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WO2007099431A2 - An aqueous liquid pharmaceutical compositions of gatifloxacin - Google Patents

An aqueous liquid pharmaceutical compositions of gatifloxacin Download PDF

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Publication number
WO2007099431A2
WO2007099431A2 PCT/IB2007/000465 IB2007000465W WO2007099431A2 WO 2007099431 A2 WO2007099431 A2 WO 2007099431A2 IB 2007000465 W IB2007000465 W IB 2007000465W WO 2007099431 A2 WO2007099431 A2 WO 2007099431A2
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WO
WIPO (PCT)
Prior art keywords
aqueous liquid
liquid pharmaceutical
pharmaceutically acceptable
pharmaceutical composition
gatifloxacin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2007/000465
Other languages
French (fr)
Other versions
WO2007099431A3 (en
Inventor
Chandrashekhar Mainde
Suresh Bora
Jigar Lalani
Aasiya Sardar
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wockhardt Ltd
Original Assignee
Wockhardt Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
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Publication of WO2007099431A2 publication Critical patent/WO2007099431A2/en
Publication of WO2007099431A3 publication Critical patent/WO2007099431A3/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/724—Cyclodextrins
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/734—Alginic acid
    • 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
    • A61K9/0043—Nose
    • 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
    • A61K9/0046—Ear

Definitions

  • the present invention relates to aqueous liquid pharmaceutical compositions that include gatifloxacin and pharmaceutically acceptable salts thereof.
  • the invention also relates to processes for the preparation of the pharmaceutical compositions.
  • Gatifloxacin is a synthetic broad-spectrum 8-methoxyfluoroquinolone antibacterial agent. Chemically, gatifloxacin is ( ⁇ )- 1 -cyclopropyl- ⁇ -fluoro- 1 ,4-dihydro-8-methoxy-7-(3- methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid of Formula 1. Gatifloxacin is indicated for the treatment of infections due to susceptible strains of microorganisms of gram-positive bacteria and some gram-negative bacteria such as Haemophilus influenzae.
  • U.S. Patent No. 6,333,045 discloses an aqueous liquid pharmaceutical composition of gatifloxacin for topical administration.
  • the patent further points out that by incorporating disodium edetate into an aqueous liquid preparation containing gatifloxacin or its salt raises the corneal permeability of gatifloxacin and prevents precipitation of gatifloxacin crystals and coloration of gatifloxacin.
  • U.S. Patent Application No. 20050009836 discloses ophthalmic compositions that include a quinolone compound and a polyhydric alcohol at a concentration that renders the composition substantially isoosmotic.
  • EP 1,627,637 discloses an aqueous ophthalmic solution that includes a quinolone antimicrobial compound or salt thereof, a water-soluble vinyl polymeric compound and a water-soluble cellulose derivative.
  • European Patent EP 275,515 and U.S. Patent No. 4,923,862 disclose aqueous pharmaceutical compositions of levofloxacin and ofloxacin or salt thereof.
  • US Patent No 6,716,830 disclose ophthalmic dosage forms of moxifloxacin or salt thereof in a concentration of 0.1% to 1% w/w and pharmaceutically acceptable vehicle.
  • quinolone antibiotics to treat eye infections is known in the ophthalmic art.
  • Several quinolone antibacterial compositions available in the market include gatifloxacin (Zymar®), Levofloxacin (Quixin® or Iquix®), Ciprofloxacin (Ciloxan®), Ofloxacin (Ocuflox®), Lomefloxacin (Lomeflox®), Moxifloxacin (Vigamox®) and Norfloxacin (available as Chibroxin®).
  • an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and hydroxypropyl beta cyclodextrin (hereinafter referred as HP- ⁇ -CD).
  • Embodiments of the composition may include one or more of the following features.
  • the composition may further include other pharmaceutically acceptable excipients.
  • the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
  • the gatifloxacin may be present from about 0.01 to about 1.0% w/v. More particularly, it may be present from about 0.1 to 0.8% w/v, for example 0.3% w/v.
  • HP- ⁇ -CD acts as a solubility enhancer component and further helps to prevent precipitation of gatifloxacin.
  • an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP- ⁇ -CD, and citric acid or a pharmaceutically acceptable salt thereof.
  • Citric acid along with HP- ⁇ -CD acts as a permeability-enhancing component and provides high permeability to gatifloxacin.
  • present invention provides a method for increasing corneal permeability.
  • Embodiments of the composition may include one or more of the following features.
  • the composition may further include other pharmaceutically acceptable excipients.
  • the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
  • an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP-D-CD, citric acid or a pharmaceutically acceptable salt thereof, and sodium metabisulphite.
  • Sodium metabisulphite serves a dual purpose of acting as a coloration inhibitor and as an antioxidant.
  • Embodiments of the composition may include one or more of the following features.
  • the composition may further include other pharmaceutically acceptable excipients.
  • the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
  • an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and polyvinyl alcohol.
  • Polyvinyl alcohol provides the increased bioavailability to gatifloxacin or its pharmaceutically acceptable salt thereof by prolonging the retention time.
  • Embodiments of the composition may include one or more of the following features.
  • the composition may further include other pharmaceutically acceptable excipients.
  • the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
  • an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and citric acid or a pharmaceutically acceptable salt thereof.
  • Citric acid provides increased permeation to poorly permeable drug gatifloxacin.
  • Embodiments of the composition may include one or more of the following features.
  • the composition may further include other pharmaceutically acceptable excipients.
  • the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
  • an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and sodium metabisulphite.
  • composition may include one or more of the following features.
  • the composition may further include other pharmaceutically acceptable excipients.
  • the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
  • an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP- ⁇ -CD, and polyvinyl alcohol.
  • Polyvinyl alcohol acts as a viscosity-increasing agent, and provides the increased bioavailability by prolonging the retention time.
  • Embodiments of the composition may include one or more of the following features.
  • the composition may further include other pharmaceutically acceptable excipients.
  • the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
  • an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP- ⁇ -CD, polyvinyl alcohol, and citric acid or a pharmaceutically acceptable salt thereof.
  • Embodiments of the composition may include one or more of the following features.
  • the composition may further include other pharmaceutically acceptable excipients.
  • the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
  • an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP- ⁇ -CD, polyvinyl alcohol, citric acid or a pharmaceutically acceptable salt thereof, and sodium metabisulphite.
  • the composition may include one or more of the following features.
  • the composition may further include other pharmaceutically acceptable excipients.
  • the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
  • the permeability enhancer component which optionally includes citric acid or a pharmaceutically acceptable salt thereof, provides a high permeation to an otherwise poor permeable drug like gatifloxacin or a pharmaceutically acceptable salt thereof.
  • the presence of sodium mctabisulphite serves a dual purpose of acting as a coloration inhibitor and an antioxidant.
  • the aqueous liquid compositions may be formulated as a solution, suspension or drops in a single use or multi-use containers for ophthalmic, otic or nasal use.
  • the compositions are preferably sterile, and have physical properties (e.g., osmolality and pH) that are specially suited for application to ophthalmic, otic and nasal tissues, including tissues that have been compromised as the result of preexisting disease, trauma, surgery or other physical conditions.
  • aqueous liquid pharmaceutical compositions containing gatifloxacin or a pharmaceutically acceptable salt thereof which eliminates the problems of poor membrane permeability; precipitation of dosage form at physiological pH and coloration of the tissue and the formulation. This was achieved by formulating aqueous liquid pharmaceutical composition containing gatifloxacin or a salt thereof with one or more of HP- ⁇ -CD, citric acid or a pharmaceutically acceptable salt thereof, and sodium metabisulphite.
  • compositions may further include other pharmaceutically acceptable excipients.
  • the other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
  • aqueous liquid compositions may be formulated as a solution, suspension or drops in a single use or multi-use containers.
  • Gatifloxacin or a pharmaceutically acceptable salt thereof includes free base, salts, solvates, hydrates, polymorphs or mixtures thereof that may be used to prepare the compositions according to the invention.
  • solubility enhancer component such as HP- ⁇ -CD not only prevents the precipitation of gatifloxacin or a pharmaceutically acceptable salt thereof, but also decreases the irritation associated with the said drug.
  • the permeability enhancer component which includes citric acid or its salt thereof, provides a high permeation to an otherwise poor pe ⁇ neable drug like gatifloxacin.
  • the presence of sodium metabisulphite serves a dual purpose of acting as a coloration inhibitor and an antioxidant.
  • the aqueous liquid compositions may be formulated as a solution, suspension or drops in a single use or multi-use containers for ophthalmic, otic or nasal use.
  • the compositions are preferably sterile, and have physical properties (e.g., osmolality and pH) that are specially suited for application to ophthalmic, otic and nasal tissues, including tissues that have been compromised as the result of preexisting disease, trauma, surgery or other physical conditions.
  • compositions are typically administered to the affected ophthalmic, otic or nasal tissues by topically applying one to four drops of a sterile solution or suspension, or a comparable amount of an ointment, gel or other solid or semisolid composition, one to four times per day.
  • the compositions may also be formulated as irrigating solutions that are applied to the affected ophthalmic, otic or nasal tissues during surgical procedures.
  • the amount of gatifloxacin or its salt 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 generally, the gatifloxacin is formulated within the range from about 0.01% to about 1.0% w/v. More particularly, it may be present from about 0.1 to about 0.8% w/v, for example 0.3% w/v of the composition.
  • the concentration of gatifloxacin or its salt and all other excipients used in the composition is expressed in the %w/v of the composition i.e. certain mass of dry solute is dissolved in the fixed volume of the composition and then the concentration is expressed in terms of percentage.
  • the ophthalmic, otic and nasal compositions of the present invention may have a pH in the range of 4.0 to 6.0.
  • the ophthalmic compositions may also be formulated to have osmotic values that are compatible with the aqueous humor of the eye and ophthalmic tissues. Such osmotic values will generally be in the range of from about 200 to about 400 milliosmoles per kilogram of water (“mOsm/kg”), but will preferably be about 300 mOsm/kg.
  • the ophthalmic, otic and nasal pharmaceutical products are typically packaged in a multidose form.
  • the preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents known to those skilled in the art. In general, such preservatives can be employed at an amount from about 0.001% to about 1.0% by weight of the composition. A surfactant or other appropriate co-solvent in the composition may enhance the solubility of the components of the present compositions.
  • co-solvents or complex forming agents helps in achieving the desired results.
  • co-solvents include polysorbate 20, 60, and 80, polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic F-68, F-84 and P-103), cyclodextrin, especially HP- ⁇ -CD, or other agents known to those skilled in the art.
  • co-solvents can be employed at an amount from about 0.01% to about 5% by weight of the composition.
  • HP- ⁇ -CD has a tendency to form inclusion complex with many drugs including gatifloxacin. This complex offers several advantages, such as reduced irritation, increased tolerability and efficacy. The dose of gatifloxacin can be further reduced based on complexation with HP- ⁇ -CD.
  • viscosity enhancing agents to provide the compositions of the invention with viscosities greater than the viscosity of simple aqueous solutions is desirable to increase ocular absorption, and reduce irritability of the active compounds by the target tissues or increase the retention time in the eye, ear or nose.
  • agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose or other agents known to those skilled in the art.
  • Such agents can be employed at an amount from about 0.01% to about 2% by weight of the composition.
  • solubility enhancer component which includes HP-D-CD, not only prevents the precipitation of gatifloxacin, but also decreases the irritation associated with the said drug.
  • the viscosity-increasing agent which includes polyvinyl alcohol, provides the increased bioavailability by prolonging the retention time.
  • the permeability enhancer component which optionally includes citric acid or a pharmaceutically acceptable salt thereof, provides a high permeation to an otherwise poor permeable drug like gatifloxacin.
  • Citric acid or a pharmaceutically acceptable salt thereof comprises one or more of sodium citrate and the like.
  • Sodium chloride used in the composition helps to maintain the required osmolality of the composition and also acts a buffering agent.
  • Table 1 provides composition of batches of the present invention.
  • Citric acid (0.08% w/v) and sodium citrate (0.18% w/v) were dissolved in water for injection.
  • a blend of gatifloxacin (0.3% w/v) and HP- ⁇ -CD in concentration of 1-1.5% w/v was dissolved.
  • a previously stirred solution of sodium chloride (0.65% w/v) and sodium metabisulfite (0.05% w/v) was added to the above solution.
  • a previously dissolved solution of benzalkonium chloride in hot water was added.
  • the pH was determined and it was adjusted to 4-6 using NaOH/HCl solution.
  • the final volume was adjusted with water for injection.
  • the resultant solution was aseptically filtered through 0.2 ⁇ filter, filled and packed in a suitable container and closure system.
  • Table 2 provides composition of batches of the present invention.
  • Table 3 provides composition of batches of the present invention.
  • Citric acid (0.08% w/v) and sodium citrate (0.18%v) were dissolved in water for injection.
  • a blend of gatifloxacin (0.3% w/v) and HP- ⁇ -CD in concentration of 1-1.5% w/v was dissolved.
  • Polyvinyl alcohol was dissolved in prefiltered hot water under continuous stirring.
  • a previously stirred solution of sodium chloride (0.65% w/v) and sodium metabisulfite (0.05% w/v) was added to the above solution.
  • benzalkonium chloride in hot water was added.
  • the pH was determined and it was adjusted to 4-6 using NaOH /HcI solution.
  • the final volume was adjusted with water for injection.
  • the resultant solution was aseptically filtered through 0.2 ⁇ filter, filled and packed in suitable container and closure system.

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Abstract

The present invention relates to aqueous liquid pharmaceutical compositions that include gatifloxacin and pharmaceutically acceptable salts thereof. The invention also relates to processes for the preparation of the pharmaceutical compositions.

Description

AN AQUEOUS LIQUID PHARMACEUTICAL COMPOSITIONS OF
GATIFLOXACIN
Field of the Invention
The present invention relates to aqueous liquid pharmaceutical compositions that include gatifloxacin and pharmaceutically acceptable salts thereof. The invention also relates to processes for the preparation of the pharmaceutical compositions.
Background of the Invention
Gatifloxacin is a synthetic broad-spectrum 8-methoxyfluoroquinolone antibacterial agent. Chemically, gatifloxacin is (±)- 1 -cyclopropyl-ό-fluoro- 1 ,4-dihydro-8-methoxy-7-(3- methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid of Formula 1. Gatifloxacin is indicated for the treatment of infections due to susceptible strains of microorganisms of gram-positive bacteria and some gram-negative bacteria such as Haemophilus influenzae.
Figure imgf000002_0001
FORMULA I
U.S. Patent No. 6,333,045 discloses an aqueous liquid pharmaceutical composition of gatifloxacin for topical administration. The patent further points out that by incorporating disodium edetate into an aqueous liquid preparation containing gatifloxacin or its salt raises the corneal permeability of gatifloxacin and prevents precipitation of gatifloxacin crystals and coloration of gatifloxacin. U.S. Patent Application No. 20050009836 discloses ophthalmic compositions that include a quinolone compound and a polyhydric alcohol at a concentration that renders the composition substantially isoosmotic.
European Patent Application No. EP 1,627,637 discloses an aqueous ophthalmic solution that includes a quinolone antimicrobial compound or salt thereof, a water-soluble vinyl polymeric compound and a water-soluble cellulose derivative.
European Patent EP 275,515 and U.S. Patent No. 4,923,862 disclose aqueous pharmaceutical compositions of levofloxacin and ofloxacin or salt thereof. US Patent No 6,716,830 disclose ophthalmic dosage forms of moxifloxacin or salt thereof in a concentration of 0.1% to 1% w/w and pharmaceutically acceptable vehicle.
The use of quinolone antibiotics to treat eye infections is known in the ophthalmic art. Several quinolone antibacterial compositions available in the market include gatifloxacin (Zymar®), Levofloxacin (Quixin® or Iquix®), Ciprofloxacin (Ciloxan®), Ofloxacin (Ocuflox®), Lomefloxacin (Lomeflox®), Moxifloxacin (Vigamox®) and Norfloxacin (available as Chibroxin®).
It was noticed from U.S. Patent No. 6,333,045 that gatifloxacin aqueous liquid pharmaceutical compositions have poor membrane permeability. Also, there exist a problem of precipitation at the physiological pH and coloration of the tissue and formulation. The present invention addresses and overcomes these problems.
Summary of the Invention
Li one aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and hydroxypropyl beta cyclodextrin (hereinafter referred as HP-β-CD). Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
The gatifloxacin may be present from about 0.01 to about 1.0% w/v. More particularly, it may be present from about 0.1 to 0.8% w/v, for example 0.3% w/v. HP-β-CD acts as a solubility enhancer component and further helps to prevent precipitation of gatifloxacin.
In another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP- β -CD, and citric acid or a pharmaceutically acceptable salt thereof.
Citric acid along with HP-β-CD acts as a permeability-enhancing component and provides high permeability to gatifloxacin. Thus present invention provides a method for increasing corneal permeability.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
In another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP-D-CD, citric acid or a pharmaceutically acceptable salt thereof, and sodium metabisulphite.
Sodium metabisulphite serves a dual purpose of acting as a coloration inhibitor and as an antioxidant.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
In another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and polyvinyl alcohol.
Polyvinyl alcohol provides the increased bioavailability to gatifloxacin or its pharmaceutically acceptable salt thereof by prolonging the retention time.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
hi another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and citric acid or a pharmaceutically acceptable salt thereof.
Citric acid provides increased permeation to poorly permeable drug gatifloxacin.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
hi another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof and sodium metabisulphite.
Sodium metabisulphite serves a dual purpose of acting as a coloration inhibitor and an antioxidant. Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
In another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP-β-CD, and polyvinyl alcohol.
Polyvinyl alcohol, acts as a viscosity-increasing agent, and provides the increased bioavailability by prolonging the retention time.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
In another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP-β-CD, polyvinyl alcohol, and citric acid or a pharmaceutically acceptable salt thereof.
Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
In another aspect there is provided an aqueous liquid pharmaceutical composition that includes gatifloxacin or a pharmaceutically acceptable salt thereof, HP-β-CD, polyvinyl alcohol, citric acid or a pharmaceutically acceptable salt thereof, and sodium metabisulphite. Embodiments of the composition may include one or more of the following features. For example, the composition may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
The permeability enhancer component, which optionally includes citric acid or a pharmaceutically acceptable salt thereof, provides a high permeation to an otherwise poor permeable drug like gatifloxacin or a pharmaceutically acceptable salt thereof. The presence of sodium mctabisulphite serves a dual purpose of acting as a coloration inhibitor and an antioxidant.
The aqueous liquid compositions may be formulated as a solution, suspension or drops in a single use or multi-use containers for ophthalmic, otic or nasal use. The compositions are preferably sterile, and have physical properties (e.g., osmolality and pH) that are specially suited for application to ophthalmic, otic and nasal tissues, including tissues that have been compromised as the result of preexisting disease, trauma, surgery or other physical conditions.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Detailed Description of the Invention
The inventors have now developed aqueous liquid pharmaceutical compositions containing gatifloxacin or a pharmaceutically acceptable salt thereof, which eliminates the problems of poor membrane permeability; precipitation of dosage form at physiological pH and coloration of the tissue and the formulation. This was achieved by formulating aqueous liquid pharmaceutical composition containing gatifloxacin or a salt thereof with one or more of HP-β-CD, citric acid or a pharmaceutically acceptable salt thereof, and sodium metabisulphite.
The compositions may further include other pharmaceutically acceptable excipients. The other excipients may include one or more of preservatives, surfactants or co-solvents, viscosity enhancing agents, and the like.
The aqueous liquid compositions may be formulated as a solution, suspension or drops in a single use or multi-use containers.
Gatifloxacin or a pharmaceutically acceptable salt thereof includes free base, salts, solvates, hydrates, polymorphs or mixtures thereof that may be used to prepare the compositions according to the invention.
The present inventors found that the solubility enhancer component such as HP-β-CD not only prevents the precipitation of gatifloxacin or a pharmaceutically acceptable salt thereof, but also decreases the irritation associated with the said drug. The permeability enhancer component, which includes citric acid or its salt thereof, provides a high permeation to an otherwise poor peπneable drug like gatifloxacin. The presence of sodium metabisulphite serves a dual purpose of acting as a coloration inhibitor and an antioxidant.
The aqueous liquid compositions may be formulated as a solution, suspension or drops in a single use or multi-use containers for ophthalmic, otic or nasal use. The compositions are preferably sterile, and have physical properties (e.g., osmolality and pH) that are specially suited for application to ophthalmic, otic and nasal tissues, including tissues that have been compromised as the result of preexisting disease, trauma, surgery or other physical conditions.
The compositions are typically administered to the affected ophthalmic, otic or nasal tissues by topically applying one to four drops of a sterile solution or suspension, or a comparable amount of an ointment, gel or other solid or semisolid composition, one to four times per day. However, the compositions may also be formulated as irrigating solutions that are applied to the affected ophthalmic, otic or nasal tissues during surgical procedures.
hi general, the amount of gatifloxacin or its salt 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 generally, the gatifloxacin is formulated within the range from about 0.01% to about 1.0% w/v. More particularly, it may be present from about 0.1 to about 0.8% w/v, for example 0.3% w/v of the composition.
The concentration of gatifloxacin or its salt and all other excipients used in the composition is expressed in the %w/v of the composition i.e. certain mass of dry solute is dissolved in the fixed volume of the composition and then the concentration is expressed in terms of percentage.
The ophthalmic, otic and nasal compositions of the present invention may have a pH in the range of 4.0 to 6.0. The ophthalmic compositions may also be formulated to have osmotic values that are compatible with the aqueous humor of the eye and ophthalmic tissues. Such osmotic values will generally be in the range of from about 200 to about 400 milliosmoles per kilogram of water ("mOsm/kg"), but will preferably be about 300 mOsm/kg.
The ophthalmic, otic and nasal pharmaceutical products are typically packaged in a multidose form. The preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include polyquaternium-1, benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents known to those skilled in the art. In general, such preservatives can be employed at an amount from about 0.001% to about 1.0% by weight of the composition. A surfactant or other appropriate co-solvent in the composition may enhance the solubility of the components of the present compositions. In case of gatifloxacin due to its poor water solubility, use of co-solvents or complex forming agents helps in achieving the desired results. Such co-solvents include polysorbate 20, 60, and 80, polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic F-68, F-84 and P-103), cyclodextrin, especially HP-β-CD, or other agents known to those skilled in the art. In general, such co-solvents can be employed at an amount from about 0.01% to about 5% by weight of the composition. HP-β-CD has a tendency to form inclusion complex with many drugs including gatifloxacin. This complex offers several advantages, such as reduced irritation, increased tolerability and efficacy. The dose of gatifloxacin can be further reduced based on complexation with HP-β-CD.
The use of viscosity enhancing agents to provide the compositions of the invention with viscosities greater than the viscosity of simple aqueous solutions is desirable to increase ocular absorption, and reduce irritability of the active compounds by the target tissues or increase the retention time in the eye, ear or nose. Such agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone, methylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose or other agents known to those skilled in the art. Such agents can be employed at an amount from about 0.01% to about 2% by weight of the composition.
It was also found by the present inventors that the solubility enhancer component, which includes HP-D-CD, not only prevents the precipitation of gatifloxacin, but also decreases the irritation associated with the said drug. The viscosity-increasing agent, which includes polyvinyl alcohol, provides the increased bioavailability by prolonging the retention time. The permeability enhancer component, which optionally includes citric acid or a pharmaceutically acceptable salt thereof, provides a high permeation to an otherwise poor permeable drug like gatifloxacin. Citric acid or a pharmaceutically acceptable salt thereof comprises one or more of sodium citrate and the like.
Sodium chloride used in the composition helps to maintain the required osmolality of the composition and also acts a buffering agent.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1 ;
Table 1 provides composition of batches of the present invention.
Table 1
Figure imgf000011_0001
Procedure: Citric acid (0.08% w/v) and sodium citrate (0.18% w/v) were dissolved in water for injection. To the clear solution so obtained, a blend of gatifloxacin (0.3% w/v) and HP-β-CD in concentration of 1-1.5% w/v was dissolved. A previously stirred solution of sodium chloride (0.65% w/v) and sodium metabisulfite (0.05% w/v) was added to the above solution. To this, a previously dissolved solution of benzalkonium chloride in hot water was added. The pH was determined and it was adjusted to 4-6 using NaOH/HCl solution. The final volume was adjusted with water for injection. The resultant solution was aseptically filtered through 0.2μ filter, filled and packed in a suitable container and closure system.
Example 2:
Table 2 provides composition of batches of the present invention.
Table 2
Figure imgf000012_0001
Procedure: Polyvinyl alcohol was dissolved in prefiltered hot water under continuous stirring. Citric acid (0.08% w/v) and sodium citrate (0.18% w/v) were dissolved in hot water for injection in a separate vessel. To the clear solution so obtained, a blend of gatifloxacin (0.3% w/v) was dissolved. A previously stirred solution of sodium chloride (0.8% w/v) and sodium metabisulfite (0.05% w/v) was added to the above solution. To this, the polyvinyl alcohol solution was added. To this, a previously dissolved solution of benzalkonium chloride in hot water was added. The pH was determined and it was adjusted to 4-6 using sodium hydroxide or hydrochloric acid solution. The final volume was adjusted with water for injection. The resultant solution was aseptically filtered through 0.2μ filter, filled and packed in suitable container and closure system.
Example 3:
Table 3 provides composition of batches of the present invention.
Table 3
Figure imgf000013_0001
Procedure: Citric acid (0.08% w/v) and sodium citrate (0.18%v) were dissolved in water for injection. To the clear solution so obtained, a blend of gatifloxacin (0.3% w/v) and HP-β-CD in concentration of 1-1.5% w/v was dissolved. Polyvinyl alcohol was dissolved in prefiltered hot water under continuous stirring. A previously stirred solution of sodium chloride (0.65% w/v) and sodium metabisulfite (0.05% w/v) was added to the above solution. To this, a previously dissolved solution of benzalkonium chloride in hot water was added. The pH was determined and it was adjusted to 4-6 using NaOH /HcI solution. The final volume was adjusted with water for injection. The resultant solution was aseptically filtered through 0.2μ filter, filled and packed in suitable container and closure system.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Claims

Claims
We claim:
1 An aqueous liquid pharmaceutical composition comprising gatifloxacin or a pharmaceutically acceptable salt thereof and HP-β-CD.
2 The aqueous liquid pharmaceutical composition according to claim 1, wherein the composition further comprises citric acid or a pharmaceutically acceptable salt thereof.
3 The aqueous liquid pharmaceutical composition according to claim 2, wherein the composition further comprises sodium metabisulphite.
4 The aqueous liquid pharmaceutical composition according to claim 1, wherein the HP-β-CD is present in a concentration of about 1.0% to about 1.5% w/v.
5 The aqueous liquid pharmaceutical composition according to claim 1, wherein the composition further comprises one or more other pharmaceutically acceptable excipients.
6 The aqueous liquid pharmaceutical composition according to claim 5, wherein the pharmaceutically acceptable excipients comprise one or more of preservatives, surfactants/co-solvents, and viscosity enhancing agents.
7 The aqueous liquid pharmaceutical composition according to claim 1, wherein the composition is having osmolality of about 200 mθsm/kg to about 400 mθsm/kg.
8 An aqueous liquid pharmaceutical composition comprising gatifloxacin or a pharmaceutically acceptable salt thereof and polyvinyl alcohol. 9 The aqueous liquid pharmaceutical composition according to claim 8, wherein the composition further comprises citric acid or a pharmaceutically acceptable salt thereof.
10 The aqueous liquid pharmaceutical composition according to claim 9, wherein the composition further comprises sodium metabisulphite.
11 The aqueous liquid pharmaceutical composition according to claims 8, wherein the polyvinyl alcohol is present in a concentration of about 0.2% w/v to about 0.4%w/v.
12 The aqueous liquid pharmaceutical composition according to claim 8, wherein the composition further comprises one or more other pharmaceutically acceptable excipients.
13 The aqueous liquid pharmaceutical composition according to claim 12, wherein the pharmaceutically acceptable excipients comprise one or more of preservatives, surfactants/co-solvents, and viscosity enhancing agents.
14 The aqueous liquid pharmaceutical composition according to claim 8, wherein the composition is having osmolality of about 200 mOsm/kg to about 400 mθsm/kg.
15 An aqueous liquid pharmaceutical composition comprising gatifloxacin or a pharmaceutically acceptable salt thereof, HP-β-CD and polyvinyl alcohol.
16 The aqueous liquid pharmaceutical composition according to claim 15, wherein the composition further comprises citric acid or a pharmaceutically acceptable salt thereof.
17 The aqueous liquid pharmaceutical composition according to claim 16, wherein the composition further comprises sodium metabisulphite. 18 The aqueous liquid pharmaceutical composition according to claim 15, wherein the composition further comprises one or more other pharmaceutically acceptable excipients.
19 The aqueous liquid pharmaceutical composition according to claim 18, wherein the pharmaceutically acceptable excipients comprise one or more of preservatives, surfactants/co-solvents, and viscosity enhancing agents.
20 The aqueous liquid pharmaceutical composition according to claim 15, wherein the composition is having osmolality of about 200 mOsm/kg to about 400 mOsm/kg.
PCT/IB2007/000465 2006-02-28 2007-02-27 An aqueous liquid pharmaceutical compositions of gatifloxacin Ceased WO2007099431A2 (en)

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