Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-04-21
2001-12-25
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S400000, C424S422000, C424S427000, C424S437000, C424S078040, C514S254080
Reexamination Certificate
active
06333045
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to an aqueous liquid pharmaceutical composition comprising as a main component a quinolone carboxylic acid derivative, Gatifloxacin (chemical nomenclature: (±)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinoline carboxylic acid). Further, the present invention relates to a method for raising corneal permeability of Gatifloxacin, a method for preventing precipitation of Gatifloxacin crystals, and a method for preventing coloration of Gatifloxacin.
BACKGROUND OF THE INVENTION
Gatifloxacin is a new quinolone antimicrobial agent which is recognized to exhibit a strong antimicrobial activity against not only Gram-negative bacteria but also Gram-positive bacteria, anaerobes and mycoplasmas. Then, it has been proposed to apply it to ophthalmological infectious diseases such as conjunctivitis, dacryocystitis, hordeolum etc. and otorhinological infectious diseases such as otitis externa, otitis media, sinusitis etc (see JP-B 8-9597).
For designing a pharmaceutical preparation in the form of eye drops containing an antimicrobial agent, an index is to raise corneal permeability of the agent to increase the amount of the agent to transfer to aqueous humor. However, in general, the agent applied to eyes can scarcely pass into inside of the eyes because of dilution with tears and the barrier function of corneas. Then, as a method of improving corneal permeability of the agent, a method using an absorption enhancer has been proposed. In addition, a method using a viscous base material has been proposed to increase the agent-retentivity at the anterior ocular segment.
OBJECTS OF THE INVENTION
With regard to Gatifloxacin, although its application. to ophthalmological or otorhinological infectious diseases has been proposed, there is no report about a study of an aqueous liquid pharmaceutical composition thereof for topical administration, which can be actually applied to eyes, for example, its passing into inside of eyes, stability, etc.
In view of these circumstances, an object of the present invention is to permit actual application of Gatifloxacin in ophthalmological or otorhinological field, in particular, to provide an aqueous liquid pharmaceutical composition comprising as an effective component Gatifloxacin.
SUMMARY OF THE INVENTION
The present inventors have intensively studied to apply Gatifloxacin in ophthalmological field and, consequently, have found that this objective can be achieved by coexistence of Gatifloxacin with disodium edetate.
Disodium edetate is considered to lower the calcium concentration in corneal epithelium cells and expanding intercellular spaces, thereby accelerating passing of a water-soluble medicament into inside of eyes. However, a rise in corneal permeability of a medicament depends on a concentration of disodium edetate (Journal of Pharmaceutical Science, 77: 3-14, 1988) and, normally, at present, disodium edetate should be used at a high concentration as much as 0.5% (Investigative Ophthalmology & Visual Science, 66: 110-113, 1985; Experimental Eye Research, 54: 747-757, 1992; Pharmaceutical Research, 12: 1146-1150). Nevertheless, the present inventors have found that corneal permeability of Gatifloxacin can be improved at a lower concentration of disodium edetate.
Further, it has been known that the solubility of Gatifloxacin depends on pH and its solubility at about physiological pH is very low. Then, in order to dissolve a sufficient amount of Gatifloxacin in an aqueous liquid pharmaceutical composition, pH of the composition should be adjusted to an acidic or alkaline range, which causes a problem such as irritation upon topical administration. However, the present inventors also have found that the solubility of Gatifloxacin at about physiological pH is improved by coexistence thereof with disodium edetate.
The present invention has been completed based on these present inventors' novel findings and, according to the present invention, there is provided an aqueous liquid pharmaceutical composition which comprises Gatifloxacin or its salt and disodium edetate. In particular, the aqueous liquid pharmaceutical composition of the present invention is an aqueous solution containing Gatifloxacin or its salt and disodium edetate.
Further, the present invention provides a method for raising corneal permeability of Gatifloxacin which comprises incorporating disodium edetate into eye drops containing Gatifloxacin or its salt; a method for preventing precipitation of Gatifloxacin crystals which comprises incorporating disodium edetate into an aqueous liquid preparation containing Gatifloxacin or its salt; and a method for preventing coloration of Gatifloxacin which comprises incorporating disodium edetate into an aqueous liquid preparation containing Gatifloxacin or its salt.
This object as well as other objects and advantages of the present invention will become apparent to those skilled in the art from the following description.
DETAILED DESCRIPTION OF THE INVENTION
In the present invention, Gatifloxacin or its salt is used as the effective component. Examples of the salt of Gatifloxacin used in the present invention include those with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, etc.; those with organic acids such as methanesulfonic acid, lactic acid, oxalic acid, acetic acid, etc.; or those with sodium, potassium, magnesium, calcium, aluminum, cerium, chromium, cobalt, copper, iron, zinc, platinum, silver, etc.
Normally, the amount of Gatifloxacin or its salt (hereinafter sometimes simply referred to as “Gatifloxacin”) to be formulated in the aqueous liquid pharmaceutical composition of the present invention is varied according to the degree of infection of a particular subject, but normally, Gatifloxacin is formulated within the range of 0.1 to 1.0 w/v %, preferably 0.1 to 0.8 w/v %, more preferably 0.3 to 0.5 w/v %.
Normally, disodium edetate is formulated in an amount of 0.001 to 0.2 w/v %, preferably 0.005 to 0.1 w/v %, more preferably 0.01 to 0.1 w/v %.
Normally, the aqueous liquid pharmaceutical composition of the present invention is adjusted to pH 5 to 8, preferably pH 5.5 to 7.5, more preferably pH 6 to 7.
If necessary, the aqueous liquid pharmaceutical composition of the present invention may further contain appropriate additives, for example, an isotonic agent. (e.g., sodium chloride, potassium chloride, boric acid, glycerin, propylene glycol, mannitol, sorbitol, glucoseetc.); a buffer solution (e.g., phosphate buffer solution, acetate butter solution, borate buffer solution, citrate buffer solution, glutamic acid, &egr;-aminocapronic acid, etc.); a preservative (e.g., benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, p-hydroxybenzoate, etc.), a thickening agent (e.g., methylcellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose, sodium hyaluronate, carboxyvinyl polymer, polyvinyl alcohol, polyvinyl pyrrolidone, Macrogol (polyethylene glycol), etc.), a pH adjusting agent (e.g., hydrochloric acid, sodium hydroxide, acetic acid, phosphoric acid, etc.), and the like.
The aqueous liquid pharmaceutical composition of the present invention can be produced by a per se known method. For example, it can be produced by the process described in the section of “Ophthalmic Solutions” or “Liquids and Solutions”, General Rules for Preparations, The Japanese Pharmacopoeia Thirteenth Edition.
The aqueous liquid pharmaceutical composition of the present invention has antimicrobial activity and can be used for prophylaxis and therapy of blepharitis, hordeolum, dacryocystitis, conjunctivitis, tarsitis, keratitis, corneal ulcer, postoperative infection, and the like. For this purpose, the composition can be instilled in the eye about three times a day at a dosage of one drop per once. For otitis externa or otitis media, normally, the composition can be instilled in the ear twice a day at a dosage of 6 to 10 drops per once. Furth
Inada Katsuhiro
Yasueda Shin-ichi
Evans Charesse L.
Page Thurman K.
Senju Pharmaceutical Co. Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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