WO2001064183A1 - Orally administered controlled delivery system for once daily administration of ciprofloxacin - Google Patents
Orally administered controlled delivery system for once daily administration of ciprofloxacin Download PDFInfo
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- WO2001064183A1 WO2001064183A1 PCT/IB2001/000279 IB0100279W WO0164183A1 WO 2001064183 A1 WO2001064183 A1 WO 2001064183A1 IB 0100279 W IB0100279 W IB 0100279W WO 0164183 A1 WO0164183 A1 WO 0164183A1
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- WIPO (PCT)
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- formulation
- ciprofloxacin
- agent
- xanthan gum
- sodium alginate
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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
- A61K9/20—Pills, tablets, discs, rods
-
- 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
-
- 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
- A61P31/04—Antibacterial agents
Definitions
- the present invention relates to a pharmaceutical composition in the form of tablets or capsules which provides a combination of spatial and temporal control of drug delivery, specifically for the drug ciprofloxacin, to a patient for effective therapeutic results.
- the pharmaceutical composition comprises ciprofloxacin, a gas generating component, a swelling agent, and at least one of either a viscolyzing agent and a gelling agent.
- the swelling agent belongs to a class of highly absorbent compounds commonly referred to as superdisinte- grants. This class of compounds includes, for example, cross-linked polyvinyl pyrrolidone and cross-linked sodium carboxymethylcellulose.
- the viscolyzing agent is a highly viscous material which upon contact with gastric fluid entraps the gas produced by the gas generating component.
- the viscolyzing agent comprises, for example, a carbohydrate gum, e.g., xanthan gum or a cellulose ether, e.g., hydroxypropyl methylcellulose (methocel).
- the gelling agent is preferably a cross-linkable gelling agent, such as a water soluble salt of one or more polyuronic acids, e.g., sodium alginate.
- the improved controlled drug delivery system of the present invention is designed to deliver effectively ciprofloxacin to a patient over a specific time period (temporal control) and from a particular portion of the patient's gastrointestinal tract (spatial control).
- the improved controlled drug delivery system avoids dose dumping and results in the most therapeutic administration of ciprofloxacin to a person. It is well known to those skilled in the art that for ailments requiring multiple doses of a particular drug, the blood levels of a drug need to be maintained above its minimum effective level and below its minimum toxic level in order to obtain the desired therapeutic effects, to avoid undesired toxic effects, and to minimize side effects. When the blood levels of a drug are in this range, the drug is eliminated from the body at a particular rate.
- a controlled drug delivery system is usually designed to deliver the drug at this particular rate; safe and effective blood levels are maintained for a period as long as the system continues to deliver the drug at this rate.
- Controlled drug delivery usually results in substantially constant blood levels of the active ingredient as compared to the uncontrolled fluctuations observed when multiple doses of quick releasing conventional dosage forms are administered to a patient. Controlled drug delivery results in optimum therapy, and not only reduces the frequency of dosing, but may also reduce the severity and frequency of side effects.
- An orally administered controlled drug delivery system encounters a wide range of highly variable conditions, such as pH, agitation intensity, and composition of the gastrointestinal fluids as it passes down the gastrointestinal tract.
- an oral controlled drug delivery system will deliver the drug at a constant and reproducible rate in spite of the varying conditions. Considerable efforts have therefore been made to design oral controlled drug delivery systems that overcome these drawbacks and deliver the drug at a constant rate as it passes down the gastrointestinal tract.
- a drug has a clear cut "absorption window,” i.e., the drug is absorbed only from specific regions of the stomach or upper parts of the small intestine, it may not be completely absorbed when administered in the form of a typical oral controlled drug delivery system. It is apparent that for a drug having such an "absorption window,” an effective oral controlled drug delivery system should be designed not only to deliver the drug at a controlled rate, but also to retain the drug in the upper parts of the gastrointestinal tract for a long period of time.
- U.S. Patent No. 5,651 ,985, assigned to Bayer AG discloses a composition comprising a pharmacologically active compound, a pharmaceutically acceptable auxiliary, polyvinylpyrrolidone, and a methacrylic acid polymer having an acidic number between 100 and 1200 mg of KOH/g of polymer solid substance.
- the composition also comprises a gas forming additive.
- the composition absorbs many times its weight of acidic water and forms a highly swollen gel of high mechanical and dimensional stability.
- the gel forming agent should be sufficient so that after administration it can swell up to a size which prevents passage through the pylorous for a relatively long time.
- At least 30% by weight and up to 90% by weight of the composition comprises the polymers, and thus dosage forms containing a high dose medicament would be large and inconvenient for oral administration.
- the release period obtained by the Nishioka tablet is so slow that only 46% of the Nishioka tablet is dissolved after 24 hours (see plot).
- the practical and significant effect of this slow dissolution is that the Nishioka formulation would not be effective as a "once daily" ciprofloxacin formulation.
- a. generates and entraps a gas in a hydrated matrix upon contact with an aqueous medium or gastric fluids, and which retains a substantially monolithic form in the stomach
- b. provides increased gastric residence and thereby a longer period of residence of the drug delivery system in the gastrointestinal tract
- c. delivers the drug at a controlled rate such that the drug is delivered over a period of time which is the same as or less than the period of residence of the delivery system in the absorptive regions of the gastrointestinal tract
- d. provides, as compared to other oral controlled drug delivery systems, increased absorption of a drug that is absorbed largely from the upper parts of the gastrointestinal tract.
- the present invention provides a novel pharmaceutical composition in the form of tablets or capsules which composition constitutes an orally administered once daily formulation for the controlled release of ciprofloxacin.
- the pharma- ceutical composition comprises ciprofloxacin, a gas generating component, a swelling agent (e.g., cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethylcellulose), at least one of either a viscolyzing agent (e.g., a carbohydrate gum such as xanthan gum or a cellulose ether such as hydroxy- propyl methylcellulose), and a gelling agent (e.g., sodium alginate).
- a viscolyzing agent e.g., a carbohydrate gum such as xanthan gum or a cellulose ether such as hydroxy- propyl methylcellulose
- a gelling agent e.g., sodium alginate
- the inventive oral controlled drug delivery system which is a pharmaceutical composition in the form of tablets or capsules comprises a pharmaceutically effective amount of ciprofloxacin, about 0.1 % to about 8% by weight of at least one of a viscolyzing agent and a gelling agent, about 5% to about 15% by weight of the gas generating component, and about 3% to about
- the amount of at least one of the viscolyzing agent and the gelling agent ranges from about 0.2% to about 5% and the amount of the swelling agent ranges from about 3% to about 15%.
- the present invention is related to a once-daily tablet formulation for oral administration in humans for the controlled release of ciprofloxacin comprising a pharmaceutically effective amount of ciprofloxacin, about 0.2% to about 0.5% sodium alginate, about 0.5 to about 2.0% xanthan gum, about 10.0% to about 25% sodium bicarbonate, and about 5.0% to about 20% cross-linked polyvinylpyrrolidone, said percentages being w/w of the composition, wherein the weight ratio of sodium alginate to xanthan gum is between about 1 :1 to about 1 :10.
- the swelling agents used herein (cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethylcellulose) belong to a class of compounds known as super-disintegrants which usually function to promote disintegration of a tablet by absorbing large amounts of water and thereby swelling. This expansion, as well as hydrostatic pressure, cause the tablet to burst.
- a tablet which also comprises a gas generating component (which may actually be a gas generating couple), one would expect the tablet to disintegrate instantly upon contact with aqueous fluid, if not blow apart.
- a tablet or capsule formed from the formulation of the present invention is retained for longer periods of time in the stomach (spatial control) than previously known hydrophilic matrix tablets, floating capsules and bioadhesive tablets when these systems are administered with food.
- the formulation of the present invention results in release of the drug into the more absorptive regions of the gastrointestinal tract, i.e., into the stomach and the small intestine rather than into the large intestine where drug absorption is poor or erratic.
- the drug is released at a constant and controlled rate, it will also be absorbed at a more or less constant rate.
- the present formulation provides the desired absorption at a rate such that effective plasma levels are maintained for a prolonged duration and the formulation is especially suitable for once-daily administration (temporal control).
- the formulation provides increased absorption of the drug as compared to other oral controlled drug delivery systems such as hydrophilic matrix tablets and floating capsules. This is achieved by adjusting the time period of release for the drug so that it is about the same as or less than the retention time of the tablets at the site of absorption.
- the tablet or capsule is not transported past the "absorption window" prior to releasing all of the drug, and maximum bioavailability is attained.
- Figs. 2 and 3 are graphs illustrating mean plasma concentration vs. time for ciprofloxacin free base when incorporated in the oral controlled drug delivery system of the present invention as compared to CiproTM immediate release tablets under fed and fasting conditions.
- the formulation of the present invention includes ciprofloxacin, a swelling agent, and at least one of either a viscolyzing agent and a gelling agent. Together these components form a hydrated gel matrix.
- the formulation further comprises a gas generating component such that a gas (generally C0 2 but in some cases S0 2 ) is generated in a controlled manner and is entrapped in the hydrated gel matrix.
- a gas generally C0 2 but in some cases S0 2
- the swelling agent which belongs to the class of compounds known as superdisintegrants, absorbs large amounts of fluid and causes the matrix to swell significantly.
- the gas generated by the gas generating component also causes matrix expansion.
- swelling of the matrix is controlled by the viscolyzing agent and/or the gelling agent, which acts both as a swelling and a drug release controlling agent.
- the characteristics of the hydrated gel matrix can be modified by altering the ratios and amounts of the swelling agent, the viscolyzing agent and/or the gelling agent, and the gas generating component without loss of physical integrity of the hydrated gel system.
- the composition can thus be designed to obtain the optimal rate of release of the ciprofloxacin. It has also been found that such a composition when administered with food is retained for longer periods in the stomach, and thereby in the gastrointestinal tract without loss of its physical integrity.
- the novel pharmaceutical composition is most suited for controlled delivery of drugs that are absorbed only from the upper parts of the gastro- intestinal tract with a specific absorption window (i.e., spatial control), i.e., ciprofloxacin (which is absorbed only from the region extending from the stomach to the jejunum).
- the pharmaceutical composition is particularly suitable for ciprofloxacin because the absorption of the drug is dependent on its solubility characteristics.
- Ciprofloxacin dissolves at lower pH values and therefore the "absorption window" is predominantly in the stomach or upper parts of the small intestine. In the case of drugs such as ciprofloxacin, the tablet is not transported past the "absorption window" prior to releasing all the drug so that maximum bioavailability can be attained.
- the pharmaceutical composition can incorporate a high dose medicament. Accordingly, the amount of ciprofloxacin to be used in the present invention typically ranges from about 0.5 mg up to about 1200 mg.
- the gas generating component comprises a substance known to produce gas upon contact with gastric fluid.
- Examples of the gas generating component that may be used in the present invention include carbonates, such as calcium carbonate, potassium carbonate or sodium carbonate, and bicarbonates such as sodium hydrogen carbonate.
- the gas generating component interacts with an acid source triggered by contact with water or simply with gastric fluid to generate carbon dioxide that gets entrapped within the hydrated gel matrix of the swelling composition.
- the gas generating component such as carbonates and bicarbonates may be present in amounts from about 5% to about 15%, by weight of the composition.
- the acid source may be one or more of an edible organic acid, a salt of an edible organic acid, or mixtures thereof.
- organic acids that may be used as the acid source in the present invention include, for example: citric acid or its salts such as sodium citrate or calcium citrate; malic acid, tartaric acid, succinic acid, fumaric acid, maleic acid, or their salts; ascorbic acid or its salts such as sodium or calcium ascorbate; glycine, sarcosine, alanine, taurine, glutamic acid, and the like.
- the organic acid salts that may be used as the acid source in the present invention include, for example, a mono-alkali salt of an organic acid having more than one carboxylic acid functional group, a bialkali metal salt of an organic acid having more than two carboxylic acid functional groups, and the like.
- the acid source may be present in an amount from about 0.5% to 15% by weight, preferably from about 0.5% to about 10% by weight, and more preferably from about 0.5 % to about 5% by weight, of the total weight of the composition.
- the pharmaceutical composition comprises a swelling agent which is capable of swelling to greater than its original volume when coming into contact with an aqueous fluid, such a gastrointestinal fluid.
- the preferred swelling agent is cross-linked polyvinylpyrrolidone; other swelling agents include cross-linked carboxymethylcellulose sodium and the like. These compounds belong to the class of compounds known as super-disintegrants.
- the swelling agent which normally swells to several times its original volume in water, exhibits a controlled swelling in the presence of the viscolyzing and/or gelling agent.
- the swelling agent may be present in an amount from about 3% to about 15% by weight of the total weight of the composition. More preferably, the swelling agent may be present in an amount from about 5% to about 15% by weight of the total weight of the composition.
- the pharmaceutical composition comprises a viscolyzing agent which, upon contact with gastrointestinal fluid, instantaneously viscolyzes to trap the gas generated by the gas generating component.
- the viscolyzing agent comprises of a carbohydrate gum, such as xanthan gum.
- carbohydrate gums include tragacanth gum, gum karaya, guar gum, acacia, and the like.
- Cellulose ethers of moderate to high viscosity, like hydroxypropyl methylcellulose can also be used.
- xanthan gum helps in maintaining tablet integrity when stirred in an aqueous medium, and in sustaining the release of the drug.
- the pharmaceutical composition comprises either said viscolyzing agent or a gelling agent or both.
- the gelling agent is preferably sodium alginate.
- the gelling agent cross-links with time to form a stable structure which entraps the generated gas.
- the gelling agent results in a hydrodynamically balanced system whereby the matrix is retained in the stomach for an extended period of time.
- the viscolyzing agent and the gelling agent provide a tortuous diffusion pathway for the drug, thereby resulting in controlled drug release.
- the viscolyzing agent and/or the gelling agent are present in an amount from about 0.1 % to about 8% by weight of the total weight of the composition. More preferably, the viscolyzing agent and/or the gelling agent are present in an amount from about 0.2% to about 5% by weight of the total weight of the composition.
- the pharmaceutical composition of the present invention comprises a gas generating component and a swelling agent which is most frequently employed as a disintegrant.
- a viscolyzing agent and/or gelling agent such as xanthan gum
- both components can result in rapid disintegration of tablets.
- Tablets containing hydroxypropylcellulose in amounts approximately the same as the amounts of carbohydrate gum in the present invention disintegrate in 10 to 15 minutes when stirred in an acidic medium.
- Such disintegration can result in a dose dumping effect, i.e., rapid delivery of a large quantity of drug from the system, and is undesirable particularly because controlled drug delivery systems contain several times the amount of drug in a conventional formulation.
- Granules formed as a result of the disintegration are also emptied from the stomach in a shorter time than intact tablets.
- the present invention avoids such disintegration with the use of small quantities of a viscolyzing agent, such as a heteropolysaccharide gum, so that tablets or capsules containing a high dose medicament are of an acceptable size to be taken orally.
- the viscolyzing agent is xanthan gum.
- Xanthan gum also known as corn sugar gum, is a high
- biosynthetic polysaccha de gum produced by a pure-culture aerobic fermentation of a carbohydrate with Xanthomonas campestris. It is extraordinarily enzymatically resistant.
- the xanthan gum has a particle size such that at least 50% by weight passes through a sieve with 44
- the xanthan gum has a particle size such that all of it passes through a 44 ⁇ m mesh
- the viscolyzing agent is present in an amount from about 0.1 % to about 8%, by weight of the total weight of the composition. More preferably, the viscolyzing agent is present in an amount from about 0.2% to about 5%, by weight of the total weight of the composition.
- the pharmaceutical composition may also contain other conventional pharmaceutical excipients, for example, water soluble diluents such as lactose, dextrose, mannitol, sorbitol, and the like; water insoluble diluents such as starch, microcrystalline cellulose, powdered cellulose, and the like; or lubricants such as talc, stearic acid or its salt, magnesium stearate, and the like.
- water soluble diluents such as lactose, dextrose, mannitol, sorbitol, and the like
- water insoluble diluents such as starch, microcrystalline cellulose, powdered cellulose, and the like
- lubricants such as talc, stearic acid or its salt, magnesium stearate, and the like.
- This material was supplied as coarse. It was milled to obtain the desired size range.
- the pharmaceutical composition when it is in the form of tablets, it may be coated with a thin layer of a rapidly dissolving water soluble pharmaceutical excipient.
- a coating of a water soluble excipient results in faster hydration and gas formation than a coating of water soluble polymer and is the preferred coating.
- water soluble pharmaceutical excipients examples include film formers like cellulose ether polymers, or soluble pharmaceutical diluents like lactose, sucrose, dextrose, mannitol, xylitol, and the like.
- the water soluble excipient used as a coating is lactose.
- the tablets may be coated to a weight build-up of about 1% to about 4%, preferably, about 1 % to about 2%.
- the coating also helps in masking any bitter taste associated with the drug.
- Ciprofloxacin is an example of a drug which is absorbed only from the upper part of the intestine.
- the pharmaceutical composition is given in Table 1. TABLE 1
- Ciprofloxacin, xanthan gum, sodium alginate, cross-linked carboxymethylcellulose, sodium bicarbonate, microcrystalline cellulose, sodium chloride, citric acid, and half of the lubricants were mixed together and sieved through a sieve (British Standard Sieve (BSS) No. 44).
- the blend was compacted on a roll- compactor and the compact sieved through a sieve (BSS No. 22) to obtain granules.
- the granules were mixed with the remaining lubricants and Carbopol and then compressed into tablets.
- the tablets were spray coated with an aqueous coating composition containing 15.8% w/w lactose, 3.18% w/w talc, and 1.587% w/w titanium dioxide to a weight build up of 1 % to 1.5%.
- This example illustrates the present invention when the active ingredient is ciprofloxacin base.
- the pharmaceutical composition is given in Table 3.
- Ciprofloxacin was sifted through British Standard Sieve (BSS) No. 22.
- Xanthan gum, sodium alginate, sodium bicarbonate, crospovidone and half the quantities of lubricants, namely, magnesium stearate and talc, were sifted through a sieve (BSS No. 44). All the above mentioned sifted ingredients were blended uniformly, compacted on a roll-compactor and the compacts sifted through a sieve (BSS No. 18) to obtain granules. Remaining magnesium stearate and talc were sifted through a sieve (BSS No.
- granule fines iner than BSS No. 60
- the tablets were optionally spray coated with an aqueous coating composition containing 15.8% w/w lactose, 3.18% w/w talc and 1.587% w/w titanium dioxide to a weight build up of 1 % to 1.5%.
- This example illustrates the present invention when the active ingredient is ciprofloxacin hydrochloride.
- the pharmaceutical composition is given in Table 5.
- Example 6 The tablets were prepared as described in Example 1 except that Ac-Di- Sol was incorporated extragranularly. Tablets were tested for dissolution as described in Example 1. The dissolution results are given in Table 6.
- the bioadhesive tablet was prepared as a bilayer tablet.
- the drug layer composition is given in Table 7, and the bioadhesive layer composition is given in Table 8.
- the tablets were prepared by conventional steps of mixing, roll compaction, sieving, blending with the lubricants and compression into bi-layered tablets. 70 mg of barium sulphate was incorporated into the bioadhesive layer to function as x-ray contrast medium. Gastric retention studies of the bioadhesive bi-layered tablets were done on healthy male volunteers who were given two tablets following a standard breakfast. X-ray images were recorded periodically. The bioadhesive tablets were retained in the stomach for 2.5 to 3.5 hrs.
- Hydrophilic matrix tablets with the composition given in Table 9 were also prepared.
- the tablets were prepared by conventional steps of mixing, roll compaction, sieving, blending with the lubricants and compression into tablets.
- barium sulphate 50 mg was incorporated into the above composition.
- Gastric retention studies were done on healthy male volunteers who were given two tablets/capsules after a standard breakfast. X-ray images were recorded periodically. The hydrophilic matrix tablets were retained for 2 to 2.5 hrs, and the floating capsules for 3.5 to 4.5 hrs.
- both the once-daily formulations (A and B) gave an extent of absorption comparable to the immediate release tablets (R).
- the time period of release of drug into gastric fluid was adjusted such that it was about the same as or less than the retention time of the tablets at the site of absorption.
- formulation B gave a serum concentration time profile that would be desirable for a once-daily formulation in that the peak serum concentration was comparable to that for the immediate release drug, and the effective serum concentrations of the drug were maintained for longer periods.
- formulation B of the prior Example did not give as good results as the twice-daily CiproTM 500 mg tablets.
- the Area Under the Curve above the Minimum Inhibitory Concentration (AUC above MIC) for formulation B was less than that of conventional CiproTM tablets.
- Tablets were prepared from the components in Table 12 and tested for dissolution as described earlier. Remarkably, it was observed that the in vitro dissolution profile of the OD formulation (Table 13) was much faster releasing than formulation B. Thus, more than 80% of the drug in the OD tablets was released within 4 hours as compared to 8 hours for formulation B. Compare Table 12 with Table 13.
- the mean stomach retention of the OD tablets was studied by magnetic resonance imaging and was found to be 5.33 hours which correlated well with the 6 hour dissolution profile of these tablets.
- Figs. 2 and 3 show the plasma concentration over time of the OD tablets (fed) vs. CiproTM (fed), and
- Fig. 3 shows the plasma concentration of the OD tablets (fed) vs. CiproTM
- Figures 2 and 3 are based on the following data listed in Table 14 and
- the OD formulation gave a plasma concentration time profile desirable for once daily dosage form in that the peak plasma concentration (Cmax) was comparable to that for the immediate release drug indicating a similar rate of
- Table 17 gives the AUC above MIC at the three levels of 0.1 ⁇ g/ml, 0.25 ⁇ g/ml and 0.5 ⁇ g/ml for ciprofloxacin OD 1000 mg vs. CiproTM 500 mg bid. These values for ciprofloxacin OD were better than those for CiproTM immediate release tablets administered twice daily under fed conditions, indicating better therapeutic efficacy of the OD formulation when both immediate and controlled dosage forms were administered after food. The therapeutic efficacy of the OD tablets under fed condition was comparable to the therapeutic efficacy of the CiproTM immediate release tablets administered under fasting conditions.
- serum/plasma concentration ranging from about 0.5 to about 4 ⁇ g/ml.
- a minimum inhibitory concentration of 0.1 ⁇ g/ml ranging from about 3 to about
- 100 mg-1 ,000 mg tablets would provide a medicament serum/plasma concentration - time curve with an area under the curve (above a minimum inhibitory
- concentration of 0.5 ⁇ m/ml ranging from about 1 to about 18 ⁇ g-hours/ml.
- EXAMPLE 6 This example illustrates the present invention when the active ingredient is ciprofloxacin base:
- the tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are given in Table 19.
- the tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are given in Table 21.
- the tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are given in Table 23.
- the tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are given in Table 25.
- the tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are given in Table 29.
- the tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are given in Table 31.
- EXAMPLE 13 This example illustrates the present invention when the active ingredient is ciprofloxacin base: TABLE 32
- the tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are given in Table 33.
- EXAMPLE 14 This example illustrates the present invention when the active ingredient is ciprofloxacin base: TABLE 34
- the tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are given in Table 35.
- the tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are given in Table 38.
- the tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are given in Table 40.
- the tablets were prepared as described in Example 2. The tablets were tested for dissolution as described in Example 1. The dissolution results are given in Table 42.
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Abstract
Description
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Priority Applications (18)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
MXPA02008568A MXPA02008568A (en) | 2000-03-03 | 2001-02-28 | Orally administered controlled delivery system for once daily administration of ciprofloxacin. |
EA200200914A EA200200914A1 (en) | 2000-03-03 | 2001-02-28 | DOSING CONTROL SYSTEM FOR SINGLE-DAY DAILY RECEPTION OF INTENDED CYPROFLOXACYN |
NZ520927A NZ520927A (en) | 2000-03-03 | 2001-02-28 | Orally administered controlled delivery system for once daily administration of ciprofloxacin |
APAP/P/2002/002627A AP1485A (en) | 2000-03-03 | 2001-02-28 | Orally administered controlled delivery system for once daily administration of ciprofloxacin. |
HU0204417A HUP0204417A3 (en) | 2000-03-03 | 2001-02-28 | Oral ciprofloxacin-composition of controlled release |
EP01908038A EP1263409A1 (en) | 2000-03-03 | 2001-02-28 | Orally administered controlled delivery system for once daily administration of ciprofloxacin |
CA002400950A CA2400950A1 (en) | 2000-03-03 | 2001-02-28 | Orally administered controlled delivery system for once daily administration of ciprofloxacin |
IL15155301A IL151553A0 (en) | 2000-03-03 | 2001-02-28 | Orally administered controlled delivery system for once daily administration of ciprofloxacin |
PL01365071A PL365071A1 (en) | 2000-03-03 | 2001-02-28 | Orally administered controlled delivery system for once daily administration of ciprofloxacin |
EEP200200497A EE200200497A (en) | 2000-03-03 | 2001-02-28 | Oral Controlled-Release Systems for Ciprofloxacin Daily Administration |
AU35897/01A AU3589701A (en) | 2000-03-03 | 2001-02-28 | Orally administered controlled delivery system for once daily administration of ciprofloxacin |
BR0108958-7A BR0108958A (en) | 2000-03-03 | 2001-02-28 | Orally administered controlled release system for daily administration of ciprofloxacin |
SK1254-2002A SK12542002A3 (en) | 2000-03-03 | 2001-02-28 | Orally administered controlled delivery system for once daily administration of ciprofloxacin |
JP2001563081A JP2003525229A (en) | 2000-03-03 | 2001-02-28 | Oral administration controlled delivery system for once-daily administration of ciprofloxacin |
NO20024108A NO20024108L (en) | 2000-03-03 | 2002-08-28 | Orally administered controlled delivery system for daily administration of ciprofloxacin |
IS6532A IS6532A (en) | 2000-03-03 | 2002-08-28 | Dosage formulation for oral administration of ziprofloxacin once daily |
HRP20020715 HRP20020715A2 (en) | 2000-03-03 | 2002-08-30 | Orally adminestered controlled delivery system for once daily administration of ciprofloxacin |
BG107055A BG107055A (en) | 2000-03-03 | 2002-09-02 | Orally administered controlled delivery system for once daily administration of ciprofloxacin |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US51788700A | 2000-03-03 | 2000-03-03 | |
US09/517,887 | 2000-03-03 |
Publications (1)
Publication Number | Publication Date |
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WO2001064183A1 true WO2001064183A1 (en) | 2001-09-07 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/IB2001/000279 WO2001064183A1 (en) | 2000-03-03 | 2001-02-28 | Orally administered controlled delivery system for once daily administration of ciprofloxacin |
Country Status (31)
Country | Link |
---|---|
EP (1) | EP1263409A1 (en) |
JP (1) | JP2003525229A (en) |
KR (1) | KR20030009374A (en) |
CN (1) | CN1420763A (en) |
AP (2) | AP2001002084A0 (en) |
AR (1) | AR032614A1 (en) |
AU (1) | AU3589701A (en) |
BG (1) | BG107055A (en) |
BR (1) | BR0108958A (en) |
CA (1) | CA2400950A1 (en) |
CZ (1) | CZ20022883A3 (en) |
DO (1) | DOP2001000130A (en) |
EA (1) | EA200200914A1 (en) |
EC (1) | ECSP013952A (en) |
EE (1) | EE200200497A (en) |
GT (1) | GT200100033A (en) |
HN (1) | HN2001000038A (en) |
HR (1) | HRP20020715A2 (en) |
HU (1) | HUP0204417A3 (en) |
IL (1) | IL151553A0 (en) |
IS (1) | IS6532A (en) |
MX (1) | MXPA02008568A (en) |
NO (1) | NO20024108L (en) |
NZ (1) | NZ520927A (en) |
OA (1) | OA12381A (en) |
PE (1) | PE20011113A1 (en) |
PL (1) | PL365071A1 (en) |
SK (1) | SK12542002A3 (en) |
WO (1) | WO2001064183A1 (en) |
YU (1) | YU66202A (en) |
ZA (1) | ZA200206764B (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2003103674A1 (en) * | 2002-06-06 | 2003-12-18 | Bernard Charles Sherman | Tablets comprising ciprofloxacin hydrochloride |
EP1745775A1 (en) * | 2005-07-19 | 2007-01-24 | Ethypharm | Gastroretentive formulations and manufacturing process thereof. |
EP1880722A1 (en) * | 2006-07-19 | 2008-01-23 | Tabuk Pharmaceutical Manufacturing Co. | Pharmaceutical compositions of ciprofloxacin |
US7858120B2 (en) | 2003-11-04 | 2010-12-28 | Bayer Animal Health Gmbh | Pharmaceutical formulations containing flavouring substances with improved pharmaceutical properties |
US9011911B2 (en) | 2002-04-23 | 2015-04-21 | Novartis Ag | High drug load tablet |
US9820957B2 (en) | 2016-03-24 | 2017-11-21 | The Regents Of The University Of Colorado, A Body Corporate | Methods of treating autoimmunity |
US10363288B2 (en) | 2015-01-14 | 2019-07-30 | National Jewish Health | Insulin mimotopes and methods of using the same |
EP3419669A4 (en) * | 2016-02-23 | 2019-10-30 | Matripharm International Inc. | Dual-rate release formulation with high drug loading |
US11013707B2 (en) | 2018-03-23 | 2021-05-25 | The Regents Of The University Of Colorado, A Body Corporate | Administration of oral methyldopa |
US11052060B2 (en) | 2018-02-12 | 2021-07-06 | The Regents Of The University Of Colorado, A Body Corporate | Compounds and methods for treating autoimmunity |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH0624959A (en) * | 1991-10-04 | 1994-02-01 | Bayer Yakuhin Kk | Medice release solid pharmaceutical preparation of gastric suspending type sustained |
US5292518A (en) * | 1988-06-28 | 1994-03-08 | Hauser-Kuhrts | Prolonged-release drug tablet formulations |
EP0669129A2 (en) * | 1994-02-28 | 1995-08-30 | Bayer Ag | Expandable release controlled medicaments |
WO2000015198A1 (en) * | 1998-09-14 | 2000-03-23 | Ranbaxy Laboratories Limited | Orally administered controlled drug delivery system providing temporal and spatial control |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE19839057A1 (en) * | 1998-08-28 | 2000-03-02 | Koch Berthold | Purge air controller for a drying device for compressed air |
-
2001
- 2001-02-28 PL PL01365071A patent/PL365071A1/en not_active Application Discontinuation
- 2001-02-28 HU HU0204417A patent/HUP0204417A3/en unknown
- 2001-02-28 OA OA1200200267A patent/OA12381A/en unknown
- 2001-02-28 EE EEP200200497A patent/EE200200497A/en unknown
- 2001-02-28 NZ NZ520927A patent/NZ520927A/en unknown
- 2001-02-28 CN CN01805998A patent/CN1420763A/en active Pending
- 2001-02-28 AP APAP/P/2001/002084A patent/AP2001002084A0/en unknown
- 2001-02-28 EP EP01908038A patent/EP1263409A1/en not_active Withdrawn
- 2001-02-28 AP APAP/P/2002/002627A patent/AP1485A/en active
- 2001-02-28 SK SK1254-2002A patent/SK12542002A3/en unknown
- 2001-02-28 JP JP2001563081A patent/JP2003525229A/en not_active Withdrawn
- 2001-02-28 IL IL15155301A patent/IL151553A0/en unknown
- 2001-02-28 CZ CZ20022883A patent/CZ20022883A3/en unknown
- 2001-02-28 YU YU66202A patent/YU66202A/en unknown
- 2001-02-28 EA EA200200914A patent/EA200200914A1/en unknown
- 2001-02-28 AR ARP010100957A patent/AR032614A1/en not_active Application Discontinuation
- 2001-02-28 WO PCT/IB2001/000279 patent/WO2001064183A1/en not_active Application Discontinuation
- 2001-02-28 BR BR0108958-7A patent/BR0108958A/en not_active Withdrawn
- 2001-02-28 CA CA002400950A patent/CA2400950A1/en not_active Abandoned
- 2001-02-28 MX MXPA02008568A patent/MXPA02008568A/en unknown
- 2001-02-28 KR KR1020027011441A patent/KR20030009374A/en not_active Application Discontinuation
- 2001-02-28 AU AU35897/01A patent/AU3589701A/en not_active Abandoned
- 2001-03-01 GT GT200100033A patent/GT200100033A/en unknown
- 2001-03-01 PE PE2001000206A patent/PE20011113A1/en not_active Application Discontinuation
- 2001-03-01 EC EC2001003952A patent/ECSP013952A/en unknown
- 2001-03-02 HN HN2001000038A patent/HN2001000038A/en unknown
- 2001-03-02 DO DO2001000130A patent/DOP2001000130A/en unknown
-
2002
- 2002-08-23 ZA ZA200206764A patent/ZA200206764B/en unknown
- 2002-08-28 NO NO20024108A patent/NO20024108L/en unknown
- 2002-08-28 IS IS6532A patent/IS6532A/en unknown
- 2002-08-30 HR HRP20020715 patent/HRP20020715A2/en not_active Application Discontinuation
- 2002-09-02 BG BG107055A patent/BG107055A/en unknown
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5292518A (en) * | 1988-06-28 | 1994-03-08 | Hauser-Kuhrts | 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 |
EP0669129A2 (en) * | 1994-02-28 | 1995-08-30 | Bayer Ag | Expandable release controlled medicaments |
WO2000015198A1 (en) * | 1998-09-14 | 2000-03-23 | Ranbaxy Laboratories Limited | Orally administered controlled drug delivery system providing temporal and spatial control |
Non-Patent Citations (1)
Title |
---|
DATABASE WPI Section Ch Week 199422, Derwent World Patents Index; Class A96, AN 1994-178692, XP002173158 * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9011911B2 (en) | 2002-04-23 | 2015-04-21 | Novartis Ag | High drug load tablet |
WO2003103674A1 (en) * | 2002-06-06 | 2003-12-18 | Bernard Charles Sherman | Tablets comprising ciprofloxacin hydrochloride |
US7858120B2 (en) | 2003-11-04 | 2010-12-28 | Bayer Animal Health Gmbh | Pharmaceutical formulations containing flavouring substances with improved pharmaceutical properties |
WO2007010400A3 (en) * | 2005-07-19 | 2007-04-05 | Ethypharm Sa | Gastroretentive formulations and manufacturing process thereof |
WO2007010400A2 (en) * | 2005-07-19 | 2007-01-25 | Ethypharm | Gastroretentive formulations and manufacturing process thereof |
EP1745775A1 (en) * | 2005-07-19 | 2007-01-24 | Ethypharm | Gastroretentive formulations and manufacturing process thereof. |
US9629800B2 (en) | 2005-07-19 | 2017-04-25 | Ethypharm | Gastroretentive formulations and manufacturing process thereof |
EP1880722A1 (en) * | 2006-07-19 | 2008-01-23 | Tabuk Pharmaceutical Manufacturing Co. | Pharmaceutical compositions of ciprofloxacin |
US10363288B2 (en) | 2015-01-14 | 2019-07-30 | National Jewish Health | Insulin mimotopes and methods of using the same |
US11602556B2 (en) | 2015-01-14 | 2023-03-14 | The Regents Of The University Of Colorado, A Body Corporate | Insulin mimotopes and methods of using the same |
EP3419669A4 (en) * | 2016-02-23 | 2019-10-30 | Matripharm International Inc. | Dual-rate release formulation with high drug loading |
US9820957B2 (en) | 2016-03-24 | 2017-11-21 | The Regents Of The University Of Colorado, A Body Corporate | Methods of treating autoimmunity |
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 |
Also Published As
Publication number | Publication date |
---|---|
EP1263409A1 (en) | 2002-12-11 |
BG107055A (en) | 2003-06-30 |
HUP0204417A3 (en) | 2005-03-29 |
DOP2001000130A (en) | 2004-03-31 |
KR20030009374A (en) | 2003-01-29 |
YU66202A (en) | 2005-09-19 |
EA200200914A1 (en) | 2003-02-27 |
AP2002002627A0 (en) | 2002-09-30 |
GT200100033A (en) | 2001-10-25 |
HUP0204417A2 (en) | 2003-05-28 |
AR032614A1 (en) | 2003-11-19 |
CZ20022883A3 (en) | 2003-04-16 |
NZ520927A (en) | 2003-06-30 |
IS6532A (en) | 2002-08-28 |
CN1420763A (en) | 2003-05-28 |
JP2003525229A (en) | 2003-08-26 |
ECSP013952A (en) | 2002-04-23 |
PL365071A1 (en) | 2004-12-27 |
NO20024108D0 (en) | 2002-08-28 |
EE200200497A (en) | 2004-02-16 |
CA2400950A1 (en) | 2001-09-07 |
NO20024108L (en) | 2002-10-25 |
AU3589701A (en) | 2001-09-12 |
HRP20020715A2 (en) | 2004-12-31 |
PE20011113A1 (en) | 2001-10-14 |
ZA200206764B (en) | 2003-03-04 |
IL151553A0 (en) | 2003-04-10 |
HN2001000038A (en) | 2005-03-23 |
SK12542002A3 (en) | 2003-05-02 |
BR0108958A (en) | 2003-09-30 |
AP1485A (en) | 2005-10-31 |
AP2001002084A0 (en) | 2001-03-31 |
MXPA02008568A (en) | 2003-02-24 |
OA12381A (en) | 2004-09-06 |
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