluid during by gastrointestinal tract as pH, stirring intensity and its.It is desirable to, though condition is becoming, the oral drugs controlled release system still can be with constant and speed release medicine repeatably.Therefore made much making great efforts to design and can overcome these defectives, and its under gastrointestinal tract and by the time oral controlled-release medicine that discharges with constant speed.
The present technique field is known, and medicine can not absorb on whole gastrointestinal tract equably, and the absorption of colon place medicine is unstable and inadequate.Some drugs only absorbs in the upper part of stomach or small intestinal.In addition, can produce a dysgenic key factor to the performance of oral drugs controlled release system is that dosage form can be transported to the less lower intestine of drug absorption from absorbing more upper intestines apace.Therefore, when medicine can not be when gastrointestinal tract evenly absorbs, although drug delivery system is gone into drug release in the gastro-intestinal Fluid with constant rate of speed, the speed of drug absorption may be unsettled.More specific is, when medicine has one clearly " absorption window ", promptly medicine may not can absorb fully with the form administration of common oral drugs controlled release system only when some specific part of stomach or upper part of small intestine absorb.Obviously, for " absorption window " medicine is arranged like this, should design and to discharge medicine with the speed of control and can in long time, allow medicine remain on the effective oral drugs controlled release system of upper gastro-intestinal tract.
United States Patent (USP) 5,651,985 (transferring Bayer AG) have been disclosed a kind of compositions, and the acid number that comprises pharmaceutical active compounds, pharmaceutically acceptable adjuvant, polyvinyl pyrrolidone and polymer solids material is the methacrylate polymer of 100-1200mg KOH/g.Optional is that said composition also contains gas and forms additive.Compositions can absorb the acid water that is several times as much as its weight, forms the high swell gel of high machinery and spatial stability.Gel former should capacity, and the result takes its swellable of back to certain size, and this prevents that in the long duration it from passing through pylorus.Compositions to be at most 90% weight at least about 30% weight be polymer, therefore volume is very big when this dosage form contains the medicine of high dose, is not easy to oral.
In general, known in the controlled release drug system field, in order to prepare the tablet or the capsule of the certain drug that can be administered once every day, must experimentize, invent out specific medicine and particular excipient compatibility.Therefore, the kind of particular excipient and its consumption can produce the effect that is administered once every day for specific active component or medicine, then do not have such effect for another kind of medicine.
Nishioka etc. (JP 06024959) are the Japan Patent open files, wherein attempt to discharge ciprofloxacin under one's belt by the tablet that contains ciprofloxacin is suspended in the long period.Be so slow the release time that the Nishioka tablet obtains, only 46%Nishioka tablet stripping (referring to chart) after 24 hours.Significant effect is that the Nishioka preparation is not a kind of effectively " once a day " ciprofloxacin preparation in the practice of this slow stripping.
Therefore, aforesaid oral controlled-release medicine none be the preparation of the controlled release ciprofloxacin that is administered once gratifying every day.
Goal of the invention
An object of the present invention is to provide the pharmaceutical composition of tablet or capsule form, it has constituted the preparation that is administered once every day of controlled release ciprofloxacin:
When a. contacting, produce gas and with gas be trapped in the hydration medium, it still is basic complete form in stomach with aqueous medium or gastric juice,
B. the time of staying increases under one's belt, thereby drug delivery system time of staying in gastrointestinal tract is longer,
C. the speed with control discharges medicine, the time that the time that the result discharges medicine and this delivery system stop in the gastrointestinal absorption zone identical or shorter and
D. compare with other oral drugs controlled release system, major part is increased in the absorption of the medicine of upper gastro-intestinal tract absorption.
Of the present invention also have a purpose to provide the preparation that is administered once every day, it is used for the controlled release ciprofloxacin, make it keep its physical integrity, when promptly contacting with aqueous medium, even when medication amount is very big, also be not damaged basically or be kept perfectly form substantially, wherein compare with other component in the system, the ratio of polymer is very little.A further object of the present invention provides the preparation once a day that is used for the controlled release ciprofloxacin, and it has mixed the medicine of high dose, does not lose above-mentioned any favourable attribute, and result, the size of this system are oral acceptable.
Summary of the invention
The invention provides the new pharmaceutical composition of a kind of tablet or Capsule form, said composition has constituted the preparation that is administered once oral every day and has come the controlled release ciprofloxacin.This pharmaceutical composition comprise ciprofloxacin, aerogenesis component, sweller (as crosslinked polyvinyl pyrrolidone or crosslinked sodium carboxymethyl cellulose), at least a sticking solvent (viscolyzing agent) (as, such as the carbohydrate natural gum of xanthan gum or such as the cellulose ether of hydroxypropyl emthylcellulose) and gel (as sodium alginate).
Preferably, the ciprofloxacin that comprises medicine effective quantity for the oral drugs controlled release system of the present invention of the pharmaceutical composition of tablet or Capsule form, about 0.1-8% weight is glued at least a of solvent and gel, and about 5-15% weight produces the component of gas and the sweller of about 3-15% weight.
Be more preferably, at least a consumption in sticking solvent and the gel is about 0.2-5% weight, and the consumption of sweller is about 3-15% weight.
Advantageously, the present invention relates to tablet once a day for the oral controlled release ciprofloxacin of human body, the ciprofloxacin that comprises medicine effective quantity, about 0.2-0.5% sodium alginate, about 0.5-2.0% xanthan gum, about 10.0-25% sodium bicarbonate and the crosslinked polyvinylpyrrolidone of about 5.0-20%, described percentage ratio is the w/w percentage ratio of compositions, and wherein the weight rate of sodium alginate and xanthan gum is about 1: 1-1: 10.
The sweller (crosslinked polyvinyl pyrrolidone or crosslinked sodium carboxymethyl cellulose) that is used for this paper belongs to a compounds that is called superdisintegrant, its common function be by absorb a large amount of water and therefore swelling promote the disintegrate of tablet.Swelling and hydrostatic make tablet rupture.Also contain aerogenesis component (in fact may be gas produce to) in the tablet, people can expect the horse back disintegrate when contact with water liquid of such tablet, if not the words that pop.Obviously, it is found that the gas of generation is trapped in the presence of the effect at once of sticking solvent and/or gel, and superdisintegrant swells to the twice at least of initial volume as sweller.Therefore, aerogenesis component, sweller (in fact being superdisintegrant) and the combination of sticking solvent make preparation work as controlled drug delivery system.In addition, as time goes by, gel and/or sticking solvent have produced crosslinked three-dimensional molecular net, have produced the hydrodynamic equilibrium system that stays in the stomach and discharge medicine in the time that continues.
Surprisingly, have found that, when taking in, compare with the bioadhesion tablet that tablet that forms or capsule are longer in the time that stomach stops (spatial control) from preparation of the present invention with existing known hydrophilic skeleton sheet, capsules floating with food.Preparation of the present invention makes medicine be released into better zone of gastrointestinal absorption, promptly enters stomach and small intestinal, rather than enters the bad or unsettled large intestine of drug absorption.Therefore, people can expect that if medicine discharges with speed constant and that control, it also can more or less absorb with constant speed.
More surprisingly, have found that, even for the medicine that only absorbs in upper gastro-intestinal tract (being that stomach is to jejunum), as ciprofloxacin, preparation of the present invention provides required absorption rate, so that at the blood level that long time is remained valid, said preparation is fit to be administered once every day (time control).In addition, with other oral drugs controlled release system, compare with the suspension colloid wafer as the hydrophilic skeleton sheet, the drug absorption that this preparation provides is more.By regulating pharmaceutical release time, make pharmaceutical release time and tablet identical or still less reach this purpose in the time of staying of absorption place.Therefore, tablet or capsule do not pass through " absorption window " before discharging all medicines and reaching maximum bioavailability.
The accompanying drawing summary
Fig. 1 shows when mixing the oral drugs controlled release system for ciprofloxacin free alkali and ciprofloxacin HCl, with commercially available Cipro
TM(Bayer Corp.) quick-release tablet is compared the figure that average serum concentration was done the time.
Fig. 2 and 3 shows, when mixing the oral drugs controlled release system for the ciprofloxacin free alkali, with Cipro
TMQuick-release tablet is compared, on the feed with fasted conditions under mean plasma concentration figure that the time is done.
Detailed Description Of The Invention
According to the present invention, preparation of the present invention comprises Ciprofloxacin, sweller and at least a material that is selected from sticking solvent or gel. These components have formed the gel-type vehicle of hydration together. Said preparation further comprises the aerogenesis component, and making gas (generally is CO2, be SO sometimes2) generally produce in a controlled manner, and be retained in the gel-type vehicle of hydration. The sweller that belongs to the superdisintegrant compound has absorbed a large amount of liquid, makes the obvious swelling of matrix. The gas that the aerogenesis component produces has also caused the matrix expansion. But among the present invention, the swelling of matrix is glued solvent and/or gel is controlled, and it has the swellable ability and can be used as based Controlled-release Drug.
Can improve the characteristic of hydrated gel matrix by the ratio and the consumption that change sweller, sticking solvent and/or gel and aerogenesis component, and not lose the physical integrity of hydrated gel system. Therefore composition can obtain the iptimum speed that Ciprofloxacin discharges. Also find, when this based composition is taken in food, at stomach, namely in intestines and stomach, stop the long time, and do not lose its physical integrity.
The gases affect that produces the medicine of tablet or capsule discharge, its mode is also not bery clear at present. For example, may affect the factor that medicine discharges comprises:
A. the gas that is trapped in the matrix can affect the diffusion path length of medicine, so controlled-release function is arranged;
B. the existence of entrap gas can affect the speed of hydration matrix gel surface etch in the matrix, so hydrodynamism and controlled-release function are arranged simultaneously;
C. the existence of turgor pressure and gas has affected the immanent structure of hydrated gel, and therefore hydrodynamism and controlled-release function are arranged simultaneously;
D. the existence of entrap gas and its turgor pressure have affected the acidic gastric juice flow in the matrix hole of flowing through, and therefore controlled-release function is arranged.
Will be appreciated that the gas that small size power in the substrate produces has higher pressure. If it has surpassed the capillary pressure that the waterborne liquid surface tension produces, then owing to gas expansion pushes waterborne liquid in the hole, until inherent gas pressure equals capillary pressure. This phenomenon can affect the hydration rate of matrix, works in determining drug release rate. In crosslinked system, it also has certain impact to forming gel structureization.
The below will disclose each component in the novel preparation in more detail.
Medicine
According to the present invention, pharmaceutical composition is for carrying out to Ciprofloxacin tablet or the Capsule form of controlled release (being time control). The present invention is particularly suitable for controlling the medicine that discharges along inhomogeneous stripping and absorption on the whole intestines and stomach length, such as Ciprofloxacin.
Novel pharmaceutical composition is particularly suitable for the medicine that control has specific absorption window (being space control), only absorbs in upper gastro-intestinal tract, i.e. Ciprofloxacin (it only absorbs in the jejunum zone at stomach). Pharmaceutical composition also is particularly suitable for Ciprofloxacin, because its dissolubility property is depended in the absorption of medicine. Ciprofloxacin stripping under lower pH value, therefore " absorption window " accounts for leading on the top of stomach or small intestine. For the medicine such as Ciprofloxacin, tablet can not transported by " absorption window " before discharging all medicines, in order to reach maximum bioavilability.
Ciprofloxacin itself or its pharmaceutically acceptable salt or ester can be used for the present invention. The consumption of Ciprofloxacin in composition is the required amount that gives in preset time. According to the present invention, pharmaceutical composition can mix the medicine of high dose, and therefore, the amount ranges that is used for Ciprofloxacin of the present invention is that about 0.5mg is to about 1200mg.
The aerogenesis component
The aerogenesis component comprises the known material that produces gas when contacting with gastric juice.The example that can be used for aerogenesis component of the present invention comprises carbonate, and as calcium carbonate, potassium carbonate or sodium carbonate, bicarbonate is as sodium bicarbonate.
Make aerogenesis component and acid source effect by contacting with water, or produce carbon dioxide with the gastric juice reaction simply, the gas that is produced is trapped within the hydrated gel substrate of swelling compositions.The aerogenesis component is about 5-15% weight of composition weight as the amount of carbonate and bicarbonate.
These salt can use separately or use with the acid source pairing.Acid source is one or more edible organic acid, edible acylate or their mixture.Comprise as the organic acid example of acid source of the present invention, as: citric acid or its salt, as sodium citrate or calcium citrate; Malic acid, tartaric acid, succinic acid, fumaric acid, maleic acid or their salt; Ascorbic acid or its salt are as sodium ascorbate or calcium ascorbate; Glycine, sarcosine, alanine, taurine, glutamic acid etc.The acylate that can be used as acid source of the present invention comprises, if any the organic acid list alkali metal salt of an above carboxylic acid functional, organic acid two alkali metal salts of two above carboxylic acid functionals etc. are arranged.The amount of acid source by composition total weight, is about 0.5-15% weight, and preferably about 0.5-10% weight is more preferably about 0.5-5% weight.
Sweller
According to the present invention, pharmaceutical composition contains and waterborne liquid, when contacting as gastrointestinal fluid, can swell to bigger than initial volume, the initial volume sweller of twice at least preferably.Preferred sweller is crosslinked polyvinyl pyrrolidone; Other sweller comprises crosslinked sodium carboxymethyl cellulose etc.These chemical compounds belong to a compounds that is called superdisintegrant.Sweller swells to the several times of its initial volume usually in water, demonstrate controlled swelling in the presence of sticking solvent and/or gel.The amount of sweller accounts for about 3-15% weight of composition total weight, preferably about 5-15% weight.
Sticking solvent and gel
According to the present invention, pharmaceutical composition contains sticking solvent, and when contacting with gastrointestinal fluid, sticking solvent is held back the gas that is produced by the aerogenesis component at once.Preferably, sticking solvent comprises carbohydrate natural gum, as xanthan gum.The example of other carbohydrate natural gum comprises tragakanta, karaya, guar gum, Radix Acaciae senegalis etc.Wait until full-bodied cellulose ether in also can using, as hydroxypropyl emthylcellulose.In the present invention, have found that when stirring, xanthan gum helps to keep the gentle slow release of integrity of tablet to put medicine in aqueous medium.
According to the present invention, pharmaceutical composition comprises described sticking solvent or gel, or both have concurrently.Gel is sodium alginate preferably.Gel forms and holds back the stable structure that produces gas along with the time is crosslinked.Like this, As time goes on, gel has obtained the hydrodynamic equilibrium system, thereby makes substrate be retained in stomach in the time that prolongs.Simultaneously, sticking solvent and gel provide crooked diffusion path for medicine, thus control drug release.
Preferably, the amount of sticking solvent and/or gel accounts for about 0.1-8% weight of compositions, preferably accounts for about 0.2-5% weight of compositions.
Even successfully use the sticking solvent and/or the gel of very low consumption, keeping the tablet integrity as xanthan gum is the fact considering, and pharmaceutical composition of the present invention contains aerogenesis component and sweller, and they can be used as the most frequently used disintegrating agent.The present technique field personnel can know clearly very much, and the result of two kinds of components makes the quick disintegrate of tablet.Contain the roughly tablet of the hydroxypropyl cellulose of consumption and carbohydrate natural gum disintegrate after stirring 10-15 minute in the acid medium equally among the present invention.This class disintegrate meeting causes that dosage is prominent and releases effect, and promptly rapid release goes out high amount of drug in the system, and this is undesirable, particularly because controlled drug delivery system contains the medication amount that is several times as much as in the conventional formulation.The granule that forms after the disintegrate also can turned in stomach in the short time than intact tablet.The present invention has avoided this class disintegrate by using a small amount of sticking solvent (as heteropolysaccharide natural gum), and tablet or capsule that the result contains high dose medicament are oral acceptable size dimensions.
In the preferred embodiment of the invention, sticking solvent is an xanthan gum.Xanthan gum is also referred to as the corn carbohydrate gum, is a kind of high molecular (about 2 * 10 of carbohydrate being carried out the anaerobic fermentation generation of pure culture with Xanthomonas campestris
6) biosynthesis polysaccharide glue.It very tolerates enzyme.
In the preferred embodiment of the invention, the particle diameter of xanthan gum be at least about 50% weight can by 44 microns screen clothes (screen size 325, ASTM).In a more preferred embodiment, the particle diameter of xanthan gum be all can both pass through 44 tm screen (screen size 325, ASTM).
Preferably, the amount of sticking solvent accounts for about 0.1-8% weight of composition total weight, is more preferably about 0.2-5% weight.
Other excipient
Pharmaceutical composition also can contain other conventional drug excipient, as, such as the water soluble excipient of lactose, dextrose, mannitol, sorbitol etc.; As water-insoluble diluent such as starch, microcrystalline Cellulose, cellulose powders; Or such as the lubricant of Pulvis Talci, stearic acid or its salt, magnesium stearate etc.
Preparation method
According to the present invention, make in medicine and aerogenesis component, sweller, sticking solvent and the gel one or both, add that other excipient and mix lubricant come pharmaceutical compositions.Mixture directly is pressed into tablet or is packed into capsule.Perhaps, pharmaceutical compositions like this: make a meromict of aforementioned component and lubricant, mixture is sieved then by roll-in, obtains granule.Granule then with remaining mix lubricant, recharge into capsule, or be pressed into tablet.
Following table has provided the ciprofloxacin alkali (measuring with Malvern MasterSizer) of the different-grain diameter that uses among the embodiment:
Particle size distribution-ciprofloxacin alkali
| Lot number | ????1 * | ????2 | ????3 | ????4 | ????5 | ????6 | ??7 | ??8 | ????9 | ????10 | ????11 |
| 90% is lower than 25 μ m | ????22.38 ????μm | ????9.01 ????μm | ????9,61 ????μm | ????9.25 ????μm | ????5.0 ????μm | ????4.52 ????μm | ??5.0 ??μm | ??5.0 ??μm | ????10.31 ????μm | ????19.31 ????μm | ????11.98 ????μm |
| 50% is lower than 10 μ m | ????3.13 ????μm | ????2.24 ????μm | ????2.34 ????μm | ????2.31 ????μm | ????2.0 ????μm | ????1.63 ????μm | ??2.0 ??μm | ??2.0 ??μm | ????3.83 ????μm | ????4.91 ????μm | ????4.59 ????μm |
* this material provides with crude product, obtains required particle diameter through grinding.
Coating
According to the present invention, when pharmaceutical composition was tablet form, the water-soluble drug excipient of available speed carried out the thin layer coating.The coating of water soluble excipient is faster than forming with the gentle body of the hydration of water-soluble polymer coating, is preferred coating.
The example of water soluble drug excipient comprises that film forms thing sample cellulose ether polymer, or the soluble agents diluent, as lactose, sucrose, dextrose, mannitol, xylitol etc.In the preferred embodiment of the invention, the water soluble excipient that is used as coating is a lactose.
Tablet can be by the heavy about 1-4% of sheet, and preferably about 1-2% carries out coating.Coating also helps to cover drug-induced bitterness.
The present invention is existing to set forth by following non-limiting examples:
Embodiment 1
Active component is a ciprofloxacin among this embodiment.Ciprofloxacin is the exemplary agents that is only absorbed by upper intestines.Drug component is as shown in table 1.
Table 1
| Component | Weight (mg/ sheet) | Weight % |
| The ciprofloxacin monohydrate | ????598.47 | ????55.16 |
| Xanthan gum (Keltrol TF) | ????20.00 | ????1.84 |
| Sodium alginate (Keltone LVCR) | ????15.00 | ????1.38 |
| Crosslinked carboxymethyl cellulose (Ac-Di-Sol) | ????110.00 | ????10.14 |
| Sodium bicarbonate | ????230.00 | ????21.20 |
| Microcrystalline Cellulose (Avicel PH 101) | ????16.53 | ????1.52 |
| Sodium chloride | ????25.0 | ????2.30 |
| Citric acid | ????20.0 | ????1.84 |
| Crosslinked polyacrylic acid (Carbopol 971P) | ????10.0 | ????0.93 |
| Pulvis Talci | ????10.00 | ????0.93 |
| Magnesium stearate | ????20.00 | ????1.84 |
| Aerosil | ????10.00 | ????0.93 |
| Amount to | ????1085.00 | ????100％ |
Half of ciprofloxacin, xanthan gum, sodium alginate, crosslinked carboxymethyl cellulose, sodium bicarbonate, microcrystalline Cellulose, sodium chloride, citric acid and lubricant mixed together, and (No. 44, B.S.screens (BSS)) sieves.Pressing mixt in the roller suppressor, the compacting thing sieve (No. the 22nd, BSS) obtain granule.Granule mixes with remaining lubricant and Carbopol, is pressed into tablet then.Tablet sprays coating with the aqueous coatings compositions that contains 15.8% weight lactose, 3.18% weight Pulvis Talci and 1.587% weight titanium dioxide, and coat weight accounts for about 1-1.5% of tablet.
In 0.1N HCl, with the stripping of USP equipment 1 test tablet, basket speed is 100 rev/mins.Table 2 has provided the stripping result.
Table 2
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????21.16 |
| ????2 | ????33.22 |
| ????4 | ????58.72 |
| ????6 | ????74.6 |
| ????8 | ????85.83 |
| ????10 | ????93.58 |
Embodiment 2
Active component is a ciprofloxacin alkali among this embodiment.Table 3 has provided the medicine composition.
Table 3
| Component | Weight (mg/ sheet) | Tablet % weight | Medicine % weight |
| Ciprofloxacin alkali | ????1000.00 | ????71.43 | ????100.0 |
| Xanthan gum (Keltrol TF) | ????15.00 | ????1.07 | ????1.5 |
| Sodium alginate (Keltone LVCR) | ????10.00 | ????0.71 | ????1.0 |
| Crosslinked polyvinyl pyrrolidone (Kollidon CL-M) | ????150.00 | ????10.71 | ????15.0 |
| Sodium bicarbonate | ????200.00 | ????14.28 | ????20.0 |
| Magnesium stearate | ????15.00 | ????1.07 | ????1.5 |
| Pulvis Talci | ????10.00 | ????0.71 | ????10.0 |
| Amount to | ????1400.00 | ????100 | ????- |
Make ciprofloxacin cross B.S.screens (BSS) No. 22.Xanthan gum, sodium alginate, sodium bicarbonate, crosslinked polyvinyl pyrrolidone and half of lubricant (being magnesium stearate and Pulvis Talci) are mixed together, and (No. the 44th, BSS) sieves.Make all above-mentioned component mix homogeneously that sieve, in the roller suppressor, suppress, the compacting thing sieve (No. the 18th, BSS) obtain granule.Remaining magnesium stearate and Pulvis Talci sieve (No. the 60th, BSS), and mix with above-mentioned granule and the granule fine powder of limited proportion (less than No. the 60th, BSS), are pressed into tablet then.Tablet sprays coating with the aqueous coatings compositions that contains 15.8% weight lactose, 3.18% weight Pulvis Talci and 1.587% weight titanium dioxide, and coat weight accounts for about 1-1.5% of tablet.
Table 4 has provided the stripping result.
Table 4
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????24.9 |
| ????2 | ????37.8 |
| ????4 | ????60.5 |
| ????6 | ????80.6 |
| ????8 | ????85.4 |
| ????10 | ????98.8 |
Embodiment 3
Active component is a ciprofloxacin among this embodiment.Table 5 has provided the medicine composition.
Table 5
| Component | Weight (mg/ sheet) | % weight |
| The ciprofloxacin monohydrate | ????600.00 | ????61.54 |
| Xanthan gum (Keltrol TF) | ????10.00 | ????1.02 |
| Sodium alginate (Keltone LVCR) | ????25.00 | ????2.57 |
| Crosslinked carboxymethyl cellulose (Ac-Di-Sol) | ????60.00 | ????6.16 |
| Sodium bicarbonate | ????250.00 | ????25.64 |
| Microcrystalline Cellulose (Avicel PH 101) | ????15.00 | ????1.54 |
| Pulvis Talci | ????5.00 | ????0.52 |
| Magnesium stearate | ????10.00 | ????1.02 |
| Amount to | ????975.00 | ????100％ |
Except mixing the Ac-Di-Sol at granule outside (extragranularly), other is as preparation tablet as described in the embodiment 1.As described in embodiment 1 tablet is carried out dissolution test, table 6 has provided the stripping result.
Table 6
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????28.16 |
| ????2 | ????38.32 |
| ????4 | ????52.37 |
| ????6 | ????64.03 |
| ????8 | ????74.23 |
| ????10 | ????82.80 |
Embodiment 4
This embodiment shows that tablet prepared in accordance with the present invention can stop the long time at stomach.
Table 7
| Component | Weight (mg/ sheet) |
| The ciprofloxacin monohydrate | ????599.99 |
| Hydroxypropyl cellulose-L | ????20.00 |
| Sodium hydrogen phosphate | ????25.00 |
| Citric acid | ????25.00 |
| Pulvis Talci | ????7.00 |
| Magnesium stearate | ????15.00 |
| Aerosil?200 | ????10.00 |
| Amount to | ????701.99 |
Table 8
| Component | Weight (mg/ sheet) |
| Hydroxypropyl emthylcellulose (Methocel K4M) | ????215.00 |
| Crosslinked polyacrylic acid (Carbopol 934P) | ????75.00 |
| Calcium hydrogen phosphate | ????145.00 |
| Sodium benzoate | ????8.00 |
| Pulvis Talci | ????2.00 |
| Aerosil-200 | ????2.50 |
| Setting sun Huang | ????2.50 |
| Amount to | ????450.00 |
By mixing, roll-in, sieve, prepare tablet with mix lubricant and the conventional steps that is pressed into bilayer tablet.70mg barium sulfate is mixed the bioadhesive layer, as the control media of X-ray.The stomach that carries out the bioadhesive double-layer tablet in healthy male volunteers on one's body stops research, allows the volunteer early take in two after the meal in standard.Periodic logging X-radial imaging.The bioadhesive sheet stopped 2.5-3.5 hour at stomach.
Also prepared hydrophilic skeleton sheet with table 9 compositions.
Table 9
| Component | Weight (mg/ sheet) |
| The ciprofloxacin monohydrate | ????599.99 |
| Hydroxypropyl emthylcellulose (Methocel K4M) | ????20.00 |
| Hydroxypropyl cellulose-L | ????40.00 |
| Citric acid | ????25.00 |
| Sodium hydrogen phosphate | ????25.00 |
| Pulvis Talci | ????10.00 |
| Magnesium stearate | ????10.00 |
| Amount to | ????729.99 |
70 milligrams of barium sulfate are mixed above-mentioned composition.By mixing, roll-in, sieve, prepare tablet with mix lubricant and the conventional steps that is pressed into tablet.
Also prepare the capsule that floats (floating capsule) with table 10 component.
Table 10
| Component | Weight (mg/ sheet) |
| The ciprofloxacin monohydrate | ????599.99 |
| Hydroxypropyl emthylcellulose (Methocel 4M) | ????30.00 |
| Hydroxypropyl cellulose-L | ????30.00 |
| Citric acid | ????5.00 |
| Sodium hydrogen phosphate | ????5.00 |
| Pulvis Talci | ????4.00 |
| Magnesium stearate | ????6.00 |
| Amount to | ????679.99 |
50 milligrams of barium sulfate are mixed in the above-mentioned composition.Carry out stomach on one's body in healthy male volunteers and stop research, allow the volunteer early take in two/two capsules after the meal in standard.Periodic logging X-radial imaging.It is 3.5-4.5 hour that hydrophilic substrate tablet keeps the 2-2.5 hour capsule that floats at stomach.Ciprofloxacin alkali preparation at embodiment 2 same combinations carries out stomach stop research.Standard early after the meal the volunteer take in two.Nuclear magnetic resonance confirms that tablet of the present invention is 5-7 hour in the time of staying of stomach.
In another experiment, to preparation A (two in the ciprofloxacin 500mg tablet of embodiment 1 preparation, be administered once every day), preparation B (press the ciprofloxacin free alkali 1000mg tablet of embodiment 2 preparations, be administered once every day) with reference to preparation R (Cipro
TM(Bayer Corp.) 500mg quick-release tablet gives twice every day) carry out the small-scale bioavailability study of three kinds of treatments at random, three periods, intersection.Early gave tablet in 30 minutes after the meal in standard.Fig. 1 has provided average serum concentration-time graph.Fig. 1 is based on the data of listing in the following table 11.
Table 11
| Time (hour) | Mean concentration (mcg/ml) | ||
| ????A | ????B | ????R | |
| ????0 | ????0.0000 | ????0.0000 | ????0.0000 |
| ????0.5 | ????* | ????* | ????0.30000 |
| ????1 | ????0.0489 | ????0.3720 | ????1.8379 |
| ????1.5 | ????* | ????* | ????2.0779 |
| ????2 | ????0.1557 | ????0.9940 | ????1.8546 |
| ????2.5 | ????* | ????* | ????1.6348 |
| ????3 | ????1.1806 | ????1.5004 | ????1.3731 |
| ????4 | ????2.7070 | ????2.1164 | ????1.0868 |
| ????5 | ????2.8478 | ????1.8898 | ????0.7638 |
| ????6 | ????1.7944 | ????1.3594 | ????0.5404 |
| ????8 | ????1.2467 | ????0.9494 | ????0.3579 |
| ????10 | ????0.9367 | ????0.7855 | ????0.2323 |
| ????12 | ????0.6503 | ????0.8714 | ????0.1687 |
| ????12.5 | ????* | ????* | ????0.1594 |
| ????13 | ????* | ????* | ????0.3916 |
| ????13.5 | ????* | ????* | ????0.8982 |
| ????14 | ????0.4171 | ????0.6831 | ????1.0993 |
| ????14.5 | ????* | ????* | ????1.1432 |
| ????15 | ????* | ????* | ????1.3889 |
| ????16 | ????0.2753 | ????0.4826 | ????1.1187 |
| ????17 | ????* | ????* | ????0.9377 |
| ????18 | ????0.1901 | ????0.3812 | ????0.7633 |
| ????20 | ????* | ????* | ????0.4864 |
| ????22 | ????* | ????* | ????0.3766 |
| ????24 | ????0.1039 | ????0.1778 | ????0.2825 |
A:500mg * 2, (OD) once a day, feed (FDA meals)
B:1000mg, once a day, feed (FDA meals)
R:500mg, every day twice, feed (FDA meals)
* for OD preparation (preparation once a day), these sample spot are not included.
Oral preparation every day (A and B) has and the comparable degree of absorption of quick-release tablet (R).Therefore, this expression can be regulated the time that drug release is gone into gastric juice, makes it absorb the identical or weak point of time that site stops with tablet.In addition, peak value serum concentration in serum concentration-time graph that be administered once the every day that preparation B obtains and immediate release drug have a comparability, effective serum concentration of medicine can keep the longer time.
Aspect some, the result of preparation B does not have the Cipro that is administered twice every day among the embodiment of front
TMThe result of 500mg tablet is good.For example, preparation B is at the Cipro of the area under curve on the minimal inhibitory concentration (AUC on the MIC) less than routine
TMTablet.
Now developed a kind of 1000mg ciprofloxacin free alkali preparation (" OD " preparation) that is administered once improved every day, its component is as shown in table 12.In the OD preparation, the consumption of gel formation polymer (sodium alginate) is half (0.49% pair 1.0%) of preparation B approximately.
Table 12
| Component | Weight (mg/ sheet) | The % weight of medicine |
| Ciprofloxacin alkali | ????1000.0 | ????69.9 |
| Sodium alginate | ????5.0 | ????0.34 |
| Xanthan gum | ????15.0 | ????1.03 |
| Sodium bicarbonate | ????200.0 | ????13.74 |
| Crosslinked polyvinyl pyrrolidone (Kollidon CL-M) | ????176.8 | ????12.15 |
| Magnesium stearate | ????33.0 | ????2.26 |
| Pulvis Talci | ????10.0 | ????0.68 |
| Amount to | ????1440 | ????100 |
Prepare tablet from the component of table 12 li, carry out dissolution test as previously mentioned.Obviously, the external stripping curve (table 13) of OD preparation is more faster than the release of preparation B.Therefore, the medicine greater than 80% in the OD tablet discharged in 4 hours, and preparation B's then is to discharge in 8 hours.Comparison sheet 12 and 13.
Table 13
| Time (hour) | Discharge accumulative total percent |
| ????1 | ????35.49 |
| ????2 | ????53.61 |
| ????4 | ????82.33 |
| ????6 | ????98.72 |
Study average stomach time of staying of OD tablet by nuclear magnetic resonance, discovery is 5.33 hours, this and with 6 hours fine coincideing of stripping curve of these tablets.
For the pharmacokinetics and the pharmacodynamic parameter of preparation more once a day, 12 18-45 year NAM carry out at random on one's body, bioavailability study that three phases, balance intersect, give potion ciprofloxacin 1000mgOD tablet after 30 minutes at the high fat breakfast of standard.The Cipro of test rapid release under fasting and feed
TMTablet.
Under the condition, give the 500mg rapid release Cipro of two oral doses on the feed
TMTablet.First oral dose gives in 30 minutes after the meal morning at the high fat of absorption, and second dosage gave at high-fat meal (dinner) in back 12 hours.
Under fasted conditions, give two oral dose 500mgCipro
TMFast-release tablet.First oral dose gives behind overnight fasting, and second oral dose is after 12 hours but give in back 4 hours in light dining.
Result of study is shown in Fig. 2 and 3, and wherein Fig. 2 has shown that OD tablet (feed) is to Cipro
TMThe plasma drug concentration of (feed) over time, Fig. 3 has shown that OD tablet (feed) is to Cipro
TMThe plasma drug concentration of (fasting) over time.Fig. 2 and Fig. 3 are separately based on data listed in following table 14 and 15.
Table 14
| Time (hour) | Mean concentration (mcg/ml) | |
| ????A | ????B | |
| ????0 | ????0.0000 | ????0.0000 |
| ????0.5 | ????0.2190 | ????* |
| ????1 | ????1.0964 | ????0.3430 |
| ????1.5 | ????1.9702 | ????* |
| ????2 | ????2.0397 | ????0.9751 |
| ????2.5 | ????1.8232 | ????* |
| ????3 | ????1.5617 | ????1.6335 |
| ????4 | ????1.2265 | ????2.6216 |
| ????5 | ????1.0123 | ????2.9162 |
| ????6 | ????0.7777 | ????2.0336 |
| ????8 | ????0.5291 | ????1.4256 |
| ????10 | ????0.3527 | ????1.3841 |
| ????12 | ????0.2608 | ????0.9790 |
| ????12.5 | ????0.3159 | ????* |
| ????13 | ????0.4176 | ????* |
| ????13.5 | ????0.8401 | ????* |
| ????14 | ????1.9238 | ????0.5942 |
| ????14.5 | ????1.8384 | ????* |
| ????15 | ????1.6543 | ????* |
| ????16 | ????1.2336 | ????0.4393 |
| ????17 | ????0.9689 | ????* |
| ????18 | ????0.8258 | ????0.3357 |
| ????20 | ????0.5962 | ????* |
| ????22 | ????0.4366 | ????* |
| ????24 | ????0.3653 | ????0.1843 |
A:500mg, every day twice, feed (FDA meals)
C:1000mg, once a day, feed (FDA meals)
* for OD preparation (preparation once a day), these sample spot are not included.
Table 15
| Time (hour) | Mean concentration (mcg/ml) | |
| ????B | ????C | |
| ????0 | ????0.0000 | ????0.0000 |
| ????0.5 | ????1.3580 | ????* |
| ????1 | ????2.4747 | ????0.3430 |
| ????1.5 | ????2.7413 | ????* |
| ????2 | ????2.3684 | ????0.9751 |
| ????2.5 | ????2.0204 | ????* |
| ????3 | ????1.5997 | ????1.6335 |
| ????4 | ????1.1985 | ????2.6216 |
| ????5 | ????0.9429 | ????2.9162 |
| ????6 | ????0.7298 | ????2.0336 |
| ????8 | ????0.5172 | ????1.4256 |
| ????10 | ????0.3575 | ????1.3841 |
| ????12 | ????0.2709 | ????0.9790 |
| ????12.5 | ????0.9855 | ????* |
| ????13 | ????2.5113 | ????* |
| ????13.5 | ????2.7718 | ????* |
| ????14 | ????2.4376 | ????0.5942 |
| ????14.5 | ????1.9856 | ????* |
| ????15 | ????1.7173 | ????* |
| ????16 | ????1.1702 | ????0.4393 |
| ????17 | ????0.8631 | ????* |
| ????18 | ????0.7360 | ????0.3357 |
| ????20 | ????0.5095 | ????* |
| ????22 | ????0.4207 | ????* |
| ????24 | ????0.3431 | ????0.1843 |
B:500mg, every day secondary, fasting
C:1000mg, once a day, feed (FDA meals)
* for OD preparation (preparation once a day), these sample spot are not included.
The OD preparation has provided the desirable plasma drug concentration-time graph of preparation once a day, its peak value plasma drug concentration (C
Maximum) with immediate release drug comparability arranged, show that the absorption rate of medicine is similar.Medicine AUC
(0-∞)But total biology availability (area under a curve) and quick-release tablet also be comparable, this shows that at stomach all medicines discharge in the time of staying from preparation.Referring to table 16
Table 16
| Research | ????C Maximum(mcg/ml) | ???AUC (0-∞)(μg.h/ml) |
| Ciprofloxacin 1000mg.OD (feed) | ????3.04 | ????24.81 |
| ??Cipro TM(fasting) 500mg secondary every day | ????3.17 | ????26.28 |
| ??Cipro TM(feed) 500mg secondary every day | ????2.66 | ????22.39 |
Table 17 has provided three kinds of level 0.1 microgram/ml, and the ciprofloxacin OD 1000mg of 0.25 microgram/ml and 0.5 microgram/ml is to Cipro
TMAUC on the MIC of 500mg secondary every day (bid).Under the condition, these values of ciprofloxacin OD are than the Cipro of secondary every day on the feed
TMQuick-release tablet good shows that the OD preparation has curative effect preferably if give rapid release and controlled release tablet on the feed.The curative effect of OD tablet and Cipro under the condition on the feed
TMCipro under the curative effect of quick-release tablet and the fasted conditions
TMThe curative effect of quick-release tablet has comparability.
Can predict according to Fig. 1,2 and 3 The above results, the pharmacokinetics performance that the slow-release solid dosage form of ciprofloxacin is provided, as the area on the minimal inhibitory concentration under average serum concentration, the blood serum concentration-time curve and minimum persistent period at least 70% etc. of suppressing on the blood serum concentration, divide the agent treatment to have comparability with rapid release.Though above-mentioned result is identical with 1000 milligrams of tablets, but can provide area under curve (time 0 is to unlimited) in the blood serum concentration-time curve of medicine in the time of can predicting the human body of 100-1000 milligram ciprofloxacin tablet orally give feed, scope is 3.5 to about 30 micrograms-hour/milliliter.Similar is, can predict, and average serum/peak plasma concentration scope that 100 milligrams of-1000 milligrams of tablets can provide is about 0.5-4 mcg/ml.Further be that the scope that also can predict the area under curve (above minimal inhibitory concentration 0.1 mcg/ml) of 100 milligrams of-1000 milligrams of drug serum/plasma concentration that tablet provides-time graphs is about 3-26 microgram-hour/milliliter.Area under curve (above the minimal inhibitory concentration 0.25 mcg/ml) scope that also can predict 100 milligrams of-1000 milligrams of drug serum/plasma concentration that tablet can provide-time graphs is about 2-22 microgram-hour/milliliter.At last, can predict, the scope of the area under curve of 100 milligrams of-1000 milligrams of drug serum/plasma concentration that tablet can provide-time graphs (above minimal inhibitory concentration 0.5 μ m/ml) is about 1-18 microgram-hour/milliliter.
Table 17
AUC on the MTC
| Treatment | ??0.1μg/ml.h | ??0.25μg/ml.h | ??0.5μg/ml.h |
| Ciprofloxacin alkali 1000mg, OD (feed) | ??20.7±4.4 | ??17.4±4.3 | ??13.2±4.1 |
| ??Cipro TM(fasting) 2 * 500mg, bid | ??21.5±3.7 | ??18.0±3.8 | ??13.4±4.0 |
| ??Cipro TM(feed) 2 * 500mg, bid | ??17.68±3.9 | ??14.2±3.9 | ??9.7±3.4 |
Therefore, hydrophilic polymer (sodium alginate) percent is when 0.71% weight of compositions changes to 0.34% weight a little, and pharmacokinetics and pharmacodynamic parameter have obvious and unexpected improvement, and this is an important measures for curative effect.
Embodiment 6
Be that ciprofloxacin alkali shows the present invention with active component among this embodiment.
Table 18
| Component | Weight (mg/ sheet) | % weight |
| Ciprofloxacin | ????1012.10 | ????68.53 |
| Xanthan gum | ????45.0 | ????3.05 |
| Sodium bicarbonate | ????200 | ????13.54 |
| Cross-linking polyethylene pyrrolidone | ????176.82 | ????11.97 |
| Magnesium stearate | ????33 | ????2.23 |
| Pulvis Talci | ????10 | ????0.68 |
| Amount to | ????1476.92 | ????100 |
As preparation tablet as described in the embodiment 2.Carry out dissolution test as described in embodiment 1, table 19 has provided the stripping result.
Table 19
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????34 |
| ????2 | ????51.4 |
| ????4 | ????69.0 |
| ????6 | ????94.8 |
| ????8 | ????100.5 |
Embodiment 7
Be that ciprofloxacin alkali shows the present invention with active component among this embodiment.
Table 20
| Component | Weight (mg/ sheet) | % weight |
| Ciprofloxacin | ????1012.10 | ????69.47 |
| Sodium alginate | ????25 | ????1.72 |
| Sodium bicarbonate | ????200 | ????13.73 |
| Cross-linking polyethylene pyrrolidone | ????176.82 | ????12.14 |
| Magnesium stearate | ????33 | ????2.27 |
| Pulvis Talci | ????10 | ????0.69 |
| Amount to | ????1456.92 | ????100.02 |
As preparation tablet as described in the embodiment 2.Carry out dissolution test as described in embodiment 1, table 21 has provided the stripping result.
Table 21
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????34.6 |
| ????2 | ????52 |
| ????3 | ????68.4 |
| ????4 | ????79.5 |
| ????6 | ????92.4 |
| ????8 | ????95.7 |
Embodiment 8
Be that ciprofloxacin alkali shows the present invention with active component among this embodiment.
Table 22
| Component | Weight (mg/ sheet) | % weight |
| Ciprofloxacin | ????1012.10 | ????69 |
| Sodium alginate | ????5.0 | ????0.34 |
| Sodium bicarbonate | ????200 | ????13.63 |
| Cross-linking polyethylene pyrrolidone | ????176.82 | ????12.05 |
| Magnesium stearate | ????33 | ????2.25 |
| Pulvis Talci | ????10 | ????0.68 |
| Methocel?K15M | ????30 | ????2.04 |
| Amount to | ????1466.92 | ????99.99 |
As preparation tablet as described in the embodiment 2.Carry out dissolution test as described in embodiment 1, table 23 has provided the stripping result.
Table 23
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????43.6 |
| ????2 | ????57.6 |
| ????3 | ????74.4 |
| ????4 | ????87.0 |
| ????6 | ????97.5 |
| ????8 | ????100.2 |
Embodiment 9
Be that ciprofloxacin alkali shows the present invention with active component among this embodiment.
Table 24
| Component | Weight (mg/ sheet) | % weight |
| Ciprofloxacin | ????1015.18 | ????75.15 |
| Sodium alginate | ????5.0 | ????0.37 |
| Xanthan gum | ????15 | ????1.11 |
| Sodium bicarbonate | ????200 | ????14.8 |
| Cross-linking polyethylene pyrrolidone | ????72.75 | ????5.39 |
| Magnesium stearate | ????33 | ????2.44 |
| Pulvis Talci | ????10 | ????0.74 |
| Amount to | ????1350.93 | ????100 |
As preparation tablet as described in the embodiment 2.Carry out dissolution test as described in embodiment 1, table 25 has provided the stripping result.
Table 25
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????39.2 |
| ????2 | ????54.2 |
| ????3 | ????72.39 |
| ????4 | ????84.9 |
| ????6 | ????100.29 |
Be that ciprofloxacin alkali shows the present invention with active component among this embodiment.
Table 26
| Component | Weight (mg/ sheet) | % weight |
| Ciprofloxacin | ????1015.18 | ????67.35 |
| Sodium alginate | ????5.0 | ????0.33 |
| Xanthan gum | ????15 | ????1.0 |
| Cross-linking polyethylene pyrrolidone | ????176.82 | ????11.73 |
| Magnesium stearate | ????33 | ????2.19 |
| Pulvis Talci | ????10 | ????0.66 |
| Sodium carbonate | ????252.32 | ????16.74 |
| Amount to | ????1507.32 | ????100 |
As preparation tablet as described in the embodiment 2.Carry out dissolution test as described in embodiment 1, table 27 has provided the stripping result.
Table 27
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????31.34 |
| ????2 | ????59.86 |
| ????3 | ????75.3 |
| ????4 | ????81.69 |
| ????6 | ????90.39 |
| ????8 | ????91.5 |
Embodiment 11
Be that ciprofloxacin alkali shows the present invention with active component among this embodiment.
Table 28
| Component | Weight (mg/ sheet) | % weight |
| Ciprofloxacin | ????1015.18 | ????69.66 |
| Sodium alginate | ????7.28 | ????0.5 |
| Xanthan gum | ????15 | ????1.03 |
| Sodium bicarbonate | ????200 | ????13.72 |
| Cross-linking polyethylene pyrrolidone | ????176.82 | ????12.13 |
| Magnesium stearate | ????33 | ????2.26 |
| Pulvis Talci | ????10 | ????0.69 |
| Amount to | ????1457.28 | ????99.99 |
As preparation tablet as described in the embodiment 2.Carry out dissolution test as described in embodiment 1, table 29 has provided the stripping result.
Table 29
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????40.06 |
| ????2 | ????59.26 |
| ????3 | ????86.19 |
| ????4 | ????96.39 |
| ????6 | ????100.2 |
Embodiment 12
Be that ciprofloxacin alkali shows the present invention with active component among this embodiment.
Table 30
| Component | Weight (mg/ sheet) | % weight |
| Ciprofloxacin | ????1015.18 | ????70.43 |
| Sodium alginate | ????5.0 | ????0.35 |
| Xanthan gum | ????1.46 | ????0.1 |
| Sodium bicarbonate | ????200 | ????13.87 |
| Cross-linking polyethylene pyrrolidone | ????176.82 | ????12.27 |
| Magnesium stearate | ????33 | ????2.29 |
| Pulvis Talci | ????10 | ????0.69 |
| Amount to | ????1441.46 | ????100 |
As preparation tablet as described in the embodiment 2.Carry out dissolution test as described in embodiment 1, table 31 has provided the stripping result.
Table 31
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????33.34 |
| ????2 | ????58.94 |
| ????3 | ????76.11 |
| ????4 | ????83.91 |
| ????6 | ????95.7 |
Embodiment 13
Be that ciprofloxacin alkali shows the present invention with active component among this embodiment.
Table 32
| Component | Weight (mg/ sheet) | % weight |
| Ciprofloxacin | ????1015.18 | ????69.44 |
| Sodium alginate | ????5.0 | ????0.34 |
| Xanthan gum | ????21.83 | ????1.5 |
| Sodium bicarbonate | ????200 | ????13.68 |
| Cross-linking polyethylene pyrrolidone | ????176.82 | ????12.1 |
| Magnesium stearate | ????33 | ????2.26 |
| Pulvis Talci | ????10 | ????0.68 |
| Amount to | ????1461.83 | ????100 |
As preparation tablet as described in the embodiment 2.Carry out dissolution test as described in embodiment 1, table 33 has provided the stripping result.
Table 33
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????44.2 |
| ????2 | ????61.86 |
| ????3 | ????87.9 |
| ????4 | ????98.7 |
| ????6 | ????106.95 |
Embodiment 14
Be that ciprofloxacin alkali shows the present invention with active component among this embodiment.
Table 34
| Component | Weight (mg/ sheet) | % weight |
| Ciprofloxacin | ????1061.19 | ????72.51 |
| Sodium alginate | ????5.0 | ????0.36 |
| Xanthan gum | ????15 | ????1.07 |
| Sodium bicarbonate | ????145.5 | ????10.38 |
| Cross-linking polyethylene pyrrolidone | ????176.82 | ????12.61 |
| Magnesium stearate | ????33 | ????2.35 |
| Pulvis Talci | ????10 | ????0.71 |
| Amount to | ????1401.51 | ????99.99 |
As preparation tablet as described in the embodiment 2.Carry out dissolution test as described in embodiment 1, table 35 has provided the stripping result.
Table 35
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????44.46 |
| ????2 | ????56.8 |
| ????3 | ????65.91 |
| ????4 | ????74.91 |
| ????6 | ????89.31 |
| ????8 | ????98.49 |
Following table 36 has been summarized the component of embodiment 5-14 and the stripping feature of each preparation.
Table 36
| Component | ||||||||||
| ????5 | ????6 | ?7 | ??8 | ???9 | ????10 | ??11 | ??12 | ??13 | ????14 | |
| Ciprofloxacin alkali | ????69.9 | ????68.53 | ?69.47 | ??69.66 | ???75.15 | ????67.35 | ??69.66 | ??70.43 | ??69.44 | ????72.15 |
| Xanthan gum 0.5-2.0 | ????1.03 | ????3.05 | Do not have | Do not have | ???1.11 | ????1.0 | ??1.03 | ??0.1 | ??1.5 | ????1.07 |
| Sodium alginate 0.2-0.9 | ????0.34 | Do not have | ?1.72 | ??0.34 | ???0.37 | ????0.33 | ??0.5 | ??0.35 | ??0.34 | ????0.36 |
| XL polyvinylpyrrolidone 5-20 | ????12.15 | ????11.97 | ?12.14 | ??12.05 | ???5.39 | ????11.73 | ??12.13 | ??12.27 | ??12.1 | ????12.61 |
| Sodium bicarbonate 10-25 | ????13.74 | ????13.54 | ?13.73 | ??13.63 | ???14.8 | Do not have | ??13.72 | ??13.87 | ??13.68 | ????10.38 |
| Sodium carbonate | ????16.74 | |||||||||
| ??Methocel?K15M | ??2.04 | |||||||||
| [xanthan gum: alginate ratio] 10: 1-1; 1 | ????3.03∶1 | ????NA | ?NA | ??NA | ???3∶1 | ????3.03∶1 | ??2.06∶1 | ??0.29∶1 | ??4.41∶1 | ???2.97∶1 |
| Time (hour) | Discharge accumulative total percent | |||||||||
| ??1 | ????35.49 | ????34 | ?34.6 | ??43.6 | ???39.2 | ????31.4 | ??40.06 | ??33.34 | ??44.2 | ???44.46 |
| ??2 | ????53.61 | ????51.4 | ?52 | ??57.6 | ???54.2 | ????59.86 | ??59.26 | ??58.94 | ??61.86 | ???56.8 |
| ??3 | ?68.4 | ??74.4 | ???72.4 | ????75.3 | ??86.19 | ??76.11 | ??87.9 | ???65.91 | ||
| ??4 | ????82.33 | ????69 | ?79.5 | ??87.0 | ???84.9 | ????81.69 | ??96.39 | ??83.91 | ??98.7 | ???74.19 |
| ??6 | ????98.72 | ????94.8 | ?92.4 | ??97.5 | ???100.29 | ????90.39 | ??100.2 | ??95.7 | ??106.95 | ???89.31 |
| ??8 | ????100.5 | ?95.7 | ??100.2 | ????91.5 | ???98.49 | |||||
Be that ciprofloxacin alkali shows the present invention with active component among this embodiment.
Table 37
| Component | Weight (mg/ sheet) | % weight |
| Ciprofloxacin | ????1015.18 | ????67.98 |
| Sodium alginate | ????5.0 | ????0.003 |
| Xanthan gum | ????15.0 | ????0.01 |
| Cross-linking polyethylene pyrrolidone | ????176.82 | ????11.84 |
| Magnesium stearate | ????33.0 | ????2.21 |
| Pulvis Talci | ????10.0 | ????0.67 |
| Calcium carbonate | ????238.27 | ????15.96 |
| Amount to | ????1493.27 | ????98.673 |
As preparation tablet as described in the embodiment 2.Carry out dissolution test as described in embodiment 1, table 38 has provided the stripping result.
Table 38
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????44.4 |
| ????2 | ????62.4 |
| ????3 | ????73.11 |
| ????4 | ????78.0 |
| ????6 | ????84.09 |
| ????8 | ????87.0 |
Embodiment 16
Be that ciprofloxacin alkali shows the present invention with active component among this embodiment.
Table 39
| Component | Weight (mg/ sheet) | % weight |
| Ciprofloxacin | ????1015.18 | ????69.32 |
| Sodium alginate | ????14.55 | ????0.009 |
| Xanthan gum | ????15.0 | ????0.01 |
| Sodium bicarbonate | ????200.0 | ????13.66 |
| Cross-linking polyethylene pyrrolidone | ????176.82 | ????12.07 |
| Magnesium stearate | ????33.0 | ????2.25 |
| Pulvis Talci | ????10.0 | ????0.68 |
| Amount to | ????1464.55 | ????97.32 |
As preparation tablet as described in the embodiment 2.Carry out dissolution test as described in embodiment 1, table 40 has provided the stripping result.
Table 40
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????37.9 |
| ????2 | ????45.06 |
| ????3 | ????65.91 |
| ????4 | ????71.1 |
| ????6 | ????78.81 |
Embodiment 17
Be that ciprofloxacin alkali shows the present invention with active component among this embodiment.
Table 41
| Component | Weight (mg/ sheet) | % weight |
| Ciprofloxacin | ????1015.18 | ????67.11 |
| Sodium alginate | ????5.0 | ????0.003 |
| Xanthan gum | ????72.75 | ????4.81 |
| Sodium bicarbonate | ????200.0 | ????13.22 |
| Cross-linking polyethylene pyrrolidone | ????176.82 | ????11.69 |
| Magnesium stearate | ????33.0 | ????2.18 |
| Pulvis Talci | ????10.0 | ????0.006 |
| Amount to | ????1512.75 | ????99.019 |
As preparation tablet as described in the embodiment 2.Carry out dissolution test as described in embodiment 1, table 42 has provided the stripping result.
Table 42
| Time (hour) | The accumulative total percent that discharges |
| ????1 | ????32.26 |
| ????2 | ????47.2 |
| ????3 | ????63.3 |
| ????4 | ????74.01 |
| ????6 | ????94.2 |
Except above-mentioned experiment, following formulation preparation is become aforesaid tablet.Following series preparation is carried out stripping and suspension characteristic measurement.Compare with the foregoing description, a kind of or further feature of the tablet of following series preparation, i.e. stripping feature or suspension feature are unsafty.
Table 43
| Component | Embodiment 18 | Embodiment 19 |
| Ciprofloxacin | ????1015.18 | ????1015.18 |
| Sodium alginate | ????0 | ????5.0 |
| Xanthan gum | ????15.0 | ????0 |
| Sodium bicarbonate | ????200.0 | ????200.0 |
| Crospolyvinylpyrrolidone | ????176.82 | ????176.82 |
| Magnesium stearate | ????33.0 | ????33.0 |
| Pulvis Talci | ????10.0 | ????10.0 |
| Amount to | ????1450.00 | ????1440.0 |
| Stripping | ||
| Time (hour) | Discharge accumulative total percent | |
| ????1 | ????68.8 | ????52.5 |
| ????2 | ????93.2 | ????68.94 |
| ????3 | ????104.1 | ????90.39 |
| ????4 | ????- | ????100.8 |
| ????6 | ????- | ????104.79 |
| ????8 | ????- | ?????- |
Table 44
| Component | Embodiment 20 | Embodiment 21 | Embodiment 22 | Embodiment 23 | Embodiment 24 |
| Ciprofloxacin | ????1016.19 | ????1016.19 | ????1012.1 | ????1016.19 | ????1012.1 |
| Sodium alginate | ????5.0 | ????5.0 | ????5.0 | ????5.0 | ????5.0 |
| Sodium bicarbonate | ????200.0 | ????200.0 | ????200.0 | ????200.0 | ????200.0 |
| Crospolyvinylpyrrolidone | ????176.82 | ????176.82 | ????176.82 | ????176.82 | ????176.82 |
| Magnesium stearate | ????33.0 | ????33.0 | ????33.0 | ????33.0 | ????33.0 |
| Pulvis Talci | ????10.0 | ????10.0 | ????10.0 | ????10.0 | ????10.0 |
| ????Methocel?K15M | ????15.0 | ????- | ????- | ????- | ????- |
| Gellan glue (Gelrite) | ????- | ????15.0 | ????30.0 | ????- | ????- |
| Chondrus ocellatus Holmes polysaccharide | ????- | ????- | ????- | ????15.0 | ????45.0 |
| Amount to | ????1456.01 | ????1456.01 | ????1466.92 | ????1456.01 | ????1481.92 |
| Stripping | |||||
| Time (hour) | Accumulative total discharges percent | ||||
| ????1 | ????48.66 | ????50.74 | ????49.6 | ????72.46 | ????88.8 |
| ????2 | ????63.54 | ????62.86 | ????58.2 | ????81.54 | ????93.2 |
| ????3 | ????80.31 | ????74.19 | ????67.2 | ????87.09 | ????97.8 |
| ????4 | ????89.49 | ????80.79 | ????74.4 | ????92.1 | ????99.0 |
| ????6 | ????100.11 | ????91.71 | ????88.2 | ????96.45 | ????100.2 |
| ????8 | ????101.7 | ????99.99 | ????95.1 | ????97.11 | ????101.1 |
Table 45
| Component | Embodiment 25 | Embodiment 26 | Embodiment 27 | Embodiment 28 | Embodiment 29 | Embodiment 30 |
| Ciprofloxacin | ????1015.18 | ????1012.1 | ????1015.18 | ????1012.1 | ????1015.18 | ????1012.1 |
| Xanthan gum | ????15.0 | ????15.0 | ????15.0 | ????15.0 | ????15.0 | ????15.0 |
| Sodium bicarbonate | ????200.0 | ????200.0 | ????200.0 | ????200.0 | ????200.0 | ????200.0 |
| Crospolyvinylpyrrolidone | ????176.82 | ????176.82 | ????176.82 | ????176.82 | ????176.82 | ????176.82 |
| Magnesium stearate | ????33.0 | ????33.0 | ????33.0 | ????33.0 | ????33.0 | ????33.0 |
| Pulvis Talci | ????10.0 | ????10.0 | ????10.0 | ????10.0 | ????10.0 | ????10.0 |
| ????Carbopol?971P | ????5.0 | ????10.0 | ????- | ????- | ????- | ????- |
| Methylcellulose | ????- | ????- | ????5.0 | ????20.0 | ????- | ????- |
| ????Eudragit?EPO | ????- | ????- | ????- | ????- | ????5.0 | ????30.0 |
| Amount to | ????1455.0 | ????1446.92 | ????1455.0 | ????1456.92 | ????1455.0 | ????1466.92 |
| Stripping | ||||||
| Time (hour) | Accumulative total discharges percent | |||||
| ????1 | ????45.2 | ????56.8 | ????74.26 | ????68.2 | ????94.26 | ????101.4 |
| ????2 | ????59.34 | ????67.0 | ????87.06 | ????83.0 | ????94.94 | ????- |
| ????3 | ????71.79 | ????76.8 | ????95.61 | ????92.4 | ????97.89 | ????- |
| ????4 | ????80.91 | ????84.9 | ????97.71 | ????95.4 | ????98.79 | ????- |
| ????6 | ????92.01 | ????95.1 | ????99.21 | ????99.0 | ????- | ????- |
| ????8 | ????93.0 | ????97.5 | ????100.59 | ????100.8 | ????- | ????- |
Table 46
| Component | Embodiment 31 | Embodiment 32 | Embodiment 33 | Embodiment 34 | Embodiment 35 | Embodiment 36 |
| Ciprofloxacin | ????1015.18 | ????1012.1 | ????1015.18 | ????1012.1 | ????1015.18 | ????1012.1 |
| Sodium alginate | ????5.0 | ????5.0 | ????5.0 | ????5.0 | ????5.0 | ????5.0 |
| Xanthan gum | ????15.0 | ????15.0 | ????15.0 | ????15.0 | ????15.0 | ????15.0 |
| Sodium bicarbonate | ????200.0 | ????200.0 | ????200.0 | ????200.0 | ????200.0 | ????200.0 |
| Magnesium stearate | ????33.0 | ????33.0 | ????33.0 | ????33.0 | ????33.0 | ????33.0 |
| Pulvis Talci | ????10.0 | ????10.0 | ????10.0 | ????10.0 | ????10.0 | ????10.0 |
| ????Ac-di-sol | ????176.82 | ????100.0 | ????- | ????- | ????- | ????- |
| Sodium starch glycol | ????- | ????- | ????176.82 | ????125.0 | ????- | ????- |
| ????MCC(Avicel ????pH101) | ????- | ????- | ????- | ????- | ????176.82 | ????125.0 |
| Amount to | ????1455.0 | ????1375.1 | ????1455.0 | ????1400.1 | ????1455.0 | ????1400.1 |
| Stripping | ||||||
| Time (hour) | Accumulative total discharges percent | |||||
| ????1 | ????42.86 | ????47.6 | ????57.46 | ????53.8 | ????67.4 | ????62.6 |
| ????2 | ????51.4 | ????55.8 | ????65.6 | ????62.4 | ????79.26 | ????74.4 |
| ????3 | ????60.21 | ????62.4 | ????72.81 | ????70.8 | ????86.7 | ????84.9 |
| ????4 | ????66.81 | ????67.5 | ????77.19 | ????75.6 | ????91.5 | ????88.2 |
| ????6 | ????81.09 | ????76.2 | ????84.69 | ????82.4 | ????95.49 | ????94.8 |
| ????8 | ????87.6 | ????83.1 | ????92.31 | ????88.2 | ????98.79 | ????97.2 |
Table 47
| Component | Embodiment 37 | Embodiment 38 | Embodiment 39 |
| Ciprofloxacin | ????1015.18 | ????1015.18 | ????1015.18 |
| Sodium alginate | ????5.0 | ????5.0 | ????5.0 |
| Xanthan gum | ????15.0 | ????15.0 | ????15.0 |
| Sodium bicarbonate | ????200.0 | ????200.0 | ????200.0 |
| Crospolyvinylpyrrolidone | ????0 | ????261.9 | ????363.75 |
| Magnesium stearate | ????33.0 | ????33.0 | ????33.0 |
| Pulvis Talci | ????10.0 | ????10.0 | ????10.0 |
| Amount to | ????1278.18 | ????1540.08 | ????1641.93 |
| Stripping | |||
| Time (hour) | Accumulative total discharges percent | ||
| ????1 | ????66.66 | ????49.2 | ????57.26 |
| ????2 | ????79.8 | ????75.66 | ????77.74 |
| ????3 | ????91.2 | ????96.99 | ????106.2 |
| ????4 | ????94.71 | ????100.71 | ????- |
| ????6 | ????97.59 | ????- | ????- |
Table 48
| Component | Embodiment 40 | Embodiment 41 | Embodiment 42 |
| Ciprofloxacin | ????1016.19 | ????1016.19 | ????1016.19 |
| Sodium alginate | ????5.0 | ????5.0 | ????5.0 |
| Sodium bicarbonate | ????200.0 | ????200.0 | ????200.0 |
| Crospolyvinylpyrrolidone | ????176.82 | ????1776.82 | ????176.82 |
| Magnesium stearate | ????33.0 | ????33.0 | ????33.0 |
| Pulvis Talci | ????10.0 | ????10.0 | ????10.0 |
| ????Methocel?K15M | ????15.0 | ????- | ????- |
| Gellan glue (Gelrite) | ????- | ????15.0 | ????- |
| The carrageenin polysaccharide | ????- | ????- | ????15.0 |
| Amount to | ????1456.01 | ????1456.01 | ????1456.01 |
| Stripping | |||
| Time (hour) | Accumulative total discharges percent | ||
| ????1 | ????48.66 | ????50.74 | ????72.46 |
| ????2 | ????63.54 | ????62.86 | ????81.54 |
| ????3 | ????80.31 | ????74.19 | ????87.09 |
| ????4 | ????89.49 | ????80.79 | ????92.1 |
| ????6 | ????100.11 | ????91.71 | ????96.45 |
| ????8 | ????101.7 | ????99.99 | ????97.11 |
Table 49
| Component | Embodiment 43 | Embodiment 44 | Embodiment 45 |
| Ciprofloxacin | ????1015.18 | ????1015.18 | ????1015.18 |
| Xanthan gum | ????15.0 | ????15.0 | ????15.0 |
| Sodium bicarbonate | ????200.0 | ????200.0 | ????200.0 |
| Crospolyvinylpyrrolidone | ????176.82 | ????176.82 | ????176.82 |
| Magnesium stearate | ????33.0 | ????33.0 | ????33.0 |
| Pulvis Talci | ????10.0 | ????10.0 | ????10.0 |
| ????Carbopol?971P | ????5.0 | ????- | ????- |
| Methylcellulose | ????- | ????5.0 | ????- |
| ????Eudragit?EPO | ????- | ????- | ????5.0 |
| Amount to | ????1455.01 | ????1455.01 | ????1455.01 |
| Stripping | |||
| Time (hour) | Accumulative total discharges percent | ||
| ????1 | ????45.2 | ????74.26 | ????94.26 |
| ????2 | ????59.34 | ????87.06 | ????94.94 |
| ????3 | ????71.79 | ????95.61 | ????97.89 |
| ????4 | ????80.91 | ????97.71 | ????98.79 |
| ????6 | ????92.01 | ????99.21 | ????- |
| ????8 | ????93.0 | ????100.59 | ????- |
Table 50
| Component | Embodiment 46 | Embodiment 47 | Embodiment 48 |
| Ciprofloxacin | ????1015.18 | ????1015.18 | ????1015.18 |
| Sodium alginate | ????5.0 | ????5.0 | ????5.0 |
| Xanthan gum | ????15.0 | ????15.0 | ????15.0 |
| Sodium bicarbonate | ????200.0 | ????200.0 | ????200.0 |
| Magnesium stearate | ????33.0 | ????33.0 | ????33.0 |
| Pulvis Talci | ????10.0 | ????10.0 | ????10.0 |
| ????Ac-di-sol | ????176.82 | ????- | ????- |
| Sodium starch glycol | ????- | ????176.82 | ????- |
| ????MCC(Avicel?pH101) | ????- | ????176.82 | ????5.0 |
| Amount to | ????1455.0 | ????1455.0 | ????1455.0 |
| Stripping | |||
| Time (hour) | Accumulative total discharges percent | ||
| ????1 | ????42.86 | ????57.46 | ????67.4 |
| ????2 | ????51.4 | ????65.6 | ????79.26 |
| ????3 | ????60.21 | ????72.81 | ????86.7 |
| ????4 | ????66.81 | ????77.19 | ????91.5 |
| ????6 | ????81.09 | ????84.69 | ????95.49 |
| ????8 | ????87.6 | ????92.31 | ????98.79 |
Table 51
| Component | Embodiment 49 |
| Ciprofloxacin | ????1015.18 |
| Sodium alginate | ????5.0 |
| Xanthan gum | ????15.0 |
| Crospolyvinylpyrrolidone | ????176.82 |
| Magnesium stearate | ????33.0 |
| Pulvis Talci | ????10.0 |
| Potassium bicarbonate | ????238.34 |
| Amount to | ????1493.34 |
| Stripping | |
| Time (hour) | Accumulative total discharges percent |
| ????1 | ????69.06 |
| ????2 | ????77.74 |
| ????3 | ????85.2 |
| ????4 | ????87.0 |
| ????6 | ????87.0 |
| ????8 | ????98.1 |
Table 52
| Component | Embodiment 50 | Embodiment 51 |
| Ciprofloxacin | ????1015.18 | ????1015.18 |
| Sodium alginate | ????0 | ????1.46 |
| Xanthan gum | ????15.0 | ????15.0 |
| Sodium bicarbonate | ????200.0 | ????200.0 |
| Crospolyvinylpyrrolidone | ????176.82 | ????176.82 |
| Magnesium stearate | ????33.0 | ????33.0 |
| Pulvis Talci | ????10.0 | ????10.0 |
| Amount to | ????1450.00 | ????1451.46 |
| Stripping | ||
| Time (hour) | Accumulative total discharges percent | |
| ????1 | ????68.8 | ????51.46 |
| ????2 | ????93.2 | ????65.34 |
| ????3 | ????104.1 | ????84.39 |
| ????4 | ????- | ????92.79 |
| ????6 | ????- | ????97.41 |
Table 53
| Component | Embodiment 52 |
| Ciprofloxacin | ????1015.18 |
| Sodium alginate | ????5.0 |
| Sodium bicarbonate | ????200.0 |
| Crospolyvinylpyrrolidone | ????176.82 |
| Magnesium stearate | ????33.0 |
| Pulvis Talci | ????10.0 |
| Amount to | ????1440.0 |
| Stripping | |
| Time (hour) | Accumulative total discharges percent |
| ????1 | ????52.5 |
| ????2 | ????68.94 |
| ????3 | ????90.39 |
| ????4 | ????100.8 |
| ????6 | ????104.79 |
Table 54
| Component | Embodiment 53 | Embodiment 54 | Embodiment 55 | Embodiment 56 |
| Ciprofloxacin | ????1015.18 | ????1016.19 | ????1015.18 | ????1015.18 |
| Sodium alginate | ????5.0 | ????5.0 | ????5.0 | ????5.0 |
| Xanthan gum | ????15.0 | ????15.0 | ????15.0 | ????15.0 |
| Sodium bicarbonate | ????0 | ????72.75 | ????291.0 | ????436.5 |
| Crospolyvinylpyrrolidone | ????176.82 | ????176.82 | ????176.82 | ????176.82 |
| Magnesium stearate | ????33.0 | ????33.0 | ????33.0 | ????33.0 |
| Pulvis Talci | ????10.0 | ????10.0 | ????10.0 | ????10.0 |
| Amount to | ????1255.0 | ????1328.76 | ????1546.0 | ????1691.5 |
| Stripping | ||||
| Time (hour) | Accumulative total discharges percent | |||
| ??1 | ????73.06 | ????50.86 | ????49.0 | ????42.46 |
| ??2 | ????73.3 | ????63.6 | ????72.14 | ????74.66 |
| ??3 | ????- | ????73.89 | ????96.3 | ????96.6 |
| ??4 | ????94.8 | ????83.7 | ????103.8 | ????104.1 |
| ??6 | ????87.9 | ????93.51 | ????- | ????- |
| ??8 | ????- | ????98.19 | ????- | ????- |
Though the present invention has done elaboration with reference to specific embodiment, these embodiment only use for setting forth.Present technique field personnel can make many variations obviously, and they are in scope of the present invention.
Claims (43)
1. one kind for the oral tablet formulation once a day that comes the controlled release ciprofloxacin of human body, the ciprofloxacin that comprises medicine effective quantity, sticking solvent of about 0.1-8.0% and/or gel, about 5.0-15% gas generating agent, with about 3.0-15% sweller, described percentage ratio is the percentage by weight that accounts for composition weight.
2. one kind for the oral tablet formulation once a day that comes the controlled release ciprofloxacin of human body, the ciprofloxacin that comprises medicine effective quantity, sticking solvent of about 0.2-5.0% and/or gel, about 5.0-15% gas generating agent, with about 5.0-15% sweller, described percentage ratio is the percentage by weight that accounts for composition weight.
3. preparation according to claim 1 and 2, wherein sticking solvent is carbohydrate natural gum or cellulose ether.
4. preparation according to claim 3, wherein carbohydrate natural gum is xanthan gum, cellulose ether is a hydroxypropyl emthylcellulose.
5. preparation according to claim 1 and 2, wherein gel is a sodium alginate.
6. preparation according to claim 1 and 2 has wherein used a kind of or both in sticking solvent and the gel to be used.
7. preparation according to claim 6, wherein sticking solvent is an xanthan gum.
8. preparation according to claim 3, wherein gas generating agent is selected from sodium bicarbonate, calcium carbonate, sodium carbonate and its mixture.
9. preparation according to claim 3, wherein sweller is a crospolyvinylpyrrolidone.
10. one kind for the oral tablet formulation once a day that comes the controlled release ciprofloxacin of human body, the ciprofloxacin that comprises medicine effective quantity, about 0.2-0.5% sodium alginate, about 0.5-2.0% xanthan gum, about 10.0-25% sodium bicarbonate, with about 5.0-20% crospolyvinylpyrrolidone, described percentage ratio is the percentage by weight that accounts for composition weight, and wherein the weight ratio of sodium alginate and xanthan gum is about 1: 1-1: 10.
11. preparation according to claim 10, it comprises 69.9% ciprofloxacin alkali, 0.34% sodium alginate, 1.03% xanthan gum, 13.7% sodium bicarbonate, 12.1% crospolyvinylpyrrolidone and optional other medicines excipient.
12. preparation according to claim 10, it is a tablet form.
13. one kind oral for human body, the top of stomach or small intestinal controlled release ciprofloxacin once a day, uniform single-layer sheet agent formulation, the ciprofloxacin that comprises medicine effective quantity, about 0.2-0.5% sodium alginate, about 0.5-2.0% xanthan gum, about 10.0-25% sodium bicarbonate, with about 5.0-20% crospolyvinylpyrrolidone, described percentage ratio is the percentage by weight that accounts for composition weight, and wherein the weight ratio of sodium alginate and xanthan gum is about 1: 1-1: 10.
14. preparation according to claim 13, it comprises 69,9% ciprofloxacin alkali, 0.34% sodium alginate, 1.03% xanthan gum, 13.7% sodium bicarbonate, 12.1% crospolyvinylpyrrolidone and optional other medicines excipient.
15. one kind oral for human body, at the tablet formulation once a day of the top of stomach or small intestinal controlled release ciprofloxacin, the ciprofloxacin that comprises medicine effective quantity, about 0.2-0.5% sodium alginate, about 0.5-2.0% xanthan gum, about 10.0-25% sodium bicarbonate, with about 5.0-20% crospolyvinylpyrrolidone, described percentage ratio is the percentage by weight that accounts for composition weight, wherein the weight ratio of sodium alginate and xanthan gum is about 1: 1-1: 10, and described component exists in monolayer with described relative scale.
16. preparation according to claim 15, it comprises 69.9% ciprofloxacin alkali, 0.34% sodium alginate, 1.03% xanthan gum, 13.7% sodium bicarbonate, 12.1% crospolyvinylpyrrolidone and optional other medicines excipient.
17. preparation according to claim 15, it is a tablet form.
18. one kind oral for human body, at the tablet formulation once a day of the top of stomach or small intestinal controlled release ciprofloxacin, the ciprofloxacin that comprises medicine effective quantity, about 0.2-0.5% sodium alginate, about 0.5-2.0% xanthan gum, about 10.0-25% sodium bicarbonate, with about 5.0-20% crospolyvinylpyrrolidone, described percentage ratio is the percentage by weight that accounts for composition weight, and wherein the weight ratio of sodium alginate and xanthan gum is about 1: 1-1: 10.
19. preparation according to claim 18, it comprises 69.9% ciprofloxacin alkali, 0.34% sodium alginate, 1.03% xanthan gum, 13.7% sodium bicarbonate, 12.1% crospolyvinylpyrrolidone and optional other medicines excipient.
20. preparation according to claim 18, it is a tablet form.
21. a slow releasing preparation, it comprises ciprofloxacin, in the burst size that is less than medicine in 4 hours more than 50%.Be less than in 8 hours, the burst size of medicine is more than 60%.
22. a slow releasing preparation, it discharged the medicine more than 50% in about 2-4 hour, discharged the medicine more than 60% in about 4-8 hour.
23. preparation according to claim 22, it is fit to be administered once every day.
24. preparation according to claim 23, it is tablet or Capsule form.
25. preparation according to claim 24, it is the tablet form with pharmaceutically acceptable excipient coating.
26. a slow releasing preparation comprises 100-1000 milligram ciprofloxacin and pharmaceutically acceptable excipient, wherein the gross weight of dosage form is lower than 2000 milligrams.
27. preparation according to claim 26, excipient comprises sticking solvent and/or gel, aerogenesis component and sweller wherein pharmaceutically acceptablely.
28. preparation according to claim 27, it comprises sticking solvent of about 0.1-8.0% and/or gel, and about 5.0-15% gas generating agent and about 3.0-15% sweller, described percent are the w/w percent of compositions.
29. preparation according to claim 28, it comprises sticking solvent of about 0.2-5.0% and/or gel, and about 5.0-15% gas generating agent and about 5.0-15% sweller, described percent are the w/w percent of compositions.
30. preparation according to claim 29, wherein sticking solvent is xanthan gum or hydroxypropyl emthylcellulose (methocel), and gel is a sodium alginate.
31. preparation according to claim 30 uses sticking solvent and sodium alginate.
32. preparation according to claim 31, wherein sticking solvent is an xanthan gum.
33. preparation according to claim 28, wherein gas generating agent is selected from sodium bicarbonate, calcium carbonate, sodium carbonate and its mixture.
34. preparation according to claim 28, wherein sweller is a crospolyvinylpyrrolidone.
35. preparation according to claim 26, it is fit to be administered once every day.
36. preparation according to claim 26, it is tablet or Capsule form.
37. preparation according to claim 26, it is the tablet form with pharmaceutically acceptable excipient coating.
38. the slow-release solid dosage form of a ciprofloxacin, when giving human body oral under the feed condition, provide average serum/peak serum concentration, at least the branch agent, the equivalent that are not less than by comparison in the area under the blood serum concentration-time curve on the minimal inhibitory concentration and minimum persistent period of suppressing on the blood serum concentration give 70% of conventional rapid release ciprofloxacin solid dosage forms.
39. according to the described slow-release solid dosage form of claim 38, when giving human body oral under the feed condition, it is about 3.5-30 microgram-hour/milliliter to unlimited area under curve scope that the drug serum/plasma concentration that provides-time graph has the time 0.
40. according to the described slow-release solid dosage form of claim 38, when under the feed condition to human body when oral, average serum/peak serum concentration scope is about 0.5-4 mcg/ml.
41. according to the described slow release formulation of claim 38, when giving human body oral under the feed condition, it is about 3-26 microgram-hour/milliliter that the drug serum/plasma concentration that provides-time graph has area under curve scope on minimal inhibitory concentration 0.1 mcg/ml.
42. according to the described slow-release solid dosage form of claim 38, when giving human body oral under the feed condition, it is about 2-22 microgram-hour/milliliter that the drug serum/plasma concentration that provides-time graph has area under curve scope on minimal inhibitory concentration 0.25 mcg/ml.
43. according to the described slow-release solid dosage form of claim 38, when giving human body oral under the feed condition, it is about 1-18 microgram-hour/milliliter that the drug serum/plasma concentration that provides-time graph has area under curve scope on minimal inhibitory concentration 0.5 mcg/ml.
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| US51788700A | 2000-03-03 | 2000-03-03 | |
| US09/517,887 | 2000-03-03 |
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| CN01805998A Pending CN1420763A (en) | 2000-03-03 | 2001-02-28 | Oral administration controlled release system for once daily administration of ciprofloxacin |
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| CN101237858B (en) * | 2005-07-19 | 2012-07-04 | 爱的发 | Gastroretentive formulations and manufacturing process thereof |
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| GB0209265D0 (en) | 2002-04-23 | 2002-06-05 | Novartis Ag | Organic compounds |
| US20030229101A1 (en) * | 2002-06-06 | 2003-12-11 | Sherman Bernard Charles | Tablets comprising ciprofloxacin hydrochloride |
| DE10351448A1 (en) | 2003-11-04 | 2005-06-09 | Bayer Healthcare Ag | Flavor-containing drug formulations with improved pharmaceutical properties |
| DE602006012962D1 (en) * | 2006-07-19 | 2010-04-29 | Tabuk Pharmaceutical Mfg Co | Pharmaceutical preparations of ciprofloxacin |
| EP3247384B1 (en) | 2015-01-14 | 2023-10-04 | The Regents of the University of Colorado, a body corporate | In vitro method of diagnosis of type 1 diabetes with insulin mimotopes |
| EP3419669A4 (en) * | 2016-02-23 | 2019-10-30 | Matripharm International Inc. | DOUBLE-SPEED RELEASE COMPOSITION WITH HIGH MEDICAL DRUG CHARGE |
| WO2017165508A1 (en) | 2016-03-24 | 2017-09-28 | Im Therapeutics | Methods of treating autoimmune disease |
| US11052060B2 (en) | 2018-02-12 | 2021-07-06 | The Regents Of The University Of Colorado, A Body Corporate | Compounds and methods for treating autoimmunity |
| US11013707B2 (en) | 2018-03-23 | 2021-05-25 | The Regents Of The University Of Colorado, A Body Corporate | Administration of oral methyldopa |
| CN109806237A (en) * | 2019-03-13 | 2019-05-28 | 悦康药业集团上海制药有限公司 | A kind of Ciprofloxacin Lactate effervescent tablet and preparation method thereof |
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| US5096714A (en) * | 1988-06-28 | 1992-03-17 | Hauser-Kuhrts, Inc. | Prolonged release drug tablet formulations |
| JPH0624959A (en) * | 1991-10-04 | 1994-02-01 | Bayer Yakuhin Kk | Medice release solid pharmaceutical preparation of gastric suspending type sustained |
| DE4406424A1 (en) * | 1994-02-28 | 1995-08-31 | Bayer Ag | Expandable dosage forms |
| DE19839057A1 (en) * | 1998-08-28 | 2000-03-02 | Koch Berthold | Purge air controller for a drying device for compressed air |
| EE200100153A (en) * | 1998-09-14 | 2002-06-17 | Ranbaxy Laboratories Limited | Controlled drug delivery system for oral drug delivery that provides temporal and spatial control |
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