Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-12
2001-07-17
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S315000, C514S317000
Reexamination Certificate
active
06262072
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to orally administered antimicrobial formulations which contain, as an active ingredient, 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (also called ciprofloxacin) or its pharmacologically acceptable salts (preferably, HCl salt monohydrate) in a solid dosage form. The ciprofloxacin is combined with effective amounts of binders (preferably, pregelatinized starch, polyvinyl pyrrolidone, or polyvinyl alcohol), diluents (preferably, lactose), disintegrants (preferably, sodium starch glycolate), wetting agent (preferably, sodium lauryl sulfate), and lubricants (preferably, magnesium stearate) to form granules or tablets. This invention also relates to methods for making the ciprofloxacin-containing tablets or granules using dry-wet-dry granulation processing before compression to tablets with granulation performed in a wet state. The tablets or capsules made from these formulations possess superior biological availability and excellent storage stability.
BACKGROUND OF THE INVENTION
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinoline carboxylic acid (also known as ciprofloxacin) belong to the class of quinolones, which are known to possess a broad antibacterial spectrum against both Gram positive and Gram negative bacteria, in particular against Enterobacteriaceae. (See e.g., U.S. Pat. Nos. 4,284,629, 4,499,091, 4,704,459, 4,668,784, 4,670,444, 5,286,754, and 5,840,333).
Ciprofloxacin is a chemotherapeutic agent. Its use as an antimicrobial agent has distinct advantages over the use of antibiotics (e.g., penicillins, cephalosporins, aminoglycosides, sulphonamides and tetracyclines) in that ciprofloxacin does not induce tolerance or resistance in bacteria. Ciprofloxacin is also known to have low toxicity to humans.
The orally administered quinolone-containing formulations can be prepared by a wet granulation process as described by Y. Shirai et al.,
Biol. Pharm. Bull.,
16(2), 172 (1993). However, the formulations produced by the wet granulation process have a tendency to generate hydrates, thus making the granules less soluble or more difficult to disperse when compared with the corresponding anhydrous form. This results in a delay in the dissolution and a delay in the release of the active ingredient, which may be a nuisance in the use of antimicrobial medicinal products.
Quinolone-containing formulations can also be prepared by a direct compression of the mixture of the quinolone with excipients, without the prior addition of mixing water. See U.S. Pat. No. 5,840,333. However, the direct compression of the mixture of the quinolone ingredient and the excipients in powder form may affect the quality of the tablets due to cleavage problems, which render some batches of tablets unsuitable for marketing.
Recently, Streuff et al. (U.S. Pat. No. 5,286,754) have disclosed an oral formulation of ciprofloxacin which is prepared by combining ciproflaxacin with cellulose as a dry binder, starch, cellulose derivatives and/or cross-linked polyvinylpyrrolidone as a disintegrant, a flow-improving agent such as Aerosil®, a highly pure X-ray-amorphous silicon dioxide, with and NAL® and NAL® RS [a pulverulent product prepared from rice starch]) and a lubricant (such as talc, calcium stearate, magnesium stearate and solid polyethylene glycols).
However, Streuff et al.'s formulation is practically prepared in dry state, although in one variant granulation can be made in a fluidized bed granulator by instantaneously spraying the formulation with water and passing it in warm air, a process which in fact results in simultaneous drying of the granules. Therefore, it is conceivable that the tablets obtained from such preparation may not be satisfactory, possibly due to cleavage problems.
In addition, Streuff et al.'s formulation requires the use of microcrystalline cellulose as the dry binder. Microcrystalline cellulose comes from natural plant fibers through complex micronization. Therefore, the high quantity of microcrystalline cellulose used by Streuff et al. not only drives up the cost of manufacturing the product but also is wasteful and therefore environmentally undesirable. In addition, microcrystalline cellulose is practically insoluble in water. Thus, the use of microcrystalline cellulose in Streuff et al.'s formulation has limited the utility of compounding such formulations in a wet state.
The present invention includes ciprofloxacin-containing formulations produced by a dry-wet-dry granulation process, which is significantly different from either the wet granulation or the dry-mixing processes described above. The process of the present invention begins with mixing the solid dosage form of ciprofloxacin with certain excipients in their dry state, followed by a wet mixing and granulation step wherein a water-solvent solution (e.g., a 1:1 (v/v) water:isopropanol solution) is added to the dry ciprofloxacin-excipients mixture. Finally, the wet granules produced by the wet mixing and granulation step are dried and compressed into solid dosage form of tablets. The present invention is significantly different from that of Streuff et al. because it does not use cellulose as dry binder. The tablets or granules produced from this method have superior bioavailibity and shelf-life than other ciprofloxacin-containing products on the market.
SUMMARY OF THE INVENTION
The present invention provides three kinds of orally administered antimicrobial formulations which contain, as an active ingredient, a solid dosage form of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid (also called ciprofloxacin) or its pharmacologically acceptable salts. The formulations can be marketed as tablets or capsules. They are non-toxic, highly dispersible, and have excellent storage stability.
The first antimicrobial formulation comprises (1) 60-75 wt % of ciprofloxacin or its pharmacologically acceptable salts; (2) 0.3-10 wt % of pregelatinized starch as binder; (3) 5-30 wt % of lactose as diluent; (4) 1-10 wt % of sodium starch glycolate as disintegrant; and (5) 0.5-2 wt % of magnesium stearate as lubricant. The formulation is prepared by a dry-wet-dry granulation method. The preferable pharmacologically acceptable salt of ciprofloxacin is the monohydrochloride monohydrate salt of ciprofloxacin. The preferable pregelatinized starch is partially pregelatinized starch. A 0.3-3 wt % of sodium lauryl sulfate can be added to the formulation as a wetting agent.
The second antimicrobial formulation comprises (1) 60-75 wt % of ciprofloxacin or its pharmacologically acceptable salts; (2) 1-5 wt % of polyvinyl purrolidone(PVP) as a binder; (3) 5-30 wt % of lactose as a diluent; (4) 1-10 wt % of sodium starch glycolate as a disintegrant; and (5) 0.5-2 wt % of magnesium stearate as a lubricant. The formulation is prepared by a dry-wet-dry granulation method. The preferable pharmacologically acceptable salt of ciprofloxacin is the monohydrochloride monohydrate salt of ciprofloxacin. The preferable PVP is PVP-K30 which has a molecular weight of 40,000. A 0.3-3 wt % of sodium lauryl sulfate can be added to the formulation as wetting agent.
The third antimicrobial formulation comprises (1) 60-75 wt % of ciprofloxacin or its pharmacologically acceptable salt; (2) 1-8 wt % of polyvinyl alcohol (PVA) as a binder; (3) 5-30 wt % of lactose as a diluent; (4) 1-10 wt % of sodium starch glycolate as a disintegrant; and (5) 0.5-2 wt % of magnesium stearate as a lubricant. The formulation is prepared by a dry-wet-dry granulation method. The preferable pharmacologically acceptable salt of ciprofloxacin is the monohydrochloride monohydrate salt of ciprofloxacin. A 0.3-3 wt % of sodium lauryl sulfate can be added to the formulation as wetting agent.
The above three antimicrobial formulations are further compressed into tablets. The tablets are coated by a coating material which comprises hydroxylpropylmethyl-cellulose (HPMC), water, polyethyleneglycol (PEG), dimethylpolysiloxane (DMPS), and Ti
Chao Fei-Fei
Venable, Baejier, Howard & Civiletti, LI
Weddington Kevin E.
Yung Shin Pharmaceutical Industrial Co. Ltd.
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