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WO2000001365A1 - Compositions ophtalmiques a liberation prolongee contenant une fluoroquinolone - Google Patents

Compositions ophtalmiques a liberation prolongee contenant une fluoroquinolone Download PDF

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Publication number
WO2000001365A1
WO2000001365A1 PCT/DK1999/000348 DK9900348W WO0001365A1 WO 2000001365 A1 WO2000001365 A1 WO 2000001365A1 DK 9900348 W DK9900348 W DK 9900348W WO 0001365 A1 WO0001365 A1 WO 0001365A1
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WO
WIPO (PCT)
Prior art keywords
composition according
composition
active substance
eye
polyacrylic acid
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PCT/DK1999/000348
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English (en)
Inventor
Erik Didriksen
Pia Klie Refer
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Leo Pharmaceutical Products Ltd. A/S (Løvens Kemiske Fabrik Produktionsaktieselskab)
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Priority to AU46023/99A priority Critical patent/AU4602399A/en
Publication of WO2000001365A1 publication Critical patent/WO2000001365A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K9/0048—Eye, e.g. artificial tears

Definitions

  • the present invention relates to a pharmaceutical prolonged release ophthalmic composition for human and veterinary use comprising as a therapeutically and/or prophylactically active substance a fluoroquinolone, a fluoroquinolone derivative or a pharmaceutically acceptable salt thereof dispersed in a gel-forming aqueous vehicle.
  • One of the major problems associated with topical ophthalmic therapy is to maintain an adequate concentration, i.e. a therapeutically and/or prophylactically effective concentration of an ophthalmic drug substance at the desired site of action and within a desired period of time. Furthermore, only a small volume of a composition containing the drug substance can be contained in the fornix inferior of an eye, i.e. at the application site, and the composition applied tends to be diluted by the tears or lacrymal fluid and to be drained through the nasolacrymal duct. In order to maintain a sufficient concentration of the drug substance in the eye, traditional ophthalmic compositions are to be applied very frequently such as 5-6 times daily which is very inconvenient for a patient and which leads to problems related to patient compliance.
  • the cationic drug substance has formed a salt with the polyanionic polymeric substance and this salt has improved properties with respect to duration of action compared with the plain cationic drug substance.
  • the gel compositions containing the polymeric salt of the cationic drug substance exhibit a duration of action which is about twice that of a conventional ophthalmic drug composition.
  • GB-A-2 01 3 084 discloses an aqueous gel for treating eye diseases.
  • the composition is a well-retained gel preparation with long-term action containing an ophthalmic drug substance.
  • the ophthalmic drug is reacted with a polymer to provide a complex and/or a salt suitable for topical application.
  • the ophthalmic drug substance is a cationic drug substance such as pilocarpine.
  • the gel-forming agent is a high-molecular weight polymer having carboxylic or anhydride functional groups and is used in gel compositions at a level from about 2 to about 8% by weight.
  • EP-B-0 21 1 020 describes ophthalmic compositions of fusidic acid.
  • a carboxyvinyl polymer has been employed and the pH of the compositions is about 5.8, i.e. at a value where the mucoadhesive properties of the polymer are pronounced.
  • prolonged release ophthalmic compositions for human and veterinary use comprising as a therapeutically and/or prophylactically active substance a fluoroquinolone, a fluoroquinolone derivative or a pharmaceutically acceptable salt thereof, can be obtained.
  • the active substances relevant in the present context are not cationic substances at a pH of about 6.5-8.5, i.e. the above-mentioned principle based on an interaction of a positively charged drug substance and a negatively charged polymeric substance is not expected to be a proper approach in order to obtain a prolonged release composition containing a fluoroquinolone.
  • NM394 (6-fluoro-1 -methyl-4-oxo-7-( 1 -piperazinyl)-4H-[ 1 ,3]-thiazeto[3,2-a]- quinoline-3-carboxylic acid), a typical substance for the fluoroquinolone class of substances, when combined with a polyanionic polymer under conditions where salt or complex formation is likely to take place.
  • the formulation of a prolonged release ophthalmic composition for the fluoroquinolone class of substances is not merely a routine matter for a person skilled in the art.
  • Formulation of suitable ophthalmic compositions for human and veterinary compositions is a complex matter within the pharmaceutical field due to restricted requirements such as, e.g.,
  • the composition must not have an irritative effect on the eye, ii) the composition may not lead to a blurred vision after application to the eye, iii) the elimination by tear turnover should be avoided or reduced, if possible, iv) the drug substance should be bio-available (e.g. the drug substance should be able to diffuse through the cornea) .
  • a mucoadhesive substance in the compositions in order to enable a bioadhesion of the composition to the ocular mucosa.
  • Suitable mucoadhesive substances for pharmaceutical use are known, e.g. within the Carbopol ® series from BFGoodrich.
  • the Carbopol ® polymers are also gel-forming substances.
  • the swelling and the bioadhesiveness of the polymers are dependent on pH (pKa for the Carbopol ® polymers is about 6.0), but as the swelling increases with increasing pH, the bioadhesiveness tends to decrease with increasing pH.
  • pH of the composition is to be adjusted to an optimal value.
  • the optimal value with respect to bioadhesion is at an acidic pH (pH 5.0 or less) .
  • compositions containing as an active substance a fluoroquinolone substance and releasing the active substance from the composition in such a manner that a therapeutically and/or prophylactically effective concentration in the lacrymal fluid of the eye for at least about 6 hours such as, e.g. about 6.5 hours, 7 hours, 7.5 hours, 8 hours, 9, 10, 1 1 or 1 2 hours is obtained.
  • the effect is assessable in the rabbit eye test described in the experimental section herein.
  • the compositions according to the invention have a pH at about neutral and even when the compositions contain a Carbopol ® polymeric substance as a gel-forming agent
  • compositions In animal experiments, such compositions have proved suitable for administration to the eye only once or twice daily, in contrast to conventional compositions which are designed to be administered 5-6 times daily.
  • composition according to the invention is evidenced by the fact that the duration of action is prolonged such that about
  • a composition according to the invention is useful in the treatment and/or prophylaxis of eye diseases especially eye infections and/or inflammatory conditions of the eye.
  • Active substances especially eye infections and/or inflammatory conditions of the eye.
  • a composition according to the invention comprises an active substance.
  • the active substance is a fluoroquinolone, a fluoroquinolone derivative or a pharmaceutically acceptable salt thereof.
  • the fluoroquinolone is selected from the group consisting of: ofloxacin, ciprofloxacin, norfloxacin, lomefloxacin, enoxacin, premafloxacin, fieroxacin, prulifloxacin and 6-fluoro-1 -methyl-4-oxo-7-( 1 -piperazinyl)-4H-[1 ,3]-thiazeto[3,2- a]-quinoline-3-carboxylic acid (NM 394).
  • NM394 an active principle of prulifloxacin, is of interest in the present context.
  • NM-394 Fluoroquinolones are synthetic, broad-spectrum, bactericidal drugs particularly active in vitro against Gram-negative bacteria. Although their spectra of activity are broadly similar, in vitro comparisons have suggested that e.g. ciprofloxacin is more active than ofloxacin against Pseudomonas aeroginosa (a cause of severe corneal ulceration), whereas ofloxacin is more active than ciprofloxacin against Chlamydia trachomatis.
  • Prulifloxacin (NM441 ) is a fluoroquinolone antibacterial prodrug of the active principle NM394, which shows potent and broad-spectrum antibacterial activity both in vitro and in vivo.
  • NM394's activity against Gram-negative bacteria has been found to be comparable to that of ofloxacin and ciprofloxacin, while its activity against Gram-negative bacteria has been found to be equal to that of ciprofloxacin.
  • NM394 has also been found to show superior activity against strains of Enterobacteriaceae and Pseudomonas aeruginosa.
  • NM394 was found to be as active as ciprofloxacin against anaerobic bacteria inhibiting most strains, but showed weak activity against Clostridium spp. and some of the Bacterioides fragilis group organisms.
  • NM394 has never before been formulated as a composition for ophthalmic use. Its prodrug, prulifloxacin, has been administered orally in clinical studies relating to e.g. external eye diseases but no studies have revealed whether prulifloxacin would have any beneficial effect on eye infections when administered directly to the eye. Prulifloxacin administered locally to the eye should be converted to the active principle NM394 by enzymes present in the eye.
  • the active substances should preferably be present in a composition according to the invention in the form of solid particles and, furthermore, the active substance should not dissolve rapidly in the lacrymal fluid upon application but rather be maintained at the application site.
  • the presence of the active substance in the form of solid particles in the eye may reduce the elimination from the eye in that the solid particles are deposited in the fornix inferior and are not easily eliminated due to the effect arising from an increase in blinking and lacrimation (which normally leads to a rapid loss of dissolved substances) .
  • the active substance should preferably also be in the form of solid particles in the composition.
  • the active substance If the active substance is dissolved in the composition, the active substance would - after application to the eye - in an uncontrollable manner precipitate in the lacrymal fluid (due to the low solubility in the lacrymal fluid) and thus lead to e.g. an inappropriate particle size which may give rise to discomfort and pain and poor patient acceptance.
  • a low solubility of the active substances in the lacrymal fluid as well as in a composition according to the invention is important.
  • the low solubility in the lacrymal fluid has two purposes; to avoid elimination from the eye due to an increase in blinking and lacrimation, and to make use of a relatively slow dissolution of the active substance in order to control the availability of the active substance to the eye (in general, it is contemplated that only dissolved drug substances are able to exert their therapeutically or prophylactical effect) and, accordingly, control the duration of action.
  • Fluoroquinolones as a class are fairly insoluble in water. All modern fluoroquinolones are zwitterionic in character due to the presence of both a carboxylic acid and a basic amine; pK a values for these functional groups have been reported to be in the range of from 5.5 to 6.3 for the carboxylic acid and in the range of from 8.6 to 9.3 for the distal amino group. At low pH both the amine and the carboxylic acid are protonated, giving the molecule an overall positive charge. Conversely, at high pH, the amine is in the free base form, while the carboxylic group exists as the carboxylate anion providing a net negative charge.
  • fluoroquinolones tend to be more soluble in water at acidic pH and at basic pH with a minimum solubility expressed at neutral (physiological) pH values (cf. "The Quinolones", 2 nd Ed. by Vincent T. Andriole, Yale School of Medicine, Chapter 2, Chemistry and Mechanism of the Quinolone Antibacterials).
  • pK a values for fluoroquinolones are: Ciprofloxacin: pK a1 about 6.1 and pK a2 about 8.7, Norfloxacin: pK a1 about 6.4 and pK a2 about 8.5, Lomefloxacin: pK a1 about 5.6 and pK a2 about 9.0, Enoxacin: pK a1 about 6.2 and pK a2 about 8.8, Prulifloxacin: pK a1 about 6.1 and NM394: pK a1 about 5.9 and pK a2 about 8.8.
  • the solubility of the active substance is at the most about 0.3 mg/ml such as e.g. about 0.25 mg/ml, about 0.2 mg/ml, about
  • This medium is a suitable aqueous medium to simulate lacrymal fluid under physiological conditions.
  • the solubility of the active substance in the composition is at the most about 0.3 mg/ml such as e.g. about 0.25 mg/ml, about 0.2 mg/ml, about 0, 1 5 mg/ml, about 0.1 25 mg/ml or about 0.1 mg/ml at room temperature.
  • the particle size of the active substance in a composition should be rather small and fulfil the requirements given in official monographs like Ph. Eur. 3 rd Edition, 1 997. The method is described in the Experimental section herein.
  • the majority of the particles should have a particle size of less than 25 ⁇ m.
  • the majority of the particles have a size of less than 1 0 ⁇ m such as in a range of about 2-5 ⁇ m.
  • a preferred compound is NM394 or a pharmaceutically acceptable salt thereof.
  • the concentration of the active substance in the composition depends on the specific fluoroquinolone employed but is generally sufficiently high to obtain a prophylactically and/or therapeutically effective concentration in the eye after administration.
  • the concentration of NM394 in a composition of the invention is within a range of from about 0.5 to about 1 5 mg/ml such as, e.g. from about 1 to about 10 mg/ml, from about 1 .5 to about 8 mg/ml, from about 1 .75 to about 6 mg/ml, from about 2 to about 5 mg/ml. from about 2.5 to about 4 mg/ml such as, e.g., from about 2.7 to about 3.3 mg/ml.
  • concentration ranges are relevant for fluoroquinolones in general. If a pharmaceutically acceptable salt (or derivative) is employed, then the concentration of the salt (or derivative) in the composition corresponds - when calculated on the fluoroquinolone - to the ranges as given above.
  • a prophylactically and/or therapeutically effective concentration is determined as the minimum inhibitory concentration (MIC) values in standard assays well known to a person skilled in the art.
  • MIC values for fluoroquinolones are mostly below 1 ⁇ g/ml for sensitive microorganisms.
  • a composition according to the invention comprises a gel- forming aqueous vehicle.
  • a vehicle suitable for use in the present context comprises an ophthalmically acceptable cross-linked polyacrylic acid polymer.
  • a preferred polyacrylic acid polymer is cross-linked with polyalkenyl ethers or divinyl glycol.
  • suitable cross-linked polyacrylic acid polymers are mucoadhesive, cf. Bulletin 1 6 of BFGoodrich.
  • Examples of preferred polymers for use in a composition according to the invention are carbomers, i.e. homopolymers of acrylic acid cross-linked with an allyl ether of pentaerythritol or an allyl ether of sucrose.
  • carbomers of the series Acrisint ® (manufactured by 3V-Sigma), Carbopol ® (manufactured by BFGoodrich), PerForMax ® (manufactured by BFGoodrich), Synthalen ® (manufactured by 3V-Sigma) and Thixol ® (manufactured by Mearl).
  • Noveon ® polycarbophils from BFGoodrich are also suitable polyacrylic acid polymers.
  • Carbopol ® resins having the type Nos. 91 0, 934, 940, 941 , 951 , 954, 971 , 980, 981 , 934P, 974P, 5984 and 1 382
  • Carbopol ® 974P is a specific example of a suitable polymer especially because this polymer is being manufactured without the use of benzene in the process.
  • the Carbopol ® series of polymers have suitable properties with respect to i) swelling ability and ii) mucoadhesive properties.
  • Carbopol ® has proved to be a suitable agent for topical application to the eye. It is substantially non-irritative and only to a minor extent a blurred vision is observed upon administration of a composition containing Carbopol ® .
  • the concentration of the polyacrylic acid polymer in a composition according to the invention is in a range of from about 0.1 to about 5% w/v such as, e.g. from about 0.1 to about 4% w/v, from about 0.2 to about 3% w/v, from about 0.2 to about 2% w/v, from about 0.2 to about 1 .5 % w/v or from about 0.3 to about 1 .0% such as, e.g., about 0.5 % w/v.
  • the pH of the composition is a very important factor inter alia with respect to the following:
  • solubility of the active substance in the composition i) solubility of the active substance in the composition, ii) adjustment of the solubility of the active substance in the lacrymal fluid (e.g. by use of buffer substances in the composition), iii) formation of a gel (swelling of the polymer), iv) maintenance of the mucoadhesive properties of the polyacrylic acid polymers, v) interaction of the active substance with the polyacrylic acid polymer
  • the pH of a composition according to the invention is normally adjusted so as to establish a balance so that i) the solubility of the active substance in the composition is at the most 0.2 mg/ml and ii) the mucoadhesive properties of the polyacrylic acid polymer is maintained sufficiently high to obtain a therapeutically and/or prophylactically effective concentration of the active substance in the lacrymal fluid of the eye for at least about 6 hours as assessable in the rabbit eye test as described herein.
  • the swelling should be of such a order of magnitude that the resulting composition has a viscosity in a range of from about 20 mPas to about 3000 mPas such as, e.g., from about 1 00 mPas to about 3000 mPas, from about 500 mPas to about 3000 mPas, from about 1 000 to about 2800 mPas or from about 1 500 mPas to about 2500 mPas such as, e.g., 1 500 mPas as measured on a Haake VT500 Viscosimeter at a temperature of 20 °C and at a shear rate of 100 s "1 .
  • the viscosity of the composition is at least 1 500 mPas so that upon application to the eye the composition is maintained in situ and releases the active substance from the composition in a prolonged manner during at least 6- 8 hours as assessable in the rabbit eye test as described herein.
  • an important feature of a composition of the invention is its ability to precipitate the polyacrylic acid polymer in the fornix inferior under the eye lid once the composition has been applied to the eye.
  • precipitation of the composition it is ensured that the composition is maintained in situ and the risk of elimination of the composition by tear turnover or an increase in lacrimation is significantly reduced. Accordingly, a prolonged release is obtainable which would not be the case if the composition is quickly eliminated from the eye.
  • the localisation of the composition under the eye lid is very favourable as the composition is not spread over the whole eye mucosa which could lead to an unwanted blurred vision or precipitation of the composition or parts or the composition on the eye surface.
  • the precipitation of the composition after application to the eye is due to a salting out of the polymeric substance(s) included in the composition.
  • a composition fulfils the above-mentioned requirement with respect to precipitation in situ the following test can be employed:
  • compositions according to the invention may be administered in the form of eye drops or - like an ointment - in the form of a hydrogel.
  • the composition may be in unit dosage form for administration of a single dose or it may be in a dosage form containing more than one dose.
  • composition according to the invention may further comprise a pharmaceutically acceptable excipient.
  • Suitable pharmaceutically acceptable excipients for use in a composition according to the invention include:
  • solvents like, e.g., water,
  • pH adjusting agents like, e.g. sodium hydroxide and hydrochloric acid
  • isotonic adjusting agents like, e.g., glycerol, mannitol, sorbitol, xylitol and the like,
  • gelling agents like, e.g., cellulose derivatives which do not precipitate at a temperature of above about 30 °C such as, e.g., hydroxyethylcellulose, hydroxypropylmethylcellulose and the like, and polymers from the Pluronic ® series,
  • viscosity-adjusting agents like, e.g., hydroxyethylcellulose and hydroxypropylmethylcellulose,
  • preservatives like, e.g., benzalkonium chloride, parabenes, chlorohexidine, chlorohexidine gluconate and chlorohexidine acetate,
  • chelating agents like, e.g., EDTA,
  • a composition according to the invention may further include a further therapeutically and/or prophylactically active substance, e.g. for use in relevant combination therapy.
  • a further therapeutically and/or prophylactically active substance e.g. for use in relevant combination therapy.
  • An especially interesting group of active substances in this context is the steroids, e.g. dexamethasone.
  • a composition according to the invention is typically in the form of eye drops, viscous eye drops or in the form of an ointment.
  • the amount applied of the composition depends on the specific formulation and the device from which it is to be administered. In general, the amount of the composition applied contains a sufficient amount of the active substance (i.e. in general from about 1 0 ⁇ g to about 300 ⁇ g such as, e.g. from about 1 0 ⁇ g to about 200 ⁇ g, from about 1 0 ⁇ g to about 1 00 ⁇ g, from about 1 2 ⁇ g to about 50 ⁇ g, from about 1 5 ⁇ g to about 30 ⁇ g or from about 20 ⁇ g to about 25 ⁇ g) .
  • the amount applied is normally about 1 5-40 ⁇ l such as, e.g. in a range corresponding to 20-30 ⁇ l.
  • composition according to the invention is normally intended for use once or twice daily, but in certain situations administration more frequent (e.g. trice daily) can be desired.
  • a composition according to the invention is one obtainable by dispersing the active substance in a gel-forming aqueous vehicle.
  • the active substance is normally dispersed in the gel-forming aqueous vehicle in the form of a suspension comprising the active substance in an aqueous medium and, optionally, a pharmaceutically acceptable excipient.
  • the gel-forming vehicle can be obtained by i) dispersing a polyacrylic acid polymer in water which, optionally, comprises a pharmaceutically acceptable excipient, followed by ii) adjusting pH of the thus obtained gel-forming aqueous vehicle to a pH in a range of from about 6.5 to about 8.5, such as, e.g., from about 7 to about 8, from about 7.2 to about 7.6, such as e.g. about 7.4.
  • the invention relates to a method for the preparation of a composition according to the invention, the method comprises dispersing the active substance in an aqueous gel-forming vehicle.
  • a method according to the invention comprises the steps of:
  • the method may comprise a further step of sterilising the dispersion of the polyacrylic acid polymer in a step before step vi).
  • This step may either be before step v) or after step v) above.
  • the sterilisation is performed by methods well known by a person skilled in the art such as by autoclaving the dispersion at 1 21 °C for 1 5 min or any other proper temperature-time relationship.
  • the invention relates to a method for the treatment and/or prophylaxis of eye diseases like eye infections of a mammal comprising administering to a mammal in need thereof a prolonged release ophthalmic composition according to the invention.
  • a method for the treatment and/or prophylaxis of eye diseases like eye infections comprises administering the prolonged release composition once or twice daily.
  • the invention relates to a method for administering a therapeutically and/or prophylactically active substance selected from the group consisting of a fluoroquinolone, a fluoroquinolone derivative and a pharmaceutically acceptable salt thereof to an eye of a mammal, the method comprising applying the active substance in the form of a prolonged composition to the fornix inferior of the eye.
  • a therapeutically and/or prophylactically active substance selected from the group consisting of a fluoroquinolone, a fluoroquinolone derivative and a pharmaceutically acceptable salt thereof
  • compositions according to the invention comprise typically
  • compositions are normally adjusted to a pH of 7.2-7.6 with a solution of sodium hydroxide.
  • Pharmaceutically acceptable excipients may also be present such as, e.g. pr. ml of the composition:
  • Preservative e.g. benzalkonium chloride
  • Isotonic adjusting agent e.g. glycerol 85%
  • the solubility of a specific fluoroquinolone in isotonic phosphate buffer solution is determined at a pH in a range of 6.5 to 8.0 and at temperatures at 24°C and 34°C, where the latter represents the tear liquid temperature, being in an interval of 30-35°C.
  • a surplus of the fluoroquinolone in question is shaken for three days with each buffer solution.
  • the suspension are centrifuged and the supernatant is diluted with buffer.
  • the content of fluoroquinolone is determined by UV measurements at the maximum (about 272 nm for NM394) and calculation against a standard. All experiments in duplicate.
  • the isotonic phosphate buffer solution was prepared as follows. Isotonic solutions of disodium hydrogen phosphate (0.1 3 M) and sodium dihydrogen phosphate (0.1 8 M) were prepared. Solution with pH 6.5, 7.0 and 8.0 were prepared by mixing different ratios of the two isotonic solutions.
  • Quantitative assay of NM394 The ophthalmic composition is dissolved in acetonitrile: methanol: 1 % acetic acid 60: 1 0:30. The carbomer polymer is precipitated by adding a small amount of KN0 3 and is removed by centrifugation. The solution is diluted appropriately with mobile phase: acetonitrile: methanol:0.01 5 M phosphoric acid:sodium laurylsulfate 0.1 M 270:31 0:395:25. The assay is performed by reversed phase HPLC at 50 °C (column oven) using UV detection at 254 nm. 4-ethoxybenzoic acid is used as an internal reference.
  • a suitable quantity of the composition is introduced with a micropipette onto a slide and an area corresponding to 10 ⁇ g of the solid phase is scanned under a microscope. For practical reasons, the whole sample is first scanned at low magnification (e.g. x 50) and particles greater than 25 ⁇ m are identified. These larger particles can then be measured at a large magnification (e.g. x 200 to x
  • Not more than 20 particles have a maximum dimension greater than 50 ⁇ m, and not more than two of these particles have a maximum dimension greater than 50 ⁇ m. None of the particles has a maximum dimension greater than 90 ⁇ m.
  • Composition I is a composition of Composition I:
  • NM394 was obtained from Nippon, Shinyaku Co. Ltd., Japan which has developed the compound in corporation with Meiji Seika, Co. Ltd., Japan.
  • NM394 can be prepared according to the method disclosed in US-A-4,843,070 (Nippon, Shinyaku Co., Ltd., Japan). All other ingredients employed were of pharmacopoeia standard.
  • NM394 In a small vessel NM394 was suspended in a 0.01 % w/v benzalkonium chloride solution. Milling beads were added to the suspension. The mixture were sterilised by autoclaving at 1 21 °C for 1 5 min and then milled according to
  • the resulting particle size was preferably in a range of 2-5 ⁇ m for the majority of the particles.
  • glycerol 85% was dissolved in sterile water.
  • Carbopol ® 974P was dispersed aseptically in the solution and sterilised by autoclaving at 1 21 °C for 1 5 min. The dispersion was cooled and the rest of the benzalkonium chloride was added aseptically as a sterile solution. The mixture was neutralised by addition of sterile sodium hydroxide solution. Finally the milling beads were separated aseptically from the autoclaved and milled NM394 suspension and the suspension was added aseptically to the gel vehicle.
  • composition I The composition (in the following called Composition I) thus prepared was compared with a composition analogue to Composition I but with 0.1 mg benzalkonium chloride (denoted "BAK” in the following tables) instead and employing another crystal modification of NM394 (Composition II) and with two conventional eyedrop compositions, one with 0,3% w/v Norfloxacin (Zoroxin®MDS) and one with 0,3% w/v Ofloxacin (Exocin®).
  • BAK benzalkonium chloride
  • compositions were compared in the following manner:
  • Samples for microbiologic determination were taken by placing 6.0 mm AA discs (Watmann®) in the fornix inferior, closing the eye lids for approximately
  • Norfloxacin or Ofloxacin standard solutions have been placed.
  • the standard solutions of NM394 were prepared in phosphate buffer pH 8.0.
  • the 30 ⁇ l volume is equivalent to that amount which the discs absorb.
  • the petri dishes were incubated for 1 6-1 8 hours at the optimum temperature for the test organisms in question (28 °C for M. luteus and 22 °C for E. coli) .
  • the inhibition zones of the samples were measured to the nearest 0.1 mm with needle point calliper and interpolated on the standard curve which was established as the best response line from the inhibition zone for the standard solutions.
  • FIG 2 is shown the results from the above-mentioned experiments.
  • the figure shows mean the concentration of the fluoroquinolone in the lacrymal fluid versus the time after administration.
  • the minimum inhibiting concentration (MIC) is about 1 ⁇ g/ml (i.e. the minimal effective concentration) .
  • MIC minimum inhibiting concentration
  • From fig. 2 it is seen that the MIC value is reached after about 5-6 hours after administration of Zoroxin and Exocin eye drops, respectively, i.e. the effect of these compositions is at the most about 5-6 hours.
  • the compositions according to the invention exhibited a concentration in the lacrymal fluid exceeding that of MIC for about 24 hours, i.e. indicating that the compositions according to the invention are suitable for administration once (or twice) daily.
  • Carbopol ® 974P was found to possess a favourable biopharmacokinetic profile superior to that of the two commercial available fluoroquinolone preparations.
  • A Sample removal at 0, Vi , 1 , 2, 4, 6 and 24 hours
  • B Sample removal at 0, 8, 1 6 and 24 hours
  • Topical application of NM394 viscous eye drop in the eye would not give rise to systemic activity because no antibiotic concentration was detected in the serum at 1 /2 , 2, 5 and 24 hours following application of one drop 1 % w/v NM394 in 0.5% w/v Carbopol ® 974P to five rabbits (NZW).
  • the concentrations of NM394 in the lacrymal fluid were at the same level as reported in Example 1 .
  • compositions according to the invention resulted generally in higher concentrations of the active substance in the lacrymal fluid after 24 hours whether samples were taken according to experiment A or B.
  • results obtained at 24 hours were about 2 to 10 times higher when compositions according to the invention were applied compared with the marketed compositions.

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique ophtalmique à libération prolongée destinée à une utilisation humaine et vétérinaire, comprenant en tant que principe thérapeutique et/ou prophylactique actif, une fluoroquinolone, un dérivé de fluoroquinolone ou un sel acceptable sur le plan pharmaceutique de ceux-ci, dispersé dans un véhicule aqueux gélifiant.
PCT/DK1999/000348 1998-06-30 1999-06-23 Compositions ophtalmiques a liberation prolongee contenant une fluoroquinolone WO2000001365A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU46023/99A AU4602399A (en) 1998-06-30 1999-06-23 Prolonged release ophthalmic compositions containing a fluoroquinolone

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DKPA199800864 1998-06-30
DKPA199800864 1998-06-30

Publications (1)

Publication Number Publication Date
WO2000001365A1 true WO2000001365A1 (fr) 2000-01-13

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003015752A1 (fr) * 2001-08-14 2003-02-27 Bakulesh Mafatlal Khamar Procede de fabrication d'une formulation ophtalmique antibiotique topique isotonique presentant un meilleur effet therapeutique
WO2007012625A1 (fr) * 2005-07-28 2007-02-01 Dr. Gerhard Mann Chem.-Pharm. Fabrik Gmbh Preparation ophtalmologique sterile, multiphase, exempte d'emulsifiant, coulant en gouttes
DE102006049091A1 (de) * 2006-10-18 2008-04-24 Dr. Gerhard Mann Chem.-Pharm. Fabrik Gmbh Emulgatorfreies ophthalmisches Präparat enthaltend Pflanzenöl
US7671070B2 (en) 1998-09-30 2010-03-02 Alcon, Inc. Method of treating ophthalmic infections with moxifloxacin compositions
WO2012150583A1 (fr) * 2011-05-05 2012-11-08 Resdevco Research And Development Co. Ltd. Gouttes ophtalmiques pour le traitement de la conjonctivochalasis
EP1589947B1 (fr) 2002-12-31 2016-06-15 Novartis AG Formulation pharmaceutique ayant un agent actif insoluble

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2678832A1 (fr) * 1991-07-10 1993-01-15 Europhta Sa Laboratoire Nouvelles compositions ophtalmiques a resorption amelioree et leurs procedes de preparation.
EP0590786A1 (fr) * 1992-08-28 1994-04-06 Alcon Laboratories, Inc. Utilisation de certains surfactants anioniques pour l'amélioration de l'activité antimicrobienne des compositions ophtalmiques
US5631004A (en) * 1993-09-30 1997-05-20 Alcon Laboratories, Inc. Use of sustained release antibiotic compositions in ophthalmic surgical procedures
WO1998025620A1 (fr) * 1996-12-11 1998-06-18 Alcon Laboratories, Inc. Procede de fabrication de suspensions ophtalmiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2678832A1 (fr) * 1991-07-10 1993-01-15 Europhta Sa Laboratoire Nouvelles compositions ophtalmiques a resorption amelioree et leurs procedes de preparation.
EP0590786A1 (fr) * 1992-08-28 1994-04-06 Alcon Laboratories, Inc. Utilisation de certains surfactants anioniques pour l'amélioration de l'activité antimicrobienne des compositions ophtalmiques
US5631004A (en) * 1993-09-30 1997-05-20 Alcon Laboratories, Inc. Use of sustained release antibiotic compositions in ophthalmic surgical procedures
WO1998025620A1 (fr) * 1996-12-11 1998-06-18 Alcon Laboratories, Inc. Procede de fabrication de suspensions ophtalmiques

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7671070B2 (en) 1998-09-30 2010-03-02 Alcon, Inc. Method of treating ophthalmic infections with moxifloxacin compositions
US8673902B2 (en) 1998-09-30 2014-03-18 Alcon Pharmaceuticals, Ltd. Method of treating otic infections with moxifloxacin compositions
US8993636B2 (en) 1998-09-30 2015-03-31 Alcon Pharamceuticals, Ltd. Compositions containing moxifloxacin for treating otic infections
WO2003015752A1 (fr) * 2001-08-14 2003-02-27 Bakulesh Mafatlal Khamar Procede de fabrication d'une formulation ophtalmique antibiotique topique isotonique presentant un meilleur effet therapeutique
EP1589947B1 (fr) 2002-12-31 2016-06-15 Novartis AG Formulation pharmaceutique ayant un agent actif insoluble
EP1589947B2 (fr) † 2002-12-31 2019-01-30 Novartis AG Formulation pharmaceutique ayant un agent actif insoluble
WO2007012625A1 (fr) * 2005-07-28 2007-02-01 Dr. Gerhard Mann Chem.-Pharm. Fabrik Gmbh Preparation ophtalmologique sterile, multiphase, exempte d'emulsifiant, coulant en gouttes
DE102005035986B4 (de) * 2005-07-28 2009-10-15 Bausch & Lomb Incorporated Steriles tropfbares mehrphasiges emulgatorfreies ophthalmisches Präparat
DE102006049091A1 (de) * 2006-10-18 2008-04-24 Dr. Gerhard Mann Chem.-Pharm. Fabrik Gmbh Emulgatorfreies ophthalmisches Präparat enthaltend Pflanzenöl
WO2012150583A1 (fr) * 2011-05-05 2012-11-08 Resdevco Research And Development Co. Ltd. Gouttes ophtalmiques pour le traitement de la conjonctivochalasis
JP2014513118A (ja) * 2011-05-05 2014-05-29 レスデブコ リサーチ アンド ディベロップメント カンパニー リミテッド 結膜弛緩症治療用の点眼薬
US8912166B2 (en) 2011-05-05 2014-12-16 Resdevco Research And Development Co. Ltd. Eye drops for treatment of conjunctivochalasis

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